Over-the-counter and Natural Remedies for Onychomycosis: Do They Really Work?

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Over-the-counter and Natural Remedies for Onychomycosis: Do They Really Work?
Author(s)
Pierre Halteh
Richard K. Scher, MD
Shari R. Lipner, MD, PhD

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.1 Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.2 It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.3 Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.4 Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.5

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.6 This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.7 Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.6

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.8 In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.9 Patients also may present with aesthetic concerns that may impact their quality of life.10

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.11 Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.12 Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.13 For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.13

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.14 Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.15 In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.16 Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.17 Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.18

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

 

 

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.19 Tea tree oil has been shown to be an effective treatment of tinea pedis,20 and it is widely used in Australia as well as in Europe and North America.21 Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro22-28 and in clinical trials.29,30

In Vitro Data

Because TTO is composed of more than 100 active components,23 the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.22 The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.24 Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,24 which are the 2 most common etiologies of onychomycosis.5 In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.25 Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.31

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.5 In C albicans, TTO causes altered permeability of plasma membranes,32 dose-dependent alteration of respiration,33 decreased glucose-induced acidification of media surrounding fungi,32 and reversible inhibition of germ tube formation.19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.29 Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.29

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.30 Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.30

 

 

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.35 The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.35 Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.40

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.36 The in vitro activity of thymol, a component of TCS, was tested against Candida species.37 The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.37 It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.38

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.36 Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.36

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.40 The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.40

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.41 Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.46 In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.47 In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.42

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.49 Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.49

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.50 The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.50

 

 

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.53 Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.57 Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,59 was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.54 It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.55 In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.56

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).58 Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).58 A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.58

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.53 One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.53

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O3) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.60 It was originally shown to have antibacterial properties in vitro,61 and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.65 The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.65

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.62 Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.64

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.65 Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.65

 

 

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.29 Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.30 Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.40 Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.49 No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.49 In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.50 A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,58 AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.53

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.65 Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

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  31. Flores FC, de Lima JA, Ribeiro RF, et al. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of Trichophyton rubrum. Mycopathologia. 2013;175:281-286.
  32. Hammer KA, Carson CF, Riley TV. Antifungal effects of Melaleuca alternifolia (tea tree) oil and its components on Candida albicans, Candida glabrata and Saccharomyces cerevisiae. J Antimicrob Chemother. 2004;53:1081-1085.
  33. Cox SD, Mann CM, Markham JL, et al. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (tea tree oil). J Appl Microbiol. 2000;88:170-175.
  34. Hammer KA, Carson CF, Riley TV. Melaleuca alternifolia (tea tree) oil inhibits germ tube formation by Candida albicans. Med Mycol. 2000;38:355-362.
  35. Vicks VapoRub [package insert]. Gross-Gerau, Germany: Proctor & Gamble; 2010.
  36. Ramsewak RS, Nair MG, Stommel M, et al. In vitro antagonistic activity of monoterpenes and their mixtures against ‘toe nail fungus’ pathogens. Phytother Res. 2003;17:376-379.
  37. Pina-Vaz C, Gonçalves Rodrigues A, Pinto E, et al. Antifungal activity of Thymus oils and their major compounds. J Eur Acad Dermatol Venereol. 2004;18:73-78.
  38. Pinto E, Pina-Vaz C, Salgueiro L, et al. Antifungal activity of the essential oil of Thymus pulegioides on Candida, Aspergillus and dermatophyte species. J Med Microbiol. 2006;55:1367-1373.
  39. Vicks VapoRub might help fight toenail fungus. Consumer Reports. 2006;71:49.
  40. Derby R, Rohal P, Jackson C, et al. Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med. 2011;24:69-74.
  41. Trapp S, Croteau R. Defensive resin biosynthesis in conifers. Ann Rev Plant Physiol Plant Mol Biol. 2001;52:689-724.
  42. Sipponen A, Laitinen K. Antimicrobial properties of natural coniferous rosin in the European Pharmacopoeia challenge test. APMIS. 2011;119:720-724.
  43. Sipponen A, Lohi J. Lappish gum care “new” treatment of pressure ulcers? People’s improvement at it’s best. Eng Med J. 2003;58:2775-2776.
  44. Benedictus O. Een Nyttigh Läkare. Malmö: Kroon; 1938.
  45. Rautio M, Sipponen A, Peltola R, et al. Antibacterial effects of home-made resin salve from Norway spruce (Picea abies). APMIS. 2007;115:335-340.
  46. Laitinen K, Sipponen A, Jokinen JJ, et al. Resin salve from Norway spruce is antifungal against dermatophytes causing nail infections. EWMA. 2009;56:289-296.
  47. Rautio M, Sipponen A, Lohi J, et al. In vitro fungistatic effects of natural coniferous resin from Norway spruce (Picea abies). Eur J Clin Microbiol Infect Dis. 2012;31:1783-1789.
  48. Sipponen A, Peltola R, Jokinen JJ, et al. Effects of Norway spruce (Picea abies) resin on cell wall and cell membrane of Staphylococcus aureus. Ultrastruct Pathol. 2009;33:128-135.
  49. Sipponen P, Sipponen A, Lohi J, et al. Natural coniferous resin lacquer in treatment of toenail onychomycosis: an observational study. Mycoses. 2013;56:289-296.
  50. Auvinen T, Tiihonen R, Soini M, et al. Efficacy of topical resin lacquer, amorolfine, and oral terbinafine for treating toenail onychomycosis: a prospective, randomized, controlled, investigator-blinded, parallel-group clinical trial. Br J Dermatol. 2015;173:940-948.
  51. Argueta A, Cano L, Rodarte M. Atlas de las Plantas de la Medicina Tradicional Mexicana. Vol 3. Mexico City, Mexico: Instituto Nacional Indigenista; 1994:72-680.
  52. Avilés M, Suárez G. Catálogo de Plantas Medicinales del Jardín Etnobotánico. Peru: Instituto Nacional de Antropología e Historia; 1994.
  53. Romero-Cerecero O, Roman-Ramos R, Zamilpa A, et al. Clinical trial to compare the effectiveness of two concentrations of the Ageratina pichinchensis extract in the topical treatment of onychomycosis. J Ethnopharmacol. 2009;126:74-78.
  54. Navarro Garcia VM, Gonzalez A, Fuentes M, et al. Antifungal activities of nine traditional Mexican medicinal plants. J Ethnopharmacol. 2003;87:85-88.
  55. Castañeda P, Gómez L, Mata R, et al. Phytogrowth-inhibitory and antifungal constituents of Helianthella quinquenervis. J Nat Prod. 1996;59:323-326.
  56. Kumar N. Inhibition of nail infecting fungi of peoples of North Eastern UP causing Tinea unguium through leaf essential oil of Ageratum houstonianum Mill. IOSR J Pharm. June 2014;4:36-42.
  57. Romero-Cerecero O, Rojas G, Navarro V, et al. Effectiveness and tolerability of a standardized extract from Ageratina pichinchensis on patients with tinea pedis: an explorative pilot study controlled with ketoconazole. Planta Med. 2006;72:1257-1261.
  58. Romero-Cerecero O, Zamilpa A, Jimenez-Ferrer JE, et al. Double-blind clinical trial for evaluating the effectiveness and tolerability of Ageratina pichinchensis extract on patients with mild to moderate onychomycosis. a comparative study with ciclopirox. Planta Med. 2008;74:1430-1435.
  59. Rzedowski J, De Rzedowski GC. Flora Fanerogámica del Valle de México. Mexico City, Mexico: Instituto de Ecología Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional; 1985.
  60. Bocci V. Biological and clinical effects of ozone. has ozone therapy a future in medicine? Br J Biomed Sci. 1999;56:270-279.
  61. Sechi LA, Lezcano I, Nunez N, et al. Antibacterial activity of ozonized sunflower oil (Oleozon). J Appl Microbiol. 2001;90:279-284.
  62. Rodrigues KL, Cardoso CC, Caputo LR, et al. Cicatrizing and antimicrobial properties of an ozonised oil from sunflower seeds. Inflammopharmacology. 2004;12:261-270.
  63. Daud FV, Ueda SMY, Navarini A, et al. The use of ozonized oil in the treatment of dermatophitosis caused by Microsporum canis in rabbits. Braz J Microbiol. 2011;42:274-281.
  64. Guerrer LV, Cunha KC, Nogueira MC, et al. “In vitro” antifungal activity of ozonized sunflower oil on yeasts from onychomycosis. Braz J Microbiol. 2012;43:1315-1318.
  65. Menéndez S, Falcón L, Maqueira Y. Therapeutic efficacy of topical OLEOZON in patients suffering from onychomycosis. Mycoses. 2011;54:E272-E277.
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Mr. Halteh is from Weill Cornell Medical College, Qatar, Ar-Rayyan. Drs. Scher and Lipner are from the Department of Dermatology, Weill Cornell Medical College, New York, New York.

Mr. Halteh reports no conflict of interest. Dr. Scher is a consultant for Valeant Pharmaceuticals International, Inc. Dr. Lipner has served on the advisory board for Sandoz, a Novartis company.

Correspondence: Shari R. Lipner, MD, PhD, Department of Dermatology, Weill Cornell Medical College, 1305 York Ave, New York, NY 10021 ([email protected])

Issue
Cutis - 98(5)
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MDedge Dermatology
Cutis
Clinician Reviews
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Hair & Nails
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Clinical Review
Author(s)
Pierre Halteh
Richard K. Scher, MD
Shari R. Lipner, MD, PhD
Author(s)
Pierre Halteh
Richard K. Scher, MD
Shari R. Lipner, MD, PhD
Author and Disclosure Information

 

Mr. Halteh is from Weill Cornell Medical College, Qatar, Ar-Rayyan. Drs. Scher and Lipner are from the Department of Dermatology, Weill Cornell Medical College, New York, New York.

Mr. Halteh reports no conflict of interest. Dr. Scher is a consultant for Valeant Pharmaceuticals International, Inc. Dr. Lipner has served on the advisory board for Sandoz, a Novartis company.

Correspondence: Shari R. Lipner, MD, PhD, Department of Dermatology, Weill Cornell Medical College, 1305 York Ave, New York, NY 10021 ([email protected])

Author and Disclosure Information

 

Mr. Halteh is from Weill Cornell Medical College, Qatar, Ar-Rayyan. Drs. Scher and Lipner are from the Department of Dermatology, Weill Cornell Medical College, New York, New York.

Mr. Halteh reports no conflict of interest. Dr. Scher is a consultant for Valeant Pharmaceuticals International, Inc. Dr. Lipner has served on the advisory board for Sandoz, a Novartis company.

Correspondence: Shari R. Lipner, MD, PhD, Department of Dermatology, Weill Cornell Medical College, 1305 York Ave, New York, NY 10021 ([email protected])

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CT098011016_e.PDF
Article PDF
CT098011016_e.PDF

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.1 Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.2 It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.3 Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.4 Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.5

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.6 This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.7 Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.6

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.8 In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.9 Patients also may present with aesthetic concerns that may impact their quality of life.10

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.11 Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.12 Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.13 For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.13

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.14 Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.15 In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.16 Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.17 Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.18

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

 

 

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.19 Tea tree oil has been shown to be an effective treatment of tinea pedis,20 and it is widely used in Australia as well as in Europe and North America.21 Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro22-28 and in clinical trials.29,30

In Vitro Data

Because TTO is composed of more than 100 active components,23 the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.22 The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.24 Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,24 which are the 2 most common etiologies of onychomycosis.5 In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.25 Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.31

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.5 In C albicans, TTO causes altered permeability of plasma membranes,32 dose-dependent alteration of respiration,33 decreased glucose-induced acidification of media surrounding fungi,32 and reversible inhibition of germ tube formation.19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.29 Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.29

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.30 Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.30

 

 

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.35 The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.35 Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.40

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.36 The in vitro activity of thymol, a component of TCS, was tested against Candida species.37 The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.37 It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.38

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.36 Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.36

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.40 The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.40

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.41 Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.46 In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.47 In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.42

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.49 Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.49

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.50 The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.50

 

 

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.53 Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.57 Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,59 was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.54 It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.55 In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.56

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).58 Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).58 A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.58

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.53 One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.53

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O3) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.60 It was originally shown to have antibacterial properties in vitro,61 and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.65 The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.65

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.62 Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.64

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.65 Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.65

 

 

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.29 Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.30 Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.40 Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.49 No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.49 In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.50 A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,58 AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.53

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.65 Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.1 Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.2 It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.3 Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.4 Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.5

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.6 This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.7 Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.6

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.8 In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.9 Patients also may present with aesthetic concerns that may impact their quality of life.10

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.11 Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.12 Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.13 For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.13

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.14 Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.15 In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.16 Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.17 Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.18

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

 

 

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.19 Tea tree oil has been shown to be an effective treatment of tinea pedis,20 and it is widely used in Australia as well as in Europe and North America.21 Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro22-28 and in clinical trials.29,30

In Vitro Data

Because TTO is composed of more than 100 active components,23 the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.22 The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.24 Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,24 which are the 2 most common etiologies of onychomycosis.5 In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.25 Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.31

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.5 In C albicans, TTO causes altered permeability of plasma membranes,32 dose-dependent alteration of respiration,33 decreased glucose-induced acidification of media surrounding fungi,32 and reversible inhibition of germ tube formation.19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.29 Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.29

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.30 Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.30

 

 

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.35 The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.35 Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.40

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.36 The in vitro activity of thymol, a component of TCS, was tested against Candida species.37 The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.37 It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.38

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.36 Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.36

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.40 The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.40

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.41 Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.46 In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.47 In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.42

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.49 Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.49

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.50 The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.50

 

 

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.53 Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.57 Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,59 was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.54 It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.55 In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.56

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).58 Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).58 A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.58

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.53 One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.53

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O3) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.60 It was originally shown to have antibacterial properties in vitro,61 and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.65 The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.65

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.62 Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.64

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.65 Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.65

 

 

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.29 Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.30 Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.40 Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.49 No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.49 In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.50 A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,58 AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.53

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.65 Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

References
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  2. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014;28:1480-1491.
  3. Thomas J, Jacobson GA, Narkowicz CK, et al. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35:497-519.
  4. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and management. Am J Clin Dermatol. 2009;10:211-220.
  5. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.
  6. Hay RJ, Baran R. Onychomycosis: a proposed revision of the clinical classification J Am Acad Dermatol. 2011;65:1219-1227.
  7. Elewski B. Clinical pearl: proximal white subungual onychomycosis in AIDS. J Am Acad Dermatol. 1993;29:631-632.
  8. Scher RK. Onychomycosis is more than a cosmetic problem. Br J Dermatol. 1994;130(suppl 43):15.
  9. Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care. 2006;29:1202-1207.
  10. Szepietowski JC, Reich A, Pacan P, et al. Evaluation of quality of life in patients with toenail onychomycosis by Polish version of an international onychomycosis-specific questionnaire. J Eur Acad Dermatol Venereol. 2007;21:491-496.
  11. Scher RK, Baron R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003;149(suppl 65):5-9.
  12. Lamisil [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.
  13. Sporanox [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2001
  14. Penlac [package insert]. Bridgewater, NJ: Dermik Laboratories; 2006.
  15. Jublia [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2014.
  16. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.
  17. Kerydin [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; 2014
  18. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies [published online May 5, 2015]. J Am Acad Dermatol. 2015;73:62-69.
  19. D’Auria FD, Laino L, Strippoli V, et al. In vitro activity of tea tree oil against Candida albicans mycelial conversion and other pathogenic fungi. J Chemother. 2001;13:377-383.
  20. Satchell AC, Saurajen A, Bell C, et al. Treatment of interdigital tinea pedis with 25% and 50% tea tree oil solution: a randomized, placebo-controlled, blinded study. Australas J Dermatol. 2002;43:175-178.
  21. Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (tea tree) oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev. 2006;19:50-62.
  22. Hammer KA, Carson CF, Riley TV. Antifungal activity of the components of Melaleuca alternifolia (tea tree) oil. J Appl Microbiol. 2003;95:853-860.
  23. Brophy JJ, Davies NW, Southwell IA, et al. Gas chromatographic quality control for oil of Melaleuca terpinen-4-ol type (Australian tea tree). J Agric Food Chem. 1989;37:1330-1335.
  24. Concha JM, Moore LS, Holloway WJ. 1998 William J. Stickel Bronze Award. Antifungal activity of Melaleuca alternifolia (tea-tree) oil against various pathogenic organisms. J Am Podiatr Med Assoc. 1998;88:489-492.
  25. Benger S, Townsend P, Ashford RL, et al. An in vitro study to determine the minimum inhibitory concentration of Melaleuca alternifolia against the dermatophyte Trichophyton rubrum. Foot. 2004;14:86-91.
  26. Hammer KA, Carson CF, Riley TV. In-vitro activity of essential oils, in particular Melaleuca alternifolia (tea tree) oil and tea tree oil products, against Candida spp. J Antimicrob Chemother. 1998;42:591-595.
  27. Altman P. Australian tea tree oil. Aust J Pharm. 1998;69:276-278.
  28. Guterres SS, Alves MP, Pohlmann AR. Polymeric nanoparticles, nanospheres and nanocapsules, for cutaneous applications. Drug Target Insights. 2007;2:147-157.
  29. Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole. J Fam Pract. 1994;38:601-605.
  30. Syed TA, Qureshi ZA, Ali SM, et al. Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream. Tropical Med Int Health. 1999;4:284-287.
  31. Flores FC, de Lima JA, Ribeiro RF, et al. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of Trichophyton rubrum. Mycopathologia. 2013;175:281-286.
  32. Hammer KA, Carson CF, Riley TV. Antifungal effects of Melaleuca alternifolia (tea tree) oil and its components on Candida albicans, Candida glabrata and Saccharomyces cerevisiae. J Antimicrob Chemother. 2004;53:1081-1085.
  33. Cox SD, Mann CM, Markham JL, et al. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (tea tree oil). J Appl Microbiol. 2000;88:170-175.
  34. Hammer KA, Carson CF, Riley TV. Melaleuca alternifolia (tea tree) oil inhibits germ tube formation by Candida albicans. Med Mycol. 2000;38:355-362.
  35. Vicks VapoRub [package insert]. Gross-Gerau, Germany: Proctor & Gamble; 2010.
  36. Ramsewak RS, Nair MG, Stommel M, et al. In vitro antagonistic activity of monoterpenes and their mixtures against ‘toe nail fungus’ pathogens. Phytother Res. 2003;17:376-379.
  37. Pina-Vaz C, Gonçalves Rodrigues A, Pinto E, et al. Antifungal activity of Thymus oils and their major compounds. J Eur Acad Dermatol Venereol. 2004;18:73-78.
  38. Pinto E, Pina-Vaz C, Salgueiro L, et al. Antifungal activity of the essential oil of Thymus pulegioides on Candida, Aspergillus and dermatophyte species. J Med Microbiol. 2006;55:1367-1373.
  39. Vicks VapoRub might help fight toenail fungus. Consumer Reports. 2006;71:49.
  40. Derby R, Rohal P, Jackson C, et al. Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med. 2011;24:69-74.
  41. Trapp S, Croteau R. Defensive resin biosynthesis in conifers. Ann Rev Plant Physiol Plant Mol Biol. 2001;52:689-724.
  42. Sipponen A, Laitinen K. Antimicrobial properties of natural coniferous rosin in the European Pharmacopoeia challenge test. APMIS. 2011;119:720-724.
  43. Sipponen A, Lohi J. Lappish gum care “new” treatment of pressure ulcers? People’s improvement at it’s best. Eng Med J. 2003;58:2775-2776.
  44. Benedictus O. Een Nyttigh Läkare. Malmö: Kroon; 1938.
  45. Rautio M, Sipponen A, Peltola R, et al. Antibacterial effects of home-made resin salve from Norway spruce (Picea abies). APMIS. 2007;115:335-340.
  46. Laitinen K, Sipponen A, Jokinen JJ, et al. Resin salve from Norway spruce is antifungal against dermatophytes causing nail infections. EWMA. 2009;56:289-296.
  47. Rautio M, Sipponen A, Lohi J, et al. In vitro fungistatic effects of natural coniferous resin from Norway spruce (Picea abies). Eur J Clin Microbiol Infect Dis. 2012;31:1783-1789.
  48. Sipponen A, Peltola R, Jokinen JJ, et al. Effects of Norway spruce (Picea abies) resin on cell wall and cell membrane of Staphylococcus aureus. Ultrastruct Pathol. 2009;33:128-135.
  49. Sipponen P, Sipponen A, Lohi J, et al. Natural coniferous resin lacquer in treatment of toenail onychomycosis: an observational study. Mycoses. 2013;56:289-296.
  50. Auvinen T, Tiihonen R, Soini M, et al. Efficacy of topical resin lacquer, amorolfine, and oral terbinafine for treating toenail onychomycosis: a prospective, randomized, controlled, investigator-blinded, parallel-group clinical trial. Br J Dermatol. 2015;173:940-948.
  51. Argueta A, Cano L, Rodarte M. Atlas de las Plantas de la Medicina Tradicional Mexicana. Vol 3. Mexico City, Mexico: Instituto Nacional Indigenista; 1994:72-680.
  52. Avilés M, Suárez G. Catálogo de Plantas Medicinales del Jardín Etnobotánico. Peru: Instituto Nacional de Antropología e Historia; 1994.
  53. Romero-Cerecero O, Roman-Ramos R, Zamilpa A, et al. Clinical trial to compare the effectiveness of two concentrations of the Ageratina pichinchensis extract in the topical treatment of onychomycosis. J Ethnopharmacol. 2009;126:74-78.
  54. Navarro Garcia VM, Gonzalez A, Fuentes M, et al. Antifungal activities of nine traditional Mexican medicinal plants. J Ethnopharmacol. 2003;87:85-88.
  55. Castañeda P, Gómez L, Mata R, et al. Phytogrowth-inhibitory and antifungal constituents of Helianthella quinquenervis. J Nat Prod. 1996;59:323-326.
  56. Kumar N. Inhibition of nail infecting fungi of peoples of North Eastern UP causing Tinea unguium through leaf essential oil of Ageratum houstonianum Mill. IOSR J Pharm. June 2014;4:36-42.
  57. Romero-Cerecero O, Rojas G, Navarro V, et al. Effectiveness and tolerability of a standardized extract from Ageratina pichinchensis on patients with tinea pedis: an explorative pilot study controlled with ketoconazole. Planta Med. 2006;72:1257-1261.
  58. Romero-Cerecero O, Zamilpa A, Jimenez-Ferrer JE, et al. Double-blind clinical trial for evaluating the effectiveness and tolerability of Ageratina pichinchensis extract on patients with mild to moderate onychomycosis. a comparative study with ciclopirox. Planta Med. 2008;74:1430-1435.
  59. Rzedowski J, De Rzedowski GC. Flora Fanerogámica del Valle de México. Mexico City, Mexico: Instituto de Ecología Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional; 1985.
  60. Bocci V. Biological and clinical effects of ozone. has ozone therapy a future in medicine? Br J Biomed Sci. 1999;56:270-279.
  61. Sechi LA, Lezcano I, Nunez N, et al. Antibacterial activity of ozonized sunflower oil (Oleozon). J Appl Microbiol. 2001;90:279-284.
  62. Rodrigues KL, Cardoso CC, Caputo LR, et al. Cicatrizing and antimicrobial properties of an ozonised oil from sunflower seeds. Inflammopharmacology. 2004;12:261-270.
  63. Daud FV, Ueda SMY, Navarini A, et al. The use of ozonized oil in the treatment of dermatophitosis caused by Microsporum canis in rabbits. Braz J Microbiol. 2011;42:274-281.
  64. Guerrer LV, Cunha KC, Nogueira MC, et al. “In vitro” antifungal activity of ozonized sunflower oil on yeasts from onychomycosis. Braz J Microbiol. 2012;43:1315-1318.
  65. Menéndez S, Falcón L, Maqueira Y. Therapeutic efficacy of topical OLEOZON in patients suffering from onychomycosis. Mycoses. 2011;54:E272-E277.
References
  1. Scher RK, Daniel CR. Nails: Diagnosis, Therapy, Surgery. 3rd ed. Oxford, England: Elsevier Saunders; 2005.
  2. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014;28:1480-1491.
  3. Thomas J, Jacobson GA, Narkowicz CK, et al. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35:497-519.
  4. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and management. Am J Clin Dermatol. 2009;10:211-220.
  5. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.
  6. Hay RJ, Baran R. Onychomycosis: a proposed revision of the clinical classification J Am Acad Dermatol. 2011;65:1219-1227.
  7. Elewski B. Clinical pearl: proximal white subungual onychomycosis in AIDS. J Am Acad Dermatol. 1993;29:631-632.
  8. Scher RK. Onychomycosis is more than a cosmetic problem. Br J Dermatol. 1994;130(suppl 43):15.
  9. Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care. 2006;29:1202-1207.
  10. Szepietowski JC, Reich A, Pacan P, et al. Evaluation of quality of life in patients with toenail onychomycosis by Polish version of an international onychomycosis-specific questionnaire. J Eur Acad Dermatol Venereol. 2007;21:491-496.
  11. Scher RK, Baron R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003;149(suppl 65):5-9.
  12. Lamisil [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.
  13. Sporanox [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2001
  14. Penlac [package insert]. Bridgewater, NJ: Dermik Laboratories; 2006.
  15. Jublia [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2014.
  16. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.
  17. Kerydin [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc; 2014
  18. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies [published online May 5, 2015]. J Am Acad Dermatol. 2015;73:62-69.
  19. D’Auria FD, Laino L, Strippoli V, et al. In vitro activity of tea tree oil against Candida albicans mycelial conversion and other pathogenic fungi. J Chemother. 2001;13:377-383.
  20. Satchell AC, Saurajen A, Bell C, et al. Treatment of interdigital tinea pedis with 25% and 50% tea tree oil solution: a randomized, placebo-controlled, blinded study. Australas J Dermatol. 2002;43:175-178.
  21. Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (tea tree) oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev. 2006;19:50-62.
  22. Hammer KA, Carson CF, Riley TV. Antifungal activity of the components of Melaleuca alternifolia (tea tree) oil. J Appl Microbiol. 2003;95:853-860.
  23. Brophy JJ, Davies NW, Southwell IA, et al. Gas chromatographic quality control for oil of Melaleuca terpinen-4-ol type (Australian tea tree). J Agric Food Chem. 1989;37:1330-1335.
  24. Concha JM, Moore LS, Holloway WJ. 1998 William J. Stickel Bronze Award. Antifungal activity of Melaleuca alternifolia (tea-tree) oil against various pathogenic organisms. J Am Podiatr Med Assoc. 1998;88:489-492.
  25. Benger S, Townsend P, Ashford RL, et al. An in vitro study to determine the minimum inhibitory concentration of Melaleuca alternifolia against the dermatophyte Trichophyton rubrum. Foot. 2004;14:86-91.
  26. Hammer KA, Carson CF, Riley TV. In-vitro activity of essential oils, in particular Melaleuca alternifolia (tea tree) oil and tea tree oil products, against Candida spp. J Antimicrob Chemother. 1998;42:591-595.
  27. Altman P. Australian tea tree oil. Aust J Pharm. 1998;69:276-278.
  28. Guterres SS, Alves MP, Pohlmann AR. Polymeric nanoparticles, nanospheres and nanocapsules, for cutaneous applications. Drug Target Insights. 2007;2:147-157.
  29. Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole. J Fam Pract. 1994;38:601-605.
  30. Syed TA, Qureshi ZA, Ali SM, et al. Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream. Tropical Med Int Health. 1999;4:284-287.
  31. Flores FC, de Lima JA, Ribeiro RF, et al. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of Trichophyton rubrum. Mycopathologia. 2013;175:281-286.
  32. Hammer KA, Carson CF, Riley TV. Antifungal effects of Melaleuca alternifolia (tea tree) oil and its components on Candida albicans, Candida glabrata and Saccharomyces cerevisiae. J Antimicrob Chemother. 2004;53:1081-1085.
  33. Cox SD, Mann CM, Markham JL, et al. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (tea tree oil). J Appl Microbiol. 2000;88:170-175.
  34. Hammer KA, Carson CF, Riley TV. Melaleuca alternifolia (tea tree) oil inhibits germ tube formation by Candida albicans. Med Mycol. 2000;38:355-362.
  35. Vicks VapoRub [package insert]. Gross-Gerau, Germany: Proctor & Gamble; 2010.
  36. Ramsewak RS, Nair MG, Stommel M, et al. In vitro antagonistic activity of monoterpenes and their mixtures against ‘toe nail fungus’ pathogens. Phytother Res. 2003;17:376-379.
  37. Pina-Vaz C, Gonçalves Rodrigues A, Pinto E, et al. Antifungal activity of Thymus oils and their major compounds. J Eur Acad Dermatol Venereol. 2004;18:73-78.
  38. Pinto E, Pina-Vaz C, Salgueiro L, et al. Antifungal activity of the essential oil of Thymus pulegioides on Candida, Aspergillus and dermatophyte species. J Med Microbiol. 2006;55:1367-1373.
  39. Vicks VapoRub might help fight toenail fungus. Consumer Reports. 2006;71:49.
  40. Derby R, Rohal P, Jackson C, et al. Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med. 2011;24:69-74.
  41. Trapp S, Croteau R. Defensive resin biosynthesis in conifers. Ann Rev Plant Physiol Plant Mol Biol. 2001;52:689-724.
  42. Sipponen A, Laitinen K. Antimicrobial properties of natural coniferous rosin in the European Pharmacopoeia challenge test. APMIS. 2011;119:720-724.
  43. Sipponen A, Lohi J. Lappish gum care “new” treatment of pressure ulcers? People’s improvement at it’s best. Eng Med J. 2003;58:2775-2776.
  44. Benedictus O. Een Nyttigh Läkare. Malmö: Kroon; 1938.
  45. Rautio M, Sipponen A, Peltola R, et al. Antibacterial effects of home-made resin salve from Norway spruce (Picea abies). APMIS. 2007;115:335-340.
  46. Laitinen K, Sipponen A, Jokinen JJ, et al. Resin salve from Norway spruce is antifungal against dermatophytes causing nail infections. EWMA. 2009;56:289-296.
  47. Rautio M, Sipponen A, Lohi J, et al. In vitro fungistatic effects of natural coniferous resin from Norway spruce (Picea abies). Eur J Clin Microbiol Infect Dis. 2012;31:1783-1789.
  48. Sipponen A, Peltola R, Jokinen JJ, et al. Effects of Norway spruce (Picea abies) resin on cell wall and cell membrane of Staphylococcus aureus. Ultrastruct Pathol. 2009;33:128-135.
  49. Sipponen P, Sipponen A, Lohi J, et al. Natural coniferous resin lacquer in treatment of toenail onychomycosis: an observational study. Mycoses. 2013;56:289-296.
  50. Auvinen T, Tiihonen R, Soini M, et al. Efficacy of topical resin lacquer, amorolfine, and oral terbinafine for treating toenail onychomycosis: a prospective, randomized, controlled, investigator-blinded, parallel-group clinical trial. Br J Dermatol. 2015;173:940-948.
  51. Argueta A, Cano L, Rodarte M. Atlas de las Plantas de la Medicina Tradicional Mexicana. Vol 3. Mexico City, Mexico: Instituto Nacional Indigenista; 1994:72-680.
  52. Avilés M, Suárez G. Catálogo de Plantas Medicinales del Jardín Etnobotánico. Peru: Instituto Nacional de Antropología e Historia; 1994.
  53. Romero-Cerecero O, Roman-Ramos R, Zamilpa A, et al. Clinical trial to compare the effectiveness of two concentrations of the Ageratina pichinchensis extract in the topical treatment of onychomycosis. J Ethnopharmacol. 2009;126:74-78.
  54. Navarro Garcia VM, Gonzalez A, Fuentes M, et al. Antifungal activities of nine traditional Mexican medicinal plants. J Ethnopharmacol. 2003;87:85-88.
  55. Castañeda P, Gómez L, Mata R, et al. Phytogrowth-inhibitory and antifungal constituents of Helianthella quinquenervis. J Nat Prod. 1996;59:323-326.
  56. Kumar N. Inhibition of nail infecting fungi of peoples of North Eastern UP causing Tinea unguium through leaf essential oil of Ageratum houstonianum Mill. IOSR J Pharm. June 2014;4:36-42.
  57. Romero-Cerecero O, Rojas G, Navarro V, et al. Effectiveness and tolerability of a standardized extract from Ageratina pichinchensis on patients with tinea pedis: an explorative pilot study controlled with ketoconazole. Planta Med. 2006;72:1257-1261.
  58. Romero-Cerecero O, Zamilpa A, Jimenez-Ferrer JE, et al. Double-blind clinical trial for evaluating the effectiveness and tolerability of Ageratina pichinchensis extract on patients with mild to moderate onychomycosis. a comparative study with ciclopirox. Planta Med. 2008;74:1430-1435.
  59. Rzedowski J, De Rzedowski GC. Flora Fanerogámica del Valle de México. Mexico City, Mexico: Instituto de Ecología Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional; 1985.
  60. Bocci V. Biological and clinical effects of ozone. has ozone therapy a future in medicine? Br J Biomed Sci. 1999;56:270-279.
  61. Sechi LA, Lezcano I, Nunez N, et al. Antibacterial activity of ozonized sunflower oil (Oleozon). J Appl Microbiol. 2001;90:279-284.
  62. Rodrigues KL, Cardoso CC, Caputo LR, et al. Cicatrizing and antimicrobial properties of an ozonised oil from sunflower seeds. Inflammopharmacology. 2004;12:261-270.
  63. Daud FV, Ueda SMY, Navarini A, et al. The use of ozonized oil in the treatment of dermatophitosis caused by Microsporum canis in rabbits. Braz J Microbiol. 2011;42:274-281.
  64. Guerrer LV, Cunha KC, Nogueira MC, et al. “In vitro” antifungal activity of ozonized sunflower oil on yeasts from onychomycosis. Braz J Microbiol. 2012;43:1315-1318.
  65. Menéndez S, Falcón L, Maqueira Y. Therapeutic efficacy of topical OLEOZON in patients suffering from onychomycosis. Mycoses. 2011;54:E272-E277.
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Over-the-counter and Natural Remedies for Onychomycosis: Do They Really Work?
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Over-the-counter and Natural Remedies for Onychomycosis: Do They Really Work?
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Practice Points

  • Natural remedies, including tea tree oil, natural topical cough suppressants, natural coniferous resin lacquer, Ageratina pichinchensis extract, and ozonized sunflower oil, have shown antifungal activities in in vitro studies.
  • Some of these products have efficacy and appear to be safe in clinical studies.
  • Larger randomized clinical trials demonstrating efficacy are required before we can recommend these products to our patients.
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2016 Update on bone health

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2016 Update on bone health
Prioritize bone health: osteoporotic fracture is a major source of morbidity and mortality in women. In this article: fracture risk with OC use in perimenopause, calcium’s role in CVD, sarcopenia management, and an emerging treatment.
Author(s)
Steven R. Goldstein, MD, NCMP, CCD

Prioritize bone health, as osteoporotic fracture is a major source of morbidity and mortality among women. In this article: fracture risk with OC use in perimenopause, data that inform calcium’s role in cardiovascular disease, sarcopenia management, and an emerging treatment.

Most women’s health care providers are aware of recent changes and controversies regarding cervical cancer screening, mammography frequency, and whether a pelvic bimanual exam should be part of our annual well woman evaluation.1 However, I believe one of the most important things we as clinicians can do is be frontline in promoting bone health. Osteoporotic fracture is a major source of morbidity and mortality.2,3 Thus, promoting the maintenance of bone health is a priority in my own practice. It is also one of my many academic interests.

What follows is an update on bone health. In past years, this update has been entitled, “Update on osteoporosis,” but what we are trying to accomplish is fracture reduction. Thus, priorities for bone health consist of recognition of risk, lifestyle and dietary counseling, as well as the use of pharmacologic agents when appropriate. Certain research stands out as informative for your practice:

  • a recent study on the risk of fracture with oral contraceptive (OC) use in perimenopause
  • 3 just-published studies that inform our understanding of calcium’s role in cardiovascular health
  • a review on sarcopenia management
  • new data on romosozumab.
 

 

Oral contraceptive use in perimenopause

Scholes D, LaCroix AZ, Hubbard RA, et al. Oral contraceptive use and fracture risk around the menopausal transition. Menopause. 2016;23(2):166-174.


The use of OCs in women of older reproductive age has increased ever since the cutoff age of 35 years was eliminated.4 Lower doses have continued to be utilized in these "older" women with excellent control of irregular bleeding due to ovulatory dysfunction (and reduction in psychosocial symptoms as well).5

The effect of OC use on risk of fracture remains unclear, and use during later reproductive life may be increasing. To determine the association between OC use during later reproductive life and risk of fracture across the menopausal transition, Scholes and colleagues conducted a population-based case-controlled study in a Pacific Northwest HMO, Group Health Cooperative.

Details of the study

Scholes and colleagues enrolled 1,204 case women aged 45 to 59 years with incident fractures, and 2,275 control women. Potential cases with fracture codes in automated data were adjudicated by electronic health record review. Potential control women without fracture codes were selected concurrently, sampling based on age. Participants received a structured study interview. Using logistic regression, associations between OC use and fracture risk were calculated as odds ratios (ORs) and 95% confidence intervals (CIs).

Participation was 69% for cases and 64% for controls. The study sample was 82% white; mean age was 54 years. The most common fracture site for cases was the wrist/forearm (32%). Adjusted fracture risk did not differ between cases and controls for OC use:

  • in the 10 years before menopause (OR, 0.90; 95% CI, 0.74-1.11)
  • after age 38 years (OR, 0.94; 95% CI, 0.78-1.14)
  • over the duration, or
  • for other OC exposures.

Related article:
2016 Update on female sexual dysfunction

Association between fractures and OC use near menopause

The current study does not show an association between fractures near the menopausal transition and OC use in the decade before menopause or after age 38 years. For women considering OC use at these times, fracture risk does not seem to be either reduced or increased.

These results, looking at fracture, seem to be further supported by trials conducted by Gambacciani and colleagues,6 in which researchers randomly assigned irregularly cycling perimenopausal women (aged 40-49 years) to 20 &#956;g ethinyl estradiol OCs or calcium/placebo. Results showed that this low-dose OC use significantly increased bone density at the femoral neck, spine, and other sites relative to control women after 24 months. 

In the current Scholes study, the use of OCs in the decade before menopause or after age 38 did not reduce fracture risk in the years around the time of menopause. It is reassuring that their use was not associated with any increased fracture risk.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
These findings provide additional clarity and guidance to women and their clinicians at a time of increasing public health concern about fractures. For women who may choose to use OCs during late premenopause (around age 38-48 years), fracture risk around the menopausal transition will not differ from women not choosing this option.
 

 

Calcium and calcium supplements: The data continue to grow

Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA) [published online ahead of print October 11, 2016]. J Am Heart Assoc. pii: e003815.

Billington EO, Bristow SM, Gamble GD, et al. Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women [published online ahead of print August 20, 2016]. Osteoporos Int. doi:10.1007/s00198-016-3744-y.

Crandall CJ, Aragaki AK, LeBoff MS, et al. Calcium plus vitamin D supplementation and height loss: findings from the Women's Health Initiative Calcium and Vitamin D clinical trial [published online ahead of print August 1, 2016]. Menopause. doi:10.1097 /GME.0000000000000704.


In 2001, a National Institutes of Health (NIH) Consensus Development Panel on osteoporosis concluded that calcium intake is crucial to maintain bone mass and should be maintained at 1,000-1,500 mg/day in older adults. The panel acknowledged that the majority of older adults did not meet the recommended intake from dietary sources alone, and therefore would require calcium supplementation. Calcium supplements are one of the most commonly used dietary supplements, and population-based surveys have shown that they are used by the majority of older men and women in the United States.7 

More recently results from large randomized controlled trials (RCTs) of calcium supplements have been reported, leading to concerns about calcium efficacy for fracture risk and safety. Bolland and colleagues8 reported that calcium supplements increased the rate of cardiovascular events in healthy older women and suggested that their role in osteoporosis management be reconsidered. More recently, the US Preventive Services Task Force recommended against calcium supplements for the primary prevention of fractures in noninstitutionalized postmenopausal women.9 

The association between calcium intake and CVD events

Anderson and colleagues acknowledged that recent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, they assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC).

Details of the study by Anderson and colleagues
The authors studied 5,448 adults free of clinically diagnosed CVD (52% female; age range, 45-84 years) from the Multi-Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles based on overall population distribution. Baseline CAC was measured by computed tomography (CT) scan, and CAC measurements were repeated in 2,742 participants approximately 10 years later. Women had higher calcium intakes than men. 

After adjustment for potential confounders, among 1,567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake is included in the TABLE. After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR, 1.22; 95% CI, 1.07-1.39). No relation was found between baseline calcium intake and 10-year changes in CAC among those participants with baseline CAC less than zero.

They concluded that high total calcium intake was associated with a decreased risk of incident atherosclerosis over long-term follow-up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.

Related article:
Does the discontinuation of menopausal hormone therapy affect a woman’s cardiovascular risk?

Calcium supplements and blood pressure

Billington and colleagues acknowledged that calcium supplements appear to increase cardiovascular risk but that the mechanism is unknown. They had previously reported that blood pressure declines over the course of the day in older women.10

Details of the study by Billington and colleagues
In this new study the investigators examined the acute effects of calcium supplements on blood pressure in a randomized controlled crossover trial in 40 healthy postmenopausal women (mean age, 71 years; body mass index [BMI], 27.2 kg/m2). Women attended on 2 occasions, with visits separated by 7 or more days. At each visit, they received either 1 g of calcium as citrate or placebo. Blood pressure and serum calcium concentrations were measured immediately before and 2, 4, and 6 hours after each intervention.

Ionized and total calcium concentrations increased after calcium (P<.0001 vs placebo). Systolic blood pressure (SBP) measurements decreased after both calcium and placebo but significantly less so after calcium (P=.02). The reduction in SBP from baseline was smaller after calcium compared with placebo by 6 mm Hg at 4 hours (P=.036) and by 9 mm Hg at 6 hours (P=.002). The reduction in diastolic blood pressure was similar after calcium and placebo.

These findings indicate that the use of calcium supplements in postmenopausal women attenuates the postbreakfast reduction in SBP by 6 to 9 mm Hg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Association between calcium, vitamin D, and height loss

Crandall and colleagues looked at the association between calcium and vitamin D supplementation and height loss in 36,282 participants of the Women's Health Initiative Calcium and Vitamin D trial.

Details of the study by Crandall and colleagues

The authors performed a post hoc analysis of data from a double-blind randomized controlled trial of 1,000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily (CaD) or placebo in postmenopausal women at 40 US clinical centers. Height was measured annually (mean follow-up, 5.9 years) with a stadiometer.

Average height loss was 1.28 mm/yr among participants assigned to CaD, versus 1.26 mm/yr for women assigned to placebo (P=.35). A strong association (P<.001) was observed between age group and height loss. The study authors concluded that, compared with placebo, calcium and vitamin D supplementation used in this trial did not prevent height loss in healthy postmenopausal women.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adequate calcium is necessary for bone health. While calcium supplementation may not be adequate to prevent fractures, it is also not involved in the inevitable loss of overall height seen in postmenopausal women. Calcium supplementation has been implicated in an increase in CVD. These data seem to indicate that, while calcium supplementation results in higher systolic blood pressure during the day, as well as higher coronary artery calcium scores, greater dietary calcium actually may decrease the incidence of atherosclerosis.

 

 

 

Sarcopenia:  Still important, clinical approaches to easily detect it

Beaudart C, McCloskey E, Bruyére O, et al. Sarcopenia in daily practice:  assessment and management. BMC Geriatr. 2016;16(1):170.


In last year's update, I reviewed the article by He and colleagues11 on the relationship between sarcopenia and body composition with osteoporosis. Sarcopenia, which is the age-related loss of muscle mass and strength, is important to address in patients. Body composition and muscle strength are directly correlated with bone density, and this is not surprising since bone and muscle share some common hormonal, genetic, nutritional, and lifestyle determinants.12,13 Sarcopenia can be diagnosed via dual-energy x-ray absorptiometry (DXA) scan looking at lean muscle mass.

The term sarcopenia was first coined by Rosenberg and colleagues in 198914 as a progressive loss of skeletal muscle mass with advancing age. Since then, the definition has expanded to incorporate the notion of impaired muscle strength or physical performance. Sarcopenia is associated with morbidity and mortality from linked physical disability, falls, fractures, poor quality of life, depression, and hospitalization.15

Current research is focusing on nutritional exercise/activity-based and other novel interventions for improving the quality and quantity of skeletal muscle in older people. Some studies demonstrated that resistance training combined with nutritional supplements can improve muscle function.16

Details of the study

Beaudart and colleagues propose some user-friendly and inexpensive methods that can be utilized to assess sarcopenia in real life settings. They acknowledge that in research settings or even specialist clinical settings, DXA or computed tomography (CT) scans are the best assessment of muscle mass.

Anthropometric measurements. In a primary care setting, anthropometric measurement, especially calf circumference and mid-upper arm muscle circumference, correlate with overall muscle mass and reflect both health and nutritional status and predict performance, health, and survival in older people.

However, with advancing age, changes in the distribution of fat and loss of skin elasticity are such that circumference incurs a loss of accuracy and precision in older people. Some studies suggest that an adjustment of anthropometric measurements for age, sex, or BMI results in a better correlation with DXA-measured lean mass.17 Anthropometric measurements are simple clinical prediction tools that can be easily applied for sarcopenia since they offer the most portable, commonly applicable, inexpensive, and noninvasive technique for assessing size, proportions, and composition of the human body. However, their validity is limited when applied to individuals because cutoff points to identify low muscle mass still need to be defined. Still, serial measurements in a patient over time may be valuable.

Related article:
2014 Update on osteoporosis

Handgrip strength, as measured with a dynamometer, appears to be the most widely used method for the measurement of muscle strength. In general, isometric handgrip strength shows a good correlation with leg strength and also with lower extremity power, and calf cross-sectional muscle area. The measurement is easy to perform, inexpensive and does not require a specialist-trained staff.

Standardized conditions for the test include seating the patient in a standard chair with her forearms resting flat on the chair arms. Clinicians should demonstrate the use of the dynamometer and show that gripping very tightly registers the best score. Six measurements should be taken, 3 with each arm. Ideally, patients should be encouraged to squeeze as hard and tightly as possible during 3 to 5 seconds for each of the 6 trials; usually the highest reading of the 6 measurements is reported as the final result. The Jamar dynamometer, or similar hydraulic dynamometer, is the gold standard for this measurement.

Gait speed measurement. The most widely used tool in clinical practice for the assessment of physical performance is the gait speed measurement. The test is highly acceptable for participants and health professionals in clinical settings. No special equipment is required; it needs only a flat floor devoid of obstacles. In the 4-meter gait speed test, men and women with a gait speed of less than 0.8 meters/sec are described as having a poor physical performance. The average extra time added to the consultation by measuring the 4-meter gait speed was only 95 seconds (SD, 20 seconds).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Loss of muscle mass correlates with loss of bone mass as our patients age. In addition, such sarcopenia increases the risk of falls, a significant component of the rising rate of fragility fractures. Anthropometric measures, grip strength, and gait speed are easy, low-cost measures that can identify patients at increased risk.
 

 

Romosozumab: An interesting new agent to look forward to

Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532-1543.


Romosozumab is a monoclonal antibody that binds sclerostin, increasing bone formation and decreasing bone resorption. Cosman and colleagues enrolled 7,180 postmenopausal women with a T score of -2.5 to -3.5 at the total hip or femoral neck. Participants were randomly assigned to receive subcutaneous injections of romosozumab 210 mg or placebo monthly for 12 months. Thereafter, women in each group received subcutaneous denosumab 60 mg for 12 months--administered every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 and 24 months. Secondary end points included clinical and nonvertebral fractures.

Details of the study

At 12 months, new vertebral fractures had occurred in 16 of 3,321 women (0.5%) in the romosozumab group, as compared with 59 of 3,322 (1.8%) in the placebo group (representing a 73% lower risk of fracture with romosozumab; P<.001). Clinical fractures had occurred in 58 of 3,589 women (1.6%) in the romosozumab group, as compared with 90 of 3,591 (2.5%) in the placebo group (a 36% lower fracture risk with romosozumab;  P = .008). Nonvertebral fractures had occurred in 56 of 3,589 women (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in the placebo group (P = .10).

At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3,325 women] in the romosozumab group vs 2.5% [84 of 3,327 women] in the placebo group, a 75% lower risk with romosozumab; P<.001). Adverse events, including cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and 2 cases of osteonecrosis of the jaw were observed in the romosozumab group.

Lower risk of fracture

Thus, in postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.

Of note, the effect of romosozumab on the risk of vertebral fracture was rapid, with only 2 additional vertebral fractures (of a total of 16 such fractures in the romosozumab group) occurring in the second 6 months of the first year of therapy. Because vertebral and clinical fractures are associated with increased morbidity and considerable  health care costs, a treatment that would reduce this risk rapidly could offer appropriate patients an important benefit.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Romosozumab is a new agent. Though not yet available, it is extremely interesting because it not only decreases bone resorption but also increases bone formation. The results of this large prospective trial show that such an agent reduces both vertebral and clinical fracture and reduces that fracture risk quite rapidly within the first 6 months of therapy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

References
  1. MacLaughlin KL, Faubion SS, Long ME, Pruthi S, Casey PM. Should the annual pelvic examination go the way of annual cervical cytology? Womens Health (Lond). 2014;10(4):373–384.
  2. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520–2526.
  3. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King AB, Tosterson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–475.
  4. Kaunitz AM. Hormonal contraception in women of older reproductive age. N Engl J Med. 2008;358:1262–1270.
  5. Kaunitz AM. Oral contraceptive use in perimenopause. Am J Obstet Gynecol. 2001;185(2 suppl):S32–S37.
  6. Gambacciani M, Cappagli B, Lazzarini V, Ciaponi M, Fruzzetti F, Genazzani AR. Longitudinal evaluation of perimenopausal bone loss: effects of different low dose oral contraceptive preparations on bone mineral density. Maturitas. 2006;54(2):176–180.
  7. Bailey R, Dodd K, Goldman J, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140(4):817–822.
  8. Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf. 2013;4(5):199–210.
  9. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(9):691–696.
  10. Bristow SM, Gamble GD, Stewart A, Horne AM, Reid IR. Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women. Br J Nutr. 2015;114(11):1868–1874.
  11. He H, Liu Y, Tian Q, Papasian CJ, Hu T, Deng HW. Relationship of sarcopenia and body composition with osteoporosis. Osteoporos Int. 2016;27(2):473–482.
  12. Coin A, Perissinotto E, Enzi G, et al. Predictors of low bone mineral density in the elderly: the role of dietary intake, nutritional status and sarcopenia. Eur J Clin Nutr. 2008;62(6):802–809.
  13. Taaffe DR, Cauley JA, Danielson M, et al. Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the Health, Aging, and Body Composition Study. J Bone Miner Res. 2001;16(7):1343–1352.
  14. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127(5 suppl):990S–991S.
  15. Beaudart C, Rizzoli R, Bruyere O, Reginster JY, Biver E. Sarcopenia: Burden and challenges for Public Health. Arch Public Health. 2014;72(1):45.
  16. Cruz-Jentoft AJ, Landi F, Schneider SM, et al. Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing. 2014;43(6):748–759.
  17. Kulkarni B, Kuper H, Taylor A, et al. Development and validation of anthropometric prediction equations for estimation of lean body mass and appendicular lean soft tissue in Indian men and women. J Appl Physiol. 2013;115(8):1156–1162.
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Prioritize bone health: osteoporotic fracture is a major source of morbidity and mortality in women. In this article: fracture risk with OC use in perimenopause, calcium’s role in CVD, sarcopenia management, and an emerging treatment.
Prioritize bone health: osteoporotic fracture is a major source of morbidity and mortality in women. In this article: fracture risk with OC use in perimenopause, calcium’s role in CVD, sarcopenia management, and an emerging treatment.

Prioritize bone health, as osteoporotic fracture is a major source of morbidity and mortality among women. In this article: fracture risk with OC use in perimenopause, data that inform calcium’s role in cardiovascular disease, sarcopenia management, and an emerging treatment.

Most women’s health care providers are aware of recent changes and controversies regarding cervical cancer screening, mammography frequency, and whether a pelvic bimanual exam should be part of our annual well woman evaluation.1 However, I believe one of the most important things we as clinicians can do is be frontline in promoting bone health. Osteoporotic fracture is a major source of morbidity and mortality.2,3 Thus, promoting the maintenance of bone health is a priority in my own practice. It is also one of my many academic interests.

What follows is an update on bone health. In past years, this update has been entitled, “Update on osteoporosis,” but what we are trying to accomplish is fracture reduction. Thus, priorities for bone health consist of recognition of risk, lifestyle and dietary counseling, as well as the use of pharmacologic agents when appropriate. Certain research stands out as informative for your practice:

  • a recent study on the risk of fracture with oral contraceptive (OC) use in perimenopause
  • 3 just-published studies that inform our understanding of calcium’s role in cardiovascular health
  • a review on sarcopenia management
  • new data on romosozumab.
 

 

Oral contraceptive use in perimenopause

Scholes D, LaCroix AZ, Hubbard RA, et al. Oral contraceptive use and fracture risk around the menopausal transition. Menopause. 2016;23(2):166-174.


The use of OCs in women of older reproductive age has increased ever since the cutoff age of 35 years was eliminated.4 Lower doses have continued to be utilized in these "older" women with excellent control of irregular bleeding due to ovulatory dysfunction (and reduction in psychosocial symptoms as well).5

The effect of OC use on risk of fracture remains unclear, and use during later reproductive life may be increasing. To determine the association between OC use during later reproductive life and risk of fracture across the menopausal transition, Scholes and colleagues conducted a population-based case-controlled study in a Pacific Northwest HMO, Group Health Cooperative.

Details of the study

Scholes and colleagues enrolled 1,204 case women aged 45 to 59 years with incident fractures, and 2,275 control women. Potential cases with fracture codes in automated data were adjudicated by electronic health record review. Potential control women without fracture codes were selected concurrently, sampling based on age. Participants received a structured study interview. Using logistic regression, associations between OC use and fracture risk were calculated as odds ratios (ORs) and 95% confidence intervals (CIs).

Participation was 69% for cases and 64% for controls. The study sample was 82% white; mean age was 54 years. The most common fracture site for cases was the wrist/forearm (32%). Adjusted fracture risk did not differ between cases and controls for OC use:

  • in the 10 years before menopause (OR, 0.90; 95% CI, 0.74-1.11)
  • after age 38 years (OR, 0.94; 95% CI, 0.78-1.14)
  • over the duration, or
  • for other OC exposures.

Related article:
2016 Update on female sexual dysfunction

Association between fractures and OC use near menopause

The current study does not show an association between fractures near the menopausal transition and OC use in the decade before menopause or after age 38 years. For women considering OC use at these times, fracture risk does not seem to be either reduced or increased.

These results, looking at fracture, seem to be further supported by trials conducted by Gambacciani and colleagues,6 in which researchers randomly assigned irregularly cycling perimenopausal women (aged 40-49 years) to 20 &#956;g ethinyl estradiol OCs or calcium/placebo. Results showed that this low-dose OC use significantly increased bone density at the femoral neck, spine, and other sites relative to control women after 24 months. 

In the current Scholes study, the use of OCs in the decade before menopause or after age 38 did not reduce fracture risk in the years around the time of menopause. It is reassuring that their use was not associated with any increased fracture risk.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
These findings provide additional clarity and guidance to women and their clinicians at a time of increasing public health concern about fractures. For women who may choose to use OCs during late premenopause (around age 38-48 years), fracture risk around the menopausal transition will not differ from women not choosing this option.
 

 

Calcium and calcium supplements: The data continue to grow

Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA) [published online ahead of print October 11, 2016]. J Am Heart Assoc. pii: e003815.

Billington EO, Bristow SM, Gamble GD, et al. Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women [published online ahead of print August 20, 2016]. Osteoporos Int. doi:10.1007/s00198-016-3744-y.

Crandall CJ, Aragaki AK, LeBoff MS, et al. Calcium plus vitamin D supplementation and height loss: findings from the Women's Health Initiative Calcium and Vitamin D clinical trial [published online ahead of print August 1, 2016]. Menopause. doi:10.1097 /GME.0000000000000704.


In 2001, a National Institutes of Health (NIH) Consensus Development Panel on osteoporosis concluded that calcium intake is crucial to maintain bone mass and should be maintained at 1,000-1,500 mg/day in older adults. The panel acknowledged that the majority of older adults did not meet the recommended intake from dietary sources alone, and therefore would require calcium supplementation. Calcium supplements are one of the most commonly used dietary supplements, and population-based surveys have shown that they are used by the majority of older men and women in the United States.7 

More recently results from large randomized controlled trials (RCTs) of calcium supplements have been reported, leading to concerns about calcium efficacy for fracture risk and safety. Bolland and colleagues8 reported that calcium supplements increased the rate of cardiovascular events in healthy older women and suggested that their role in osteoporosis management be reconsidered. More recently, the US Preventive Services Task Force recommended against calcium supplements for the primary prevention of fractures in noninstitutionalized postmenopausal women.9 

The association between calcium intake and CVD events

Anderson and colleagues acknowledged that recent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, they assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC).

Details of the study by Anderson and colleagues
The authors studied 5,448 adults free of clinically diagnosed CVD (52% female; age range, 45-84 years) from the Multi-Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles based on overall population distribution. Baseline CAC was measured by computed tomography (CT) scan, and CAC measurements were repeated in 2,742 participants approximately 10 years later. Women had higher calcium intakes than men. 

After adjustment for potential confounders, among 1,567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake is included in the TABLE. After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR, 1.22; 95% CI, 1.07-1.39). No relation was found between baseline calcium intake and 10-year changes in CAC among those participants with baseline CAC less than zero.

They concluded that high total calcium intake was associated with a decreased risk of incident atherosclerosis over long-term follow-up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.

Related article:
Does the discontinuation of menopausal hormone therapy affect a woman’s cardiovascular risk?

Calcium supplements and blood pressure

Billington and colleagues acknowledged that calcium supplements appear to increase cardiovascular risk but that the mechanism is unknown. They had previously reported that blood pressure declines over the course of the day in older women.10

Details of the study by Billington and colleagues
In this new study the investigators examined the acute effects of calcium supplements on blood pressure in a randomized controlled crossover trial in 40 healthy postmenopausal women (mean age, 71 years; body mass index [BMI], 27.2 kg/m2). Women attended on 2 occasions, with visits separated by 7 or more days. At each visit, they received either 1 g of calcium as citrate or placebo. Blood pressure and serum calcium concentrations were measured immediately before and 2, 4, and 6 hours after each intervention.

Ionized and total calcium concentrations increased after calcium (P<.0001 vs placebo). Systolic blood pressure (SBP) measurements decreased after both calcium and placebo but significantly less so after calcium (P=.02). The reduction in SBP from baseline was smaller after calcium compared with placebo by 6 mm Hg at 4 hours (P=.036) and by 9 mm Hg at 6 hours (P=.002). The reduction in diastolic blood pressure was similar after calcium and placebo.

These findings indicate that the use of calcium supplements in postmenopausal women attenuates the postbreakfast reduction in SBP by 6 to 9 mm Hg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Association between calcium, vitamin D, and height loss

Crandall and colleagues looked at the association between calcium and vitamin D supplementation and height loss in 36,282 participants of the Women's Health Initiative Calcium and Vitamin D trial.

Details of the study by Crandall and colleagues

The authors performed a post hoc analysis of data from a double-blind randomized controlled trial of 1,000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily (CaD) or placebo in postmenopausal women at 40 US clinical centers. Height was measured annually (mean follow-up, 5.9 years) with a stadiometer.

Average height loss was 1.28 mm/yr among participants assigned to CaD, versus 1.26 mm/yr for women assigned to placebo (P=.35). A strong association (P<.001) was observed between age group and height loss. The study authors concluded that, compared with placebo, calcium and vitamin D supplementation used in this trial did not prevent height loss in healthy postmenopausal women.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adequate calcium is necessary for bone health. While calcium supplementation may not be adequate to prevent fractures, it is also not involved in the inevitable loss of overall height seen in postmenopausal women. Calcium supplementation has been implicated in an increase in CVD. These data seem to indicate that, while calcium supplementation results in higher systolic blood pressure during the day, as well as higher coronary artery calcium scores, greater dietary calcium actually may decrease the incidence of atherosclerosis.

 

 

 

Sarcopenia:  Still important, clinical approaches to easily detect it

Beaudart C, McCloskey E, Bruyére O, et al. Sarcopenia in daily practice:  assessment and management. BMC Geriatr. 2016;16(1):170.


In last year's update, I reviewed the article by He and colleagues11 on the relationship between sarcopenia and body composition with osteoporosis. Sarcopenia, which is the age-related loss of muscle mass and strength, is important to address in patients. Body composition and muscle strength are directly correlated with bone density, and this is not surprising since bone and muscle share some common hormonal, genetic, nutritional, and lifestyle determinants.12,13 Sarcopenia can be diagnosed via dual-energy x-ray absorptiometry (DXA) scan looking at lean muscle mass.

The term sarcopenia was first coined by Rosenberg and colleagues in 198914 as a progressive loss of skeletal muscle mass with advancing age. Since then, the definition has expanded to incorporate the notion of impaired muscle strength or physical performance. Sarcopenia is associated with morbidity and mortality from linked physical disability, falls, fractures, poor quality of life, depression, and hospitalization.15

Current research is focusing on nutritional exercise/activity-based and other novel interventions for improving the quality and quantity of skeletal muscle in older people. Some studies demonstrated that resistance training combined with nutritional supplements can improve muscle function.16

Details of the study

Beaudart and colleagues propose some user-friendly and inexpensive methods that can be utilized to assess sarcopenia in real life settings. They acknowledge that in research settings or even specialist clinical settings, DXA or computed tomography (CT) scans are the best assessment of muscle mass.

Anthropometric measurements. In a primary care setting, anthropometric measurement, especially calf circumference and mid-upper arm muscle circumference, correlate with overall muscle mass and reflect both health and nutritional status and predict performance, health, and survival in older people.

However, with advancing age, changes in the distribution of fat and loss of skin elasticity are such that circumference incurs a loss of accuracy and precision in older people. Some studies suggest that an adjustment of anthropometric measurements for age, sex, or BMI results in a better correlation with DXA-measured lean mass.17 Anthropometric measurements are simple clinical prediction tools that can be easily applied for sarcopenia since they offer the most portable, commonly applicable, inexpensive, and noninvasive technique for assessing size, proportions, and composition of the human body. However, their validity is limited when applied to individuals because cutoff points to identify low muscle mass still need to be defined. Still, serial measurements in a patient over time may be valuable.

Related article:
2014 Update on osteoporosis

Handgrip strength, as measured with a dynamometer, appears to be the most widely used method for the measurement of muscle strength. In general, isometric handgrip strength shows a good correlation with leg strength and also with lower extremity power, and calf cross-sectional muscle area. The measurement is easy to perform, inexpensive and does not require a specialist-trained staff.

Standardized conditions for the test include seating the patient in a standard chair with her forearms resting flat on the chair arms. Clinicians should demonstrate the use of the dynamometer and show that gripping very tightly registers the best score. Six measurements should be taken, 3 with each arm. Ideally, patients should be encouraged to squeeze as hard and tightly as possible during 3 to 5 seconds for each of the 6 trials; usually the highest reading of the 6 measurements is reported as the final result. The Jamar dynamometer, or similar hydraulic dynamometer, is the gold standard for this measurement.

Gait speed measurement. The most widely used tool in clinical practice for the assessment of physical performance is the gait speed measurement. The test is highly acceptable for participants and health professionals in clinical settings. No special equipment is required; it needs only a flat floor devoid of obstacles. In the 4-meter gait speed test, men and women with a gait speed of less than 0.8 meters/sec are described as having a poor physical performance. The average extra time added to the consultation by measuring the 4-meter gait speed was only 95 seconds (SD, 20 seconds).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Loss of muscle mass correlates with loss of bone mass as our patients age. In addition, such sarcopenia increases the risk of falls, a significant component of the rising rate of fragility fractures. Anthropometric measures, grip strength, and gait speed are easy, low-cost measures that can identify patients at increased risk.
 

 

Romosozumab: An interesting new agent to look forward to

Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532-1543.


Romosozumab is a monoclonal antibody that binds sclerostin, increasing bone formation and decreasing bone resorption. Cosman and colleagues enrolled 7,180 postmenopausal women with a T score of -2.5 to -3.5 at the total hip or femoral neck. Participants were randomly assigned to receive subcutaneous injections of romosozumab 210 mg or placebo monthly for 12 months. Thereafter, women in each group received subcutaneous denosumab 60 mg for 12 months--administered every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 and 24 months. Secondary end points included clinical and nonvertebral fractures.

Details of the study

At 12 months, new vertebral fractures had occurred in 16 of 3,321 women (0.5%) in the romosozumab group, as compared with 59 of 3,322 (1.8%) in the placebo group (representing a 73% lower risk of fracture with romosozumab; P<.001). Clinical fractures had occurred in 58 of 3,589 women (1.6%) in the romosozumab group, as compared with 90 of 3,591 (2.5%) in the placebo group (a 36% lower fracture risk with romosozumab;  P = .008). Nonvertebral fractures had occurred in 56 of 3,589 women (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in the placebo group (P = .10).

At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3,325 women] in the romosozumab group vs 2.5% [84 of 3,327 women] in the placebo group, a 75% lower risk with romosozumab; P<.001). Adverse events, including cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and 2 cases of osteonecrosis of the jaw were observed in the romosozumab group.

Lower risk of fracture

Thus, in postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.

Of note, the effect of romosozumab on the risk of vertebral fracture was rapid, with only 2 additional vertebral fractures (of a total of 16 such fractures in the romosozumab group) occurring in the second 6 months of the first year of therapy. Because vertebral and clinical fractures are associated with increased morbidity and considerable  health care costs, a treatment that would reduce this risk rapidly could offer appropriate patients an important benefit.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Romosozumab is a new agent. Though not yet available, it is extremely interesting because it not only decreases bone resorption but also increases bone formation. The results of this large prospective trial show that such an agent reduces both vertebral and clinical fracture and reduces that fracture risk quite rapidly within the first 6 months of therapy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Prioritize bone health, as osteoporotic fracture is a major source of morbidity and mortality among women. In this article: fracture risk with OC use in perimenopause, data that inform calcium’s role in cardiovascular disease, sarcopenia management, and an emerging treatment.

Most women’s health care providers are aware of recent changes and controversies regarding cervical cancer screening, mammography frequency, and whether a pelvic bimanual exam should be part of our annual well woman evaluation.1 However, I believe one of the most important things we as clinicians can do is be frontline in promoting bone health. Osteoporotic fracture is a major source of morbidity and mortality.2,3 Thus, promoting the maintenance of bone health is a priority in my own practice. It is also one of my many academic interests.

What follows is an update on bone health. In past years, this update has been entitled, “Update on osteoporosis,” but what we are trying to accomplish is fracture reduction. Thus, priorities for bone health consist of recognition of risk, lifestyle and dietary counseling, as well as the use of pharmacologic agents when appropriate. Certain research stands out as informative for your practice:

  • a recent study on the risk of fracture with oral contraceptive (OC) use in perimenopause
  • 3 just-published studies that inform our understanding of calcium’s role in cardiovascular health
  • a review on sarcopenia management
  • new data on romosozumab.
 

 

Oral contraceptive use in perimenopause

Scholes D, LaCroix AZ, Hubbard RA, et al. Oral contraceptive use and fracture risk around the menopausal transition. Menopause. 2016;23(2):166-174.


The use of OCs in women of older reproductive age has increased ever since the cutoff age of 35 years was eliminated.4 Lower doses have continued to be utilized in these "older" women with excellent control of irregular bleeding due to ovulatory dysfunction (and reduction in psychosocial symptoms as well).5

The effect of OC use on risk of fracture remains unclear, and use during later reproductive life may be increasing. To determine the association between OC use during later reproductive life and risk of fracture across the menopausal transition, Scholes and colleagues conducted a population-based case-controlled study in a Pacific Northwest HMO, Group Health Cooperative.

Details of the study

Scholes and colleagues enrolled 1,204 case women aged 45 to 59 years with incident fractures, and 2,275 control women. Potential cases with fracture codes in automated data were adjudicated by electronic health record review. Potential control women without fracture codes were selected concurrently, sampling based on age. Participants received a structured study interview. Using logistic regression, associations between OC use and fracture risk were calculated as odds ratios (ORs) and 95% confidence intervals (CIs).

Participation was 69% for cases and 64% for controls. The study sample was 82% white; mean age was 54 years. The most common fracture site for cases was the wrist/forearm (32%). Adjusted fracture risk did not differ between cases and controls for OC use:

  • in the 10 years before menopause (OR, 0.90; 95% CI, 0.74-1.11)
  • after age 38 years (OR, 0.94; 95% CI, 0.78-1.14)
  • over the duration, or
  • for other OC exposures.

Related article:
2016 Update on female sexual dysfunction

Association between fractures and OC use near menopause

The current study does not show an association between fractures near the menopausal transition and OC use in the decade before menopause or after age 38 years. For women considering OC use at these times, fracture risk does not seem to be either reduced or increased.

These results, looking at fracture, seem to be further supported by trials conducted by Gambacciani and colleagues,6 in which researchers randomly assigned irregularly cycling perimenopausal women (aged 40-49 years) to 20 &#956;g ethinyl estradiol OCs or calcium/placebo. Results showed that this low-dose OC use significantly increased bone density at the femoral neck, spine, and other sites relative to control women after 24 months. 

In the current Scholes study, the use of OCs in the decade before menopause or after age 38 did not reduce fracture risk in the years around the time of menopause. It is reassuring that their use was not associated with any increased fracture risk.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
These findings provide additional clarity and guidance to women and their clinicians at a time of increasing public health concern about fractures. For women who may choose to use OCs during late premenopause (around age 38-48 years), fracture risk around the menopausal transition will not differ from women not choosing this option.
 

 

Calcium and calcium supplements: The data continue to grow

Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA) [published online ahead of print October 11, 2016]. J Am Heart Assoc. pii: e003815.

Billington EO, Bristow SM, Gamble GD, et al. Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women [published online ahead of print August 20, 2016]. Osteoporos Int. doi:10.1007/s00198-016-3744-y.

Crandall CJ, Aragaki AK, LeBoff MS, et al. Calcium plus vitamin D supplementation and height loss: findings from the Women's Health Initiative Calcium and Vitamin D clinical trial [published online ahead of print August 1, 2016]. Menopause. doi:10.1097 /GME.0000000000000704.


In 2001, a National Institutes of Health (NIH) Consensus Development Panel on osteoporosis concluded that calcium intake is crucial to maintain bone mass and should be maintained at 1,000-1,500 mg/day in older adults. The panel acknowledged that the majority of older adults did not meet the recommended intake from dietary sources alone, and therefore would require calcium supplementation. Calcium supplements are one of the most commonly used dietary supplements, and population-based surveys have shown that they are used by the majority of older men and women in the United States.7 

More recently results from large randomized controlled trials (RCTs) of calcium supplements have been reported, leading to concerns about calcium efficacy for fracture risk and safety. Bolland and colleagues8 reported that calcium supplements increased the rate of cardiovascular events in healthy older women and suggested that their role in osteoporosis management be reconsidered. More recently, the US Preventive Services Task Force recommended against calcium supplements for the primary prevention of fractures in noninstitutionalized postmenopausal women.9 

The association between calcium intake and CVD events

Anderson and colleagues acknowledged that recent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, they assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC).

Details of the study by Anderson and colleagues
The authors studied 5,448 adults free of clinically diagnosed CVD (52% female; age range, 45-84 years) from the Multi-Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles based on overall population distribution. Baseline CAC was measured by computed tomography (CT) scan, and CAC measurements were repeated in 2,742 participants approximately 10 years later. Women had higher calcium intakes than men. 

After adjustment for potential confounders, among 1,567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake is included in the TABLE. After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR, 1.22; 95% CI, 1.07-1.39). No relation was found between baseline calcium intake and 10-year changes in CAC among those participants with baseline CAC less than zero.

They concluded that high total calcium intake was associated with a decreased risk of incident atherosclerosis over long-term follow-up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.

Related article:
Does the discontinuation of menopausal hormone therapy affect a woman’s cardiovascular risk?

Calcium supplements and blood pressure

Billington and colleagues acknowledged that calcium supplements appear to increase cardiovascular risk but that the mechanism is unknown. They had previously reported that blood pressure declines over the course of the day in older women.10

Details of the study by Billington and colleagues
In this new study the investigators examined the acute effects of calcium supplements on blood pressure in a randomized controlled crossover trial in 40 healthy postmenopausal women (mean age, 71 years; body mass index [BMI], 27.2 kg/m2). Women attended on 2 occasions, with visits separated by 7 or more days. At each visit, they received either 1 g of calcium as citrate or placebo. Blood pressure and serum calcium concentrations were measured immediately before and 2, 4, and 6 hours after each intervention.

Ionized and total calcium concentrations increased after calcium (P<.0001 vs placebo). Systolic blood pressure (SBP) measurements decreased after both calcium and placebo but significantly less so after calcium (P=.02). The reduction in SBP from baseline was smaller after calcium compared with placebo by 6 mm Hg at 4 hours (P=.036) and by 9 mm Hg at 6 hours (P=.002). The reduction in diastolic blood pressure was similar after calcium and placebo.

These findings indicate that the use of calcium supplements in postmenopausal women attenuates the postbreakfast reduction in SBP by 6 to 9 mm Hg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Association between calcium, vitamin D, and height loss

Crandall and colleagues looked at the association between calcium and vitamin D supplementation and height loss in 36,282 participants of the Women's Health Initiative Calcium and Vitamin D trial.

Details of the study by Crandall and colleagues

The authors performed a post hoc analysis of data from a double-blind randomized controlled trial of 1,000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily (CaD) or placebo in postmenopausal women at 40 US clinical centers. Height was measured annually (mean follow-up, 5.9 years) with a stadiometer.

Average height loss was 1.28 mm/yr among participants assigned to CaD, versus 1.26 mm/yr for women assigned to placebo (P=.35). A strong association (P<.001) was observed between age group and height loss. The study authors concluded that, compared with placebo, calcium and vitamin D supplementation used in this trial did not prevent height loss in healthy postmenopausal women.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adequate calcium is necessary for bone health. While calcium supplementation may not be adequate to prevent fractures, it is also not involved in the inevitable loss of overall height seen in postmenopausal women. Calcium supplementation has been implicated in an increase in CVD. These data seem to indicate that, while calcium supplementation results in higher systolic blood pressure during the day, as well as higher coronary artery calcium scores, greater dietary calcium actually may decrease the incidence of atherosclerosis.

 

 

 

Sarcopenia:  Still important, clinical approaches to easily detect it

Beaudart C, McCloskey E, Bruyére O, et al. Sarcopenia in daily practice:  assessment and management. BMC Geriatr. 2016;16(1):170.


In last year's update, I reviewed the article by He and colleagues11 on the relationship between sarcopenia and body composition with osteoporosis. Sarcopenia, which is the age-related loss of muscle mass and strength, is important to address in patients. Body composition and muscle strength are directly correlated with bone density, and this is not surprising since bone and muscle share some common hormonal, genetic, nutritional, and lifestyle determinants.12,13 Sarcopenia can be diagnosed via dual-energy x-ray absorptiometry (DXA) scan looking at lean muscle mass.

The term sarcopenia was first coined by Rosenberg and colleagues in 198914 as a progressive loss of skeletal muscle mass with advancing age. Since then, the definition has expanded to incorporate the notion of impaired muscle strength or physical performance. Sarcopenia is associated with morbidity and mortality from linked physical disability, falls, fractures, poor quality of life, depression, and hospitalization.15

Current research is focusing on nutritional exercise/activity-based and other novel interventions for improving the quality and quantity of skeletal muscle in older people. Some studies demonstrated that resistance training combined with nutritional supplements can improve muscle function.16

Details of the study

Beaudart and colleagues propose some user-friendly and inexpensive methods that can be utilized to assess sarcopenia in real life settings. They acknowledge that in research settings or even specialist clinical settings, DXA or computed tomography (CT) scans are the best assessment of muscle mass.

Anthropometric measurements. In a primary care setting, anthropometric measurement, especially calf circumference and mid-upper arm muscle circumference, correlate with overall muscle mass and reflect both health and nutritional status and predict performance, health, and survival in older people.

However, with advancing age, changes in the distribution of fat and loss of skin elasticity are such that circumference incurs a loss of accuracy and precision in older people. Some studies suggest that an adjustment of anthropometric measurements for age, sex, or BMI results in a better correlation with DXA-measured lean mass.17 Anthropometric measurements are simple clinical prediction tools that can be easily applied for sarcopenia since they offer the most portable, commonly applicable, inexpensive, and noninvasive technique for assessing size, proportions, and composition of the human body. However, their validity is limited when applied to individuals because cutoff points to identify low muscle mass still need to be defined. Still, serial measurements in a patient over time may be valuable.

Related article:
2014 Update on osteoporosis

Handgrip strength, as measured with a dynamometer, appears to be the most widely used method for the measurement of muscle strength. In general, isometric handgrip strength shows a good correlation with leg strength and also with lower extremity power, and calf cross-sectional muscle area. The measurement is easy to perform, inexpensive and does not require a specialist-trained staff.

Standardized conditions for the test include seating the patient in a standard chair with her forearms resting flat on the chair arms. Clinicians should demonstrate the use of the dynamometer and show that gripping very tightly registers the best score. Six measurements should be taken, 3 with each arm. Ideally, patients should be encouraged to squeeze as hard and tightly as possible during 3 to 5 seconds for each of the 6 trials; usually the highest reading of the 6 measurements is reported as the final result. The Jamar dynamometer, or similar hydraulic dynamometer, is the gold standard for this measurement.

Gait speed measurement. The most widely used tool in clinical practice for the assessment of physical performance is the gait speed measurement. The test is highly acceptable for participants and health professionals in clinical settings. No special equipment is required; it needs only a flat floor devoid of obstacles. In the 4-meter gait speed test, men and women with a gait speed of less than 0.8 meters/sec are described as having a poor physical performance. The average extra time added to the consultation by measuring the 4-meter gait speed was only 95 seconds (SD, 20 seconds).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Loss of muscle mass correlates with loss of bone mass as our patients age. In addition, such sarcopenia increases the risk of falls, a significant component of the rising rate of fragility fractures. Anthropometric measures, grip strength, and gait speed are easy, low-cost measures that can identify patients at increased risk.
 

 

Romosozumab: An interesting new agent to look forward to

Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532-1543.


Romosozumab is a monoclonal antibody that binds sclerostin, increasing bone formation and decreasing bone resorption. Cosman and colleagues enrolled 7,180 postmenopausal women with a T score of -2.5 to -3.5 at the total hip or femoral neck. Participants were randomly assigned to receive subcutaneous injections of romosozumab 210 mg or placebo monthly for 12 months. Thereafter, women in each group received subcutaneous denosumab 60 mg for 12 months--administered every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 and 24 months. Secondary end points included clinical and nonvertebral fractures.

Details of the study

At 12 months, new vertebral fractures had occurred in 16 of 3,321 women (0.5%) in the romosozumab group, as compared with 59 of 3,322 (1.8%) in the placebo group (representing a 73% lower risk of fracture with romosozumab; P<.001). Clinical fractures had occurred in 58 of 3,589 women (1.6%) in the romosozumab group, as compared with 90 of 3,591 (2.5%) in the placebo group (a 36% lower fracture risk with romosozumab;  P = .008). Nonvertebral fractures had occurred in 56 of 3,589 women (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in the placebo group (P = .10).

At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3,325 women] in the romosozumab group vs 2.5% [84 of 3,327 women] in the placebo group, a 75% lower risk with romosozumab; P<.001). Adverse events, including cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and 2 cases of osteonecrosis of the jaw were observed in the romosozumab group.

Lower risk of fracture

Thus, in postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.

Of note, the effect of romosozumab on the risk of vertebral fracture was rapid, with only 2 additional vertebral fractures (of a total of 16 such fractures in the romosozumab group) occurring in the second 6 months of the first year of therapy. Because vertebral and clinical fractures are associated with increased morbidity and considerable  health care costs, a treatment that would reduce this risk rapidly could offer appropriate patients an important benefit.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Romosozumab is a new agent. Though not yet available, it is extremely interesting because it not only decreases bone resorption but also increases bone formation. The results of this large prospective trial show that such an agent reduces both vertebral and clinical fracture and reduces that fracture risk quite rapidly within the first 6 months of therapy.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

References
  1. MacLaughlin KL, Faubion SS, Long ME, Pruthi S, Casey PM. Should the annual pelvic examination go the way of annual cervical cytology? Womens Health (Lond). 2014;10(4):373–384.
  2. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520–2526.
  3. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King AB, Tosterson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–475.
  4. Kaunitz AM. Hormonal contraception in women of older reproductive age. N Engl J Med. 2008;358:1262–1270.
  5. Kaunitz AM. Oral contraceptive use in perimenopause. Am J Obstet Gynecol. 2001;185(2 suppl):S32–S37.
  6. Gambacciani M, Cappagli B, Lazzarini V, Ciaponi M, Fruzzetti F, Genazzani AR. Longitudinal evaluation of perimenopausal bone loss: effects of different low dose oral contraceptive preparations on bone mineral density. Maturitas. 2006;54(2):176–180.
  7. Bailey R, Dodd K, Goldman J, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140(4):817–822.
  8. Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf. 2013;4(5):199–210.
  9. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(9):691–696.
  10. Bristow SM, Gamble GD, Stewart A, Horne AM, Reid IR. Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women. Br J Nutr. 2015;114(11):1868–1874.
  11. He H, Liu Y, Tian Q, Papasian CJ, Hu T, Deng HW. Relationship of sarcopenia and body composition with osteoporosis. Osteoporos Int. 2016;27(2):473–482.
  12. Coin A, Perissinotto E, Enzi G, et al. Predictors of low bone mineral density in the elderly: the role of dietary intake, nutritional status and sarcopenia. Eur J Clin Nutr. 2008;62(6):802–809.
  13. Taaffe DR, Cauley JA, Danielson M, et al. Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the Health, Aging, and Body Composition Study. J Bone Miner Res. 2001;16(7):1343–1352.
  14. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127(5 suppl):990S–991S.
  15. Beaudart C, Rizzoli R, Bruyere O, Reginster JY, Biver E. Sarcopenia: Burden and challenges for Public Health. Arch Public Health. 2014;72(1):45.
  16. Cruz-Jentoft AJ, Landi F, Schneider SM, et al. Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing. 2014;43(6):748–759.
  17. Kulkarni B, Kuper H, Taylor A, et al. Development and validation of anthropometric prediction equations for estimation of lean body mass and appendicular lean soft tissue in Indian men and women. J Appl Physiol. 2013;115(8):1156–1162.
References
  1. MacLaughlin KL, Faubion SS, Long ME, Pruthi S, Casey PM. Should the annual pelvic examination go the way of annual cervical cytology? Womens Health (Lond). 2014;10(4):373–384.
  2. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520–2526.
  3. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King AB, Tosterson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–475.
  4. Kaunitz AM. Hormonal contraception in women of older reproductive age. N Engl J Med. 2008;358:1262–1270.
  5. Kaunitz AM. Oral contraceptive use in perimenopause. Am J Obstet Gynecol. 2001;185(2 suppl):S32–S37.
  6. Gambacciani M, Cappagli B, Lazzarini V, Ciaponi M, Fruzzetti F, Genazzani AR. Longitudinal evaluation of perimenopausal bone loss: effects of different low dose oral contraceptive preparations on bone mineral density. Maturitas. 2006;54(2):176–180.
  7. Bailey R, Dodd K, Goldman J, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140(4):817–822.
  8. Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf. 2013;4(5):199–210.
  9. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(9):691–696.
  10. Bristow SM, Gamble GD, Stewart A, Horne AM, Reid IR. Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women. Br J Nutr. 2015;114(11):1868–1874.
  11. He H, Liu Y, Tian Q, Papasian CJ, Hu T, Deng HW. Relationship of sarcopenia and body composition with osteoporosis. Osteoporos Int. 2016;27(2):473–482.
  12. Coin A, Perissinotto E, Enzi G, et al. Predictors of low bone mineral density in the elderly: the role of dietary intake, nutritional status and sarcopenia. Eur J Clin Nutr. 2008;62(6):802–809.
  13. Taaffe DR, Cauley JA, Danielson M, et al. Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the Health, Aging, and Body Composition Study. J Bone Miner Res. 2001;16(7):1343–1352.
  14. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127(5 suppl):990S–991S.
  15. Beaudart C, Rizzoli R, Bruyere O, Reginster JY, Biver E. Sarcopenia: Burden and challenges for Public Health. Arch Public Health. 2014;72(1):45.
  16. Cruz-Jentoft AJ, Landi F, Schneider SM, et al. Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing. 2014;43(6):748–759.
  17. Kulkarni B, Kuper H, Taylor A, et al. Development and validation of anthropometric prediction equations for estimation of lean body mass and appendicular lean soft tissue in Indian men and women. J Appl Physiol. 2013;115(8):1156–1162.
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Preventing infection after cesarean delivery: 5 more evidence-based ­measures to consider

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Preventing infection after cesarean delivery: 5 more evidence-based ­measures to consider
Besides antibiotic prophylaxis and proper body hair and skin preparation discussed in part 1, studies offer guidance on vaginal cleansing and other measures you might have used or deliberated on
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Kathryn E. Patrick, MD
Sara L. Deatsman, MD
Patrick Duff, MD

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

 

 

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).1 The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).1

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).2 The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.3 They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).3

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.4 They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.5 The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.6 These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.7 Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

 

 

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).8 A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).9

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.10 In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).11 Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

 

 

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.12 Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.13 In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,14 Wilcox et al in 2003,15 and Colling et al in 201516 all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).16

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.17 All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.18 Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).19 A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.20

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

 

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

References
  1. Starr RV, Zurawski J, Ismail M. Preoperative vaginal preparation with povidone-iodine and the risk of postcesarean endometritis. Obstet Gynecol. 2005;105(5 pt 1):1024–1029.
  2. Haas DM, Pazouki F, Smith RR, et al. Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidity: a randomized controlled trial. Am J Obstet Gynecol. 2010;202(3):310.e1–e6.
  3. Asghania M, Mirblouk F, Shakiba M, Faraji R. Preoperative vaginal preparation with povidone-iodine on post-caesarean infectious morbidity. J Obstet Gynaecol. 2011;31(5):400–403.
  4. Yildirim G, Güngördük K, Asicioglu O, et al. Does vaginal preparation with povidone-iodine prior to caesarean delivery reduce the risk of endometritis? A randomized controlled trial. J Matern Fetal Neonatal Med. 2012;25(11):2316–2321.
  5. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Sys Rev. 2014;(12):CD007892.
  6. Reid VC, Hartmann KE, McMahon M, Fry EP. Vaginal preparation with povidone iodine and postcesarean infectious morbidity: a randomized controlled trial. Obstet Gynecol. 2001;97(1):147–152.
  7. Pitt C, Sanchez-Ramos L, Kaunitz AM. Adjunctive intravaginal metronidazole for the prevention of postcesarean endometritis: a randomized controlled trial. Obstet Gynecol. 2001;98(5 pt 1):745–750.
  8. Lasley DS, Eblen A, Yancey MK, Duff P. The effect of placental removal method on the incidence of postcesarean infections. Am J Obstet Gynecol. 1997;176(6):1250–1254.
  9. Methods of delivering the placenta at caesarean section [comment]. Obstet Gynecol. 2008;112(5):1173–1174.
  10. Chelmow D, Rodriguez EJ, Sabatini MM. Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis. Obstet Gynecol. 2004;103(5 pt 1):974–980.
  11. Mackeen AD, Schuster M, Berghella V. Suture versus staples for skin closure after cesarean: a metaanalysis. Am J Obstet Gynecol. 2015;212(5):621.e1–e10.
  12. Kaiser AB , Kernodle DS , Barg NL , Petracek MR . Influence of preoperative showers on staphylococcal skin colonization: a comparative trial of antiseptic skin cleansers . Ann Thorac Surg. 1988 ; 45(1) : 35 –3 8 .
  13. Cruse PJ , Foord R . The epidemiology of wound infection. A 10-year prospective study of 62,939 wounds . Surg Clin North Am. 1980 ; 60 ( 1 ): 27 – 40 .
  14. Brady LM , Thomson M , Palmer MA , Harkness JL. Successful control of endemic MRSA in a cardiothoracic surgical unit . Med J Aust. 1990 ; 152(5) : 240 –24 5 .
  15. Wilcox MH , Hall J , Pike H , et al. Use of perioperative mupirocin to prevent methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic surgical site infections. J Hosp Infect. 2003 ; 54(3) : 196 – 201 .
  16. Colling K , Statz C , Glover J , Banton K, Bellman G. Pre-operative antiseptic shower and bath policy decreases the rate of S aureus and methicillin-resistant S aureus surgical site infections in patients undergoing joint arthroplasty . Surg Infect. 2015 ; 16(2):124–132.
  17. Webster J, Osborne S. Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. 2012;(9):CD004985.
  18. Kamel C , McGahan L , Polisena J , Mierzwinski-Urban M, Embil JM. Preoperative skin antiseptic preparations for preventing surgical site infections: a systematic review . Infect Control Hosp Epidemiol. 2012 ; 33(6) : 608 – 617 .
  19. Chlebicki MP , Safdar N , O’Horo JC , Maki DG. Preoperative chlorhexidine shower or bath for prevention of surgical site infection: a meta-analysis . Am J Infect Control. 2013 ; 41(2) : 167 –1 73 .
  20. Global guidelines for the prevention of surgical site infection. Geneva, Switzerland: World Health Organization; November 2016. http://www.who.int/gpsc/global-guidelines-web.pdf?ua=1. Accessed November 9, 2016.
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Dr. Patrick is a Maternal-Fetal Medicine Fellow in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

Dr. Deatsman is an Obstetrician-Gynecologist, Bronson Methodist Hospital, Kalamazoo, Michigan.

Dr. Duff is Associate Dean for Student Affairs and Professor of Obstetrics and Gynecology in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

The authors report no financial relationships relevant to this article.

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OBG Management
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Author(s)
Kathryn E. Patrick, MD
Sara L. Deatsman, MD
Patrick Duff, MD
Author(s)
Kathryn E. Patrick, MD
Sara L. Deatsman, MD
Patrick Duff, MD
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Dr. Patrick is a Maternal-Fetal Medicine Fellow in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

Dr. Deatsman is an Obstetrician-Gynecologist, Bronson Methodist Hospital, Kalamazoo, Michigan.

Dr. Duff is Associate Dean for Student Affairs and Professor of Obstetrics and Gynecology in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

The authors report no financial relationships relevant to this article.

Author and Disclosure Information

Dr. Patrick is a Maternal-Fetal Medicine Fellow in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

Dr. Deatsman is an Obstetrician-Gynecologist, Bronson Methodist Hospital, Kalamazoo, Michigan.

Dr. Duff is Associate Dean for Student Affairs and Professor of Obstetrics and Gynecology in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.

The authors report no financial relationships relevant to this article.

Article PDF
OBGM028012018.PDF
Article PDF
OBGM028012018.PDF
Besides antibiotic prophylaxis and proper body hair and skin preparation discussed in part 1, studies offer guidance on vaginal cleansing and other measures you might have used or deliberated on
Besides antibiotic prophylaxis and proper body hair and skin preparation discussed in part 1, studies offer guidance on vaginal cleansing and other measures you might have used or deliberated on

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

 

 

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).1 The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).1

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).2 The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.3 They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).3

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.4 They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.5 The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.6 These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.7 Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

 

 

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).8 A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).9

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.10 In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).11 Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

 

 

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.12 Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.13 In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,14 Wilcox et al in 2003,15 and Colling et al in 201516 all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).16

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.17 All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.18 Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).19 A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.20

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

 

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

 

 

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).1 The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).1

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).2 The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.3 They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).3

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.4 They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.5 The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.6 These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.7 Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

 

 

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).8 A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).9

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.10 In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).11 Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

 

 

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.12 Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.13 In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,14 Wilcox et al in 2003,15 and Colling et al in 201516 all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).16

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.17 All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.18 Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).19 A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.20

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

 

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

References
  1. Starr RV, Zurawski J, Ismail M. Preoperative vaginal preparation with povidone-iodine and the risk of postcesarean endometritis. Obstet Gynecol. 2005;105(5 pt 1):1024–1029.
  2. Haas DM, Pazouki F, Smith RR, et al. Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidity: a randomized controlled trial. Am J Obstet Gynecol. 2010;202(3):310.e1–e6.
  3. Asghania M, Mirblouk F, Shakiba M, Faraji R. Preoperative vaginal preparation with povidone-iodine on post-caesarean infectious morbidity. J Obstet Gynaecol. 2011;31(5):400–403.
  4. Yildirim G, Güngördük K, Asicioglu O, et al. Does vaginal preparation with povidone-iodine prior to caesarean delivery reduce the risk of endometritis? A randomized controlled trial. J Matern Fetal Neonatal Med. 2012;25(11):2316–2321.
  5. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Sys Rev. 2014;(12):CD007892.
  6. Reid VC, Hartmann KE, McMahon M, Fry EP. Vaginal preparation with povidone iodine and postcesarean infectious morbidity: a randomized controlled trial. Obstet Gynecol. 2001;97(1):147–152.
  7. Pitt C, Sanchez-Ramos L, Kaunitz AM. Adjunctive intravaginal metronidazole for the prevention of postcesarean endometritis: a randomized controlled trial. Obstet Gynecol. 2001;98(5 pt 1):745–750.
  8. Lasley DS, Eblen A, Yancey MK, Duff P. The effect of placental removal method on the incidence of postcesarean infections. Am J Obstet Gynecol. 1997;176(6):1250–1254.
  9. Methods of delivering the placenta at caesarean section [comment]. Obstet Gynecol. 2008;112(5):1173–1174.
  10. Chelmow D, Rodriguez EJ, Sabatini MM. Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis. Obstet Gynecol. 2004;103(5 pt 1):974–980.
  11. Mackeen AD, Schuster M, Berghella V. Suture versus staples for skin closure after cesarean: a metaanalysis. Am J Obstet Gynecol. 2015;212(5):621.e1–e10.
  12. Kaiser AB , Kernodle DS , Barg NL , Petracek MR . Influence of preoperative showers on staphylococcal skin colonization: a comparative trial of antiseptic skin cleansers . Ann Thorac Surg. 1988 ; 45(1) : 35 –3 8 .
  13. Cruse PJ , Foord R . The epidemiology of wound infection. A 10-year prospective study of 62,939 wounds . Surg Clin North Am. 1980 ; 60 ( 1 ): 27 – 40 .
  14. Brady LM , Thomson M , Palmer MA , Harkness JL. Successful control of endemic MRSA in a cardiothoracic surgical unit . Med J Aust. 1990 ; 152(5) : 240 –24 5 .
  15. Wilcox MH , Hall J , Pike H , et al. Use of perioperative mupirocin to prevent methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic surgical site infections. J Hosp Infect. 2003 ; 54(3) : 196 – 201 .
  16. Colling K , Statz C , Glover J , Banton K, Bellman G. Pre-operative antiseptic shower and bath policy decreases the rate of S aureus and methicillin-resistant S aureus surgical site infections in patients undergoing joint arthroplasty . Surg Infect. 2015 ; 16(2):124–132.
  17. Webster J, Osborne S. Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. 2012;(9):CD004985.
  18. Kamel C , McGahan L , Polisena J , Mierzwinski-Urban M, Embil JM. Preoperative skin antiseptic preparations for preventing surgical site infections: a systematic review . Infect Control Hosp Epidemiol. 2012 ; 33(6) : 608 – 617 .
  19. Chlebicki MP , Safdar N , O’Horo JC , Maki DG. Preoperative chlorhexidine shower or bath for prevention of surgical site infection: a meta-analysis . Am J Infect Control. 2013 ; 41(2) : 167 –1 73 .
  20. Global guidelines for the prevention of surgical site infection. Geneva, Switzerland: World Health Organization; November 2016. http://www.who.int/gpsc/global-guidelines-web.pdf?ua=1. Accessed November 9, 2016.
References
  1. Starr RV, Zurawski J, Ismail M. Preoperative vaginal preparation with povidone-iodine and the risk of postcesarean endometritis. Obstet Gynecol. 2005;105(5 pt 1):1024–1029.
  2. Haas DM, Pazouki F, Smith RR, et al. Vaginal cleansing before cesarean delivery to reduce postoperative infectious morbidity: a randomized controlled trial. Am J Obstet Gynecol. 2010;202(3):310.e1–e6.
  3. Asghania M, Mirblouk F, Shakiba M, Faraji R. Preoperative vaginal preparation with povidone-iodine on post-caesarean infectious morbidity. J Obstet Gynaecol. 2011;31(5):400–403.
  4. Yildirim G, Güngördük K, Asicioglu O, et al. Does vaginal preparation with povidone-iodine prior to caesarean delivery reduce the risk of endometritis? A randomized controlled trial. J Matern Fetal Neonatal Med. 2012;25(11):2316–2321.
  5. Haas DM, Morgan S, Contreras K. Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. Cochrane Database Sys Rev. 2014;(12):CD007892.
  6. Reid VC, Hartmann KE, McMahon M, Fry EP. Vaginal preparation with povidone iodine and postcesarean infectious morbidity: a randomized controlled trial. Obstet Gynecol. 2001;97(1):147–152.
  7. Pitt C, Sanchez-Ramos L, Kaunitz AM. Adjunctive intravaginal metronidazole for the prevention of postcesarean endometritis: a randomized controlled trial. Obstet Gynecol. 2001;98(5 pt 1):745–750.
  8. Lasley DS, Eblen A, Yancey MK, Duff P. The effect of placental removal method on the incidence of postcesarean infections. Am J Obstet Gynecol. 1997;176(6):1250–1254.
  9. Methods of delivering the placenta at caesarean section [comment]. Obstet Gynecol. 2008;112(5):1173–1174.
  10. Chelmow D, Rodriguez EJ, Sabatini MM. Suture closure of subcutaneous fat and wound disruption after cesarean delivery: a meta-analysis. Obstet Gynecol. 2004;103(5 pt 1):974–980.
  11. Mackeen AD, Schuster M, Berghella V. Suture versus staples for skin closure after cesarean: a metaanalysis. Am J Obstet Gynecol. 2015;212(5):621.e1–e10.
  12. Kaiser AB , Kernodle DS , Barg NL , Petracek MR . Influence of preoperative showers on staphylococcal skin colonization: a comparative trial of antiseptic skin cleansers . Ann Thorac Surg. 1988 ; 45(1) : 35 –3 8 .
  13. Cruse PJ , Foord R . The epidemiology of wound infection. A 10-year prospective study of 62,939 wounds . Surg Clin North Am. 1980 ; 60 ( 1 ): 27 – 40 .
  14. Brady LM , Thomson M , Palmer MA , Harkness JL. Successful control of endemic MRSA in a cardiothoracic surgical unit . Med J Aust. 1990 ; 152(5) : 240 –24 5 .
  15. Wilcox MH , Hall J , Pike H , et al. Use of perioperative mupirocin to prevent methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic surgical site infections. J Hosp Infect. 2003 ; 54(3) : 196 – 201 .
  16. Colling K , Statz C , Glover J , Banton K, Bellman G. Pre-operative antiseptic shower and bath policy decreases the rate of S aureus and methicillin-resistant S aureus surgical site infections in patients undergoing joint arthroplasty . Surg Infect. 2015 ; 16(2):124–132.
  17. Webster J, Osborne S. Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. 2012;(9):CD004985.
  18. Kamel C , McGahan L , Polisena J , Mierzwinski-Urban M, Embil JM. Preoperative skin antiseptic preparations for preventing surgical site infections: a systematic review . Infect Control Hosp Epidemiol. 2012 ; 33(6) : 608 – 617 .
  19. Chlebicki MP , Safdar N , O’Horo JC , Maki DG. Preoperative chlorhexidine shower or bath for prevention of surgical site infection: a meta-analysis . Am J Infect Control. 2013 ; 41(2) : 167 –1 73 .
  20. Global guidelines for the prevention of surgical site infection. Geneva, Switzerland: World Health Organization; November 2016. http://www.who.int/gpsc/global-guidelines-web.pdf?ua=1. Accessed November 9, 2016.
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An Overview of the History of Orthopedic Surgery

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An Overview of the History of Orthopedic Surgery
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Ishaan Swarup
MD; Jospeh F. O'Donnell
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The modern term orthopedics stems from the older word orthopedia, which was the title of a book published in 1741 by Nicholas Andry, a professor of medicine at the University of Paris.1 The term orthopedia is a composite of 2 Greek words: orthos, meaning “straight and free from deformity,” and paidios, meaning “child.” Together, orthopedics literally means straight child, suggesting the importance of pediatric injuries and deformities in the development of this field. Interestingly, Andry’s book also depicted a crooked young tree attached to a straight and strong staff, which has become the universal symbol of orthopedic surgery and underscores the focus on correcting deformities in the young (Figure).1

While the history of the term is relatively recent, the practice of orthopedics is an ancient art.

Orthopedic surgery is a rapidly advancing medical field with several recent advances noted within orthopedic subspecialties,2-4 basic science,5 and clinical research.6 It is important to recognize the role of history with regards to innovation and research, especially for young trainees and medical students interested in a particular medical specialty. More specifically, it is important to understand the successes and failures of the past in order to advance research and practice, and ultimately improve patient care and outcomes.

In the recent literature, there is no concise yet comprehensive article focusing on the history of orthopedic surgery. The goal of this review is to provide an overview of the history and development of orthopedic surgery from ancient practices to the modern era.

Ancient Orthopedics

While the evidence is limited, the practice of orthopedics dates back to the primitive man.7 Fossil evidence suggests that the orthopedic pathology of today, such as fractures and traumatic amputations, existed in primitive times.8 The union of fractures in fair alignment has also been observed, which emphasizes the efficacy of nonoperative orthopedics and suggests the early use of splints and rehabilitation practices.8,9 Since procedures such as trepanation and crude amputations occurred during the New Stone Age, it is feasible that sophisticated techniques had also been developed for the treatment of injuries.7-9 However, evidence continues to remain limited.7

Later civilizations also developed creative ways to manage orthopedic injuries. For example, the Shoshone Indians, who were known to exist around 700-2000 BCE, made a splint of fresh rawhide that had been soaked in water.9,10 Similarly, some South Australian tribes made splints of clay, which when dried were as good as plaster of Paris.9 Furthermore, bone-setting or reductions was practiced as a profession in many tribes, underscoring the importance of orthopedic injuries in early civilizations.8,9

Ancient Egypt

The ancient Egyptians seemed to have carried on the practices of splinting. For example, 2 splinted specimens were discovered during the Hearst Egyptian Expedition in 1903.7 More specifically, these specimens included a femur and forearm and dated to approximately 300 BCE.7 Other examples of splints made of bamboo and reed padded with linen have been found on mummies as well.8 Similarly, crutches were also used by this civilization, as depicted on a carving made on an Egyptian tomb in 2830 BCE.8

One of the earliest and most significant documents on medicine was discovered in 1862, known as the Edwin Smith papyrus. This document is thought to have been composed by Imhotep, a prominent Egyptian physician, astrologer, architect, and politician, and it specifically categorizes diseases and treatments. Many scholars recognize this medical document as the oldest surgical textbook.11,12 With regards to orthopedic conditions, this document describes the reduction of a dislocated mandible, signs of spinal or vertebral injuries, description of torticollis, and the treatment of fractures such as clavicle fractures.8 This document also discusses ryt, which refers to the purulent discharge from osteomyelitis.8 The following is an excerpt from this ancient document:9

“Instructions on erring a break in his upper arm…Thou shouldst spread out with his two shoulders in order to stretch apart his upper arm until that break falls into its place. Thou shouldst make for him two splints of linen, and thou shouldst apply for him one of them both on the inside of his arm, and the other of them both on the underside of his arm.”

This account illustrates the methodical and meticulous nature of this textbook, and it highlights some of the essentials of medical practice from diagnosis to medical decision-making to treatment.

There are various other contributions to the field of medicine from the Far East; however, many of these pertain to the fields of plastic surgery and general surgery.9

Greeks and Romans

The Greeks are considered to be the first to systematically employ the scientific approach to medicine.8 In the period between 430 BCE to 330 BCE, the Corpus Hippocrates was compiled, which is a Greek text on medicine. It is named for Hippocrates (460 BCE-370 BCE), the father of medicine, and it contains text that applies specifically to the field of orthopedic surgery. For example, this text discuses shoulder dislocations and describes various reduction maneuvers. Hippocrates had a keen understanding of the principles of traction and countertraction, especially as it pertains to the musculoskeletal system.8 In fact, the Hippocratic method is still used for reducing anterior shoulder dislocations, and its description can be found in several modern orthopedic texts, including recent articles.13 The Corpus Hippocrates also describes the correction of clubfoot deformity, and the treatment of infected open fractures with pitch cerate and wine compresses.8

 

 

Hippocrates also described the treatment of fractures, the principles of traction, and the implications of malunions. For example, Hippocrates wrote, “For the arm, when shortened, might be concealed and the mistake will not be great, but a shortened thigh bone will leave a man maimed.”1 In addition, spinal deformities were recognized by the Greeks, and Hippocrates devised an extension bench for the correction of such deformities.1 From their contributions to anatomy and surgical practice, the Greeks have made significant contributions to the field of surgery.9

During the Roman period, another Greek surgeon by the name of Galen described the musculoskeletal and nervous systems. He served as a gladiatorial surgeon in Rome, and today, he is considered to be the father of sports medicine.8 He is also credited with coining the terms scoliosis, kyphosis, and lordosis to denote the spinal deformities that were first described by Hippocrates.1 In the Roman period, amputations were also performed, and primitive prostheses were developed.9

The Middle Ages

There was relatively little progress in the study of medicine for a thousand years after the fall of the Roman Empire.9 This stagnation was predominantly due to the early Christian Church inhibiting freedom of thought and observation, as well as prohibiting human dissection and the study of anatomy. The first medical school in Europe was established in Salerno, Italy, during the ninth century. This school provided primarily pedantic teaching to its students and perpetuated the theories of the elements and humors. Later on, the University of Bologna became one of the first academic institutions to offer hands-on surgical training.9 One of the most famous surgeons of the Middle Ages was Guy de Chuauliac, who studied at Montpellier and Bologna. He was a leader in the ethical principles of surgery as well as the practice of surgery, and wrote the following with regards to femur fractures:9

“After the application of splints, I attach to the foot a mass of lead as a weight, taking care to pass the cord which supports the weight over a small pulley in such a manner that it shall pull on the leg in a horizontal direction.”

This description is strikingly similar to the modern-day nonoperative management of femur fractures, and underscores the importance of traction, which as mentioned above, was first described by Hippocrates.

Eventually, medicine began to separate from the Church, most likely due to an increase in the complexity of medical theories, the rise of secular universities, and an increase in medical knowledge from Eastern and Middle-Eastern groups.9

The Renaissance and the Foundations of Modern Orthopedics

Until the 16th century, the majority of medical theories were heavily influenced by the work of Hippocrates.8 The scientific study of anatomy gained prominence during this time, especially due to the work done by great artists, such as Leonardo Di Vinci.9 The Table

provides a list of some of the most prominent figures in the field of orthopedic surgery from across the world, as well as their contributions to the field. Collectively, these scholar and surgeons provided a strong foundation for the field of modern orthopedics.8 Additional discoveries by Joseph Lister, Louis Pasteur, Robert Koch, and Ignaz Semmelweis relating to antisepsis appeared to revolutionize the surgical management of orthopedic injuries.7

After a period of rapid expansion of the field of orthopedics, and following the Renaissance, many hospitals were built focusing on the sick and disabled, which solidified orthopedics’ position as a major medical specialty.1 For example, in 1863, James Knight founded the Hospital for the Ruptured and Crippled in New York City. This hospital became the oldest orthopedic hospital in the United States, and it later became known as the Hospital for Special Surgery.14,15 Several additional orthopedic institutions were formed, including the New York Orthopedic Dispensary in 1886 and Hospital for Deformities and Joint Diseases in 1917. Orthopedic surgery residency programs also began to be developed in the late 1800s.14 More specifically, Virgil Gibney at Hospital for the Ruptured and Crippled began the first orthopedic training program in the United States in 1888. Young doctors in this program trained for 1 year as junior assistant, senior assistant, and house surgeon, and began to be known as resident doctors.14

The Modern Era

In the 20th century, rapid development continued to better control infections as well as develop and introduce novel technology. For example, the invention of x-ray in 1895 by Wilhelm Conrad Röntgen improved our ability to diagnose and manage orthopedic conditions ranging from fractures to avascular necrosis of the femoral head to osteoarthritis.8,14 Spinal surgery also developed rapidly with Russell Hibbs describing a technique for spinal fusion at the New York Orthopedic Hospital.8 Similarly, the World Wars served as a catalyst in the development of the subspecialty of orthopedic trauma, with increasing attention placed on open wounds and proficiency with amputations, internal fixation, and wound care. In 1942, Austin Moore performed the first metal hip arthroplasty, and the field of joint replacement was subsequently advanced by the work of Sir John Charnley in the 1960s.8

 

 

Conclusion

Despite its relatively recent specialization, orthopedic surgery has a rich history rooted in ancient practices dating back to the primitive man. Over time, there has been significant development in the field in terms of surgical and nonsurgical treatment of orthopedic pathology and disease. Various cultures have played an instrumental role in developing this field, and it is remarkable to see that several practices have persisted since the time of these ancient civilizations. During the Renaissance, there was a considerable emphasis placed on pediatric deformity, but orthopedic surgeons have now branched out to subspecialty practice ranging from orthopedic trauma to joint replacement to oncology.1 For students of medicine and orthopedics, it is important to learn about the origins of this field and to appreciate its gradual development. Orthopedic surgery is a diverse and fascinating field that will most likely continue to develop with increased subspecialization and improved research at the molecular and population level. With a growing emphasis placed on outcomes and healthcare cost by today’s society, it will be fascinating to see how this field continues to evolve in the future.

Am J Orthop. 2016;45(7):E434-E438. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

1. Ponseti IV. History of orthopedic surgery. Iowa Orthop J. 1991;11:59-64.

2. Ninomiya JT, Dean JC, Incavo SJ. What’s new in hip replacement. J Bone Joint Surg Am. 2015;97(18):1543-1551.

3. Sabharwal S, Nelson SC, Sontich JK. What’s new in limb lengthening and deformity correction. J Bone Joint Surg Am. 2015;97(16):1375-1384.

4. Ricci WM, Black JC, McAndrew CM, Gardner MJ. What’s new in orthopedic trauma. J Bone Joint Surg Am. 2015;97(14):1200-1207.

5. Rodeo SA, Sugiguchi F, Fortier LA, Cunningham ME, Maher S. What’s new in orthopedic research. J Bone Joint Surg Am. 2014;96(23):2015-2019.

6. Pugley AJ, Martin CT, Harwood J, Ong KL, Bozic KJ, Callaghan JJ. Database and registry research in orthopedic surgery. Part 1: Claims-based data. J Bone Joint Surg Am. 2015;97(15):1278-1287.

7. Colton CL. The history of fracture treatment. In: Browner BD, Jupiter JB, Levine AM, Trafton PG, Krettek C, eds. Skeletal Trauma: Basic Science, Management, and Reconstruction. 4th ed. Philadelphia, PA: Saunders Elsevier; 2009:3-32.

8. Brakoulias,V. History of orthopaedics. WorldOrtho Web site. http://pioa.net/documents/Historyoforthopaedics.pdf. Accessed October 6, 2016.

9. Bishop WJ. The Early History of Surgery. New York, NY: Barnes & Noble Books; 1995.

10. Watson T. Wyoming site reveals more prehistoric mountain villages. USA Today. October 20, 2013. http://www.usatoday.com/story/news/nation/2013/10/20/wyoming-prehistoric-villages/2965263. Accessed October 6, 2016.

11. Minagar A, Ragheb J, Kelley RE. The Edwin Smith surgical papyrus: description and analysis of the earliest case of aphasia. J Med Biogr. 2003;11(2):114-117.

12. Atta HM. Edwin Smith Surgical Papyrus: the oldest known surgical treatise. Am Surg. 1999;65(12):1190-1192.

13. Sayegh FE, Kenanidis EI, Papavasiliou KA, Potoupnis ME, Kirkos JM, Kapetanos GA. Reduction of acute anterior dislocations: a prospective randomized study comparing a new technique with the Hippocratic and Kocher methods. J Bone Joint Surg Am. 2009;91(12):2775-2782.

14. Levine DB. Anatomy of a Hospital: Hospital for Special Surgery 1863-2013. New York, NY: Print Mattes; 2013.

15. Wilson PD, Levine DB. Hospital for special surgery. A brief review of its development and current position. Clin Orthop Relat Res. 2000;(374):90-106.

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MD
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The modern term orthopedics stems from the older word orthopedia, which was the title of a book published in 1741 by Nicholas Andry, a professor of medicine at the University of Paris.1 The term orthopedia is a composite of 2 Greek words: orthos, meaning “straight and free from deformity,” and paidios, meaning “child.” Together, orthopedics literally means straight child, suggesting the importance of pediatric injuries and deformities in the development of this field. Interestingly, Andry’s book also depicted a crooked young tree attached to a straight and strong staff, which has become the universal symbol of orthopedic surgery and underscores the focus on correcting deformities in the young (Figure).1

While the history of the term is relatively recent, the practice of orthopedics is an ancient art.

Orthopedic surgery is a rapidly advancing medical field with several recent advances noted within orthopedic subspecialties,2-4 basic science,5 and clinical research.6 It is important to recognize the role of history with regards to innovation and research, especially for young trainees and medical students interested in a particular medical specialty. More specifically, it is important to understand the successes and failures of the past in order to advance research and practice, and ultimately improve patient care and outcomes.

In the recent literature, there is no concise yet comprehensive article focusing on the history of orthopedic surgery. The goal of this review is to provide an overview of the history and development of orthopedic surgery from ancient practices to the modern era.

Ancient Orthopedics

While the evidence is limited, the practice of orthopedics dates back to the primitive man.7 Fossil evidence suggests that the orthopedic pathology of today, such as fractures and traumatic amputations, existed in primitive times.8 The union of fractures in fair alignment has also been observed, which emphasizes the efficacy of nonoperative orthopedics and suggests the early use of splints and rehabilitation practices.8,9 Since procedures such as trepanation and crude amputations occurred during the New Stone Age, it is feasible that sophisticated techniques had also been developed for the treatment of injuries.7-9 However, evidence continues to remain limited.7

Later civilizations also developed creative ways to manage orthopedic injuries. For example, the Shoshone Indians, who were known to exist around 700-2000 BCE, made a splint of fresh rawhide that had been soaked in water.9,10 Similarly, some South Australian tribes made splints of clay, which when dried were as good as plaster of Paris.9 Furthermore, bone-setting or reductions was practiced as a profession in many tribes, underscoring the importance of orthopedic injuries in early civilizations.8,9

Ancient Egypt

The ancient Egyptians seemed to have carried on the practices of splinting. For example, 2 splinted specimens were discovered during the Hearst Egyptian Expedition in 1903.7 More specifically, these specimens included a femur and forearm and dated to approximately 300 BCE.7 Other examples of splints made of bamboo and reed padded with linen have been found on mummies as well.8 Similarly, crutches were also used by this civilization, as depicted on a carving made on an Egyptian tomb in 2830 BCE.8

One of the earliest and most significant documents on medicine was discovered in 1862, known as the Edwin Smith papyrus. This document is thought to have been composed by Imhotep, a prominent Egyptian physician, astrologer, architect, and politician, and it specifically categorizes diseases and treatments. Many scholars recognize this medical document as the oldest surgical textbook.11,12 With regards to orthopedic conditions, this document describes the reduction of a dislocated mandible, signs of spinal or vertebral injuries, description of torticollis, and the treatment of fractures such as clavicle fractures.8 This document also discusses ryt, which refers to the purulent discharge from osteomyelitis.8 The following is an excerpt from this ancient document:9

“Instructions on erring a break in his upper arm…Thou shouldst spread out with his two shoulders in order to stretch apart his upper arm until that break falls into its place. Thou shouldst make for him two splints of linen, and thou shouldst apply for him one of them both on the inside of his arm, and the other of them both on the underside of his arm.”

This account illustrates the methodical and meticulous nature of this textbook, and it highlights some of the essentials of medical practice from diagnosis to medical decision-making to treatment.

There are various other contributions to the field of medicine from the Far East; however, many of these pertain to the fields of plastic surgery and general surgery.9

Greeks and Romans

The Greeks are considered to be the first to systematically employ the scientific approach to medicine.8 In the period between 430 BCE to 330 BCE, the Corpus Hippocrates was compiled, which is a Greek text on medicine. It is named for Hippocrates (460 BCE-370 BCE), the father of medicine, and it contains text that applies specifically to the field of orthopedic surgery. For example, this text discuses shoulder dislocations and describes various reduction maneuvers. Hippocrates had a keen understanding of the principles of traction and countertraction, especially as it pertains to the musculoskeletal system.8 In fact, the Hippocratic method is still used for reducing anterior shoulder dislocations, and its description can be found in several modern orthopedic texts, including recent articles.13 The Corpus Hippocrates also describes the correction of clubfoot deformity, and the treatment of infected open fractures with pitch cerate and wine compresses.8

 

 

Hippocrates also described the treatment of fractures, the principles of traction, and the implications of malunions. For example, Hippocrates wrote, “For the arm, when shortened, might be concealed and the mistake will not be great, but a shortened thigh bone will leave a man maimed.”1 In addition, spinal deformities were recognized by the Greeks, and Hippocrates devised an extension bench for the correction of such deformities.1 From their contributions to anatomy and surgical practice, the Greeks have made significant contributions to the field of surgery.9

During the Roman period, another Greek surgeon by the name of Galen described the musculoskeletal and nervous systems. He served as a gladiatorial surgeon in Rome, and today, he is considered to be the father of sports medicine.8 He is also credited with coining the terms scoliosis, kyphosis, and lordosis to denote the spinal deformities that were first described by Hippocrates.1 In the Roman period, amputations were also performed, and primitive prostheses were developed.9

The Middle Ages

There was relatively little progress in the study of medicine for a thousand years after the fall of the Roman Empire.9 This stagnation was predominantly due to the early Christian Church inhibiting freedom of thought and observation, as well as prohibiting human dissection and the study of anatomy. The first medical school in Europe was established in Salerno, Italy, during the ninth century. This school provided primarily pedantic teaching to its students and perpetuated the theories of the elements and humors. Later on, the University of Bologna became one of the first academic institutions to offer hands-on surgical training.9 One of the most famous surgeons of the Middle Ages was Guy de Chuauliac, who studied at Montpellier and Bologna. He was a leader in the ethical principles of surgery as well as the practice of surgery, and wrote the following with regards to femur fractures:9

“After the application of splints, I attach to the foot a mass of lead as a weight, taking care to pass the cord which supports the weight over a small pulley in such a manner that it shall pull on the leg in a horizontal direction.”

This description is strikingly similar to the modern-day nonoperative management of femur fractures, and underscores the importance of traction, which as mentioned above, was first described by Hippocrates.

Eventually, medicine began to separate from the Church, most likely due to an increase in the complexity of medical theories, the rise of secular universities, and an increase in medical knowledge from Eastern and Middle-Eastern groups.9

The Renaissance and the Foundations of Modern Orthopedics

Until the 16th century, the majority of medical theories were heavily influenced by the work of Hippocrates.8 The scientific study of anatomy gained prominence during this time, especially due to the work done by great artists, such as Leonardo Di Vinci.9 The Table

provides a list of some of the most prominent figures in the field of orthopedic surgery from across the world, as well as their contributions to the field. Collectively, these scholar and surgeons provided a strong foundation for the field of modern orthopedics.8 Additional discoveries by Joseph Lister, Louis Pasteur, Robert Koch, and Ignaz Semmelweis relating to antisepsis appeared to revolutionize the surgical management of orthopedic injuries.7

After a period of rapid expansion of the field of orthopedics, and following the Renaissance, many hospitals were built focusing on the sick and disabled, which solidified orthopedics’ position as a major medical specialty.1 For example, in 1863, James Knight founded the Hospital for the Ruptured and Crippled in New York City. This hospital became the oldest orthopedic hospital in the United States, and it later became known as the Hospital for Special Surgery.14,15 Several additional orthopedic institutions were formed, including the New York Orthopedic Dispensary in 1886 and Hospital for Deformities and Joint Diseases in 1917. Orthopedic surgery residency programs also began to be developed in the late 1800s.14 More specifically, Virgil Gibney at Hospital for the Ruptured and Crippled began the first orthopedic training program in the United States in 1888. Young doctors in this program trained for 1 year as junior assistant, senior assistant, and house surgeon, and began to be known as resident doctors.14

The Modern Era

In the 20th century, rapid development continued to better control infections as well as develop and introduce novel technology. For example, the invention of x-ray in 1895 by Wilhelm Conrad Röntgen improved our ability to diagnose and manage orthopedic conditions ranging from fractures to avascular necrosis of the femoral head to osteoarthritis.8,14 Spinal surgery also developed rapidly with Russell Hibbs describing a technique for spinal fusion at the New York Orthopedic Hospital.8 Similarly, the World Wars served as a catalyst in the development of the subspecialty of orthopedic trauma, with increasing attention placed on open wounds and proficiency with amputations, internal fixation, and wound care. In 1942, Austin Moore performed the first metal hip arthroplasty, and the field of joint replacement was subsequently advanced by the work of Sir John Charnley in the 1960s.8

 

 

Conclusion

Despite its relatively recent specialization, orthopedic surgery has a rich history rooted in ancient practices dating back to the primitive man. Over time, there has been significant development in the field in terms of surgical and nonsurgical treatment of orthopedic pathology and disease. Various cultures have played an instrumental role in developing this field, and it is remarkable to see that several practices have persisted since the time of these ancient civilizations. During the Renaissance, there was a considerable emphasis placed on pediatric deformity, but orthopedic surgeons have now branched out to subspecialty practice ranging from orthopedic trauma to joint replacement to oncology.1 For students of medicine and orthopedics, it is important to learn about the origins of this field and to appreciate its gradual development. Orthopedic surgery is a diverse and fascinating field that will most likely continue to develop with increased subspecialization and improved research at the molecular and population level. With a growing emphasis placed on outcomes and healthcare cost by today’s society, it will be fascinating to see how this field continues to evolve in the future.

Am J Orthop. 2016;45(7):E434-E438. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

The modern term orthopedics stems from the older word orthopedia, which was the title of a book published in 1741 by Nicholas Andry, a professor of medicine at the University of Paris.1 The term orthopedia is a composite of 2 Greek words: orthos, meaning “straight and free from deformity,” and paidios, meaning “child.” Together, orthopedics literally means straight child, suggesting the importance of pediatric injuries and deformities in the development of this field. Interestingly, Andry’s book also depicted a crooked young tree attached to a straight and strong staff, which has become the universal symbol of orthopedic surgery and underscores the focus on correcting deformities in the young (Figure).1

While the history of the term is relatively recent, the practice of orthopedics is an ancient art.

Orthopedic surgery is a rapidly advancing medical field with several recent advances noted within orthopedic subspecialties,2-4 basic science,5 and clinical research.6 It is important to recognize the role of history with regards to innovation and research, especially for young trainees and medical students interested in a particular medical specialty. More specifically, it is important to understand the successes and failures of the past in order to advance research and practice, and ultimately improve patient care and outcomes.

In the recent literature, there is no concise yet comprehensive article focusing on the history of orthopedic surgery. The goal of this review is to provide an overview of the history and development of orthopedic surgery from ancient practices to the modern era.

Ancient Orthopedics

While the evidence is limited, the practice of orthopedics dates back to the primitive man.7 Fossil evidence suggests that the orthopedic pathology of today, such as fractures and traumatic amputations, existed in primitive times.8 The union of fractures in fair alignment has also been observed, which emphasizes the efficacy of nonoperative orthopedics and suggests the early use of splints and rehabilitation practices.8,9 Since procedures such as trepanation and crude amputations occurred during the New Stone Age, it is feasible that sophisticated techniques had also been developed for the treatment of injuries.7-9 However, evidence continues to remain limited.7

Later civilizations also developed creative ways to manage orthopedic injuries. For example, the Shoshone Indians, who were known to exist around 700-2000 BCE, made a splint of fresh rawhide that had been soaked in water.9,10 Similarly, some South Australian tribes made splints of clay, which when dried were as good as plaster of Paris.9 Furthermore, bone-setting or reductions was practiced as a profession in many tribes, underscoring the importance of orthopedic injuries in early civilizations.8,9

Ancient Egypt

The ancient Egyptians seemed to have carried on the practices of splinting. For example, 2 splinted specimens were discovered during the Hearst Egyptian Expedition in 1903.7 More specifically, these specimens included a femur and forearm and dated to approximately 300 BCE.7 Other examples of splints made of bamboo and reed padded with linen have been found on mummies as well.8 Similarly, crutches were also used by this civilization, as depicted on a carving made on an Egyptian tomb in 2830 BCE.8

One of the earliest and most significant documents on medicine was discovered in 1862, known as the Edwin Smith papyrus. This document is thought to have been composed by Imhotep, a prominent Egyptian physician, astrologer, architect, and politician, and it specifically categorizes diseases and treatments. Many scholars recognize this medical document as the oldest surgical textbook.11,12 With regards to orthopedic conditions, this document describes the reduction of a dislocated mandible, signs of spinal or vertebral injuries, description of torticollis, and the treatment of fractures such as clavicle fractures.8 This document also discusses ryt, which refers to the purulent discharge from osteomyelitis.8 The following is an excerpt from this ancient document:9

“Instructions on erring a break in his upper arm…Thou shouldst spread out with his two shoulders in order to stretch apart his upper arm until that break falls into its place. Thou shouldst make for him two splints of linen, and thou shouldst apply for him one of them both on the inside of his arm, and the other of them both on the underside of his arm.”

This account illustrates the methodical and meticulous nature of this textbook, and it highlights some of the essentials of medical practice from diagnosis to medical decision-making to treatment.

There are various other contributions to the field of medicine from the Far East; however, many of these pertain to the fields of plastic surgery and general surgery.9

Greeks and Romans

The Greeks are considered to be the first to systematically employ the scientific approach to medicine.8 In the period between 430 BCE to 330 BCE, the Corpus Hippocrates was compiled, which is a Greek text on medicine. It is named for Hippocrates (460 BCE-370 BCE), the father of medicine, and it contains text that applies specifically to the field of orthopedic surgery. For example, this text discuses shoulder dislocations and describes various reduction maneuvers. Hippocrates had a keen understanding of the principles of traction and countertraction, especially as it pertains to the musculoskeletal system.8 In fact, the Hippocratic method is still used for reducing anterior shoulder dislocations, and its description can be found in several modern orthopedic texts, including recent articles.13 The Corpus Hippocrates also describes the correction of clubfoot deformity, and the treatment of infected open fractures with pitch cerate and wine compresses.8

 

 

Hippocrates also described the treatment of fractures, the principles of traction, and the implications of malunions. For example, Hippocrates wrote, “For the arm, when shortened, might be concealed and the mistake will not be great, but a shortened thigh bone will leave a man maimed.”1 In addition, spinal deformities were recognized by the Greeks, and Hippocrates devised an extension bench for the correction of such deformities.1 From their contributions to anatomy and surgical practice, the Greeks have made significant contributions to the field of surgery.9

During the Roman period, another Greek surgeon by the name of Galen described the musculoskeletal and nervous systems. He served as a gladiatorial surgeon in Rome, and today, he is considered to be the father of sports medicine.8 He is also credited with coining the terms scoliosis, kyphosis, and lordosis to denote the spinal deformities that were first described by Hippocrates.1 In the Roman period, amputations were also performed, and primitive prostheses were developed.9

The Middle Ages

There was relatively little progress in the study of medicine for a thousand years after the fall of the Roman Empire.9 This stagnation was predominantly due to the early Christian Church inhibiting freedom of thought and observation, as well as prohibiting human dissection and the study of anatomy. The first medical school in Europe was established in Salerno, Italy, during the ninth century. This school provided primarily pedantic teaching to its students and perpetuated the theories of the elements and humors. Later on, the University of Bologna became one of the first academic institutions to offer hands-on surgical training.9 One of the most famous surgeons of the Middle Ages was Guy de Chuauliac, who studied at Montpellier and Bologna. He was a leader in the ethical principles of surgery as well as the practice of surgery, and wrote the following with regards to femur fractures:9

“After the application of splints, I attach to the foot a mass of lead as a weight, taking care to pass the cord which supports the weight over a small pulley in such a manner that it shall pull on the leg in a horizontal direction.”

This description is strikingly similar to the modern-day nonoperative management of femur fractures, and underscores the importance of traction, which as mentioned above, was first described by Hippocrates.

Eventually, medicine began to separate from the Church, most likely due to an increase in the complexity of medical theories, the rise of secular universities, and an increase in medical knowledge from Eastern and Middle-Eastern groups.9

The Renaissance and the Foundations of Modern Orthopedics

Until the 16th century, the majority of medical theories were heavily influenced by the work of Hippocrates.8 The scientific study of anatomy gained prominence during this time, especially due to the work done by great artists, such as Leonardo Di Vinci.9 The Table

provides a list of some of the most prominent figures in the field of orthopedic surgery from across the world, as well as their contributions to the field. Collectively, these scholar and surgeons provided a strong foundation for the field of modern orthopedics.8 Additional discoveries by Joseph Lister, Louis Pasteur, Robert Koch, and Ignaz Semmelweis relating to antisepsis appeared to revolutionize the surgical management of orthopedic injuries.7

After a period of rapid expansion of the field of orthopedics, and following the Renaissance, many hospitals were built focusing on the sick and disabled, which solidified orthopedics’ position as a major medical specialty.1 For example, in 1863, James Knight founded the Hospital for the Ruptured and Crippled in New York City. This hospital became the oldest orthopedic hospital in the United States, and it later became known as the Hospital for Special Surgery.14,15 Several additional orthopedic institutions were formed, including the New York Orthopedic Dispensary in 1886 and Hospital for Deformities and Joint Diseases in 1917. Orthopedic surgery residency programs also began to be developed in the late 1800s.14 More specifically, Virgil Gibney at Hospital for the Ruptured and Crippled began the first orthopedic training program in the United States in 1888. Young doctors in this program trained for 1 year as junior assistant, senior assistant, and house surgeon, and began to be known as resident doctors.14

The Modern Era

In the 20th century, rapid development continued to better control infections as well as develop and introduce novel technology. For example, the invention of x-ray in 1895 by Wilhelm Conrad Röntgen improved our ability to diagnose and manage orthopedic conditions ranging from fractures to avascular necrosis of the femoral head to osteoarthritis.8,14 Spinal surgery also developed rapidly with Russell Hibbs describing a technique for spinal fusion at the New York Orthopedic Hospital.8 Similarly, the World Wars served as a catalyst in the development of the subspecialty of orthopedic trauma, with increasing attention placed on open wounds and proficiency with amputations, internal fixation, and wound care. In 1942, Austin Moore performed the first metal hip arthroplasty, and the field of joint replacement was subsequently advanced by the work of Sir John Charnley in the 1960s.8

 

 

Conclusion

Despite its relatively recent specialization, orthopedic surgery has a rich history rooted in ancient practices dating back to the primitive man. Over time, there has been significant development in the field in terms of surgical and nonsurgical treatment of orthopedic pathology and disease. Various cultures have played an instrumental role in developing this field, and it is remarkable to see that several practices have persisted since the time of these ancient civilizations. During the Renaissance, there was a considerable emphasis placed on pediatric deformity, but orthopedic surgeons have now branched out to subspecialty practice ranging from orthopedic trauma to joint replacement to oncology.1 For students of medicine and orthopedics, it is important to learn about the origins of this field and to appreciate its gradual development. Orthopedic surgery is a diverse and fascinating field that will most likely continue to develop with increased subspecialization and improved research at the molecular and population level. With a growing emphasis placed on outcomes and healthcare cost by today’s society, it will be fascinating to see how this field continues to evolve in the future.

Am J Orthop. 2016;45(7):E434-E438. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

1. Ponseti IV. History of orthopedic surgery. Iowa Orthop J. 1991;11:59-64.

2. Ninomiya JT, Dean JC, Incavo SJ. What’s new in hip replacement. J Bone Joint Surg Am. 2015;97(18):1543-1551.

3. Sabharwal S, Nelson SC, Sontich JK. What’s new in limb lengthening and deformity correction. J Bone Joint Surg Am. 2015;97(16):1375-1384.

4. Ricci WM, Black JC, McAndrew CM, Gardner MJ. What’s new in orthopedic trauma. J Bone Joint Surg Am. 2015;97(14):1200-1207.

5. Rodeo SA, Sugiguchi F, Fortier LA, Cunningham ME, Maher S. What’s new in orthopedic research. J Bone Joint Surg Am. 2014;96(23):2015-2019.

6. Pugley AJ, Martin CT, Harwood J, Ong KL, Bozic KJ, Callaghan JJ. Database and registry research in orthopedic surgery. Part 1: Claims-based data. J Bone Joint Surg Am. 2015;97(15):1278-1287.

7. Colton CL. The history of fracture treatment. In: Browner BD, Jupiter JB, Levine AM, Trafton PG, Krettek C, eds. Skeletal Trauma: Basic Science, Management, and Reconstruction. 4th ed. Philadelphia, PA: Saunders Elsevier; 2009:3-32.

8. Brakoulias,V. History of orthopaedics. WorldOrtho Web site. http://pioa.net/documents/Historyoforthopaedics.pdf. Accessed October 6, 2016.

9. Bishop WJ. The Early History of Surgery. New York, NY: Barnes & Noble Books; 1995.

10. Watson T. Wyoming site reveals more prehistoric mountain villages. USA Today. October 20, 2013. http://www.usatoday.com/story/news/nation/2013/10/20/wyoming-prehistoric-villages/2965263. Accessed October 6, 2016.

11. Minagar A, Ragheb J, Kelley RE. The Edwin Smith surgical papyrus: description and analysis of the earliest case of aphasia. J Med Biogr. 2003;11(2):114-117.

12. Atta HM. Edwin Smith Surgical Papyrus: the oldest known surgical treatise. Am Surg. 1999;65(12):1190-1192.

13. Sayegh FE, Kenanidis EI, Papavasiliou KA, Potoupnis ME, Kirkos JM, Kapetanos GA. Reduction of acute anterior dislocations: a prospective randomized study comparing a new technique with the Hippocratic and Kocher methods. J Bone Joint Surg Am. 2009;91(12):2775-2782.

14. Levine DB. Anatomy of a Hospital: Hospital for Special Surgery 1863-2013. New York, NY: Print Mattes; 2013.

15. Wilson PD, Levine DB. Hospital for special surgery. A brief review of its development and current position. Clin Orthop Relat Res. 2000;(374):90-106.

References

1. Ponseti IV. History of orthopedic surgery. Iowa Orthop J. 1991;11:59-64.

2. Ninomiya JT, Dean JC, Incavo SJ. What’s new in hip replacement. J Bone Joint Surg Am. 2015;97(18):1543-1551.

3. Sabharwal S, Nelson SC, Sontich JK. What’s new in limb lengthening and deformity correction. J Bone Joint Surg Am. 2015;97(16):1375-1384.

4. Ricci WM, Black JC, McAndrew CM, Gardner MJ. What’s new in orthopedic trauma. J Bone Joint Surg Am. 2015;97(14):1200-1207.

5. Rodeo SA, Sugiguchi F, Fortier LA, Cunningham ME, Maher S. What’s new in orthopedic research. J Bone Joint Surg Am. 2014;96(23):2015-2019.

6. Pugley AJ, Martin CT, Harwood J, Ong KL, Bozic KJ, Callaghan JJ. Database and registry research in orthopedic surgery. Part 1: Claims-based data. J Bone Joint Surg Am. 2015;97(15):1278-1287.

7. Colton CL. The history of fracture treatment. In: Browner BD, Jupiter JB, Levine AM, Trafton PG, Krettek C, eds. Skeletal Trauma: Basic Science, Management, and Reconstruction. 4th ed. Philadelphia, PA: Saunders Elsevier; 2009:3-32.

8. Brakoulias,V. History of orthopaedics. WorldOrtho Web site. http://pioa.net/documents/Historyoforthopaedics.pdf. Accessed October 6, 2016.

9. Bishop WJ. The Early History of Surgery. New York, NY: Barnes & Noble Books; 1995.

10. Watson T. Wyoming site reveals more prehistoric mountain villages. USA Today. October 20, 2013. http://www.usatoday.com/story/news/nation/2013/10/20/wyoming-prehistoric-villages/2965263. Accessed October 6, 2016.

11. Minagar A, Ragheb J, Kelley RE. The Edwin Smith surgical papyrus: description and analysis of the earliest case of aphasia. J Med Biogr. 2003;11(2):114-117.

12. Atta HM. Edwin Smith Surgical Papyrus: the oldest known surgical treatise. Am Surg. 1999;65(12):1190-1192.

13. Sayegh FE, Kenanidis EI, Papavasiliou KA, Potoupnis ME, Kirkos JM, Kapetanos GA. Reduction of acute anterior dislocations: a prospective randomized study comparing a new technique with the Hippocratic and Kocher methods. J Bone Joint Surg Am. 2009;91(12):2775-2782.

14. Levine DB. Anatomy of a Hospital: Hospital for Special Surgery 1863-2013. New York, NY: Print Mattes; 2013.

15. Wilson PD, Levine DB. Hospital for special surgery. A brief review of its development and current position. Clin Orthop Relat Res. 2000;(374):90-106.

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When Losing Weight Leads to Gaining Weight

Article Type
News
Changed
Study data finds patients with diabetes taking canagliflozin experienced an increase of appetite and calorie intake without realizing it.

Just what someone with diabetes who’s successfully losing weight doesn’t want to hear: Losing weight may boost appetite significantly.

NIH researchers analyzed data from a year-long study of 242 people, of whom 153 were taking canagliflozin, a drug that increases the amount of glucose excreted in urine. That calorie loss led to a gradual weight loss that averaged 8 pounds. The patients were not “directly aware” of the calorie loss, the researchers say.

Related: A VA-Based, Multidisciplinary Weight Management Program

The participants could eat and drink without restriction. Using a math model, the researchers calculated the changes in the amount of calories consumed during the study. They found no long-term calorie intake changes in the 89 people on placebo. By contrast, for every pound of lost weight, the canagliflozin patients consumed about 50 calories more per day than they were eating before the study. After about 6 months, the extra appetite-fueled calories led to a plateau in weight loss.

The findings didn’t entirely surprise the researchers. In an earlier study of participants in a weight loss program not involving canagliflozin, something similar happened. Despite the dieters’ consistent efforts, increased appetite led to a calorie intake 3 times stronger than the changes in caloric expenditure that typically accompany weight loss, the researchers say—and a plateau.

Related: Keeping Diabetes at Bay

The study provides the “first quantification of the homeostatic control of energy intake in free-living humans,” the researchers say. While energy expenditure adaptations often are thought to be the main reasons for slowing of weight loss and subsequent regain, feedback control of energy intake plays an even larger role and helps explain why long-term maintenance of a reduced body weight is so difficult, the researchers say.

The conclusion? “Persistent effort is required to avoid weight gain,” the NIH report notes. Unfortunately, “weight regain is typical in the absence of heroic and vigilant efforts to maintain behavior changes in the face of an omnipresent obesogenic environment.”

Related: A Call to Action: Intensive Lifestyle Intervention Against Diabesity

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Study data finds patients with diabetes taking canagliflozin experienced an increase of appetite and calorie intake without realizing it.
Study data finds patients with diabetes taking canagliflozin experienced an increase of appetite and calorie intake without realizing it.

Just what someone with diabetes who’s successfully losing weight doesn’t want to hear: Losing weight may boost appetite significantly.

NIH researchers analyzed data from a year-long study of 242 people, of whom 153 were taking canagliflozin, a drug that increases the amount of glucose excreted in urine. That calorie loss led to a gradual weight loss that averaged 8 pounds. The patients were not “directly aware” of the calorie loss, the researchers say.

Related: A VA-Based, Multidisciplinary Weight Management Program

The participants could eat and drink without restriction. Using a math model, the researchers calculated the changes in the amount of calories consumed during the study. They found no long-term calorie intake changes in the 89 people on placebo. By contrast, for every pound of lost weight, the canagliflozin patients consumed about 50 calories more per day than they were eating before the study. After about 6 months, the extra appetite-fueled calories led to a plateau in weight loss.

The findings didn’t entirely surprise the researchers. In an earlier study of participants in a weight loss program not involving canagliflozin, something similar happened. Despite the dieters’ consistent efforts, increased appetite led to a calorie intake 3 times stronger than the changes in caloric expenditure that typically accompany weight loss, the researchers say—and a plateau.

Related: Keeping Diabetes at Bay

The study provides the “first quantification of the homeostatic control of energy intake in free-living humans,” the researchers say. While energy expenditure adaptations often are thought to be the main reasons for slowing of weight loss and subsequent regain, feedback control of energy intake plays an even larger role and helps explain why long-term maintenance of a reduced body weight is so difficult, the researchers say.

The conclusion? “Persistent effort is required to avoid weight gain,” the NIH report notes. Unfortunately, “weight regain is typical in the absence of heroic and vigilant efforts to maintain behavior changes in the face of an omnipresent obesogenic environment.”

Related: A Call to Action: Intensive Lifestyle Intervention Against Diabesity

Just what someone with diabetes who’s successfully losing weight doesn’t want to hear: Losing weight may boost appetite significantly.

NIH researchers analyzed data from a year-long study of 242 people, of whom 153 were taking canagliflozin, a drug that increases the amount of glucose excreted in urine. That calorie loss led to a gradual weight loss that averaged 8 pounds. The patients were not “directly aware” of the calorie loss, the researchers say.

Related: A VA-Based, Multidisciplinary Weight Management Program

The participants could eat and drink without restriction. Using a math model, the researchers calculated the changes in the amount of calories consumed during the study. They found no long-term calorie intake changes in the 89 people on placebo. By contrast, for every pound of lost weight, the canagliflozin patients consumed about 50 calories more per day than they were eating before the study. After about 6 months, the extra appetite-fueled calories led to a plateau in weight loss.

The findings didn’t entirely surprise the researchers. In an earlier study of participants in a weight loss program not involving canagliflozin, something similar happened. Despite the dieters’ consistent efforts, increased appetite led to a calorie intake 3 times stronger than the changes in caloric expenditure that typically accompany weight loss, the researchers say—and a plateau.

Related: Keeping Diabetes at Bay

The study provides the “first quantification of the homeostatic control of energy intake in free-living humans,” the researchers say. While energy expenditure adaptations often are thought to be the main reasons for slowing of weight loss and subsequent regain, feedback control of energy intake plays an even larger role and helps explain why long-term maintenance of a reduced body weight is so difficult, the researchers say.

The conclusion? “Persistent effort is required to avoid weight gain,” the NIH report notes. Unfortunately, “weight regain is typical in the absence of heroic and vigilant efforts to maintain behavior changes in the face of an omnipresent obesogenic environment.”

Related: A Call to Action: Intensive Lifestyle Intervention Against Diabesity

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Application of Amniotic Tissue in Orthopedic Surgery

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Application of Amniotic Tissue in Orthopedic Surgery
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Nathanael Heckmann
MD; Richard Auran
BS; Raffy Mirzayan
MD

The amniotic membrane is a multilayer tissue forming the innermost layer of the amniotic sac that surrounds the developing fetus. It is comprised of 5 layers, from the inside out: a single layer of epithelial cells, a thick basement membrane, a compact layer, a fibroblast layer, and a spongy layer that abuts the surrounding chorion (Figure 1).1

The amniotic membrane serves several functions, including synthesis of growth factors and cytokines, regulation of pH, transport of water and solutes, and provision of a permeable barrier to amniotic macromolecules.2

Amniotic epithelial cells are derived from the pluripotent epiblast at approximately day 8 of gestation. This is well before gastrulation occurs at days 15 to 17, considered the “tipping point” when pluripotent cells differentiate into ectoderm, mesoderm, and endoderm.3 These cells express Oct-4 and Nanog, 2 molecular markers that are indicative of pluripotency.3 Two cell types have been identified in amniotic tissues that possess stem cell-like characteristics: human amniotic epithelial cells and human amniotic mesenchymal stromal cells.4 Both of these cell types have demonstrated the ability to differentiate into various cell lineages, including endothelial cells, adipocytes, myogenic cells, neurogenic cells, chondrocytes, tenocytes, and osteogenic cells.5-7 These previously reported findings indicate that amniotic cells and tissue have the capability to generate mesenchymal tissues.

FDA Classification and Available Forms

The US Food and Drug Administration (FDA) classifies amnion as an allograft tissue under Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 361. To meet criteria, the tissue needs to be minimally manipulated. It is to be for homologous use and cannot be combined with other cells or tissues. There can be no systemic effect or dependence on the metabolic activity of living cells to achieve its primary function. The tissue has to have a localized effect in vivo. Therefore, amnion allograft tissue can be commercialized, provided it is not marketed as a stem cell product or to contain viable cells.

Amniotic tissue is commercially available in several forms.

These include fresh-frozen injectable amniotic liquid that may contain viable amniotic cells and/or particulated amniotic membrane, a micronized freeze-dried (lyophilized) particulate powder that is directly applied to a wound or resuspended for injection, and a cross-linked dehydrated membrane acting as an adhesion barrier (Figure 2).

Safety

Amniotic tissue has been used for over 100 years in burn, ophthalmology, and chronic wound patients with favorable outcomes and no adverse effects reported in the literature. Unlike embryonic stem cells, which may be tumorigenic,8 amniotic cells do not possess any known tumorigenicity.9 In one study, 50 immunodeficient mice were injected with 1 to 2 million amniotic epithelial cells and observed for a maximum of 516 days with no tumorigenicity observed in any of the animals.10 In another study, amniotic epithelial cells were implanted into the forearms of healthy volunteers and no immunologic response was observed in any of the recipients.11 Furthermore, viable amniotic cells were recovered via biopsy 7 weeks following transplantation, demonstrating viability of the transplanted cells.11 The lack of tumorigenicity and immunologic response in hosts is due in part to the fact that amniotic cells do not express human leukocyte antigen class II antigens and only express class I antigens in small amounts.3

Advantages of Amnion Tissue

Amniotic tissue is readily available, as it is often discarded after childbirth. The use of this tissue poses no added risk to the fetus or mother, eliminating the ethical concerns associated with obtaining embryonic stem cells. Amniotic tissue is comprised of an extracellular matrix, which acts as a natural scaffold for cellular attachment and structural support for cells as well as collagen types I, III, IV, V, and VI, hyaluronic acid, and a host of growth factors.12 In addition, it possesses antimicrobial properties, including beta-defensins.13

Amniotic tissue has been shown to exert an anti-inflammatory effect by inhibiting the inflammatory cascade. Specifically, it has been shown to inhibit cytokines such as tumor necrosis factor-alpha in the presence of dendritic cells,14 as well as inhibiting transforming growth factor-beta, interleukin-8, and fibroblast proliferation.15 These findings indicate that amniotic tissue has the ability to dampen the “cytokine storm” that occurs after an injury in an adult, which would lead to beneficial impacts on healing and scar formation in patients.16

Basic Science and Animal Studies

Several studies have demonstrated promising outcomes for orthopedic applications in vitro. A comparison of osteogenic potential found that amniotic fluid-derived cells were able to produce approximately 5 times more mineralized matrix than bone marrow-derived mesenchymal stem cells.17 More recently, Si and colleagues18 compared the osteogenic potential of human amniotic epithelial cells, amniotic cells, and human bone marrow-derived mesenchymal stem cells. They found that all 3 cell lines were osteogenic, though the amniotic epithelial cells had better immunomodulatory properties and marginally less osteogenic potential than the other 2 cell types. Furthermore, several in vivo animal studies have demonstrated the ability of human amniotic cells to stimulate bone growth in rats,19,20 rabbits,21 and sheep.22

 

 

Amniotic tissue also possesses potential for chondrogenesis. Cryopreserved human amniotic membrane cells used for in vitro human osteoarthritis tissue scaffolds did not differentiate in culture, and they integrated and repaired damaged articular cartilage.23 Various in vitro24,25 and animal in vivo26,27 studies have reported similar supportive findings. Kunisaki and colleagues28 used sheep amniotic fluid mesenchymal stem cells to reconstruct lamb tracheal cartilage in utero, concluding that cells obtained from the amniotic fluid possess chondrogenic capabilities. Further in utero lamb studies of cartilage artificial defects, given 7 days to settle before adding a hypocellular matrix as a scaffold, showed chondrocyte density and cell architecture was restored at the defect site after 28 days without the formation of an inflammatory response or scar tissue.29

Amniotic tissue has had similar success in tendon repair studies in vivo.9,30,31 Barboni and colleagues32 implanted amniotic epithelial cells (AECs) into artificially created sheep Achilles tendon defects in situ, inducing superior structural and mechanical recovery in the defects at a faster rate compared to controls not receiving AECs. Healing via AECs started at the healthy tissue around the borders of the defect and progressed centrally, suggesting recruitment of native progenitor cells to the lesion.32 Kueckelhaus and colleagues33 investigated the role of amnion-derived cellular cytokine solution in the healing of transections of rat Achilles tendons, reporting improved mechanical properties of healing tendons at early time points compared to controls. Beredjiklian and colleagues34 compared the healing of transected extensor tendons of pregnant ewes and of their fetus in utero, reporting a reparative form of healing with scar formation in adult subjects and regenerative form of healing without scar formation or inflammation in fetal subjects.

Amniotic tissue has properties that prevent adhesion formation around tendons following injury and reconstruction.35 Ozgenel36 investigated the effects of hyaluronic acid and amniotic membrane alone and in combination on the presence of adhesions and the rate of healing following chicken flexor tendon repair. The study found amniotic membrane wrapped around the repaired tendon was superior in preventing adhesion formation. Kim and colleagues37 report a similar reduction in fibrosis and adhesion following application of a human amniotic membrane wrap to rabbit ulnar neurorrhaphy sites.

This barrier function of amniotic tissue has also been investigated in the prevention of surgical scarring and peridural fibrosis in animal models following spinal discectomy. A study in canine models showed a reduction of scarring following the application of cross-linked amniotic membrane compared to freeze dried amniotic membrane.38 Similar reductions in scarring in rat models with the application of freeze-dried amniotic membrane compared to negative controls have been reported.39

Human Studies

A randomized trial investigated the outcomes of prenatal vs postnatal repair of myelomeningocele in humans, finding a reduced need for implanted shunts and improved functional outcomes at 30 months of life in the prenatal intervention group compared to the postnatal group.40 This study was concluded early due to the efficacy of prenatal surgery and the benefit of nervous system repair in utero in the presence of amniotic growth factors.

Vines and colleagues41 performed a 6-patient feasibility study using amnion injections to treat symptomatic knee osteoarthritis. Each patient received a single intra-articular cryopreserved amniotic suspension allograft (ASA) injection and was followed for 1 year. No adverse outcomes were reported, with the only abnormal finding being a small increase in serum immunoglobulin G and immunoglobulin E levels. Intra-articular ASA injection was found to be safe, but a large-scale trial investigating symptomatic relief was recommended.41

Most of the human studies using amnion pertain to foot and ankle surgery. Its use as a treatment for diabetic foot ulcers and recalcitrant plantar fasciitis was one of the early-recognized successes.42-45 Zelen and colleagues46 investigated the applications of injectable micronized dehydrated human amniotic/chorionic membrane as an alternative to surgical intervention in the treatment of refractory plantar fasciitis. This prospective, randomized trial with 45 patients showed significant improvement in plantar fasciitis symptoms at 8 weeks compared to controls (saline injections). A similar study compared the use of cryopreserved human amniotic membrane (c-hAM) injections to corticosteroid injections in plantar fasciitis patients.47 The results indicated that c-hAM is safe and comparable to corticosteroids, with the authors noting that pain improvement was greatest in patients receiving 2 injections of c-hAM at 18 weeks.

Tendon wrapping, in which the amniotic membrane is laid over a tendon repair, has been reported with success. Amniotic membrane is superior to collagen for tendon wrapping as it actively contributes to healing while minimizing adhesions, which collagen alone cannot do.48 The membrane serves as a protective sheath around repaired tendons with anti-inflammatory, anti-adhesive, immunomodulatory, and antimicrobial benefits. A 124-patient study demonstrated the safety of using amnion in this manner, and the authors reported a decreased rate of complication compared to previously published data.49 Another study of 14 patients undergoing foot and ankle surgery with tendon wrapping reported clinical improvement with reduced pain and greater functional outcomes postoperatively compared to preoperative measurements.50

 

 

Conclusion

Amniotic membrane-derived tissues are safe and non-tumorigenic, producing an abundance of growth factors that have shown promise as tissue scaffolds and as aids in the regeneration of human bone and soft tissues. Amnion applications in orthopedic surgery may be numerous, but development is ongoing. Given the vast array of in vitro and in vivo animal data supporting the benefits of amnion in tissue regeneration, orthopedic surgeons and researchers should place emphasis on conducting clinical studies to validate the safety and efficacy of amniotic cells in the treatment of orthopedic conditions.


Am J Orthop. 2016;45(7):E421-E425. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

1. Benirschke K, Kaufman P. Anatomy and pathology of the placental membranes. In: Pathology of the Human Placent., 4th ed. New York, NY: Springer-Verlag; 2000:281-334.

2. Mamede AC, Carvalho MJ, Abrantes AM, Laranjo M, Maia CJ, Botelho MF. Amniotic membrane: from structure and functions to clinical applications. Cell Tissue Res. 2012;349(2):447-458.

3. Miki T, Strom SC. Amnion-derived pluripotent/multipotent stem cells. Stem Cell Rev. 2006;2(2):133-142.

4. Parolini O, Alviano F, Bagnara GP, et al. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international workshop on placenta derived stem cells. Stem Cells. 2008;26(2):300-311.

5. Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod. 2007;77(3):577-588.

6. Alviano F, Fossati V, Marchionni C, et al. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol. 2007;7:11.

7. Barboni B, Curini V, Russo V, et al. Indirect co-culture with tendons or tenocytes can program amniotic epithelial cells towards stepwise tenogenic differentiation. PLoS One. 2012;7(2):e30974.

8. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews Cancer. 2011;11(4):268-277.

9. Lange-Consiglio A, Rossi D, Tassan S, Perego R, Cremonesi F, Parolini O. Conditioned medium from horse amniotic membrane-derived multipotent progenitor cells: immunomodulatory activity in vitro and first clinical application in tendon and ligament injuries in vivo. Stem Cells Dev. 2013;22(22):3015-3024.

10. Miki T. Amnion-derived stem cells: in quest of clinical applications. Stem Cell Res Ther. 2011;2(3):25.

11. Akle CA, Adinolfi M, Welsh KI, Leibowitz S, McColl I. Immunogenicity of human amniotic epithelial cells after transplantation into volunteers. Lancet. 1981;2(8254):1003-1035.

12. Gupta A, Kedige SD, Jain K. Amnion and chorion membranes: potential stem cell reservoir with wide applications in periodontics. Int J Biomater. 2015;2015:274082.

13. Buhimschi IA, Jabr M, Buhimschi CS, Petkova AP, Weiner CP, Saed GM. The novel antimicrobial peptide beta3-defensin is produced by the amnion: a possible role of the fetal membranes in innate immunity of the amniotic cavity. Am J Obstet Gynecol. 2004;191(5):1678-1687.

14. Magatti M, De Munari S, Vertua E, et al. Amniotic mesenchymal tissue cells inhibit dendritic cell differentiation of peripheral blood and amnion resident monocytes. Cell Transplant. 2009;18(8):899-914.

15. Solomon A, Wajngarten M, Alviano F, et al. Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix. Clin Exp Allergy. 2005;35(7):941-948.

16. Silini A, Parolini O, Huppertz B, Lang I. Soluble factors of amnion-derived cells in treatment of inflammatory and fibrotic pathologies. Curr Stem Cell Res Ther. 2013;8(1):6-14.

17. Peister A, Woodruff MA, Prince JJ, Gray DP, Hutmacher DW, Guldberg RE. Cell sourcing for bone tissue engineering: amniotic fluid stem cells have a delayed, robust differentiation compared to mesenchymal stem cells. Stem Cell Res. 2011;7(1):17-27.

18. Si J, Dai J, Zhang J, et al. Comparative investigation of human amniotic epithelial cells and mesenchymal stem cells for application in bone tissue engineering. Stem Cells Int. 2015;2015:565732.

19. Starecki M, Schwartz JA, Grande DA. Evaluation of amniotic-derived membrane biomaterial as an adjunct for repair of critical sized bone defects. Advances in Orthopedic Surgery. 2014;2014:572586.

20. Kerimoglu S, Livaoglu M, Sönmez B, et al. Effects of human amniotic fluid on fracture healing in rat tibia. J Surg Res. 2009;152(2):281-287.

21. Karaçal N, Kocucu P, Cobanglu U, Kutlu N. Effect of human amniotic fluid on bone healing. J Surg Res. 2005;129(2):283-287.

22. Barboni B, Mangano C, Valbonetti L, et al. Synthetic bone substitute engineered with amniotic epithelial cells enhances bone regeneration after maxillary sinus augmentation. PLoS One. 2013;8(5):e63256.

23. Díaz-Prado S, Rendal-Vázquez ME, Muiños-Lopez E, et al. Potential use of the human amniotic membrane as a scaffold in human articular cartilage repair. Cell Tissue Bank. 2010;11(2):183-195.

24. Krishnamurithy G, Shilpa PN, Ahmad RE, Sulaiman S, Ng CL, Kamarul T. Human amniotic membrane as a chondrocyte carrier vehicle/substrate: in vitro study. J Biomed Mater Res A. 2011;99(3):500-506.

25. Tan SL, Sulaiman S, Pingguan-Murphy B, Selvaratnam L, Tai CC, Kamarul T. Human amnion as a novel cell delivery vehicle for chondrogenic mesenchymal stem cells. Cell Tissue Bank. 2011;12(1):59-70.

26. Jin CZ, Park SR, Choi BH, Lee KY, Kang CK, Min BH. Human amniotic membrane as a delivery matrix for articular cartilage repair. Tissue Eng. 2007;13(4):693-702.

27. Garcia D, Longo UG, Vaquero J, et al. Amniotic membrane transplant for articular cartilage repair: an experimental study in sheep. Curr Stem Cell Res Ther. 2014;10(1):77-83.

28. Kunisaki SM, Freedman DA, Fauza DO. Fetal tracheal reconstruction with cartilaginous grafts engineered from mesenchymal amniocytes. J Pediatr Surg. 2006;41(4):675-682.

29. Namba RS, Meuli M, Sullivan KM, Le AX, Adzick NS. Spontaneous repair of superficial defects in articular cartilage in a fetal lamb model. J Bone Joint Surg Am. 1998;80(1):4-10.

30. Philip J, Hackl F, Canseco JA, et al. Amnion-derived multipotent progenitor cells improve achilles tendon repair in rats. Eplasty. 2013;13:e31.

31. Lange-Consiglio A, Tassan S, Corradetti B, et al. Investigating the efficacy of amnion-derived compared with bone marrow–derived mesenchymal stromal cells in equine tendon and ligament injuries. Cytotherapy. 2013;15(8):1011-1020.

32. Barboni B, Russo V, Curini V, et al. Achilles tendon regeneration can be improved by amniotic epithelial cell allotransplantation. Cell Transplant. 2012;21(11):2377-2395.

33. Kueckelhaus M, Philip J, Kamel RA, et al. Sustained release of amnion-derived cellular cytokine solution facilitates achilles tendon healing in rats. Eplasty. 2014;14:e29.

34. Beredjiklian PK, Favata M, Cartmell JS, Flanagan CL, Crombleholme TM, Soslowski LJ. Regenerative versus reparative healing in tendon: a study of biomechanical and histological properties in fetal sheep. Ann Biomed Eng. 2003;31(10):1143-1152.

35. Demirkan F, Colakoglu N, Herek O, Erkula G. The use of amniotic membrane in flexor tendon repair: an experimental model. Arch Orthop Trauma Surg. 2002;122(7):396-369.

36. Ozgenel GY. The effects of a combination of hyaluronic and amniotic membrane on the formation of peritendinous adhesions after flexor tendon surgery in chickens. J Bone Joint Surg Br. 2004;86(2):301-307.

37. Kim SS, Sohn SK, Lee KY, Lee MJ, Roh MS, Kim CH. Use of human amniotic membrane wrap in reducing perineural adhesions in a rabbit model of ulnar nerve neurorrhaphy. J Hand Surg Eur Vol. 2010;35(3):214-219.

38. Tao H, Fan H. Implantation of amniotic membrane to reduce postlaminectomy epidural adhesions. Eur Spine J. 2009;18(8):1202-1212.

39. Choi HJ, Kim KB, Kwon YM. Effect of amniotic membrane to reduce postlaminectomy epidural adhesion on a rat model. J Korean Neurosurg Soc. 2011;49(6):323-328.

40. Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993-1004.

41. Vines JB, Aliprantis AO, Gomoll AH, Farr J. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. 2016;29(6):443-450.

42. Zelen CM. An evaluation of dehydrated human amniotic membrane allografts in patients with DFUs. J Wound Care. 2013;22(7):347-348,350-351.

43. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.

44. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014;11(2):122-128.

45. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135-146.

46. Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis: a feasibility study. Foot Ankle Int. 2013;34(10):1332-1339.

47. Hanselman AE, Tidwell JE, Santrock RD. Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study. Foot Ankle Int. 2015;36(2):151-158.

48. Jay RM. Initial clinical experience with the use of human amniotic membrane tissue during repair of posterior tibial and achilles tendons. 2009. http://encompassbiologics.com/wp-content/uploads/2015/07/DrJayClinicalExperience.pdf. Accessed September 29, 2016.

49. DeMill SL, Granata JD, McAlister JE, Berlet GC, Hyer CF. Safety analysis of cryopreserved amniotic membrane/umbilical cord tissue in foot and ankle surgery: a consecutive case series of 124 patients. Surg Technol Int. 2014;25:257-261.

50. Warner M, Lasyone L. An open-label, single-center, retrospective study of cryopreserved amniotic membrane and umbilical cord tissue as an adjunct for foot and ankle surgery. Surg Technol Int. 2014;25:251-255.

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Nathanael Heckmann
MD; Richard Auran
BS; Raffy Mirzayan
MD
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MD; Richard Auran
BS; Raffy Mirzayan
MD
Author and Disclosure Information

Authors’ Disclosure Statement: Dr. Mirzayan reports that he receives royalties from Thieme and Lippincott; receives research grants from Arthrex, Joint Restoration Foundation, and BioD, LLC; receives educational grants from Arthrex; and holds stock in Alignmed, Cayenne Medical, and USIS/ITS. The other authors report no actual or potential conflict of interest in relation to this article.

Author and Disclosure Information

Authors’ Disclosure Statement: Dr. Mirzayan reports that he receives royalties from Thieme and Lippincott; receives research grants from Arthrex, Joint Restoration Foundation, and BioD, LLC; receives educational grants from Arthrex; and holds stock in Alignmed, Cayenne Medical, and USIS/ITS. The other authors report no actual or potential conflict of interest in relation to this article.

Article PDF
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The amniotic membrane is a multilayer tissue forming the innermost layer of the amniotic sac that surrounds the developing fetus. It is comprised of 5 layers, from the inside out: a single layer of epithelial cells, a thick basement membrane, a compact layer, a fibroblast layer, and a spongy layer that abuts the surrounding chorion (Figure 1).1

The amniotic membrane serves several functions, including synthesis of growth factors and cytokines, regulation of pH, transport of water and solutes, and provision of a permeable barrier to amniotic macromolecules.2

Amniotic epithelial cells are derived from the pluripotent epiblast at approximately day 8 of gestation. This is well before gastrulation occurs at days 15 to 17, considered the “tipping point” when pluripotent cells differentiate into ectoderm, mesoderm, and endoderm.3 These cells express Oct-4 and Nanog, 2 molecular markers that are indicative of pluripotency.3 Two cell types have been identified in amniotic tissues that possess stem cell-like characteristics: human amniotic epithelial cells and human amniotic mesenchymal stromal cells.4 Both of these cell types have demonstrated the ability to differentiate into various cell lineages, including endothelial cells, adipocytes, myogenic cells, neurogenic cells, chondrocytes, tenocytes, and osteogenic cells.5-7 These previously reported findings indicate that amniotic cells and tissue have the capability to generate mesenchymal tissues.

FDA Classification and Available Forms

The US Food and Drug Administration (FDA) classifies amnion as an allograft tissue under Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 361. To meet criteria, the tissue needs to be minimally manipulated. It is to be for homologous use and cannot be combined with other cells or tissues. There can be no systemic effect or dependence on the metabolic activity of living cells to achieve its primary function. The tissue has to have a localized effect in vivo. Therefore, amnion allograft tissue can be commercialized, provided it is not marketed as a stem cell product or to contain viable cells.

Amniotic tissue is commercially available in several forms.

These include fresh-frozen injectable amniotic liquid that may contain viable amniotic cells and/or particulated amniotic membrane, a micronized freeze-dried (lyophilized) particulate powder that is directly applied to a wound or resuspended for injection, and a cross-linked dehydrated membrane acting as an adhesion barrier (Figure 2).

Safety

Amniotic tissue has been used for over 100 years in burn, ophthalmology, and chronic wound patients with favorable outcomes and no adverse effects reported in the literature. Unlike embryonic stem cells, which may be tumorigenic,8 amniotic cells do not possess any known tumorigenicity.9 In one study, 50 immunodeficient mice were injected with 1 to 2 million amniotic epithelial cells and observed for a maximum of 516 days with no tumorigenicity observed in any of the animals.10 In another study, amniotic epithelial cells were implanted into the forearms of healthy volunteers and no immunologic response was observed in any of the recipients.11 Furthermore, viable amniotic cells were recovered via biopsy 7 weeks following transplantation, demonstrating viability of the transplanted cells.11 The lack of tumorigenicity and immunologic response in hosts is due in part to the fact that amniotic cells do not express human leukocyte antigen class II antigens and only express class I antigens in small amounts.3

Advantages of Amnion Tissue

Amniotic tissue is readily available, as it is often discarded after childbirth. The use of this tissue poses no added risk to the fetus or mother, eliminating the ethical concerns associated with obtaining embryonic stem cells. Amniotic tissue is comprised of an extracellular matrix, which acts as a natural scaffold for cellular attachment and structural support for cells as well as collagen types I, III, IV, V, and VI, hyaluronic acid, and a host of growth factors.12 In addition, it possesses antimicrobial properties, including beta-defensins.13

Amniotic tissue has been shown to exert an anti-inflammatory effect by inhibiting the inflammatory cascade. Specifically, it has been shown to inhibit cytokines such as tumor necrosis factor-alpha in the presence of dendritic cells,14 as well as inhibiting transforming growth factor-beta, interleukin-8, and fibroblast proliferation.15 These findings indicate that amniotic tissue has the ability to dampen the “cytokine storm” that occurs after an injury in an adult, which would lead to beneficial impacts on healing and scar formation in patients.16

Basic Science and Animal Studies

Several studies have demonstrated promising outcomes for orthopedic applications in vitro. A comparison of osteogenic potential found that amniotic fluid-derived cells were able to produce approximately 5 times more mineralized matrix than bone marrow-derived mesenchymal stem cells.17 More recently, Si and colleagues18 compared the osteogenic potential of human amniotic epithelial cells, amniotic cells, and human bone marrow-derived mesenchymal stem cells. They found that all 3 cell lines were osteogenic, though the amniotic epithelial cells had better immunomodulatory properties and marginally less osteogenic potential than the other 2 cell types. Furthermore, several in vivo animal studies have demonstrated the ability of human amniotic cells to stimulate bone growth in rats,19,20 rabbits,21 and sheep.22

 

 

Amniotic tissue also possesses potential for chondrogenesis. Cryopreserved human amniotic membrane cells used for in vitro human osteoarthritis tissue scaffolds did not differentiate in culture, and they integrated and repaired damaged articular cartilage.23 Various in vitro24,25 and animal in vivo26,27 studies have reported similar supportive findings. Kunisaki and colleagues28 used sheep amniotic fluid mesenchymal stem cells to reconstruct lamb tracheal cartilage in utero, concluding that cells obtained from the amniotic fluid possess chondrogenic capabilities. Further in utero lamb studies of cartilage artificial defects, given 7 days to settle before adding a hypocellular matrix as a scaffold, showed chondrocyte density and cell architecture was restored at the defect site after 28 days without the formation of an inflammatory response or scar tissue.29

Amniotic tissue has had similar success in tendon repair studies in vivo.9,30,31 Barboni and colleagues32 implanted amniotic epithelial cells (AECs) into artificially created sheep Achilles tendon defects in situ, inducing superior structural and mechanical recovery in the defects at a faster rate compared to controls not receiving AECs. Healing via AECs started at the healthy tissue around the borders of the defect and progressed centrally, suggesting recruitment of native progenitor cells to the lesion.32 Kueckelhaus and colleagues33 investigated the role of amnion-derived cellular cytokine solution in the healing of transections of rat Achilles tendons, reporting improved mechanical properties of healing tendons at early time points compared to controls. Beredjiklian and colleagues34 compared the healing of transected extensor tendons of pregnant ewes and of their fetus in utero, reporting a reparative form of healing with scar formation in adult subjects and regenerative form of healing without scar formation or inflammation in fetal subjects.

Amniotic tissue has properties that prevent adhesion formation around tendons following injury and reconstruction.35 Ozgenel36 investigated the effects of hyaluronic acid and amniotic membrane alone and in combination on the presence of adhesions and the rate of healing following chicken flexor tendon repair. The study found amniotic membrane wrapped around the repaired tendon was superior in preventing adhesion formation. Kim and colleagues37 report a similar reduction in fibrosis and adhesion following application of a human amniotic membrane wrap to rabbit ulnar neurorrhaphy sites.

This barrier function of amniotic tissue has also been investigated in the prevention of surgical scarring and peridural fibrosis in animal models following spinal discectomy. A study in canine models showed a reduction of scarring following the application of cross-linked amniotic membrane compared to freeze dried amniotic membrane.38 Similar reductions in scarring in rat models with the application of freeze-dried amniotic membrane compared to negative controls have been reported.39

Human Studies

A randomized trial investigated the outcomes of prenatal vs postnatal repair of myelomeningocele in humans, finding a reduced need for implanted shunts and improved functional outcomes at 30 months of life in the prenatal intervention group compared to the postnatal group.40 This study was concluded early due to the efficacy of prenatal surgery and the benefit of nervous system repair in utero in the presence of amniotic growth factors.

Vines and colleagues41 performed a 6-patient feasibility study using amnion injections to treat symptomatic knee osteoarthritis. Each patient received a single intra-articular cryopreserved amniotic suspension allograft (ASA) injection and was followed for 1 year. No adverse outcomes were reported, with the only abnormal finding being a small increase in serum immunoglobulin G and immunoglobulin E levels. Intra-articular ASA injection was found to be safe, but a large-scale trial investigating symptomatic relief was recommended.41

Most of the human studies using amnion pertain to foot and ankle surgery. Its use as a treatment for diabetic foot ulcers and recalcitrant plantar fasciitis was one of the early-recognized successes.42-45 Zelen and colleagues46 investigated the applications of injectable micronized dehydrated human amniotic/chorionic membrane as an alternative to surgical intervention in the treatment of refractory plantar fasciitis. This prospective, randomized trial with 45 patients showed significant improvement in plantar fasciitis symptoms at 8 weeks compared to controls (saline injections). A similar study compared the use of cryopreserved human amniotic membrane (c-hAM) injections to corticosteroid injections in plantar fasciitis patients.47 The results indicated that c-hAM is safe and comparable to corticosteroids, with the authors noting that pain improvement was greatest in patients receiving 2 injections of c-hAM at 18 weeks.

Tendon wrapping, in which the amniotic membrane is laid over a tendon repair, has been reported with success. Amniotic membrane is superior to collagen for tendon wrapping as it actively contributes to healing while minimizing adhesions, which collagen alone cannot do.48 The membrane serves as a protective sheath around repaired tendons with anti-inflammatory, anti-adhesive, immunomodulatory, and antimicrobial benefits. A 124-patient study demonstrated the safety of using amnion in this manner, and the authors reported a decreased rate of complication compared to previously published data.49 Another study of 14 patients undergoing foot and ankle surgery with tendon wrapping reported clinical improvement with reduced pain and greater functional outcomes postoperatively compared to preoperative measurements.50

 

 

Conclusion

Amniotic membrane-derived tissues are safe and non-tumorigenic, producing an abundance of growth factors that have shown promise as tissue scaffolds and as aids in the regeneration of human bone and soft tissues. Amnion applications in orthopedic surgery may be numerous, but development is ongoing. Given the vast array of in vitro and in vivo animal data supporting the benefits of amnion in tissue regeneration, orthopedic surgeons and researchers should place emphasis on conducting clinical studies to validate the safety and efficacy of amniotic cells in the treatment of orthopedic conditions.


Am J Orthop. 2016;45(7):E421-E425. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

The amniotic membrane is a multilayer tissue forming the innermost layer of the amniotic sac that surrounds the developing fetus. It is comprised of 5 layers, from the inside out: a single layer of epithelial cells, a thick basement membrane, a compact layer, a fibroblast layer, and a spongy layer that abuts the surrounding chorion (Figure 1).1

The amniotic membrane serves several functions, including synthesis of growth factors and cytokines, regulation of pH, transport of water and solutes, and provision of a permeable barrier to amniotic macromolecules.2

Amniotic epithelial cells are derived from the pluripotent epiblast at approximately day 8 of gestation. This is well before gastrulation occurs at days 15 to 17, considered the “tipping point” when pluripotent cells differentiate into ectoderm, mesoderm, and endoderm.3 These cells express Oct-4 and Nanog, 2 molecular markers that are indicative of pluripotency.3 Two cell types have been identified in amniotic tissues that possess stem cell-like characteristics: human amniotic epithelial cells and human amniotic mesenchymal stromal cells.4 Both of these cell types have demonstrated the ability to differentiate into various cell lineages, including endothelial cells, adipocytes, myogenic cells, neurogenic cells, chondrocytes, tenocytes, and osteogenic cells.5-7 These previously reported findings indicate that amniotic cells and tissue have the capability to generate mesenchymal tissues.

FDA Classification and Available Forms

The US Food and Drug Administration (FDA) classifies amnion as an allograft tissue under Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 361. To meet criteria, the tissue needs to be minimally manipulated. It is to be for homologous use and cannot be combined with other cells or tissues. There can be no systemic effect or dependence on the metabolic activity of living cells to achieve its primary function. The tissue has to have a localized effect in vivo. Therefore, amnion allograft tissue can be commercialized, provided it is not marketed as a stem cell product or to contain viable cells.

Amniotic tissue is commercially available in several forms.

These include fresh-frozen injectable amniotic liquid that may contain viable amniotic cells and/or particulated amniotic membrane, a micronized freeze-dried (lyophilized) particulate powder that is directly applied to a wound or resuspended for injection, and a cross-linked dehydrated membrane acting as an adhesion barrier (Figure 2).

Safety

Amniotic tissue has been used for over 100 years in burn, ophthalmology, and chronic wound patients with favorable outcomes and no adverse effects reported in the literature. Unlike embryonic stem cells, which may be tumorigenic,8 amniotic cells do not possess any known tumorigenicity.9 In one study, 50 immunodeficient mice were injected with 1 to 2 million amniotic epithelial cells and observed for a maximum of 516 days with no tumorigenicity observed in any of the animals.10 In another study, amniotic epithelial cells were implanted into the forearms of healthy volunteers and no immunologic response was observed in any of the recipients.11 Furthermore, viable amniotic cells were recovered via biopsy 7 weeks following transplantation, demonstrating viability of the transplanted cells.11 The lack of tumorigenicity and immunologic response in hosts is due in part to the fact that amniotic cells do not express human leukocyte antigen class II antigens and only express class I antigens in small amounts.3

Advantages of Amnion Tissue

Amniotic tissue is readily available, as it is often discarded after childbirth. The use of this tissue poses no added risk to the fetus or mother, eliminating the ethical concerns associated with obtaining embryonic stem cells. Amniotic tissue is comprised of an extracellular matrix, which acts as a natural scaffold for cellular attachment and structural support for cells as well as collagen types I, III, IV, V, and VI, hyaluronic acid, and a host of growth factors.12 In addition, it possesses antimicrobial properties, including beta-defensins.13

Amniotic tissue has been shown to exert an anti-inflammatory effect by inhibiting the inflammatory cascade. Specifically, it has been shown to inhibit cytokines such as tumor necrosis factor-alpha in the presence of dendritic cells,14 as well as inhibiting transforming growth factor-beta, interleukin-8, and fibroblast proliferation.15 These findings indicate that amniotic tissue has the ability to dampen the “cytokine storm” that occurs after an injury in an adult, which would lead to beneficial impacts on healing and scar formation in patients.16

Basic Science and Animal Studies

Several studies have demonstrated promising outcomes for orthopedic applications in vitro. A comparison of osteogenic potential found that amniotic fluid-derived cells were able to produce approximately 5 times more mineralized matrix than bone marrow-derived mesenchymal stem cells.17 More recently, Si and colleagues18 compared the osteogenic potential of human amniotic epithelial cells, amniotic cells, and human bone marrow-derived mesenchymal stem cells. They found that all 3 cell lines were osteogenic, though the amniotic epithelial cells had better immunomodulatory properties and marginally less osteogenic potential than the other 2 cell types. Furthermore, several in vivo animal studies have demonstrated the ability of human amniotic cells to stimulate bone growth in rats,19,20 rabbits,21 and sheep.22

 

 

Amniotic tissue also possesses potential for chondrogenesis. Cryopreserved human amniotic membrane cells used for in vitro human osteoarthritis tissue scaffolds did not differentiate in culture, and they integrated and repaired damaged articular cartilage.23 Various in vitro24,25 and animal in vivo26,27 studies have reported similar supportive findings. Kunisaki and colleagues28 used sheep amniotic fluid mesenchymal stem cells to reconstruct lamb tracheal cartilage in utero, concluding that cells obtained from the amniotic fluid possess chondrogenic capabilities. Further in utero lamb studies of cartilage artificial defects, given 7 days to settle before adding a hypocellular matrix as a scaffold, showed chondrocyte density and cell architecture was restored at the defect site after 28 days without the formation of an inflammatory response or scar tissue.29

Amniotic tissue has had similar success in tendon repair studies in vivo.9,30,31 Barboni and colleagues32 implanted amniotic epithelial cells (AECs) into artificially created sheep Achilles tendon defects in situ, inducing superior structural and mechanical recovery in the defects at a faster rate compared to controls not receiving AECs. Healing via AECs started at the healthy tissue around the borders of the defect and progressed centrally, suggesting recruitment of native progenitor cells to the lesion.32 Kueckelhaus and colleagues33 investigated the role of amnion-derived cellular cytokine solution in the healing of transections of rat Achilles tendons, reporting improved mechanical properties of healing tendons at early time points compared to controls. Beredjiklian and colleagues34 compared the healing of transected extensor tendons of pregnant ewes and of their fetus in utero, reporting a reparative form of healing with scar formation in adult subjects and regenerative form of healing without scar formation or inflammation in fetal subjects.

Amniotic tissue has properties that prevent adhesion formation around tendons following injury and reconstruction.35 Ozgenel36 investigated the effects of hyaluronic acid and amniotic membrane alone and in combination on the presence of adhesions and the rate of healing following chicken flexor tendon repair. The study found amniotic membrane wrapped around the repaired tendon was superior in preventing adhesion formation. Kim and colleagues37 report a similar reduction in fibrosis and adhesion following application of a human amniotic membrane wrap to rabbit ulnar neurorrhaphy sites.

This barrier function of amniotic tissue has also been investigated in the prevention of surgical scarring and peridural fibrosis in animal models following spinal discectomy. A study in canine models showed a reduction of scarring following the application of cross-linked amniotic membrane compared to freeze dried amniotic membrane.38 Similar reductions in scarring in rat models with the application of freeze-dried amniotic membrane compared to negative controls have been reported.39

Human Studies

A randomized trial investigated the outcomes of prenatal vs postnatal repair of myelomeningocele in humans, finding a reduced need for implanted shunts and improved functional outcomes at 30 months of life in the prenatal intervention group compared to the postnatal group.40 This study was concluded early due to the efficacy of prenatal surgery and the benefit of nervous system repair in utero in the presence of amniotic growth factors.

Vines and colleagues41 performed a 6-patient feasibility study using amnion injections to treat symptomatic knee osteoarthritis. Each patient received a single intra-articular cryopreserved amniotic suspension allograft (ASA) injection and was followed for 1 year. No adverse outcomes were reported, with the only abnormal finding being a small increase in serum immunoglobulin G and immunoglobulin E levels. Intra-articular ASA injection was found to be safe, but a large-scale trial investigating symptomatic relief was recommended.41

Most of the human studies using amnion pertain to foot and ankle surgery. Its use as a treatment for diabetic foot ulcers and recalcitrant plantar fasciitis was one of the early-recognized successes.42-45 Zelen and colleagues46 investigated the applications of injectable micronized dehydrated human amniotic/chorionic membrane as an alternative to surgical intervention in the treatment of refractory plantar fasciitis. This prospective, randomized trial with 45 patients showed significant improvement in plantar fasciitis symptoms at 8 weeks compared to controls (saline injections). A similar study compared the use of cryopreserved human amniotic membrane (c-hAM) injections to corticosteroid injections in plantar fasciitis patients.47 The results indicated that c-hAM is safe and comparable to corticosteroids, with the authors noting that pain improvement was greatest in patients receiving 2 injections of c-hAM at 18 weeks.

Tendon wrapping, in which the amniotic membrane is laid over a tendon repair, has been reported with success. Amniotic membrane is superior to collagen for tendon wrapping as it actively contributes to healing while minimizing adhesions, which collagen alone cannot do.48 The membrane serves as a protective sheath around repaired tendons with anti-inflammatory, anti-adhesive, immunomodulatory, and antimicrobial benefits. A 124-patient study demonstrated the safety of using amnion in this manner, and the authors reported a decreased rate of complication compared to previously published data.49 Another study of 14 patients undergoing foot and ankle surgery with tendon wrapping reported clinical improvement with reduced pain and greater functional outcomes postoperatively compared to preoperative measurements.50

 

 

Conclusion

Amniotic membrane-derived tissues are safe and non-tumorigenic, producing an abundance of growth factors that have shown promise as tissue scaffolds and as aids in the regeneration of human bone and soft tissues. Amnion applications in orthopedic surgery may be numerous, but development is ongoing. Given the vast array of in vitro and in vivo animal data supporting the benefits of amnion in tissue regeneration, orthopedic surgeons and researchers should place emphasis on conducting clinical studies to validate the safety and efficacy of amniotic cells in the treatment of orthopedic conditions.


Am J Orthop. 2016;45(7):E421-E425. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

1. Benirschke K, Kaufman P. Anatomy and pathology of the placental membranes. In: Pathology of the Human Placent., 4th ed. New York, NY: Springer-Verlag; 2000:281-334.

2. Mamede AC, Carvalho MJ, Abrantes AM, Laranjo M, Maia CJ, Botelho MF. Amniotic membrane: from structure and functions to clinical applications. Cell Tissue Res. 2012;349(2):447-458.

3. Miki T, Strom SC. Amnion-derived pluripotent/multipotent stem cells. Stem Cell Rev. 2006;2(2):133-142.

4. Parolini O, Alviano F, Bagnara GP, et al. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international workshop on placenta derived stem cells. Stem Cells. 2008;26(2):300-311.

5. Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod. 2007;77(3):577-588.

6. Alviano F, Fossati V, Marchionni C, et al. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol. 2007;7:11.

7. Barboni B, Curini V, Russo V, et al. Indirect co-culture with tendons or tenocytes can program amniotic epithelial cells towards stepwise tenogenic differentiation. PLoS One. 2012;7(2):e30974.

8. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews Cancer. 2011;11(4):268-277.

9. Lange-Consiglio A, Rossi D, Tassan S, Perego R, Cremonesi F, Parolini O. Conditioned medium from horse amniotic membrane-derived multipotent progenitor cells: immunomodulatory activity in vitro and first clinical application in tendon and ligament injuries in vivo. Stem Cells Dev. 2013;22(22):3015-3024.

10. Miki T. Amnion-derived stem cells: in quest of clinical applications. Stem Cell Res Ther. 2011;2(3):25.

11. Akle CA, Adinolfi M, Welsh KI, Leibowitz S, McColl I. Immunogenicity of human amniotic epithelial cells after transplantation into volunteers. Lancet. 1981;2(8254):1003-1035.

12. Gupta A, Kedige SD, Jain K. Amnion and chorion membranes: potential stem cell reservoir with wide applications in periodontics. Int J Biomater. 2015;2015:274082.

13. Buhimschi IA, Jabr M, Buhimschi CS, Petkova AP, Weiner CP, Saed GM. The novel antimicrobial peptide beta3-defensin is produced by the amnion: a possible role of the fetal membranes in innate immunity of the amniotic cavity. Am J Obstet Gynecol. 2004;191(5):1678-1687.

14. Magatti M, De Munari S, Vertua E, et al. Amniotic mesenchymal tissue cells inhibit dendritic cell differentiation of peripheral blood and amnion resident monocytes. Cell Transplant. 2009;18(8):899-914.

15. Solomon A, Wajngarten M, Alviano F, et al. Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix. Clin Exp Allergy. 2005;35(7):941-948.

16. Silini A, Parolini O, Huppertz B, Lang I. Soluble factors of amnion-derived cells in treatment of inflammatory and fibrotic pathologies. Curr Stem Cell Res Ther. 2013;8(1):6-14.

17. Peister A, Woodruff MA, Prince JJ, Gray DP, Hutmacher DW, Guldberg RE. Cell sourcing for bone tissue engineering: amniotic fluid stem cells have a delayed, robust differentiation compared to mesenchymal stem cells. Stem Cell Res. 2011;7(1):17-27.

18. Si J, Dai J, Zhang J, et al. Comparative investigation of human amniotic epithelial cells and mesenchymal stem cells for application in bone tissue engineering. Stem Cells Int. 2015;2015:565732.

19. Starecki M, Schwartz JA, Grande DA. Evaluation of amniotic-derived membrane biomaterial as an adjunct for repair of critical sized bone defects. Advances in Orthopedic Surgery. 2014;2014:572586.

20. Kerimoglu S, Livaoglu M, Sönmez B, et al. Effects of human amniotic fluid on fracture healing in rat tibia. J Surg Res. 2009;152(2):281-287.

21. Karaçal N, Kocucu P, Cobanglu U, Kutlu N. Effect of human amniotic fluid on bone healing. J Surg Res. 2005;129(2):283-287.

22. Barboni B, Mangano C, Valbonetti L, et al. Synthetic bone substitute engineered with amniotic epithelial cells enhances bone regeneration after maxillary sinus augmentation. PLoS One. 2013;8(5):e63256.

23. Díaz-Prado S, Rendal-Vázquez ME, Muiños-Lopez E, et al. Potential use of the human amniotic membrane as a scaffold in human articular cartilage repair. Cell Tissue Bank. 2010;11(2):183-195.

24. Krishnamurithy G, Shilpa PN, Ahmad RE, Sulaiman S, Ng CL, Kamarul T. Human amniotic membrane as a chondrocyte carrier vehicle/substrate: in vitro study. J Biomed Mater Res A. 2011;99(3):500-506.

25. Tan SL, Sulaiman S, Pingguan-Murphy B, Selvaratnam L, Tai CC, Kamarul T. Human amnion as a novel cell delivery vehicle for chondrogenic mesenchymal stem cells. Cell Tissue Bank. 2011;12(1):59-70.

26. Jin CZ, Park SR, Choi BH, Lee KY, Kang CK, Min BH. Human amniotic membrane as a delivery matrix for articular cartilage repair. Tissue Eng. 2007;13(4):693-702.

27. Garcia D, Longo UG, Vaquero J, et al. Amniotic membrane transplant for articular cartilage repair: an experimental study in sheep. Curr Stem Cell Res Ther. 2014;10(1):77-83.

28. Kunisaki SM, Freedman DA, Fauza DO. Fetal tracheal reconstruction with cartilaginous grafts engineered from mesenchymal amniocytes. J Pediatr Surg. 2006;41(4):675-682.

29. Namba RS, Meuli M, Sullivan KM, Le AX, Adzick NS. Spontaneous repair of superficial defects in articular cartilage in a fetal lamb model. J Bone Joint Surg Am. 1998;80(1):4-10.

30. Philip J, Hackl F, Canseco JA, et al. Amnion-derived multipotent progenitor cells improve achilles tendon repair in rats. Eplasty. 2013;13:e31.

31. Lange-Consiglio A, Tassan S, Corradetti B, et al. Investigating the efficacy of amnion-derived compared with bone marrow–derived mesenchymal stromal cells in equine tendon and ligament injuries. Cytotherapy. 2013;15(8):1011-1020.

32. Barboni B, Russo V, Curini V, et al. Achilles tendon regeneration can be improved by amniotic epithelial cell allotransplantation. Cell Transplant. 2012;21(11):2377-2395.

33. Kueckelhaus M, Philip J, Kamel RA, et al. Sustained release of amnion-derived cellular cytokine solution facilitates achilles tendon healing in rats. Eplasty. 2014;14:e29.

34. Beredjiklian PK, Favata M, Cartmell JS, Flanagan CL, Crombleholme TM, Soslowski LJ. Regenerative versus reparative healing in tendon: a study of biomechanical and histological properties in fetal sheep. Ann Biomed Eng. 2003;31(10):1143-1152.

35. Demirkan F, Colakoglu N, Herek O, Erkula G. The use of amniotic membrane in flexor tendon repair: an experimental model. Arch Orthop Trauma Surg. 2002;122(7):396-369.

36. Ozgenel GY. The effects of a combination of hyaluronic and amniotic membrane on the formation of peritendinous adhesions after flexor tendon surgery in chickens. J Bone Joint Surg Br. 2004;86(2):301-307.

37. Kim SS, Sohn SK, Lee KY, Lee MJ, Roh MS, Kim CH. Use of human amniotic membrane wrap in reducing perineural adhesions in a rabbit model of ulnar nerve neurorrhaphy. J Hand Surg Eur Vol. 2010;35(3):214-219.

38. Tao H, Fan H. Implantation of amniotic membrane to reduce postlaminectomy epidural adhesions. Eur Spine J. 2009;18(8):1202-1212.

39. Choi HJ, Kim KB, Kwon YM. Effect of amniotic membrane to reduce postlaminectomy epidural adhesion on a rat model. J Korean Neurosurg Soc. 2011;49(6):323-328.

40. Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993-1004.

41. Vines JB, Aliprantis AO, Gomoll AH, Farr J. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. 2016;29(6):443-450.

42. Zelen CM. An evaluation of dehydrated human amniotic membrane allografts in patients with DFUs. J Wound Care. 2013;22(7):347-348,350-351.

43. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.

44. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014;11(2):122-128.

45. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135-146.

46. Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis: a feasibility study. Foot Ankle Int. 2013;34(10):1332-1339.

47. Hanselman AE, Tidwell JE, Santrock RD. Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study. Foot Ankle Int. 2015;36(2):151-158.

48. Jay RM. Initial clinical experience with the use of human amniotic membrane tissue during repair of posterior tibial and achilles tendons. 2009. http://encompassbiologics.com/wp-content/uploads/2015/07/DrJayClinicalExperience.pdf. Accessed September 29, 2016.

49. DeMill SL, Granata JD, McAlister JE, Berlet GC, Hyer CF. Safety analysis of cryopreserved amniotic membrane/umbilical cord tissue in foot and ankle surgery: a consecutive case series of 124 patients. Surg Technol Int. 2014;25:257-261.

50. Warner M, Lasyone L. An open-label, single-center, retrospective study of cryopreserved amniotic membrane and umbilical cord tissue as an adjunct for foot and ankle surgery. Surg Technol Int. 2014;25:251-255.

References

1. Benirschke K, Kaufman P. Anatomy and pathology of the placental membranes. In: Pathology of the Human Placent., 4th ed. New York, NY: Springer-Verlag; 2000:281-334.

2. Mamede AC, Carvalho MJ, Abrantes AM, Laranjo M, Maia CJ, Botelho MF. Amniotic membrane: from structure and functions to clinical applications. Cell Tissue Res. 2012;349(2):447-458.

3. Miki T, Strom SC. Amnion-derived pluripotent/multipotent stem cells. Stem Cell Rev. 2006;2(2):133-142.

4. Parolini O, Alviano F, Bagnara GP, et al. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international workshop on placenta derived stem cells. Stem Cells. 2008;26(2):300-311.

5. Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod. 2007;77(3):577-588.

6. Alviano F, Fossati V, Marchionni C, et al. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol. 2007;7:11.

7. Barboni B, Curini V, Russo V, et al. Indirect co-culture with tendons or tenocytes can program amniotic epithelial cells towards stepwise tenogenic differentiation. PLoS One. 2012;7(2):e30974.

8. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews Cancer. 2011;11(4):268-277.

9. Lange-Consiglio A, Rossi D, Tassan S, Perego R, Cremonesi F, Parolini O. Conditioned medium from horse amniotic membrane-derived multipotent progenitor cells: immunomodulatory activity in vitro and first clinical application in tendon and ligament injuries in vivo. Stem Cells Dev. 2013;22(22):3015-3024.

10. Miki T. Amnion-derived stem cells: in quest of clinical applications. Stem Cell Res Ther. 2011;2(3):25.

11. Akle CA, Adinolfi M, Welsh KI, Leibowitz S, McColl I. Immunogenicity of human amniotic epithelial cells after transplantation into volunteers. Lancet. 1981;2(8254):1003-1035.

12. Gupta A, Kedige SD, Jain K. Amnion and chorion membranes: potential stem cell reservoir with wide applications in periodontics. Int J Biomater. 2015;2015:274082.

13. Buhimschi IA, Jabr M, Buhimschi CS, Petkova AP, Weiner CP, Saed GM. The novel antimicrobial peptide beta3-defensin is produced by the amnion: a possible role of the fetal membranes in innate immunity of the amniotic cavity. Am J Obstet Gynecol. 2004;191(5):1678-1687.

14. Magatti M, De Munari S, Vertua E, et al. Amniotic mesenchymal tissue cells inhibit dendritic cell differentiation of peripheral blood and amnion resident monocytes. Cell Transplant. 2009;18(8):899-914.

15. Solomon A, Wajngarten M, Alviano F, et al. Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix. Clin Exp Allergy. 2005;35(7):941-948.

16. Silini A, Parolini O, Huppertz B, Lang I. Soluble factors of amnion-derived cells in treatment of inflammatory and fibrotic pathologies. Curr Stem Cell Res Ther. 2013;8(1):6-14.

17. Peister A, Woodruff MA, Prince JJ, Gray DP, Hutmacher DW, Guldberg RE. Cell sourcing for bone tissue engineering: amniotic fluid stem cells have a delayed, robust differentiation compared to mesenchymal stem cells. Stem Cell Res. 2011;7(1):17-27.

18. Si J, Dai J, Zhang J, et al. Comparative investigation of human amniotic epithelial cells and mesenchymal stem cells for application in bone tissue engineering. Stem Cells Int. 2015;2015:565732.

19. Starecki M, Schwartz JA, Grande DA. Evaluation of amniotic-derived membrane biomaterial as an adjunct for repair of critical sized bone defects. Advances in Orthopedic Surgery. 2014;2014:572586.

20. Kerimoglu S, Livaoglu M, Sönmez B, et al. Effects of human amniotic fluid on fracture healing in rat tibia. J Surg Res. 2009;152(2):281-287.

21. Karaçal N, Kocucu P, Cobanglu U, Kutlu N. Effect of human amniotic fluid on bone healing. J Surg Res. 2005;129(2):283-287.

22. Barboni B, Mangano C, Valbonetti L, et al. Synthetic bone substitute engineered with amniotic epithelial cells enhances bone regeneration after maxillary sinus augmentation. PLoS One. 2013;8(5):e63256.

23. Díaz-Prado S, Rendal-Vázquez ME, Muiños-Lopez E, et al. Potential use of the human amniotic membrane as a scaffold in human articular cartilage repair. Cell Tissue Bank. 2010;11(2):183-195.

24. Krishnamurithy G, Shilpa PN, Ahmad RE, Sulaiman S, Ng CL, Kamarul T. Human amniotic membrane as a chondrocyte carrier vehicle/substrate: in vitro study. J Biomed Mater Res A. 2011;99(3):500-506.

25. Tan SL, Sulaiman S, Pingguan-Murphy B, Selvaratnam L, Tai CC, Kamarul T. Human amnion as a novel cell delivery vehicle for chondrogenic mesenchymal stem cells. Cell Tissue Bank. 2011;12(1):59-70.

26. Jin CZ, Park SR, Choi BH, Lee KY, Kang CK, Min BH. Human amniotic membrane as a delivery matrix for articular cartilage repair. Tissue Eng. 2007;13(4):693-702.

27. Garcia D, Longo UG, Vaquero J, et al. Amniotic membrane transplant for articular cartilage repair: an experimental study in sheep. Curr Stem Cell Res Ther. 2014;10(1):77-83.

28. Kunisaki SM, Freedman DA, Fauza DO. Fetal tracheal reconstruction with cartilaginous grafts engineered from mesenchymal amniocytes. J Pediatr Surg. 2006;41(4):675-682.

29. Namba RS, Meuli M, Sullivan KM, Le AX, Adzick NS. Spontaneous repair of superficial defects in articular cartilage in a fetal lamb model. J Bone Joint Surg Am. 1998;80(1):4-10.

30. Philip J, Hackl F, Canseco JA, et al. Amnion-derived multipotent progenitor cells improve achilles tendon repair in rats. Eplasty. 2013;13:e31.

31. Lange-Consiglio A, Tassan S, Corradetti B, et al. Investigating the efficacy of amnion-derived compared with bone marrow–derived mesenchymal stromal cells in equine tendon and ligament injuries. Cytotherapy. 2013;15(8):1011-1020.

32. Barboni B, Russo V, Curini V, et al. Achilles tendon regeneration can be improved by amniotic epithelial cell allotransplantation. Cell Transplant. 2012;21(11):2377-2395.

33. Kueckelhaus M, Philip J, Kamel RA, et al. Sustained release of amnion-derived cellular cytokine solution facilitates achilles tendon healing in rats. Eplasty. 2014;14:e29.

34. Beredjiklian PK, Favata M, Cartmell JS, Flanagan CL, Crombleholme TM, Soslowski LJ. Regenerative versus reparative healing in tendon: a study of biomechanical and histological properties in fetal sheep. Ann Biomed Eng. 2003;31(10):1143-1152.

35. Demirkan F, Colakoglu N, Herek O, Erkula G. The use of amniotic membrane in flexor tendon repair: an experimental model. Arch Orthop Trauma Surg. 2002;122(7):396-369.

36. Ozgenel GY. The effects of a combination of hyaluronic and amniotic membrane on the formation of peritendinous adhesions after flexor tendon surgery in chickens. J Bone Joint Surg Br. 2004;86(2):301-307.

37. Kim SS, Sohn SK, Lee KY, Lee MJ, Roh MS, Kim CH. Use of human amniotic membrane wrap in reducing perineural adhesions in a rabbit model of ulnar nerve neurorrhaphy. J Hand Surg Eur Vol. 2010;35(3):214-219.

38. Tao H, Fan H. Implantation of amniotic membrane to reduce postlaminectomy epidural adhesions. Eur Spine J. 2009;18(8):1202-1212.

39. Choi HJ, Kim KB, Kwon YM. Effect of amniotic membrane to reduce postlaminectomy epidural adhesion on a rat model. J Korean Neurosurg Soc. 2011;49(6):323-328.

40. Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993-1004.

41. Vines JB, Aliprantis AO, Gomoll AH, Farr J. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. 2016;29(6):443-450.

42. Zelen CM. An evaluation of dehydrated human amniotic membrane allografts in patients with DFUs. J Wound Care. 2013;22(7):347-348,350-351.

43. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.

44. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014;11(2):122-128.

45. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135-146.

46. Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis: a feasibility study. Foot Ankle Int. 2013;34(10):1332-1339.

47. Hanselman AE, Tidwell JE, Santrock RD. Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study. Foot Ankle Int. 2015;36(2):151-158.

48. Jay RM. Initial clinical experience with the use of human amniotic membrane tissue during repair of posterior tibial and achilles tendons. 2009. http://encompassbiologics.com/wp-content/uploads/2015/07/DrJayClinicalExperience.pdf. Accessed September 29, 2016.

49. DeMill SL, Granata JD, McAlister JE, Berlet GC, Hyer CF. Safety analysis of cryopreserved amniotic membrane/umbilical cord tissue in foot and ankle surgery: a consecutive case series of 124 patients. Surg Technol Int. 2014;25:257-261.

50. Warner M, Lasyone L. An open-label, single-center, retrospective study of cryopreserved amniotic membrane and umbilical cord tissue as an adjunct for foot and ankle surgery. Surg Technol Int. 2014;25:251-255.

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Allografts for Ligament Reconstruction: Where Are We Now?

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Allografts for Ligament Reconstruction: Where Are We Now?
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Frank B. Wydra
MD; Philip J. York
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Musculoskeletal allografts are becoming increasingly accepted as a viable alternative to autografts in a variety of orthopedic procedures. A 2006 American Orthopaedic Society for Sports Medicine (AOSSM) survey indicated that 86% of the participating 365 orthopedic surgeons use allografts in their practice.1 Although the overwhelming majority of orthopedic surgeons use allografts, they share common concerns, including safety, tissue integrity, and biologic incorporation. It is essential for the orthopedic surgeon to understand the current standards of tissue banking, risks and benefits related to the use of allografts, and common indications for safe use in clinical practice. This article reviews the current status of musculoskeletal allografts, including tissue procurement and processing, infections, complications, and specific uses tailored to ligament reconstruction.

Donor Bank, Processing, Sterilization, and Regulation

In the United States, the American Association of Tissue Banks (AATB) is responsible for establishing the standards for more than 100 accredited tissue banks. These tissue banks recover tissue from approximately 30,000 donors annually and account for an estimated 90% of the available musculoskeletal allografts used in the United States. While not all tissue banks are accredited by the AATB, all are required to register with the Food and Drug Administration (FDA), which allows for unannounced inspections of any facility. Facilities are required to abide by the FDA-implemented Current Good Tissue Practices (CGTP), which encompasses regulations on all donor tissue collected after May 2005 to help prevent the transmission of communicable diseases. The FDA released an updated draft in January 2009 that emphasizes safe practices and regulations spanning from environmental control to specific equipment.2

The safety of a transplanted allograft tissue begins within the tissue bank. Donor screening and testing is the first step in reducing the risk of transmission. Screening consists of collecting medical and social history from the family and any healthcare resources to assess the eligibility of the donor. If prior blood donations or autopsy information is available, that information is scrutinized. Donor tissue undergoes nucleic acid testing (NAT), which is required by both the AATB and FDA. All donor tissue must be screened for both types of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), treponema pallidum, and human transmissible spongiform encephalopathies.3 NAT of donor tissue effectively reduces the risk of viral transmission. Additionally, routine preprocessing swabs for bacterial and fungal cultures are performed, although the sensitivity of these cultures ranges from 78% to 92%.4

After donor screening and testing, allograft tissues are usually obtained under aseptic conditions, though this is not FDA-required.5 Once procured, the tissue undergoes sterilization. Currently, there is no standard method ubiquitous to all tissue banks, nor does the FDA require a specific method. Rather, the FDA and AATB require tissue banks to validate their sterilization process and provide supporting data. The goal of sterilization is to inactivate viruses and eradicate bacteria while maintaining the biological and mechanical properties of the tissue. The AATB requires a Sterility Assurance Level (SAL) of 10-6, meaning there is no more than one in a million chance that a nonviral viable microbe exists on or within the tissue. Sterilization techniques may include both radiation and a variety of chemical reagents. Gamma irradiation is a commonly used method of sterilizing soft tissue allografts, although some studies indicate that it is detrimental to tissue biology.6 Newer methods of sterilization are being tested, one of which includes carbon dioxide in combination with antioxidants and irradiation. Bui and colleagues7 directly compared the biomechanical and histological properties of allograft tissue after either the standard 25 kGy gamma irradiation or supercritical carbon dioxide techniques. Although there is no histological difference, the samples treated with supercritical carbon dioxide had less biomechanical damage.7 Finally, the terminally sterilized allograft tissue is frozen to temperatures between -40°C and -80°C.5

Infections

One major concern of allografts is the risk of disease transmission. While numerous studies have investigated the incidence of bacterial infection following transplantation of allograft tissue, there are challenges associated with differentiating common postoperative infections from ones directly associated with the transmission of bacteria within the graft. There is a wide array of reported incidences of infection in the literature, from the Tomford and colleagues8 1981 study that reported a 6.9% rateto the 2001 study by Munting and colleagues,9 who reported 0% in their series. Multiple confounding variables exist, such as possible contamination during handling of an otherwise noncontaminated or properly sterilized allograft with inappropriate inclusion of all postoperative infections. In contrast, recognizing viral transmission has been somewhat easier, although reporting of these incidences has been variable in the past. In either case, there is no accredited reporting system for infections related to allografts.

 

 

Bacterial Transmission

Clostridium species. Clostridium species are commonly found among intestinal flora. There is a general consensus that between 24 to 48 hours after death intestinal flora transmigrates into the surrounding tissue and blood. Therefore, a commonly accepted recommendation is that cadaveric tissue needs to be excised prior to 24 hours postmortem.10

In 2001, a 23-year-old man underwent reconstructive knee surgery with a femoral condyle allograft. A few days after surgery, he became septic and ultimately died from the infection. Clostridium sordellii was cultured from the tissue. Several days later, a 17-year-old boy underwent reconstructive knee surgery with a fresh femoral condyle and frozen meniscus from the same donor. Twenty-four hours after surgery, he developed a fever and was readmitted a week later for presumed infection and treated effectively with penicillin and ampicillin/sulbactam. Tissue from the same cadaveric donor had been transplanted into 7 other patients without reports of infection. In a 2002 Centers for Disease Control and Prevention (CDC) update report,11 there were 26 total bacterial cases from allografts and 13 cases were attributed to Clostridium. Malinin and colleagues10 reviewed 795 consecutive cadaveric donors and found that 64 (8.1%) had positive cultures for Clostridia. Of all the positive cultures for Clostridia, 81.3% had positive blood cultures, 57.8% had positive bone marrow aspirate cultures, and 46.9% had positive tissue cultures. They concluded that multiple cultures are required for cadaveric tissue donors in order to reach a higher sensitivity for Clostridial contamination, and these should be done routinely to guide the sterilization process.

Strep species. In 2003, a 17-year-old boy underwent anterior cruciate ligament (ACL) reconstruction with a patellar tendon allograft.12 About 1 week later, he was admitted for signs of infection and received intravenous antibiotics. He required surgical debridement, and intraoperative cultures grew Group A Streptococcus (GAS) that was also identified in the postmortem donor cultures. The tissues underwent processing in an antimicrobial solution and postprocessing cultures were negative for bacteria, but they were not sterilized. Tissues from this donor had been implanted in 5 other patients without report of infection. Following this event, recommendations have been made for prompt rejection of tissue with cultures positive for GAS, unless a sterilizing procedure is used.

Other bacteria. According to the 2002 CDC update, 11 of the 26 cases of bacterial infection reported to the agency were a combination of gram-negative bacilli, polymicrobial flora, or culture negative.11

Viral Transmission

The most effective way to prevent transmission of a viral disease from allografts is thorough donor screening. Since the AATB implemented NAT in 2005 for HIV and HCV, there have been no reported cases of transmission.3 Even prior to this, regular blood screening along with social questionnaires completed by donors or donor families eliminated high-risk donors and significantly decreased the rate of transmission.

Human Immunodeficiency Virus. The first reported case of HIV transmission via implantation of allograft was in 1988. Further investigation revealed that there were 8 transmissions between 1984 and 1986, when routine screening of donors had not yet been implemented. The last reported case of HIV transmission occurred in 1996 with an untested donor.13Hepatitis C Virus. There are several reported cases of HCV transmission that occurred where the donors initially tested negative for HCV. In one case, 40 allografts from the same donor were transplanted over a period of nearly 2 years. This resulted in at least 8 patients being infected with HCV.14 Another case of HCV transmission was reported in 2005 after a patient developed acute HCV 6 weeks after transplantation of a patellar tendon allograft. Further investigation revealed that there had been 3 additional cases over a year from the same donor. Researchers determined that if the initial case had been reported, at least 3 transmissions could have been prevented.15Human T-cell Lymphotropic Virus (HTLV).The first reported transmission of HTLV was in 1991. This was reported in an asymptomatic patient who received a femoral head allograft from a donor who had been previously infected via a blood transfusion.16Zika virus. With recent outbreaks of the Zika virus, the FDA recently released recommendations regarding the screening and deferral of donors, mainly for blood transfusion. Orthopedists should take into consideration the potential for transmission through allografts. The FDA states that all potential donors should be screened for Zika virus using questionnaires and whole blood tests. Symptomatic donors are deferred at least 4 weeks following resolution of symptoms. While this is a recent recommendation from the FDA, orthopedists must be cognizant of the potential harms from this unfamiliar and evolving situation.17

Graft Specifics

Anterior Cruciate Ligament

ACL reconstruction is one of the most commonly performed surgeries by orthopedic surgeons, with an estimated 200,000 reconstructions per year.18Despite the popularity of this surgery, controversies remain regarding the optimal graft for reconstruction.19,20 One would provide adequate strength, be readily available, not elicit an immunologic response from the host, rapidly incorporate, elicit low morbidity, and vascularize early. Current options include both autografts and allografts. Common autograft options include patellar bone-tendon-bone (PBTB), hamstrings tendon, quadriceps tendon, and iliotibial band. PBTB autograft remains a common choice among orthopedic surgeons, as it allows early incorporation of the graft into bone and eliminates immune rejection. However, donor site morbidity, including anterior knee pain, weakness of knee extension, joint stiffness, increased postoperative pain, and iatrogenic patella fractures, have been reported in the literature.21 Commonly used allograft options include donor bone-patellar tendon-bone, quadriceps tendon, Achilles tendon, anterior and posterior tibialis tendons, hamstring tendons, and iliotibial band. Allografts provide the advantage of avoiding donor site morbidity, being readily available, allowing for shorter operative times, and providing lower postoperative pain compared to autografts, although they carry the risk of disease transmission, rejection, and slower incorporation into bone.22-27

 

 

Autograft donor site morbidities. One of the general disadvantages of autografts is the donor site morbidity associated with harvesting the grafts. In specific, PBTB grafts allow for bony blocks on both ends of the graft to incorporate into the host bone. However, this technique comes with the risk of disrupting the extensor mechanism.28,29 Milankov and colleagues30 published a retrospective review of over 2000 ACLs using autologous PBTB graft. They noted a 0.45% incidence of patella fracture and 0.18% patellar tendon rupture.30 Others have reported that intraoperative repair of the patellar tendon after tendon harvesting can increase infrapatellar fibrosis, thus increasing the risk for stiffness.31-33

Hamstring autografts include the semitendinosus and the gracilis tendons. The harvesting process is technically demanding and can be complicated by inadvertent amputation of the tendons, making the graft unsuitable for reconstructive purposes.34 Additionally, several reports have identified persistent numbness and hyperesthesia following hamstring harvesting due to iatrogenic injury to the prepatellar branches of the saphenous nerve.35,36A comprehensive review by Slone and colleagues37 reported comparable functional outcomes with quadriceps tendon autograft compared to PBTB; however, this comes with the risk of postoperative hematoma formation and the potential for thigh compartment syndrome.

Biology and Biomechanics of Allografts

One of the major disadvantages of allografts is the reduced ability to incorporate into the host tissue. Several in vitro and animal studies have suggested that allografts incorporate in the host slower than autografts.24,26,38 Early studies by Jackson and colleagues24 on goat models demonstrated that allografts and autografts have similar structural and biological properties initially, but allografts display significantly slower incorporation into the host tissue at 6 months. Histologically, allografts demonstrated lower revascularization, a smaller cross-sectional area, and a prolonged inflammatory response at 6 months postoperatively.24,39,40 Muramatsu and colleagues41 further showed through the use of magnetic resonance imaging a slower rate of revascularization of allografts over 2 years post-reconstruction.

Given the delayed biologic incorporation of allografts, studies have identified a lower strength-to-failure rate in the early postoperative period compared to autografts. An animal model study by Nikolaou and colleagues38 showed that the strength of allografts was lower for up to 2 years following surgery. Additional biomechanical studies demonstrated that allografts were nearly 75% structurally weaker compared to autografts at 1 year following surgery.42

Acknowledging these limitations, one should use caution when choosing to use an allograft or starting aggressive early rehabilitation after an allograft reconstruction, especially in athletes and young patients.

Clinical Outcomes

Although in vitro studies demonstrate inferior strength and delayed incorporation of allografts in the early postoperative period, there is still controversy surrounding the clinical and functional outcomes. Numerous studies have identified allografts as a viable option for ACL reconstruction, with similar reported patient satisfaction scores compared to autografts.43,44

The MOON Consortium recently published a prospective study of nearly 2500 subjects looking to identify risk factors for failure of ACL reconstruction. The study found that allografts had an odds ratio for failure 5.2 times that of PBTB autografts, correlating this factor to an increased re-tear rate of 6.9% in the allograft group compared to 3.2% in the PBTB group (P < .01).45 The elevated risk is more prevalent in younger patients, especially athletic teenagers. This issue has been reiterated in multiple studies.45-50A meta-analysis by Hu and colleagues23 identified 9 studies, either randomized control trials or prospective cohort studies, that looked at clinical outcomes between the different graft choices. They showed there was no significant difference between graft options in terms of instrumental laxity (P = .59), Lachman test (P = .41), pivot shift test (P = .88), and multiple functional outcome scores, including the International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores.23,51-59Processing and sterilization techniques are thought to play a role in allograft failure. Guo and other researchers have demonstrated a significantly higher rate of failure for patients who received gamma-irradiated allografts compared to fresh frozen allografts.23,58-64 With improved sterilization techniques and a strict selection process of donors, gamma radiation has fallen out of favor to protect the biological characteristics of the tissue graft.5,65,66Several factors need to be considered when selecting between allograft or autograft tissue for ligamentous reconstruction. The selection must be balanced between the surgeon’s experience, patient and surgeon preferences, age of the patient, level of physical activity, primary or revision surgical setting, multiligamentous failure, geographical availability of donor grafts, and economical factors.

Medial Patellofemoral Ligament Reconstruction

Another relatively recent application for allografts has been described for the reconstruction of the medial patellofemoral ligament (MPFL) in recurrent lateral patellar dislocations.67-74

Typically, MPFL reconstructions make use of autografts, including quadriceps tendon, patellar tendon, and hamstring ligaments. However, allografts have the potential to limit postoperative donor site morbidity and to allow a faster rehabilitation.75,76 Allografts include semitendinosus, gracilis, anterior tibialis, posterior tibialis, and quadriceps tendons.

Calvo Rodríguez and colleagues76 performed a retrospective review in 2015 comparing allografts to autografts for MPFL reconstruction with respect to postoperative knee function and re-dislocation rates. Among the collective 28 patients, there was no difference in overall functional scores or dislocation rates between the grafts. Although this was a retrospective review and had a small number of subjects, the findings identify allografts as a reliable graft option for MPFL reconstruction.76While there has been a surge of interest in techniques for MPFL reconstruction, there is limited research available regarding the superiority of allografts compared to autografts. For this specific application, it seems that clinical outcomes correlate more to adequate stabilization of the patellofemoral joint than to the type of graft used.77,78 Future research should be dedicated to prospective randomized control trials to delineate any disadvantages to using allografts for MPFL reconstruction.

 

 

Discussion

Musculoskeletal allografts are gaining popularity for ligamentous reconstruction as their safety and efficacy continue to improve. With the great majority of tissue banks being accredited by the AATB and specific regulations such as NAT screening becoming common practice, infection rates and transmission of diseases have become incredibly rare. However, a thorough consideration needs to be taken into account when choosing between autograft and allograft on a case-by-case basis (Table).

Although the incidence of donor site complications is low with autografts, there are inherent risks, such as harvest site hyperesthesia, persistent numbness, cosmetic dissatisfaction, pain, weakness, functional implications, and unsuitability of the harvested graft. While it may appear that allografts may obviate donor site morbidity, one must consider the reduced potential for the donor tissue to incorporate into the host. Several studies have suggested that incorporation into the host tissue is inferior and slower for allografts. With this knowledge, factors such as clinical outcomes, future expectations, rehabilitation protocol, and individual patient characteristics all need to be considered when selecting the source of the tissue to be transplanted. Given that there is a growing need for availability of allografts, a well-rounded understanding of the biologic and physiologic aspects of the transplanted tissues is imperative. Future research will need to focus on improving the rate and quality of the biological incorporation of the transplanted graft into the host while eliminating the risk of disease transmission and infection.

Am J Orthop. 2016;45(7):446-453. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

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2. US Department of Health and Human Services, Food and Drug Administration. Guidance for industry: Current good tissue practice (CGTP) and additional requirements for manufacturers of human cells, tissues, and cellular and tissue-based products (HCT/Ps). http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM285223.pdf. Published December 2011. Accessed August 17, 2015.

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4. Veen MR, Bloem RM, Petit PL. Sensitivity and negative predictive value of swab cultures in musculoskeletal allograft procurement. Clin Orthop Relat Res. 1994;(300):259-263.

5. McAllister DR, Joyce MJ, Mann BJ, Vangsness CT Jr. Allograft update: the current status of tissue regulation, procurement, processing, and sterilization. Am J Sports Med. 2007;35(12):2148-2158.

6. Mickiewicz P, Binkowski M, Bursig H, Wróbel Z. Preservation and sterilization methods of the meniscal allografts: literature review. Cell Tissue Bank. 2014;15(3):307-317.

7. Bui D, Lovric V, Oliver R, Bertollo N, Broe D, Walsh WR. Meniscal allograft sterilisation: effect on biomechanical and histological properties. Cell Tissue Bank. 2015;16(3):467-475.

8. Tomford WW, Starkweather RJ, Goldman MH. A study of the clinical incidence of infection in the use of banked allograft bone. J Bone Joint Surg Am. 1981;63(2):244-248.

9. Munting E, Faundez A, Manche E. Vertebral reconstruction with cortical allograft: long-term evaluation. Eur Spine J. 2001;10 Suppl 2:S153-S157.

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11. Centers for Disease Control and Prevention (CDC). Update: allograft-associated bacterial infections--United States, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(10):207-210.

12. Centers for Disease Control and Prevention (CDC). Invasive Streptococcus pyogenes after allograft implantation--Colorado, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(48):1174-1176.

13. Hinsenkamp M, Muylle L, Eastlund T, Fehily D, Noël L, Strong DM. Adverse reactions and events related to musculoskeletal allografts: reviewed by the World Health Organisation project NOTIFY. Int Orthop. 2012;36(3):633-641.

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15. Tugwell BD, Patel PR, Williams IT, et al. Transmission of hepatitis C virus to several organ and tissue recipients from an antibody-negative donor. Ann Intern Med. 2005;143(9):648-654.

16. Sanzén L, Carlsson A. Transmission of human T-cell lymphotrophic virus type 1 by a deep-frozen bone allograft. Acta Orthop Scand. 1997;68(1):72-74.

17. US Department of Health and Human Services, Food and Drug Administration. Recommendations for donor screening, deferral, and product management to reduce the risk of transfusion-transmission of Zika virus. Guidance for industry. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM486360.pdf. Published February 2016. Accessed August 10, 2016.

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19. Fu F, Christel P, Miller MD, Johnson DL. Graft selection for anterior cruciate ligament reconstruction. Instr Course Lect. 2009;58:337-354.

20. Chechik O, Amar E, Khashan M, Lador R, Eyal G, Gold A. An international survey on anterior cruciate ligament reconstruction practices. Int Orthop. 2013;37(2):201-206.

21. Spindler KP, Kuhn JE, Freedman KB, Matthews CE, Dittus RS, Harrell FE Jr. Anterior cruciate ligament reconstruction autograft choice: bone-tendon-bone versus hamstring: does it really matter? A systematic review. Am J Sports Med. 2004;32(8):1986-1995.

22. Harner CD, Irrgang JJ, Paul J, Dearwater S, Fu FH. Loss of motion after anterior cruciate ligament reconstruction. Am J Sports Med. 1992;20(5):499-506.

23. Hu J, Qu J, Xu D, Zhou J, Lu H. Allograft versus autograft for anterior cruciate ligament reconstruction: an up-to-date meta-analysis of prospective studies. Int Orthop. 2013;37(2):311-320.

24. Jackson DW, Grood ES, Goldstein JD, et al. A comparison of patellar tendon autograft and allograft used for anterior cruciate ligament reconstruction in the goat model. Am J Sports Med. 1993;21(2):176-185.

25. Mroz TE, Joyce MJ, Steinmetz MP, Lieberman IH, Wang JC. Musculoskeletal allograft risks and recalls in the United States. J Am Acad Orthop Surg. 2008;16(10):559-565.

26. Malinin TI, Levitt RL, Bashore C, Temple HT, Mnaymneh W. A study of retrieved allografts used to replace anterior cruciate ligaments. Arthroscopy. 2002;18(2):163-170.

27. Foster TE, Wolfe BL, Ryan S, Silvestri L, Kaye EK. Does the graft source really matter in the outcome of patients undergoing anterior cruciate ligament reconstruction? An evaluation of autograft versus allograft reconstruction results: a systematic review. Am J Sports Med. 2010;38(1):189-199.

28. Lee GH, McCulloch P, Cole BJ, Bush-Joseph CA, Bach BR Jr. The incidence of acute patellar tendon harvest complications for anterior cruciate ligament reconstruction. Arthroscopy. 2008;24(2):162-166.

29. Marumoto JM, Mitsunaga MM, Richardson AB, Medoff RJ, Mayfield GW. Late patellar tendon ruptures after removal of the central third for anterior cruciate ligament reconstruction. A report of two cases. Am J Sports Med. 1996;24(5):698-701.

30 Milankov M, Kecojević V, Rasović P, Kovacević N, Gvozdenović N, Obradović M. Disruption of the knee extensor apparatus complicating anterior cruciate ligament reconstruction. Acta Chir Iugosl. 2013;60(2):13-21.

31. Atkinson TS, Atkinson PJ, Mendenhall HV, Haut RC. Patellar tendon and infrapatellar fat pad healing after harvest of an ACL graft. J Surg Res. 1998;79(1):25-30.

32. Tang G, Niitsu M, Ikeda K, Endo H, Itai Y. Fibrous scar in the infrapatellar fat pad after arthroscopy: MR imaging. Radiat Med. 2000;18(1):1-5.

33. Unterhauser FN, Bosch U, Zeichen J, Weiler A. Alpha-smooth muscle actin containing contractile fibroblastic cells in human knee arthrofibrosis tissue. Winner of the AGA-DonJoy Award 2003. Arch Orthop Trauma Surg. 2004;124(9):585-591.

34. Prodromos CC, Fu FH, Howell SM, Johnson DH, Lawhorn K. Controversies in soft-tissue anterior cruciate ligament reconstruction: grafts, bundles, tunnels, fixation, and harvest. J Am Acad Orthop Surg. 2008;16(7):376-384.

35. Sabat D, Kumar V. Nerve injury during hamstring graft harvest: a prospective comparative study of three different incisions. Knee Surg Sports Traumatol Arthrosc. 2013;21(9):2089-2095.

36. Kjaergaard J, Faunø LZ, Faunø P. Sensibility loss after ACL reconstruction with hamstring graft. Int J Sports Med. 2008;29(6):507-511.

37. Slone HS, Romine SE, Premkumar A, Xerogeanes JW. Quadriceps tendon autograft for anterior cruciate ligament reconstruction: a comprehensive review of current literature and systematic review of clinical results. Arthroscopy. 2015;31(3):541-554.

38. Nikolaou PK, Seaber AV, Glisson RR, Ribbeck BM, Bassett FH 3rd. Anterior cruciate ligament allograft transplantation. Long-term function, histology, revascularization, and operative technique. Am J Sports Med. 1986;14(5):348-360.

39. Arnoczky SP, Warren RF, Ashlock MA. Replacement of the anterior cruciate ligament using a patellar tendon allograft. An experimental study. J Bone Joint Surg Am. 1986;68(3):376-385.

40. Scheffler SU, Schmidt T, Gangéy I, Dustmann M, Unterhauser F, Weiler A. Fresh-frozen free-tendon allografts versus autografts in anterior cruciate ligament reconstruction: delayed remodeling and inferior mechanical function during long-term healing in sheep. Arthroscopy. 2008;24(4):448-458.

41. Muramatsu K, Hachiya Y, Izawa H. Serial evaluation of human anterior cruciate ligament grafts by contrast-enhanced magnetic resonance imaging: comparison of allografts and autografts. Arthroscopy. 2008;24(9):1038-1044.

42. Jackson DW, Grood ES, Arnoczky SP, Butler DL, Simon TM. Freeze dried anterior cruciate ligament allografts. Preliminary studies in a goat model. Am J Sports Med. 1987;15(4):295-303.

43. Chang SK, Egami DK, Shaieb MD, Kan DM, Richardson AB. Anterior cruciate ligament reconstruction: allograft versus autograft. Arthroscopy. 2003;19(5):453-462.

44. Poehling GG, Curl WW, Lee CA, et al. Analysis of outcomes of anterior cruciate ligament repair with 5-year follow-up: allograft versus autograft. Arthroscopy. 2005;21(7):774-785.

45. Kaeding CC, Pedroza AD, Reinke EK, Huston LJ; MOON Consortium, Spindler KP. Risk factors and predictors of subsequent ACL injury in either knee after ACL reconstruction: prospective analysis of 2488 primary ACL reconstructions from the MOON cohort. Am J Sports Med. 2015;43(7):1583-1590.

46. Kaeding CC, Aros B, Pedroza A, et al. Allograft versus autograft anterior cruciate ligament reconstruction: predictors of failure from a MOON prospective longitudinal cohort. Sports Health. 2011;3(1):73-81.

47. Lynch TS, Parker RD, Patel RM, et al. The impact of the Multicenter Orthopaedic Outcomes Network (MOON) research on anterior cruciate ligament reconstruction and orthopaedic practice. J Am Acad Orthop Surg. 2015;23(3):154-163.

48. Hettrich CM, Dunn WR, Reinke EK; MOON Group, Spindler KP. The rate of subsequent surgery and predictors after anterior cruciate ligament reconstruction: two- and 6-year follow-up results from a multicenter cohort. Am J Sports Med. 2013;41(7):1534-1540.

49. Steadman JR, Matheny LM, Hurst JM, Briggs KK. Patient-centered outcomes and revision rate in patients undergoing ACL reconstruction using bone-patellar tendon-bone autograft compared with bone-patellar tendon-bone allograft: a matched case-control study. Arthroscopy. 2015;31(12):2320-2326.

50. Lenehan EA, Payne WB, Askam BM, Grana WA, Farrow LD. Long-term outcomes of allograft reconstruction of the anterior cruciate ligament. Am J Orthop. 2015;44(5):217-222.

51. Noh JH, Yi SR, Song SJ, Kim SW, Kim W. Comparison between hamstring autograft and free tendon achilles allograft: minimum 2-year follow-up after anterior cruciate ligament reconstruction using EndoButton and Intrafix. Knee Surg Sports Traumatol Arthrosc. 2011;19(5):816-822.

52. Victor J, Bellemans J, Witvrouw E, Govaers K, Fabry G. Graft selection in anterior cruciate ligament reconstruction--prospective analysis of patellar tendon autografts compared with allografts. Int Orthop. 1997;21(2):93-97.

53. Kleipool AE, Zijl JA, Willems WJ. Arthroscopic anterior cruciate ligament reconstruction with bone-patellar tendon-bone allograft or autograft. A prospective study with an average follow up of 4 years. Knee Surg Sports Traumatol Arthrosc. 1998;6(4):224-230.

54. Peterson RK, Shelton WR, Bomboy AL. Allograft versus autograft patellar tendon anterior cruciate ligament reconstruction: a 5-year follow-up. Arthroscopy. 2001;17(1):9-13.

55. Edgar CM, Zimmer S, Kakar S, Jones H, Schepsis AA. Prospective comparison of auto and allograft hamstring tendon constructs for ACL reconstruction. Clin Orthop Relat Res. 2008;466(9):2238-2246.

56. Sun K, Tian S, Zhang J, Xia C, Zhang C, Yu T. Anterior cruciate ligament reconstruction with BPTB autograft, irradiated versus non-irradiated allograft: a prospective randomized clinical study. Knee Surg Sports Traumatol Arthrosc. 2009;17(5):464-474.

57. Leal-Blanquet J, Alentorn-Geli E, Tuneu J, Valentí JR, Maestro A. Anterior cruciate ligament reconstruction: a multicenter prospective cohort study evaluating 3 different grafts using same bone drilling method. Clin J Sport Med. 2011;21(4):294-300.

58. Sun K, Zhang J, Wang Y, et al. Arthroscopic reconstruction of the anterior cruciate ligament with hamstring tendon autograft and fresh-frozen allograft: a prospective, randomized controlled study. Am J Sports Med. 2011;39(7):1430-1438.

59. Lawhorn KW, Howell SM, Traina SM, Gottlieb JE, Meade TD, Freedberg HI. The effect of graft tissue on anterior cruciate ligament outcomes: a multicenter, prospective, randomized controlled trial comparing autograft hamstrings with fresh-frozen anterior tibialis allograft. Arthroscopy. 2012;28(8):1079-1086.

60. Guo L, Yang L, Duan XJ, et al. Anterior cruciate ligament reconstruction with bone-patellar tendon-bone graft: comparison of autograft, fresh-frozen allograft, and γ-irradiated allograft. Arthroscopy. 2012;28(2):211-217.

61. Lamblin CJ, Waterman BR, Lubowitz JH. Anterior cruciate ligament reconstruction with autografts compared with non-irradiated, non-chemically treated allografts. Arthroscopy. 2013;29(6):1113-1122.

62. Mayr HO, Willkomm D, Stoehr A, et al. Revision of anterior cruciate ligament reconstruction with patellar tendon allograft and autograft: 2- and 5-year results. Arch Orthop Trauma Surg. 2012;132(6):867-874.

63. Mariscalco MW, Magnussen RA, Mehta D, Hewett TE, Flanigan DC, Kaeding CC. Autograft versus nonirradiated allograft tissue for anterior cruciate ligament reconstruction: a systematic review. Am J Sports Med. 2014;42(2):492-499.

64. Mehta VM, Mandala C, Foster D, Petsche TS. Comparison of revision rates in bone-patella tendon-bone autograft and allograft anterior cruciate ligament reconstruction. Orthopedics. 2010;33(1):12.

65. Vangsness CT Jr, Garcia IA, Mills CR, Kainer MA, Roberts MR, Moore TM. Allograft transplantation in the knee: tissue regulation, procurement, processing, and sterilization. Am J Sports Med. 2003;31(3):474-481.

66. Barrett GR, Luber K, Replogle WH, Manley JL. Allograft anterior cruciate ligament reconstruction in the young, active patient: tegner activity level and failure rate. Arthroscopy. 2010;26(12):1593-1601.

67. Reagan J, Kullar R, Burks R. MPFL reconstruction: technique and results. Clin Sports Med. 2014;33(3):501-516.

68. Christiansen SE, Jacobsen BW, Lund B, Lind M. Reconstruction of the medial patellofemoral ligament with gracilis tendon autograft in transverse patellar drill holes. Arthroscopy. 2008;24(1):82-87.

69. Schöttle PB, Fucentese SF, Romero J. Clinical and radiological outcome of medial patellofemoral ligament reconstruction with a semitendinosus autograft for patella instability. Knee Surg Sports Traumatol Arthrosc. 2005;13(7):516-521.

70. Deie M, Ochi M, Sumen Y, Adachi N, Kobayashi K, Yasumoto M. A long-term follow-up study after medial patellofemoral ligament reconstruction using the transferred semitendinosus tendon for patellar dislocation. Knee Surg Sports Traumatol Arthrosc. 2005;13(7):522-528.

71. Nomura E, Inoue M. Hybrid medial patellofemoral ligament reconstruction using the semitendinous tendon for recurrent patellar dislocation: minimum 3 years’ follow-up. Arthroscopy. 2006;22(7):787-793.

72. Nomura E, Inoue M. Surgical technique and rationale for medial patellofemoral ligament reconstruction for recurrent patellar dislocation. Arthroscopy. 2003;19(5):E47.

73. Hautamaa PV, Fithian DC, Kaufman KR, Daniel DM, Pohlmeyer AM. Medial soft tissue restraints in lateral patellar instability and repair. Clin Orthop Relat Res. 1998;(349):174-182.

74. Drez D Jr, Edwards TB, Williams CS. Results of medial patellofemoral ligament reconstruction in the treatment of patellar dislocation. Arthroscopy. 2001;17(3):298-306.

75. Fink C, Veselko M, Herbort M, Hoser C. MPFL reconstruction using a quadriceps tendon graft: part 2: operative technique and short term clinical results. Knee. 2014;21(6):1175-1179.

76. Calvo Rodríguez R, Figueroa Poblete D, Anastasiadis Le Roy Z, Etchegaray Bascur F, Vaisman Burucker A, Calvo Mena R. Reconstruction of the medial patellofemoral ligament: evaluation of the clinical results of autografts versus allografts. Rev Esp Cir Ortop Traumatol. 2015;59(5):348-353.

77. Becher C, Kley K, Lobenhoffer P, Ezechieli M, Smith T, Ostermeier S. Dynamic versus static reconstruction of the medial patellofemoral ligament for recurrent lateral patellar dislocation. Knee Surg Sports Traumatol Arthrosc. 2014;22(10):2452-2457.

78. Gomes JE. Comparison between a static and a dynamic technique for medial patellofemoral ligament reconstruction. Arthroscopy. 2008;24(4):430-435.

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Issue
The American Journal of Orthopedics - 45(7)
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The American Journal of Orthopedics
MDedge Surgery
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Biologics
Musculoskeletal Disorders
Arthroplasty/Joint Replacement
Orthopedics
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Clinical Review
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Frank B. Wydra
MD; Philip J. York
MD; Christopher R. Johnson; Lorenzo Silvestri
MD
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Frank B. Wydra
MD; Philip J. York
MD; Christopher R. Johnson; Lorenzo Silvestri
MD
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Musculoskeletal allografts are becoming increasingly accepted as a viable alternative to autografts in a variety of orthopedic procedures. A 2006 American Orthopaedic Society for Sports Medicine (AOSSM) survey indicated that 86% of the participating 365 orthopedic surgeons use allografts in their practice.1 Although the overwhelming majority of orthopedic surgeons use allografts, they share common concerns, including safety, tissue integrity, and biologic incorporation. It is essential for the orthopedic surgeon to understand the current standards of tissue banking, risks and benefits related to the use of allografts, and common indications for safe use in clinical practice. This article reviews the current status of musculoskeletal allografts, including tissue procurement and processing, infections, complications, and specific uses tailored to ligament reconstruction.

Donor Bank, Processing, Sterilization, and Regulation

In the United States, the American Association of Tissue Banks (AATB) is responsible for establishing the standards for more than 100 accredited tissue banks. These tissue banks recover tissue from approximately 30,000 donors annually and account for an estimated 90% of the available musculoskeletal allografts used in the United States. While not all tissue banks are accredited by the AATB, all are required to register with the Food and Drug Administration (FDA), which allows for unannounced inspections of any facility. Facilities are required to abide by the FDA-implemented Current Good Tissue Practices (CGTP), which encompasses regulations on all donor tissue collected after May 2005 to help prevent the transmission of communicable diseases. The FDA released an updated draft in January 2009 that emphasizes safe practices and regulations spanning from environmental control to specific equipment.2

The safety of a transplanted allograft tissue begins within the tissue bank. Donor screening and testing is the first step in reducing the risk of transmission. Screening consists of collecting medical and social history from the family and any healthcare resources to assess the eligibility of the donor. If prior blood donations or autopsy information is available, that information is scrutinized. Donor tissue undergoes nucleic acid testing (NAT), which is required by both the AATB and FDA. All donor tissue must be screened for both types of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), treponema pallidum, and human transmissible spongiform encephalopathies.3 NAT of donor tissue effectively reduces the risk of viral transmission. Additionally, routine preprocessing swabs for bacterial and fungal cultures are performed, although the sensitivity of these cultures ranges from 78% to 92%.4

After donor screening and testing, allograft tissues are usually obtained under aseptic conditions, though this is not FDA-required.5 Once procured, the tissue undergoes sterilization. Currently, there is no standard method ubiquitous to all tissue banks, nor does the FDA require a specific method. Rather, the FDA and AATB require tissue banks to validate their sterilization process and provide supporting data. The goal of sterilization is to inactivate viruses and eradicate bacteria while maintaining the biological and mechanical properties of the tissue. The AATB requires a Sterility Assurance Level (SAL) of 10-6, meaning there is no more than one in a million chance that a nonviral viable microbe exists on or within the tissue. Sterilization techniques may include both radiation and a variety of chemical reagents. Gamma irradiation is a commonly used method of sterilizing soft tissue allografts, although some studies indicate that it is detrimental to tissue biology.6 Newer methods of sterilization are being tested, one of which includes carbon dioxide in combination with antioxidants and irradiation. Bui and colleagues7 directly compared the biomechanical and histological properties of allograft tissue after either the standard 25 kGy gamma irradiation or supercritical carbon dioxide techniques. Although there is no histological difference, the samples treated with supercritical carbon dioxide had less biomechanical damage.7 Finally, the terminally sterilized allograft tissue is frozen to temperatures between -40°C and -80°C.5

Infections

One major concern of allografts is the risk of disease transmission. While numerous studies have investigated the incidence of bacterial infection following transplantation of allograft tissue, there are challenges associated with differentiating common postoperative infections from ones directly associated with the transmission of bacteria within the graft. There is a wide array of reported incidences of infection in the literature, from the Tomford and colleagues8 1981 study that reported a 6.9% rateto the 2001 study by Munting and colleagues,9 who reported 0% in their series. Multiple confounding variables exist, such as possible contamination during handling of an otherwise noncontaminated or properly sterilized allograft with inappropriate inclusion of all postoperative infections. In contrast, recognizing viral transmission has been somewhat easier, although reporting of these incidences has been variable in the past. In either case, there is no accredited reporting system for infections related to allografts.

 

 

Bacterial Transmission

Clostridium species. Clostridium species are commonly found among intestinal flora. There is a general consensus that between 24 to 48 hours after death intestinal flora transmigrates into the surrounding tissue and blood. Therefore, a commonly accepted recommendation is that cadaveric tissue needs to be excised prior to 24 hours postmortem.10

In 2001, a 23-year-old man underwent reconstructive knee surgery with a femoral condyle allograft. A few days after surgery, he became septic and ultimately died from the infection. Clostridium sordellii was cultured from the tissue. Several days later, a 17-year-old boy underwent reconstructive knee surgery with a fresh femoral condyle and frozen meniscus from the same donor. Twenty-four hours after surgery, he developed a fever and was readmitted a week later for presumed infection and treated effectively with penicillin and ampicillin/sulbactam. Tissue from the same cadaveric donor had been transplanted into 7 other patients without reports of infection. In a 2002 Centers for Disease Control and Prevention (CDC) update report,11 there were 26 total bacterial cases from allografts and 13 cases were attributed to Clostridium. Malinin and colleagues10 reviewed 795 consecutive cadaveric donors and found that 64 (8.1%) had positive cultures for Clostridia. Of all the positive cultures for Clostridia, 81.3% had positive blood cultures, 57.8% had positive bone marrow aspirate cultures, and 46.9% had positive tissue cultures. They concluded that multiple cultures are required for cadaveric tissue donors in order to reach a higher sensitivity for Clostridial contamination, and these should be done routinely to guide the sterilization process.

Strep species. In 2003, a 17-year-old boy underwent anterior cruciate ligament (ACL) reconstruction with a patellar tendon allograft.12 About 1 week later, he was admitted for signs of infection and received intravenous antibiotics. He required surgical debridement, and intraoperative cultures grew Group A Streptococcus (GAS) that was also identified in the postmortem donor cultures. The tissues underwent processing in an antimicrobial solution and postprocessing cultures were negative for bacteria, but they were not sterilized. Tissues from this donor had been implanted in 5 other patients without report of infection. Following this event, recommendations have been made for prompt rejection of tissue with cultures positive for GAS, unless a sterilizing procedure is used.

Other bacteria. According to the 2002 CDC update, 11 of the 26 cases of bacterial infection reported to the agency were a combination of gram-negative bacilli, polymicrobial flora, or culture negative.11

Viral Transmission

The most effective way to prevent transmission of a viral disease from allografts is thorough donor screening. Since the AATB implemented NAT in 2005 for HIV and HCV, there have been no reported cases of transmission.3 Even prior to this, regular blood screening along with social questionnaires completed by donors or donor families eliminated high-risk donors and significantly decreased the rate of transmission.

Human Immunodeficiency Virus. The first reported case of HIV transmission via implantation of allograft was in 1988. Further investigation revealed that there were 8 transmissions between 1984 and 1986, when routine screening of donors had not yet been implemented. The last reported case of HIV transmission occurred in 1996 with an untested donor.13Hepatitis C Virus. There are several reported cases of HCV transmission that occurred where the donors initially tested negative for HCV. In one case, 40 allografts from the same donor were transplanted over a period of nearly 2 years. This resulted in at least 8 patients being infected with HCV.14 Another case of HCV transmission was reported in 2005 after a patient developed acute HCV 6 weeks after transplantation of a patellar tendon allograft. Further investigation revealed that there had been 3 additional cases over a year from the same donor. Researchers determined that if the initial case had been reported, at least 3 transmissions could have been prevented.15Human T-cell Lymphotropic Virus (HTLV).The first reported transmission of HTLV was in 1991. This was reported in an asymptomatic patient who received a femoral head allograft from a donor who had been previously infected via a blood transfusion.16Zika virus. With recent outbreaks of the Zika virus, the FDA recently released recommendations regarding the screening and deferral of donors, mainly for blood transfusion. Orthopedists should take into consideration the potential for transmission through allografts. The FDA states that all potential donors should be screened for Zika virus using questionnaires and whole blood tests. Symptomatic donors are deferred at least 4 weeks following resolution of symptoms. While this is a recent recommendation from the FDA, orthopedists must be cognizant of the potential harms from this unfamiliar and evolving situation.17

Graft Specifics

Anterior Cruciate Ligament

ACL reconstruction is one of the most commonly performed surgeries by orthopedic surgeons, with an estimated 200,000 reconstructions per year.18Despite the popularity of this surgery, controversies remain regarding the optimal graft for reconstruction.19,20 One would provide adequate strength, be readily available, not elicit an immunologic response from the host, rapidly incorporate, elicit low morbidity, and vascularize early. Current options include both autografts and allografts. Common autograft options include patellar bone-tendon-bone (PBTB), hamstrings tendon, quadriceps tendon, and iliotibial band. PBTB autograft remains a common choice among orthopedic surgeons, as it allows early incorporation of the graft into bone and eliminates immune rejection. However, donor site morbidity, including anterior knee pain, weakness of knee extension, joint stiffness, increased postoperative pain, and iatrogenic patella fractures, have been reported in the literature.21 Commonly used allograft options include donor bone-patellar tendon-bone, quadriceps tendon, Achilles tendon, anterior and posterior tibialis tendons, hamstring tendons, and iliotibial band. Allografts provide the advantage of avoiding donor site morbidity, being readily available, allowing for shorter operative times, and providing lower postoperative pain compared to autografts, although they carry the risk of disease transmission, rejection, and slower incorporation into bone.22-27

 

 

Autograft donor site morbidities. One of the general disadvantages of autografts is the donor site morbidity associated with harvesting the grafts. In specific, PBTB grafts allow for bony blocks on both ends of the graft to incorporate into the host bone. However, this technique comes with the risk of disrupting the extensor mechanism.28,29 Milankov and colleagues30 published a retrospective review of over 2000 ACLs using autologous PBTB graft. They noted a 0.45% incidence of patella fracture and 0.18% patellar tendon rupture.30 Others have reported that intraoperative repair of the patellar tendon after tendon harvesting can increase infrapatellar fibrosis, thus increasing the risk for stiffness.31-33

Hamstring autografts include the semitendinosus and the gracilis tendons. The harvesting process is technically demanding and can be complicated by inadvertent amputation of the tendons, making the graft unsuitable for reconstructive purposes.34 Additionally, several reports have identified persistent numbness and hyperesthesia following hamstring harvesting due to iatrogenic injury to the prepatellar branches of the saphenous nerve.35,36A comprehensive review by Slone and colleagues37 reported comparable functional outcomes with quadriceps tendon autograft compared to PBTB; however, this comes with the risk of postoperative hematoma formation and the potential for thigh compartment syndrome.

Biology and Biomechanics of Allografts

One of the major disadvantages of allografts is the reduced ability to incorporate into the host tissue. Several in vitro and animal studies have suggested that allografts incorporate in the host slower than autografts.24,26,38 Early studies by Jackson and colleagues24 on goat models demonstrated that allografts and autografts have similar structural and biological properties initially, but allografts display significantly slower incorporation into the host tissue at 6 months. Histologically, allografts demonstrated lower revascularization, a smaller cross-sectional area, and a prolonged inflammatory response at 6 months postoperatively.24,39,40 Muramatsu and colleagues41 further showed through the use of magnetic resonance imaging a slower rate of revascularization of allografts over 2 years post-reconstruction.

Given the delayed biologic incorporation of allografts, studies have identified a lower strength-to-failure rate in the early postoperative period compared to autografts. An animal model study by Nikolaou and colleagues38 showed that the strength of allografts was lower for up to 2 years following surgery. Additional biomechanical studies demonstrated that allografts were nearly 75% structurally weaker compared to autografts at 1 year following surgery.42

Acknowledging these limitations, one should use caution when choosing to use an allograft or starting aggressive early rehabilitation after an allograft reconstruction, especially in athletes and young patients.

Clinical Outcomes

Although in vitro studies demonstrate inferior strength and delayed incorporation of allografts in the early postoperative period, there is still controversy surrounding the clinical and functional outcomes. Numerous studies have identified allografts as a viable option for ACL reconstruction, with similar reported patient satisfaction scores compared to autografts.43,44

The MOON Consortium recently published a prospective study of nearly 2500 subjects looking to identify risk factors for failure of ACL reconstruction. The study found that allografts had an odds ratio for failure 5.2 times that of PBTB autografts, correlating this factor to an increased re-tear rate of 6.9% in the allograft group compared to 3.2% in the PBTB group (P < .01).45 The elevated risk is more prevalent in younger patients, especially athletic teenagers. This issue has been reiterated in multiple studies.45-50A meta-analysis by Hu and colleagues23 identified 9 studies, either randomized control trials or prospective cohort studies, that looked at clinical outcomes between the different graft choices. They showed there was no significant difference between graft options in terms of instrumental laxity (P = .59), Lachman test (P = .41), pivot shift test (P = .88), and multiple functional outcome scores, including the International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores.23,51-59Processing and sterilization techniques are thought to play a role in allograft failure. Guo and other researchers have demonstrated a significantly higher rate of failure for patients who received gamma-irradiated allografts compared to fresh frozen allografts.23,58-64 With improved sterilization techniques and a strict selection process of donors, gamma radiation has fallen out of favor to protect the biological characteristics of the tissue graft.5,65,66Several factors need to be considered when selecting between allograft or autograft tissue for ligamentous reconstruction. The selection must be balanced between the surgeon’s experience, patient and surgeon preferences, age of the patient, level of physical activity, primary or revision surgical setting, multiligamentous failure, geographical availability of donor grafts, and economical factors.

Medial Patellofemoral Ligament Reconstruction

Another relatively recent application for allografts has been described for the reconstruction of the medial patellofemoral ligament (MPFL) in recurrent lateral patellar dislocations.67-74

Typically, MPFL reconstructions make use of autografts, including quadriceps tendon, patellar tendon, and hamstring ligaments. However, allografts have the potential to limit postoperative donor site morbidity and to allow a faster rehabilitation.75,76 Allografts include semitendinosus, gracilis, anterior tibialis, posterior tibialis, and quadriceps tendons.

Calvo Rodríguez and colleagues76 performed a retrospective review in 2015 comparing allografts to autografts for MPFL reconstruction with respect to postoperative knee function and re-dislocation rates. Among the collective 28 patients, there was no difference in overall functional scores or dislocation rates between the grafts. Although this was a retrospective review and had a small number of subjects, the findings identify allografts as a reliable graft option for MPFL reconstruction.76While there has been a surge of interest in techniques for MPFL reconstruction, there is limited research available regarding the superiority of allografts compared to autografts. For this specific application, it seems that clinical outcomes correlate more to adequate stabilization of the patellofemoral joint than to the type of graft used.77,78 Future research should be dedicated to prospective randomized control trials to delineate any disadvantages to using allografts for MPFL reconstruction.

 

 

Discussion

Musculoskeletal allografts are gaining popularity for ligamentous reconstruction as their safety and efficacy continue to improve. With the great majority of tissue banks being accredited by the AATB and specific regulations such as NAT screening becoming common practice, infection rates and transmission of diseases have become incredibly rare. However, a thorough consideration needs to be taken into account when choosing between autograft and allograft on a case-by-case basis (Table).

Although the incidence of donor site complications is low with autografts, there are inherent risks, such as harvest site hyperesthesia, persistent numbness, cosmetic dissatisfaction, pain, weakness, functional implications, and unsuitability of the harvested graft. While it may appear that allografts may obviate donor site morbidity, one must consider the reduced potential for the donor tissue to incorporate into the host. Several studies have suggested that incorporation into the host tissue is inferior and slower for allografts. With this knowledge, factors such as clinical outcomes, future expectations, rehabilitation protocol, and individual patient characteristics all need to be considered when selecting the source of the tissue to be transplanted. Given that there is a growing need for availability of allografts, a well-rounded understanding of the biologic and physiologic aspects of the transplanted tissues is imperative. Future research will need to focus on improving the rate and quality of the biological incorporation of the transplanted graft into the host while eliminating the risk of disease transmission and infection.

Am J Orthop. 2016;45(7):446-453. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Musculoskeletal allografts are becoming increasingly accepted as a viable alternative to autografts in a variety of orthopedic procedures. A 2006 American Orthopaedic Society for Sports Medicine (AOSSM) survey indicated that 86% of the participating 365 orthopedic surgeons use allografts in their practice.1 Although the overwhelming majority of orthopedic surgeons use allografts, they share common concerns, including safety, tissue integrity, and biologic incorporation. It is essential for the orthopedic surgeon to understand the current standards of tissue banking, risks and benefits related to the use of allografts, and common indications for safe use in clinical practice. This article reviews the current status of musculoskeletal allografts, including tissue procurement and processing, infections, complications, and specific uses tailored to ligament reconstruction.

Donor Bank, Processing, Sterilization, and Regulation

In the United States, the American Association of Tissue Banks (AATB) is responsible for establishing the standards for more than 100 accredited tissue banks. These tissue banks recover tissue from approximately 30,000 donors annually and account for an estimated 90% of the available musculoskeletal allografts used in the United States. While not all tissue banks are accredited by the AATB, all are required to register with the Food and Drug Administration (FDA), which allows for unannounced inspections of any facility. Facilities are required to abide by the FDA-implemented Current Good Tissue Practices (CGTP), which encompasses regulations on all donor tissue collected after May 2005 to help prevent the transmission of communicable diseases. The FDA released an updated draft in January 2009 that emphasizes safe practices and regulations spanning from environmental control to specific equipment.2

The safety of a transplanted allograft tissue begins within the tissue bank. Donor screening and testing is the first step in reducing the risk of transmission. Screening consists of collecting medical and social history from the family and any healthcare resources to assess the eligibility of the donor. If prior blood donations or autopsy information is available, that information is scrutinized. Donor tissue undergoes nucleic acid testing (NAT), which is required by both the AATB and FDA. All donor tissue must be screened for both types of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), treponema pallidum, and human transmissible spongiform encephalopathies.3 NAT of donor tissue effectively reduces the risk of viral transmission. Additionally, routine preprocessing swabs for bacterial and fungal cultures are performed, although the sensitivity of these cultures ranges from 78% to 92%.4

After donor screening and testing, allograft tissues are usually obtained under aseptic conditions, though this is not FDA-required.5 Once procured, the tissue undergoes sterilization. Currently, there is no standard method ubiquitous to all tissue banks, nor does the FDA require a specific method. Rather, the FDA and AATB require tissue banks to validate their sterilization process and provide supporting data. The goal of sterilization is to inactivate viruses and eradicate bacteria while maintaining the biological and mechanical properties of the tissue. The AATB requires a Sterility Assurance Level (SAL) of 10-6, meaning there is no more than one in a million chance that a nonviral viable microbe exists on or within the tissue. Sterilization techniques may include both radiation and a variety of chemical reagents. Gamma irradiation is a commonly used method of sterilizing soft tissue allografts, although some studies indicate that it is detrimental to tissue biology.6 Newer methods of sterilization are being tested, one of which includes carbon dioxide in combination with antioxidants and irradiation. Bui and colleagues7 directly compared the biomechanical and histological properties of allograft tissue after either the standard 25 kGy gamma irradiation or supercritical carbon dioxide techniques. Although there is no histological difference, the samples treated with supercritical carbon dioxide had less biomechanical damage.7 Finally, the terminally sterilized allograft tissue is frozen to temperatures between -40°C and -80°C.5

Infections

One major concern of allografts is the risk of disease transmission. While numerous studies have investigated the incidence of bacterial infection following transplantation of allograft tissue, there are challenges associated with differentiating common postoperative infections from ones directly associated with the transmission of bacteria within the graft. There is a wide array of reported incidences of infection in the literature, from the Tomford and colleagues8 1981 study that reported a 6.9% rateto the 2001 study by Munting and colleagues,9 who reported 0% in their series. Multiple confounding variables exist, such as possible contamination during handling of an otherwise noncontaminated or properly sterilized allograft with inappropriate inclusion of all postoperative infections. In contrast, recognizing viral transmission has been somewhat easier, although reporting of these incidences has been variable in the past. In either case, there is no accredited reporting system for infections related to allografts.

 

 

Bacterial Transmission

Clostridium species. Clostridium species are commonly found among intestinal flora. There is a general consensus that between 24 to 48 hours after death intestinal flora transmigrates into the surrounding tissue and blood. Therefore, a commonly accepted recommendation is that cadaveric tissue needs to be excised prior to 24 hours postmortem.10

In 2001, a 23-year-old man underwent reconstructive knee surgery with a femoral condyle allograft. A few days after surgery, he became septic and ultimately died from the infection. Clostridium sordellii was cultured from the tissue. Several days later, a 17-year-old boy underwent reconstructive knee surgery with a fresh femoral condyle and frozen meniscus from the same donor. Twenty-four hours after surgery, he developed a fever and was readmitted a week later for presumed infection and treated effectively with penicillin and ampicillin/sulbactam. Tissue from the same cadaveric donor had been transplanted into 7 other patients without reports of infection. In a 2002 Centers for Disease Control and Prevention (CDC) update report,11 there were 26 total bacterial cases from allografts and 13 cases were attributed to Clostridium. Malinin and colleagues10 reviewed 795 consecutive cadaveric donors and found that 64 (8.1%) had positive cultures for Clostridia. Of all the positive cultures for Clostridia, 81.3% had positive blood cultures, 57.8% had positive bone marrow aspirate cultures, and 46.9% had positive tissue cultures. They concluded that multiple cultures are required for cadaveric tissue donors in order to reach a higher sensitivity for Clostridial contamination, and these should be done routinely to guide the sterilization process.

Strep species. In 2003, a 17-year-old boy underwent anterior cruciate ligament (ACL) reconstruction with a patellar tendon allograft.12 About 1 week later, he was admitted for signs of infection and received intravenous antibiotics. He required surgical debridement, and intraoperative cultures grew Group A Streptococcus (GAS) that was also identified in the postmortem donor cultures. The tissues underwent processing in an antimicrobial solution and postprocessing cultures were negative for bacteria, but they were not sterilized. Tissues from this donor had been implanted in 5 other patients without report of infection. Following this event, recommendations have been made for prompt rejection of tissue with cultures positive for GAS, unless a sterilizing procedure is used.

Other bacteria. According to the 2002 CDC update, 11 of the 26 cases of bacterial infection reported to the agency were a combination of gram-negative bacilli, polymicrobial flora, or culture negative.11

Viral Transmission

The most effective way to prevent transmission of a viral disease from allografts is thorough donor screening. Since the AATB implemented NAT in 2005 for HIV and HCV, there have been no reported cases of transmission.3 Even prior to this, regular blood screening along with social questionnaires completed by donors or donor families eliminated high-risk donors and significantly decreased the rate of transmission.

Human Immunodeficiency Virus. The first reported case of HIV transmission via implantation of allograft was in 1988. Further investigation revealed that there were 8 transmissions between 1984 and 1986, when routine screening of donors had not yet been implemented. The last reported case of HIV transmission occurred in 1996 with an untested donor.13Hepatitis C Virus. There are several reported cases of HCV transmission that occurred where the donors initially tested negative for HCV. In one case, 40 allografts from the same donor were transplanted over a period of nearly 2 years. This resulted in at least 8 patients being infected with HCV.14 Another case of HCV transmission was reported in 2005 after a patient developed acute HCV 6 weeks after transplantation of a patellar tendon allograft. Further investigation revealed that there had been 3 additional cases over a year from the same donor. Researchers determined that if the initial case had been reported, at least 3 transmissions could have been prevented.15Human T-cell Lymphotropic Virus (HTLV).The first reported transmission of HTLV was in 1991. This was reported in an asymptomatic patient who received a femoral head allograft from a donor who had been previously infected via a blood transfusion.16Zika virus. With recent outbreaks of the Zika virus, the FDA recently released recommendations regarding the screening and deferral of donors, mainly for blood transfusion. Orthopedists should take into consideration the potential for transmission through allografts. The FDA states that all potential donors should be screened for Zika virus using questionnaires and whole blood tests. Symptomatic donors are deferred at least 4 weeks following resolution of symptoms. While this is a recent recommendation from the FDA, orthopedists must be cognizant of the potential harms from this unfamiliar and evolving situation.17

Graft Specifics

Anterior Cruciate Ligament

ACL reconstruction is one of the most commonly performed surgeries by orthopedic surgeons, with an estimated 200,000 reconstructions per year.18Despite the popularity of this surgery, controversies remain regarding the optimal graft for reconstruction.19,20 One would provide adequate strength, be readily available, not elicit an immunologic response from the host, rapidly incorporate, elicit low morbidity, and vascularize early. Current options include both autografts and allografts. Common autograft options include patellar bone-tendon-bone (PBTB), hamstrings tendon, quadriceps tendon, and iliotibial band. PBTB autograft remains a common choice among orthopedic surgeons, as it allows early incorporation of the graft into bone and eliminates immune rejection. However, donor site morbidity, including anterior knee pain, weakness of knee extension, joint stiffness, increased postoperative pain, and iatrogenic patella fractures, have been reported in the literature.21 Commonly used allograft options include donor bone-patellar tendon-bone, quadriceps tendon, Achilles tendon, anterior and posterior tibialis tendons, hamstring tendons, and iliotibial band. Allografts provide the advantage of avoiding donor site morbidity, being readily available, allowing for shorter operative times, and providing lower postoperative pain compared to autografts, although they carry the risk of disease transmission, rejection, and slower incorporation into bone.22-27

 

 

Autograft donor site morbidities. One of the general disadvantages of autografts is the donor site morbidity associated with harvesting the grafts. In specific, PBTB grafts allow for bony blocks on both ends of the graft to incorporate into the host bone. However, this technique comes with the risk of disrupting the extensor mechanism.28,29 Milankov and colleagues30 published a retrospective review of over 2000 ACLs using autologous PBTB graft. They noted a 0.45% incidence of patella fracture and 0.18% patellar tendon rupture.30 Others have reported that intraoperative repair of the patellar tendon after tendon harvesting can increase infrapatellar fibrosis, thus increasing the risk for stiffness.31-33

Hamstring autografts include the semitendinosus and the gracilis tendons. The harvesting process is technically demanding and can be complicated by inadvertent amputation of the tendons, making the graft unsuitable for reconstructive purposes.34 Additionally, several reports have identified persistent numbness and hyperesthesia following hamstring harvesting due to iatrogenic injury to the prepatellar branches of the saphenous nerve.35,36A comprehensive review by Slone and colleagues37 reported comparable functional outcomes with quadriceps tendon autograft compared to PBTB; however, this comes with the risk of postoperative hematoma formation and the potential for thigh compartment syndrome.

Biology and Biomechanics of Allografts

One of the major disadvantages of allografts is the reduced ability to incorporate into the host tissue. Several in vitro and animal studies have suggested that allografts incorporate in the host slower than autografts.24,26,38 Early studies by Jackson and colleagues24 on goat models demonstrated that allografts and autografts have similar structural and biological properties initially, but allografts display significantly slower incorporation into the host tissue at 6 months. Histologically, allografts demonstrated lower revascularization, a smaller cross-sectional area, and a prolonged inflammatory response at 6 months postoperatively.24,39,40 Muramatsu and colleagues41 further showed through the use of magnetic resonance imaging a slower rate of revascularization of allografts over 2 years post-reconstruction.

Given the delayed biologic incorporation of allografts, studies have identified a lower strength-to-failure rate in the early postoperative period compared to autografts. An animal model study by Nikolaou and colleagues38 showed that the strength of allografts was lower for up to 2 years following surgery. Additional biomechanical studies demonstrated that allografts were nearly 75% structurally weaker compared to autografts at 1 year following surgery.42

Acknowledging these limitations, one should use caution when choosing to use an allograft or starting aggressive early rehabilitation after an allograft reconstruction, especially in athletes and young patients.

Clinical Outcomes

Although in vitro studies demonstrate inferior strength and delayed incorporation of allografts in the early postoperative period, there is still controversy surrounding the clinical and functional outcomes. Numerous studies have identified allografts as a viable option for ACL reconstruction, with similar reported patient satisfaction scores compared to autografts.43,44

The MOON Consortium recently published a prospective study of nearly 2500 subjects looking to identify risk factors for failure of ACL reconstruction. The study found that allografts had an odds ratio for failure 5.2 times that of PBTB autografts, correlating this factor to an increased re-tear rate of 6.9% in the allograft group compared to 3.2% in the PBTB group (P < .01).45 The elevated risk is more prevalent in younger patients, especially athletic teenagers. This issue has been reiterated in multiple studies.45-50A meta-analysis by Hu and colleagues23 identified 9 studies, either randomized control trials or prospective cohort studies, that looked at clinical outcomes between the different graft choices. They showed there was no significant difference between graft options in terms of instrumental laxity (P = .59), Lachman test (P = .41), pivot shift test (P = .88), and multiple functional outcome scores, including the International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores.23,51-59Processing and sterilization techniques are thought to play a role in allograft failure. Guo and other researchers have demonstrated a significantly higher rate of failure for patients who received gamma-irradiated allografts compared to fresh frozen allografts.23,58-64 With improved sterilization techniques and a strict selection process of donors, gamma radiation has fallen out of favor to protect the biological characteristics of the tissue graft.5,65,66Several factors need to be considered when selecting between allograft or autograft tissue for ligamentous reconstruction. The selection must be balanced between the surgeon’s experience, patient and surgeon preferences, age of the patient, level of physical activity, primary or revision surgical setting, multiligamentous failure, geographical availability of donor grafts, and economical factors.

Medial Patellofemoral Ligament Reconstruction

Another relatively recent application for allografts has been described for the reconstruction of the medial patellofemoral ligament (MPFL) in recurrent lateral patellar dislocations.67-74

Typically, MPFL reconstructions make use of autografts, including quadriceps tendon, patellar tendon, and hamstring ligaments. However, allografts have the potential to limit postoperative donor site morbidity and to allow a faster rehabilitation.75,76 Allografts include semitendinosus, gracilis, anterior tibialis, posterior tibialis, and quadriceps tendons.

Calvo Rodríguez and colleagues76 performed a retrospective review in 2015 comparing allografts to autografts for MPFL reconstruction with respect to postoperative knee function and re-dislocation rates. Among the collective 28 patients, there was no difference in overall functional scores or dislocation rates between the grafts. Although this was a retrospective review and had a small number of subjects, the findings identify allografts as a reliable graft option for MPFL reconstruction.76While there has been a surge of interest in techniques for MPFL reconstruction, there is limited research available regarding the superiority of allografts compared to autografts. For this specific application, it seems that clinical outcomes correlate more to adequate stabilization of the patellofemoral joint than to the type of graft used.77,78 Future research should be dedicated to prospective randomized control trials to delineate any disadvantages to using allografts for MPFL reconstruction.

 

 

Discussion

Musculoskeletal allografts are gaining popularity for ligamentous reconstruction as their safety and efficacy continue to improve. With the great majority of tissue banks being accredited by the AATB and specific regulations such as NAT screening becoming common practice, infection rates and transmission of diseases have become incredibly rare. However, a thorough consideration needs to be taken into account when choosing between autograft and allograft on a case-by-case basis (Table).

Although the incidence of donor site complications is low with autografts, there are inherent risks, such as harvest site hyperesthesia, persistent numbness, cosmetic dissatisfaction, pain, weakness, functional implications, and unsuitability of the harvested graft. While it may appear that allografts may obviate donor site morbidity, one must consider the reduced potential for the donor tissue to incorporate into the host. Several studies have suggested that incorporation into the host tissue is inferior and slower for allografts. With this knowledge, factors such as clinical outcomes, future expectations, rehabilitation protocol, and individual patient characteristics all need to be considered when selecting the source of the tissue to be transplanted. Given that there is a growing need for availability of allografts, a well-rounded understanding of the biologic and physiologic aspects of the transplanted tissues is imperative. Future research will need to focus on improving the rate and quality of the biological incorporation of the transplanted graft into the host while eliminating the risk of disease transmission and infection.

Am J Orthop. 2016;45(7):446-453. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

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References

1. The American Orthopaedic Society for Sports Medicine. Allografts for ACL Reconstruction Survey Report. 2013. http://www.sportsmed.org/AOSSMIMIS/members/downloads/research/AllograftACLReconstructionSurveyReport.pdf. Accessed October 21, 2016.

2. US Department of Health and Human Services, Food and Drug Administration. Guidance for industry: Current good tissue practice (CGTP) and additional requirements for manufacturers of human cells, tissues, and cellular and tissue-based products (HCT/Ps). http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM285223.pdf. Published December 2011. Accessed August 17, 2015.

3. Vaishnav S, Thomas Vangsness C Jr, Dellamaggiora R. New techniques in allograft tissue processing. Clin Sports Med. 2009;28(1):127-141.

4. Veen MR, Bloem RM, Petit PL. Sensitivity and negative predictive value of swab cultures in musculoskeletal allograft procurement. Clin Orthop Relat Res. 1994;(300):259-263.

5. McAllister DR, Joyce MJ, Mann BJ, Vangsness CT Jr. Allograft update: the current status of tissue regulation, procurement, processing, and sterilization. Am J Sports Med. 2007;35(12):2148-2158.

6. Mickiewicz P, Binkowski M, Bursig H, Wróbel Z. Preservation and sterilization methods of the meniscal allografts: literature review. Cell Tissue Bank. 2014;15(3):307-317.

7. Bui D, Lovric V, Oliver R, Bertollo N, Broe D, Walsh WR. Meniscal allograft sterilisation: effect on biomechanical and histological properties. Cell Tissue Bank. 2015;16(3):467-475.

8. Tomford WW, Starkweather RJ, Goldman MH. A study of the clinical incidence of infection in the use of banked allograft bone. J Bone Joint Surg Am. 1981;63(2):244-248.

9. Munting E, Faundez A, Manche E. Vertebral reconstruction with cortical allograft: long-term evaluation. Eur Spine J. 2001;10 Suppl 2:S153-S157.

10. Malinin TI, Buck BE, Temple HT, Martinez OV, Fox WP. Incidence of clostridial contamination in donors’ musculoskeletal tissue. J Bone Joint Surg Br. 2003;85(7):1051-1054.

11. Centers for Disease Control and Prevention (CDC). Update: allograft-associated bacterial infections--United States, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(10):207-210.

12. Centers for Disease Control and Prevention (CDC). Invasive Streptococcus pyogenes after allograft implantation--Colorado, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(48):1174-1176.

13. Hinsenkamp M, Muylle L, Eastlund T, Fehily D, Noël L, Strong DM. Adverse reactions and events related to musculoskeletal allografts: reviewed by the World Health Organisation project NOTIFY. Int Orthop. 2012;36(3):633-641.

14. Schratt HE, Regel G, Kiesewetter B, Tscherne H. HIV infection caused by cold preserved bone transplants. Unfallchirurg. 1996;99(9):679-684.

15. Tugwell BD, Patel PR, Williams IT, et al. Transmission of hepatitis C virus to several organ and tissue recipients from an antibody-negative donor. Ann Intern Med. 2005;143(9):648-654.

16. Sanzén L, Carlsson A. Transmission of human T-cell lymphotrophic virus type 1 by a deep-frozen bone allograft. Acta Orthop Scand. 1997;68(1):72-74.

17. US Department of Health and Human Services, Food and Drug Administration. Recommendations for donor screening, deferral, and product management to reduce the risk of transfusion-transmission of Zika virus. Guidance for industry. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM486360.pdf. Published February 2016. Accessed August 10, 2016.

18. Gottlob CA, Baker CL Jr, Pellissier JM, Colvin L. Cost effectiveness of anterior cruciate ligament reconstruction in young adults. Clin Orthop Relat Res. 1999;(367):272-282.

19. Fu F, Christel P, Miller MD, Johnson DL. Graft selection for anterior cruciate ligament reconstruction. Instr Course Lect. 2009;58:337-354.

20. Chechik O, Amar E, Khashan M, Lador R, Eyal G, Gold A. An international survey on anterior cruciate ligament reconstruction practices. Int Orthop. 2013;37(2):201-206.

21. Spindler KP, Kuhn JE, Freedman KB, Matthews CE, Dittus RS, Harrell FE Jr. Anterior cruciate ligament reconstruction autograft choice: bone-tendon-bone versus hamstring: does it really matter? A systematic review. Am J Sports Med. 2004;32(8):1986-1995.

22. Harner CD, Irrgang JJ, Paul J, Dearwater S, Fu FH. Loss of motion after anterior cruciate ligament reconstruction. Am J Sports Med. 1992;20(5):499-506.

23. Hu J, Qu J, Xu D, Zhou J, Lu H. Allograft versus autograft for anterior cruciate ligament reconstruction: an up-to-date meta-analysis of prospective studies. Int Orthop. 2013;37(2):311-320.

24. Jackson DW, Grood ES, Goldstein JD, et al. A comparison of patellar tendon autograft and allograft used for anterior cruciate ligament reconstruction in the goat model. Am J Sports Med. 1993;21(2):176-185.

25. Mroz TE, Joyce MJ, Steinmetz MP, Lieberman IH, Wang JC. Musculoskeletal allograft risks and recalls in the United States. J Am Acad Orthop Surg. 2008;16(10):559-565.

26. Malinin TI, Levitt RL, Bashore C, Temple HT, Mnaymneh W. A study of retrieved allografts used to replace anterior cruciate ligaments. Arthroscopy. 2002;18(2):163-170.

27. Foster TE, Wolfe BL, Ryan S, Silvestri L, Kaye EK. Does the graft source really matter in the outcome of patients undergoing anterior cruciate ligament reconstruction? An evaluation of autograft versus allograft reconstruction results: a systematic review. Am J Sports Med. 2010;38(1):189-199.

28. Lee GH, McCulloch P, Cole BJ, Bush-Joseph CA, Bach BR Jr. The incidence of acute patellar tendon harvest complications for anterior cruciate ligament reconstruction. Arthroscopy. 2008;24(2):162-166.

29. Marumoto JM, Mitsunaga MM, Richardson AB, Medoff RJ, Mayfield GW. Late patellar tendon ruptures after removal of the central third for anterior cruciate ligament reconstruction. A report of two cases. Am J Sports Med. 1996;24(5):698-701.

30 Milankov M, Kecojević V, Rasović P, Kovacević N, Gvozdenović N, Obradović M. Disruption of the knee extensor apparatus complicating anterior cruciate ligament reconstruction. Acta Chir Iugosl. 2013;60(2):13-21.

31. Atkinson TS, Atkinson PJ, Mendenhall HV, Haut RC. Patellar tendon and infrapatellar fat pad healing after harvest of an ACL graft. J Surg Res. 1998;79(1):25-30.

32. Tang G, Niitsu M, Ikeda K, Endo H, Itai Y. Fibrous scar in the infrapatellar fat pad after arthroscopy: MR imaging. Radiat Med. 2000;18(1):1-5.

33. Unterhauser FN, Bosch U, Zeichen J, Weiler A. Alpha-smooth muscle actin containing contractile fibroblastic cells in human knee arthrofibrosis tissue. Winner of the AGA-DonJoy Award 2003. Arch Orthop Trauma Surg. 2004;124(9):585-591.

34. Prodromos CC, Fu FH, Howell SM, Johnson DH, Lawhorn K. Controversies in soft-tissue anterior cruciate ligament reconstruction: grafts, bundles, tunnels, fixation, and harvest. J Am Acad Orthop Surg. 2008;16(7):376-384.

35. Sabat D, Kumar V. Nerve injury during hamstring graft harvest: a prospective comparative study of three different incisions. Knee Surg Sports Traumatol Arthrosc. 2013;21(9):2089-2095.

36. Kjaergaard J, Faunø LZ, Faunø P. Sensibility loss after ACL reconstruction with hamstring graft. Int J Sports Med. 2008;29(6):507-511.

37. Slone HS, Romine SE, Premkumar A, Xerogeanes JW. Quadriceps tendon autograft for anterior cruciate ligament reconstruction: a comprehensive review of current literature and systematic review of clinical results. Arthroscopy. 2015;31(3):541-554.

38. Nikolaou PK, Seaber AV, Glisson RR, Ribbeck BM, Bassett FH 3rd. Anterior cruciate ligament allograft transplantation. Long-term function, histology, revascularization, and operative technique. Am J Sports Med. 1986;14(5):348-360.

39. Arnoczky SP, Warren RF, Ashlock MA. Replacement of the anterior cruciate ligament using a patellar tendon allograft. An experimental study. J Bone Joint Surg Am. 1986;68(3):376-385.

40. Scheffler SU, Schmidt T, Gangéy I, Dustmann M, Unterhauser F, Weiler A. Fresh-frozen free-tendon allografts versus autografts in anterior cruciate ligament reconstruction: delayed remodeling and inferior mechanical function during long-term healing in sheep. Arthroscopy. 2008;24(4):448-458.

41. Muramatsu K, Hachiya Y, Izawa H. Serial evaluation of human anterior cruciate ligament grafts by contrast-enhanced magnetic resonance imaging: comparison of allografts and autografts. Arthroscopy. 2008;24(9):1038-1044.

42. Jackson DW, Grood ES, Arnoczky SP, Butler DL, Simon TM. Freeze dried anterior cruciate ligament allografts. Preliminary studies in a goat model. Am J Sports Med. 1987;15(4):295-303.

43. Chang SK, Egami DK, Shaieb MD, Kan DM, Richardson AB. Anterior cruciate ligament reconstruction: allograft versus autograft. Arthroscopy. 2003;19(5):453-462.

44. Poehling GG, Curl WW, Lee CA, et al. Analysis of outcomes of anterior cruciate ligament repair with 5-year follow-up: allograft versus autograft. Arthroscopy. 2005;21(7):774-785.

45. Kaeding CC, Pedroza AD, Reinke EK, Huston LJ; MOON Consortium, Spindler KP. Risk factors and predictors of subsequent ACL injury in either knee after ACL reconstruction: prospective analysis of 2488 primary ACL reconstructions from the MOON cohort. Am J Sports Med. 2015;43(7):1583-1590.

46. Kaeding CC, Aros B, Pedroza A, et al. Allograft versus autograft anterior cruciate ligament reconstruction: predictors of failure from a MOON prospective longitudinal cohort. Sports Health. 2011;3(1):73-81.

47. Lynch TS, Parker RD, Patel RM, et al. The impact of the Multicenter Orthopaedic Outcomes Network (MOON) research on anterior cruciate ligament reconstruction and orthopaedic practice. J Am Acad Orthop Surg. 2015;23(3):154-163.

48. Hettrich CM, Dunn WR, Reinke EK; MOON Group, Spindler KP. The rate of subsequent surgery and predictors after anterior cruciate ligament reconstruction: two- and 6-year follow-up results from a multicenter cohort. Am J Sports Med. 2013;41(7):1534-1540.

49. Steadman JR, Matheny LM, Hurst JM, Briggs KK. Patient-centered outcomes and revision rate in patients undergoing ACL reconstruction using bone-patellar tendon-bone autograft compared with bone-patellar tendon-bone allograft: a matched case-control study. Arthroscopy. 2015;31(12):2320-2326.

50. Lenehan EA, Payne WB, Askam BM, Grana WA, Farrow LD. Long-term outcomes of allograft reconstruction of the anterior cruciate ligament. Am J Orthop. 2015;44(5):217-222.

51. Noh JH, Yi SR, Song SJ, Kim SW, Kim W. Comparison between hamstring autograft and free tendon achilles allograft: minimum 2-year follow-up after anterior cruciate ligament reconstruction using EndoButton and Intrafix. Knee Surg Sports Traumatol Arthrosc. 2011;19(5):816-822.

52. Victor J, Bellemans J, Witvrouw E, Govaers K, Fabry G. Graft selection in anterior cruciate ligament reconstruction--prospective analysis of patellar tendon autografts compared with allografts. Int Orthop. 1997;21(2):93-97.

53. Kleipool AE, Zijl JA, Willems WJ. Arthroscopic anterior cruciate ligament reconstruction with bone-patellar tendon-bone allograft or autograft. A prospective study with an average follow up of 4 years. Knee Surg Sports Traumatol Arthrosc. 1998;6(4):224-230.

54. Peterson RK, Shelton WR, Bomboy AL. Allograft versus autograft patellar tendon anterior cruciate ligament reconstruction: a 5-year follow-up. Arthroscopy. 2001;17(1):9-13.

55. Edgar CM, Zimmer S, Kakar S, Jones H, Schepsis AA. Prospective comparison of auto and allograft hamstring tendon constructs for ACL reconstruction. Clin Orthop Relat Res. 2008;466(9):2238-2246.

56. Sun K, Tian S, Zhang J, Xia C, Zhang C, Yu T. Anterior cruciate ligament reconstruction with BPTB autograft, irradiated versus non-irradiated allograft: a prospective randomized clinical study. Knee Surg Sports Traumatol Arthrosc. 2009;17(5):464-474.

57. Leal-Blanquet J, Alentorn-Geli E, Tuneu J, Valentí JR, Maestro A. Anterior cruciate ligament reconstruction: a multicenter prospective cohort study evaluating 3 different grafts using same bone drilling method. Clin J Sport Med. 2011;21(4):294-300.

58. Sun K, Zhang J, Wang Y, et al. Arthroscopic reconstruction of the anterior cruciate ligament with hamstring tendon autograft and fresh-frozen allograft: a prospective, randomized controlled study. Am J Sports Med. 2011;39(7):1430-1438.

59. Lawhorn KW, Howell SM, Traina SM, Gottlieb JE, Meade TD, Freedberg HI. The effect of graft tissue on anterior cruciate ligament outcomes: a multicenter, prospective, randomized controlled trial comparing autograft hamstrings with fresh-frozen anterior tibialis allograft. Arthroscopy. 2012;28(8):1079-1086.

60. Guo L, Yang L, Duan XJ, et al. Anterior cruciate ligament reconstruction with bone-patellar tendon-bone graft: comparison of autograft, fresh-frozen allograft, and γ-irradiated allograft. Arthroscopy. 2012;28(2):211-217.

61. Lamblin CJ, Waterman BR, Lubowitz JH. Anterior cruciate ligament reconstruction with autografts compared with non-irradiated, non-chemically treated allografts. Arthroscopy. 2013;29(6):1113-1122.

62. Mayr HO, Willkomm D, Stoehr A, et al. Revision of anterior cruciate ligament reconstruction with patellar tendon allograft and autograft: 2- and 5-year results. Arch Orthop Trauma Surg. 2012;132(6):867-874.

63. Mariscalco MW, Magnussen RA, Mehta D, Hewett TE, Flanigan DC, Kaeding CC. Autograft versus nonirradiated allograft tissue for anterior cruciate ligament reconstruction: a systematic review. Am J Sports Med. 2014;42(2):492-499.

64. Mehta VM, Mandala C, Foster D, Petsche TS. Comparison of revision rates in bone-patella tendon-bone autograft and allograft anterior cruciate ligament reconstruction. Orthopedics. 2010;33(1):12.

65. Vangsness CT Jr, Garcia IA, Mills CR, Kainer MA, Roberts MR, Moore TM. Allograft transplantation in the knee: tissue regulation, procurement, processing, and sterilization. Am J Sports Med. 2003;31(3):474-481.

66. Barrett GR, Luber K, Replogle WH, Manley JL. Allograft anterior cruciate ligament reconstruction in the young, active patient: tegner activity level and failure rate. Arthroscopy. 2010;26(12):1593-1601.

67. Reagan J, Kullar R, Burks R. MPFL reconstruction: technique and results. Clin Sports Med. 2014;33(3):501-516.

68. Christiansen SE, Jacobsen BW, Lund B, Lind M. Reconstruction of the medial patellofemoral ligament with gracilis tendon autograft in transverse patellar drill holes. Arthroscopy. 2008;24(1):82-87.

69. Schöttle PB, Fucentese SF, Romero J. Clinical and radiological outcome of medial patellofemoral ligament reconstruction with a semitendinosus autograft for patella instability. Knee Surg Sports Traumatol Arthrosc. 2005;13(7):516-521.

70. Deie M, Ochi M, Sumen Y, Adachi N, Kobayashi K, Yasumoto M. A long-term follow-up study after medial patellofemoral ligament reconstruction using the transferred semitendinosus tendon for patellar dislocation. Knee Surg Sports Traumatol Arthrosc. 2005;13(7):522-528.

71. Nomura E, Inoue M. Hybrid medial patellofemoral ligament reconstruction using the semitendinous tendon for recurrent patellar dislocation: minimum 3 years’ follow-up. Arthroscopy. 2006;22(7):787-793.

72. Nomura E, Inoue M. Surgical technique and rationale for medial patellofemoral ligament reconstruction for recurrent patellar dislocation. Arthroscopy. 2003;19(5):E47.

73. Hautamaa PV, Fithian DC, Kaufman KR, Daniel DM, Pohlmeyer AM. Medial soft tissue restraints in lateral patellar instability and repair. Clin Orthop Relat Res. 1998;(349):174-182.

74. Drez D Jr, Edwards TB, Williams CS. Results of medial patellofemoral ligament reconstruction in the treatment of patellar dislocation. Arthroscopy. 2001;17(3):298-306.

75. Fink C, Veselko M, Herbort M, Hoser C. MPFL reconstruction using a quadriceps tendon graft: part 2: operative technique and short term clinical results. Knee. 2014;21(6):1175-1179.

76. Calvo Rodríguez R, Figueroa Poblete D, Anastasiadis Le Roy Z, Etchegaray Bascur F, Vaisman Burucker A, Calvo Mena R. Reconstruction of the medial patellofemoral ligament: evaluation of the clinical results of autografts versus allografts. Rev Esp Cir Ortop Traumatol. 2015;59(5):348-353.

77. Becher C, Kley K, Lobenhoffer P, Ezechieli M, Smith T, Ostermeier S. Dynamic versus static reconstruction of the medial patellofemoral ligament for recurrent lateral patellar dislocation. Knee Surg Sports Traumatol Arthrosc. 2014;22(10):2452-2457.

78. Gomes JE. Comparison between a static and a dynamic technique for medial patellofemoral ligament reconstruction. Arthroscopy. 2008;24(4):430-435.

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Allografts for Ligament Reconstruction: Where Are We Now?
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Why Do Lateral Unicompartmental Knee Arthroplasties Fail Today?

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Why Do Lateral Unicompartmental Knee Arthroplasties Fail Today?
Author(s)
Jelle P. van der List
MD; Hendrik A. Zuiderbaan
MD; Andrew D. Pearle
MD

In 1975, Skolnick and colleagues1 introduced unicompartmental knee arthroplasty (UKA) for patients with isolated unicompartmental osteoarthritis (OA). They reported a study of 14 UKA procedures, of which 12 were at the medial and 2 at the lateral side. Forty years since this procedure was introduced, UKA is used in 8% to 12% of all knee arthroplasties.2-6 A minority of these procedures are performed at the lateral side (5%-10%).6-8

The considerable anatomical and kinematical differences between compartments9-14 make it impossible to directly compare outcomes of medial and lateral UKA. For example, a greater degree of femoral roll and more posterior translation at the lateral side in flexion9,10,13 can contribute to different pattern and volume differences of cartilage wear.15 Because of these differences, and because of implant design factors and lower surgical volume, lateral UKA is considered a technically more challenging surgery compared to medial UKA.12,16,17

Since isolated lateral compartment OA is relatively scarce, current literature on lateral UKA is limited, and most studies combine medial and lateral outcomes to report UKA outcomes and failure modes.3,4,18-20 However, as the UKA has grown in popularity over the last decade,2,21-25 the number of reports about the lateral UKA also has increased. Recent studies reported excellent short-term survivorship results of the lateral UKA (96%-99%)26,27 and smaller lateral UKA studies reported the 10-year survivorship with varying outcomes from good (84%)14,28-30 to excellent (94%-100%).8,31,32 Indeed, a recent systematic review showed survivorship of lateral UKA at 5, 10, and 15 years of 93%, 91%, and 89%, respectively.33Because of the differences between the medial and lateral compartment, it is important to know the failure modes of lateral UKA in order to improve clinical outcomes and revision rates. We performed a systematic review of cohort studies and registry-based studies that reported lateral UKA failure to assess the causes of lateral UKA failure. In addition, we compared the failure modes in cohort studies with those found in registry-based studies.

Patients and Methods

Search Strategy and Criteria

Databases of PubMed, Embase, and Cochrane (Cochrane Central Register of Clinical Trials) were searched with the terms “knee, arthroplasty, replacement,” “unicompartmental,” “unicondylar,” “partial,” “UKA,” “UKR,” “UCA,” “UCR,” “PKA,” “PKR,” “PCA,” “prosthesis failure,” “reoperation,” “survivorship,” and “treatment failure.” After removal of duplicates, 2 authors (JPvdL and HAZ) scanned the articles for their title and abstract to assess eligibility for the study.

The full text of these eligible articles was further viewed and useful studies were selected using the inclusion and exclusion criteria. The references of these articles were scanned for additional studies and national registries (Figure).

Inclusion criteria were: (I) English language articles describing studies in humans published in the last 25 years, (II) retrospective and prospective studies, (III) featured lateral UKA, (IV) OA was indication for surgery, and (V) included failure modes data. The exclusion criteria were studies that featured: (I) only a specific group of failure (eg, bearing dislocations only), (II) previous surgery in ipsilateral knee (high tibial osteotomy, medial UKA), (III) acute concurrent knee diagnoses (acute anterior cruciate ligament rupture, acute meniscal tear), (IV) combined reporting of medial and lateral UKA, or (V) multiple studies with the same patient database.

Data Collection

All studies that reported modes of failure were used in this study and these failure modes were noted in a datasheet in Microsoft Excel 2011 (Microsoft).

The data of failures of lateral UKA are presented in Table 1 and are divided in cohort studies and registry-based studies. The final failure mode rates were presented in percentages (Table 2).

Statistical Analysis

For this systematic review, statistical analysis was performed with IBM SPSS Statistics 22 (SPSS Inc.). We performed chi square tests and Fisher’s exact tests to assess a difference between cohort studies and registry-based studies with the null hypothesis of no difference between both groups. A difference was considered significant when P < .05.

Results

Through the search of the databases, 1294 studies were identified and 26 handpicked studies were added. Initially, based on the title and abstract, 184 of these studies were found eligible.

After reviewing the full text of these articles, 25 studies (23 cohort studies and 2 registry-based studies) met the inclusion criteria and were included for the analysis of lateral UKA failure (Figure).

A total of 366 lateral UKA failures were included. The most common failure modes were progression of OA (29%), aseptic loosening (23%), and bearing dislocation (10%). Infection (6%), instability (6%), unexplained pain (6%), and fractures (4%) were less common causes of failure of lateral UKA (Table 2).

One hundred fifty-five of these failures were reported in the cohort studies. The most common modes of failure were OA progression (36%), bearing dislocation (17%) and aseptic loosening (16%). Less common were infection (10%), fractures (5%), pain (5%), and other causes (6%). In registry-based studies, with 211 lateral UKA failures, the most common modes of failure were aseptic loosening (28%), OA progression (24%), other causes (12%), instability (10%), pain (7%), bearing dislocation (5%), and polyethylene wear (4%) (Table 2).

When pooling cohort and registry-based studies, progression of OA was significantly more common than aseptic loosening (29% vs 23%, respectively; P < .01). It was also significantly more common in the cohort studies (36% vs 16%, respectively; P < .01) but no significant difference was found between progression of OA and aseptic loosening in registry-based studies (24% and 28%, respectively; P = .16) (Table 2).

When comparing cohort with registry-based studies, progression of OA was higher in cohort studies (36% vs. 24%; P < .01). Other failures modes that were more common in cohort studies compared with registry-based studies were bearing dislocation (17% vs 5%, respectively; P < .01) and infections (10% vs 3%, P < .01). Failure modes that were more common in registry-based studies than cohort studies were aseptic loosening (28% vs 16%, respectively; P < .01), other causes (12% vs 6%, respectively, P = .02), and instability (10% vs 1%, respectively, P < .01) (Table 2).

 

 

Discussion

In this systematic review, the most common failure modes in lateral UKA review were OA progression (29%), aseptic loosening (23%), and bearing dislocation (10%). Progression of OA and bearing dislocation were the most common modes of failure in cohort studies (36% and 17%, respectively), while aseptic loosening and OA progression were the most common failure modes in registry-based studies (28% and 24%, respectively).

As mentioned above, there are differences in anatomy and kinematics between the medial and lateral compartment. When the lateral UKA failure modes are compared with studies reporting medial UKA failure modes, differences in failure modes are seen.34 Siddiqui and Ahmad35 performed a systematic review of outcomes after UKA revision and presented a table with the failure modes of included studies. Unfortunately they did not report the ratio of medial and lateral UKA. However, when assuming an average percentage of 90% to 95% of medial UKA,6,7,36 the main failure mode in their review in 17 out of 21 studies was aseptic loosening. Indeed, a recent systematic review on medial UKA failure modes showed that aseptic loosening is the most common cause of failure following this procedure.34 Similarly, a search through registry-based studies6,7 and large cohort studies37-40 that only reported medial UKA failures showed that the majority of these studies7,37-39 also reported aseptic loosening as the main cause of failure in medial UKA. When comparing the results of our systematic review of lateral UKA failures with the results of these studies of medial UKA failures, it seems that OA progression seems to play a more dominant role in failures of lateral UKA, while aseptic loosening seems to be more common in medial UKA.

Differences in anatomy and kinematics of the medial and lateral compartment can explain this. Malalignment of the joint is an important factor in the etiology of OA41,42 and biomechanical studies showed that this malalignment can cause decreased viability and further degenerative changes of cartilage of the knee.43 Hernigou and Deschamps44 showed that the alignment of the knee after medial UKA is an important factor in postoperative joint changes. They found that overcorrection of varus deformity during medial UKA surgery, measured by the hip-knee-ankle (HKA) angle, was associated with increased OA at the lateral condyle and less tibial wear of the medial UKA. Undercorrection of the varus caused an increase in tibial wear of polyethylene. Chatellard and colleagues45 found the same results in the correction of varus, measured by HKA. In addition, they found that when the prosthetic (medial) joint space was smaller than healthy (lateral) joint space, this was correlated with lower prosthesis survival. A smaller joint space at the healthy side was correlated with OA progression at the lateral compartment and tibial component wear.

These studies explain the mechanism of progression of OA and aseptic loosening. Harrington46 assessed the load in patients with valgus and varus deformity. Patients with a valgus deformity have high mechanical load on the lateral condyle during the static phase, but during the dynamic phase, a major part of this load shifts to the medial condyle. In the patients with varus deformity, the mechanical load was noted on the medial condyle during both the static and dynamic phase. Ohdera and colleagues47 advised, based on this biomechanical study and their own experiences, to correct the knee during lateral UKA to a slight valgus angle (5°-7°) to prevent OA progression at the medial side. van der List and colleagues48 similarly showed that undercorrection of 3° to 7° was correlated with better functional outcomes when compared to more neutral alignment. Moreover, Khamaisy and colleagues49 recently showed that overcorrection during UKA surgery is more common in lateral than medial UKA.

These studies are important to understanding why OA progression is more common as a failure mode in lateral UKA. The shift of mechanical load from the lateral to medial epicondyle during the dynamic phase also could explain why aseptic loosening is less common in lateral UKA. As Hernigou and Deschamps44 and Chatellard and colleagues45 stated, undercorrection of varus deformity in medial UKA is associated with higher mechanical load on the medial prosthesis side and smaller joint space width. These factors are correlated with mechanical failure of medial UKA. We think this process can be applied to lateral UKA, with the addition that the mechanical load is higher on the healthy medial compartment during the dynamic phase. This causes more forces on the healthy (medial) side in lateral UKA, and in medial UKA more forces on the prosthesis (medial) side, which results in more OA progression in lateral UKA and more aseptic loosening in medial UKA. This finding is consistent with the results of our review of more OA progression and less aseptic loosening in lateral UKA. This study also suggests that medial and lateral UKA should not be reported together in studies that present survivorship, failure modes, or clinical outcomes.

A large discrepancy was seen in bearing dislocation between cohort studies (17%) and registry-based studies (5%). When we take a closer look to the bearing dislocation failures in the cohort studies, most of the failures were reported in only 2 cohort studies.50,51 In a study by Pandit and colleagues,50 3 different prosthesis designs were used in 3 different time periods. In the first series of lateral UKA (1983-1991), 6 out of 51 (12%) bearings dislocated. In the second series (1998-2004), a modified technique was used and 3 out of 65 (5%) bearings dislocated. In the third series (2004-2008), a modified technique and a domed tibial component was used and only 1 out of 68 bearings dislocated (1%). In a study published in 1996, Gunther and colleagues51 also used surgical techniques and implants that were modified over the course of the study period. Because of these modified techniques, different implant designs, and year of publication, bearing dislocation most likely plays a smaller role than the 17% reported in the cohort studies. This discrepancy is a good example of the important role for the registries and registry-based studies in reporting failure modes and survivorship, especially in lateral UKA due to the low surgical frequency. Pabinger and colleagues52 recently performed a systematic review of cohort studies and registry-based studies in which they stated that the reliability in non-registry-based studies should be questioned and they considered registry-based studies superior in reporting UKA outcomes and revision rates. Furthermore, given the differences in anatomic and kinematic differences between the medial and lateral compartment and different failure modes between medial and lateral UKA, it would be better if future studies presented the medial and lateral failures separately. As stated above, most large cohort studies and especially annual registries currently do not report modes of failure of medial and lateral UKA separately.3,4,18-20

There are limitations in this study. First, this systematic review is not a full meta-analysis but a pooled analysis of collected study series and retrospective studies. Therefore, we cannot exclude sampling bias, confounders, and selection bias from the literature. We included all studies reporting failure modes of lateral UKA and excluded all case reports. We made a conscious choice about including all lateral UKA failures because this is the first systematic review of lateral UKA failure modes. Another limitation is that the follow-up period of the studies differed (Table 1) and we did not correct for the follow-up period. As stated in the example of bearing dislocations, some of these studies reported old or different techniques, while other, more recently published studies used more modified techniques11,29,53-56 Unfortunately, most studies did not report the time of arthroplasty survival and therefore we could not correct for the follow-up period.

In conclusion, progression of OA is the most common failure mode in lateral UKA, followed by aseptic loosening. Anatomic and kinematic factors such as alignment, mechanical forces during dynamic phase, and correction of valgus seem to play important roles in failure modes of lateral UKA. In the future, failure modes of medial and lateral UKA should be reported separately.

Am J Orthop. 2016;45(7):432-438, 462. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

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22. Nwachukwu BU, McCormick FM, Schairer WW, Frank RM, Provencher MT, Roche MW. Unicompartmental knee arthroplasty versus high tibial osteotomy: United States practice patterns for the surgical treatment of unicompartmental arthritis. J Arthroplasty. 2014;29(8):1586-1589.

23. van der List JP, Chawla H, Pearle AD. Robotic-assisted knee arthroplasty: an overview. Am J Orthop. 2016;45(4):202-211.

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25. Zuiderbaan HA, van der List JP, Kleeblad LJ, et al. Modern indications, results and global trends in the use of unicompartmental knee arthroplasty and high tibial osteotomy for the treatment of medial unicondylar knee osteoarthritis. Am J Orthop. 2016;45(6):E355-E361.

26. Smith JR, Robinson JR, Porteous AJ, et al. Fixed bearing lateral unicompartmental knee arthroplasty--short to midterm survivorship and knee scores for 101 prostheses. Knee. 2014;21(4):843-847.

27. Berend KR, Kolczun MC 2nd, George JW Jr, Lombardi AV Jr. Lateral unicompartmental knee arthroplasty through a lateral parapatellar approach has high early survivorship. Clin Orthop Relat Res. 2012;470(1):77-83.

28. Keblish PA, Briard JL. Mobile-bearing unicompartmental knee arthroplasty: a 2-center study with an 11-year (mean) follow-up. J Arthroplasty. 2004;19(7 Suppl 2):87-94.

29. Bertani A, Flecher X, Parratte S, Aubaniac JM, Argenson JN. Unicompartmental-knee arthroplasty for treatment of lateral gonarthrosis: about 30 cases. Midterm results. Rev Chir Orthop Reparatrice Appar Mot. 2008;94(8):763-770.

30. Sebilo A, Casin C, Lebel B, et al. Clinical and technical factors influencing outcomes of unicompartmental knee arthroplasty: Retrospective multicentre study of 944 knees. Orthop Traumatol Surg Res. 2013;99(4 Suppl):S227-S234.

31. Cartier P, Khefacha A, Sanouiller JL, Frederick K. Unicondylar knee arthroplasty in middle-aged patients: A minimum 5-year follow-up. Orthopedics. 2007;30(8 Suppl):62-65.

32. Lustig S, Paillot JL, Servien E, Henry J, Ait Si Selmi T, Neyret P. Cemented all polyethylene tibial insert unicompartimental knee arthroplasty: a long term follow-up study. Orthop Traumatol Surg Res. 2009;95(1):12-21.

33. van der List JP, McDonald LS, Pearle AD. Systematic review of medial versus lateral survivorship in unicompartmental knee arthroplasty. Knee. 2015;22(6):454-460.

34. van der List JP, Zuiderbaan HA, Pearle AD. Why do medial unicompartmental knee arthroplasties fail today? J Arthroplasty. 2016;31(5):1016-1021.

35. Siddiqui NA, Ahmad ZM. Revision of unicondylar to total knee arthroplasty: a systematic review. Open Orthop J. 2012;6:268-275.

36. Pennington DW, Swienckowski JJ, Lutes WB, Drake GN. Lateral unicompartmental knee arthroplasty: survivorship and technical considerations at an average follow-up of 12.4 years. J Arthroplasty. 2006;21(1):13-17.

37. Kalra S, Smith TO, Berko B, Walton NP. Assessment of radiolucent lines around the Oxford unicompartmental knee replacement: sensitivity and specificity for loosening. J Bone Joint Surg Br. 2011;93(6):777-781.

38. Wynn Jones H, Chan W, Harrison T, Smith TO, Masonda P, Walton NP. Revision of medial Oxford unicompartmental knee replacement to a total knee replacement: similar to a primary? Knee. 2012;19(4):339-343.

39. Sierra RJ, Kassel CA, Wetters NG, Berend KR, Della Valle CJ, Lombardi AV. Revision of unicompartmental arthroplasty to total knee arthroplasty: not always a slam dunk! J Arthroplasty. 2013;28(8 Suppl):128-132.

40. Citak M, Dersch K, Kamath AF, Haasper C, Gehrke T, Kendoff D. Common causes of failed unicompartmental knee arthroplasty: a single-centre analysis of four hundred and seventy one cases. Int Orthop. 2014;38(5):961-965.

41. Hunter DJ, Wilson DR. Role of alignment and biomechanics in osteoarthritis and implications for imaging. Radiol Clin North Am. 2009;47(4):553-566.

42. Hunter DJ, Sharma L, Skaife T. Alignment and osteoarthritis of the knee. J Bone Joint Surg Am. 2009;91 Suppl 1:85-89.

43. Roemhildt ML, Beynnon BD, Gauthier AE, Gardner-Morse M, Ertem F, Badger GJ. Chronic in vivo load alteration induces degenerative changes in the rat tibiofemoral joint. Osteoarthritis Cartilage. 2013;21(2):346-357.

44. Hernigou P, Deschamps G. Alignment influences wear in the knee after medial unicompartmental arthroplasty. Clin Orthop Relat Res. 2004;(423):161-165.

45. Chatellard R, Sauleau V, Colmar M, et al. Medial unicompartmental knee arthroplasty: does tibial component position influence clinical outcomes and arthroplasty survival? Orthop Traumatol Surg Res. 2013;99(4 Suppl):S219-S225.

46. Harrington IJ. Static and dynamic loading patterns in knee joints with deformities. J Bone Joint Surg Am. 1983;65(2):247-259.

47. Ohdera T, Tokunaga J, Kobayashi A. Unicompartmental knee arthroplasty for lateral gonarthrosis: midterm results. J Arthroplasty. 2001;16(2):196-200.

48. van der List JP, Chawla H, Villa JC, Zuiderbaan HA, Pearle AD. Early functional outcome after lateral UKA is sensitive to postoperative lower limb alignment. Knee Surg Sports Traumatol Arthrosc. 2015 Nov 26. [Epub ahead of print]

49. Khamaisy S, Gladnick BP, Nam D, Reinhardt KR, Heyse TJ, Pearle AD. Lower limb alignment control: Is it more challenging in lateral compared to medial unicondylar knee arthroplasty? Knee. 2015;22(4):347-350.

50. Pandit H, Jenkins C, Beard DJ, et al. Mobile bearing dislocation in lateral unicompartmental knee replacement. Knee. 2010;17(6):392-397.

51. Gunther TV, Murray DW, Miller R, et al. Lateral unicompartmental arthroplasty with the Oxford meniscal knee. Knee. 1996;3(1):33-39.

52. Pabinger C, Lumenta DB, Cupak D, Berghold A, Boehler N, Labek G. Quality of outcome data in knee arthroplasty: Comparison of registry data and worldwide non-registry studies from 4 decades. Acta Orthopaedica. 2015;86(1):58-62.

53. Lustig S, Elguindy A, Servien E, et al. 5- to 16-year follow-up of 54 consecutive lateral unicondylar knee arthroplasties with a fixed-all polyethylene bearing. J Arthroplasty. 2011;26(8):1318-1325.

54. Walton MJ, Weale AE, Newman JH. The progression of arthritis following lateral unicompartmental knee replacement. Knee. 2006;13(5):374-377.

55. Lustig S, Lording T, Frank F, Debette C, Servien E, Neyret P. Progression of medial osteoarthritis and long term results of lateral unicompartmental arthroplasty: 10 to 18 year follow-up of 54 consecutive implants. Knee. 2014;21(S1):S26-S32.

56. O’Rourke MR, Gardner JJ, Callaghan JJ, et al. Unicompartmental knee replacement: a minimum twenty-one-year followup, end-result study. Clin Orthop Relat Res. 2005;440:27-37.

57. Citak M, Cross MB, Gehrke T, Dersch K, Kendoff D. Modes of failure and revision of failed lateral unicompartmental knee arthroplasties. Knee. 2015;22(4):338-340.

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In 1975, Skolnick and colleagues1 introduced unicompartmental knee arthroplasty (UKA) for patients with isolated unicompartmental osteoarthritis (OA). They reported a study of 14 UKA procedures, of which 12 were at the medial and 2 at the lateral side. Forty years since this procedure was introduced, UKA is used in 8% to 12% of all knee arthroplasties.2-6 A minority of these procedures are performed at the lateral side (5%-10%).6-8

The considerable anatomical and kinematical differences between compartments9-14 make it impossible to directly compare outcomes of medial and lateral UKA. For example, a greater degree of femoral roll and more posterior translation at the lateral side in flexion9,10,13 can contribute to different pattern and volume differences of cartilage wear.15 Because of these differences, and because of implant design factors and lower surgical volume, lateral UKA is considered a technically more challenging surgery compared to medial UKA.12,16,17

Since isolated lateral compartment OA is relatively scarce, current literature on lateral UKA is limited, and most studies combine medial and lateral outcomes to report UKA outcomes and failure modes.3,4,18-20 However, as the UKA has grown in popularity over the last decade,2,21-25 the number of reports about the lateral UKA also has increased. Recent studies reported excellent short-term survivorship results of the lateral UKA (96%-99%)26,27 and smaller lateral UKA studies reported the 10-year survivorship with varying outcomes from good (84%)14,28-30 to excellent (94%-100%).8,31,32 Indeed, a recent systematic review showed survivorship of lateral UKA at 5, 10, and 15 years of 93%, 91%, and 89%, respectively.33Because of the differences between the medial and lateral compartment, it is important to know the failure modes of lateral UKA in order to improve clinical outcomes and revision rates. We performed a systematic review of cohort studies and registry-based studies that reported lateral UKA failure to assess the causes of lateral UKA failure. In addition, we compared the failure modes in cohort studies with those found in registry-based studies.

Patients and Methods

Search Strategy and Criteria

Databases of PubMed, Embase, and Cochrane (Cochrane Central Register of Clinical Trials) were searched with the terms “knee, arthroplasty, replacement,” “unicompartmental,” “unicondylar,” “partial,” “UKA,” “UKR,” “UCA,” “UCR,” “PKA,” “PKR,” “PCA,” “prosthesis failure,” “reoperation,” “survivorship,” and “treatment failure.” After removal of duplicates, 2 authors (JPvdL and HAZ) scanned the articles for their title and abstract to assess eligibility for the study.

The full text of these eligible articles was further viewed and useful studies were selected using the inclusion and exclusion criteria. The references of these articles were scanned for additional studies and national registries (Figure).

Inclusion criteria were: (I) English language articles describing studies in humans published in the last 25 years, (II) retrospective and prospective studies, (III) featured lateral UKA, (IV) OA was indication for surgery, and (V) included failure modes data. The exclusion criteria were studies that featured: (I) only a specific group of failure (eg, bearing dislocations only), (II) previous surgery in ipsilateral knee (high tibial osteotomy, medial UKA), (III) acute concurrent knee diagnoses (acute anterior cruciate ligament rupture, acute meniscal tear), (IV) combined reporting of medial and lateral UKA, or (V) multiple studies with the same patient database.

Data Collection

All studies that reported modes of failure were used in this study and these failure modes were noted in a datasheet in Microsoft Excel 2011 (Microsoft).

The data of failures of lateral UKA are presented in Table 1 and are divided in cohort studies and registry-based studies. The final failure mode rates were presented in percentages (Table 2).

Statistical Analysis

For this systematic review, statistical analysis was performed with IBM SPSS Statistics 22 (SPSS Inc.). We performed chi square tests and Fisher’s exact tests to assess a difference between cohort studies and registry-based studies with the null hypothesis of no difference between both groups. A difference was considered significant when P < .05.

Results

Through the search of the databases, 1294 studies were identified and 26 handpicked studies were added. Initially, based on the title and abstract, 184 of these studies were found eligible.

After reviewing the full text of these articles, 25 studies (23 cohort studies and 2 registry-based studies) met the inclusion criteria and were included for the analysis of lateral UKA failure (Figure).

A total of 366 lateral UKA failures were included. The most common failure modes were progression of OA (29%), aseptic loosening (23%), and bearing dislocation (10%). Infection (6%), instability (6%), unexplained pain (6%), and fractures (4%) were less common causes of failure of lateral UKA (Table 2).

One hundred fifty-five of these failures were reported in the cohort studies. The most common modes of failure were OA progression (36%), bearing dislocation (17%) and aseptic loosening (16%). Less common were infection (10%), fractures (5%), pain (5%), and other causes (6%). In registry-based studies, with 211 lateral UKA failures, the most common modes of failure were aseptic loosening (28%), OA progression (24%), other causes (12%), instability (10%), pain (7%), bearing dislocation (5%), and polyethylene wear (4%) (Table 2).

When pooling cohort and registry-based studies, progression of OA was significantly more common than aseptic loosening (29% vs 23%, respectively; P < .01). It was also significantly more common in the cohort studies (36% vs 16%, respectively; P < .01) but no significant difference was found between progression of OA and aseptic loosening in registry-based studies (24% and 28%, respectively; P = .16) (Table 2).

When comparing cohort with registry-based studies, progression of OA was higher in cohort studies (36% vs. 24%; P < .01). Other failures modes that were more common in cohort studies compared with registry-based studies were bearing dislocation (17% vs 5%, respectively; P < .01) and infections (10% vs 3%, P < .01). Failure modes that were more common in registry-based studies than cohort studies were aseptic loosening (28% vs 16%, respectively; P < .01), other causes (12% vs 6%, respectively, P = .02), and instability (10% vs 1%, respectively, P < .01) (Table 2).

 

 

Discussion

In this systematic review, the most common failure modes in lateral UKA review were OA progression (29%), aseptic loosening (23%), and bearing dislocation (10%). Progression of OA and bearing dislocation were the most common modes of failure in cohort studies (36% and 17%, respectively), while aseptic loosening and OA progression were the most common failure modes in registry-based studies (28% and 24%, respectively).

As mentioned above, there are differences in anatomy and kinematics between the medial and lateral compartment. When the lateral UKA failure modes are compared with studies reporting medial UKA failure modes, differences in failure modes are seen.34 Siddiqui and Ahmad35 performed a systematic review of outcomes after UKA revision and presented a table with the failure modes of included studies. Unfortunately they did not report the ratio of medial and lateral UKA. However, when assuming an average percentage of 90% to 95% of medial UKA,6,7,36 the main failure mode in their review in 17 out of 21 studies was aseptic loosening. Indeed, a recent systematic review on medial UKA failure modes showed that aseptic loosening is the most common cause of failure following this procedure.34 Similarly, a search through registry-based studies6,7 and large cohort studies37-40 that only reported medial UKA failures showed that the majority of these studies7,37-39 also reported aseptic loosening as the main cause of failure in medial UKA. When comparing the results of our systematic review of lateral UKA failures with the results of these studies of medial UKA failures, it seems that OA progression seems to play a more dominant role in failures of lateral UKA, while aseptic loosening seems to be more common in medial UKA.

Differences in anatomy and kinematics of the medial and lateral compartment can explain this. Malalignment of the joint is an important factor in the etiology of OA41,42 and biomechanical studies showed that this malalignment can cause decreased viability and further degenerative changes of cartilage of the knee.43 Hernigou and Deschamps44 showed that the alignment of the knee after medial UKA is an important factor in postoperative joint changes. They found that overcorrection of varus deformity during medial UKA surgery, measured by the hip-knee-ankle (HKA) angle, was associated with increased OA at the lateral condyle and less tibial wear of the medial UKA. Undercorrection of the varus caused an increase in tibial wear of polyethylene. Chatellard and colleagues45 found the same results in the correction of varus, measured by HKA. In addition, they found that when the prosthetic (medial) joint space was smaller than healthy (lateral) joint space, this was correlated with lower prosthesis survival. A smaller joint space at the healthy side was correlated with OA progression at the lateral compartment and tibial component wear.

These studies explain the mechanism of progression of OA and aseptic loosening. Harrington46 assessed the load in patients with valgus and varus deformity. Patients with a valgus deformity have high mechanical load on the lateral condyle during the static phase, but during the dynamic phase, a major part of this load shifts to the medial condyle. In the patients with varus deformity, the mechanical load was noted on the medial condyle during both the static and dynamic phase. Ohdera and colleagues47 advised, based on this biomechanical study and their own experiences, to correct the knee during lateral UKA to a slight valgus angle (5°-7°) to prevent OA progression at the medial side. van der List and colleagues48 similarly showed that undercorrection of 3° to 7° was correlated with better functional outcomes when compared to more neutral alignment. Moreover, Khamaisy and colleagues49 recently showed that overcorrection during UKA surgery is more common in lateral than medial UKA.

These studies are important to understanding why OA progression is more common as a failure mode in lateral UKA. The shift of mechanical load from the lateral to medial epicondyle during the dynamic phase also could explain why aseptic loosening is less common in lateral UKA. As Hernigou and Deschamps44 and Chatellard and colleagues45 stated, undercorrection of varus deformity in medial UKA is associated with higher mechanical load on the medial prosthesis side and smaller joint space width. These factors are correlated with mechanical failure of medial UKA. We think this process can be applied to lateral UKA, with the addition that the mechanical load is higher on the healthy medial compartment during the dynamic phase. This causes more forces on the healthy (medial) side in lateral UKA, and in medial UKA more forces on the prosthesis (medial) side, which results in more OA progression in lateral UKA and more aseptic loosening in medial UKA. This finding is consistent with the results of our review of more OA progression and less aseptic loosening in lateral UKA. This study also suggests that medial and lateral UKA should not be reported together in studies that present survivorship, failure modes, or clinical outcomes.

A large discrepancy was seen in bearing dislocation between cohort studies (17%) and registry-based studies (5%). When we take a closer look to the bearing dislocation failures in the cohort studies, most of the failures were reported in only 2 cohort studies.50,51 In a study by Pandit and colleagues,50 3 different prosthesis designs were used in 3 different time periods. In the first series of lateral UKA (1983-1991), 6 out of 51 (12%) bearings dislocated. In the second series (1998-2004), a modified technique was used and 3 out of 65 (5%) bearings dislocated. In the third series (2004-2008), a modified technique and a domed tibial component was used and only 1 out of 68 bearings dislocated (1%). In a study published in 1996, Gunther and colleagues51 also used surgical techniques and implants that were modified over the course of the study period. Because of these modified techniques, different implant designs, and year of publication, bearing dislocation most likely plays a smaller role than the 17% reported in the cohort studies. This discrepancy is a good example of the important role for the registries and registry-based studies in reporting failure modes and survivorship, especially in lateral UKA due to the low surgical frequency. Pabinger and colleagues52 recently performed a systematic review of cohort studies and registry-based studies in which they stated that the reliability in non-registry-based studies should be questioned and they considered registry-based studies superior in reporting UKA outcomes and revision rates. Furthermore, given the differences in anatomic and kinematic differences between the medial and lateral compartment and different failure modes between medial and lateral UKA, it would be better if future studies presented the medial and lateral failures separately. As stated above, most large cohort studies and especially annual registries currently do not report modes of failure of medial and lateral UKA separately.3,4,18-20

There are limitations in this study. First, this systematic review is not a full meta-analysis but a pooled analysis of collected study series and retrospective studies. Therefore, we cannot exclude sampling bias, confounders, and selection bias from the literature. We included all studies reporting failure modes of lateral UKA and excluded all case reports. We made a conscious choice about including all lateral UKA failures because this is the first systematic review of lateral UKA failure modes. Another limitation is that the follow-up period of the studies differed (Table 1) and we did not correct for the follow-up period. As stated in the example of bearing dislocations, some of these studies reported old or different techniques, while other, more recently published studies used more modified techniques11,29,53-56 Unfortunately, most studies did not report the time of arthroplasty survival and therefore we could not correct for the follow-up period.

In conclusion, progression of OA is the most common failure mode in lateral UKA, followed by aseptic loosening. Anatomic and kinematic factors such as alignment, mechanical forces during dynamic phase, and correction of valgus seem to play important roles in failure modes of lateral UKA. In the future, failure modes of medial and lateral UKA should be reported separately.

Am J Orthop. 2016;45(7):432-438, 462. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

In 1975, Skolnick and colleagues1 introduced unicompartmental knee arthroplasty (UKA) for patients with isolated unicompartmental osteoarthritis (OA). They reported a study of 14 UKA procedures, of which 12 were at the medial and 2 at the lateral side. Forty years since this procedure was introduced, UKA is used in 8% to 12% of all knee arthroplasties.2-6 A minority of these procedures are performed at the lateral side (5%-10%).6-8

The considerable anatomical and kinematical differences between compartments9-14 make it impossible to directly compare outcomes of medial and lateral UKA. For example, a greater degree of femoral roll and more posterior translation at the lateral side in flexion9,10,13 can contribute to different pattern and volume differences of cartilage wear.15 Because of these differences, and because of implant design factors and lower surgical volume, lateral UKA is considered a technically more challenging surgery compared to medial UKA.12,16,17

Since isolated lateral compartment OA is relatively scarce, current literature on lateral UKA is limited, and most studies combine medial and lateral outcomes to report UKA outcomes and failure modes.3,4,18-20 However, as the UKA has grown in popularity over the last decade,2,21-25 the number of reports about the lateral UKA also has increased. Recent studies reported excellent short-term survivorship results of the lateral UKA (96%-99%)26,27 and smaller lateral UKA studies reported the 10-year survivorship with varying outcomes from good (84%)14,28-30 to excellent (94%-100%).8,31,32 Indeed, a recent systematic review showed survivorship of lateral UKA at 5, 10, and 15 years of 93%, 91%, and 89%, respectively.33Because of the differences between the medial and lateral compartment, it is important to know the failure modes of lateral UKA in order to improve clinical outcomes and revision rates. We performed a systematic review of cohort studies and registry-based studies that reported lateral UKA failure to assess the causes of lateral UKA failure. In addition, we compared the failure modes in cohort studies with those found in registry-based studies.

Patients and Methods

Search Strategy and Criteria

Databases of PubMed, Embase, and Cochrane (Cochrane Central Register of Clinical Trials) were searched with the terms “knee, arthroplasty, replacement,” “unicompartmental,” “unicondylar,” “partial,” “UKA,” “UKR,” “UCA,” “UCR,” “PKA,” “PKR,” “PCA,” “prosthesis failure,” “reoperation,” “survivorship,” and “treatment failure.” After removal of duplicates, 2 authors (JPvdL and HAZ) scanned the articles for their title and abstract to assess eligibility for the study.

The full text of these eligible articles was further viewed and useful studies were selected using the inclusion and exclusion criteria. The references of these articles were scanned for additional studies and national registries (Figure).

Inclusion criteria were: (I) English language articles describing studies in humans published in the last 25 years, (II) retrospective and prospective studies, (III) featured lateral UKA, (IV) OA was indication for surgery, and (V) included failure modes data. The exclusion criteria were studies that featured: (I) only a specific group of failure (eg, bearing dislocations only), (II) previous surgery in ipsilateral knee (high tibial osteotomy, medial UKA), (III) acute concurrent knee diagnoses (acute anterior cruciate ligament rupture, acute meniscal tear), (IV) combined reporting of medial and lateral UKA, or (V) multiple studies with the same patient database.

Data Collection

All studies that reported modes of failure were used in this study and these failure modes were noted in a datasheet in Microsoft Excel 2011 (Microsoft).

The data of failures of lateral UKA are presented in Table 1 and are divided in cohort studies and registry-based studies. The final failure mode rates were presented in percentages (Table 2).

Statistical Analysis

For this systematic review, statistical analysis was performed with IBM SPSS Statistics 22 (SPSS Inc.). We performed chi square tests and Fisher’s exact tests to assess a difference between cohort studies and registry-based studies with the null hypothesis of no difference between both groups. A difference was considered significant when P < .05.

Results

Through the search of the databases, 1294 studies were identified and 26 handpicked studies were added. Initially, based on the title and abstract, 184 of these studies were found eligible.

After reviewing the full text of these articles, 25 studies (23 cohort studies and 2 registry-based studies) met the inclusion criteria and were included for the analysis of lateral UKA failure (Figure).

A total of 366 lateral UKA failures were included. The most common failure modes were progression of OA (29%), aseptic loosening (23%), and bearing dislocation (10%). Infection (6%), instability (6%), unexplained pain (6%), and fractures (4%) were less common causes of failure of lateral UKA (Table 2).

One hundred fifty-five of these failures were reported in the cohort studies. The most common modes of failure were OA progression (36%), bearing dislocation (17%) and aseptic loosening (16%). Less common were infection (10%), fractures (5%), pain (5%), and other causes (6%). In registry-based studies, with 211 lateral UKA failures, the most common modes of failure were aseptic loosening (28%), OA progression (24%), other causes (12%), instability (10%), pain (7%), bearing dislocation (5%), and polyethylene wear (4%) (Table 2).

When pooling cohort and registry-based studies, progression of OA was significantly more common than aseptic loosening (29% vs 23%, respectively; P < .01). It was also significantly more common in the cohort studies (36% vs 16%, respectively; P < .01) but no significant difference was found between progression of OA and aseptic loosening in registry-based studies (24% and 28%, respectively; P = .16) (Table 2).

When comparing cohort with registry-based studies, progression of OA was higher in cohort studies (36% vs. 24%; P < .01). Other failures modes that were more common in cohort studies compared with registry-based studies were bearing dislocation (17% vs 5%, respectively; P < .01) and infections (10% vs 3%, P < .01). Failure modes that were more common in registry-based studies than cohort studies were aseptic loosening (28% vs 16%, respectively; P < .01), other causes (12% vs 6%, respectively, P = .02), and instability (10% vs 1%, respectively, P < .01) (Table 2).

 

 

Discussion

In this systematic review, the most common failure modes in lateral UKA review were OA progression (29%), aseptic loosening (23%), and bearing dislocation (10%). Progression of OA and bearing dislocation were the most common modes of failure in cohort studies (36% and 17%, respectively), while aseptic loosening and OA progression were the most common failure modes in registry-based studies (28% and 24%, respectively).

As mentioned above, there are differences in anatomy and kinematics between the medial and lateral compartment. When the lateral UKA failure modes are compared with studies reporting medial UKA failure modes, differences in failure modes are seen.34 Siddiqui and Ahmad35 performed a systematic review of outcomes after UKA revision and presented a table with the failure modes of included studies. Unfortunately they did not report the ratio of medial and lateral UKA. However, when assuming an average percentage of 90% to 95% of medial UKA,6,7,36 the main failure mode in their review in 17 out of 21 studies was aseptic loosening. Indeed, a recent systematic review on medial UKA failure modes showed that aseptic loosening is the most common cause of failure following this procedure.34 Similarly, a search through registry-based studies6,7 and large cohort studies37-40 that only reported medial UKA failures showed that the majority of these studies7,37-39 also reported aseptic loosening as the main cause of failure in medial UKA. When comparing the results of our systematic review of lateral UKA failures with the results of these studies of medial UKA failures, it seems that OA progression seems to play a more dominant role in failures of lateral UKA, while aseptic loosening seems to be more common in medial UKA.

Differences in anatomy and kinematics of the medial and lateral compartment can explain this. Malalignment of the joint is an important factor in the etiology of OA41,42 and biomechanical studies showed that this malalignment can cause decreased viability and further degenerative changes of cartilage of the knee.43 Hernigou and Deschamps44 showed that the alignment of the knee after medial UKA is an important factor in postoperative joint changes. They found that overcorrection of varus deformity during medial UKA surgery, measured by the hip-knee-ankle (HKA) angle, was associated with increased OA at the lateral condyle and less tibial wear of the medial UKA. Undercorrection of the varus caused an increase in tibial wear of polyethylene. Chatellard and colleagues45 found the same results in the correction of varus, measured by HKA. In addition, they found that when the prosthetic (medial) joint space was smaller than healthy (lateral) joint space, this was correlated with lower prosthesis survival. A smaller joint space at the healthy side was correlated with OA progression at the lateral compartment and tibial component wear.

These studies explain the mechanism of progression of OA and aseptic loosening. Harrington46 assessed the load in patients with valgus and varus deformity. Patients with a valgus deformity have high mechanical load on the lateral condyle during the static phase, but during the dynamic phase, a major part of this load shifts to the medial condyle. In the patients with varus deformity, the mechanical load was noted on the medial condyle during both the static and dynamic phase. Ohdera and colleagues47 advised, based on this biomechanical study and their own experiences, to correct the knee during lateral UKA to a slight valgus angle (5°-7°) to prevent OA progression at the medial side. van der List and colleagues48 similarly showed that undercorrection of 3° to 7° was correlated with better functional outcomes when compared to more neutral alignment. Moreover, Khamaisy and colleagues49 recently showed that overcorrection during UKA surgery is more common in lateral than medial UKA.

These studies are important to understanding why OA progression is more common as a failure mode in lateral UKA. The shift of mechanical load from the lateral to medial epicondyle during the dynamic phase also could explain why aseptic loosening is less common in lateral UKA. As Hernigou and Deschamps44 and Chatellard and colleagues45 stated, undercorrection of varus deformity in medial UKA is associated with higher mechanical load on the medial prosthesis side and smaller joint space width. These factors are correlated with mechanical failure of medial UKA. We think this process can be applied to lateral UKA, with the addition that the mechanical load is higher on the healthy medial compartment during the dynamic phase. This causes more forces on the healthy (medial) side in lateral UKA, and in medial UKA more forces on the prosthesis (medial) side, which results in more OA progression in lateral UKA and more aseptic loosening in medial UKA. This finding is consistent with the results of our review of more OA progression and less aseptic loosening in lateral UKA. This study also suggests that medial and lateral UKA should not be reported together in studies that present survivorship, failure modes, or clinical outcomes.

A large discrepancy was seen in bearing dislocation between cohort studies (17%) and registry-based studies (5%). When we take a closer look to the bearing dislocation failures in the cohort studies, most of the failures were reported in only 2 cohort studies.50,51 In a study by Pandit and colleagues,50 3 different prosthesis designs were used in 3 different time periods. In the first series of lateral UKA (1983-1991), 6 out of 51 (12%) bearings dislocated. In the second series (1998-2004), a modified technique was used and 3 out of 65 (5%) bearings dislocated. In the third series (2004-2008), a modified technique and a domed tibial component was used and only 1 out of 68 bearings dislocated (1%). In a study published in 1996, Gunther and colleagues51 also used surgical techniques and implants that were modified over the course of the study period. Because of these modified techniques, different implant designs, and year of publication, bearing dislocation most likely plays a smaller role than the 17% reported in the cohort studies. This discrepancy is a good example of the important role for the registries and registry-based studies in reporting failure modes and survivorship, especially in lateral UKA due to the low surgical frequency. Pabinger and colleagues52 recently performed a systematic review of cohort studies and registry-based studies in which they stated that the reliability in non-registry-based studies should be questioned and they considered registry-based studies superior in reporting UKA outcomes and revision rates. Furthermore, given the differences in anatomic and kinematic differences between the medial and lateral compartment and different failure modes between medial and lateral UKA, it would be better if future studies presented the medial and lateral failures separately. As stated above, most large cohort studies and especially annual registries currently do not report modes of failure of medial and lateral UKA separately.3,4,18-20

There are limitations in this study. First, this systematic review is not a full meta-analysis but a pooled analysis of collected study series and retrospective studies. Therefore, we cannot exclude sampling bias, confounders, and selection bias from the literature. We included all studies reporting failure modes of lateral UKA and excluded all case reports. We made a conscious choice about including all lateral UKA failures because this is the first systematic review of lateral UKA failure modes. Another limitation is that the follow-up period of the studies differed (Table 1) and we did not correct for the follow-up period. As stated in the example of bearing dislocations, some of these studies reported old or different techniques, while other, more recently published studies used more modified techniques11,29,53-56 Unfortunately, most studies did not report the time of arthroplasty survival and therefore we could not correct for the follow-up period.

In conclusion, progression of OA is the most common failure mode in lateral UKA, followed by aseptic loosening. Anatomic and kinematic factors such as alignment, mechanical forces during dynamic phase, and correction of valgus seem to play important roles in failure modes of lateral UKA. In the future, failure modes of medial and lateral UKA should be reported separately.

Am J Orthop. 2016;45(7):432-438, 462. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

References

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63. Streit MR, Walker T, Bruckner T, et al. Mobile-bearing lateral unicompartmental knee replacement with the Oxford domed tibial component: an independent series. J Bone Joint Surg Br. 2012;94(10):1356-1361.

64. Altuntas AO, Alsop H, Cobb JP. Early results of a domed tibia, mobile bearing lateral unicompartmental knee arthroplasty from an independent centre. Knee. 2013;20(6):466-470.

65. Ashraf T, Newman JH, Desai VV, Beard D, Nevelos JE. Polyethylene wear in a non-congruous unicompartmental knee replacement: a retrieval analysis. Knee. 2004;11(3):177-181.

66. Schelfaut S, Beckers L, Verdonk P, Bellemans J, Victor J. The risk of bearing dislocation in lateral unicompartmental knee arthroplasty using a mobile biconcave design. Knee Surg Sports Traumatol Arthrosc. 2013;21(11):2487-2494.

67. Marson B, Prasad N, Jenkins R, Lewis M. Lateral unicompartmental knee replacements: Early results from a District General Hospital. Eur J Orthop Surg Traumatol. 2014;24(6):987-991.

68. Walker T, Gotterbarm T, Bruckner T, Merle C, Streit MR. Total versus unicompartmental knee replacement for isolated lateral osteoarthritis: a matched-pairs study. Int Orthop. 2014;38(11):2259-2264.

References

1. Skolnick MD, Bryan RS, Peterson LFA. Unicompartmental polycentric knee arthroplasty. Description and preliminary results. Clin Orthop Relat Res. 1975;(112):208-214.

2. Riddle DL, Jiranek WA, McGlynn FJ. Yearly Incidence of Unicompartmental Knee Arthroplasty in the United States. J Arthroplasty. 2008;23(3):408-412.

3. Australian Orthopaedic Association. Hip and Knee Arthroplasty 2014 Annual Report. https://aoanjrr.sahmri.com/documents/10180/172286/Annual%20Report%202014. Accessed June 3, 2015.

4. Swedish Knee Arthroplasty Register. 2013 Annual Report.http://myknee.se/pdf/SKAR2013_Eng.pdf. Accessed June 3, 2015.

5. The New Zealand Joint Registry. Fourteen Year Report. January 1999 to December 2012. 2013. http://nzoa.org.nz/system/files/NJR 14 Year Report.pdf. Accessed June 3, 2015.

6. Baker PN, Jameson SS, Deehan DJ, Gregg PJ, Porter M, Tucker K. Mid-term equivalent survival of medial and lateral unicondylar knee replacement: an analysis of data from a National Joint Registry. J Bone Joint Surg Br. 2012;94(12):1641-1648.

7. Lewold S, Robertsson O, Knutson K, Lidgren L. Revision of unicompartmental knee arthroplasty: outcome in 1,135 cases from the Swedish Knee Arthroplasty study. Acta Orthop Scand. 1998;69(5):469-474.

8. Pennington DW, Swienckowski JJ, Lutes WB, Drake GN. Lateral unicompartmental knee arthroplasty: survivorship and technical considerations at an average follow-up of 12.4 years. J Arthroplasty. 2006;21(1):13-17.

9. Hill PF, Vedi V, Williams A, Iwaki H, Pinskerova V, Freeman MA. Tibiofemoral movement 2: the loaded and unloaded living knee studied by MRI. J Bone Joint Surg Br. 2000;82(8):1196-1198.

10. Nakagawa S, Kadoya Y, Todo S, et al. Tibiofemoral movement 3: full flexion in the living knee studied by MRI. J Bone Joint Surg Br. 2000;82(8):1199-1200.

11. Ashraf T, Newman JH, Evans RL, Ackroyd CE. Lateral unicompartmental knee replacement survivorship and clinical experience over 21 years. J Bone Joint Surg Br. 2002;84(8):1126-1130.

12. Scott RD. Lateral unicompartmental replacement: a road less traveled. Orthopedics. 2005;28(9):983-984.

13. Sah AP, Scott RD. Lateral unicompartmental knee arthroplasty through a medial approach. Study with an average five-year follow-up. J Bone Joint Surg Am. 2007;89(9):1948-1954.

14. Argenson JN, Parratte S, Bertani A, Flecher X, Aubaniac JM. Long-term results with a lateral unicondylar replacement. Clin Orthop Relat Res. 2008;466(11):2686-2693.

15. Weidow J, Pak J, Karrholm J. Different patterns of cartilage wear in medial and lateral gonarthrosis. Acta Orthop Scand. 2002;73(3):326-329.

16. Ollivier M, Abdel MP, Parratte S, Argenson JN. Lateral unicondylar knee arthroplasty (UKA): contemporary indications, surgical technique, and results. Int Orthop. 2014;38(2):449-455.

17. Demange MK, Von Keudell A, Probst C, Yoshioka H, Gomoll AH. Patient-specific implants for lateral unicompartmental knee arthroplasty. Int Orthop. 2015;39(8):1519-1526.

18. Khan Z, Nawaz SZ, Kahane S, Esler C, Chatterji U. Conversion of unicompartmental knee arthroplasty to total knee arthroplasty: the challenges and need for augments. Acta Orthop Belg. 2013;79(6):699-705.

19. Epinette JA, Brunschweiler B, Mertl P, et al. Unicompartmental knee arthroplasty modes of failure: wear is not the main reason for failure: a multicentre study of 418 failed knees. Orthop Traumatol Surg Res. 2012;98(6 Suppl):S124-S130.

20. Bordini B, Stea S, Falcioni S, Ancarani C, Toni A. Unicompartmental knee arthroplasty: 11-year experience from 3929 implants in RIPO register. Knee. 2014;21(6):1275-1279.

21. Bolognesi MP, Greiner MA, Attarian DE, et al. Unicompartmental knee arthroplasty and total knee arthroplasty among medicare beneficiaries, 2000 to 2009. J Bone Joint Surg Am. 2013;95(22):e174.

22. Nwachukwu BU, McCormick FM, Schairer WW, Frank RM, Provencher MT, Roche MW. Unicompartmental knee arthroplasty versus high tibial osteotomy: United States practice patterns for the surgical treatment of unicompartmental arthritis. J Arthroplasty. 2014;29(8):1586-1589.

23. van der List JP, Chawla H, Pearle AD. Robotic-assisted knee arthroplasty: an overview. Am J Orthop. 2016;45(4):202-211.

24. van der List JP, Chawla H, Joskowicz L, Pearle AD. Current state of computer navigation and robotics in unicompartmental and total knee arthroplasty: a systematic review with meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2016 Sep 6. [Epub ahead of print]

25. Zuiderbaan HA, van der List JP, Kleeblad LJ, et al. Modern indications, results and global trends in the use of unicompartmental knee arthroplasty and high tibial osteotomy for the treatment of medial unicondylar knee osteoarthritis. Am J Orthop. 2016;45(6):E355-E361.

26. Smith JR, Robinson JR, Porteous AJ, et al. Fixed bearing lateral unicompartmental knee arthroplasty--short to midterm survivorship and knee scores for 101 prostheses. Knee. 2014;21(4):843-847.

27. Berend KR, Kolczun MC 2nd, George JW Jr, Lombardi AV Jr. Lateral unicompartmental knee arthroplasty through a lateral parapatellar approach has high early survivorship. Clin Orthop Relat Res. 2012;470(1):77-83.

28. Keblish PA, Briard JL. Mobile-bearing unicompartmental knee arthroplasty: a 2-center study with an 11-year (mean) follow-up. J Arthroplasty. 2004;19(7 Suppl 2):87-94.

29. Bertani A, Flecher X, Parratte S, Aubaniac JM, Argenson JN. Unicompartmental-knee arthroplasty for treatment of lateral gonarthrosis: about 30 cases. Midterm results. Rev Chir Orthop Reparatrice Appar Mot. 2008;94(8):763-770.

30. Sebilo A, Casin C, Lebel B, et al. Clinical and technical factors influencing outcomes of unicompartmental knee arthroplasty: Retrospective multicentre study of 944 knees. Orthop Traumatol Surg Res. 2013;99(4 Suppl):S227-S234.

31. Cartier P, Khefacha A, Sanouiller JL, Frederick K. Unicondylar knee arthroplasty in middle-aged patients: A minimum 5-year follow-up. Orthopedics. 2007;30(8 Suppl):62-65.

32. Lustig S, Paillot JL, Servien E, Henry J, Ait Si Selmi T, Neyret P. Cemented all polyethylene tibial insert unicompartimental knee arthroplasty: a long term follow-up study. Orthop Traumatol Surg Res. 2009;95(1):12-21.

33. van der List JP, McDonald LS, Pearle AD. Systematic review of medial versus lateral survivorship in unicompartmental knee arthroplasty. Knee. 2015;22(6):454-460.

34. van der List JP, Zuiderbaan HA, Pearle AD. Why do medial unicompartmental knee arthroplasties fail today? J Arthroplasty. 2016;31(5):1016-1021.

35. Siddiqui NA, Ahmad ZM. Revision of unicondylar to total knee arthroplasty: a systematic review. Open Orthop J. 2012;6:268-275.

36. Pennington DW, Swienckowski JJ, Lutes WB, Drake GN. Lateral unicompartmental knee arthroplasty: survivorship and technical considerations at an average follow-up of 12.4 years. J Arthroplasty. 2006;21(1):13-17.

37. Kalra S, Smith TO, Berko B, Walton NP. Assessment of radiolucent lines around the Oxford unicompartmental knee replacement: sensitivity and specificity for loosening. J Bone Joint Surg Br. 2011;93(6):777-781.

38. Wynn Jones H, Chan W, Harrison T, Smith TO, Masonda P, Walton NP. Revision of medial Oxford unicompartmental knee replacement to a total knee replacement: similar to a primary? Knee. 2012;19(4):339-343.

39. Sierra RJ, Kassel CA, Wetters NG, Berend KR, Della Valle CJ, Lombardi AV. Revision of unicompartmental arthroplasty to total knee arthroplasty: not always a slam dunk! J Arthroplasty. 2013;28(8 Suppl):128-132.

40. Citak M, Dersch K, Kamath AF, Haasper C, Gehrke T, Kendoff D. Common causes of failed unicompartmental knee arthroplasty: a single-centre analysis of four hundred and seventy one cases. Int Orthop. 2014;38(5):961-965.

41. Hunter DJ, Wilson DR. Role of alignment and biomechanics in osteoarthritis and implications for imaging. Radiol Clin North Am. 2009;47(4):553-566.

42. Hunter DJ, Sharma L, Skaife T. Alignment and osteoarthritis of the knee. J Bone Joint Surg Am. 2009;91 Suppl 1:85-89.

43. Roemhildt ML, Beynnon BD, Gauthier AE, Gardner-Morse M, Ertem F, Badger GJ. Chronic in vivo load alteration induces degenerative changes in the rat tibiofemoral joint. Osteoarthritis Cartilage. 2013;21(2):346-357.

44. Hernigou P, Deschamps G. Alignment influences wear in the knee after medial unicompartmental arthroplasty. Clin Orthop Relat Res. 2004;(423):161-165.

45. Chatellard R, Sauleau V, Colmar M, et al. Medial unicompartmental knee arthroplasty: does tibial component position influence clinical outcomes and arthroplasty survival? Orthop Traumatol Surg Res. 2013;99(4 Suppl):S219-S225.

46. Harrington IJ. Static and dynamic loading patterns in knee joints with deformities. J Bone Joint Surg Am. 1983;65(2):247-259.

47. Ohdera T, Tokunaga J, Kobayashi A. Unicompartmental knee arthroplasty for lateral gonarthrosis: midterm results. J Arthroplasty. 2001;16(2):196-200.

48. van der List JP, Chawla H, Villa JC, Zuiderbaan HA, Pearle AD. Early functional outcome after lateral UKA is sensitive to postoperative lower limb alignment. Knee Surg Sports Traumatol Arthrosc. 2015 Nov 26. [Epub ahead of print]

49. Khamaisy S, Gladnick BP, Nam D, Reinhardt KR, Heyse TJ, Pearle AD. Lower limb alignment control: Is it more challenging in lateral compared to medial unicondylar knee arthroplasty? Knee. 2015;22(4):347-350.

50. Pandit H, Jenkins C, Beard DJ, et al. Mobile bearing dislocation in lateral unicompartmental knee replacement. Knee. 2010;17(6):392-397.

51. Gunther TV, Murray DW, Miller R, et al. Lateral unicompartmental arthroplasty with the Oxford meniscal knee. Knee. 1996;3(1):33-39.

52. Pabinger C, Lumenta DB, Cupak D, Berghold A, Boehler N, Labek G. Quality of outcome data in knee arthroplasty: Comparison of registry data and worldwide non-registry studies from 4 decades. Acta Orthopaedica. 2015;86(1):58-62.

53. Lustig S, Elguindy A, Servien E, et al. 5- to 16-year follow-up of 54 consecutive lateral unicondylar knee arthroplasties with a fixed-all polyethylene bearing. J Arthroplasty. 2011;26(8):1318-1325.

54. Walton MJ, Weale AE, Newman JH. The progression of arthritis following lateral unicompartmental knee replacement. Knee. 2006;13(5):374-377.

55. Lustig S, Lording T, Frank F, Debette C, Servien E, Neyret P. Progression of medial osteoarthritis and long term results of lateral unicompartmental arthroplasty: 10 to 18 year follow-up of 54 consecutive implants. Knee. 2014;21(S1):S26-S32.

56. O’Rourke MR, Gardner JJ, Callaghan JJ, et al. Unicompartmental knee replacement: a minimum twenty-one-year followup, end-result study. Clin Orthop Relat Res. 2005;440:27-37.

57. Citak M, Cross MB, Gehrke T, Dersch K, Kendoff D. Modes of failure and revision of failed lateral unicompartmental knee arthroplasties. Knee. 2015;22(4):338-340.

58. Liebs TR, Herzberg W. Better quality of life after medial versus lateral unicondylar knee arthroplasty knee. Clin Orthop Relat Res. 2013;471(8):2629-2640.

59. Weston-Simons JS, Pandit H, Kendrick BJ, et al. The mid-term outcomes of the Oxford Domed Lateral unicompartmental knee replacement. Bone Joint J. 2014;96-B(1):59-64.

60. Thompson SA, Liabaud B, Nellans KW, Geller JA. Factors associated with poor outcomes following unicompartmental knee arthroplasty: redefining the “classic” indications for surgery. J Arthroplasty. 2013;28(9):1561-1564.

61. Saxler G, Temmen D, Bontemps G. Medium-term results of the AMC-unicompartmental knee arthroplasty. Knee. 2004;11(5):349-355.

62. Forster MC, Bauze AJ, Keene GCR. Lateral unicompartmental knee replacement: Fixed or mobile bearing? Knee Surg Sports Traumatol Arthrosc. 2007;15(9):1107-1111.

63. Streit MR, Walker T, Bruckner T, et al. Mobile-bearing lateral unicompartmental knee replacement with the Oxford domed tibial component: an independent series. J Bone Joint Surg Br. 2012;94(10):1356-1361.

64. Altuntas AO, Alsop H, Cobb JP. Early results of a domed tibia, mobile bearing lateral unicompartmental knee arthroplasty from an independent centre. Knee. 2013;20(6):466-470.

65. Ashraf T, Newman JH, Desai VV, Beard D, Nevelos JE. Polyethylene wear in a non-congruous unicompartmental knee replacement: a retrieval analysis. Knee. 2004;11(3):177-181.

66. Schelfaut S, Beckers L, Verdonk P, Bellemans J, Victor J. The risk of bearing dislocation in lateral unicompartmental knee arthroplasty using a mobile biconcave design. Knee Surg Sports Traumatol Arthrosc. 2013;21(11):2487-2494.

67. Marson B, Prasad N, Jenkins R, Lewis M. Lateral unicompartmental knee replacements: Early results from a District General Hospital. Eur J Orthop Surg Traumatol. 2014;24(6):987-991.

68. Walker T, Gotterbarm T, Bruckner T, Merle C, Streit MR. Total versus unicompartmental knee replacement for isolated lateral osteoarthritis: a matched-pairs study. Int Orthop. 2014;38(11):2259-2264.

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Diagnosis at a Glance: Debilitating Thigh Mass in an Obese Patient

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Diagnosis at a Glance: Debilitating Thigh Mass in an Obese Patient
A 60-year-old morbidly obese man presented for evaluation of a painless mass on his left thigh.
Author(s)
Sri Rahul Balusu
MD; Michelle D. Lall
MD
MHS

Case

A 60-year-old morbidly obese man presented to the ED with a painless mass on his left thigh (Figure 1), which he stated had formed over a several day period 2 months earlier.

He further noted that although there had been no further growth in the mass since its initial formation, it had become debilitating and was interfering with his gait. The patient denied any drainage from the mass or any prior trauma to the area.

On examination, the patient appeared well, with normal vital signs and a body mass index of 56 kg/m2. A computed tomography (CT) scan was obtained to further evaluate the mass (Figure 2), and dermatology services were consulted.

After examining the patient, the dermatologist diagnosed the patient with massive localized lymphedema (MLL). He was discharged home with a referral to an outpatient surgeon to discuss removal of the mass.

Discussion

Massive localized lymphedema is a complication associated with morbid obesity. First described in 1998 by Farshid and Weiss,1 MLL is characterized by a benign pedunculated mass primarily of the lower extremity that slowly enlarges over years.2 The pathogenesis of MLL is currently unknown. Histologically, MLL contains lobules of mature fat with expanded connective tissue septa without the degree of cellular atypia in well-differentiated liposarcoma (WDL). Though similar to WDL, MLL can be differentiated by the clinical history of a slowly growing mass in a morbidly obese patient and examination findings of overlying reactive skin and soft-tissue changes associated with chronic lymphedema (eg, thickened peau d’orange skin).1,2

The diagnosis of MLL may be made clinically, and if there is no evidence of infection, the patient may be referred to a surgeon. If diagnostic uncertainty remains, biopsy and further CT imaging studies should be considered. The treatment for MLL is a direct excision if the mass is interfering with the patient’s gait. If left untreated, MLL can progress to angiosarcoma. Recurrence is possible, even after surgical excision.3

References

1. Farshid G, Weiss SW. Massive localized lymphedema in the morbidly obese: a histologically distinct reactive lesion simulating liposarcoma. Am J Surg Pathol. 1998;22(10):1277-1283.

2. Evans RJ, Scilley C. Massive localized lymphedema: A case series and literature review. Can J Plast Surg. 2011;19(3):e30-e31.

3. Moon Y, Pyon JK. A rare case of massive localized lymphedema in a morbidly obese patient. Arch of Plast Surg. 2016;43(1):125-127. doi:10.5999/aps.2016.43.1.125.

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MHS
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A 60-year-old morbidly obese man presented for evaluation of a painless mass on his left thigh.
A 60-year-old morbidly obese man presented for evaluation of a painless mass on his left thigh.

Case

A 60-year-old morbidly obese man presented to the ED with a painless mass on his left thigh (Figure 1), which he stated had formed over a several day period 2 months earlier.

He further noted that although there had been no further growth in the mass since its initial formation, it had become debilitating and was interfering with his gait. The patient denied any drainage from the mass or any prior trauma to the area.

On examination, the patient appeared well, with normal vital signs and a body mass index of 56 kg/m2. A computed tomography (CT) scan was obtained to further evaluate the mass (Figure 2), and dermatology services were consulted.

After examining the patient, the dermatologist diagnosed the patient with massive localized lymphedema (MLL). He was discharged home with a referral to an outpatient surgeon to discuss removal of the mass.

Discussion

Massive localized lymphedema is a complication associated with morbid obesity. First described in 1998 by Farshid and Weiss,1 MLL is characterized by a benign pedunculated mass primarily of the lower extremity that slowly enlarges over years.2 The pathogenesis of MLL is currently unknown. Histologically, MLL contains lobules of mature fat with expanded connective tissue septa without the degree of cellular atypia in well-differentiated liposarcoma (WDL). Though similar to WDL, MLL can be differentiated by the clinical history of a slowly growing mass in a morbidly obese patient and examination findings of overlying reactive skin and soft-tissue changes associated with chronic lymphedema (eg, thickened peau d’orange skin).1,2

The diagnosis of MLL may be made clinically, and if there is no evidence of infection, the patient may be referred to a surgeon. If diagnostic uncertainty remains, biopsy and further CT imaging studies should be considered. The treatment for MLL is a direct excision if the mass is interfering with the patient’s gait. If left untreated, MLL can progress to angiosarcoma. Recurrence is possible, even after surgical excision.3

Case

A 60-year-old morbidly obese man presented to the ED with a painless mass on his left thigh (Figure 1), which he stated had formed over a several day period 2 months earlier.

He further noted that although there had been no further growth in the mass since its initial formation, it had become debilitating and was interfering with his gait. The patient denied any drainage from the mass or any prior trauma to the area.

On examination, the patient appeared well, with normal vital signs and a body mass index of 56 kg/m2. A computed tomography (CT) scan was obtained to further evaluate the mass (Figure 2), and dermatology services were consulted.

After examining the patient, the dermatologist diagnosed the patient with massive localized lymphedema (MLL). He was discharged home with a referral to an outpatient surgeon to discuss removal of the mass.

Discussion

Massive localized lymphedema is a complication associated with morbid obesity. First described in 1998 by Farshid and Weiss,1 MLL is characterized by a benign pedunculated mass primarily of the lower extremity that slowly enlarges over years.2 The pathogenesis of MLL is currently unknown. Histologically, MLL contains lobules of mature fat with expanded connective tissue septa without the degree of cellular atypia in well-differentiated liposarcoma (WDL). Though similar to WDL, MLL can be differentiated by the clinical history of a slowly growing mass in a morbidly obese patient and examination findings of overlying reactive skin and soft-tissue changes associated with chronic lymphedema (eg, thickened peau d’orange skin).1,2

The diagnosis of MLL may be made clinically, and if there is no evidence of infection, the patient may be referred to a surgeon. If diagnostic uncertainty remains, biopsy and further CT imaging studies should be considered. The treatment for MLL is a direct excision if the mass is interfering with the patient’s gait. If left untreated, MLL can progress to angiosarcoma. Recurrence is possible, even after surgical excision.3

References

1. Farshid G, Weiss SW. Massive localized lymphedema in the morbidly obese: a histologically distinct reactive lesion simulating liposarcoma. Am J Surg Pathol. 1998;22(10):1277-1283.

2. Evans RJ, Scilley C. Massive localized lymphedema: A case series and literature review. Can J Plast Surg. 2011;19(3):e30-e31.

3. Moon Y, Pyon JK. A rare case of massive localized lymphedema in a morbidly obese patient. Arch of Plast Surg. 2016;43(1):125-127. doi:10.5999/aps.2016.43.1.125.

References

1. Farshid G, Weiss SW. Massive localized lymphedema in the morbidly obese: a histologically distinct reactive lesion simulating liposarcoma. Am J Surg Pathol. 1998;22(10):1277-1283.

2. Evans RJ, Scilley C. Massive localized lymphedema: A case series and literature review. Can J Plast Surg. 2011;19(3):e30-e31.

3. Moon Y, Pyon JK. A rare case of massive localized lymphedema in a morbidly obese patient. Arch of Plast Surg. 2016;43(1):125-127. doi:10.5999/aps.2016.43.1.125.

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The Burden of COPD

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Author(s)
Susan C. Stone
MD
Mph

Case Scenario

A 62-year-old man who regularly presented to the ED for exacerbations of chronic obstructive pulmonary disease (COPD) after running out of his medications presented again for evaluation and treatment. His outpatient care had been poorly coordinated, and he relied on the ED to provide him with the support he needed. This presentation represented his fifth visit to the ED over the past 3 months.

The patient’s medical history was positive for asthma since childhood, tobacco use, hypertension, and a recent diagnosis of congestive heart failure (CHF). Over the past year, he had four hospital admissions, and was currently unable to walk from his bedroom to another room without becoming short of breath. He also had recently experienced a 20-lb weight loss.

At this visit, the patient complained of chest pain and lightheadedness, which he described as suffocating. Prior to these recent symptoms, he enjoyed walking in his neighborhood and talking with friends. He was an avid reader and sports fan, but admitted that he now had trouble focusing on reading and following games on television. He lived alone, and his family lived across the country. The patient further admitted that although he had attempted to quit cigarette smoking, he was unable to give up his 50-pack per year habit. He had no completed advance health care directive and had significant challenges tending to his basic needs.

The Trajectory of COPD

Chronic obstructive pulmonary disease is a common chronic illness that causes significant morbidity and mortality. A 2016 National Health Services report cited respiratory illness, primarily from COPD, as the third leading cause of death in the United States in 2014.1The trajectory of this disease is marked by frequent exacerbations with partial recovery to baseline function. The burden of those living with COPD is significant and marked by a poor overall health-related quality of life (QOL). The ED has become a staging area for patients seeking care for exacerbations of COPD.2

The World Health Organization (WHO) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have defined COPD as a spectrum of diseases including emphysema, chronic bronchitis, and chronic obstructive asthma characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response to noxious particles or gases in the airways and lungs.3 Exacerbations and comorbidities contribute to the overall severity of COPD in individual patients.4

The case presented in this article illustrates the common scenario of a patient whose COPD has become severe and highly symptomatic with declining function to the point where he requires home support. His physical decline had been rapid and resulted in many unmet needs. When a patient such as this presents for emergent care, he must first be stabilized; then a care plan will need to be developed prior to discharge.

Management Goals

The overall goals of treating COPD are based on preserving function and are not curative in nature. Chronic obstructive pulmonary disease is a progressive illness that will intensify over time.5 As such, palliative care services are warranted. However, many patients with COPD do not receive palliative care services compared to patients with such other serious and life-limiting disease as cancer and heart disease.

Acute Exacerbations of COPD

Incidence

The frequency of acute exacerbations of COPD (AECOPD) increases with age, productive cough, long-standing COPD, previous hospitalizations related to COPD, eosinophilia, and comorbidities (eg, CHF). Patients with moderate to severe COPD and a history of prior exacerbations were found to have a higher likelihood of future exacerbations. From a quality and cost perspective, it may be useful to identify high-risk patients and strengthen their outpatient program to lessen the need for ED care and more intensive support.6,7

In our case scenario, the patient could have been stabilized at home with a well-controlled plan and home support, which would have resulted in an improved QOL and more time free from his high symptom burden.

Causes

Bacterial and viral respiratory infections are the most likely cause of AECOPD. Environmental pollution and pulmonary embolism are also triggers. Typically, patients with AECOPD present to the ED up to several times a year2 and represent the third most common cause of 30-day readmissions to the hospital.8 Prior exacerbations, dyspnea, and other medical comorbidities are also risk factors for more frequent hospital visits.

 

 

Presenting Signs and Symptoms

Each occurrence of AECOPD represents a worsening of a patient’s respiratory symptoms beyond normal variations. This might include increases in cough, sputum production, and dyspnea. The goal in caring for a person with an AECOPD is to stabilize the acute event and provide a treatment plan. The range of acuity for moderate to severe disease makes devising an appropriate treatment plan challenging, and after implementing the best plans, the patient’s course may be characterized by a prolonged cycle of admissions and readmissions without substantial return to baseline.

Management

In practice, ED management of AECOPD in older adults typically differs significantly from published guideline recommendations,9 which may result in pooroutcomes related to shortcomings in quality of care. Better adherence to guideline recommendations when caring for elderly patients with COPD may lead to improved clinical outcomes and better resource usage.6,9

Risk Stratification

Complicating ED management is the challenge of determining the severity of illness and degree of the exacerbation. Airflow obstruction alone is not sufficient to predict outcomes, as any particular measure of obstruction is associated with a spectrum of forced expiratory volume in the first second (FEV1) and varying performance. Moreover, peak-flow measurements are not useful in the setting of AECOPD, as opposed to their use in acute asthma exacerbations, and are not predictive of changes in clinical status.

GOLD and NICE Criteria

Guidelines have been developed and widely promoted to assist ED and hospital and community clinicians in providing evidence-based management for COPD patients. The GOLD Criteria and the National Institute for Clinical Excellence (NICE) are both clinical guidelines on management of COPD.10

Although well recognized and commonly used, the original GOLD criteria did not take into account the frequency and importance of the extrapulmonary manifestations of COPD in predicting outcome. Typically, those with severe or very severe COPD have an average of 12 co-occurring symptoms, an even greater number of signs and symptoms than those occurring in patients with cancer or heart or renal disease.11

The newly revised GOLD criteria not only reflect mortality prediction but also include the symptoms driving the risk for exacerbations (Table 1).12

BODE Criteria

The body mass index, airflow obstruction, dyspnea and exercise capacity (BODE) criteria assess and predict the health-related QOL and mortality risk for patients with COPD. Risk is adjusted based on four factors—weight, airway obstruction, dyspnea, and exercise capacity (ie, 6-minute walk distance).13

Table 2 provides a summary of the BODE criteria.

Initial Evaluation and Work-Up

As previously noted, when an AECOPD patient arrives to the ED, the first priority is to stabilize the patient and initiate treatment. In this respect, initial identification of the patient’s pulse oxygen saturation (SpO2) is important.

Laboratory Evaluation

In cases of respiratory failure, obtaining arterial blood gas (ABG) values are critical. The ABG test will assist in determining acute exacerbations of chronic hypercapnia and the need for ventilatory support. When considering CHF, a plasma B-type natriuretic peptide is useful to assess for CHF.

Imaging Studies

A chest radiograph may be useful in the initial evaluation to identify abnormalities, including barotrauma (ie, pneumothorax) and infiltrates. Additionally, in patients with comorbidities, it is important to assess cardiac status, and a chest X-ray may assist in identification of pulmonary edema, pleural effusions, and cardiomegaly. If the radiograph does show a pulmonary infiltrate (ie, pneumonia), it will help identify the probable triggers, but even in these instances, a sputum gram stain will not assist in the diagnosis.

Treatment

Relieving airflow obstruction is achieved with inhaled short-acting bronchodilators and systemic glucocorticoids, by treating infection, and by providing supplemental oxygen and ventilatory support.

Bronchodilators

The short-acting beta-adrenergic agonists (eg, albuterol) act rapidly and are effective in producing bronchodilation. Nebulized therapy may be most comfortable for the acutely ill patient. Typical dosing is 2.5 mg albuterol diluted to 3 cc by nebulizer every hour. Higher doses are not more effective, and there is no evidence of a higher response rate from constant nebulized therapy, which can cause anxiety and tachycardia in patients.14 Anticholinergic agents (eg, ipratropium) are often added despite unclear data regarding clinical advantage. In one study evaluating the effectiveness of adding ipratropium to albuterol, patients receiving a combination had the same improvement in FEV1 at 90 minutes.15 Patients receiving ipratropium alone had the lowest rate of reported side effects.15

Systemic Glucocorticoids

Short-course systemic glucocorticoids are an important addition to treatment and have been found to improve spirometry and decrease relapse rate. The oral and intravenous (IV) routes provide the same benefit. For the acutely ill patient with challenges swallowing, the IV route is preferred. The optimal dose is not clear, but hydrocortisone doses of 100 mg to 125 mg every 6 hours for 3 days are effective, as is oral prednisone 30 mg per day for 14 days, or 60 mg per day for 3 days with a taper.

 

 

Antibiotic Therapy

Antibiotics are indicated for patients with moderate to severe AECOPD who are ill enough to be admitted to the hospital. Empiric broad spectrum treatment is recommended. The initial antibiotic regimen should target likely bacterial pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in most patients) and take into account local patterns of antibiotic resistance. Flouroquinolones or third-generation cephalosporins generally provide sufficient coverage. For patients experiencing only a mild exacerbation, antibiotics are not warranted.

Magnesium Sulfate

Other supplemental medications that have been evaluated include magnesium sulfate for bronchial smooth muscle relaxation. Studies have found that while magnesium is helpful in asthma, results are mixed with COPD.16

Supplemental Oxygen

Oxygen therapy is important during an AECOPD episode. Often, concerns arise about decreasing respiratory drive, which is typically driven by hypoxia in patients who have chronic hypercapnia. Arterial blood gas determinations are important in managing a patient’s respiratory status and will assist in determining actual oxygenation and any coexistent metabolic disturbances.

Noninvasive Ventilation. Oxygen can be administered efficiently by a venturi mask, which delivers precise fractions of oxygen, or by nasal cannula. A facemask is less comfortable, but is available for higher oxygen requirements, providing up to 55% oxygen, while a nonrebreather mask delivers up to 90% oxygen.

When necessary, noninvasive positive pressure ventilation (NPPV) improves outcomes for those with severe dyspnea and signs of respiratory fatigue manifested as increased work of breathing. Noninvasive positive pressure ventilation can improve clinical outcomes and is the ventilator mode of choice for those patients with COPD. Indications include severe dyspnea with signs of increased work of breathing and respiratory acidosis (arterial pH <7.35) and partial pressure of arterial carbon dioxide (PaCO2) >45 mm Hg.

Whenever possible, NPPV should be initiated with a triggered mode to allow spontaneous breaths. Inspiratory pressure of 8 cm to 12 cm H2O and expiratory pressure of 3 cm to 5 cm of H2 are recommended.

Mechanical Ventilation. Mechanical ventilation is often undesirable because it may be extraordinarily difficult to wean a patient off the device and permit safe extubation. However, if a patient cannot be stabilized with NPPV, intubation and mechanical ventilation must be considered. Typically, this occurs when there is severe respiratory distress, tachypnea >30 breaths/min, accessory muscle use, and altered mentation.

Goals of intubation/mechanical respiration include correcting oxygenation and severe respiratory acidosis as well as reducing the work of breathing. Barotrauma is a significant risk when patients with COPD require mechanical ventilation. Volume-limited modes of ventilation are commonly used, while pressure support or pressure-limited modes are less suitable for patients with airflow limitation. Again, invasive ventilation should only be administered if a patient cannot tolerate NPPV.

Palliative Care in the ED

Palliative care is an approach that improves the QOL of patients and their families facing the issues associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and accurate assessment and treatment of pain and physical, psychosocial, and spiritual problems.3 This approach to care is warranted for COPD patients given the myriad of burdensome symptoms and functional decline that occurs.17

Palliative care expands traditional treatment goals to include enhancing QOL; helping with medical decision making; and identifying the goals of care. Palliative care is provided by board-certified physicians for the most complex of cases. However, the primary practice of palliative care must be delivered at the bedside by the treating provider. Managing pain, dyspnea, nausea, vomiting, and changes in bowel habits, as well as discussing goals of care, are among the basic palliative care skills all providers need to have and apply when indicated.

Palliative Care for Dyspnea

Opioids. Primary palliative care in the ED includes the appropriate use of low-dose oral and parenteral opioids to treat dyspnea in AECOPD. The use of a low-dose opioid, such as morphine 2 mg IV, titrated up to a desired response, is a safe and effective practice.18 Note the 2-mg starting dose is considered low-dose.19

With respect to managing dyspnea in AECOPD patients, nebulized opioids have not been found to be better than nebulized saline. More specific data regarding the use of oral opioids for managing refractory dyspnea in patients with predominantly COPD have been recently published: Long-acting morphine 20 mg once daily provides symptomatic relief in refractory dyspnea in the community setting. For the opioid-naïve patient, a lower dose is recommended.20

Oxygenation. There is no hard evidence of the effectiveness of oxygen in the palliation of breathlessness. Humidified air is effective initially, as is providing a fan at the bedside. Short-burst oxygen therapy should only be considered for episodes of severe breathlessness in patients whose COPD is not relieved by other treatments. Oxygen should continue to be prescribed only if an improvement in breathlessness following therapy has been documented. The American Thoracic Society recommends continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (PaCO2 ≤55 mm Hg or SpO2 ≤88%).21

 

 

POLST Form

The Physicians Order for Life-Sustaining Treatment (POLST) form is a set of medical orders, similar to the “do not resuscitate” (allow natural death) order. A POLST form is not an advance directive and does not serve as a substitute for a patient’s assignation of a health care agent or durable power of attorney for health care.22

The POLST form enables physicians to order treatments patients would want, identify those treatments that patients would not want, and not provide those the patient considers “extraordinary” and excessively burdensome. A POLST form does not allow for active euthanasia or physician-assisted suicide.

Identifying treatment preferences is an important part of the initial evaluation of all patients. When dealing with an airway issue in a COPD patient, management can become complex. Ideally, the POLST form should arrive with the patient in the ED and list preferences regarding possible intensive interventions such as intubation and chest compressions. Discussing these issues with a patient in extreme distress is difficult or impossible, and in these cases, access to pertinent medical records, discussing preferences with family caregivers, and availability of a POLST form are much better ways to determine therapy.

Palliative Home Care

Patient Safety Considerations

Weight loss and associated muscle wasting are common features in patients with severe COPD, creating a high-risk situation for falls and a need for assistance with activities of daily living. The patient who is frail when discharged home from the ED requires a home-care plan before leaving the ED, and strict follow-up with the patient’s primary care provider will typically be needed within 2 to 4 weeks.

Psychological Considerations

Being mindful of the anxiety and depression that accompany the physical limitations of those with COPD is important. Mood disturbances serve as risk factors for re-hospitalization and mortality.13Multiple palliative care interventions provide patients assistance with these issues, including the use of antidepressants that may aid sleep, stabilize mood, and stimulate appetite.

Early referral to the palliative care team will provide improved care for the patient and family. Palliative care referral will provide continued management of the physical symptoms and evaluation and treatment of the psychosocial issues that accompany COPD. Additionally, the palliative care team can assist with safe discharge planning and follow-up, including the provision of the patient’s home needs as well as the family’s ability to cope with the home setting.

Prognosis

Predicting prognosis is difficult for the COPD patient due to the highly variable illness trajectory. Some patients have a low FEV1 and yet are very functional. However, assessment of severity of lung function impairment, frequency of exacerbations, and need for long-term oxygen therapy helps identify those patients who are entering the final 12 months of life. Evaluating symptom burden and impact on activities of daily living for patients with COPD is comparable to those of cancer patients, and in both cases, palliative care approaches are necessary.

Predicting Morbidity and Mortality

A profile developed from observational studies can help predict 6- to 12-month morbidity and mortality in patients with advanced COPD. This profile includes the following criteria:

  • Significant dyspnea;
  • FEV1 <30%;
  • Number of exacerbations;
  • Left heart failure or other comorbidities;
  • Weight loss or cachexia;
  • Decreasing performance status;
  • Age older than 70 years; and
  • Depression.

Although additional research is required to refine and verify this profile, reviewing these data points can prompt providers to initiate discussions with patients about treatment preferences and end-of-life care.23,24

Palliative Performance Scale

The Palliative Performance Scale (PPS) is another scale used to predict prognosis and eligibility for hospice care.25 This score provides a patient’s estimated survival.25 For a patient with a PPS score of 50%, hospice education may be appropriate.

Case Scenario Continued

Both the BODE and GOLD criteria scores assisted in determining prognosis and risk profiles of the patient in our case scenario. By applying the BODE criteria, our patient had a 4-year survival benefit of under 18%. The GOLD criteria results for this patient also were consistent with the BODE criteria and reflected end-stage COPD. Since this patient also had a PPS score of 50%, hospice education and care were discussed and initiated.

Conclusion

Patients with AECOPD commonly present to the ED. Such patients suffer with a high burden of illness and a need for immediate symptom management. However, after these measures have been instituted, strong evidence suggests that these patients typically do not receive palliative care with the same frequency compared to cancer or heart disease patients.

 

 

Management of AECOPD in the ED must include rapid treatment of dyspnea and pain, but also a determination of treatment preferences and an understanding of the prognosis. Several criteria are available to guide prognostic awareness and may help further the goals of care and disposition. Primary palliative care should be started by the ED provider for appropriate patients, with early referral to the palliative care team.

References

1. National Center for Health Statistics. Health, United States 2015 With Special Feature on Racial and Ethnic Health Disparities. Hyattsville, MD: US Dept. Health and Human Services; 2016. http://www.cdc.gov/nchs/hus/. Accessed October 17, 2016.

2. Khialani B, Sivakumaran P, Keijzers G, Sriram KB. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease and factors associated with hospitalization. J Res Med Sci . 2014;19(4):297-303.

3. World Health Organization Web site. Chronic respiratory diseases. COPD: Definition. http://www.who.int/respiratory/copd/definition/en/. Accessed October 17, 2016.

4. Rabe KF, Hurd S, Anzueto A, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med . 2007;176(6):532-555.

5. Fan VS, Ramsey SD, Make BJ, Martinez FJ. Physiologic variables and functional status independently predict COPD hospitalizations and emergency department visits in patients with severe COPD. COPD . 2007;4(1):29-39.

6. Cydulka RK, Rowe BH, Clark S, Emerman CL, Camargo CA Jr; MARC Investigators. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease in the elderly: the Multicenter Airway Research Collaboration. J Am Geriatr Soc . 2003;51(7):908-916.

7. Strassels SA, Smith DH, Sullivan SD, et al. The costs of treating COPD in the United States. Chest . 2001;119:3.

8. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med . 2009;360(14):1418-1428. doi:10.1056/NEJMsa0803563.

9. Rowe BH, Bhutani M, Stickland MK, Cydulka R. Assessment and management of chronic obstructive pulmonary disease in the emergency department and beyond. Expert Rev Respir Med . 2011;5(4):549-559. doi:10.1586/ers.11.43.

10. National Institute for Clinical Excellence Web site. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical Guideline CG101. https://www.nice.org.uk/Guidance/cg101. Published June 2010. Accessed October 17, 2016.

11. Christensen VL, Holm AM, Cooper B, Paul SM, Miaskowski C, Rustøen T. Differences in symptom burden among patients with moderate, severe, or very severe chronic obstructive pulmonary disease. J Pain Symptom Manage . 2016;51(5):849-859. doi:10.1016/j.jpainsymman.2015.12.324.

12. GOLD Reports. Global Initiative for Chronic Obstructive Lung Disease Web site. http://goldcopd.org/gold-reports/. Accessed October 17, 2016.

13. Funk GC, Kirchheiner K, Burghuber OC, Hartl S. BODE index versus GOLD classification for explaining anxious and depressive symptoms in patients with COPD—a cross-sectional study. Respir Res . 2009;10:1. doi:10.1186/1465-9921-10-1.

14. Bach PB, Brown C, Gelfand SE, McCrory DC; American College of Physicians-American Society of Internal Medicine; American College of Chest Physicians. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med . 2001;134(7):600-620.

15. McCrory DC, Brown CD. Inhaled short-acting beta 2-agonists versus ipratropium for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev . 2001;(2):CD002984.

16. Shivanthan MC, Rajapakse S. Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. Ann Thorac Med . 2014;9(2):77-80. doi:10.4103/1817-1737.128844.

17. Curtis JR. Palliative and end of life care for patients with severe COPD. Eur Respir J . 2008;32(3):796-803.

18. Rocker GM, Simpson AC, Young J, et al. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients’ experiences and outcomes. CMAJ Open . 2013;1(1):E27-E36.

19. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnea. Thorax . 2002;57(11):939-944.

20. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ . 2003;327(7414):523-528.

21. Qaseem A, Wilt TJ, Weinberger SE, et al; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med . 2011;155(3):179-191. doi:10.7326/0003-4819-155-3-201108020-00008.

22. National POLST Paradigm. http://polst.org/professionals-page/?pro=1. Accessed October 17, 2016.

23. Hansen-Flaschen J. Chronic obstructive pulmonary disease: the last year of life. Respir Care. 2004;49(1):90-97; discussion 97-98.

24. Spathis A, Booth S. End of life care in chronic obstructive pulmonary disease: in search of a good death. Int J Chron Obstruct Pulmon Dis . 2008;3(1):11-29.

25. Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative performance scale (PPS): a new tool. J Palliat Care . 1996;12(1):5-11.

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Case Scenario

A 62-year-old man who regularly presented to the ED for exacerbations of chronic obstructive pulmonary disease (COPD) after running out of his medications presented again for evaluation and treatment. His outpatient care had been poorly coordinated, and he relied on the ED to provide him with the support he needed. This presentation represented his fifth visit to the ED over the past 3 months.

The patient’s medical history was positive for asthma since childhood, tobacco use, hypertension, and a recent diagnosis of congestive heart failure (CHF). Over the past year, he had four hospital admissions, and was currently unable to walk from his bedroom to another room without becoming short of breath. He also had recently experienced a 20-lb weight loss.

At this visit, the patient complained of chest pain and lightheadedness, which he described as suffocating. Prior to these recent symptoms, he enjoyed walking in his neighborhood and talking with friends. He was an avid reader and sports fan, but admitted that he now had trouble focusing on reading and following games on television. He lived alone, and his family lived across the country. The patient further admitted that although he had attempted to quit cigarette smoking, he was unable to give up his 50-pack per year habit. He had no completed advance health care directive and had significant challenges tending to his basic needs.

The Trajectory of COPD

Chronic obstructive pulmonary disease is a common chronic illness that causes significant morbidity and mortality. A 2016 National Health Services report cited respiratory illness, primarily from COPD, as the third leading cause of death in the United States in 2014.1The trajectory of this disease is marked by frequent exacerbations with partial recovery to baseline function. The burden of those living with COPD is significant and marked by a poor overall health-related quality of life (QOL). The ED has become a staging area for patients seeking care for exacerbations of COPD.2

The World Health Organization (WHO) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have defined COPD as a spectrum of diseases including emphysema, chronic bronchitis, and chronic obstructive asthma characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response to noxious particles or gases in the airways and lungs.3 Exacerbations and comorbidities contribute to the overall severity of COPD in individual patients.4

The case presented in this article illustrates the common scenario of a patient whose COPD has become severe and highly symptomatic with declining function to the point where he requires home support. His physical decline had been rapid and resulted in many unmet needs. When a patient such as this presents for emergent care, he must first be stabilized; then a care plan will need to be developed prior to discharge.

Management Goals

The overall goals of treating COPD are based on preserving function and are not curative in nature. Chronic obstructive pulmonary disease is a progressive illness that will intensify over time.5 As such, palliative care services are warranted. However, many patients with COPD do not receive palliative care services compared to patients with such other serious and life-limiting disease as cancer and heart disease.

Acute Exacerbations of COPD

Incidence

The frequency of acute exacerbations of COPD (AECOPD) increases with age, productive cough, long-standing COPD, previous hospitalizations related to COPD, eosinophilia, and comorbidities (eg, CHF). Patients with moderate to severe COPD and a history of prior exacerbations were found to have a higher likelihood of future exacerbations. From a quality and cost perspective, it may be useful to identify high-risk patients and strengthen their outpatient program to lessen the need for ED care and more intensive support.6,7

In our case scenario, the patient could have been stabilized at home with a well-controlled plan and home support, which would have resulted in an improved QOL and more time free from his high symptom burden.

Causes

Bacterial and viral respiratory infections are the most likely cause of AECOPD. Environmental pollution and pulmonary embolism are also triggers. Typically, patients with AECOPD present to the ED up to several times a year2 and represent the third most common cause of 30-day readmissions to the hospital.8 Prior exacerbations, dyspnea, and other medical comorbidities are also risk factors for more frequent hospital visits.

 

 

Presenting Signs and Symptoms

Each occurrence of AECOPD represents a worsening of a patient’s respiratory symptoms beyond normal variations. This might include increases in cough, sputum production, and dyspnea. The goal in caring for a person with an AECOPD is to stabilize the acute event and provide a treatment plan. The range of acuity for moderate to severe disease makes devising an appropriate treatment plan challenging, and after implementing the best plans, the patient’s course may be characterized by a prolonged cycle of admissions and readmissions without substantial return to baseline.

Management

In practice, ED management of AECOPD in older adults typically differs significantly from published guideline recommendations,9 which may result in pooroutcomes related to shortcomings in quality of care. Better adherence to guideline recommendations when caring for elderly patients with COPD may lead to improved clinical outcomes and better resource usage.6,9

Risk Stratification

Complicating ED management is the challenge of determining the severity of illness and degree of the exacerbation. Airflow obstruction alone is not sufficient to predict outcomes, as any particular measure of obstruction is associated with a spectrum of forced expiratory volume in the first second (FEV1) and varying performance. Moreover, peak-flow measurements are not useful in the setting of AECOPD, as opposed to their use in acute asthma exacerbations, and are not predictive of changes in clinical status.

GOLD and NICE Criteria

Guidelines have been developed and widely promoted to assist ED and hospital and community clinicians in providing evidence-based management for COPD patients. The GOLD Criteria and the National Institute for Clinical Excellence (NICE) are both clinical guidelines on management of COPD.10

Although well recognized and commonly used, the original GOLD criteria did not take into account the frequency and importance of the extrapulmonary manifestations of COPD in predicting outcome. Typically, those with severe or very severe COPD have an average of 12 co-occurring symptoms, an even greater number of signs and symptoms than those occurring in patients with cancer or heart or renal disease.11

The newly revised GOLD criteria not only reflect mortality prediction but also include the symptoms driving the risk for exacerbations (Table 1).12

BODE Criteria

The body mass index, airflow obstruction, dyspnea and exercise capacity (BODE) criteria assess and predict the health-related QOL and mortality risk for patients with COPD. Risk is adjusted based on four factors—weight, airway obstruction, dyspnea, and exercise capacity (ie, 6-minute walk distance).13

Table 2 provides a summary of the BODE criteria.

Initial Evaluation and Work-Up

As previously noted, when an AECOPD patient arrives to the ED, the first priority is to stabilize the patient and initiate treatment. In this respect, initial identification of the patient’s pulse oxygen saturation (SpO2) is important.

Laboratory Evaluation

In cases of respiratory failure, obtaining arterial blood gas (ABG) values are critical. The ABG test will assist in determining acute exacerbations of chronic hypercapnia and the need for ventilatory support. When considering CHF, a plasma B-type natriuretic peptide is useful to assess for CHF.

Imaging Studies

A chest radiograph may be useful in the initial evaluation to identify abnormalities, including barotrauma (ie, pneumothorax) and infiltrates. Additionally, in patients with comorbidities, it is important to assess cardiac status, and a chest X-ray may assist in identification of pulmonary edema, pleural effusions, and cardiomegaly. If the radiograph does show a pulmonary infiltrate (ie, pneumonia), it will help identify the probable triggers, but even in these instances, a sputum gram stain will not assist in the diagnosis.

Treatment

Relieving airflow obstruction is achieved with inhaled short-acting bronchodilators and systemic glucocorticoids, by treating infection, and by providing supplemental oxygen and ventilatory support.

Bronchodilators

The short-acting beta-adrenergic agonists (eg, albuterol) act rapidly and are effective in producing bronchodilation. Nebulized therapy may be most comfortable for the acutely ill patient. Typical dosing is 2.5 mg albuterol diluted to 3 cc by nebulizer every hour. Higher doses are not more effective, and there is no evidence of a higher response rate from constant nebulized therapy, which can cause anxiety and tachycardia in patients.14 Anticholinergic agents (eg, ipratropium) are often added despite unclear data regarding clinical advantage. In one study evaluating the effectiveness of adding ipratropium to albuterol, patients receiving a combination had the same improvement in FEV1 at 90 minutes.15 Patients receiving ipratropium alone had the lowest rate of reported side effects.15

Systemic Glucocorticoids

Short-course systemic glucocorticoids are an important addition to treatment and have been found to improve spirometry and decrease relapse rate. The oral and intravenous (IV) routes provide the same benefit. For the acutely ill patient with challenges swallowing, the IV route is preferred. The optimal dose is not clear, but hydrocortisone doses of 100 mg to 125 mg every 6 hours for 3 days are effective, as is oral prednisone 30 mg per day for 14 days, or 60 mg per day for 3 days with a taper.

 

 

Antibiotic Therapy

Antibiotics are indicated for patients with moderate to severe AECOPD who are ill enough to be admitted to the hospital. Empiric broad spectrum treatment is recommended. The initial antibiotic regimen should target likely bacterial pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in most patients) and take into account local patterns of antibiotic resistance. Flouroquinolones or third-generation cephalosporins generally provide sufficient coverage. For patients experiencing only a mild exacerbation, antibiotics are not warranted.

Magnesium Sulfate

Other supplemental medications that have been evaluated include magnesium sulfate for bronchial smooth muscle relaxation. Studies have found that while magnesium is helpful in asthma, results are mixed with COPD.16

Supplemental Oxygen

Oxygen therapy is important during an AECOPD episode. Often, concerns arise about decreasing respiratory drive, which is typically driven by hypoxia in patients who have chronic hypercapnia. Arterial blood gas determinations are important in managing a patient’s respiratory status and will assist in determining actual oxygenation and any coexistent metabolic disturbances.

Noninvasive Ventilation. Oxygen can be administered efficiently by a venturi mask, which delivers precise fractions of oxygen, or by nasal cannula. A facemask is less comfortable, but is available for higher oxygen requirements, providing up to 55% oxygen, while a nonrebreather mask delivers up to 90% oxygen.

When necessary, noninvasive positive pressure ventilation (NPPV) improves outcomes for those with severe dyspnea and signs of respiratory fatigue manifested as increased work of breathing. Noninvasive positive pressure ventilation can improve clinical outcomes and is the ventilator mode of choice for those patients with COPD. Indications include severe dyspnea with signs of increased work of breathing and respiratory acidosis (arterial pH <7.35) and partial pressure of arterial carbon dioxide (PaCO2) >45 mm Hg.

Whenever possible, NPPV should be initiated with a triggered mode to allow spontaneous breaths. Inspiratory pressure of 8 cm to 12 cm H2O and expiratory pressure of 3 cm to 5 cm of H2 are recommended.

Mechanical Ventilation. Mechanical ventilation is often undesirable because it may be extraordinarily difficult to wean a patient off the device and permit safe extubation. However, if a patient cannot be stabilized with NPPV, intubation and mechanical ventilation must be considered. Typically, this occurs when there is severe respiratory distress, tachypnea >30 breaths/min, accessory muscle use, and altered mentation.

Goals of intubation/mechanical respiration include correcting oxygenation and severe respiratory acidosis as well as reducing the work of breathing. Barotrauma is a significant risk when patients with COPD require mechanical ventilation. Volume-limited modes of ventilation are commonly used, while pressure support or pressure-limited modes are less suitable for patients with airflow limitation. Again, invasive ventilation should only be administered if a patient cannot tolerate NPPV.

Palliative Care in the ED

Palliative care is an approach that improves the QOL of patients and their families facing the issues associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and accurate assessment and treatment of pain and physical, psychosocial, and spiritual problems.3 This approach to care is warranted for COPD patients given the myriad of burdensome symptoms and functional decline that occurs.17

Palliative care expands traditional treatment goals to include enhancing QOL; helping with medical decision making; and identifying the goals of care. Palliative care is provided by board-certified physicians for the most complex of cases. However, the primary practice of palliative care must be delivered at the bedside by the treating provider. Managing pain, dyspnea, nausea, vomiting, and changes in bowel habits, as well as discussing goals of care, are among the basic palliative care skills all providers need to have and apply when indicated.

Palliative Care for Dyspnea

Opioids. Primary palliative care in the ED includes the appropriate use of low-dose oral and parenteral opioids to treat dyspnea in AECOPD. The use of a low-dose opioid, such as morphine 2 mg IV, titrated up to a desired response, is a safe and effective practice.18 Note the 2-mg starting dose is considered low-dose.19

With respect to managing dyspnea in AECOPD patients, nebulized opioids have not been found to be better than nebulized saline. More specific data regarding the use of oral opioids for managing refractory dyspnea in patients with predominantly COPD have been recently published: Long-acting morphine 20 mg once daily provides symptomatic relief in refractory dyspnea in the community setting. For the opioid-naïve patient, a lower dose is recommended.20

Oxygenation. There is no hard evidence of the effectiveness of oxygen in the palliation of breathlessness. Humidified air is effective initially, as is providing a fan at the bedside. Short-burst oxygen therapy should only be considered for episodes of severe breathlessness in patients whose COPD is not relieved by other treatments. Oxygen should continue to be prescribed only if an improvement in breathlessness following therapy has been documented. The American Thoracic Society recommends continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (PaCO2 ≤55 mm Hg or SpO2 ≤88%).21

 

 

POLST Form

The Physicians Order for Life-Sustaining Treatment (POLST) form is a set of medical orders, similar to the “do not resuscitate” (allow natural death) order. A POLST form is not an advance directive and does not serve as a substitute for a patient’s assignation of a health care agent or durable power of attorney for health care.22

The POLST form enables physicians to order treatments patients would want, identify those treatments that patients would not want, and not provide those the patient considers “extraordinary” and excessively burdensome. A POLST form does not allow for active euthanasia or physician-assisted suicide.

Identifying treatment preferences is an important part of the initial evaluation of all patients. When dealing with an airway issue in a COPD patient, management can become complex. Ideally, the POLST form should arrive with the patient in the ED and list preferences regarding possible intensive interventions such as intubation and chest compressions. Discussing these issues with a patient in extreme distress is difficult or impossible, and in these cases, access to pertinent medical records, discussing preferences with family caregivers, and availability of a POLST form are much better ways to determine therapy.

Palliative Home Care

Patient Safety Considerations

Weight loss and associated muscle wasting are common features in patients with severe COPD, creating a high-risk situation for falls and a need for assistance with activities of daily living. The patient who is frail when discharged home from the ED requires a home-care plan before leaving the ED, and strict follow-up with the patient’s primary care provider will typically be needed within 2 to 4 weeks.

Psychological Considerations

Being mindful of the anxiety and depression that accompany the physical limitations of those with COPD is important. Mood disturbances serve as risk factors for re-hospitalization and mortality.13Multiple palliative care interventions provide patients assistance with these issues, including the use of antidepressants that may aid sleep, stabilize mood, and stimulate appetite.

Early referral to the palliative care team will provide improved care for the patient and family. Palliative care referral will provide continued management of the physical symptoms and evaluation and treatment of the psychosocial issues that accompany COPD. Additionally, the palliative care team can assist with safe discharge planning and follow-up, including the provision of the patient’s home needs as well as the family’s ability to cope with the home setting.

Prognosis

Predicting prognosis is difficult for the COPD patient due to the highly variable illness trajectory. Some patients have a low FEV1 and yet are very functional. However, assessment of severity of lung function impairment, frequency of exacerbations, and need for long-term oxygen therapy helps identify those patients who are entering the final 12 months of life. Evaluating symptom burden and impact on activities of daily living for patients with COPD is comparable to those of cancer patients, and in both cases, palliative care approaches are necessary.

Predicting Morbidity and Mortality

A profile developed from observational studies can help predict 6- to 12-month morbidity and mortality in patients with advanced COPD. This profile includes the following criteria:

  • Significant dyspnea;
  • FEV1 <30%;
  • Number of exacerbations;
  • Left heart failure or other comorbidities;
  • Weight loss or cachexia;
  • Decreasing performance status;
  • Age older than 70 years; and
  • Depression.

Although additional research is required to refine and verify this profile, reviewing these data points can prompt providers to initiate discussions with patients about treatment preferences and end-of-life care.23,24

Palliative Performance Scale

The Palliative Performance Scale (PPS) is another scale used to predict prognosis and eligibility for hospice care.25 This score provides a patient’s estimated survival.25 For a patient with a PPS score of 50%, hospice education may be appropriate.

Case Scenario Continued

Both the BODE and GOLD criteria scores assisted in determining prognosis and risk profiles of the patient in our case scenario. By applying the BODE criteria, our patient had a 4-year survival benefit of under 18%. The GOLD criteria results for this patient also were consistent with the BODE criteria and reflected end-stage COPD. Since this patient also had a PPS score of 50%, hospice education and care were discussed and initiated.

Conclusion

Patients with AECOPD commonly present to the ED. Such patients suffer with a high burden of illness and a need for immediate symptom management. However, after these measures have been instituted, strong evidence suggests that these patients typically do not receive palliative care with the same frequency compared to cancer or heart disease patients.

 

 

Management of AECOPD in the ED must include rapid treatment of dyspnea and pain, but also a determination of treatment preferences and an understanding of the prognosis. Several criteria are available to guide prognostic awareness and may help further the goals of care and disposition. Primary palliative care should be started by the ED provider for appropriate patients, with early referral to the palliative care team.

Case Scenario

A 62-year-old man who regularly presented to the ED for exacerbations of chronic obstructive pulmonary disease (COPD) after running out of his medications presented again for evaluation and treatment. His outpatient care had been poorly coordinated, and he relied on the ED to provide him with the support he needed. This presentation represented his fifth visit to the ED over the past 3 months.

The patient’s medical history was positive for asthma since childhood, tobacco use, hypertension, and a recent diagnosis of congestive heart failure (CHF). Over the past year, he had four hospital admissions, and was currently unable to walk from his bedroom to another room without becoming short of breath. He also had recently experienced a 20-lb weight loss.

At this visit, the patient complained of chest pain and lightheadedness, which he described as suffocating. Prior to these recent symptoms, he enjoyed walking in his neighborhood and talking with friends. He was an avid reader and sports fan, but admitted that he now had trouble focusing on reading and following games on television. He lived alone, and his family lived across the country. The patient further admitted that although he had attempted to quit cigarette smoking, he was unable to give up his 50-pack per year habit. He had no completed advance health care directive and had significant challenges tending to his basic needs.

The Trajectory of COPD

Chronic obstructive pulmonary disease is a common chronic illness that causes significant morbidity and mortality. A 2016 National Health Services report cited respiratory illness, primarily from COPD, as the third leading cause of death in the United States in 2014.1The trajectory of this disease is marked by frequent exacerbations with partial recovery to baseline function. The burden of those living with COPD is significant and marked by a poor overall health-related quality of life (QOL). The ED has become a staging area for patients seeking care for exacerbations of COPD.2

The World Health Organization (WHO) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have defined COPD as a spectrum of diseases including emphysema, chronic bronchitis, and chronic obstructive asthma characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response to noxious particles or gases in the airways and lungs.3 Exacerbations and comorbidities contribute to the overall severity of COPD in individual patients.4

The case presented in this article illustrates the common scenario of a patient whose COPD has become severe and highly symptomatic with declining function to the point where he requires home support. His physical decline had been rapid and resulted in many unmet needs. When a patient such as this presents for emergent care, he must first be stabilized; then a care plan will need to be developed prior to discharge.

Management Goals

The overall goals of treating COPD are based on preserving function and are not curative in nature. Chronic obstructive pulmonary disease is a progressive illness that will intensify over time.5 As such, palliative care services are warranted. However, many patients with COPD do not receive palliative care services compared to patients with such other serious and life-limiting disease as cancer and heart disease.

Acute Exacerbations of COPD

Incidence

The frequency of acute exacerbations of COPD (AECOPD) increases with age, productive cough, long-standing COPD, previous hospitalizations related to COPD, eosinophilia, and comorbidities (eg, CHF). Patients with moderate to severe COPD and a history of prior exacerbations were found to have a higher likelihood of future exacerbations. From a quality and cost perspective, it may be useful to identify high-risk patients and strengthen their outpatient program to lessen the need for ED care and more intensive support.6,7

In our case scenario, the patient could have been stabilized at home with a well-controlled plan and home support, which would have resulted in an improved QOL and more time free from his high symptom burden.

Causes

Bacterial and viral respiratory infections are the most likely cause of AECOPD. Environmental pollution and pulmonary embolism are also triggers. Typically, patients with AECOPD present to the ED up to several times a year2 and represent the third most common cause of 30-day readmissions to the hospital.8 Prior exacerbations, dyspnea, and other medical comorbidities are also risk factors for more frequent hospital visits.

 

 

Presenting Signs and Symptoms

Each occurrence of AECOPD represents a worsening of a patient’s respiratory symptoms beyond normal variations. This might include increases in cough, sputum production, and dyspnea. The goal in caring for a person with an AECOPD is to stabilize the acute event and provide a treatment plan. The range of acuity for moderate to severe disease makes devising an appropriate treatment plan challenging, and after implementing the best plans, the patient’s course may be characterized by a prolonged cycle of admissions and readmissions without substantial return to baseline.

Management

In practice, ED management of AECOPD in older adults typically differs significantly from published guideline recommendations,9 which may result in pooroutcomes related to shortcomings in quality of care. Better adherence to guideline recommendations when caring for elderly patients with COPD may lead to improved clinical outcomes and better resource usage.6,9

Risk Stratification

Complicating ED management is the challenge of determining the severity of illness and degree of the exacerbation. Airflow obstruction alone is not sufficient to predict outcomes, as any particular measure of obstruction is associated with a spectrum of forced expiratory volume in the first second (FEV1) and varying performance. Moreover, peak-flow measurements are not useful in the setting of AECOPD, as opposed to their use in acute asthma exacerbations, and are not predictive of changes in clinical status.

GOLD and NICE Criteria

Guidelines have been developed and widely promoted to assist ED and hospital and community clinicians in providing evidence-based management for COPD patients. The GOLD Criteria and the National Institute for Clinical Excellence (NICE) are both clinical guidelines on management of COPD.10

Although well recognized and commonly used, the original GOLD criteria did not take into account the frequency and importance of the extrapulmonary manifestations of COPD in predicting outcome. Typically, those with severe or very severe COPD have an average of 12 co-occurring symptoms, an even greater number of signs and symptoms than those occurring in patients with cancer or heart or renal disease.11

The newly revised GOLD criteria not only reflect mortality prediction but also include the symptoms driving the risk for exacerbations (Table 1).12

BODE Criteria

The body mass index, airflow obstruction, dyspnea and exercise capacity (BODE) criteria assess and predict the health-related QOL and mortality risk for patients with COPD. Risk is adjusted based on four factors—weight, airway obstruction, dyspnea, and exercise capacity (ie, 6-minute walk distance).13

Table 2 provides a summary of the BODE criteria.

Initial Evaluation and Work-Up

As previously noted, when an AECOPD patient arrives to the ED, the first priority is to stabilize the patient and initiate treatment. In this respect, initial identification of the patient’s pulse oxygen saturation (SpO2) is important.

Laboratory Evaluation

In cases of respiratory failure, obtaining arterial blood gas (ABG) values are critical. The ABG test will assist in determining acute exacerbations of chronic hypercapnia and the need for ventilatory support. When considering CHF, a plasma B-type natriuretic peptide is useful to assess for CHF.

Imaging Studies

A chest radiograph may be useful in the initial evaluation to identify abnormalities, including barotrauma (ie, pneumothorax) and infiltrates. Additionally, in patients with comorbidities, it is important to assess cardiac status, and a chest X-ray may assist in identification of pulmonary edema, pleural effusions, and cardiomegaly. If the radiograph does show a pulmonary infiltrate (ie, pneumonia), it will help identify the probable triggers, but even in these instances, a sputum gram stain will not assist in the diagnosis.

Treatment

Relieving airflow obstruction is achieved with inhaled short-acting bronchodilators and systemic glucocorticoids, by treating infection, and by providing supplemental oxygen and ventilatory support.

Bronchodilators

The short-acting beta-adrenergic agonists (eg, albuterol) act rapidly and are effective in producing bronchodilation. Nebulized therapy may be most comfortable for the acutely ill patient. Typical dosing is 2.5 mg albuterol diluted to 3 cc by nebulizer every hour. Higher doses are not more effective, and there is no evidence of a higher response rate from constant nebulized therapy, which can cause anxiety and tachycardia in patients.14 Anticholinergic agents (eg, ipratropium) are often added despite unclear data regarding clinical advantage. In one study evaluating the effectiveness of adding ipratropium to albuterol, patients receiving a combination had the same improvement in FEV1 at 90 minutes.15 Patients receiving ipratropium alone had the lowest rate of reported side effects.15

Systemic Glucocorticoids

Short-course systemic glucocorticoids are an important addition to treatment and have been found to improve spirometry and decrease relapse rate. The oral and intravenous (IV) routes provide the same benefit. For the acutely ill patient with challenges swallowing, the IV route is preferred. The optimal dose is not clear, but hydrocortisone doses of 100 mg to 125 mg every 6 hours for 3 days are effective, as is oral prednisone 30 mg per day for 14 days, or 60 mg per day for 3 days with a taper.

 

 

Antibiotic Therapy

Antibiotics are indicated for patients with moderate to severe AECOPD who are ill enough to be admitted to the hospital. Empiric broad spectrum treatment is recommended. The initial antibiotic regimen should target likely bacterial pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in most patients) and take into account local patterns of antibiotic resistance. Flouroquinolones or third-generation cephalosporins generally provide sufficient coverage. For patients experiencing only a mild exacerbation, antibiotics are not warranted.

Magnesium Sulfate

Other supplemental medications that have been evaluated include magnesium sulfate for bronchial smooth muscle relaxation. Studies have found that while magnesium is helpful in asthma, results are mixed with COPD.16

Supplemental Oxygen

Oxygen therapy is important during an AECOPD episode. Often, concerns arise about decreasing respiratory drive, which is typically driven by hypoxia in patients who have chronic hypercapnia. Arterial blood gas determinations are important in managing a patient’s respiratory status and will assist in determining actual oxygenation and any coexistent metabolic disturbances.

Noninvasive Ventilation. Oxygen can be administered efficiently by a venturi mask, which delivers precise fractions of oxygen, or by nasal cannula. A facemask is less comfortable, but is available for higher oxygen requirements, providing up to 55% oxygen, while a nonrebreather mask delivers up to 90% oxygen.

When necessary, noninvasive positive pressure ventilation (NPPV) improves outcomes for those with severe dyspnea and signs of respiratory fatigue manifested as increased work of breathing. Noninvasive positive pressure ventilation can improve clinical outcomes and is the ventilator mode of choice for those patients with COPD. Indications include severe dyspnea with signs of increased work of breathing and respiratory acidosis (arterial pH <7.35) and partial pressure of arterial carbon dioxide (PaCO2) >45 mm Hg.

Whenever possible, NPPV should be initiated with a triggered mode to allow spontaneous breaths. Inspiratory pressure of 8 cm to 12 cm H2O and expiratory pressure of 3 cm to 5 cm of H2 are recommended.

Mechanical Ventilation. Mechanical ventilation is often undesirable because it may be extraordinarily difficult to wean a patient off the device and permit safe extubation. However, if a patient cannot be stabilized with NPPV, intubation and mechanical ventilation must be considered. Typically, this occurs when there is severe respiratory distress, tachypnea >30 breaths/min, accessory muscle use, and altered mentation.

Goals of intubation/mechanical respiration include correcting oxygenation and severe respiratory acidosis as well as reducing the work of breathing. Barotrauma is a significant risk when patients with COPD require mechanical ventilation. Volume-limited modes of ventilation are commonly used, while pressure support or pressure-limited modes are less suitable for patients with airflow limitation. Again, invasive ventilation should only be administered if a patient cannot tolerate NPPV.

Palliative Care in the ED

Palliative care is an approach that improves the QOL of patients and their families facing the issues associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and accurate assessment and treatment of pain and physical, psychosocial, and spiritual problems.3 This approach to care is warranted for COPD patients given the myriad of burdensome symptoms and functional decline that occurs.17

Palliative care expands traditional treatment goals to include enhancing QOL; helping with medical decision making; and identifying the goals of care. Palliative care is provided by board-certified physicians for the most complex of cases. However, the primary practice of palliative care must be delivered at the bedside by the treating provider. Managing pain, dyspnea, nausea, vomiting, and changes in bowel habits, as well as discussing goals of care, are among the basic palliative care skills all providers need to have and apply when indicated.

Palliative Care for Dyspnea

Opioids. Primary palliative care in the ED includes the appropriate use of low-dose oral and parenteral opioids to treat dyspnea in AECOPD. The use of a low-dose opioid, such as morphine 2 mg IV, titrated up to a desired response, is a safe and effective practice.18 Note the 2-mg starting dose is considered low-dose.19

With respect to managing dyspnea in AECOPD patients, nebulized opioids have not been found to be better than nebulized saline. More specific data regarding the use of oral opioids for managing refractory dyspnea in patients with predominantly COPD have been recently published: Long-acting morphine 20 mg once daily provides symptomatic relief in refractory dyspnea in the community setting. For the opioid-naïve patient, a lower dose is recommended.20

Oxygenation. There is no hard evidence of the effectiveness of oxygen in the palliation of breathlessness. Humidified air is effective initially, as is providing a fan at the bedside. Short-burst oxygen therapy should only be considered for episodes of severe breathlessness in patients whose COPD is not relieved by other treatments. Oxygen should continue to be prescribed only if an improvement in breathlessness following therapy has been documented. The American Thoracic Society recommends continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (PaCO2 ≤55 mm Hg or SpO2 ≤88%).21

 

 

POLST Form

The Physicians Order for Life-Sustaining Treatment (POLST) form is a set of medical orders, similar to the “do not resuscitate” (allow natural death) order. A POLST form is not an advance directive and does not serve as a substitute for a patient’s assignation of a health care agent or durable power of attorney for health care.22

The POLST form enables physicians to order treatments patients would want, identify those treatments that patients would not want, and not provide those the patient considers “extraordinary” and excessively burdensome. A POLST form does not allow for active euthanasia or physician-assisted suicide.

Identifying treatment preferences is an important part of the initial evaluation of all patients. When dealing with an airway issue in a COPD patient, management can become complex. Ideally, the POLST form should arrive with the patient in the ED and list preferences regarding possible intensive interventions such as intubation and chest compressions. Discussing these issues with a patient in extreme distress is difficult or impossible, and in these cases, access to pertinent medical records, discussing preferences with family caregivers, and availability of a POLST form are much better ways to determine therapy.

Palliative Home Care

Patient Safety Considerations

Weight loss and associated muscle wasting are common features in patients with severe COPD, creating a high-risk situation for falls and a need for assistance with activities of daily living. The patient who is frail when discharged home from the ED requires a home-care plan before leaving the ED, and strict follow-up with the patient’s primary care provider will typically be needed within 2 to 4 weeks.

Psychological Considerations

Being mindful of the anxiety and depression that accompany the physical limitations of those with COPD is important. Mood disturbances serve as risk factors for re-hospitalization and mortality.13Multiple palliative care interventions provide patients assistance with these issues, including the use of antidepressants that may aid sleep, stabilize mood, and stimulate appetite.

Early referral to the palliative care team will provide improved care for the patient and family. Palliative care referral will provide continued management of the physical symptoms and evaluation and treatment of the psychosocial issues that accompany COPD. Additionally, the palliative care team can assist with safe discharge planning and follow-up, including the provision of the patient’s home needs as well as the family’s ability to cope with the home setting.

Prognosis

Predicting prognosis is difficult for the COPD patient due to the highly variable illness trajectory. Some patients have a low FEV1 and yet are very functional. However, assessment of severity of lung function impairment, frequency of exacerbations, and need for long-term oxygen therapy helps identify those patients who are entering the final 12 months of life. Evaluating symptom burden and impact on activities of daily living for patients with COPD is comparable to those of cancer patients, and in both cases, palliative care approaches are necessary.

Predicting Morbidity and Mortality

A profile developed from observational studies can help predict 6- to 12-month morbidity and mortality in patients with advanced COPD. This profile includes the following criteria:

  • Significant dyspnea;
  • FEV1 <30%;
  • Number of exacerbations;
  • Left heart failure or other comorbidities;
  • Weight loss or cachexia;
  • Decreasing performance status;
  • Age older than 70 years; and
  • Depression.

Although additional research is required to refine and verify this profile, reviewing these data points can prompt providers to initiate discussions with patients about treatment preferences and end-of-life care.23,24

Palliative Performance Scale

The Palliative Performance Scale (PPS) is another scale used to predict prognosis and eligibility for hospice care.25 This score provides a patient’s estimated survival.25 For a patient with a PPS score of 50%, hospice education may be appropriate.

Case Scenario Continued

Both the BODE and GOLD criteria scores assisted in determining prognosis and risk profiles of the patient in our case scenario. By applying the BODE criteria, our patient had a 4-year survival benefit of under 18%. The GOLD criteria results for this patient also were consistent with the BODE criteria and reflected end-stage COPD. Since this patient also had a PPS score of 50%, hospice education and care were discussed and initiated.

Conclusion

Patients with AECOPD commonly present to the ED. Such patients suffer with a high burden of illness and a need for immediate symptom management. However, after these measures have been instituted, strong evidence suggests that these patients typically do not receive palliative care with the same frequency compared to cancer or heart disease patients.

 

 

Management of AECOPD in the ED must include rapid treatment of dyspnea and pain, but also a determination of treatment preferences and an understanding of the prognosis. Several criteria are available to guide prognostic awareness and may help further the goals of care and disposition. Primary palliative care should be started by the ED provider for appropriate patients, with early referral to the palliative care team.

References

1. National Center for Health Statistics. Health, United States 2015 With Special Feature on Racial and Ethnic Health Disparities. Hyattsville, MD: US Dept. Health and Human Services; 2016. http://www.cdc.gov/nchs/hus/. Accessed October 17, 2016.

2. Khialani B, Sivakumaran P, Keijzers G, Sriram KB. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease and factors associated with hospitalization. J Res Med Sci . 2014;19(4):297-303.

3. World Health Organization Web site. Chronic respiratory diseases. COPD: Definition. http://www.who.int/respiratory/copd/definition/en/. Accessed October 17, 2016.

4. Rabe KF, Hurd S, Anzueto A, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med . 2007;176(6):532-555.

5. Fan VS, Ramsey SD, Make BJ, Martinez FJ. Physiologic variables and functional status independently predict COPD hospitalizations and emergency department visits in patients with severe COPD. COPD . 2007;4(1):29-39.

6. Cydulka RK, Rowe BH, Clark S, Emerman CL, Camargo CA Jr; MARC Investigators. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease in the elderly: the Multicenter Airway Research Collaboration. J Am Geriatr Soc . 2003;51(7):908-916.

7. Strassels SA, Smith DH, Sullivan SD, et al. The costs of treating COPD in the United States. Chest . 2001;119:3.

8. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med . 2009;360(14):1418-1428. doi:10.1056/NEJMsa0803563.

9. Rowe BH, Bhutani M, Stickland MK, Cydulka R. Assessment and management of chronic obstructive pulmonary disease in the emergency department and beyond. Expert Rev Respir Med . 2011;5(4):549-559. doi:10.1586/ers.11.43.

10. National Institute for Clinical Excellence Web site. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical Guideline CG101. https://www.nice.org.uk/Guidance/cg101. Published June 2010. Accessed October 17, 2016.

11. Christensen VL, Holm AM, Cooper B, Paul SM, Miaskowski C, Rustøen T. Differences in symptom burden among patients with moderate, severe, or very severe chronic obstructive pulmonary disease. J Pain Symptom Manage . 2016;51(5):849-859. doi:10.1016/j.jpainsymman.2015.12.324.

12. GOLD Reports. Global Initiative for Chronic Obstructive Lung Disease Web site. http://goldcopd.org/gold-reports/. Accessed October 17, 2016.

13. Funk GC, Kirchheiner K, Burghuber OC, Hartl S. BODE index versus GOLD classification for explaining anxious and depressive symptoms in patients with COPD—a cross-sectional study. Respir Res . 2009;10:1. doi:10.1186/1465-9921-10-1.

14. Bach PB, Brown C, Gelfand SE, McCrory DC; American College of Physicians-American Society of Internal Medicine; American College of Chest Physicians. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med . 2001;134(7):600-620.

15. McCrory DC, Brown CD. Inhaled short-acting beta 2-agonists versus ipratropium for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev . 2001;(2):CD002984.

16. Shivanthan MC, Rajapakse S. Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. Ann Thorac Med . 2014;9(2):77-80. doi:10.4103/1817-1737.128844.

17. Curtis JR. Palliative and end of life care for patients with severe COPD. Eur Respir J . 2008;32(3):796-803.

18. Rocker GM, Simpson AC, Young J, et al. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients’ experiences and outcomes. CMAJ Open . 2013;1(1):E27-E36.

19. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnea. Thorax . 2002;57(11):939-944.

20. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ . 2003;327(7414):523-528.

21. Qaseem A, Wilt TJ, Weinberger SE, et al; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med . 2011;155(3):179-191. doi:10.7326/0003-4819-155-3-201108020-00008.

22. National POLST Paradigm. http://polst.org/professionals-page/?pro=1. Accessed October 17, 2016.

23. Hansen-Flaschen J. Chronic obstructive pulmonary disease: the last year of life. Respir Care. 2004;49(1):90-97; discussion 97-98.

24. Spathis A, Booth S. End of life care in chronic obstructive pulmonary disease: in search of a good death. Int J Chron Obstruct Pulmon Dis . 2008;3(1):11-29.

25. Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative performance scale (PPS): a new tool. J Palliat Care . 1996;12(1):5-11.

References

1. National Center for Health Statistics. Health, United States 2015 With Special Feature on Racial and Ethnic Health Disparities. Hyattsville, MD: US Dept. Health and Human Services; 2016. http://www.cdc.gov/nchs/hus/. Accessed October 17, 2016.

2. Khialani B, Sivakumaran P, Keijzers G, Sriram KB. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease and factors associated with hospitalization. J Res Med Sci . 2014;19(4):297-303.

3. World Health Organization Web site. Chronic respiratory diseases. COPD: Definition. http://www.who.int/respiratory/copd/definition/en/. Accessed October 17, 2016.

4. Rabe KF, Hurd S, Anzueto A, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med . 2007;176(6):532-555.

5. Fan VS, Ramsey SD, Make BJ, Martinez FJ. Physiologic variables and functional status independently predict COPD hospitalizations and emergency department visits in patients with severe COPD. COPD . 2007;4(1):29-39.

6. Cydulka RK, Rowe BH, Clark S, Emerman CL, Camargo CA Jr; MARC Investigators. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease in the elderly: the Multicenter Airway Research Collaboration. J Am Geriatr Soc . 2003;51(7):908-916.

7. Strassels SA, Smith DH, Sullivan SD, et al. The costs of treating COPD in the United States. Chest . 2001;119:3.

8. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med . 2009;360(14):1418-1428. doi:10.1056/NEJMsa0803563.

9. Rowe BH, Bhutani M, Stickland MK, Cydulka R. Assessment and management of chronic obstructive pulmonary disease in the emergency department and beyond. Expert Rev Respir Med . 2011;5(4):549-559. doi:10.1586/ers.11.43.

10. National Institute for Clinical Excellence Web site. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical Guideline CG101. https://www.nice.org.uk/Guidance/cg101. Published June 2010. Accessed October 17, 2016.

11. Christensen VL, Holm AM, Cooper B, Paul SM, Miaskowski C, Rustøen T. Differences in symptom burden among patients with moderate, severe, or very severe chronic obstructive pulmonary disease. J Pain Symptom Manage . 2016;51(5):849-859. doi:10.1016/j.jpainsymman.2015.12.324.

12. GOLD Reports. Global Initiative for Chronic Obstructive Lung Disease Web site. http://goldcopd.org/gold-reports/. Accessed October 17, 2016.

13. Funk GC, Kirchheiner K, Burghuber OC, Hartl S. BODE index versus GOLD classification for explaining anxious and depressive symptoms in patients with COPD—a cross-sectional study. Respir Res . 2009;10:1. doi:10.1186/1465-9921-10-1.

14. Bach PB, Brown C, Gelfand SE, McCrory DC; American College of Physicians-American Society of Internal Medicine; American College of Chest Physicians. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med . 2001;134(7):600-620.

15. McCrory DC, Brown CD. Inhaled short-acting beta 2-agonists versus ipratropium for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev . 2001;(2):CD002984.

16. Shivanthan MC, Rajapakse S. Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. Ann Thorac Med . 2014;9(2):77-80. doi:10.4103/1817-1737.128844.

17. Curtis JR. Palliative and end of life care for patients with severe COPD. Eur Respir J . 2008;32(3):796-803.

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Issue
Emergency Medicine - 48(11)
Issue
Emergency Medicine - 48(11)
Page Number
496-504
Page Number
496-504
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Emergency Medicine
MDedge Emergency Medicine
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The Burden of COPD
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