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How menopause affects oral health, and what we can do about it

Article Type
Article
Changed
Mon, 03/05/2018 - 14:46
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How menopause affects oral health, and what we can do about it
Author(s)
Maria Clarinda A. Buencamino, MD
Leena Palomo, DDS, MSD
Holly L. Thacker, MD, CDD

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

Figure 1. Red swollen gums of gingivitis.
Gingivitis is a reversible inflammatory response to bacterial plaque buildup that is limited to the gingiva (Figure 1).

Figure 2. Healthy gums and bones (left) vs periodontal disease (right). Note the lower bone height and resulting deeper pockets in periodontal disease.
If unchecked, gingivitis progresses to periodontitis, an inflammation of the supporting tissues of the teeth, including the gingiva, alveolar bone, and periodontal ligament (Figure 2). Periodontitis leads to progressive and irreversible loss of bone and periodontal ligament attachment, as inflammation extends from the gingiva into adjacent bone and ligament. Signs and symptoms of progressing periodontitis include red, swollen gums that may appear to have pulled away from the teeth, persistent bad breath, pus between the teeth and gums (Figure 3), loose or separating teeth, and the common complaint that “my teeth don’t fit together anymore.”

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

Figure 3. Red swollen gums with pus in periodontitis.
In menopause, estrogen levels decline rapidly, which can lead to systemic bone loss.1

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.2 In fact, Kribbs3 found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,3–11 these findings are not universal. In a longitudinal study, Famili et al12 found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.13

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.10 In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.14

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al15 found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.7

However, Hildebolt16 reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al17 found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.13

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al18 reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

 

 

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al19 reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.20

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.21 Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman22 suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,23 in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.24

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.20 More-recent studies had similar findings. A cross-sectional study by Meisel et al25 found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.26

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,27 Framingham,28 and Nurses Health Study29 cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al30 evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.30 Meisel et al25 reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.
Figure 4. Proposed model for how estrogen deficiency contributes to severe periodontal disease.
Genco and Grossi26 have proposed a model for estrogen deficiency as a risk factor for periodontal disease (Figure 4). In this model, estrogen deficiency leads to more production of bone-resorbing cytokines produced by immune cells (monocytes and macrophages) and osteoblasts. When challenged by products related to periodontal bacterial plaque biofilm, by bone-resorbing factors such as lipopolysaccharides, and by toxins, the host immune system produces more inflammatory cytokines that activate osteoclasts, which reabsorb bone. The buildup of bacterial plaque biofilm made up of periopathogenic bacteria35 seems to be necessary for an estrogen-deficient woman to actually show changes such as loss of tooth attachment and alveolar bone. The host’s inflammatory response to this biofilm starts the inflammation cascade and may lead to constant activation of tissue proteinases and degradative enzymes, leading to connective tissue destruction, alveolar bone resorption, and ultimately tooth loss, which can explain the increased risk of periodontal disease in postmenopausal women.26,3

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

 

 

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.36 Specific findings:

  • In the Fracture Intervention Trial,37 alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
  • In the Hip Intervention Program,38 risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.39
  • In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,40 annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.41–43 Findings:

  • In a cross-sectional study by Palomo et al,41 postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
  • In a double-blind, controlled, prospective study by Rocha et al,42 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
  • Jeffcoat et al43 reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

Figure 5. Osteonecrosis of the jaw.
Despite these benefits, there has been much concern about bisphosphonate-associated osteonecrosis of the jaw (Figure 5). Osteonecrosis of the jaw is a rare disorder characterized by exposure and loss of bone in the maxillofacial complex that is resistant or refractory to conventional therapy (reviewed by Carey and Palomo44). Most of the information on an association with bisphosphonates comes from case reports involving cancer patients who received high intravenous doses and who had other risk factors for jaw disease.45–48

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are47:

  • Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
  • Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,1 eg:

  • Alendronate 70 mg by mouth once a week
  • Risedronate 35 mg by mouth once a week or 150 mg once a month
  • Ibandronate 150 mg by mouth once a month
  • Ibandronate 3 mg intravenously every 3 months
  • Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,49 whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,50 which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.51 In a systematic review,45 patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,47 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.51

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.53 In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.43

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.51 To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

While we await further studies exploring this relationship, clinicians in direct care of patients who are or will be taking bisphosphonates should carefully assess risk factors before starting treatment and during treatment. In 2007, the American Association of Oral and Maxillofacial Surgeons released a position paper on bisphosphonate-associated osteonecrosis of the jaw,52 listing potential risk factors (Table 1) for its development, as well as management strategies for patients treated with bisphosphonates. To prevent this possible complication, they recommended a thorough oral examination before treatment with an intravenous bisphosphonate, and that “any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved.”52 They also proposed that “discontinuation of oral bisphosphonate for a period of 3 months prior to and 3 months after elective invasive dental surgery may lower the risk.”52 This should, however, be done in consultation with the treating physician and the patient.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

 

 

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

  • Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
  • Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
  • Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
  • Cleaning interproximally (between teeth) with floss or interdental cleaner
  • Maintaining a balanced diet
  • No smoking.
References
  1. North American Menopause Society. Menopause Practice: A Clinician’s Guide. 3rd ed; 2007.
  2. Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip and spine. Calcif Tissue Int 1996; 59:433–437.
  3. Kribbs PJ. Comparison of mandibular bone in normal and osteoporotic women. J Prosthet Dent 1990; 63:218–222.
  4. Kribbs PJ, Chesnut CH, Ott SM, Kilcoyne RF. Relationship between mandibular and skeletal bone in an osteoporotic population. J Prosthet Dent 1989; 62:703–707.
  5. Kribbs PJ, Chestnut CH, Ott SM, Kilcyne RE. Relationship between mandibular and skeletal bone in a population of normal women. J Prosthet Dent 1990; 63:86–89.
  6. Kribbs PJ, Smith DE, Chestnut CH. Oral findings in osteoporosis. Part II: relationship between residual ridge and alveolar bone resorption and generalized skeletal osteopenia. J Prosthet Dent 1983; 50:719–724.
  7. von Wowern N, Klausen B, Kollerup G. Osteoporosis: a risk factor in periodontal disease. J Periodontol 1994; 65:1134–1138.
  8. Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in oral bone loss and periodontal disease. J Peridontol 1996; 67(suppl 10):1076–1084.
  9. Ronderos M, Jacobs DR, Himes JH, Pihlstrom BL. Associations of periodontal disease with femoral bone mineral density and estrogen replacement therapy: cross-sectional evaluation of US adults from the NHANES III. J Clin Periodontol 2000; 27:778–86.
  10. American Dental Association Council on Access, Prevention and Interprofessional Relations. Women’s Oral Health Issues. November 2006.
  11. Jeffcoat MK, Lewis CE, Reddy MS, Wang CY, Redford M. Post-menopausal bone loss and its relationship to oral bone loss. Periodontol 2000 2000; 23:94–102.
  12. Famili P, Cauley J, Suzuki JB, Weyant R. Longitudinal study of periodontal disease and edentulism with rates of bone loss in older women. J Periodontol 2005; 76:11–15.
  13. Pilgram TK, Hildebolt CF, Yokoyama N, et al. Relationships between longitudinal changes in radiographic alveolar bone height and probing depth measurements: data from postmenopausal women. J Periodontol 1999; 70:829–833.
  14. Jeffcoat MK, Lewis CE, Reddy MS, et al. Oral bone loss and systemic osteopenia, osteoporosis. InMarcus R, Feldman D, Kelsey J, editors. Osteoporosis. New York Academic Press 1996:969–990.
  15. Klemetti E, Collin HL, Forss H, Markkanen H, Lassila V. Mineral status of skeletal and advanced periodontal disease. J Clin Periodontol 1994; 21:184–188.
  16. Hildebolt CF. Osteoporosis and oral bone loss. Dentomaxillofac Radiol 1997; 26:3–15.
  17. Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ. The relationship between bone mineral density and periodontitis in postmenopausal women. J Periodontol 2000; 71:1492–1498.
  18. Taguchi A, Tanimoto K, Suei Y, Ohama K, Wada T. Relationship between the mandibular and lumbar vertebral bone mineral density at different postmenopausal stages. Dentomaxillofac Radiol 1996; 25:130–135.
  19. Payne JB, Reinhardt RA, Nummikoski PV, Patil KD. Longitudinal alveolar bone loss in postmenopausal osteoporotic/osteopenic women. Osteoporos Int 1999; 10:34–40.
  20. Payne JB, Zachs NR, Reinhardt RA, Nummikoski PV, Patil K. The association between estrogen status and alveolar bone density changes in postmenopausal women with a history of periodontitis. J Periodontol 1997; 68:24–31.
  21. Civitelli R, Pilgram TK, Dotson M, et al. Alveolar and postcranial bone density in postmenopausal women receiving hormone/estrogen replacement: a randomized, double blind, placebo-controlled trial. Arch Intern Med 2002; 162:1409–1415.
  22. Albandar JM, Kingman A. Gingival recession, gingival bleeding, and dental calculus in adults 30 years of age and older in the United States, 1988–1994. J Periodontol 1999; 70:30–43.
  23. Norderyd OM, Grossi SG, Machtel EE, et al. Periodontal status of women taking postmenopausal estrogen supplementation. J Periodontol 1993; 64:957–962.
  24. Jacobs R, Ghyselen J, Koninckx P, van Steenberghe D. Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci 1996; 104:10–16.
  25. Meisel P, Reifenberger J, Haase R, Nauck M, Bandt C, Kocher T. Women are periodontally healthier than men, but why don’t they have more teeth than men? Menopause 2008; 15:270–275.
  26. Genco RJ, Grossi SG. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.
  27. Paganini-Hill A. The benefits of estrogen replacement therapy on oral health. The Leisure World cohort. Arch Intern Med 1995; 155:2325–2329.
  28. Krall EA, Dawson-Hughes B, Hannan MT, Wilson PW, Kiel DP. Post-menopausal estrogen replacement and tooth retention. Am J Med 1997; 102:536–542.
  29. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and tooth loss: a prospective study. J Am Dent Assoc 1996; 127:370–377.
  30. Taguchi A, Sanada M, Suei Y, et al. Effect of estrogen use on tooth retention, oral bone height, and oral bone porosity in Japanese postmenopausal women. Menopause 2004; 11:556–562.
  31. Pacifici R. Estrogen, cytokines and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996; 11:1043–1051.
  32. Pacifici R. Is there a causal role for IL-1 in postmenopausal bone loss? Calcif Tissue Int 1992; 50:295–299.
  33. Girasole G, Jilka RL, Passeri G, et al. 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 1992; 89:883–891.
  34. Pacifici R, Brown C, Pusheck E, et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 1991; 88:5134–5138.
  35. Brennan RM, Genco RJ, Wilding GE, Hovey KM, Trevisan M, Wactawski-Wende J. Bacterial species in subgingival plaque and oral bone loss in postmenopausal women. J Periodontol 2007; 78:1051–1061.
  36. Chestnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in post-menopausal osteoporosis. J Bone Miner Res 2004; 19:1241–1249.
  37. Black DM, Cummings SR, Karpf DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348:1535–1541.
  38. McClung MR, Geusen P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344:333–340.
  39. Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11:83–91.
  40. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799–1809.
  41. Palomo L, Bissada N, Liu J. Periodontal assessment of postmenopausal women receiving risedronate. Menopause 2005; 12:685–690.
  42. Rocha ML, Malacara JM, Sánchez-Marin FJ, Vazquez de la Torre CJ, Fajardo ME. Effect of alendronate on periodontal disease in postmenopausal women: a randomized placebo-controlled trial. J Periodontol 2004; 75:1579–1585.
  43. Jeffcoat MK, Cizza G, Shih WJ, Genco R, Lombardi A. Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. J Int Acad Periodontol 2007; 9:70–76.
  44. Carey JJ, Palomo L. Bisphosphonates and osteonecrosis of the jaw: innocent association or significant risk? Cleve Clin J Med 2008; 75:871–879.
  45. Woo SB, Hellstein JW, Kalamare JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753–761.
  46. Dodson TB, Raje NS, Caruso PA, Rosenberg AE. Case records of the Massachusetts General Hospital. Case 9–2008. A 65-year-old woman with a nonhealing ulcer of the jaw. N Engl J Med 2008; 358:1283–1291.
  47. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofacial Surg 2004; 62:527–534.
  48. Palomo L, Liu J, Bissada NF. Skeletal bone diseases impact the periodontium: a review of bisphosphonate therapy. Expert Opin Pharmacother 2007; 8:309–315.
  49. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 2000; 42:175–195.
  50. Berenson JR, Rosen L, Vescio R, et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37:285–290.
  51. American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006; 137:1144–1150.
  52. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofacial Surg 2007; 65:369–376.
  53. Grbic JT, Landesberg R, Lin SQ, et al; Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial. J Am Dent Assoc 2008; 139:32–40.
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Maria Clarinda A. Buencamino, MD
Women’s Health Institute, Cleveland Clinic

Leena Palomo, DDS, MSD
Assistant Professor of Periodontology, Director of Predoctoral Periodontics, Case Western Reserve University School of Dental Medicine, Cleveland, OH

Holly L. Thacker, MD, CDD
Director, Center for Specialized Women’s Health, Women’s Health Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maria Clarinda A. Buencamino, MD, Internal Diagnostic Department, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Palomo has disclosed that she has received honoraria for speaking and teaching from Procter and Gamble.

Dr. Thacker has disclosed that she has received honoraria for speaking and teaching from Bayer, Novartis, Procter and Gamble, Sanofi-Aventis, Ther-Rx, Upsher-Smith Laboratories, and Wyeth companies, and the Alliance for Better Bone Health.

Issue
Cleveland Clinic Journal of Medicine - 76(8)
Publications
Cleveland Clinic Journal of Medicine
Topics
Women's Health
Geriatrics
Drug Therapy
Endocrinology
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Sections
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Author(s)
Maria Clarinda A. Buencamino, MD
Leena Palomo, DDS, MSD
Holly L. Thacker, MD, CDD
Author(s)
Maria Clarinda A. Buencamino, MD
Leena Palomo, DDS, MSD
Holly L. Thacker, MD, CDD
Author and Disclosure Information

Maria Clarinda A. Buencamino, MD
Women’s Health Institute, Cleveland Clinic

Leena Palomo, DDS, MSD
Assistant Professor of Periodontology, Director of Predoctoral Periodontics, Case Western Reserve University School of Dental Medicine, Cleveland, OH

Holly L. Thacker, MD, CDD
Director, Center for Specialized Women’s Health, Women’s Health Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maria Clarinda A. Buencamino, MD, Internal Diagnostic Department, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Palomo has disclosed that she has received honoraria for speaking and teaching from Procter and Gamble.

Dr. Thacker has disclosed that she has received honoraria for speaking and teaching from Bayer, Novartis, Procter and Gamble, Sanofi-Aventis, Ther-Rx, Upsher-Smith Laboratories, and Wyeth companies, and the Alliance for Better Bone Health.

Author and Disclosure Information

Maria Clarinda A. Buencamino, MD
Women’s Health Institute, Cleveland Clinic

Leena Palomo, DDS, MSD
Assistant Professor of Periodontology, Director of Predoctoral Periodontics, Case Western Reserve University School of Dental Medicine, Cleveland, OH

Holly L. Thacker, MD, CDD
Director, Center for Specialized Women’s Health, Women’s Health Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maria Clarinda A. Buencamino, MD, Internal Diagnostic Department, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Palomo has disclosed that she has received honoraria for speaking and teaching from Procter and Gamble.

Dr. Thacker has disclosed that she has received honoraria for speaking and teaching from Bayer, Novartis, Procter and Gamble, Sanofi-Aventis, Ther-Rx, Upsher-Smith Laboratories, and Wyeth companies, and the Alliance for Better Bone Health.

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Related Articles
Menopause, vitamin D, and oral health
In reply: Menopause, vitamin D, and oral health

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

Figure 1. Red swollen gums of gingivitis.
Gingivitis is a reversible inflammatory response to bacterial plaque buildup that is limited to the gingiva (Figure 1).

Figure 2. Healthy gums and bones (left) vs periodontal disease (right). Note the lower bone height and resulting deeper pockets in periodontal disease.
If unchecked, gingivitis progresses to periodontitis, an inflammation of the supporting tissues of the teeth, including the gingiva, alveolar bone, and periodontal ligament (Figure 2). Periodontitis leads to progressive and irreversible loss of bone and periodontal ligament attachment, as inflammation extends from the gingiva into adjacent bone and ligament. Signs and symptoms of progressing periodontitis include red, swollen gums that may appear to have pulled away from the teeth, persistent bad breath, pus between the teeth and gums (Figure 3), loose or separating teeth, and the common complaint that “my teeth don’t fit together anymore.”

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

Figure 3. Red swollen gums with pus in periodontitis.
In menopause, estrogen levels decline rapidly, which can lead to systemic bone loss.1

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.2 In fact, Kribbs3 found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,3–11 these findings are not universal. In a longitudinal study, Famili et al12 found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.13

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.10 In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.14

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al15 found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.7

However, Hildebolt16 reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al17 found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.13

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al18 reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

 

 

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al19 reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.20

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.21 Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman22 suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,23 in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.24

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.20 More-recent studies had similar findings. A cross-sectional study by Meisel et al25 found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.26

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,27 Framingham,28 and Nurses Health Study29 cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al30 evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.30 Meisel et al25 reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.
Figure 4. Proposed model for how estrogen deficiency contributes to severe periodontal disease.
Genco and Grossi26 have proposed a model for estrogen deficiency as a risk factor for periodontal disease (Figure 4). In this model, estrogen deficiency leads to more production of bone-resorbing cytokines produced by immune cells (monocytes and macrophages) and osteoblasts. When challenged by products related to periodontal bacterial plaque biofilm, by bone-resorbing factors such as lipopolysaccharides, and by toxins, the host immune system produces more inflammatory cytokines that activate osteoclasts, which reabsorb bone. The buildup of bacterial plaque biofilm made up of periopathogenic bacteria35 seems to be necessary for an estrogen-deficient woman to actually show changes such as loss of tooth attachment and alveolar bone. The host’s inflammatory response to this biofilm starts the inflammation cascade and may lead to constant activation of tissue proteinases and degradative enzymes, leading to connective tissue destruction, alveolar bone resorption, and ultimately tooth loss, which can explain the increased risk of periodontal disease in postmenopausal women.26,3

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

 

 

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.36 Specific findings:

  • In the Fracture Intervention Trial,37 alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
  • In the Hip Intervention Program,38 risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.39
  • In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,40 annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.41–43 Findings:

  • In a cross-sectional study by Palomo et al,41 postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
  • In a double-blind, controlled, prospective study by Rocha et al,42 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
  • Jeffcoat et al43 reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

Figure 5. Osteonecrosis of the jaw.
Despite these benefits, there has been much concern about bisphosphonate-associated osteonecrosis of the jaw (Figure 5). Osteonecrosis of the jaw is a rare disorder characterized by exposure and loss of bone in the maxillofacial complex that is resistant or refractory to conventional therapy (reviewed by Carey and Palomo44). Most of the information on an association with bisphosphonates comes from case reports involving cancer patients who received high intravenous doses and who had other risk factors for jaw disease.45–48

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are47:

  • Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
  • Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,1 eg:

  • Alendronate 70 mg by mouth once a week
  • Risedronate 35 mg by mouth once a week or 150 mg once a month
  • Ibandronate 150 mg by mouth once a month
  • Ibandronate 3 mg intravenously every 3 months
  • Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,49 whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,50 which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.51 In a systematic review,45 patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,47 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.51

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.53 In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.43

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.51 To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

While we await further studies exploring this relationship, clinicians in direct care of patients who are or will be taking bisphosphonates should carefully assess risk factors before starting treatment and during treatment. In 2007, the American Association of Oral and Maxillofacial Surgeons released a position paper on bisphosphonate-associated osteonecrosis of the jaw,52 listing potential risk factors (Table 1) for its development, as well as management strategies for patients treated with bisphosphonates. To prevent this possible complication, they recommended a thorough oral examination before treatment with an intravenous bisphosphonate, and that “any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved.”52 They also proposed that “discontinuation of oral bisphosphonate for a period of 3 months prior to and 3 months after elective invasive dental surgery may lower the risk.”52 This should, however, be done in consultation with the treating physician and the patient.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

 

 

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

  • Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
  • Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
  • Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
  • Cleaning interproximally (between teeth) with floss or interdental cleaner
  • Maintaining a balanced diet
  • No smoking.

Menopause can bring oral health problems that physicians ought to keep in mind. The same processes that lead to loss of bone in the spine and hips can also lead to loss of the alveolar bone of the jaws, resulting in periodontal disease, loose teeth, and tooth loss. Although the mouth is traditionally the dentist’s responsibility, patients may need encouragement from their physicians to practice good oral hygiene and to see their dentists, and should be referred to a periodontist at the first sign of periodontal disease.

Moreover, bisphosphonates, the class of drugs most often prescribed for osteoporosis, have been linked by case reports (unfairly, we believe) to osteonecrosis of the jaw. This low-evidence-level information, its far-reaching interpretation, and misinformation in the lay media about hormonal changes associated with menopause have led to confusion among women; for clarification and reliable information, they are driven to ask their physicians challenging questions related to oral health.

This article reviews the published studies of the association between menopause and periodontal disease, specifically, the effects of hormonal changes, osteoporosis, and bisphosphonate use on the periodontal status of postmenopausal women. We will highlight the interrelationship of dental health and postmenopausal health and underscore the need for cross-communication and patient referral between physicians and dentists.

GINGIVITIS CAN PROGRESS TO PERIODONTITIS

Figure 1. Red swollen gums of gingivitis.
Gingivitis is a reversible inflammatory response to bacterial plaque buildup that is limited to the gingiva (Figure 1).

Figure 2. Healthy gums and bones (left) vs periodontal disease (right). Note the lower bone height and resulting deeper pockets in periodontal disease.
If unchecked, gingivitis progresses to periodontitis, an inflammation of the supporting tissues of the teeth, including the gingiva, alveolar bone, and periodontal ligament (Figure 2). Periodontitis leads to progressive and irreversible loss of bone and periodontal ligament attachment, as inflammation extends from the gingiva into adjacent bone and ligament. Signs and symptoms of progressing periodontitis include red, swollen gums that may appear to have pulled away from the teeth, persistent bad breath, pus between the teeth and gums (Figure 3), loose or separating teeth, and the common complaint that “my teeth don’t fit together anymore.”

AS ESTROGEN DECLINES, SO DO THE BONES AND, MAYBE, THE TEETH

Figure 3. Red swollen gums with pus in periodontitis.
In menopause, estrogen levels decline rapidly, which can lead to systemic bone loss.1

The rate of bone loss in postmenopausal women predicts tooth loss—for every 1%-per-year decrease in whole-body bone mineral density, the risk of tooth loss increases more than four times.2 In fact, Kribbs3 found that women with severe osteoporosis were three times more likely than healthy, age-matched controls to be edentulous (ie, to have fewer teeth).

Although a number of studies have found that the density of the alveolar bone in the mandible correlated with the density of the bone in the rest of the skeleton and that generalized bone loss may render the jaw susceptible to accelerated alveolar bone resorption,3–11 these findings are not universal. In a longitudinal study, Famili et al12 found no association between systemic bone loss, periodontal disease, and edentulism. This shows that the relationship between alveolar bone loss and systemic bone loss is multifactorial and not yet fully understood.13

Nevertheless, the American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease.10 In fact, alveolar bone loss has been related not only to osteoporosis but also to osteopenia.14

Bone mineral density has also been studied in relation to the loss of periodontal ligament—the collagenous attachment of tooth to bone. Klemetti et al15 found that healthy postmenopausal women with high bone mineral density seemed to retain teeth more readily than those with low bone density or those with osteoporosis, even if they had deep periodontal pockets (a sign of periodontal disease). These findings were reiterated when osteoporotic women were found to have significantly greater loss of attachment compared with nonosteoporotic women.7

However, Hildebolt16 reported that loss of tooth attachment correlated with tooth loss but not with the density of the vertebrae or the proximal femur. This study called into question the findings of the previous studies and provoked debate.

Tezal et al17 found that low bone mineral density was related to the loss of interproximal alveolar bone (the alveolar bone between adjacent teeth) and, to a lesser extent, ligamentous attachment loss. These data implicated osteoporosis as a possible risk indicator for periodontal disease in white women. (This study was limited to white women because of different demographics in the incidence of osteoporosis.)

Another study showed only a weak correlation between changes in alveolar bone height (in periodontal disease, bone height decreases) and attachment levels. Although a correlation might be present, the relationship was complex and required further examination. The authors found no clear association between clinical attachment levels and bone mineral density in the lumbar spine, but they recognized that attachment loss often precedes the loss of alveolar bone by a significant time period.13

Several studies have found a possible relationship between the bone density in the jaw and the density in the rest of the skeleton. It appears that loss of bone mineral density in the hip, wrist, and lumbar areas is correlated with low density in the mandible. Taguchi et al18 reported that the density in the lumbar spine correlated with the density of the mandibular cortex in early menopause, and with the density of both the cortex and cancellous bone in later menopause.

But whatever the statistical measurement, the susceptibility to progressive periodontitis increases after menopause, and the primary cause is bacterial plaque. The best hedge against this increased susceptibility is regular dental care to remove bacterial plaque biofilm under the gum-line.

 

 

HORMONE THERAPY PRESERVES BONE IN THE JAW

Hormones have long been recognized as having some role in periodontal disease.

Payne et al19 reported that postmenopausal women who were estrogen-deficient had a higher frequency of sites with a net loss of alveolar bone density at follow-up. Furthermore, estrogen-deficient women undergoing supportive periodontal therapy following treatment of moderate to severe periodontitis had three times as many sites losing more than 0.4 mm of interproximal alveolar bone height. Patients who had sufficient estrogen levels did not lose bone during 1 year of follow-up.20

Estrogen replacement improves bone density in postmenopausal women. In a 3-year randomized trial in postmenopausal women with moderate or advanced periodontal disease, estrogen therapy significantly increased alveolar bone mass compared with placebo (P = .04), and it increased bone density in the femur but not the lumbar spine.21 Furthermore, women receiving hormonal therapy had significantly less gingival inflammation, lower plaque scores, and less loss of attachment.

On the other hand, a report by Albandar and Kingman22 suggested that women who comply with hormonal therapy also comply with oral hygiene instructions. This compliance could explain the lower gingival inflammation scores, lower plaque scores, and lesser loss of attachment.

Norderyd et al,23 in a cross-sectional study, found less periodontal disease in postmenopausal women who were on estrogen therapy than in those who were not, although the difference was not statistically significant.

In a 5-year longitudinal study of 69 postmenopausal women receiving estrogen, a moderate but significant relationship was found between bone mineral density of the lumbar spine and the mandible, and estrogen replacement therapy had a positive effect on the mandibular bone mass.24

In a longitudinal study of 24 postmenopausal women, estrogen-deficient women had a mean net loss of alveolar bone density over time, while estrogen-sufficient women had a mean net gain, suggesting that estrogen deficiency may be a risk factor for alveolar bone loss.20 More-recent studies had similar findings. A cross-sectional study by Meisel et al25 found that hormone therapy significantly reduced the extent of clinical attachment loss and, hence, periodontal disease.

The findings of these studies are generally consistent, suggesting that estrogen builds up mandibular bone mass and attenuates the severity of periodontal disease in postmenopausal women.26

DOES ESTROGEN THERAPY PROTECT THE TEETH?

Studies of the Leisure World,27 Framingham,28 and Nurses Health Study29 cohorts suggest that hormone therapy protects against tooth loss in postmenopausal women.

On the other hand, Taguchi et al30 evaluated more than 300 postmenopausal Japanese women and found no significant difference in the total number of teeth between estrogen users and nonusers. The population in this study was younger than in the other studies mentioned above,27–29 which may explain the negative finding. However, the duration of estrogen use was significantly associated with the total number of teeth remaining, independent of age.30 Meisel et al25 reported that women receiving hormonal therapy had more teeth, though the difference was not significant.

CYTOKINES, PERIODONTITIS, AND SKELETAL BONE LOSS

Studies suggest that low estrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, which stimulate mature osteoclasts, modulate bone cell proliferation, and induce resorption of both skeletal and alveolar bone.31–34

Based on Genco RJ, et al. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.
Figure 4. Proposed model for how estrogen deficiency contributes to severe periodontal disease.
Genco and Grossi26 have proposed a model for estrogen deficiency as a risk factor for periodontal disease (Figure 4). In this model, estrogen deficiency leads to more production of bone-resorbing cytokines produced by immune cells (monocytes and macrophages) and osteoblasts. When challenged by products related to periodontal bacterial plaque biofilm, by bone-resorbing factors such as lipopolysaccharides, and by toxins, the host immune system produces more inflammatory cytokines that activate osteoclasts, which reabsorb bone. The buildup of bacterial plaque biofilm made up of periopathogenic bacteria35 seems to be necessary for an estrogen-deficient woman to actually show changes such as loss of tooth attachment and alveolar bone. The host’s inflammatory response to this biofilm starts the inflammation cascade and may lead to constant activation of tissue proteinases and degradative enzymes, leading to connective tissue destruction, alveolar bone resorption, and ultimately tooth loss, which can explain the increased risk of periodontal disease in postmenopausal women.26,3

In this regard, osteoporosis and periodontitis appear to be mediated by common cytokines. Managing osteoporosis, removing bacterial plaque biofilm with good oral hygiene, and regular dental visits are important in avoiding periodontitis in susceptible women.

 

 

BISPHOSPHONATES PROTECT BONE

In the skeleton

Bisphosphonates, the most commonly prescribed therapy for osteoporosis, inhibit systemic bone resorption and reduce the incidence of vertebral and nonvertebral fractures. Among the bisphosphonates, alendronate (Fosamax), risedronate (Actonel), and intravenous zoledronic acid (Reclast) have been shown to reduce the risk of both hip and vertebral fractures, whereas ibandronate (Boniva) has only been shown to decrease the risk of vertebral fracture.36 Specific findings:

  • In the Fracture Intervention Trial,37 alendronate reduced the risk of vertebral fracture by 47% and hip fracture by 51% in women with low bone mineral density and previous vertebral fractures.
  • In the Hip Intervention Program,38 risedronate decreased the risk of hip fracture by 40% in postmenopausal women 70 to 79 years old with osteoporosis, but not in those 80 years and older, who are at high risk of falls. Risedronate also reduced vertebral fracture risk by 49% after 3 years of treatment.39
  • In the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial,40 annual infusion of zoledronic acid after a hip fracture reduced the rates of new clinical vertebral and nonvertebral fractures and death from all causes.

In the jaw

Not surprisingly, recent studies suggest that bisphosphonates slow the resorption of alveolar bone of the maxilla and mandible as well. Alendronate and risedronate, in particular, have been noted to improve periodontal status.41–43 Findings:

  • In a cross-sectional study by Palomo et al,41 postmenopausal women with low bone density using risedronate for at least 3 months showed significantly less plaque accumulation, less gingival inflammation, lower probing-depth measurments, less periodontal attachment loss, and greater alveolar bone levels.
  • In a double-blind, controlled, prospective study by Rocha et al,42 6 months of alendronate therapy significantly improved periodontal disease as assessed radiographically and clinically in 40 postmenopausal women with established periodontal disease.
  • Jeffcoat et al43 reported that 2 years of alendronate treatment significantly reduced alveolar bone loss relative to placebo in patients with low mandibular bone mineral density at baseline but not in those with normal baseline mandibular bone mineral density.

DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW?

Figure 5. Osteonecrosis of the jaw.
Despite these benefits, there has been much concern about bisphosphonate-associated osteonecrosis of the jaw (Figure 5). Osteonecrosis of the jaw is a rare disorder characterized by exposure and loss of bone in the maxillofacial complex that is resistant or refractory to conventional therapy (reviewed by Carey and Palomo44). Most of the information on an association with bisphosphonates comes from case reports involving cancer patients who received high intravenous doses and who had other risk factors for jaw disease.45–48

The intravenous bisphosphonates most commonly used to treat hypercalcemia of malignancy, multiple myeloma, or metastatic bone disease are47:

  • Pamidronate (Aredia) 90 mg infused over 2 to 24 hours every 3 to 4 weeks
  • Zoledronic acid (Zometa) 4 mg infused over 15 minutes monthly.

The doses of bisphosphonates indicated for the treatment of osteoporosis are much lower,1 eg:

  • Alendronate 70 mg by mouth once a week
  • Risedronate 35 mg by mouth once a week or 150 mg once a month
  • Ibandronate 150 mg by mouth once a month
  • Ibandronate 3 mg intravenously every 3 months
  • Zoledronic acid 5 mg intravenously once a year.

Moreover, less than 1% of an oral dose is absorbed by the gastrointestinal tract,49 whereas more than 50% of the dose of bisphosphonates given intravenously is bioavailable,50 which may account for the lower incidence of jaw ostenonecrosis with oral agents.

Osteonecrosis of the jaw can occur spontaneously but is more often associated with dental procedures that traumatize bone, such as tooth extraction.51 In a systematic review,45 patients with multiple myeloma and metastatic cancer to the bone who were receiving intravenous bisphosphonates accounted for 94% of published cases. Sixty percent of cases were preceded by dental surgical procedures, and in 39% of cases that occurred spontaneously the lesions were located on bony exostoses, a possible source of trauma. Of 63 cases reported by Ruggiero et al,47 56 patients were receiving intravenous bisphosphonates and 7 were receiving oral bisphosphonates. Older age (> 65 years), chronic systemic steroid use, periodontitis, and prolonged use of bisphosphonates have also been associated with a higher risk of osteonecrosis of the jaw.51

The risk of developing osteonecrosis of the jaw in people taking bisphosphonates in doses recommended by the US Food and Drug Administration for treating osteoporosis is very low (the incidence is calculated at 0.7 per 100,000 person-years of exposure to alendronate).51,52 In a 3-year prospective study in more than 7,000 women with post-menopausal osteoporosis, the incidence of osteonecrosis of the jaw was no different in those treated with zoledronic acid 5 mg intravenously than in those receiving placebo.53 In a randomized, placebo-controlled study of the effect of 2 years of alendronate treatment on alveolar bone loss involving 335 patients with periodontal disease, no cases of osteonecrosis of the jaw were reported.43

The American Dental Association (ADA) released a statement noting that osteonecrosis of the jaw can occur with or without bisphosphonate use.51 To date, a true cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate use has not been established. Further studies are needed to fully explore this relationship. Our group is currently exploring novel periodontal assessments comparing the oral health of postmenopausal women with osteoporosis who are on no bone therapy vs postmenopausal women with osteoporosis treated with bisphosphonates for 2 or more years.

While we await further studies exploring this relationship, clinicians in direct care of patients who are or will be taking bisphosphonates should carefully assess risk factors before starting treatment and during treatment. In 2007, the American Association of Oral and Maxillofacial Surgeons released a position paper on bisphosphonate-associated osteonecrosis of the jaw,52 listing potential risk factors (Table 1) for its development, as well as management strategies for patients treated with bisphosphonates. To prevent this possible complication, they recommended a thorough oral examination before treatment with an intravenous bisphosphonate, and that “any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved.”52 They also proposed that “discontinuation of oral bisphosphonate for a period of 3 months prior to and 3 months after elective invasive dental surgery may lower the risk.”52 This should, however, be done in consultation with the treating physician and the patient.

Discussion of treatment for bisphosphonate-associated osteonecrosis of the jaw is beyond the scope of this article.

 

 

REGULAR DENTAL CARE IS ESSENTIAL

Regardless of whether the patient is receiving a bisphosphonate drug, physicians caring for postmenopausal women should be vigilant and encourage their patients to seek regular dental evaluation for prevention and early management of oral disorders. Conversely, dentists should be aware of the potential effects of menopause and its treatments on bone and dental health.

Questions from postmenopausal women can be managed, in part, by returning to the basics suggested by the ADA:

  • Regular dental examinations; regular professional cleaning to remove bacterial plaque biofilm under the gum-line where a toothbrush will not reach
  • Daily oral hygiene practices to remove biofilm at and above the gum-line including brushing twice daily with an ADA-accepted toothpaste
  • Replacing the toothbrush every 3 to 4 months (or sooner if the bristles begin to look frayed)
  • Cleaning interproximally (between teeth) with floss or interdental cleaner
  • Maintaining a balanced diet
  • No smoking.
References
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  36. Chestnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in post-menopausal osteoporosis. J Bone Miner Res 2004; 19:1241–1249.
  37. Black DM, Cummings SR, Karpf DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348:1535–1541.
  38. McClung MR, Geusen P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344:333–340.
  39. Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11:83–91.
  40. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799–1809.
  41. Palomo L, Bissada N, Liu J. Periodontal assessment of postmenopausal women receiving risedronate. Menopause 2005; 12:685–690.
  42. Rocha ML, Malacara JM, Sánchez-Marin FJ, Vazquez de la Torre CJ, Fajardo ME. Effect of alendronate on periodontal disease in postmenopausal women: a randomized placebo-controlled trial. J Periodontol 2004; 75:1579–1585.
  43. Jeffcoat MK, Cizza G, Shih WJ, Genco R, Lombardi A. Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. J Int Acad Periodontol 2007; 9:70–76.
  44. Carey JJ, Palomo L. Bisphosphonates and osteonecrosis of the jaw: innocent association or significant risk? Cleve Clin J Med 2008; 75:871–879.
  45. Woo SB, Hellstein JW, Kalamare JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753–761.
  46. Dodson TB, Raje NS, Caruso PA, Rosenberg AE. Case records of the Massachusetts General Hospital. Case 9–2008. A 65-year-old woman with a nonhealing ulcer of the jaw. N Engl J Med 2008; 358:1283–1291.
  47. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofacial Surg 2004; 62:527–534.
  48. Palomo L, Liu J, Bissada NF. Skeletal bone diseases impact the periodontium: a review of bisphosphonate therapy. Expert Opin Pharmacother 2007; 8:309–315.
  49. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 2000; 42:175–195.
  50. Berenson JR, Rosen L, Vescio R, et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37:285–290.
  51. American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006; 137:1144–1150.
  52. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofacial Surg 2007; 65:369–376.
  53. Grbic JT, Landesberg R, Lin SQ, et al; Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial. J Am Dent Assoc 2008; 139:32–40.
References
  1. North American Menopause Society. Menopause Practice: A Clinician’s Guide. 3rd ed; 2007.
  2. Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip and spine. Calcif Tissue Int 1996; 59:433–437.
  3. Kribbs PJ. Comparison of mandibular bone in normal and osteoporotic women. J Prosthet Dent 1990; 63:218–222.
  4. Kribbs PJ, Chesnut CH, Ott SM, Kilcoyne RF. Relationship between mandibular and skeletal bone in an osteoporotic population. J Prosthet Dent 1989; 62:703–707.
  5. Kribbs PJ, Chestnut CH, Ott SM, Kilcyne RE. Relationship between mandibular and skeletal bone in a population of normal women. J Prosthet Dent 1990; 63:86–89.
  6. Kribbs PJ, Smith DE, Chestnut CH. Oral findings in osteoporosis. Part II: relationship between residual ridge and alveolar bone resorption and generalized skeletal osteopenia. J Prosthet Dent 1983; 50:719–724.
  7. von Wowern N, Klausen B, Kollerup G. Osteoporosis: a risk factor in periodontal disease. J Periodontol 1994; 65:1134–1138.
  8. Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in oral bone loss and periodontal disease. J Peridontol 1996; 67(suppl 10):1076–1084.
  9. Ronderos M, Jacobs DR, Himes JH, Pihlstrom BL. Associations of periodontal disease with femoral bone mineral density and estrogen replacement therapy: cross-sectional evaluation of US adults from the NHANES III. J Clin Periodontol 2000; 27:778–86.
  10. American Dental Association Council on Access, Prevention and Interprofessional Relations. Women’s Oral Health Issues. November 2006.
  11. Jeffcoat MK, Lewis CE, Reddy MS, Wang CY, Redford M. Post-menopausal bone loss and its relationship to oral bone loss. Periodontol 2000 2000; 23:94–102.
  12. Famili P, Cauley J, Suzuki JB, Weyant R. Longitudinal study of periodontal disease and edentulism with rates of bone loss in older women. J Periodontol 2005; 76:11–15.
  13. Pilgram TK, Hildebolt CF, Yokoyama N, et al. Relationships between longitudinal changes in radiographic alveolar bone height and probing depth measurements: data from postmenopausal women. J Periodontol 1999; 70:829–833.
  14. Jeffcoat MK, Lewis CE, Reddy MS, et al. Oral bone loss and systemic osteopenia, osteoporosis. InMarcus R, Feldman D, Kelsey J, editors. Osteoporosis. New York Academic Press 1996:969–990.
  15. Klemetti E, Collin HL, Forss H, Markkanen H, Lassila V. Mineral status of skeletal and advanced periodontal disease. J Clin Periodontol 1994; 21:184–188.
  16. Hildebolt CF. Osteoporosis and oral bone loss. Dentomaxillofac Radiol 1997; 26:3–15.
  17. Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ. The relationship between bone mineral density and periodontitis in postmenopausal women. J Periodontol 2000; 71:1492–1498.
  18. Taguchi A, Tanimoto K, Suei Y, Ohama K, Wada T. Relationship between the mandibular and lumbar vertebral bone mineral density at different postmenopausal stages. Dentomaxillofac Radiol 1996; 25:130–135.
  19. Payne JB, Reinhardt RA, Nummikoski PV, Patil KD. Longitudinal alveolar bone loss in postmenopausal osteoporotic/osteopenic women. Osteoporos Int 1999; 10:34–40.
  20. Payne JB, Zachs NR, Reinhardt RA, Nummikoski PV, Patil K. The association between estrogen status and alveolar bone density changes in postmenopausal women with a history of periodontitis. J Periodontol 1997; 68:24–31.
  21. Civitelli R, Pilgram TK, Dotson M, et al. Alveolar and postcranial bone density in postmenopausal women receiving hormone/estrogen replacement: a randomized, double blind, placebo-controlled trial. Arch Intern Med 2002; 162:1409–1415.
  22. Albandar JM, Kingman A. Gingival recession, gingival bleeding, and dental calculus in adults 30 years of age and older in the United States, 1988–1994. J Periodontol 1999; 70:30–43.
  23. Norderyd OM, Grossi SG, Machtel EE, et al. Periodontal status of women taking postmenopausal estrogen supplementation. J Periodontol 1993; 64:957–962.
  24. Jacobs R, Ghyselen J, Koninckx P, van Steenberghe D. Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci 1996; 104:10–16.
  25. Meisel P, Reifenberger J, Haase R, Nauck M, Bandt C, Kocher T. Women are periodontally healthier than men, but why don’t they have more teeth than men? Menopause 2008; 15:270–275.
  26. Genco RJ, Grossi SG. Is estrogen deficiency a risk factor for periodontal disease? Compend Contin Educ Dent Suppl 1998; 22:S23–S29.
  27. Paganini-Hill A. The benefits of estrogen replacement therapy on oral health. The Leisure World cohort. Arch Intern Med 1995; 155:2325–2329.
  28. Krall EA, Dawson-Hughes B, Hannan MT, Wilson PW, Kiel DP. Post-menopausal estrogen replacement and tooth retention. Am J Med 1997; 102:536–542.
  29. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and tooth loss: a prospective study. J Am Dent Assoc 1996; 127:370–377.
  30. Taguchi A, Sanada M, Suei Y, et al. Effect of estrogen use on tooth retention, oral bone height, and oral bone porosity in Japanese postmenopausal women. Menopause 2004; 11:556–562.
  31. Pacifici R. Estrogen, cytokines and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996; 11:1043–1051.
  32. Pacifici R. Is there a causal role for IL-1 in postmenopausal bone loss? Calcif Tissue Int 1992; 50:295–299.
  33. Girasole G, Jilka RL, Passeri G, et al. 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 1992; 89:883–891.
  34. Pacifici R, Brown C, Pusheck E, et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 1991; 88:5134–5138.
  35. Brennan RM, Genco RJ, Wilding GE, Hovey KM, Trevisan M, Wactawski-Wende J. Bacterial species in subgingival plaque and oral bone loss in postmenopausal women. J Periodontol 2007; 78:1051–1061.
  36. Chestnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in post-menopausal osteoporosis. J Bone Miner Res 2004; 19:1241–1249.
  37. Black DM, Cummings SR, Karpf DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996; 348:1535–1541.
  38. McClung MR, Geusen P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344:333–340.
  39. Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11:83–91.
  40. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357:1799–1809.
  41. Palomo L, Bissada N, Liu J. Periodontal assessment of postmenopausal women receiving risedronate. Menopause 2005; 12:685–690.
  42. Rocha ML, Malacara JM, Sánchez-Marin FJ, Vazquez de la Torre CJ, Fajardo ME. Effect of alendronate on periodontal disease in postmenopausal women: a randomized placebo-controlled trial. J Periodontol 2004; 75:1579–1585.
  43. Jeffcoat MK, Cizza G, Shih WJ, Genco R, Lombardi A. Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. J Int Acad Periodontol 2007; 9:70–76.
  44. Carey JJ, Palomo L. Bisphosphonates and osteonecrosis of the jaw: innocent association or significant risk? Cleve Clin J Med 2008; 75:871–879.
  45. Woo SB, Hellstein JW, Kalamare JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753–761.
  46. Dodson TB, Raje NS, Caruso PA, Rosenberg AE. Case records of the Massachusetts General Hospital. Case 9–2008. A 65-year-old woman with a nonhealing ulcer of the jaw. N Engl J Med 2008; 358:1283–1291.
  47. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofacial Surg 2004; 62:527–534.
  48. Palomo L, Liu J, Bissada NF. Skeletal bone diseases impact the periodontium: a review of bisphosphonate therapy. Expert Opin Pharmacother 2007; 8:309–315.
  49. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 2000; 42:175–195.
  50. Berenson JR, Rosen L, Vescio R, et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37:285–290.
  51. American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006; 137:1144–1150.
  52. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofacial Surg 2007; 65:369–376.
  53. Grbic JT, Landesberg R, Lin SQ, et al; Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial. J Am Dent Assoc 2008; 139:32–40.
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Cleveland Clinic Journal of Medicine - 76(8)
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KEY POINTS

  • Physicians should be vigilant for dental problems and should encourage their patients to practice good oral hygiene and to seek regular dental care.
  • Available information suggests that hormone therapy and bisphosphonate drugs may be developed to protect against alveolar bone loss and perhaps slow the progression of periodontal disease.
  • Bisphosphonate-associated osteonecrosis of the jaw is rare, and most of the reported cases have been in cancer patients who received high doses of bisphosphonates intravenously and who had other risk factors for it.
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Alternative modes of mechanical ventilation: A review for the hospitalist

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Alternative modes of mechanical ventilation: A review for the hospitalist
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Eduardo Mireles-Cabodevila, MD
Enrique Diaz-Guzman, MD
Gustavo A. Heresi, MD
Robert L. Chatburn, BS, RRT-NPS

Technologic advances and computerized control of mechanical ventilators have made it possible to deliver ventilatory assistance in new modes. Driving these innovations is the desire to prevent ventilator-induced lung injury, improve patient comfort, and liberate the patient from mechanical ventilation as soon as possible.

We call these innovations “alternative” modes to differentiate them from the plain volume-control and pressure-control modes. Some clinicians rarely use these new modes, but in some medical centers they have become the most common ones used, or are being used unknowingly (the operator misunderstands the mode name). The information we provide on these modes of ventilation is by no means an endorsement of their use, but rather a tool to help the clinician understand their physiologic, theoretical, and clinical effects.

We focused on two goals:

  • Explain what the mode does
  • Briefly review the theoretical benefits and the actual evidence supporting these alternative modes of ventilation.

STANDARD NOMENCLATURE NEEDED

Since its invention, mechanical ventilation has been plagued by multiple names being used to describe the same things. For example, volume-control ventilation is also called volume-cycled ventilation, assist-control ventilation, volume-limited ventilation, and controlled mechanical ventilation. Similarly, multiple abbreviations are used, each depending on the brand of ventilator, and new acronyms have been added in recent years as new modes have been developed. The vast number of names and modes can confuse even the most seasoned critical care physician.

Efforts to establish a common nomenclature are under way.1

WHAT IS A MODE?

A mode of mechanical ventilation has three essential components:

  • The control variable
  • The breath sequence
  • The targeting scheme.

Similar modes may require more detailed descriptions to distinguish them, but the basic function can be explained by these three components.

The control variable

In general, inspiration is an active process, driven by the patient’s effort, the ventilator, or both, while expiration is passive. For simplicity, in this article a mechanical breath means the inspiratory phase of the breath.

The machine can only control the volume (and flow) or the pressure given. The breaths can be further described on the basis of what triggers the breath, what limits it (the maximum value of a control variable), and what ends (cycles) it.

Figure 1. Volume control (top) and pressure control (bottom) are modes of continuous mandatory ventilation. Each mode is depicted as patient effort increases. Notice that the mode’s control variable (volume or pressure) remains constant as patient effort increases. Contrast these findings with those in Figure 2.
Therefore, a volume-controlled breath is triggered by the patient or by the machine, limited by flow, and cycled by volume (Figure 1). A pressure-controlled breath is triggered by the patient or the machine, limited by pressure, and cycled by time or flow (Figure 1).

The breath sequence

There are three possible breath sequences:

  • Continuous mandatory ventilation, in which all breaths are controlled by the machine (but can be triggered by the patient)
  • Intermittent mandatory ventilation, in which the patient can take spontaneous breaths between mandatory breaths
  • Continuous spontaneous ventilation, in which all breaths are spontaneous (Table 1).

The targeting scheme

The targeting or feedback scheme refers to the ventilator settings and programming that dictate its response to the patient’s lung compliance, lung resistance, and respiratory effort. The regulation can be as simple as controlling the pressure in pressure-control mode, or it can be based on a complicated algorithm.

In the sections that follow, we describe some of the available alternative modes of mechanical ventilation. We will explain only the targeting schemes in the modes reviewed (Table 1, Table 2), but more information on other targeting schemes can be found elsewhere.1,2 We will focus on evidence generated in adult patients receiving invasive mechanical ventilation.

 

 

ADAPTIVE PRESSURE CONTROL

Figure 2. A machine in adaptive pressure control mode (top) adjusts the inspiratory pressure to maintain a set tidal volume. Adaptive support ventilation (bottom) automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and the target minute ventilation.
One of the concerns with pressure-control ventilation is that it cannot guarantee a minimum minute ventilation (the volume of air that goes in and out in 1 minute; the tidal volume × breaths per minute) in the face of changing lung mechanics or patient effort, or both. To solve this problem, in 1991 the Siemens Servo 300 ventilator (Siemens, Maquet Critical Care AB, Solna, Sweden) introduced Pressure Regulated Volume Control, a mode that delivers pressure-controlled breaths with a target tidal volume and that is otherwise known as adaptive pressure control (APC) (Figure 2).

Other names for adaptive pressure control

  • Pressure Regulated Volume Control (Maquet Servo-i, Rastatt, Germany)
  • AutoFlow (Dräger Medical AG, Lübeck, Germany)
  • Adaptive Pressure Ventilation (Hamilton Galileo, Hamilton Medical AG, Bonaduz, Switzerland)
  • Volume Control+ (Puritan Bennett, Tyco Healthcare; Mansfield, MA)
  • Volume Targeted Pressure Control, Pressure Controlled Volume Guaranteed (Engström, General Electric, Madison, WI).

What does adaptive pressure control do?

The APC mode delivers pressure-controlled breaths with an adaptive targeting scheme (Table 2).

In pressure-control ventilation, tidal volumes depend on the lung’s physiologic mechanics (compliance and resistance) and patient effort (Figure 1). Therefore, the tidal volume varies with changes in lung physiology (ie, larger or smaller tidal volumes than targeted).

To overcome this effect, a machine in APC mode adjusts the inspiratory pressure to deliver the set minimal target tidal volume. If tidal volume increases, the machine decreases the inspiratory pressure, and if tidal volume decreases, the machine increases the inspiratory pressure. However, if the patient effort is large enough, the tidal volume will increase in spite of decreasing the inspiratory pressure (Figure 2). The adjustments to the inspiratory pressure occur after the tidal volume is off-target in a number of breaths.

Common sources of confusion with adaptive pressure control

First, APC is not a volume-control mode. In volume control, the tidal volume does not change; in APC the tidal volume can increase or decrease, and the ventilator will adjust the inflation pressure to achieve the target volume. Thus, APC guarantees an average minimum tidal volume but not a maximum tidal volume.

Second, a characteristic of pressure control (and hence, APC) is that the flow of gas varies to maintain constant airway pressure (ie, maintain the set inspiratory pressure). This characteristic allows a patient who generates an inspiratory effort to receive flow as demanded, which is likely more comfortable. This is essentially different from volume control, in which flow is set by the operator and hence is fixed. Thus, if the patient effort is strong enough (Figure 1), this leads to what is called flow asynchrony, in which the patient does not get the flow asked for in a breath.

Ventilator settings in adaptive pressure control

Ventilator settings in APC are:

  • Tidal volume
  • Time spent in inspiration (inspiratory time)
  • Frequency
  • Fraction of inspired oxygen (Fio2)
  • Positive end-expiratory pressure (PEEP).

Some ventilators also require setting the speed to reach the peak pressure (also known as slope percent or inspiratory rise time).

Clinical applications of adaptive pressure control

This mode is designed to maintain a consistent tidal volume during pressure-control ventilation and to promote inspiratory flow synchrony. It is a means of automatically reducing ventilatory support (ie, weaning) as the patient’s inspiratory effort becomes stronger, as in awakening from anesthesia.

APC may not be ideal for patients who have an inappropriately increased respiratory drive (eg, in severe metabolic acidosis), since the inspiratory pressure will decrease to maintain the targeted average tidal volume, inappropriately shifting the work of breathing onto the patient.

Theoretical benefits of adaptive pressure control

APC guarantees a minimum average tidal volume (unless the pressure alarm threshold is set too low, so that the target tidal volume is not delivered). Other theoretical benefits are flow synchrony, less ventilator manipulation by the operator, and automatic weaning of ventilator support.

Evidence of benefit of adaptive pressure control

Physiologic benefits. This mode has lower peak inspiratory pressures than does volume-control ventilation,3,4 which is often reported as a positive finding. However, in volume-control mode (the usual comparator), the peak inspiratory pressure is a manifestation of both resistance and compliance. Hence, peak inspiratory pressure is expected to be higher but does not reflect actual lung-distending pressures. It is the plateau pressure, a manifestation of lung compliance, that is related to lung injury.

Patient comfort. APC may increase the work of breathing when using low tidal volume ventilation and when there is increased respiratory effort (drive).5 Interestingly, APC was less comfortable than pressure support ventilation in a small trial.6

Outcomes have not been studied.7

Adaptive pressure control: Bottom line

APC is widely available and widely used, sometimes unknowingly (eg, if the operator thinks it is volume control). It is relatively easy to use and to set; however, evidence of its benefit is scant.

 

 

ADAPTIVE SUPPORT VENTILATION

Adaptive support ventilation (ASV) evolved as a form of mandatory minute ventilation implemented with adaptive pressure control. Mandatory minute ventilation is a mode that allows the operator to preset a target minute ventilation, and the ventilator then supplies mandatory breaths, either volume- or pressure-controlled, if the patient’s spontaneous breaths generate a lower minute ventilation.

ASV automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and target minute alveolar ventilation.

Described in 1994 by Laubscher et al,8,9 ASV became commercially available in 1998 in Europe and in 2007 in the United States (Hamilton Galileo ventilator, Hamilton Medical AG). This is the first commercially available ventilator that uses an “optimal” targeting scheme (see below).

What does adaptive support ventilation do?

ASV delivers pressure-controlled breaths using an adaptive (optimal) scheme (Table 2). “Optimal,” in this context, means minimizing the mechanical work of breathing: the machine selects a tidal volume and frequency that the patient’s brain would presumably select if the patient were not connected to a ventilator. This pattern is assumed to encourage the patient to generate spontaneous breaths.

The ventilator calculates the normal required minute ventilation based on the patient’s ideal weight and estimated dead space volume (ie, 2.2 mL/kg). This calculation represents 100% of minute ventilation. The clinician at the bedside sets a target percent of minute ventilation that the ventilator will support—higher than 100% if the patient has increased requirements due, eg, to sepsis or increased dead space, or less than 100% during weaning.

The ventilator initially delivers test breaths, in which it measures the expiratory time constant for the respiratory system and then uses this along with the estimated dead space and normal minute ventilation to calculate an optimal breathing frequency in terms of mechanical work.

The optimal or target tidal volume is calculated as the normal minute ventilation divided by the optimal frequency. The target tidal volume is achieved by the use of APC (see above) (Figure 2). This means that the pressure limit is automatically adjusted to achieve an average delivered tidal volume equal to the target. The ventilator continuously monitors the respiratory system mechanics and adjusts its settings accordingly.

The ventilator adjusts its breaths to avoid air trapping by allowing enough time to exhale, to avoid hypoventilation by delivering tidal volume greater than the dead space, and to avoid volutrauma by avoiding large tidal volumes.

Ventilator settings in adaptive support ventilation

Ventilator settings in ASV are:

  • Patient height (to calculate the ideal body weight)
  • Sex
  • Percent of normal predicted minute ventilation goal
  • Fio2
  • PEEP.

Clinical applications of adaptive support ventilation

ASV is intended as a sole mode of ventilation, from initial support to weaning.

Theoretical benefits of adaptive support ventilation

In theory, ASV offers automatic selection of ventilator settings, automatic adaptation to changing patient lung mechanics, less need for human manipulation of the machine, improved synchrony, and automatic weaning.

Evidence of benefit of adaptive support ventilation

Physiologic benefits. Ventilator settings are adjusted automatically. ASV selects different tidal volume-respiratory rate combinations based on respiratory mechanics in passive and paralyzed patients.10–12 In actively breathing patients, there was no difference in the ventilator settings chosen by ASV for different clinical scenarios (and lung physiology).10 Compared with pressure-controlled intermittent mandatory ventilation, with ASV, the inspiratory load is less and patient-ventilator interaction is better.13

Patient-ventilator synchrony and comfort have not been studied.

Outcomes. Two trials suggest that ASV may decrease time on mechanical ventilation.14,15 However, in another trial,16 compared with a standard protocol, ASV led to fewer ventilator adjustments but achieved similar postsurgical weaning outcomes. The effect of this mode on the death rate has not been examined.17,18

Adaptive support ventilation: Bottom line

ASV is the first commercially available mode that automatically selects all the ventilator settings except PEEP and Fio2. These seem appropriate for different clinical scenarios in patients with poor respiratory effort or in paralyzed patients. Evidence of the effect in actively breathing patients and on outcomes such as length of stay or death is still lacking.

PROPORTIONAL ASSIST VENTILATION

Patients who have normal respiratory drive but who have difficulty sustaining adequate spontaneous ventilation are often subjected to pressure support ventilation (PSV), in which the ventilator generates a constant pressure throughout inspiration regardless of the intensity of the patient’s effort.

In 1992, Younes and colleagues19,20 developed proportional assist ventilation (PAV) as an alternative in which the ventilator generates pressure in proportion to the patient’s effort. PAV became commercially available in Europe in 1999 and was approved in the United States in 2006, available on the Puritan Bennett 840 ventilator (Puritan Bennett Co, Boulder, CO). PAV has also been used for noninvasive ventilation, but this is not available in the United States.

Other names for proportional assist ventilation

Proportional Pressure Support (Dräger Medical; not yet available in the United States).

 

 

What does proportional assist ventilation do?

This mode delivers pressure-controlled breaths with a servo control scheme (Table 2).

To better understand PAV, we can compare it with PSV. With PSV, the pressure applied by the ventilator rises to a preset level that is held constant (a set-point scheme) until a cycling criterion (a percent of the maximum inspiratory flow value) is reached. The inspiratory flow and tidal volume are the result of the patient’s inspiratory effort, the level of pressure applied, and the respiratory system mechanics.

Figure 3. In proportional assist ventilation, the flow, pressure, and volume delivered are adjusted proportionally to the patient’s effort.
In contrast, during PAV, the pressure applied is a function of patient effort: the greater the inspiratory effort, the greater the increase in applied pressure (servo targeting scheme) (Figure 3). The operator sets the percentage of support to be delivered by the ventilator. The ventilator intermittently measures the compliance and resistance of the patient’s respiratory system and the instantaneous patient-generated flow and volume, and on the basis of these it delivers a proportional amount of inspiratory pressure.

In PAV, as in PSV, all breaths are spontaneous (Table 1). The patient controls the timing and size of the breath. There are no preset pressure, flow, or volume goals, but safety limits on the volume and pressure delivered can be set.

Ventilator settings in proportional assist ventilation

Ventilator settings in PAV are:

  • Airway type (endotracheal tube, tracheostomy)
  • Airway size (inner diameter)
  • Percentage of work supported (assist range 5%–95%)
  • Tidal volume limit
  • Pressure limit
  • Expiratory sensitivity (normally, as inspiration ends, flow should stop; this parameter tells the ventilator at what flow to end inspiration).

Caution when assessing the literature. Earlier ventilator versions, ie, Dräger and Manitoba (University of Manitoba, Winnipeg, MB, Canada), which are not available in the United States, required the repeated calculation of the respiratory system mechanics and the manual setting of flow and volume assists (amplification factors) independently. To overcome this limitation, new software automatically adjusts the flow and volume amplification to support the loads imposed by the automatically measured values of resistance and elastance (inverse of compliance) of the respiratory system.21 This software is included in the model (Puritan Bennett) available in the United States.

Clinical applications of proportional assist ventilation

The PAV mode is indicated for maximizing ventilator patient synchrony for assisted spontaneous ventilation.

PAV is contraindicated in patients with respiratory depression (bradypnea) or large air leaks (eg, bronchopleural fistulas). It should be used with caution in patients with severe hyperinflation, in which the patient may still be exhaling but the ventilator doesn’t recognize it. Another group in which PAV should be used with caution is those with high ventilatory drives, in which the ventilator overestimates respiratory system mechanics. This situation can lead to overassistance due to the “runaway phenomenon,” in which the ventilator continues to provide support even if the patient has stopped inspiration.22

Theoretical benefits of proportional assist ventilation

In theory, PAV should reduce the work of breathing, improve synchrony, automatically adapt to changing patient lung mechanics and effort, decrease the need for ventilator intervention and manipulation, decrease the need for sedation, and improve sleep.

Evidence of benefit of proportional assist ventilation

Physiologic benefits. PAV reduces the work of breathing better than PSV,21 even in the face of changing respiratory mechanics or increased respiratory demand (hypercapnia).23–25 The hemodynamic profile is similar to that in PSV. Tidal volumes are variable; however, in recent reports the tidal volumes were within the lung-protective range (6–8 mL/kg, plateau pressure < 30 cm H20).26,27

Comfort. PAV entails less patient effort and discomfort that PSV does.23,25 PAV significantly reduces asynchrony,27 which in turn may favorably affect sleep in critically ill patients. 28

Outcomes. The probability of spontaneous breathing without assistance was significantly better in critically ill patients ventilated with PAV than with PSV. No trial has reported the effect of PAV on deaths.27,29

Proportional assist ventilation: Bottom line

Extensive basic research has been done with PAV in different forms of respiratory failure, such as obstructive lung disease, acute respiratory distress syndrome (ARDS), and chronic respiratory failure. It fulfills its main goal, which is to improve patient-ventilator synchrony. Clinical experience with PAV in the United States is limited, as it was only recently approved.

 

 

AIRWAY PRESSURE-RELEASE VENTILATION AND BIPHASIC POSITIVE AIRWAY PRESSURE

Airway pressure-release ventilation (APRV) was described in 1987 by Stock et al30 as a mode for delivering ventilation in acute lung injury while avoiding high airway pressures. APRV combines high constant positive airway pressure (improving oxygenation and promoting alveolar recruitment) with intermittent releases (causing exhalation).

Figure 4. Airway pressure-release ventilation (top) and biphasic positive airway pressure (bottom) are forms of pressure-controlled intermittent mandatory ventilation in which spontaneous breaths can occur at any point without altering the ventilator-delivered breaths. The difference is that the time spent in high pressure is greater in airway pressure-release ventilation.
In 1989, Baum et al31 described biphasic positive airway pressure ventilation as a mode in which spontaneous ventilation could be achieved at any point in the mechanical ventilation cycle—inspiration or exhalation (Figure 4). The goal was to allow unrestricted spontaneous breathing to reduce sedation and promote weaning. These modes are conceptually the same, the main difference being that the time spent in low pressure (Tlow; see below) is less than 1.5 seconds for APRV. Otherwise, they have identical characteristics, thus allowing any ventilator with the capability of delivering APRV to deliver biphasic positive airway pressure, and vice versa. Machines with these modes became commercially available in the mid 1990s.

Other names for biphasic positive airway pressure

Other names for biphasic positive airway pressure are:

  • BiLevel (Puritan Bennett)
  • BIPAP (Dräger Europe)
  • Bi Vent (Siemens)
  • BiPhasic (Avea, Cardinal Health, Inc, Dublin, OH)
  • PCV+ (Dräger Medical)
  • DuoPAP (Hamilton).

Caution—name confusion. In North America, BiPAP (Respironics, Murrysville, PA) and BiLevel are used to refer to noninvasive modes of ventilation.

APRV has no other name.

What do these modes do?

These modes deliver pressure-controlled, time-triggered, and time-cycled breaths using a set-point targeting scheme (Table 2). This means that the ventilator maintains a constant pressure (set point) even in the face of spontaneous breaths.

Caution—source of confusion. The term continuous positive airway pressure (CPAP) is often used to describe this mode. However, CPAP is pressure that is applied continuously at the same level; the patient generates all the work to maintain ventilation (“pressure-controlled continuous spontaneous ventilation” in the current nomenclature). In APRV, the airway pressure is intermittently released and reapplied, generating a tidal volume that supports ventilation. In other words, this is a pressure-controlled breath with a very prolonged inspiratory time and a short expiratory time in which spontaneous ventilation is possible at any point (“pressure-controlled intermittent mandatory ventilation” in the current nomenclature).

How these modes are set in the ventilator may also be a source of confusion. To describe the time spent in high and low airway pressures, we use the terms Thigh and Tlow, respectively. By convention, the difference between APRV and biphasic mode is the duration of Tlow (< 1.5 sec for APRV).

Similarly, Phigh and Plow are used to describe the high and low airway pressure. To better understand this concept, you can create the same mode in conventional pressure-control ventilation by thinking of the Thigh as the inspiratory time, the Tlow as the expiratory time, the Phigh as inspiratory pressure, and the Plow as PEEP.

Hence, APRV is an extreme form of inverse ratio ventilation, with an inspiration-to-expiration ratio of 4:1. This means a patient spends most of the time in Phigh and Thigh, and exhalations are short (Tlow and Plow). In contrast, the biphasic mode uses conventional inspiration-expiration ratios (Figure 4).

As with any form of pressure control, the tidal volume is generated by airway pressure rising above baseline (ie, the end-expiratory value). Hence, to ensure an increase in minute ventilation, the mandatory breath rate must be increased (ie, decreasing Thigh, Tlow, or both) or the tidal volume must be increased (ie, increasing the difference between Phigh and Plow). This means that in APRV the Tlow has to happen more often (by increasing the number of breaths) or be more prolonged (allowing more air to exhale). Because unrestricted spontaneous breaths are permitted at any point of the cycle, the patient contributes to the total minute ventilation (usually 10%–40%).

In APRV and biphasic mode, the operator’s set time and pressure in inspiration and expiration will be delivered regardless of the patient’s breathing efforts—the patient’s spontaneous breath does not trigger a mechanical breath. Some ventilators have automatic adjustments to improve the trigger synchrony.

Ventilator settings in APRV and biphasic mode

These modes require the setting of two pressure levels (Phigh and Plow) and two time durations (Thigh and Tlow). One can add pressure support or automatic tube compensation to assist spontaneous breaths. The difference in Tlow generates differences in the Thigh:Tlow ratio: APRV has a short Tlow (an inspiration-expiration ratio of 4:1). Biphasic mode has a conventional inspiration-expiration ratio of 1:1 to 1:4.

Clinical applications

APRV is used in acute lung injury and ARDS. This mode should be used with caution or not at all in patients with obstructive lung disease or inappropriately increased respiratory drive.32–35

Biphasic mode is intended for both ventilation and weaning. In a patient who has poor respiratory effort or who is paralyzed, biphasic is identical to pressure-control/continuous mandatory ventilation.

Theoretical benefits of APRV and biphasic mode

Multiple benefits have been ascribed to these modes. In theory, APRV will maximize and maintain alveolar recruitment, improve oxygenation, lower inflation pressures, and decrease overinflation. Both APRV and biphasic, by preserving spontaneous breathing, will improve ventilation-perfusion matching and gas diffusion, improve the hemodynamic profile (less need for vasopressors, higher cardiac output, reduced ventricular workload, improved organ perfusion), and improve synchrony (decrease the work of breathing and the need for sedation).

Evidence of benefit of APRV and biphasic mode

APRV and biphasic are different modes. However studies evaluating their effects are combined. This is in part the result of the nomenclature confusion and different practice in different countries.36

Physiologic benefits. In studies, spontaneous breaths contributed to 10% to 40% of minute ventilation,37,38 improved ventilation of dependent areas of the lung, improved ventilation-perfusion match and recruitment,39 and improved hemodynamic profile.40

Patient comfort. These modes are thought to decrease the need for analgesia and sedation,38 but a recent trial showed no difference with pressure-controlled intermittent mandatory ventilation.41 Patient ventilator synchrony and comfort have not been studied.32,42

Outcomes. In small trials, these modes made no difference in terms of deaths, but they may decrease the length of mechanical ventilation.38,41,43,44

APRV and biphasic mode: Bottom line

Maintaining spontaneous breathing while on mechanical ventilation has hemodynamic and ventilatory benefits.

APRV and biphasic mode are not the same thing. APRV’s main goal is to maximize mean airway pressure and, hence, lung recruitment, whereas the main goal of the biphasic mode is synchrony.

There is a plethora of ventilator settings and questions related to physiologic effects.33,34,36

Although these modes are widely used in some centers, there is no evidence yet that they are superior to conventional volume- or pressure-control ventilation with low tidal volume for ARDS and acute lung injury. There is no conclusive evidence that these modes improve synchrony, time to weaning, or patient comfort.

 

 

HIGH-FREQUENCY OSCILLATORY VENTILATION

High-frequency oscillatory ventilation (HFOV) was first described and patented in 1952 by Emerson and was clinically developed in the early 1970s by Lunkenheimer.45

The goal of HFOV is to minimize lung injury; its characteristics (discussed below) make it useful in patients with severe ARDS. The US Food and Drug Administration approved it for infants in 1991 and for children in 1995. The adult model has been available since 1993, but it was not approved until 2001 (SensorMedics 3100B, Cardinal Health, Inc).

Other names for high-frequency oscillatory ventilation

While HFOV has no alternative names, the following acronyms describe similar modes:

  • HFPPV (high-frequency positive pressure ventilation)
  • HFJV (high-frequency jet ventilation)
  • HFFI (high-frequency flow interruption)
  • HFPV (high-frequency percussive ventilation)
  • HFCWO (high-frequency chest wall oscillation).

All of these modes require different specialized ventilators.

What does high-frequency oscillatory ventilation do?

Conceptually, HFOV is a form of pressure-controlled intermittent mandatory ventilation with a set-point control scheme. In contrast to conventional pressure-controlled intermittent mandatory ventilation, in which relatively small spontaneous breaths may be superimposed on relatively large mandatory breaths, HFOV superimposes very small mandatory breaths (oscillations) on top of spontaneous breaths.

Figure 5. High-frequency oscillatory ventilation delivers very small mandatory breaths (oscillations) at frequencies of up to 900 breaths per minute.
HFOV can be delivered only with a special ventilator. The ventilator delivers a constant flow (bias flow), while a valve creates resistance to maintain airway pressure, on top of which a piston pump oscillates at frequencies of 3 to 15 Hz (160–900 breaths/minute). This creates a constant airway pressure with small oscillations (Figure 5); often, clinicians at the bedside look for the “chest wiggle” to assess the appropriate amplitude settings, although this has not been systematically studied.

Adult patients are usually paralyzed or deeply sedated, since deep spontaneous breathing will trigger alarms and affect ventilator performance.

To manage ventilation (CO2 clearance), one or several of the following maneuvers can be done: decrease the oscillation frequency, increase the amplitude of the oscillations, increase the inspiratory time, or increase bias flow (while allowing an endotracheal tube cuff leak). Oxygenation adjustments are controlled by manipulating the mean airway pressure and the Fio2.

Ventilator settings in high-frequency oscillatory ventilation

Ventilator settings in HFOV are46:

  • Airway pressure amplitude (delta P or power)
  • Mean airway pressure
  • Percent inspiration
  • Inspiratory bias flow
  • Fio2.

Clinical applications of high-frequency oscillatory ventilation

This mode is usually reserved for ARDS patients for whom conventional ventilation is failing. A recently published protocol46 suggests considering HFOV when there is oxygenation failure (Fio2 ≥ 0.7 and PEEP ≥ 14 cm H2O) or ventilation failure (pH < 7.25 with tidal volume ≥ 6 mL/kg predicted body weight and plateau airway pressure ≥ 30 cm H2O).

This mode is contraindicated when there is known severe airflow obstruction or intracranial hypertension.

Theoretical benefits of high-frequency oscillatory ventilation

Conceptually, HFOV can provide the highest mean airway pressure paired with the lowest tidal volume of any mode. These benefits might make HFOV the ideal lung-protective ventilation strategy.

Evidence of benefit of high-frequency oscillatory ventilation

Physiologic benefits. Animal models have shown less histologic damage and lung inflammation with HFOV than with high-tidal-volume conventional ventilation47,48 and low-tidal-volume conventional ventilation.49

Patient comfort has not been studied. However, current technology does impose undue work of breathing in spontaneously breathing patients.50

Outcomes. Several retrospective case series have described better oxygenation with HFOV as rescue therapy for severe ARDS than with conventional mechanical ventilation. Two randomized controlled trials have studied HFOV vs high-tidal-volume conventional mechanical ventilation for early severe ARDS; HFOV was safe but made no difference in terms of deaths.42,51–54

High-frequency oscillatory ventilation: Bottom line

In theory, HFOV provides all the benefits of an ideal lung-protective strategy, at least for paralyzed or deeply sedated patients. Animal studies support these concepts. In human adults, HFOV has been shown to be safe and to provide better oxygenation but no improvement in death rates compared with conventional mechanical ventilation. Currently, HFOV is better reserved for patients with severe ARDS for whom conventional mechanical ventilation is failing.

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  37. Sydow M, Burchardi H, Ephraim E, Zielmann S, Crozier TA. Longterm effects of two different ventilatory modes on oxygenation in acute lung injury. Comparison of airway pressure release ventilation and volume-controlled inverse ratio ventilation. Am J Respir Crit Care Med 1994; 149:1550–1556.
  38. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med 2001; 164:43–49.
  39. Davis K, Johnson DJ, Branson RD, Campbell RS, Johannigman JA, Porembka D. Airway pressure release ventilation. Arch Surg 1993; 128:1348–1352.
  40. Kaplan LJ, Bailey H, Formosa V. Airway pressure release ventilation increases cardiac performance in patients with acute lung injury/adult respiratory distress syndrome. Crit Care 2001; 5:221–226.
  41. Varpula T, Valta P, Niemi R, Takkunen O, Hynynen M, Pettilä VV. Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol Scand 2004; 48:722–731.
  42. Siau C, Stewart TE. Current role of high frequency oscillatory ventilation and airway pressure release ventilation in acute lung injury and acute respiratory distress syndrome. Clin Chest Med 2008; 29:265–275.
  43. Rathgeber J, Schorn B, Falk V, Kazmaier S, Spiegel T, Burchardi H. The influence of controlled mandatory ventilation (CMV), intermittent mandatory ventilation (IMV) and biphasic intermittent positive airway pressure (BIPAP) on duration of intubation and consumption of analgesics and sedatives. A prospective analysis in 596 patients following adult cardiac surgery. Eur J Anaesthesiol 1997; 14:576–582.
  44. Habashi NM. Other approaches to open lung ventilation: airway pressure release ventilation. Crit Care Med 2005; 33 suppl 3:S228–S240.
  45. Hess D, Mason S, Branson R. High-frequency ventilation design and equipment issues. Respir Care Clin North Am 2001; 7:577–598.
  46. Fessler HE, Derdak S, Ferguson ND, et al. A protocol for high frequency oscillatory ventilation in adults: results from a roundtable discussion. Crit Care Med 2007; 35:1649–1654.
  47. Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of conventional and high-frequency ventilation: oxygenation and lung pathology. J Appl Physiol 1983; 55:131–138.
  48. Sedeek KA, Takeuchi M, Suchodolski K, et al. Open-lung protective ventilation with pressure control ventilation, high-frequency oscillation, and intratracheal pulmonary ventilation results in similar gas exchange, hemodynamics, and lung mechanics. Anesthesiology 2003; 99:1102–1111.
  49. Imai Y, Nakagawa S, Ito Y, Kawano T, Slutsky AS, Miyasaka K. Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation. J Appl Physiol 2001; 91:1836–1844.
  50. van Heerde M, Roubik K, Kopelent V, Plötz FB, Markhorst DG. Unloading work of breathing during high-frequency oscillatory ventilation: a bench study. Crit Care 2006; 10:R103.
  51. Derdak S, Mehta S, Stewart TE, et al., Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial (MOAT) Study Investigators. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:801–808.
  52. Bollen CW, van Well GT, Sherry T, et al. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669]. Crit Care 2005; 9:R430–R439.
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Eduardo Mireles-Cabodevila, MD
Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, Little Rock, AR

Enrique Diaz-Guzman, MD
Respiratory Institute, Cleveland Clinic

Gustavo A. Heresi, MD
Respiratory Institute, Cleveland Clinic

Robert L. Chatburn, BS, RRT-NPS
Respiratory Institute, Respiratory Therapy Section, Cleveland Clinic

Address: Eduardo Mireles-Cabodevila, MD, Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 555, Little Rock, AR 77205; e mail [email protected]

Mr. Chatburn has disclosed that he has received fees from Cardinal Health for serving on advisory committees or review panels and from Strategic Dynamics Inc for consulting.

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Robert L. Chatburn, BS, RRT-NPS
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Eduardo Mireles-Cabodevila, MD
Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, Little Rock, AR

Enrique Diaz-Guzman, MD
Respiratory Institute, Cleveland Clinic

Gustavo A. Heresi, MD
Respiratory Institute, Cleveland Clinic

Robert L. Chatburn, BS, RRT-NPS
Respiratory Institute, Respiratory Therapy Section, Cleveland Clinic

Address: Eduardo Mireles-Cabodevila, MD, Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 555, Little Rock, AR 77205; e mail [email protected]

Mr. Chatburn has disclosed that he has received fees from Cardinal Health for serving on advisory committees or review panels and from Strategic Dynamics Inc for consulting.

Author and Disclosure Information

Eduardo Mireles-Cabodevila, MD
Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, Little Rock, AR

Enrique Diaz-Guzman, MD
Respiratory Institute, Cleveland Clinic

Gustavo A. Heresi, MD
Respiratory Institute, Cleveland Clinic

Robert L. Chatburn, BS, RRT-NPS
Respiratory Institute, Respiratory Therapy Section, Cleveland Clinic

Address: Eduardo Mireles-Cabodevila, MD, Department of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 555, Little Rock, AR 77205; e mail [email protected]

Mr. Chatburn has disclosed that he has received fees from Cardinal Health for serving on advisory committees or review panels and from Strategic Dynamics Inc for consulting.

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Related Articles
Correction: Newer modes of mechanical ventilation

Technologic advances and computerized control of mechanical ventilators have made it possible to deliver ventilatory assistance in new modes. Driving these innovations is the desire to prevent ventilator-induced lung injury, improve patient comfort, and liberate the patient from mechanical ventilation as soon as possible.

We call these innovations “alternative” modes to differentiate them from the plain volume-control and pressure-control modes. Some clinicians rarely use these new modes, but in some medical centers they have become the most common ones used, or are being used unknowingly (the operator misunderstands the mode name). The information we provide on these modes of ventilation is by no means an endorsement of their use, but rather a tool to help the clinician understand their physiologic, theoretical, and clinical effects.

We focused on two goals:

  • Explain what the mode does
  • Briefly review the theoretical benefits and the actual evidence supporting these alternative modes of ventilation.

STANDARD NOMENCLATURE NEEDED

Since its invention, mechanical ventilation has been plagued by multiple names being used to describe the same things. For example, volume-control ventilation is also called volume-cycled ventilation, assist-control ventilation, volume-limited ventilation, and controlled mechanical ventilation. Similarly, multiple abbreviations are used, each depending on the brand of ventilator, and new acronyms have been added in recent years as new modes have been developed. The vast number of names and modes can confuse even the most seasoned critical care physician.

Efforts to establish a common nomenclature are under way.1

WHAT IS A MODE?

A mode of mechanical ventilation has three essential components:

  • The control variable
  • The breath sequence
  • The targeting scheme.

Similar modes may require more detailed descriptions to distinguish them, but the basic function can be explained by these three components.

The control variable

In general, inspiration is an active process, driven by the patient’s effort, the ventilator, or both, while expiration is passive. For simplicity, in this article a mechanical breath means the inspiratory phase of the breath.

The machine can only control the volume (and flow) or the pressure given. The breaths can be further described on the basis of what triggers the breath, what limits it (the maximum value of a control variable), and what ends (cycles) it.

Figure 1. Volume control (top) and pressure control (bottom) are modes of continuous mandatory ventilation. Each mode is depicted as patient effort increases. Notice that the mode’s control variable (volume or pressure) remains constant as patient effort increases. Contrast these findings with those in Figure 2.
Therefore, a volume-controlled breath is triggered by the patient or by the machine, limited by flow, and cycled by volume (Figure 1). A pressure-controlled breath is triggered by the patient or the machine, limited by pressure, and cycled by time or flow (Figure 1).

The breath sequence

There are three possible breath sequences:

  • Continuous mandatory ventilation, in which all breaths are controlled by the machine (but can be triggered by the patient)
  • Intermittent mandatory ventilation, in which the patient can take spontaneous breaths between mandatory breaths
  • Continuous spontaneous ventilation, in which all breaths are spontaneous (Table 1).

The targeting scheme

The targeting or feedback scheme refers to the ventilator settings and programming that dictate its response to the patient’s lung compliance, lung resistance, and respiratory effort. The regulation can be as simple as controlling the pressure in pressure-control mode, or it can be based on a complicated algorithm.

In the sections that follow, we describe some of the available alternative modes of mechanical ventilation. We will explain only the targeting schemes in the modes reviewed (Table 1, Table 2), but more information on other targeting schemes can be found elsewhere.1,2 We will focus on evidence generated in adult patients receiving invasive mechanical ventilation.

 

 

ADAPTIVE PRESSURE CONTROL

Figure 2. A machine in adaptive pressure control mode (top) adjusts the inspiratory pressure to maintain a set tidal volume. Adaptive support ventilation (bottom) automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and the target minute ventilation.
One of the concerns with pressure-control ventilation is that it cannot guarantee a minimum minute ventilation (the volume of air that goes in and out in 1 minute; the tidal volume × breaths per minute) in the face of changing lung mechanics or patient effort, or both. To solve this problem, in 1991 the Siemens Servo 300 ventilator (Siemens, Maquet Critical Care AB, Solna, Sweden) introduced Pressure Regulated Volume Control, a mode that delivers pressure-controlled breaths with a target tidal volume and that is otherwise known as adaptive pressure control (APC) (Figure 2).

Other names for adaptive pressure control

  • Pressure Regulated Volume Control (Maquet Servo-i, Rastatt, Germany)
  • AutoFlow (Dräger Medical AG, Lübeck, Germany)
  • Adaptive Pressure Ventilation (Hamilton Galileo, Hamilton Medical AG, Bonaduz, Switzerland)
  • Volume Control+ (Puritan Bennett, Tyco Healthcare; Mansfield, MA)
  • Volume Targeted Pressure Control, Pressure Controlled Volume Guaranteed (Engström, General Electric, Madison, WI).

What does adaptive pressure control do?

The APC mode delivers pressure-controlled breaths with an adaptive targeting scheme (Table 2).

In pressure-control ventilation, tidal volumes depend on the lung’s physiologic mechanics (compliance and resistance) and patient effort (Figure 1). Therefore, the tidal volume varies with changes in lung physiology (ie, larger or smaller tidal volumes than targeted).

To overcome this effect, a machine in APC mode adjusts the inspiratory pressure to deliver the set minimal target tidal volume. If tidal volume increases, the machine decreases the inspiratory pressure, and if tidal volume decreases, the machine increases the inspiratory pressure. However, if the patient effort is large enough, the tidal volume will increase in spite of decreasing the inspiratory pressure (Figure 2). The adjustments to the inspiratory pressure occur after the tidal volume is off-target in a number of breaths.

Common sources of confusion with adaptive pressure control

First, APC is not a volume-control mode. In volume control, the tidal volume does not change; in APC the tidal volume can increase or decrease, and the ventilator will adjust the inflation pressure to achieve the target volume. Thus, APC guarantees an average minimum tidal volume but not a maximum tidal volume.

Second, a characteristic of pressure control (and hence, APC) is that the flow of gas varies to maintain constant airway pressure (ie, maintain the set inspiratory pressure). This characteristic allows a patient who generates an inspiratory effort to receive flow as demanded, which is likely more comfortable. This is essentially different from volume control, in which flow is set by the operator and hence is fixed. Thus, if the patient effort is strong enough (Figure 1), this leads to what is called flow asynchrony, in which the patient does not get the flow asked for in a breath.

Ventilator settings in adaptive pressure control

Ventilator settings in APC are:

  • Tidal volume
  • Time spent in inspiration (inspiratory time)
  • Frequency
  • Fraction of inspired oxygen (Fio2)
  • Positive end-expiratory pressure (PEEP).

Some ventilators also require setting the speed to reach the peak pressure (also known as slope percent or inspiratory rise time).

Clinical applications of adaptive pressure control

This mode is designed to maintain a consistent tidal volume during pressure-control ventilation and to promote inspiratory flow synchrony. It is a means of automatically reducing ventilatory support (ie, weaning) as the patient’s inspiratory effort becomes stronger, as in awakening from anesthesia.

APC may not be ideal for patients who have an inappropriately increased respiratory drive (eg, in severe metabolic acidosis), since the inspiratory pressure will decrease to maintain the targeted average tidal volume, inappropriately shifting the work of breathing onto the patient.

Theoretical benefits of adaptive pressure control

APC guarantees a minimum average tidal volume (unless the pressure alarm threshold is set too low, so that the target tidal volume is not delivered). Other theoretical benefits are flow synchrony, less ventilator manipulation by the operator, and automatic weaning of ventilator support.

Evidence of benefit of adaptive pressure control

Physiologic benefits. This mode has lower peak inspiratory pressures than does volume-control ventilation,3,4 which is often reported as a positive finding. However, in volume-control mode (the usual comparator), the peak inspiratory pressure is a manifestation of both resistance and compliance. Hence, peak inspiratory pressure is expected to be higher but does not reflect actual lung-distending pressures. It is the plateau pressure, a manifestation of lung compliance, that is related to lung injury.

Patient comfort. APC may increase the work of breathing when using low tidal volume ventilation and when there is increased respiratory effort (drive).5 Interestingly, APC was less comfortable than pressure support ventilation in a small trial.6

Outcomes have not been studied.7

Adaptive pressure control: Bottom line

APC is widely available and widely used, sometimes unknowingly (eg, if the operator thinks it is volume control). It is relatively easy to use and to set; however, evidence of its benefit is scant.

 

 

ADAPTIVE SUPPORT VENTILATION

Adaptive support ventilation (ASV) evolved as a form of mandatory minute ventilation implemented with adaptive pressure control. Mandatory minute ventilation is a mode that allows the operator to preset a target minute ventilation, and the ventilator then supplies mandatory breaths, either volume- or pressure-controlled, if the patient’s spontaneous breaths generate a lower minute ventilation.

ASV automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and target minute alveolar ventilation.

Described in 1994 by Laubscher et al,8,9 ASV became commercially available in 1998 in Europe and in 2007 in the United States (Hamilton Galileo ventilator, Hamilton Medical AG). This is the first commercially available ventilator that uses an “optimal” targeting scheme (see below).

What does adaptive support ventilation do?

ASV delivers pressure-controlled breaths using an adaptive (optimal) scheme (Table 2). “Optimal,” in this context, means minimizing the mechanical work of breathing: the machine selects a tidal volume and frequency that the patient’s brain would presumably select if the patient were not connected to a ventilator. This pattern is assumed to encourage the patient to generate spontaneous breaths.

The ventilator calculates the normal required minute ventilation based on the patient’s ideal weight and estimated dead space volume (ie, 2.2 mL/kg). This calculation represents 100% of minute ventilation. The clinician at the bedside sets a target percent of minute ventilation that the ventilator will support—higher than 100% if the patient has increased requirements due, eg, to sepsis or increased dead space, or less than 100% during weaning.

The ventilator initially delivers test breaths, in which it measures the expiratory time constant for the respiratory system and then uses this along with the estimated dead space and normal minute ventilation to calculate an optimal breathing frequency in terms of mechanical work.

The optimal or target tidal volume is calculated as the normal minute ventilation divided by the optimal frequency. The target tidal volume is achieved by the use of APC (see above) (Figure 2). This means that the pressure limit is automatically adjusted to achieve an average delivered tidal volume equal to the target. The ventilator continuously monitors the respiratory system mechanics and adjusts its settings accordingly.

The ventilator adjusts its breaths to avoid air trapping by allowing enough time to exhale, to avoid hypoventilation by delivering tidal volume greater than the dead space, and to avoid volutrauma by avoiding large tidal volumes.

Ventilator settings in adaptive support ventilation

Ventilator settings in ASV are:

  • Patient height (to calculate the ideal body weight)
  • Sex
  • Percent of normal predicted minute ventilation goal
  • Fio2
  • PEEP.

Clinical applications of adaptive support ventilation

ASV is intended as a sole mode of ventilation, from initial support to weaning.

Theoretical benefits of adaptive support ventilation

In theory, ASV offers automatic selection of ventilator settings, automatic adaptation to changing patient lung mechanics, less need for human manipulation of the machine, improved synchrony, and automatic weaning.

Evidence of benefit of adaptive support ventilation

Physiologic benefits. Ventilator settings are adjusted automatically. ASV selects different tidal volume-respiratory rate combinations based on respiratory mechanics in passive and paralyzed patients.10–12 In actively breathing patients, there was no difference in the ventilator settings chosen by ASV for different clinical scenarios (and lung physiology).10 Compared with pressure-controlled intermittent mandatory ventilation, with ASV, the inspiratory load is less and patient-ventilator interaction is better.13

Patient-ventilator synchrony and comfort have not been studied.

Outcomes. Two trials suggest that ASV may decrease time on mechanical ventilation.14,15 However, in another trial,16 compared with a standard protocol, ASV led to fewer ventilator adjustments but achieved similar postsurgical weaning outcomes. The effect of this mode on the death rate has not been examined.17,18

Adaptive support ventilation: Bottom line

ASV is the first commercially available mode that automatically selects all the ventilator settings except PEEP and Fio2. These seem appropriate for different clinical scenarios in patients with poor respiratory effort or in paralyzed patients. Evidence of the effect in actively breathing patients and on outcomes such as length of stay or death is still lacking.

PROPORTIONAL ASSIST VENTILATION

Patients who have normal respiratory drive but who have difficulty sustaining adequate spontaneous ventilation are often subjected to pressure support ventilation (PSV), in which the ventilator generates a constant pressure throughout inspiration regardless of the intensity of the patient’s effort.

In 1992, Younes and colleagues19,20 developed proportional assist ventilation (PAV) as an alternative in which the ventilator generates pressure in proportion to the patient’s effort. PAV became commercially available in Europe in 1999 and was approved in the United States in 2006, available on the Puritan Bennett 840 ventilator (Puritan Bennett Co, Boulder, CO). PAV has also been used for noninvasive ventilation, but this is not available in the United States.

Other names for proportional assist ventilation

Proportional Pressure Support (Dräger Medical; not yet available in the United States).

 

 

What does proportional assist ventilation do?

This mode delivers pressure-controlled breaths with a servo control scheme (Table 2).

To better understand PAV, we can compare it with PSV. With PSV, the pressure applied by the ventilator rises to a preset level that is held constant (a set-point scheme) until a cycling criterion (a percent of the maximum inspiratory flow value) is reached. The inspiratory flow and tidal volume are the result of the patient’s inspiratory effort, the level of pressure applied, and the respiratory system mechanics.

Figure 3. In proportional assist ventilation, the flow, pressure, and volume delivered are adjusted proportionally to the patient’s effort.
In contrast, during PAV, the pressure applied is a function of patient effort: the greater the inspiratory effort, the greater the increase in applied pressure (servo targeting scheme) (Figure 3). The operator sets the percentage of support to be delivered by the ventilator. The ventilator intermittently measures the compliance and resistance of the patient’s respiratory system and the instantaneous patient-generated flow and volume, and on the basis of these it delivers a proportional amount of inspiratory pressure.

In PAV, as in PSV, all breaths are spontaneous (Table 1). The patient controls the timing and size of the breath. There are no preset pressure, flow, or volume goals, but safety limits on the volume and pressure delivered can be set.

Ventilator settings in proportional assist ventilation

Ventilator settings in PAV are:

  • Airway type (endotracheal tube, tracheostomy)
  • Airway size (inner diameter)
  • Percentage of work supported (assist range 5%–95%)
  • Tidal volume limit
  • Pressure limit
  • Expiratory sensitivity (normally, as inspiration ends, flow should stop; this parameter tells the ventilator at what flow to end inspiration).

Caution when assessing the literature. Earlier ventilator versions, ie, Dräger and Manitoba (University of Manitoba, Winnipeg, MB, Canada), which are not available in the United States, required the repeated calculation of the respiratory system mechanics and the manual setting of flow and volume assists (amplification factors) independently. To overcome this limitation, new software automatically adjusts the flow and volume amplification to support the loads imposed by the automatically measured values of resistance and elastance (inverse of compliance) of the respiratory system.21 This software is included in the model (Puritan Bennett) available in the United States.

Clinical applications of proportional assist ventilation

The PAV mode is indicated for maximizing ventilator patient synchrony for assisted spontaneous ventilation.

PAV is contraindicated in patients with respiratory depression (bradypnea) or large air leaks (eg, bronchopleural fistulas). It should be used with caution in patients with severe hyperinflation, in which the patient may still be exhaling but the ventilator doesn’t recognize it. Another group in which PAV should be used with caution is those with high ventilatory drives, in which the ventilator overestimates respiratory system mechanics. This situation can lead to overassistance due to the “runaway phenomenon,” in which the ventilator continues to provide support even if the patient has stopped inspiration.22

Theoretical benefits of proportional assist ventilation

In theory, PAV should reduce the work of breathing, improve synchrony, automatically adapt to changing patient lung mechanics and effort, decrease the need for ventilator intervention and manipulation, decrease the need for sedation, and improve sleep.

Evidence of benefit of proportional assist ventilation

Physiologic benefits. PAV reduces the work of breathing better than PSV,21 even in the face of changing respiratory mechanics or increased respiratory demand (hypercapnia).23–25 The hemodynamic profile is similar to that in PSV. Tidal volumes are variable; however, in recent reports the tidal volumes were within the lung-protective range (6–8 mL/kg, plateau pressure < 30 cm H20).26,27

Comfort. PAV entails less patient effort and discomfort that PSV does.23,25 PAV significantly reduces asynchrony,27 which in turn may favorably affect sleep in critically ill patients. 28

Outcomes. The probability of spontaneous breathing without assistance was significantly better in critically ill patients ventilated with PAV than with PSV. No trial has reported the effect of PAV on deaths.27,29

Proportional assist ventilation: Bottom line

Extensive basic research has been done with PAV in different forms of respiratory failure, such as obstructive lung disease, acute respiratory distress syndrome (ARDS), and chronic respiratory failure. It fulfills its main goal, which is to improve patient-ventilator synchrony. Clinical experience with PAV in the United States is limited, as it was only recently approved.

 

 

AIRWAY PRESSURE-RELEASE VENTILATION AND BIPHASIC POSITIVE AIRWAY PRESSURE

Airway pressure-release ventilation (APRV) was described in 1987 by Stock et al30 as a mode for delivering ventilation in acute lung injury while avoiding high airway pressures. APRV combines high constant positive airway pressure (improving oxygenation and promoting alveolar recruitment) with intermittent releases (causing exhalation).

Figure 4. Airway pressure-release ventilation (top) and biphasic positive airway pressure (bottom) are forms of pressure-controlled intermittent mandatory ventilation in which spontaneous breaths can occur at any point without altering the ventilator-delivered breaths. The difference is that the time spent in high pressure is greater in airway pressure-release ventilation.
In 1989, Baum et al31 described biphasic positive airway pressure ventilation as a mode in which spontaneous ventilation could be achieved at any point in the mechanical ventilation cycle—inspiration or exhalation (Figure 4). The goal was to allow unrestricted spontaneous breathing to reduce sedation and promote weaning. These modes are conceptually the same, the main difference being that the time spent in low pressure (Tlow; see below) is less than 1.5 seconds for APRV. Otherwise, they have identical characteristics, thus allowing any ventilator with the capability of delivering APRV to deliver biphasic positive airway pressure, and vice versa. Machines with these modes became commercially available in the mid 1990s.

Other names for biphasic positive airway pressure

Other names for biphasic positive airway pressure are:

  • BiLevel (Puritan Bennett)
  • BIPAP (Dräger Europe)
  • Bi Vent (Siemens)
  • BiPhasic (Avea, Cardinal Health, Inc, Dublin, OH)
  • PCV+ (Dräger Medical)
  • DuoPAP (Hamilton).

Caution—name confusion. In North America, BiPAP (Respironics, Murrysville, PA) and BiLevel are used to refer to noninvasive modes of ventilation.

APRV has no other name.

What do these modes do?

These modes deliver pressure-controlled, time-triggered, and time-cycled breaths using a set-point targeting scheme (Table 2). This means that the ventilator maintains a constant pressure (set point) even in the face of spontaneous breaths.

Caution—source of confusion. The term continuous positive airway pressure (CPAP) is often used to describe this mode. However, CPAP is pressure that is applied continuously at the same level; the patient generates all the work to maintain ventilation (“pressure-controlled continuous spontaneous ventilation” in the current nomenclature). In APRV, the airway pressure is intermittently released and reapplied, generating a tidal volume that supports ventilation. In other words, this is a pressure-controlled breath with a very prolonged inspiratory time and a short expiratory time in which spontaneous ventilation is possible at any point (“pressure-controlled intermittent mandatory ventilation” in the current nomenclature).

How these modes are set in the ventilator may also be a source of confusion. To describe the time spent in high and low airway pressures, we use the terms Thigh and Tlow, respectively. By convention, the difference between APRV and biphasic mode is the duration of Tlow (< 1.5 sec for APRV).

Similarly, Phigh and Plow are used to describe the high and low airway pressure. To better understand this concept, you can create the same mode in conventional pressure-control ventilation by thinking of the Thigh as the inspiratory time, the Tlow as the expiratory time, the Phigh as inspiratory pressure, and the Plow as PEEP.

Hence, APRV is an extreme form of inverse ratio ventilation, with an inspiration-to-expiration ratio of 4:1. This means a patient spends most of the time in Phigh and Thigh, and exhalations are short (Tlow and Plow). In contrast, the biphasic mode uses conventional inspiration-expiration ratios (Figure 4).

As with any form of pressure control, the tidal volume is generated by airway pressure rising above baseline (ie, the end-expiratory value). Hence, to ensure an increase in minute ventilation, the mandatory breath rate must be increased (ie, decreasing Thigh, Tlow, or both) or the tidal volume must be increased (ie, increasing the difference between Phigh and Plow). This means that in APRV the Tlow has to happen more often (by increasing the number of breaths) or be more prolonged (allowing more air to exhale). Because unrestricted spontaneous breaths are permitted at any point of the cycle, the patient contributes to the total minute ventilation (usually 10%–40%).

In APRV and biphasic mode, the operator’s set time and pressure in inspiration and expiration will be delivered regardless of the patient’s breathing efforts—the patient’s spontaneous breath does not trigger a mechanical breath. Some ventilators have automatic adjustments to improve the trigger synchrony.

Ventilator settings in APRV and biphasic mode

These modes require the setting of two pressure levels (Phigh and Plow) and two time durations (Thigh and Tlow). One can add pressure support or automatic tube compensation to assist spontaneous breaths. The difference in Tlow generates differences in the Thigh:Tlow ratio: APRV has a short Tlow (an inspiration-expiration ratio of 4:1). Biphasic mode has a conventional inspiration-expiration ratio of 1:1 to 1:4.

Clinical applications

APRV is used in acute lung injury and ARDS. This mode should be used with caution or not at all in patients with obstructive lung disease or inappropriately increased respiratory drive.32–35

Biphasic mode is intended for both ventilation and weaning. In a patient who has poor respiratory effort or who is paralyzed, biphasic is identical to pressure-control/continuous mandatory ventilation.

Theoretical benefits of APRV and biphasic mode

Multiple benefits have been ascribed to these modes. In theory, APRV will maximize and maintain alveolar recruitment, improve oxygenation, lower inflation pressures, and decrease overinflation. Both APRV and biphasic, by preserving spontaneous breathing, will improve ventilation-perfusion matching and gas diffusion, improve the hemodynamic profile (less need for vasopressors, higher cardiac output, reduced ventricular workload, improved organ perfusion), and improve synchrony (decrease the work of breathing and the need for sedation).

Evidence of benefit of APRV and biphasic mode

APRV and biphasic are different modes. However studies evaluating their effects are combined. This is in part the result of the nomenclature confusion and different practice in different countries.36

Physiologic benefits. In studies, spontaneous breaths contributed to 10% to 40% of minute ventilation,37,38 improved ventilation of dependent areas of the lung, improved ventilation-perfusion match and recruitment,39 and improved hemodynamic profile.40

Patient comfort. These modes are thought to decrease the need for analgesia and sedation,38 but a recent trial showed no difference with pressure-controlled intermittent mandatory ventilation.41 Patient ventilator synchrony and comfort have not been studied.32,42

Outcomes. In small trials, these modes made no difference in terms of deaths, but they may decrease the length of mechanical ventilation.38,41,43,44

APRV and biphasic mode: Bottom line

Maintaining spontaneous breathing while on mechanical ventilation has hemodynamic and ventilatory benefits.

APRV and biphasic mode are not the same thing. APRV’s main goal is to maximize mean airway pressure and, hence, lung recruitment, whereas the main goal of the biphasic mode is synchrony.

There is a plethora of ventilator settings and questions related to physiologic effects.33,34,36

Although these modes are widely used in some centers, there is no evidence yet that they are superior to conventional volume- or pressure-control ventilation with low tidal volume for ARDS and acute lung injury. There is no conclusive evidence that these modes improve synchrony, time to weaning, or patient comfort.

 

 

HIGH-FREQUENCY OSCILLATORY VENTILATION

High-frequency oscillatory ventilation (HFOV) was first described and patented in 1952 by Emerson and was clinically developed in the early 1970s by Lunkenheimer.45

The goal of HFOV is to minimize lung injury; its characteristics (discussed below) make it useful in patients with severe ARDS. The US Food and Drug Administration approved it for infants in 1991 and for children in 1995. The adult model has been available since 1993, but it was not approved until 2001 (SensorMedics 3100B, Cardinal Health, Inc).

Other names for high-frequency oscillatory ventilation

While HFOV has no alternative names, the following acronyms describe similar modes:

  • HFPPV (high-frequency positive pressure ventilation)
  • HFJV (high-frequency jet ventilation)
  • HFFI (high-frequency flow interruption)
  • HFPV (high-frequency percussive ventilation)
  • HFCWO (high-frequency chest wall oscillation).

All of these modes require different specialized ventilators.

What does high-frequency oscillatory ventilation do?

Conceptually, HFOV is a form of pressure-controlled intermittent mandatory ventilation with a set-point control scheme. In contrast to conventional pressure-controlled intermittent mandatory ventilation, in which relatively small spontaneous breaths may be superimposed on relatively large mandatory breaths, HFOV superimposes very small mandatory breaths (oscillations) on top of spontaneous breaths.

Figure 5. High-frequency oscillatory ventilation delivers very small mandatory breaths (oscillations) at frequencies of up to 900 breaths per minute.
HFOV can be delivered only with a special ventilator. The ventilator delivers a constant flow (bias flow), while a valve creates resistance to maintain airway pressure, on top of which a piston pump oscillates at frequencies of 3 to 15 Hz (160–900 breaths/minute). This creates a constant airway pressure with small oscillations (Figure 5); often, clinicians at the bedside look for the “chest wiggle” to assess the appropriate amplitude settings, although this has not been systematically studied.

Adult patients are usually paralyzed or deeply sedated, since deep spontaneous breathing will trigger alarms and affect ventilator performance.

To manage ventilation (CO2 clearance), one or several of the following maneuvers can be done: decrease the oscillation frequency, increase the amplitude of the oscillations, increase the inspiratory time, or increase bias flow (while allowing an endotracheal tube cuff leak). Oxygenation adjustments are controlled by manipulating the mean airway pressure and the Fio2.

Ventilator settings in high-frequency oscillatory ventilation

Ventilator settings in HFOV are46:

  • Airway pressure amplitude (delta P or power)
  • Mean airway pressure
  • Percent inspiration
  • Inspiratory bias flow
  • Fio2.

Clinical applications of high-frequency oscillatory ventilation

This mode is usually reserved for ARDS patients for whom conventional ventilation is failing. A recently published protocol46 suggests considering HFOV when there is oxygenation failure (Fio2 ≥ 0.7 and PEEP ≥ 14 cm H2O) or ventilation failure (pH < 7.25 with tidal volume ≥ 6 mL/kg predicted body weight and plateau airway pressure ≥ 30 cm H2O).

This mode is contraindicated when there is known severe airflow obstruction or intracranial hypertension.

Theoretical benefits of high-frequency oscillatory ventilation

Conceptually, HFOV can provide the highest mean airway pressure paired with the lowest tidal volume of any mode. These benefits might make HFOV the ideal lung-protective ventilation strategy.

Evidence of benefit of high-frequency oscillatory ventilation

Physiologic benefits. Animal models have shown less histologic damage and lung inflammation with HFOV than with high-tidal-volume conventional ventilation47,48 and low-tidal-volume conventional ventilation.49

Patient comfort has not been studied. However, current technology does impose undue work of breathing in spontaneously breathing patients.50

Outcomes. Several retrospective case series have described better oxygenation with HFOV as rescue therapy for severe ARDS than with conventional mechanical ventilation. Two randomized controlled trials have studied HFOV vs high-tidal-volume conventional mechanical ventilation for early severe ARDS; HFOV was safe but made no difference in terms of deaths.42,51–54

High-frequency oscillatory ventilation: Bottom line

In theory, HFOV provides all the benefits of an ideal lung-protective strategy, at least for paralyzed or deeply sedated patients. Animal studies support these concepts. In human adults, HFOV has been shown to be safe and to provide better oxygenation but no improvement in death rates compared with conventional mechanical ventilation. Currently, HFOV is better reserved for patients with severe ARDS for whom conventional mechanical ventilation is failing.

Technologic advances and computerized control of mechanical ventilators have made it possible to deliver ventilatory assistance in new modes. Driving these innovations is the desire to prevent ventilator-induced lung injury, improve patient comfort, and liberate the patient from mechanical ventilation as soon as possible.

We call these innovations “alternative” modes to differentiate them from the plain volume-control and pressure-control modes. Some clinicians rarely use these new modes, but in some medical centers they have become the most common ones used, or are being used unknowingly (the operator misunderstands the mode name). The information we provide on these modes of ventilation is by no means an endorsement of their use, but rather a tool to help the clinician understand their physiologic, theoretical, and clinical effects.

We focused on two goals:

  • Explain what the mode does
  • Briefly review the theoretical benefits and the actual evidence supporting these alternative modes of ventilation.

STANDARD NOMENCLATURE NEEDED

Since its invention, mechanical ventilation has been plagued by multiple names being used to describe the same things. For example, volume-control ventilation is also called volume-cycled ventilation, assist-control ventilation, volume-limited ventilation, and controlled mechanical ventilation. Similarly, multiple abbreviations are used, each depending on the brand of ventilator, and new acronyms have been added in recent years as new modes have been developed. The vast number of names and modes can confuse even the most seasoned critical care physician.

Efforts to establish a common nomenclature are under way.1

WHAT IS A MODE?

A mode of mechanical ventilation has three essential components:

  • The control variable
  • The breath sequence
  • The targeting scheme.

Similar modes may require more detailed descriptions to distinguish them, but the basic function can be explained by these three components.

The control variable

In general, inspiration is an active process, driven by the patient’s effort, the ventilator, or both, while expiration is passive. For simplicity, in this article a mechanical breath means the inspiratory phase of the breath.

The machine can only control the volume (and flow) or the pressure given. The breaths can be further described on the basis of what triggers the breath, what limits it (the maximum value of a control variable), and what ends (cycles) it.

Figure 1. Volume control (top) and pressure control (bottom) are modes of continuous mandatory ventilation. Each mode is depicted as patient effort increases. Notice that the mode’s control variable (volume or pressure) remains constant as patient effort increases. Contrast these findings with those in Figure 2.
Therefore, a volume-controlled breath is triggered by the patient or by the machine, limited by flow, and cycled by volume (Figure 1). A pressure-controlled breath is triggered by the patient or the machine, limited by pressure, and cycled by time or flow (Figure 1).

The breath sequence

There are three possible breath sequences:

  • Continuous mandatory ventilation, in which all breaths are controlled by the machine (but can be triggered by the patient)
  • Intermittent mandatory ventilation, in which the patient can take spontaneous breaths between mandatory breaths
  • Continuous spontaneous ventilation, in which all breaths are spontaneous (Table 1).

The targeting scheme

The targeting or feedback scheme refers to the ventilator settings and programming that dictate its response to the patient’s lung compliance, lung resistance, and respiratory effort. The regulation can be as simple as controlling the pressure in pressure-control mode, or it can be based on a complicated algorithm.

In the sections that follow, we describe some of the available alternative modes of mechanical ventilation. We will explain only the targeting schemes in the modes reviewed (Table 1, Table 2), but more information on other targeting schemes can be found elsewhere.1,2 We will focus on evidence generated in adult patients receiving invasive mechanical ventilation.

 

 

ADAPTIVE PRESSURE CONTROL

Figure 2. A machine in adaptive pressure control mode (top) adjusts the inspiratory pressure to maintain a set tidal volume. Adaptive support ventilation (bottom) automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and the target minute ventilation.
One of the concerns with pressure-control ventilation is that it cannot guarantee a minimum minute ventilation (the volume of air that goes in and out in 1 minute; the tidal volume × breaths per minute) in the face of changing lung mechanics or patient effort, or both. To solve this problem, in 1991 the Siemens Servo 300 ventilator (Siemens, Maquet Critical Care AB, Solna, Sweden) introduced Pressure Regulated Volume Control, a mode that delivers pressure-controlled breaths with a target tidal volume and that is otherwise known as adaptive pressure control (APC) (Figure 2).

Other names for adaptive pressure control

  • Pressure Regulated Volume Control (Maquet Servo-i, Rastatt, Germany)
  • AutoFlow (Dräger Medical AG, Lübeck, Germany)
  • Adaptive Pressure Ventilation (Hamilton Galileo, Hamilton Medical AG, Bonaduz, Switzerland)
  • Volume Control+ (Puritan Bennett, Tyco Healthcare; Mansfield, MA)
  • Volume Targeted Pressure Control, Pressure Controlled Volume Guaranteed (Engström, General Electric, Madison, WI).

What does adaptive pressure control do?

The APC mode delivers pressure-controlled breaths with an adaptive targeting scheme (Table 2).

In pressure-control ventilation, tidal volumes depend on the lung’s physiologic mechanics (compliance and resistance) and patient effort (Figure 1). Therefore, the tidal volume varies with changes in lung physiology (ie, larger or smaller tidal volumes than targeted).

To overcome this effect, a machine in APC mode adjusts the inspiratory pressure to deliver the set minimal target tidal volume. If tidal volume increases, the machine decreases the inspiratory pressure, and if tidal volume decreases, the machine increases the inspiratory pressure. However, if the patient effort is large enough, the tidal volume will increase in spite of decreasing the inspiratory pressure (Figure 2). The adjustments to the inspiratory pressure occur after the tidal volume is off-target in a number of breaths.

Common sources of confusion with adaptive pressure control

First, APC is not a volume-control mode. In volume control, the tidal volume does not change; in APC the tidal volume can increase or decrease, and the ventilator will adjust the inflation pressure to achieve the target volume. Thus, APC guarantees an average minimum tidal volume but not a maximum tidal volume.

Second, a characteristic of pressure control (and hence, APC) is that the flow of gas varies to maintain constant airway pressure (ie, maintain the set inspiratory pressure). This characteristic allows a patient who generates an inspiratory effort to receive flow as demanded, which is likely more comfortable. This is essentially different from volume control, in which flow is set by the operator and hence is fixed. Thus, if the patient effort is strong enough (Figure 1), this leads to what is called flow asynchrony, in which the patient does not get the flow asked for in a breath.

Ventilator settings in adaptive pressure control

Ventilator settings in APC are:

  • Tidal volume
  • Time spent in inspiration (inspiratory time)
  • Frequency
  • Fraction of inspired oxygen (Fio2)
  • Positive end-expiratory pressure (PEEP).

Some ventilators also require setting the speed to reach the peak pressure (also known as slope percent or inspiratory rise time).

Clinical applications of adaptive pressure control

This mode is designed to maintain a consistent tidal volume during pressure-control ventilation and to promote inspiratory flow synchrony. It is a means of automatically reducing ventilatory support (ie, weaning) as the patient’s inspiratory effort becomes stronger, as in awakening from anesthesia.

APC may not be ideal for patients who have an inappropriately increased respiratory drive (eg, in severe metabolic acidosis), since the inspiratory pressure will decrease to maintain the targeted average tidal volume, inappropriately shifting the work of breathing onto the patient.

Theoretical benefits of adaptive pressure control

APC guarantees a minimum average tidal volume (unless the pressure alarm threshold is set too low, so that the target tidal volume is not delivered). Other theoretical benefits are flow synchrony, less ventilator manipulation by the operator, and automatic weaning of ventilator support.

Evidence of benefit of adaptive pressure control

Physiologic benefits. This mode has lower peak inspiratory pressures than does volume-control ventilation,3,4 which is often reported as a positive finding. However, in volume-control mode (the usual comparator), the peak inspiratory pressure is a manifestation of both resistance and compliance. Hence, peak inspiratory pressure is expected to be higher but does not reflect actual lung-distending pressures. It is the plateau pressure, a manifestation of lung compliance, that is related to lung injury.

Patient comfort. APC may increase the work of breathing when using low tidal volume ventilation and when there is increased respiratory effort (drive).5 Interestingly, APC was less comfortable than pressure support ventilation in a small trial.6

Outcomes have not been studied.7

Adaptive pressure control: Bottom line

APC is widely available and widely used, sometimes unknowingly (eg, if the operator thinks it is volume control). It is relatively easy to use and to set; however, evidence of its benefit is scant.

 

 

ADAPTIVE SUPPORT VENTILATION

Adaptive support ventilation (ASV) evolved as a form of mandatory minute ventilation implemented with adaptive pressure control. Mandatory minute ventilation is a mode that allows the operator to preset a target minute ventilation, and the ventilator then supplies mandatory breaths, either volume- or pressure-controlled, if the patient’s spontaneous breaths generate a lower minute ventilation.

ASV automatically selects the appropriate tidal volume and frequency for mandatory breaths and the appropriate tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and target minute alveolar ventilation.

Described in 1994 by Laubscher et al,8,9 ASV became commercially available in 1998 in Europe and in 2007 in the United States (Hamilton Galileo ventilator, Hamilton Medical AG). This is the first commercially available ventilator that uses an “optimal” targeting scheme (see below).

What does adaptive support ventilation do?

ASV delivers pressure-controlled breaths using an adaptive (optimal) scheme (Table 2). “Optimal,” in this context, means minimizing the mechanical work of breathing: the machine selects a tidal volume and frequency that the patient’s brain would presumably select if the patient were not connected to a ventilator. This pattern is assumed to encourage the patient to generate spontaneous breaths.

The ventilator calculates the normal required minute ventilation based on the patient’s ideal weight and estimated dead space volume (ie, 2.2 mL/kg). This calculation represents 100% of minute ventilation. The clinician at the bedside sets a target percent of minute ventilation that the ventilator will support—higher than 100% if the patient has increased requirements due, eg, to sepsis or increased dead space, or less than 100% during weaning.

The ventilator initially delivers test breaths, in which it measures the expiratory time constant for the respiratory system and then uses this along with the estimated dead space and normal minute ventilation to calculate an optimal breathing frequency in terms of mechanical work.

The optimal or target tidal volume is calculated as the normal minute ventilation divided by the optimal frequency. The target tidal volume is achieved by the use of APC (see above) (Figure 2). This means that the pressure limit is automatically adjusted to achieve an average delivered tidal volume equal to the target. The ventilator continuously monitors the respiratory system mechanics and adjusts its settings accordingly.

The ventilator adjusts its breaths to avoid air trapping by allowing enough time to exhale, to avoid hypoventilation by delivering tidal volume greater than the dead space, and to avoid volutrauma by avoiding large tidal volumes.

Ventilator settings in adaptive support ventilation

Ventilator settings in ASV are:

  • Patient height (to calculate the ideal body weight)
  • Sex
  • Percent of normal predicted minute ventilation goal
  • Fio2
  • PEEP.

Clinical applications of adaptive support ventilation

ASV is intended as a sole mode of ventilation, from initial support to weaning.

Theoretical benefits of adaptive support ventilation

In theory, ASV offers automatic selection of ventilator settings, automatic adaptation to changing patient lung mechanics, less need for human manipulation of the machine, improved synchrony, and automatic weaning.

Evidence of benefit of adaptive support ventilation

Physiologic benefits. Ventilator settings are adjusted automatically. ASV selects different tidal volume-respiratory rate combinations based on respiratory mechanics in passive and paralyzed patients.10–12 In actively breathing patients, there was no difference in the ventilator settings chosen by ASV for different clinical scenarios (and lung physiology).10 Compared with pressure-controlled intermittent mandatory ventilation, with ASV, the inspiratory load is less and patient-ventilator interaction is better.13

Patient-ventilator synchrony and comfort have not been studied.

Outcomes. Two trials suggest that ASV may decrease time on mechanical ventilation.14,15 However, in another trial,16 compared with a standard protocol, ASV led to fewer ventilator adjustments but achieved similar postsurgical weaning outcomes. The effect of this mode on the death rate has not been examined.17,18

Adaptive support ventilation: Bottom line

ASV is the first commercially available mode that automatically selects all the ventilator settings except PEEP and Fio2. These seem appropriate for different clinical scenarios in patients with poor respiratory effort or in paralyzed patients. Evidence of the effect in actively breathing patients and on outcomes such as length of stay or death is still lacking.

PROPORTIONAL ASSIST VENTILATION

Patients who have normal respiratory drive but who have difficulty sustaining adequate spontaneous ventilation are often subjected to pressure support ventilation (PSV), in which the ventilator generates a constant pressure throughout inspiration regardless of the intensity of the patient’s effort.

In 1992, Younes and colleagues19,20 developed proportional assist ventilation (PAV) as an alternative in which the ventilator generates pressure in proportion to the patient’s effort. PAV became commercially available in Europe in 1999 and was approved in the United States in 2006, available on the Puritan Bennett 840 ventilator (Puritan Bennett Co, Boulder, CO). PAV has also been used for noninvasive ventilation, but this is not available in the United States.

Other names for proportional assist ventilation

Proportional Pressure Support (Dräger Medical; not yet available in the United States).

 

 

What does proportional assist ventilation do?

This mode delivers pressure-controlled breaths with a servo control scheme (Table 2).

To better understand PAV, we can compare it with PSV. With PSV, the pressure applied by the ventilator rises to a preset level that is held constant (a set-point scheme) until a cycling criterion (a percent of the maximum inspiratory flow value) is reached. The inspiratory flow and tidal volume are the result of the patient’s inspiratory effort, the level of pressure applied, and the respiratory system mechanics.

Figure 3. In proportional assist ventilation, the flow, pressure, and volume delivered are adjusted proportionally to the patient’s effort.
In contrast, during PAV, the pressure applied is a function of patient effort: the greater the inspiratory effort, the greater the increase in applied pressure (servo targeting scheme) (Figure 3). The operator sets the percentage of support to be delivered by the ventilator. The ventilator intermittently measures the compliance and resistance of the patient’s respiratory system and the instantaneous patient-generated flow and volume, and on the basis of these it delivers a proportional amount of inspiratory pressure.

In PAV, as in PSV, all breaths are spontaneous (Table 1). The patient controls the timing and size of the breath. There are no preset pressure, flow, or volume goals, but safety limits on the volume and pressure delivered can be set.

Ventilator settings in proportional assist ventilation

Ventilator settings in PAV are:

  • Airway type (endotracheal tube, tracheostomy)
  • Airway size (inner diameter)
  • Percentage of work supported (assist range 5%–95%)
  • Tidal volume limit
  • Pressure limit
  • Expiratory sensitivity (normally, as inspiration ends, flow should stop; this parameter tells the ventilator at what flow to end inspiration).

Caution when assessing the literature. Earlier ventilator versions, ie, Dräger and Manitoba (University of Manitoba, Winnipeg, MB, Canada), which are not available in the United States, required the repeated calculation of the respiratory system mechanics and the manual setting of flow and volume assists (amplification factors) independently. To overcome this limitation, new software automatically adjusts the flow and volume amplification to support the loads imposed by the automatically measured values of resistance and elastance (inverse of compliance) of the respiratory system.21 This software is included in the model (Puritan Bennett) available in the United States.

Clinical applications of proportional assist ventilation

The PAV mode is indicated for maximizing ventilator patient synchrony for assisted spontaneous ventilation.

PAV is contraindicated in patients with respiratory depression (bradypnea) or large air leaks (eg, bronchopleural fistulas). It should be used with caution in patients with severe hyperinflation, in which the patient may still be exhaling but the ventilator doesn’t recognize it. Another group in which PAV should be used with caution is those with high ventilatory drives, in which the ventilator overestimates respiratory system mechanics. This situation can lead to overassistance due to the “runaway phenomenon,” in which the ventilator continues to provide support even if the patient has stopped inspiration.22

Theoretical benefits of proportional assist ventilation

In theory, PAV should reduce the work of breathing, improve synchrony, automatically adapt to changing patient lung mechanics and effort, decrease the need for ventilator intervention and manipulation, decrease the need for sedation, and improve sleep.

Evidence of benefit of proportional assist ventilation

Physiologic benefits. PAV reduces the work of breathing better than PSV,21 even in the face of changing respiratory mechanics or increased respiratory demand (hypercapnia).23–25 The hemodynamic profile is similar to that in PSV. Tidal volumes are variable; however, in recent reports the tidal volumes were within the lung-protective range (6–8 mL/kg, plateau pressure < 30 cm H20).26,27

Comfort. PAV entails less patient effort and discomfort that PSV does.23,25 PAV significantly reduces asynchrony,27 which in turn may favorably affect sleep in critically ill patients. 28

Outcomes. The probability of spontaneous breathing without assistance was significantly better in critically ill patients ventilated with PAV than with PSV. No trial has reported the effect of PAV on deaths.27,29

Proportional assist ventilation: Bottom line

Extensive basic research has been done with PAV in different forms of respiratory failure, such as obstructive lung disease, acute respiratory distress syndrome (ARDS), and chronic respiratory failure. It fulfills its main goal, which is to improve patient-ventilator synchrony. Clinical experience with PAV in the United States is limited, as it was only recently approved.

 

 

AIRWAY PRESSURE-RELEASE VENTILATION AND BIPHASIC POSITIVE AIRWAY PRESSURE

Airway pressure-release ventilation (APRV) was described in 1987 by Stock et al30 as a mode for delivering ventilation in acute lung injury while avoiding high airway pressures. APRV combines high constant positive airway pressure (improving oxygenation and promoting alveolar recruitment) with intermittent releases (causing exhalation).

Figure 4. Airway pressure-release ventilation (top) and biphasic positive airway pressure (bottom) are forms of pressure-controlled intermittent mandatory ventilation in which spontaneous breaths can occur at any point without altering the ventilator-delivered breaths. The difference is that the time spent in high pressure is greater in airway pressure-release ventilation.
In 1989, Baum et al31 described biphasic positive airway pressure ventilation as a mode in which spontaneous ventilation could be achieved at any point in the mechanical ventilation cycle—inspiration or exhalation (Figure 4). The goal was to allow unrestricted spontaneous breathing to reduce sedation and promote weaning. These modes are conceptually the same, the main difference being that the time spent in low pressure (Tlow; see below) is less than 1.5 seconds for APRV. Otherwise, they have identical characteristics, thus allowing any ventilator with the capability of delivering APRV to deliver biphasic positive airway pressure, and vice versa. Machines with these modes became commercially available in the mid 1990s.

Other names for biphasic positive airway pressure

Other names for biphasic positive airway pressure are:

  • BiLevel (Puritan Bennett)
  • BIPAP (Dräger Europe)
  • Bi Vent (Siemens)
  • BiPhasic (Avea, Cardinal Health, Inc, Dublin, OH)
  • PCV+ (Dräger Medical)
  • DuoPAP (Hamilton).

Caution—name confusion. In North America, BiPAP (Respironics, Murrysville, PA) and BiLevel are used to refer to noninvasive modes of ventilation.

APRV has no other name.

What do these modes do?

These modes deliver pressure-controlled, time-triggered, and time-cycled breaths using a set-point targeting scheme (Table 2). This means that the ventilator maintains a constant pressure (set point) even in the face of spontaneous breaths.

Caution—source of confusion. The term continuous positive airway pressure (CPAP) is often used to describe this mode. However, CPAP is pressure that is applied continuously at the same level; the patient generates all the work to maintain ventilation (“pressure-controlled continuous spontaneous ventilation” in the current nomenclature). In APRV, the airway pressure is intermittently released and reapplied, generating a tidal volume that supports ventilation. In other words, this is a pressure-controlled breath with a very prolonged inspiratory time and a short expiratory time in which spontaneous ventilation is possible at any point (“pressure-controlled intermittent mandatory ventilation” in the current nomenclature).

How these modes are set in the ventilator may also be a source of confusion. To describe the time spent in high and low airway pressures, we use the terms Thigh and Tlow, respectively. By convention, the difference between APRV and biphasic mode is the duration of Tlow (< 1.5 sec for APRV).

Similarly, Phigh and Plow are used to describe the high and low airway pressure. To better understand this concept, you can create the same mode in conventional pressure-control ventilation by thinking of the Thigh as the inspiratory time, the Tlow as the expiratory time, the Phigh as inspiratory pressure, and the Plow as PEEP.

Hence, APRV is an extreme form of inverse ratio ventilation, with an inspiration-to-expiration ratio of 4:1. This means a patient spends most of the time in Phigh and Thigh, and exhalations are short (Tlow and Plow). In contrast, the biphasic mode uses conventional inspiration-expiration ratios (Figure 4).

As with any form of pressure control, the tidal volume is generated by airway pressure rising above baseline (ie, the end-expiratory value). Hence, to ensure an increase in minute ventilation, the mandatory breath rate must be increased (ie, decreasing Thigh, Tlow, or both) or the tidal volume must be increased (ie, increasing the difference between Phigh and Plow). This means that in APRV the Tlow has to happen more often (by increasing the number of breaths) or be more prolonged (allowing more air to exhale). Because unrestricted spontaneous breaths are permitted at any point of the cycle, the patient contributes to the total minute ventilation (usually 10%–40%).

In APRV and biphasic mode, the operator’s set time and pressure in inspiration and expiration will be delivered regardless of the patient’s breathing efforts—the patient’s spontaneous breath does not trigger a mechanical breath. Some ventilators have automatic adjustments to improve the trigger synchrony.

Ventilator settings in APRV and biphasic mode

These modes require the setting of two pressure levels (Phigh and Plow) and two time durations (Thigh and Tlow). One can add pressure support or automatic tube compensation to assist spontaneous breaths. The difference in Tlow generates differences in the Thigh:Tlow ratio: APRV has a short Tlow (an inspiration-expiration ratio of 4:1). Biphasic mode has a conventional inspiration-expiration ratio of 1:1 to 1:4.

Clinical applications

APRV is used in acute lung injury and ARDS. This mode should be used with caution or not at all in patients with obstructive lung disease or inappropriately increased respiratory drive.32–35

Biphasic mode is intended for both ventilation and weaning. In a patient who has poor respiratory effort or who is paralyzed, biphasic is identical to pressure-control/continuous mandatory ventilation.

Theoretical benefits of APRV and biphasic mode

Multiple benefits have been ascribed to these modes. In theory, APRV will maximize and maintain alveolar recruitment, improve oxygenation, lower inflation pressures, and decrease overinflation. Both APRV and biphasic, by preserving spontaneous breathing, will improve ventilation-perfusion matching and gas diffusion, improve the hemodynamic profile (less need for vasopressors, higher cardiac output, reduced ventricular workload, improved organ perfusion), and improve synchrony (decrease the work of breathing and the need for sedation).

Evidence of benefit of APRV and biphasic mode

APRV and biphasic are different modes. However studies evaluating their effects are combined. This is in part the result of the nomenclature confusion and different practice in different countries.36

Physiologic benefits. In studies, spontaneous breaths contributed to 10% to 40% of minute ventilation,37,38 improved ventilation of dependent areas of the lung, improved ventilation-perfusion match and recruitment,39 and improved hemodynamic profile.40

Patient comfort. These modes are thought to decrease the need for analgesia and sedation,38 but a recent trial showed no difference with pressure-controlled intermittent mandatory ventilation.41 Patient ventilator synchrony and comfort have not been studied.32,42

Outcomes. In small trials, these modes made no difference in terms of deaths, but they may decrease the length of mechanical ventilation.38,41,43,44

APRV and biphasic mode: Bottom line

Maintaining spontaneous breathing while on mechanical ventilation has hemodynamic and ventilatory benefits.

APRV and biphasic mode are not the same thing. APRV’s main goal is to maximize mean airway pressure and, hence, lung recruitment, whereas the main goal of the biphasic mode is synchrony.

There is a plethora of ventilator settings and questions related to physiologic effects.33,34,36

Although these modes are widely used in some centers, there is no evidence yet that they are superior to conventional volume- or pressure-control ventilation with low tidal volume for ARDS and acute lung injury. There is no conclusive evidence that these modes improve synchrony, time to weaning, or patient comfort.

 

 

HIGH-FREQUENCY OSCILLATORY VENTILATION

High-frequency oscillatory ventilation (HFOV) was first described and patented in 1952 by Emerson and was clinically developed in the early 1970s by Lunkenheimer.45

The goal of HFOV is to minimize lung injury; its characteristics (discussed below) make it useful in patients with severe ARDS. The US Food and Drug Administration approved it for infants in 1991 and for children in 1995. The adult model has been available since 1993, but it was not approved until 2001 (SensorMedics 3100B, Cardinal Health, Inc).

Other names for high-frequency oscillatory ventilation

While HFOV has no alternative names, the following acronyms describe similar modes:

  • HFPPV (high-frequency positive pressure ventilation)
  • HFJV (high-frequency jet ventilation)
  • HFFI (high-frequency flow interruption)
  • HFPV (high-frequency percussive ventilation)
  • HFCWO (high-frequency chest wall oscillation).

All of these modes require different specialized ventilators.

What does high-frequency oscillatory ventilation do?

Conceptually, HFOV is a form of pressure-controlled intermittent mandatory ventilation with a set-point control scheme. In contrast to conventional pressure-controlled intermittent mandatory ventilation, in which relatively small spontaneous breaths may be superimposed on relatively large mandatory breaths, HFOV superimposes very small mandatory breaths (oscillations) on top of spontaneous breaths.

Figure 5. High-frequency oscillatory ventilation delivers very small mandatory breaths (oscillations) at frequencies of up to 900 breaths per minute.
HFOV can be delivered only with a special ventilator. The ventilator delivers a constant flow (bias flow), while a valve creates resistance to maintain airway pressure, on top of which a piston pump oscillates at frequencies of 3 to 15 Hz (160–900 breaths/minute). This creates a constant airway pressure with small oscillations (Figure 5); often, clinicians at the bedside look for the “chest wiggle” to assess the appropriate amplitude settings, although this has not been systematically studied.

Adult patients are usually paralyzed or deeply sedated, since deep spontaneous breathing will trigger alarms and affect ventilator performance.

To manage ventilation (CO2 clearance), one or several of the following maneuvers can be done: decrease the oscillation frequency, increase the amplitude of the oscillations, increase the inspiratory time, or increase bias flow (while allowing an endotracheal tube cuff leak). Oxygenation adjustments are controlled by manipulating the mean airway pressure and the Fio2.

Ventilator settings in high-frequency oscillatory ventilation

Ventilator settings in HFOV are46:

  • Airway pressure amplitude (delta P or power)
  • Mean airway pressure
  • Percent inspiration
  • Inspiratory bias flow
  • Fio2.

Clinical applications of high-frequency oscillatory ventilation

This mode is usually reserved for ARDS patients for whom conventional ventilation is failing. A recently published protocol46 suggests considering HFOV when there is oxygenation failure (Fio2 ≥ 0.7 and PEEP ≥ 14 cm H2O) or ventilation failure (pH < 7.25 with tidal volume ≥ 6 mL/kg predicted body weight and plateau airway pressure ≥ 30 cm H2O).

This mode is contraindicated when there is known severe airflow obstruction or intracranial hypertension.

Theoretical benefits of high-frequency oscillatory ventilation

Conceptually, HFOV can provide the highest mean airway pressure paired with the lowest tidal volume of any mode. These benefits might make HFOV the ideal lung-protective ventilation strategy.

Evidence of benefit of high-frequency oscillatory ventilation

Physiologic benefits. Animal models have shown less histologic damage and lung inflammation with HFOV than with high-tidal-volume conventional ventilation47,48 and low-tidal-volume conventional ventilation.49

Patient comfort has not been studied. However, current technology does impose undue work of breathing in spontaneously breathing patients.50

Outcomes. Several retrospective case series have described better oxygenation with HFOV as rescue therapy for severe ARDS than with conventional mechanical ventilation. Two randomized controlled trials have studied HFOV vs high-tidal-volume conventional mechanical ventilation for early severe ARDS; HFOV was safe but made no difference in terms of deaths.42,51–54

High-frequency oscillatory ventilation: Bottom line

In theory, HFOV provides all the benefits of an ideal lung-protective strategy, at least for paralyzed or deeply sedated patients. Animal studies support these concepts. In human adults, HFOV has been shown to be safe and to provide better oxygenation but no improvement in death rates compared with conventional mechanical ventilation. Currently, HFOV is better reserved for patients with severe ARDS for whom conventional mechanical ventilation is failing.

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References
  1. Chatburn RL. Classification of ventilator modes: update and proposal for implementation. Respir Care 2007; 52:301–323.
  2. Chatburn RL. Computer control of mechanical ventilation. Respir Care 2004; 49:507–517.
  3. Alvarez A, Subirana M, Benito S. Decelerating flow ventilation effects in acute respiratory failure. J Crit Care 1998; 13:21–25.
  4. Guldager H, Nielsen SL, Carl P, Soerensen MB. A comparison of volume control and pressure regulated volume control ventilation in acute respiratory failure. Crit Care 1997; 1:75–77.
  5. Kallet RH, Campbell AR, Dicker RA, Katz JA, Mackersie RC. Work of breathing during lung protective ventilation in patients with acute lung injury and acute respiratory distress syndrome: a comparison between volume and pressure regulated breathing modes. Respir Care 2005; 50:1623–1631.
  6. Betensley AD, Khalid I, Crawford J, Pensler RA, DiGiovine B. Patient comfort during pressure support and volume controlled continuous mandatory ventilation. Respir Care 2008; 53:897–902.
  7. Branson RD, Chatburn RL. Controversies in the critical care setting. Should adaptive pressure control modes be utilized for virtually all patients receiving mechanical ventilation? Respir Care 2007; 52:478–485.
  8. Laubscher TP, Frutiger A, Fanconi S, Jutzi H, Brunner JX. Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation. Int J Clin Monit Comput 1994; 11:19–30.
  9. Laubscher TP, Heinrichs W, Weiler N, Hartmann G, Brunner JX. An adaptive lung ventilation controller. IEEE Trans Biomed Eng 1994; 41:51–59.
  10. Arnal JM, Wysocki M, Nafati C, et al. Automatic selection of breathing pattern using adaptive support ventilation. Intensive Care Med 2008; 34:75–81.
  11. Campbell RS, Sinamban RP, Johannigman JA, et al. Clinical evaluation of a new closed loop ventilation mode: adaptive supportive ventilation (ASV). Crit Care 1999; 3( suppl 1):083.
  12. Belliato M, Palo A, Pasero D, Iotti GA, Mojoli F, Braschi A. Evaluation of adaptive support ventilation in paralysed patients and in a physical lung model. Int J Artif Organs 2004; 27:709–716.
  13. Tassaux D, Dalmas E, Gratadour P, Jolliet P. Patient ventilator interactions during partial ventilatory support: a preliminary study comparing the effects of adaptive support ventilation with synchronized intermittent mandatory ventilation plus inspiratory pressure support. Crit Care Med 2002; 30:801–807.
  14. Gruber PC, Gomersall CD, Leung P, et al. Randomized controlled trial comparing adaptive-support ventilation with pressure-regulated volume-controlled ventilation with automode in weaning patients after cardiac surgery. Anesthesiology 2008; 109:81–87.
  15. Sulzer CF, Chiolero R, Chassot PG, et al. Adaptive support ventilation for fast tracheal extubation after cardiac surgery: a randomized controlled study. Anesthesiology 2001; 95:1339–1345.
  16. Petter AH, Chiolèro RL, Cassina T, Chassot PG, Müller XM, Revelly JP. Automatic “respirator/weaning” with adaptive support ventilation: the effect on duration of endotracheal intubation and patient management. Anesth Analg 2003; 97:1743–1750.
  17. Brunner JX, Iotti GA. Adaptive support ventilation (ASV). Minerva Anestesiol 2002; 68:365–368.
  18. Campbell RS, Branson RD, Johannigman JA. Adaptive support ventilation. Respir Care Clin North Am 2001; 7:425–440.
  19. Younes M. Proportional assist ventilation, a new approach to ventilatory support. Theory. Am Rev Respir Dis 1992; 145:114–120.
  20. Younes M, Puddy A, Roberts D, et al. Proportional assist ventilation. Results of an initial clinical trial. Am Rev Respir Dis 1992; 145:121–129.
  21. Kondili E, Prinianakis G, Alexopoulou C, Vakouti E, Klimathianaki M, Georgopoulos D. Respiratory load compensation during mechanical ventilatio—proportional assist ventilation with load-adjustable gain factors versus pressure support. Intensive Care Med 2006; 32:692–699.
  22. Kondili E, Prinianakis G, Alexopoulou C, Vakouti E, Klimathianaki M, Georgopoulos D. Effect of different levels of pressure support and proportional assist ventilation on breathing pattern, work of breathing and gas exchange in mechanically ventilated hypercapnic COPD patients with acute respiratory failure. Respiration 2003; 70:355–361.
  23. Grasso S, Puntillo F, Mascia L, et al. Compensation for increase in respiratory workload during mechanical ventilation. Pressure support versus proportional assist ventilation. Am J Respir Crit Care Med 2000; 161:819–826.
  24. Wrigge H, Golisch W, Zinserling J, Sydow M, Almeling G, Burchardi H. Proportional assist versus pressure support ventilation: effects on breathing pattern and respiratory work of patients with chronic obstructive pulmonary disease. Intensive Care Med 1999; 25:790–798.
  25. Ranieri VM, Giuliani R, Mascia L, et al. Patient ventilator interaction during acute hypercapnia: pressure support vs. proportional assist ventilation. J Appl Physiol 1996; 81:426–436.
  26. Kondili E, Xirouchaki N, Vaporidi K, Klimathianaki M, Georgopoulos D. Short-term cardiorespiratory effects of proportional assist and pressure support ventilation in patients with acute lung injury/acute respiratory distress syndrome. Anesthesiology 2006; 105:703–708.
  27. Xirouchaki N, Kondili E, Vaporidi K, et al. Proportional assist ventilation with load-adjustable gain factors in critically ill patients: comparison with pressure support. Intensive Care Med 2008; 34:2026–2034.
  28. Bosma K, Ferreyra G, Ambrogio C, et al. Patient ventilator interaction and sleep in mechanically ventilated patients: pressure support versus proportional assist ventilation. Crit Care Med 2007; 35:1048–1054.
  29. Sinderby C, Beck J. Proportional assist ventilation and neurally adjusted ventilatory assist—better approaches to patient ventilator synchrony? Clin Chest Med 2008; 29:329–342.
  30. Stock MC, Downs JB, Frolicher DA. Airway pressure release ventilation. Crit Care Med 1987; 15:462–466.
  31. Baum M, Benzer H, Putensen C, Koller W, Putz G. [Biphasic positive airway pressure (BIPAP)—a new form of augmented ventilation]. Anaesthesist 1989; 38:452–458.
  32. Seymour CW, Frazer M, Reilly PM, Fuchs BD. Airway pressure release and biphasic intermittent positive airway pressure ventilation: are they ready for prime time? J Trauma 2007; 62:1298–1308.
  33. Myers TR, MacIntyre NR. Respiratory controversies in the critical care setting. Does airway pressure release ventilation offer important new advantages in mechanical ventilator support? Respir Care 2007; 52:452–458.
  34. Neumann P, Golisch W, Strohmeyer A, Buscher H, Burchardi H, Sydow M. Influence of different release times on spontaneous breathing pattern during airway pressure release ventilation. Intensive Care Med 2002; 28:1742–1749.
  35. Calzia E, Lindner KH, Witt S, et al. Pressure-time product and work of breathing during biphasic continuous positive airway pressure and assisted spontaneous breathing. Am J Respir Crit Care Med 1994; 150:904–910.
  36. Rose L, Hawkins M. Airway pressure release ventilation and biphasic positive airway pressure: a systematic review of definitional criteria. Intensive Care Med 2008; 34:1766–1773.
  37. Sydow M, Burchardi H, Ephraim E, Zielmann S, Crozier TA. Longterm effects of two different ventilatory modes on oxygenation in acute lung injury. Comparison of airway pressure release ventilation and volume-controlled inverse ratio ventilation. Am J Respir Crit Care Med 1994; 149:1550–1556.
  38. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med 2001; 164:43–49.
  39. Davis K, Johnson DJ, Branson RD, Campbell RS, Johannigman JA, Porembka D. Airway pressure release ventilation. Arch Surg 1993; 128:1348–1352.
  40. Kaplan LJ, Bailey H, Formosa V. Airway pressure release ventilation increases cardiac performance in patients with acute lung injury/adult respiratory distress syndrome. Crit Care 2001; 5:221–226.
  41. Varpula T, Valta P, Niemi R, Takkunen O, Hynynen M, Pettilä VV. Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol Scand 2004; 48:722–731.
  42. Siau C, Stewart TE. Current role of high frequency oscillatory ventilation and airway pressure release ventilation in acute lung injury and acute respiratory distress syndrome. Clin Chest Med 2008; 29:265–275.
  43. Rathgeber J, Schorn B, Falk V, Kazmaier S, Spiegel T, Burchardi H. The influence of controlled mandatory ventilation (CMV), intermittent mandatory ventilation (IMV) and biphasic intermittent positive airway pressure (BIPAP) on duration of intubation and consumption of analgesics and sedatives. A prospective analysis in 596 patients following adult cardiac surgery. Eur J Anaesthesiol 1997; 14:576–582.
  44. Habashi NM. Other approaches to open lung ventilation: airway pressure release ventilation. Crit Care Med 2005; 33 suppl 3:S228–S240.
  45. Hess D, Mason S, Branson R. High-frequency ventilation design and equipment issues. Respir Care Clin North Am 2001; 7:577–598.
  46. Fessler HE, Derdak S, Ferguson ND, et al. A protocol for high frequency oscillatory ventilation in adults: results from a roundtable discussion. Crit Care Med 2007; 35:1649–1654.
  47. Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of conventional and high-frequency ventilation: oxygenation and lung pathology. J Appl Physiol 1983; 55:131–138.
  48. Sedeek KA, Takeuchi M, Suchodolski K, et al. Open-lung protective ventilation with pressure control ventilation, high-frequency oscillation, and intratracheal pulmonary ventilation results in similar gas exchange, hemodynamics, and lung mechanics. Anesthesiology 2003; 99:1102–1111.
  49. Imai Y, Nakagawa S, Ito Y, Kawano T, Slutsky AS, Miyasaka K. Comparison of lung protection strategies using conventional and high-frequency oscillatory ventilation. J Appl Physiol 2001; 91:1836–1844.
  50. van Heerde M, Roubik K, Kopelent V, Plötz FB, Markhorst DG. Unloading work of breathing during high-frequency oscillatory ventilation: a bench study. Crit Care 2006; 10:R103.
  51. Derdak S, Mehta S, Stewart TE, et al., Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial (MOAT) Study Investigators. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:801–808.
  52. Bollen CW, van Well GT, Sherry T, et al. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669]. Crit Care 2005; 9:R430–R439.
  53. Mehta S, Granton J, MacDonald RJ, et al. High frequency oscillatory ventilation in adults: the Toronto experience. Chest 2004; 126:518–527.
  54. Chan KP, Stewart TE, Mehta S. High-frequency oscillatory ventilation for adult patients with ARDS. Chest 2007; 131:1907–1916.
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Alternative modes of mechanical ventilation: A review for the hospitalist
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KEY POINTS

  • The alternative modes of ventilation were developed to prevent lung injury and asynchrony, promote better oxygenation and faster weaning, and be easier to use. However, evidence of their benefit is scant.
  • Until now, we have lacked a standard nomenclature for mechanical ventilation, leading to confusion.
  • Regardless of the mode used, the goals are to avoid lung injury, keep the patient comfortable, and wean the patient from mechanical ventilation as soon as possible.
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A 48-year-old man with uncontrolled diabetes

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A 48-year-old man with uncontrolled diabetes
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Mengjun Hu, BS
J. Harry Isaacson, MD

A 48-year-old white man who has had diabetes mellitus for 6 years presents to the outpatient clinic because his blood sugar levels have been rising for the past week.

Both his parents had diabetes, and at the time of his diagnosis he weighed 278 pounds, all of which supported a diagnosis of type 2 diabetes mellitus. His disease was initially managed with diet, exercise, and metformin (Glucophage). Four months later, with weight loss and exercise, his blood sugar levels were consistently under 100 mg/dL, and metformin was discontinued.

He did well until 1 week ago, when he noted polyuria, polydipsia, and rising fingerstick glucose values, higher than 200 mg/dL. He has been eating well, with no nausea, vomiting, or symptoms of dehydration. He denies having any fever, chills, cough, nasal congestion, chest pain, abdominal pain, or dysuria.

In addition to his type 2 diabetes, he has hypertension, for which he takes losartan (Cozaar); hyperlipidemia, for which he takes atorvastatin (Lipitor); and gout, for which he takes allopurinol (Zyloprim).

His blood pressure is 148/70 mm Hg, pulse 100, and weight 273 pounds, and he is afebrile. On examination, his skin, head, eyes, ears, nose, throat, lungs, heart, and abdomen are normal. Urinalysis in the clinic shows large amounts of glucose and ketones.

WHAT IS THE LEAST LIKELY CAUSE OF HIS POOR CONTROL?

1. Which of the following is the least likely cause of his poorly controlled diabetes?

  • Occult infection
  • Poor adherence to diet and exercise
  • Diabetic ketoacidosis
  • Pancreatitis

Until 1 week ago, this patient’s diabetes had been well controlled for several years. Pancreatitis is the least likely cause of his uncontrolled diabetes, because he has no history of pancreatitis and has none of the symptoms of acute pancreatitis (fever, vomiting, or severe midepigastric pain radiating into the back).

Poor adherence to medication and lifestyle issues are very common in patients with poorly controlled diabetes and should always be included in the differential diagnosis.

Occult infection should also be considered in a patient with uncontrolled diabetes. Although this patient had no symptoms or signs of infection, urinalysis was done to look for an occult urinary tract infection and, surprisingly, it showed a large amount of ketones.

Case continued: He is treated for diabetic ketoacidosis

Additional testing (Table 1) confirms he has a high serum ketone level and acidosis with a high anion gap, consistent with diabetic ketoacidosis. Blood cultures are negative. He is admitted to the hospital and treated with intravenous fluids and an insulin drip at 6 units/hour. Within 48 hours his anion gap normalizes, and he is discharged on a regimen of insulin glargine (Lantus) and insulin lispro (Humalog). A fasting C-peptide level drawn 7 days after his presentation is 1.9 ng/dL (normal 0.8–3.2 ng/dL).

Diabetic ketoacidosis in ‘atypical diabetes’

Diabetic ketoacidosis is one of the most serious complications of diabetes. Many patients present with nausea, vomiting, and abdominal pain. Dehydration is often present because hyperglycemia leads to glucosuria and volume depletion. Interestingly, our patient showed none of these symptoms or signs.

Diabetic ketoacidosis is increasingly being recognized as a complication in patients with type 2 diabetes mellitus.1–4 Since the mid-1990s, clinicians have become increasingly aware of a condition variably termed “atypical diabetes,” “Flatbush diabetes,” “diabetes type 1B,” and “ketosis-prone type 2 diabetes mellitus,” in which patients, usually obese, present with diabetic ketoacidosis as their first manifestation, but are subsequently found to have type 2 diabetes mellitus. These patients typically are African American or of African, Hispanic, or Caribbean descent.

Ketoacidosis results from transient suppression of beta-cell function, the cause of which is unknown. A recent study comparing patients who have type 2 diabetes mellitus with and without diabetic ketoacidosis presenting with decompensated diabetes suggested insulinopenia was the predominant mechanism.5 For many of these patients, insulinopenia is transient: as the ketoacidosis resolves, betacell function improves and, with adequate insulin, lipolysis is reduced.

 

 

WHAT CAUSES DIABETIC KETOACIDOSIS?

2. Which of the following hormonal changes underlies the development of diabetic ketoacidosis?

  • Insulin resistance
  • Insulin deficiency
  • Glucagon excess
  • Glucagon deficiency
  • Insulin deficiency and glucagon excess
  • Insulin deficiency and glucagon deficiency

Diabetic ketoacidosis can occur when there is too much glucagon and not enough insulin. Insulin lowers the serum glucose level by promoting glucose uptake in peripheral tissues and by inhibiting gluconeogenesis and glycogenolysis in the liver. Insulin is also anabolic: it inhibits lipolysis in adipocytes and thus decreases the amount of substrate for ketogenesis.

Glucagon is the primary counterregulatory hormone responsible for ketogenesis.6 In the presence of glucagon excess, malonyl CoA production decreases, causing unblocking of carnitine acyltransferase I (CAT I) and allowing beta-oxidation to occur.6

Therefore, the sequence initiating ketogenesis begins with a shift in the ratio of glucagon to insulin, so that there is a relative or absolute excess of glucagon and a deficiency of insulin. A deficiency of insulin accelerates lipolysis, providing more substrate for ketogenesis, while excess glucagon turns on the oxidative sequence for fatty acids in the liver.

Three ketone bodies are produced in diabetic ketoacidosis: two ketoacids (beta-hydroxybutyric acid and acetoacetic acid), and one neutral ketone (acetone). The concentration of insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization.7 Diabetic ketoacidosis is uncommon in patients with type 2 diabetes because they typically have enough insulin to inhibit lipolysis (and therefore ketoacid formation) but not enough to promote glucose utilization.

RISK FACTORS FOR DIABETIC KETOACIDOSIS

3. Which of the following is not a risk factor for diabetic ketoacidosis in type 2 diabetes mellitus?

  • Acute illness
  • Age > 65
  • Inadequate insulin doses
  • Antipsychotic drugs
  • Ethnicity

Diabetic ketoacidosis is often precipitated by an acute illness such as an infection, cerebrovascular accident, myocardial infarction, or acute pancreatitis.8–12 These acute illnesses induce stress in the body and elevate counterregulatory hormones.

Inadequate insulin doses can also lead to diabetic ketoacidosis.

Drugs that affect carbohydrate metabolism are also risk factors. These include glucocorticoids, thiazide diuretics in high doses (> 50 mg daily), sympathomimetic agents, and second-generation antipsychotic agents (also called “atypical” antipsychotics) such as clozapine (Clozaril) and olanzapine (Zyprexa), although some are worse than others.13,14

Ketosis-prone type 2 diabetes mellitus is more prevalent in African Americans and Hispanics.8,15,16

Age is not a risk factor for developing diabetic ketoacidosis. In fact, diabetic ketoacidosis is the leading cause of morbidity and death in children with type 1 diabetes and can also occur in children with type 2 diabetes, particularly in obese African American adolescents.2

DISTINGUISHING TYPE 1 FROM TYPE 2

4. Which of the following is most specific in distinguishing type 1 from type 2 diabetes mellitus?

  • C-peptide levels
  • Islet cell antibodies
  • Body mass index
  • Family history
  • Hemoglobin A1c level

Type 1 diabetes is characterized by destruction of pancreatic beta cells, leading to absolute insulin deficiency. The process is usually mediated by autoimmunity; therefore, testing for antibodies to islet cells, glutamic acid decarboxylase, insulin, and tyrosine phosphatase is the most specific way to distinguish type 1 from type 2 diabetes mellitus.

The hemoglobin A1c level correlates with the mean blood glucose level over the previous 8 to 12 weeks. The hemoglobin A1c is typically elevated in both type 1 and type 2 diabetes mellitus and therefore is not a useful distinguishing feature.

C-peptide is made when proinsulin is cleaved into insulin and C-peptide. It is released from endocytic vesicles with insulin in a one-to-one molar ratio. Thus, the level of C-peptide in the blood can show how much insulin is being made by the pancreas. C-peptide levels can help distinguish between type 1 and type 2 diabetes mellitus later in the course of the disease (levels are usually lower in a patient with type 1 diabetes), but they are not as useful early on because they can be normal early in the course of type 1 diabetes.17

A family history of diabetes is more common in type 2 diabetes, but patients with either type 1 or type 2 can have an affected close relative.

Patients with type 2 diabetes are generally overweight, with a body mass index greater than the 85th percentile for their age and sex. In contrast, patients with type 1 diabetes are usually not overweight and often have a recent history of weight loss. There are exceptions, however, and some patients with type 1 diabetes have an elevated body mass index, while some patients with type 2 diabetes are thin.

Although individually, C-peptide, family history, and body mass index are not very specific in distinguishing type 1 from type 2 diabetes mellitus, together they often give the clinician a good idea of the type of diabetes the patient has. In our case, although islet cell antibodies were not drawn, the normal C-peptide level, high body mass index, and family history all support a diagnosis of type 2 diabetes mellitus.

 

 

THE PATIENT CONTINUES TO DO WELL

The patient is discharged from the hospital on an insulin regimen. His blood sugar levels are closely monitored and remain near normal. Six months after the episode of diabetic ketoacidosis, his insulin is discontinued.

TAKE-HOME POINTS

Diabetic ketoacidosis is not unique to type 1 diabetes mellitus. It can occur in type 2, more commonly in patients who are nonwhite and who have precipitating factors such as acute illness, inadequate insulin treatment, or newly diagnosed diabetes. Clinicians should be aware of the possibility of diabetic ketoacidosis even in patients with type 2 diabetes who may not have these risk factors.

One approach to recognizing diabetic ketoacidosis better in patients with type 2 diabetes mellitus would include checking urine for ketones and serum electrolytes for high anion gap acidosis when patients with type 2 diabetes present with uncontrolled blood sugar levels. If ketonuria or acidosis is present, serum ketone and beta-hydroxybutyrate levels should be obtained to evaluate for diabetic ketoacidosis.

Patients should take insulin for an indeterminate period of time after initial treatment of diabetic ketoacidosis. As our case illustrates, in many cases, beta-cell function will return sufficiently to allow insulin to be discontinued. There are no clear guidelines for how long to continue insulin, but most practitioners continue it for weeks to months and discontinue it when glucose levels are stable and remain so with tapering doses. Sometimes oral agents need to be added as insulin is tapered.

Insulin therapy is tailored to the individual patient on the basis of blood glucose values. There are no data on which type of insulin is the most effective, and there are no data on whether these patients are at greater risk of hypoglycemia than other patients taking insulin. In general, there is no evidence that “prophylactic” insulin (ie, giving insulin to prevent diabetic ketoacidosis during times of illness or stress) is required. However, blood glucose monitoring is appropriate during infection or stress, and if hyperglycemia occurs in these situations, insulin use is prudent to reduce the risks of recurrent diabetic ketoacidosis.

References
  1. Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes 1995; 44:790–795.
  2. Valabhji J, Watson M, Cox J, Poulter C, Elwig C, Elkeles RS. Type 2 diabetes presenting as diabetic ketacidosis in adolescence. Diabet Med 2003; 20:416–417.
  3. Westphal SA. The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults. Am J Med 1996; 101:19–24.
  4. Welch B, Zib I. Case study: diabetic ketoacidosis in type 2 diabetes: “look under the sheets.” Clin Diabetes 2004; 22:198–200.
  5. Linfoot P, Bergstrom C, Ipp E. Pathophysiology of ketoacidosis in type 2 diabetes mellitus. Diabet Med 2005; 22:1414–1419.
  6. Foster DW, McGarry JD. The regulation of ketogenesis. Ciba Found Symp 1982; 87:120–131.
  7. Zierler KL, Rabinowitz D. Effect of very small concentrations of insulin on forearm metabolism: persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 1964; 43:950–962.
  8. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004; 164:1925–1931.
  9. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med 1997; 157:669–675.
  10. Jabbour SA, Miller JL. Uncontrolled diabetes mellitus. Clin Lab Med 2001; 21:99–110.
  11. Ennis ED, Kreisberg RA. Diabetic ketoacidosis and the hyperglycemic hyperosmolar syndrome. In: Leroith D, Taylor SI, Olefsky JM, editors. Diabetes Mellitus. Lippincott-Raven Publishers; Philadelphia, 1996:276–286.
  12. Case CC, Maldonado M. Diabetic ketoacidosis associated with Metabolife: a report of two cases. Diabetes Obes Metab 2002; 4:402–406.
  13. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. In:DeFronzo RA, Ferrannini E, Keen H, Zimmet P, editors. International Textbook of Diabetes Mellitus, 3rd ed. John Wiley and Sons, Ltd: Chichester, UK, 2004:1101–1119.
  14. Newcomer JW. Second generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19( suppl 1):1–93.
  15. Balasubramanyam A, Zern JW, Hyman DJ, Pavlik V. New profiles of diabetic ketoacidosis: type 1 vs. type 2 diabetes and the effect of ethnicity. Arch Intern Med 1999; 159:2317–2322.
  16. Davis SN, Umpierrez GE. Diabetic ketoacidosis in type 2 diabetes mellitus—pathophsyiology and clinical presentation. Nat Clin Pract Endocrinol Metab 2007; 3:730–731.
  17. Hoogwerf B, Rich S, Barbosa J. Meal-stimulated Cpeptide and insulin antibodies in type I diabetic subjects and their nondiabetic siblings characterized by HLA-DR antigens. Diabetes 1985; 34:440–445.
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Related Articles
Diabetic ketoacidosis
In reply: Diabetic ketoacidosis

A 48-year-old white man who has had diabetes mellitus for 6 years presents to the outpatient clinic because his blood sugar levels have been rising for the past week.

Both his parents had diabetes, and at the time of his diagnosis he weighed 278 pounds, all of which supported a diagnosis of type 2 diabetes mellitus. His disease was initially managed with diet, exercise, and metformin (Glucophage). Four months later, with weight loss and exercise, his blood sugar levels were consistently under 100 mg/dL, and metformin was discontinued.

He did well until 1 week ago, when he noted polyuria, polydipsia, and rising fingerstick glucose values, higher than 200 mg/dL. He has been eating well, with no nausea, vomiting, or symptoms of dehydration. He denies having any fever, chills, cough, nasal congestion, chest pain, abdominal pain, or dysuria.

In addition to his type 2 diabetes, he has hypertension, for which he takes losartan (Cozaar); hyperlipidemia, for which he takes atorvastatin (Lipitor); and gout, for which he takes allopurinol (Zyloprim).

His blood pressure is 148/70 mm Hg, pulse 100, and weight 273 pounds, and he is afebrile. On examination, his skin, head, eyes, ears, nose, throat, lungs, heart, and abdomen are normal. Urinalysis in the clinic shows large amounts of glucose and ketones.

WHAT IS THE LEAST LIKELY CAUSE OF HIS POOR CONTROL?

1. Which of the following is the least likely cause of his poorly controlled diabetes?

  • Occult infection
  • Poor adherence to diet and exercise
  • Diabetic ketoacidosis
  • Pancreatitis

Until 1 week ago, this patient’s diabetes had been well controlled for several years. Pancreatitis is the least likely cause of his uncontrolled diabetes, because he has no history of pancreatitis and has none of the symptoms of acute pancreatitis (fever, vomiting, or severe midepigastric pain radiating into the back).

Poor adherence to medication and lifestyle issues are very common in patients with poorly controlled diabetes and should always be included in the differential diagnosis.

Occult infection should also be considered in a patient with uncontrolled diabetes. Although this patient had no symptoms or signs of infection, urinalysis was done to look for an occult urinary tract infection and, surprisingly, it showed a large amount of ketones.

Case continued: He is treated for diabetic ketoacidosis

Additional testing (Table 1) confirms he has a high serum ketone level and acidosis with a high anion gap, consistent with diabetic ketoacidosis. Blood cultures are negative. He is admitted to the hospital and treated with intravenous fluids and an insulin drip at 6 units/hour. Within 48 hours his anion gap normalizes, and he is discharged on a regimen of insulin glargine (Lantus) and insulin lispro (Humalog). A fasting C-peptide level drawn 7 days after his presentation is 1.9 ng/dL (normal 0.8–3.2 ng/dL).

Diabetic ketoacidosis in ‘atypical diabetes’

Diabetic ketoacidosis is one of the most serious complications of diabetes. Many patients present with nausea, vomiting, and abdominal pain. Dehydration is often present because hyperglycemia leads to glucosuria and volume depletion. Interestingly, our patient showed none of these symptoms or signs.

Diabetic ketoacidosis is increasingly being recognized as a complication in patients with type 2 diabetes mellitus.1–4 Since the mid-1990s, clinicians have become increasingly aware of a condition variably termed “atypical diabetes,” “Flatbush diabetes,” “diabetes type 1B,” and “ketosis-prone type 2 diabetes mellitus,” in which patients, usually obese, present with diabetic ketoacidosis as their first manifestation, but are subsequently found to have type 2 diabetes mellitus. These patients typically are African American or of African, Hispanic, or Caribbean descent.

Ketoacidosis results from transient suppression of beta-cell function, the cause of which is unknown. A recent study comparing patients who have type 2 diabetes mellitus with and without diabetic ketoacidosis presenting with decompensated diabetes suggested insulinopenia was the predominant mechanism.5 For many of these patients, insulinopenia is transient: as the ketoacidosis resolves, betacell function improves and, with adequate insulin, lipolysis is reduced.

 

 

WHAT CAUSES DIABETIC KETOACIDOSIS?

2. Which of the following hormonal changes underlies the development of diabetic ketoacidosis?

  • Insulin resistance
  • Insulin deficiency
  • Glucagon excess
  • Glucagon deficiency
  • Insulin deficiency and glucagon excess
  • Insulin deficiency and glucagon deficiency

Diabetic ketoacidosis can occur when there is too much glucagon and not enough insulin. Insulin lowers the serum glucose level by promoting glucose uptake in peripheral tissues and by inhibiting gluconeogenesis and glycogenolysis in the liver. Insulin is also anabolic: it inhibits lipolysis in adipocytes and thus decreases the amount of substrate for ketogenesis.

Glucagon is the primary counterregulatory hormone responsible for ketogenesis.6 In the presence of glucagon excess, malonyl CoA production decreases, causing unblocking of carnitine acyltransferase I (CAT I) and allowing beta-oxidation to occur.6

Therefore, the sequence initiating ketogenesis begins with a shift in the ratio of glucagon to insulin, so that there is a relative or absolute excess of glucagon and a deficiency of insulin. A deficiency of insulin accelerates lipolysis, providing more substrate for ketogenesis, while excess glucagon turns on the oxidative sequence for fatty acids in the liver.

Three ketone bodies are produced in diabetic ketoacidosis: two ketoacids (beta-hydroxybutyric acid and acetoacetic acid), and one neutral ketone (acetone). The concentration of insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization.7 Diabetic ketoacidosis is uncommon in patients with type 2 diabetes because they typically have enough insulin to inhibit lipolysis (and therefore ketoacid formation) but not enough to promote glucose utilization.

RISK FACTORS FOR DIABETIC KETOACIDOSIS

3. Which of the following is not a risk factor for diabetic ketoacidosis in type 2 diabetes mellitus?

  • Acute illness
  • Age > 65
  • Inadequate insulin doses
  • Antipsychotic drugs
  • Ethnicity

Diabetic ketoacidosis is often precipitated by an acute illness such as an infection, cerebrovascular accident, myocardial infarction, or acute pancreatitis.8–12 These acute illnesses induce stress in the body and elevate counterregulatory hormones.

Inadequate insulin doses can also lead to diabetic ketoacidosis.

Drugs that affect carbohydrate metabolism are also risk factors. These include glucocorticoids, thiazide diuretics in high doses (> 50 mg daily), sympathomimetic agents, and second-generation antipsychotic agents (also called “atypical” antipsychotics) such as clozapine (Clozaril) and olanzapine (Zyprexa), although some are worse than others.13,14

Ketosis-prone type 2 diabetes mellitus is more prevalent in African Americans and Hispanics.8,15,16

Age is not a risk factor for developing diabetic ketoacidosis. In fact, diabetic ketoacidosis is the leading cause of morbidity and death in children with type 1 diabetes and can also occur in children with type 2 diabetes, particularly in obese African American adolescents.2

DISTINGUISHING TYPE 1 FROM TYPE 2

4. Which of the following is most specific in distinguishing type 1 from type 2 diabetes mellitus?

  • C-peptide levels
  • Islet cell antibodies
  • Body mass index
  • Family history
  • Hemoglobin A1c level

Type 1 diabetes is characterized by destruction of pancreatic beta cells, leading to absolute insulin deficiency. The process is usually mediated by autoimmunity; therefore, testing for antibodies to islet cells, glutamic acid decarboxylase, insulin, and tyrosine phosphatase is the most specific way to distinguish type 1 from type 2 diabetes mellitus.

The hemoglobin A1c level correlates with the mean blood glucose level over the previous 8 to 12 weeks. The hemoglobin A1c is typically elevated in both type 1 and type 2 diabetes mellitus and therefore is not a useful distinguishing feature.

C-peptide is made when proinsulin is cleaved into insulin and C-peptide. It is released from endocytic vesicles with insulin in a one-to-one molar ratio. Thus, the level of C-peptide in the blood can show how much insulin is being made by the pancreas. C-peptide levels can help distinguish between type 1 and type 2 diabetes mellitus later in the course of the disease (levels are usually lower in a patient with type 1 diabetes), but they are not as useful early on because they can be normal early in the course of type 1 diabetes.17

A family history of diabetes is more common in type 2 diabetes, but patients with either type 1 or type 2 can have an affected close relative.

Patients with type 2 diabetes are generally overweight, with a body mass index greater than the 85th percentile for their age and sex. In contrast, patients with type 1 diabetes are usually not overweight and often have a recent history of weight loss. There are exceptions, however, and some patients with type 1 diabetes have an elevated body mass index, while some patients with type 2 diabetes are thin.

Although individually, C-peptide, family history, and body mass index are not very specific in distinguishing type 1 from type 2 diabetes mellitus, together they often give the clinician a good idea of the type of diabetes the patient has. In our case, although islet cell antibodies were not drawn, the normal C-peptide level, high body mass index, and family history all support a diagnosis of type 2 diabetes mellitus.

 

 

THE PATIENT CONTINUES TO DO WELL

The patient is discharged from the hospital on an insulin regimen. His blood sugar levels are closely monitored and remain near normal. Six months after the episode of diabetic ketoacidosis, his insulin is discontinued.

TAKE-HOME POINTS

Diabetic ketoacidosis is not unique to type 1 diabetes mellitus. It can occur in type 2, more commonly in patients who are nonwhite and who have precipitating factors such as acute illness, inadequate insulin treatment, or newly diagnosed diabetes. Clinicians should be aware of the possibility of diabetic ketoacidosis even in patients with type 2 diabetes who may not have these risk factors.

One approach to recognizing diabetic ketoacidosis better in patients with type 2 diabetes mellitus would include checking urine for ketones and serum electrolytes for high anion gap acidosis when patients with type 2 diabetes present with uncontrolled blood sugar levels. If ketonuria or acidosis is present, serum ketone and beta-hydroxybutyrate levels should be obtained to evaluate for diabetic ketoacidosis.

Patients should take insulin for an indeterminate period of time after initial treatment of diabetic ketoacidosis. As our case illustrates, in many cases, beta-cell function will return sufficiently to allow insulin to be discontinued. There are no clear guidelines for how long to continue insulin, but most practitioners continue it for weeks to months and discontinue it when glucose levels are stable and remain so with tapering doses. Sometimes oral agents need to be added as insulin is tapered.

Insulin therapy is tailored to the individual patient on the basis of blood glucose values. There are no data on which type of insulin is the most effective, and there are no data on whether these patients are at greater risk of hypoglycemia than other patients taking insulin. In general, there is no evidence that “prophylactic” insulin (ie, giving insulin to prevent diabetic ketoacidosis during times of illness or stress) is required. However, blood glucose monitoring is appropriate during infection or stress, and if hyperglycemia occurs in these situations, insulin use is prudent to reduce the risks of recurrent diabetic ketoacidosis.

A 48-year-old white man who has had diabetes mellitus for 6 years presents to the outpatient clinic because his blood sugar levels have been rising for the past week.

Both his parents had diabetes, and at the time of his diagnosis he weighed 278 pounds, all of which supported a diagnosis of type 2 diabetes mellitus. His disease was initially managed with diet, exercise, and metformin (Glucophage). Four months later, with weight loss and exercise, his blood sugar levels were consistently under 100 mg/dL, and metformin was discontinued.

He did well until 1 week ago, when he noted polyuria, polydipsia, and rising fingerstick glucose values, higher than 200 mg/dL. He has been eating well, with no nausea, vomiting, or symptoms of dehydration. He denies having any fever, chills, cough, nasal congestion, chest pain, abdominal pain, or dysuria.

In addition to his type 2 diabetes, he has hypertension, for which he takes losartan (Cozaar); hyperlipidemia, for which he takes atorvastatin (Lipitor); and gout, for which he takes allopurinol (Zyloprim).

His blood pressure is 148/70 mm Hg, pulse 100, and weight 273 pounds, and he is afebrile. On examination, his skin, head, eyes, ears, nose, throat, lungs, heart, and abdomen are normal. Urinalysis in the clinic shows large amounts of glucose and ketones.

WHAT IS THE LEAST LIKELY CAUSE OF HIS POOR CONTROL?

1. Which of the following is the least likely cause of his poorly controlled diabetes?

  • Occult infection
  • Poor adherence to diet and exercise
  • Diabetic ketoacidosis
  • Pancreatitis

Until 1 week ago, this patient’s diabetes had been well controlled for several years. Pancreatitis is the least likely cause of his uncontrolled diabetes, because he has no history of pancreatitis and has none of the symptoms of acute pancreatitis (fever, vomiting, or severe midepigastric pain radiating into the back).

Poor adherence to medication and lifestyle issues are very common in patients with poorly controlled diabetes and should always be included in the differential diagnosis.

Occult infection should also be considered in a patient with uncontrolled diabetes. Although this patient had no symptoms or signs of infection, urinalysis was done to look for an occult urinary tract infection and, surprisingly, it showed a large amount of ketones.

Case continued: He is treated for diabetic ketoacidosis

Additional testing (Table 1) confirms he has a high serum ketone level and acidosis with a high anion gap, consistent with diabetic ketoacidosis. Blood cultures are negative. He is admitted to the hospital and treated with intravenous fluids and an insulin drip at 6 units/hour. Within 48 hours his anion gap normalizes, and he is discharged on a regimen of insulin glargine (Lantus) and insulin lispro (Humalog). A fasting C-peptide level drawn 7 days after his presentation is 1.9 ng/dL (normal 0.8–3.2 ng/dL).

Diabetic ketoacidosis in ‘atypical diabetes’

Diabetic ketoacidosis is one of the most serious complications of diabetes. Many patients present with nausea, vomiting, and abdominal pain. Dehydration is often present because hyperglycemia leads to glucosuria and volume depletion. Interestingly, our patient showed none of these symptoms or signs.

Diabetic ketoacidosis is increasingly being recognized as a complication in patients with type 2 diabetes mellitus.1–4 Since the mid-1990s, clinicians have become increasingly aware of a condition variably termed “atypical diabetes,” “Flatbush diabetes,” “diabetes type 1B,” and “ketosis-prone type 2 diabetes mellitus,” in which patients, usually obese, present with diabetic ketoacidosis as their first manifestation, but are subsequently found to have type 2 diabetes mellitus. These patients typically are African American or of African, Hispanic, or Caribbean descent.

Ketoacidosis results from transient suppression of beta-cell function, the cause of which is unknown. A recent study comparing patients who have type 2 diabetes mellitus with and without diabetic ketoacidosis presenting with decompensated diabetes suggested insulinopenia was the predominant mechanism.5 For many of these patients, insulinopenia is transient: as the ketoacidosis resolves, betacell function improves and, with adequate insulin, lipolysis is reduced.

 

 

WHAT CAUSES DIABETIC KETOACIDOSIS?

2. Which of the following hormonal changes underlies the development of diabetic ketoacidosis?

  • Insulin resistance
  • Insulin deficiency
  • Glucagon excess
  • Glucagon deficiency
  • Insulin deficiency and glucagon excess
  • Insulin deficiency and glucagon deficiency

Diabetic ketoacidosis can occur when there is too much glucagon and not enough insulin. Insulin lowers the serum glucose level by promoting glucose uptake in peripheral tissues and by inhibiting gluconeogenesis and glycogenolysis in the liver. Insulin is also anabolic: it inhibits lipolysis in adipocytes and thus decreases the amount of substrate for ketogenesis.

Glucagon is the primary counterregulatory hormone responsible for ketogenesis.6 In the presence of glucagon excess, malonyl CoA production decreases, causing unblocking of carnitine acyltransferase I (CAT I) and allowing beta-oxidation to occur.6

Therefore, the sequence initiating ketogenesis begins with a shift in the ratio of glucagon to insulin, so that there is a relative or absolute excess of glucagon and a deficiency of insulin. A deficiency of insulin accelerates lipolysis, providing more substrate for ketogenesis, while excess glucagon turns on the oxidative sequence for fatty acids in the liver.

Three ketone bodies are produced in diabetic ketoacidosis: two ketoacids (beta-hydroxybutyric acid and acetoacetic acid), and one neutral ketone (acetone). The concentration of insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization.7 Diabetic ketoacidosis is uncommon in patients with type 2 diabetes because they typically have enough insulin to inhibit lipolysis (and therefore ketoacid formation) but not enough to promote glucose utilization.

RISK FACTORS FOR DIABETIC KETOACIDOSIS

3. Which of the following is not a risk factor for diabetic ketoacidosis in type 2 diabetes mellitus?

  • Acute illness
  • Age > 65
  • Inadequate insulin doses
  • Antipsychotic drugs
  • Ethnicity

Diabetic ketoacidosis is often precipitated by an acute illness such as an infection, cerebrovascular accident, myocardial infarction, or acute pancreatitis.8–12 These acute illnesses induce stress in the body and elevate counterregulatory hormones.

Inadequate insulin doses can also lead to diabetic ketoacidosis.

Drugs that affect carbohydrate metabolism are also risk factors. These include glucocorticoids, thiazide diuretics in high doses (> 50 mg daily), sympathomimetic agents, and second-generation antipsychotic agents (also called “atypical” antipsychotics) such as clozapine (Clozaril) and olanzapine (Zyprexa), although some are worse than others.13,14

Ketosis-prone type 2 diabetes mellitus is more prevalent in African Americans and Hispanics.8,15,16

Age is not a risk factor for developing diabetic ketoacidosis. In fact, diabetic ketoacidosis is the leading cause of morbidity and death in children with type 1 diabetes and can also occur in children with type 2 diabetes, particularly in obese African American adolescents.2

DISTINGUISHING TYPE 1 FROM TYPE 2

4. Which of the following is most specific in distinguishing type 1 from type 2 diabetes mellitus?

  • C-peptide levels
  • Islet cell antibodies
  • Body mass index
  • Family history
  • Hemoglobin A1c level

Type 1 diabetes is characterized by destruction of pancreatic beta cells, leading to absolute insulin deficiency. The process is usually mediated by autoimmunity; therefore, testing for antibodies to islet cells, glutamic acid decarboxylase, insulin, and tyrosine phosphatase is the most specific way to distinguish type 1 from type 2 diabetes mellitus.

The hemoglobin A1c level correlates with the mean blood glucose level over the previous 8 to 12 weeks. The hemoglobin A1c is typically elevated in both type 1 and type 2 diabetes mellitus and therefore is not a useful distinguishing feature.

C-peptide is made when proinsulin is cleaved into insulin and C-peptide. It is released from endocytic vesicles with insulin in a one-to-one molar ratio. Thus, the level of C-peptide in the blood can show how much insulin is being made by the pancreas. C-peptide levels can help distinguish between type 1 and type 2 diabetes mellitus later in the course of the disease (levels are usually lower in a patient with type 1 diabetes), but they are not as useful early on because they can be normal early in the course of type 1 diabetes.17

A family history of diabetes is more common in type 2 diabetes, but patients with either type 1 or type 2 can have an affected close relative.

Patients with type 2 diabetes are generally overweight, with a body mass index greater than the 85th percentile for their age and sex. In contrast, patients with type 1 diabetes are usually not overweight and often have a recent history of weight loss. There are exceptions, however, and some patients with type 1 diabetes have an elevated body mass index, while some patients with type 2 diabetes are thin.

Although individually, C-peptide, family history, and body mass index are not very specific in distinguishing type 1 from type 2 diabetes mellitus, together they often give the clinician a good idea of the type of diabetes the patient has. In our case, although islet cell antibodies were not drawn, the normal C-peptide level, high body mass index, and family history all support a diagnosis of type 2 diabetes mellitus.

 

 

THE PATIENT CONTINUES TO DO WELL

The patient is discharged from the hospital on an insulin regimen. His blood sugar levels are closely monitored and remain near normal. Six months after the episode of diabetic ketoacidosis, his insulin is discontinued.

TAKE-HOME POINTS

Diabetic ketoacidosis is not unique to type 1 diabetes mellitus. It can occur in type 2, more commonly in patients who are nonwhite and who have precipitating factors such as acute illness, inadequate insulin treatment, or newly diagnosed diabetes. Clinicians should be aware of the possibility of diabetic ketoacidosis even in patients with type 2 diabetes who may not have these risk factors.

One approach to recognizing diabetic ketoacidosis better in patients with type 2 diabetes mellitus would include checking urine for ketones and serum electrolytes for high anion gap acidosis when patients with type 2 diabetes present with uncontrolled blood sugar levels. If ketonuria or acidosis is present, serum ketone and beta-hydroxybutyrate levels should be obtained to evaluate for diabetic ketoacidosis.

Patients should take insulin for an indeterminate period of time after initial treatment of diabetic ketoacidosis. As our case illustrates, in many cases, beta-cell function will return sufficiently to allow insulin to be discontinued. There are no clear guidelines for how long to continue insulin, but most practitioners continue it for weeks to months and discontinue it when glucose levels are stable and remain so with tapering doses. Sometimes oral agents need to be added as insulin is tapered.

Insulin therapy is tailored to the individual patient on the basis of blood glucose values. There are no data on which type of insulin is the most effective, and there are no data on whether these patients are at greater risk of hypoglycemia than other patients taking insulin. In general, there is no evidence that “prophylactic” insulin (ie, giving insulin to prevent diabetic ketoacidosis during times of illness or stress) is required. However, blood glucose monitoring is appropriate during infection or stress, and if hyperglycemia occurs in these situations, insulin use is prudent to reduce the risks of recurrent diabetic ketoacidosis.

References
  1. Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes 1995; 44:790–795.
  2. Valabhji J, Watson M, Cox J, Poulter C, Elwig C, Elkeles RS. Type 2 diabetes presenting as diabetic ketacidosis in adolescence. Diabet Med 2003; 20:416–417.
  3. Westphal SA. The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults. Am J Med 1996; 101:19–24.
  4. Welch B, Zib I. Case study: diabetic ketoacidosis in type 2 diabetes: “look under the sheets.” Clin Diabetes 2004; 22:198–200.
  5. Linfoot P, Bergstrom C, Ipp E. Pathophysiology of ketoacidosis in type 2 diabetes mellitus. Diabet Med 2005; 22:1414–1419.
  6. Foster DW, McGarry JD. The regulation of ketogenesis. Ciba Found Symp 1982; 87:120–131.
  7. Zierler KL, Rabinowitz D. Effect of very small concentrations of insulin on forearm metabolism: persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 1964; 43:950–962.
  8. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004; 164:1925–1931.
  9. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med 1997; 157:669–675.
  10. Jabbour SA, Miller JL. Uncontrolled diabetes mellitus. Clin Lab Med 2001; 21:99–110.
  11. Ennis ED, Kreisberg RA. Diabetic ketoacidosis and the hyperglycemic hyperosmolar syndrome. In: Leroith D, Taylor SI, Olefsky JM, editors. Diabetes Mellitus. Lippincott-Raven Publishers; Philadelphia, 1996:276–286.
  12. Case CC, Maldonado M. Diabetic ketoacidosis associated with Metabolife: a report of two cases. Diabetes Obes Metab 2002; 4:402–406.
  13. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. In:DeFronzo RA, Ferrannini E, Keen H, Zimmet P, editors. International Textbook of Diabetes Mellitus, 3rd ed. John Wiley and Sons, Ltd: Chichester, UK, 2004:1101–1119.
  14. Newcomer JW. Second generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19( suppl 1):1–93.
  15. Balasubramanyam A, Zern JW, Hyman DJ, Pavlik V. New profiles of diabetic ketoacidosis: type 1 vs. type 2 diabetes and the effect of ethnicity. Arch Intern Med 1999; 159:2317–2322.
  16. Davis SN, Umpierrez GE. Diabetic ketoacidosis in type 2 diabetes mellitus—pathophsyiology and clinical presentation. Nat Clin Pract Endocrinol Metab 2007; 3:730–731.
  17. Hoogwerf B, Rich S, Barbosa J. Meal-stimulated Cpeptide and insulin antibodies in type I diabetic subjects and their nondiabetic siblings characterized by HLA-DR antigens. Diabetes 1985; 34:440–445.
References
  1. Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS. Diabetic ketoacidosis in obese African-Americans. Diabetes 1995; 44:790–795.
  2. Valabhji J, Watson M, Cox J, Poulter C, Elwig C, Elkeles RS. Type 2 diabetes presenting as diabetic ketacidosis in adolescence. Diabet Med 2003; 20:416–417.
  3. Westphal SA. The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults. Am J Med 1996; 101:19–24.
  4. Welch B, Zib I. Case study: diabetic ketoacidosis in type 2 diabetes: “look under the sheets.” Clin Diabetes 2004; 22:198–200.
  5. Linfoot P, Bergstrom C, Ipp E. Pathophysiology of ketoacidosis in type 2 diabetes mellitus. Diabet Med 2005; 22:1414–1419.
  6. Foster DW, McGarry JD. The regulation of ketogenesis. Ciba Found Symp 1982; 87:120–131.
  7. Zierler KL, Rabinowitz D. Effect of very small concentrations of insulin on forearm metabolism: persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest 1964; 43:950–962.
  8. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004; 164:1925–1931.
  9. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med 1997; 157:669–675.
  10. Jabbour SA, Miller JL. Uncontrolled diabetes mellitus. Clin Lab Med 2001; 21:99–110.
  11. Ennis ED, Kreisberg RA. Diabetic ketoacidosis and the hyperglycemic hyperosmolar syndrome. In: Leroith D, Taylor SI, Olefsky JM, editors. Diabetes Mellitus. Lippincott-Raven Publishers; Philadelphia, 1996:276–286.
  12. Case CC, Maldonado M. Diabetic ketoacidosis associated with Metabolife: a report of two cases. Diabetes Obes Metab 2002; 4:402–406.
  13. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. In:DeFronzo RA, Ferrannini E, Keen H, Zimmet P, editors. International Textbook of Diabetes Mellitus, 3rd ed. John Wiley and Sons, Ltd: Chichester, UK, 2004:1101–1119.
  14. Newcomer JW. Second generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19( suppl 1):1–93.
  15. Balasubramanyam A, Zern JW, Hyman DJ, Pavlik V. New profiles of diabetic ketoacidosis: type 1 vs. type 2 diabetes and the effect of ethnicity. Arch Intern Med 1999; 159:2317–2322.
  16. Davis SN, Umpierrez GE. Diabetic ketoacidosis in type 2 diabetes mellitus—pathophsyiology and clinical presentation. Nat Clin Pract Endocrinol Metab 2007; 3:730–731.
  17. Hoogwerf B, Rich S, Barbosa J. Meal-stimulated Cpeptide and insulin antibodies in type I diabetic subjects and their nondiabetic siblings characterized by HLA-DR antigens. Diabetes 1985; 34:440–445.
Issue
Cleveland Clinic Journal of Medicine - 76(7)
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Cleveland Clinic Journal of Medicine - 76(7)
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Type 2 Diabetes ICYMI
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A 48-year-old man with uncontrolled diabetes
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Painful eye with a facial rash

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Article
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Display Headline
Painful eye with a facial rash
Author(s)
Jose Luis Vallejo-Garcia, MD
Sergio Vañó-Galván, MD
Omar Rayward, MD
Paula Moreno-Martin, MD, SE

A 75-year-old man presents 4 days after painful cutaneous lesions appeared on the left side of his face, associated with severe ocular pain. Two days before the eruption, he had had an intense headache, which was diagnosed as a tension headache and was treated with oral acetaminophen (Tylenol), but with no improvement.

Figure 1. Typical vesicular rash affects the first trigeminal branch dermatome without trespassing the midline.
He has a history of hypertension and hyperuricemia. No recent changes have been made in his medications. Physical examination shows grouped herpetiform vesicles on an erythematous base confined to the cutaneous surface and innervated by the left first trigeminal branch (Figure 1). Palpation detects regional preauricular and submaxillary lymphadenopathies.

Figure 2. Typical corneal fluorescein stain of dendritic keratitis under cobalt blue light.
Ophthalmologic examination with fluorescein stain shows moderate perilimbal injection and dendritic keratitis (Figure 2).

The remainder of his physical examination is normal. Laboratory tests, including red and white blood cell counts, hemoglobin, and basic metabolic and coagulation tests reveal no abnormalities.

Q: What is your diagnosis?

  • Allergic contact dermatitis
  • Herpes simplex
  • Varicella
  • Ramsay-Hunt syndrome
  • Herpes zoster ophthalmicus and herpetic keratitis

A: Herpes zoster ophthalmicus is the correct diagnosis. It represents a reactivation of the varicella zoster virus.1

Varicella zoster virus, like others of the herpes family, has developed a complex control of virus-host interactions to ensure its survival in humans. It lies dormant in the sensory ganglia and, when reactivated, moves down the neurons and satellite cells along the sensory axons to the skin.1 The reactivation is related to diminished cell-mediated immunity, which occurs as a physiologic part of aging, which is why the elderly tend to be the most often affected. 2 The incidence of herpes zoster varies from 2.2 to 3.4 per 1,000 people per year.3 Its incidence in people over age 80 is about 10 per 1,000 people per year.3

CLINICAL PRESENTATION

Herpes zoster typically presents as a dermatome-grouped vesicular eruption over an erythematous base, accompanied or preceded by local pain. It has two main complications, postherpetic neuralgia and ocular involvement. Postherpetic neuralgia is neuropathic pain that persists or develops after the dermatomal rash has healed.4 Independent predictors of postherpetic neuralgia are older age, severe acute pain, severe rash, a shorter duration of rash before consultation, and ocular involvement.5 It occurs in 36.6% of patients over age 60, and in 47.5% over 70.6 Persistent postherpetic neuralgia has been linked to suicide in patients over 70.7

Ocular infection occurs with involvement of the ophthalmic division of the fifth cranial nerve. Before the antiviral era, it was seen in as many as 50% of patients.8 Hutchinson’s sign is skin lesions on the tip, side, or root of the nose and is an important predictor of ocular involvement.1 Lesions may include folliculopapillar conjunctivitis, episcleritis, scleritis, keratitis (dendritic, pseudodendritic, and interstitial), uveitis, and necrotizing retinitis.

 

 

DIAGNOSIS

The diagnosis of herpes zoster is usually based on clinical observation of the characteristic rash, although viral culture and molecular techniques are available when definitive diagnosis is required. When ophthalmic division is affected and Hutchinson’s sign, unexplained ocular redness with pain, or complaints of visual problems are present, the patient should be referred promptly to an ophthalmologist, because serious visual impairment can occur. The fluorescein dye may show no staining or the typical dendritic keratitis (Figure 2).

TREATMENT

Oral antiviral drugs have made the treatment of zoster possible when, effectively, no treatment existed before. Ideally, an antiviral should be given within 72 hours of symptom onset. Starting treatment as early as possible—especially within 72 hours of onset—has been shown to be effective in alleviating acute pain and in preventing or limiting the duration and severity of postherpetic neuralgia.3

Acyclovir (Zovirax) 800 mg five times a day for 7 days or one of its derivatives—eg, famciclovir (Famvir), penciclovir (Denavir), or valacyclovir (Valtrex)—has been shown to be safe and effective in the treatment of active disease, as well as in preventing or shortening the duration of postherpetic neuralgia.3 It has also been shown to reduce the rate of eye involvement from 50% to 20% or 30%.9 This is why all patients with this dermatomal involvement must be treated.

Second-generation antivirals

Valacyclovir 1,000 mg three times a day and famciclovir 500 mg three times a day seem to be as effective as acyclovir in reducing zoster-associated pain, but their efficacy in reducing eye involvement has not been studied. In clinical practice, however, these second-generation antivirals may be more effective than acyclovir because patients are more likely to comply with the treatment regimen of three rather than five daily doses.

Other considerations

In patients with kidney failure, the non-nephrotoxic antiviral brivudine is preferred, but it is not available in the United States. Therefore, one must use acyclovir or one of the other drugs, carefully adjusting the dose according to the creatinine clearance and making sure the patient is well hydrated.

The efficacy of antiviral treatment that is started more than 72 hours after the onset of skin rash has never been confirmed.

Although the additional effectiveness of acyclovir eye ointment has never been established, topical acyclovir can be considered in cases of dendritic or pseudodendritic keratitis.

References
  1. Liesegang TJ. Herpes zoster ophthalmicus: natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115( suppl 2):S3–S12.
  2. Opstelten W, Eekhof J, Neven AK, Verheij T. Treatment of herpes zoster. Can Fam Physician 2008; 54:373–377.
  3. Opstelten W, Zaal MJ. Managing ophthalmic herpes zoster in primary care. BMJ 2005; 331:147–151.
  4. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995; 155:1605–1609.
  5. Opstelten W, Zuithoff NP, van Essen GA, et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study. Pain 2007; 132( suppl 1):S52–S59.
  6. De Morgas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm 1957; 75:193–196.
  7. Hess TM, Lutz LJ, Nauss LA, Lamer TJ. Treatment of acute herpetic neuralgia. A case report and review of the literature. Minn Med 1990; 73:37–40.
  8. Harding SP, Lipton JR, Wells JC. Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987; 71:353–358.
  9. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986; 93:763–770.
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Author and Disclosure Information

José Luis Vallejo-García, MD
Department of Ophthalmology, Hospital Universitario La Paz, Madrid, Spain

Sergio Vañó-Galván, MD
Department of Dermatology, Ramón y Cajal Hospital, University of Alcalá, Madrid, Spain

Omar Rayward, MD
Department of Ophthalmology, Hospital Universitario Clínico San Carlos, Madrid, Spain

Paula Moreno-Martin, MD
Department of Ophthalmology, La Princesa University Hospital, Madrid, Spain

Address: José Luis Vallejo-García, MD, Paseo de la Castellana Nº 261, 28046 Madrid, Spain; e-mail [email protected]

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Cleveland Clinic Journal of Medicine - 76(7)
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Neurology
Pain
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410-412
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The Clinical Picture
Author(s)
Jose Luis Vallejo-Garcia, MD
Sergio Vañó-Galván, MD
Omar Rayward, MD
Paula Moreno-Martin, MD, SE
Author(s)
Jose Luis Vallejo-Garcia, MD
Sergio Vañó-Galván, MD
Omar Rayward, MD
Paula Moreno-Martin, MD, SE
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José Luis Vallejo-García, MD
Department of Ophthalmology, Hospital Universitario La Paz, Madrid, Spain

Sergio Vañó-Galván, MD
Department of Dermatology, Ramón y Cajal Hospital, University of Alcalá, Madrid, Spain

Omar Rayward, MD
Department of Ophthalmology, Hospital Universitario Clínico San Carlos, Madrid, Spain

Paula Moreno-Martin, MD
Department of Ophthalmology, La Princesa University Hospital, Madrid, Spain

Address: José Luis Vallejo-García, MD, Paseo de la Castellana Nº 261, 28046 Madrid, Spain; e-mail [email protected]

Author and Disclosure Information

José Luis Vallejo-García, MD
Department of Ophthalmology, Hospital Universitario La Paz, Madrid, Spain

Sergio Vañó-Galván, MD
Department of Dermatology, Ramón y Cajal Hospital, University of Alcalá, Madrid, Spain

Omar Rayward, MD
Department of Ophthalmology, Hospital Universitario Clínico San Carlos, Madrid, Spain

Paula Moreno-Martin, MD
Department of Ophthalmology, La Princesa University Hospital, Madrid, Spain

Address: José Luis Vallejo-García, MD, Paseo de la Castellana Nº 261, 28046 Madrid, Spain; e-mail [email protected]

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A 75-year-old man presents 4 days after painful cutaneous lesions appeared on the left side of his face, associated with severe ocular pain. Two days before the eruption, he had had an intense headache, which was diagnosed as a tension headache and was treated with oral acetaminophen (Tylenol), but with no improvement.

Figure 1. Typical vesicular rash affects the first trigeminal branch dermatome without trespassing the midline.
He has a history of hypertension and hyperuricemia. No recent changes have been made in his medications. Physical examination shows grouped herpetiform vesicles on an erythematous base confined to the cutaneous surface and innervated by the left first trigeminal branch (Figure 1). Palpation detects regional preauricular and submaxillary lymphadenopathies.

Figure 2. Typical corneal fluorescein stain of dendritic keratitis under cobalt blue light.
Ophthalmologic examination with fluorescein stain shows moderate perilimbal injection and dendritic keratitis (Figure 2).

The remainder of his physical examination is normal. Laboratory tests, including red and white blood cell counts, hemoglobin, and basic metabolic and coagulation tests reveal no abnormalities.

Q: What is your diagnosis?

  • Allergic contact dermatitis
  • Herpes simplex
  • Varicella
  • Ramsay-Hunt syndrome
  • Herpes zoster ophthalmicus and herpetic keratitis

A: Herpes zoster ophthalmicus is the correct diagnosis. It represents a reactivation of the varicella zoster virus.1

Varicella zoster virus, like others of the herpes family, has developed a complex control of virus-host interactions to ensure its survival in humans. It lies dormant in the sensory ganglia and, when reactivated, moves down the neurons and satellite cells along the sensory axons to the skin.1 The reactivation is related to diminished cell-mediated immunity, which occurs as a physiologic part of aging, which is why the elderly tend to be the most often affected. 2 The incidence of herpes zoster varies from 2.2 to 3.4 per 1,000 people per year.3 Its incidence in people over age 80 is about 10 per 1,000 people per year.3

CLINICAL PRESENTATION

Herpes zoster typically presents as a dermatome-grouped vesicular eruption over an erythematous base, accompanied or preceded by local pain. It has two main complications, postherpetic neuralgia and ocular involvement. Postherpetic neuralgia is neuropathic pain that persists or develops after the dermatomal rash has healed.4 Independent predictors of postherpetic neuralgia are older age, severe acute pain, severe rash, a shorter duration of rash before consultation, and ocular involvement.5 It occurs in 36.6% of patients over age 60, and in 47.5% over 70.6 Persistent postherpetic neuralgia has been linked to suicide in patients over 70.7

Ocular infection occurs with involvement of the ophthalmic division of the fifth cranial nerve. Before the antiviral era, it was seen in as many as 50% of patients.8 Hutchinson’s sign is skin lesions on the tip, side, or root of the nose and is an important predictor of ocular involvement.1 Lesions may include folliculopapillar conjunctivitis, episcleritis, scleritis, keratitis (dendritic, pseudodendritic, and interstitial), uveitis, and necrotizing retinitis.

 

 

DIAGNOSIS

The diagnosis of herpes zoster is usually based on clinical observation of the characteristic rash, although viral culture and molecular techniques are available when definitive diagnosis is required. When ophthalmic division is affected and Hutchinson’s sign, unexplained ocular redness with pain, or complaints of visual problems are present, the patient should be referred promptly to an ophthalmologist, because serious visual impairment can occur. The fluorescein dye may show no staining or the typical dendritic keratitis (Figure 2).

TREATMENT

Oral antiviral drugs have made the treatment of zoster possible when, effectively, no treatment existed before. Ideally, an antiviral should be given within 72 hours of symptom onset. Starting treatment as early as possible—especially within 72 hours of onset—has been shown to be effective in alleviating acute pain and in preventing or limiting the duration and severity of postherpetic neuralgia.3

Acyclovir (Zovirax) 800 mg five times a day for 7 days or one of its derivatives—eg, famciclovir (Famvir), penciclovir (Denavir), or valacyclovir (Valtrex)—has been shown to be safe and effective in the treatment of active disease, as well as in preventing or shortening the duration of postherpetic neuralgia.3 It has also been shown to reduce the rate of eye involvement from 50% to 20% or 30%.9 This is why all patients with this dermatomal involvement must be treated.

Second-generation antivirals

Valacyclovir 1,000 mg three times a day and famciclovir 500 mg three times a day seem to be as effective as acyclovir in reducing zoster-associated pain, but their efficacy in reducing eye involvement has not been studied. In clinical practice, however, these second-generation antivirals may be more effective than acyclovir because patients are more likely to comply with the treatment regimen of three rather than five daily doses.

Other considerations

In patients with kidney failure, the non-nephrotoxic antiviral brivudine is preferred, but it is not available in the United States. Therefore, one must use acyclovir or one of the other drugs, carefully adjusting the dose according to the creatinine clearance and making sure the patient is well hydrated.

The efficacy of antiviral treatment that is started more than 72 hours after the onset of skin rash has never been confirmed.

Although the additional effectiveness of acyclovir eye ointment has never been established, topical acyclovir can be considered in cases of dendritic or pseudodendritic keratitis.

A 75-year-old man presents 4 days after painful cutaneous lesions appeared on the left side of his face, associated with severe ocular pain. Two days before the eruption, he had had an intense headache, which was diagnosed as a tension headache and was treated with oral acetaminophen (Tylenol), but with no improvement.

Figure 1. Typical vesicular rash affects the first trigeminal branch dermatome without trespassing the midline.
He has a history of hypertension and hyperuricemia. No recent changes have been made in his medications. Physical examination shows grouped herpetiform vesicles on an erythematous base confined to the cutaneous surface and innervated by the left first trigeminal branch (Figure 1). Palpation detects regional preauricular and submaxillary lymphadenopathies.

Figure 2. Typical corneal fluorescein stain of dendritic keratitis under cobalt blue light.
Ophthalmologic examination with fluorescein stain shows moderate perilimbal injection and dendritic keratitis (Figure 2).

The remainder of his physical examination is normal. Laboratory tests, including red and white blood cell counts, hemoglobin, and basic metabolic and coagulation tests reveal no abnormalities.

Q: What is your diagnosis?

  • Allergic contact dermatitis
  • Herpes simplex
  • Varicella
  • Ramsay-Hunt syndrome
  • Herpes zoster ophthalmicus and herpetic keratitis

A: Herpes zoster ophthalmicus is the correct diagnosis. It represents a reactivation of the varicella zoster virus.1

Varicella zoster virus, like others of the herpes family, has developed a complex control of virus-host interactions to ensure its survival in humans. It lies dormant in the sensory ganglia and, when reactivated, moves down the neurons and satellite cells along the sensory axons to the skin.1 The reactivation is related to diminished cell-mediated immunity, which occurs as a physiologic part of aging, which is why the elderly tend to be the most often affected. 2 The incidence of herpes zoster varies from 2.2 to 3.4 per 1,000 people per year.3 Its incidence in people over age 80 is about 10 per 1,000 people per year.3

CLINICAL PRESENTATION

Herpes zoster typically presents as a dermatome-grouped vesicular eruption over an erythematous base, accompanied or preceded by local pain. It has two main complications, postherpetic neuralgia and ocular involvement. Postherpetic neuralgia is neuropathic pain that persists or develops after the dermatomal rash has healed.4 Independent predictors of postherpetic neuralgia are older age, severe acute pain, severe rash, a shorter duration of rash before consultation, and ocular involvement.5 It occurs in 36.6% of patients over age 60, and in 47.5% over 70.6 Persistent postherpetic neuralgia has been linked to suicide in patients over 70.7

Ocular infection occurs with involvement of the ophthalmic division of the fifth cranial nerve. Before the antiviral era, it was seen in as many as 50% of patients.8 Hutchinson’s sign is skin lesions on the tip, side, or root of the nose and is an important predictor of ocular involvement.1 Lesions may include folliculopapillar conjunctivitis, episcleritis, scleritis, keratitis (dendritic, pseudodendritic, and interstitial), uveitis, and necrotizing retinitis.

 

 

DIAGNOSIS

The diagnosis of herpes zoster is usually based on clinical observation of the characteristic rash, although viral culture and molecular techniques are available when definitive diagnosis is required. When ophthalmic division is affected and Hutchinson’s sign, unexplained ocular redness with pain, or complaints of visual problems are present, the patient should be referred promptly to an ophthalmologist, because serious visual impairment can occur. The fluorescein dye may show no staining or the typical dendritic keratitis (Figure 2).

TREATMENT

Oral antiviral drugs have made the treatment of zoster possible when, effectively, no treatment existed before. Ideally, an antiviral should be given within 72 hours of symptom onset. Starting treatment as early as possible—especially within 72 hours of onset—has been shown to be effective in alleviating acute pain and in preventing or limiting the duration and severity of postherpetic neuralgia.3

Acyclovir (Zovirax) 800 mg five times a day for 7 days or one of its derivatives—eg, famciclovir (Famvir), penciclovir (Denavir), or valacyclovir (Valtrex)—has been shown to be safe and effective in the treatment of active disease, as well as in preventing or shortening the duration of postherpetic neuralgia.3 It has also been shown to reduce the rate of eye involvement from 50% to 20% or 30%.9 This is why all patients with this dermatomal involvement must be treated.

Second-generation antivirals

Valacyclovir 1,000 mg three times a day and famciclovir 500 mg three times a day seem to be as effective as acyclovir in reducing zoster-associated pain, but their efficacy in reducing eye involvement has not been studied. In clinical practice, however, these second-generation antivirals may be more effective than acyclovir because patients are more likely to comply with the treatment regimen of three rather than five daily doses.

Other considerations

In patients with kidney failure, the non-nephrotoxic antiviral brivudine is preferred, but it is not available in the United States. Therefore, one must use acyclovir or one of the other drugs, carefully adjusting the dose according to the creatinine clearance and making sure the patient is well hydrated.

The efficacy of antiviral treatment that is started more than 72 hours after the onset of skin rash has never been confirmed.

Although the additional effectiveness of acyclovir eye ointment has never been established, topical acyclovir can be considered in cases of dendritic or pseudodendritic keratitis.

References
  1. Liesegang TJ. Herpes zoster ophthalmicus: natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115( suppl 2):S3–S12.
  2. Opstelten W, Eekhof J, Neven AK, Verheij T. Treatment of herpes zoster. Can Fam Physician 2008; 54:373–377.
  3. Opstelten W, Zaal MJ. Managing ophthalmic herpes zoster in primary care. BMJ 2005; 331:147–151.
  4. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995; 155:1605–1609.
  5. Opstelten W, Zuithoff NP, van Essen GA, et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study. Pain 2007; 132( suppl 1):S52–S59.
  6. De Morgas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm 1957; 75:193–196.
  7. Hess TM, Lutz LJ, Nauss LA, Lamer TJ. Treatment of acute herpetic neuralgia. A case report and review of the literature. Minn Med 1990; 73:37–40.
  8. Harding SP, Lipton JR, Wells JC. Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987; 71:353–358.
  9. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986; 93:763–770.
References
  1. Liesegang TJ. Herpes zoster ophthalmicus: natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115( suppl 2):S3–S12.
  2. Opstelten W, Eekhof J, Neven AK, Verheij T. Treatment of herpes zoster. Can Fam Physician 2008; 54:373–377.
  3. Opstelten W, Zaal MJ. Managing ophthalmic herpes zoster in primary care. BMJ 2005; 331:147–151.
  4. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995; 155:1605–1609.
  5. Opstelten W, Zuithoff NP, van Essen GA, et al. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study. Pain 2007; 132( suppl 1):S52–S59.
  6. De Morgas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm 1957; 75:193–196.
  7. Hess TM, Lutz LJ, Nauss LA, Lamer TJ. Treatment of acute herpetic neuralgia. A case report and review of the literature. Minn Med 1990; 73:37–40.
  8. Harding SP, Lipton JR, Wells JC. Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement. Br J Ophthalmol 1987; 71:353–358.
  9. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986; 93:763–770.
Issue
Cleveland Clinic Journal of Medicine - 76(7)
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Cleveland Clinic Journal of Medicine - 76(7)
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410-412
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Cleveland Clinic Journal of Medicine
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Black esophagus

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Article
Changed
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Display Headline
Black esophagus
Author(s)
Sudha Akkinepally, MD
Vijayarama Poreddy, MD
Alejandro Moreno, MD, MPH

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

Figure 1.
At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

Figure 2.
This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.1 Complications include stricture, perforation, and death.1,3 The death rate is about 30% in these patients.3

 

 

References
  1. Khan AM, Hundal R, Ramaswamy V, Korsten M, Dhuper S. Acute esophageal necrosis and liver pathology, a rare combination. World J Gastroenterol 2004; 10:2457–2458.
  2. Le K, Ahmed A. Acute necrotizing esophagitis: case report and review of the literature. J La State Med Soc 2007; 159:330,333–338.
  3. Katsinelos P, Pilpilidis I, Dimiropoulos S, et al. Black esophagus induced by severe vomiting in a healthy young man. Surg Endosc 2003; 17:521.
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Sudha Akkinepally, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Vijayarama Poreddy, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Austin Programs, Austin, TX

Alejandro Moreno, MD, MPH
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Address: Sudha Akkinepally, MD, University Medical Center at Brackenridge, 601 East 15th Street, Annex Building, Internal Medicine, Austin, TX, 78701; e-mail [email protected]

Issue
Cleveland Clinic Journal of Medicine - 76(7)
Publications
Cleveland Clinic Journal of Medicine
Topics
Gastroenterology
Page Number
400
Sections
The Clinical Picture
Author(s)
Sudha Akkinepally, MD
Vijayarama Poreddy, MD
Alejandro Moreno, MD, MPH
Author(s)
Sudha Akkinepally, MD
Vijayarama Poreddy, MD
Alejandro Moreno, MD, MPH
Author and Disclosure Information

Sudha Akkinepally, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Vijayarama Poreddy, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Austin Programs, Austin, TX

Alejandro Moreno, MD, MPH
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Address: Sudha Akkinepally, MD, University Medical Center at Brackenridge, 601 East 15th Street, Annex Building, Internal Medicine, Austin, TX, 78701; e-mail [email protected]

Author and Disclosure Information

Sudha Akkinepally, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Vijayarama Poreddy, MD
University Medical Center at Brackenridge, and Department of Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Austin Programs, Austin, TX

Alejandro Moreno, MD, MPH
University Medical Center at Brackenridge, and Department of Internal Medicine, University of Texas Medical Branch, Austin Programs, Austin, TX

Address: Sudha Akkinepally, MD, University Medical Center at Brackenridge, 601 East 15th Street, Annex Building, Internal Medicine, Austin, TX, 78701; e-mail [email protected]

Article PDF
media_26a2f4b_400.pdf
Article PDF
media_26a2f4b_400.pdf

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

Figure 1.
At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

Figure 2.
This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.1 Complications include stricture, perforation, and death.1,3 The death rate is about 30% in these patients.3

 

 

A 60-year-old man with a history of alcoholic cirrhosis and gastrointestinal bleeding was admitted after being found unconscious. He had coffee-ground emesis and melena.

Figure 1.
At the time of the physical examination, he was intubated and was unresponsive and hypotensive. On endoscopy, the upper half of the esophagus was normal (Figure 1), but the lower half showed signs of necrosis: the mucosa was black and covered by an exudate of the same color (Figure 2). Endoscopy also found signs of severe portal hypertensive gastropathy and multiple small ischemic ulcers in the distal duodenum. No biopsy was done because of the risk of bleeding due to coagulopathy. The patient died of hepatorenal syndrome and sepsis.

ASSOCIATED CONDITIONS

Figure 2.
This patient had alcoholic cirrhosis and hypotension, which are significant comorbidities associated with necrotic (“black”) esophagus. Other conditions associated with black esophagus are gastric outlet obstruction, myocardial ischemia, hypersensitivity to antibiotics, certain viral infections, ketoacidosis, alcoholic hepatitis, acute renal failure, severe acid reflux, and acute pancreatitis.1,2 The differential diagnosis includes melanosis, malignant melanoma, pseudomelanosis, acanthosis nigrans, adverse drug effects (quinidine and tetracycline), and infection (Candida and herpes).1,3

TREATMENT AND COURSE

The treatment is mainly supportive, with intravenous fluids, proton pump inhibitors, and nothing taken orally.1 Complications include stricture, perforation, and death.1,3 The death rate is about 30% in these patients.3

 

 

References
  1. Khan AM, Hundal R, Ramaswamy V, Korsten M, Dhuper S. Acute esophageal necrosis and liver pathology, a rare combination. World J Gastroenterol 2004; 10:2457–2458.
  2. Le K, Ahmed A. Acute necrotizing esophagitis: case report and review of the literature. J La State Med Soc 2007; 159:330,333–338.
  3. Katsinelos P, Pilpilidis I, Dimiropoulos S, et al. Black esophagus induced by severe vomiting in a healthy young man. Surg Endosc 2003; 17:521.
References
  1. Khan AM, Hundal R, Ramaswamy V, Korsten M, Dhuper S. Acute esophageal necrosis and liver pathology, a rare combination. World J Gastroenterol 2004; 10:2457–2458.
  2. Le K, Ahmed A. Acute necrotizing esophagitis: case report and review of the literature. J La State Med Soc 2007; 159:330,333–338.
  3. Katsinelos P, Pilpilidis I, Dimiropoulos S, et al. Black esophagus induced by severe vomiting in a healthy young man. Surg Endosc 2003; 17:521.
Issue
Cleveland Clinic Journal of Medicine - 76(7)
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Cleveland Clinic Journal of Medicine - 76(7)
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400
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Cleveland Clinic Journal of Medicine
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Cleveland Clinic Journal of Medicine
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Back pain made simple: An approach based on principles and evidence

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Back pain made simple: An approach based on principles and evidence
Author(s)
Samir D. Bhangle, MD
Sunil Sapru, MD
Richard S. Panush, MD, MACP, MACR

Low back pain should be understood as a remittent, intermittent predicament of life. Its cause is indeterminate, but its course is predictable. Its link to work-related injury is tenuous and confounded by psychosocial issues, including workers’ compensation. It challenges function, compromises performance, and calls for empathy and understanding.1

In this brief paper, we offer a simple approach to one of the most common human afflictions, based on principles and evidence.

WHY IS BACK PAIN IMPORTANT?

Low back pain is common and affects people of all ages. It is second only to the common cold as the most common affliction of mankind, and it is among the leading complaints bringing patients to physicians’ offices. Its lifetime prevalence exceeds 70% in most industrialized countries, with an annual incidence of 15% to 20% in the United States.

Its social and economic impact is substantial. It is the most frequent cause of disability for people under age 45. In 2005, the mean age- and sex-adjusted medical expenditure among respondents with spine problems was $6,096 vs $3,516 in those without spine problems, and it had increased by 65% (adjusted for inflation) from 1997 to 2005.2

WHAT ARE THE GOALS AND PRINCIPLES OF MANAGING LOW BACK PAIN?

The goals of management for patients with low back pain are to:

  • Decrease the pain
  • Restore mobility
  • Hasten recovery so the patient can resume normal daily activities as soon as possible
  • Prevent development of a chronic recurrent condition: low back pain is considered acute when it persists for less than 6 weeks, subacute between 6 weeks and 3 months, and chronic when it lasts longer than 3 months
  • Restore and preserve physical and financial independence and comfort.

Principles of management

  • Most back pain has no recognizable cause and is therefore termed “mechanical” or “musculoskeletal.”
  • Underlying systemic disease is rare.
  • Most episodes of back pain are unpreventable.
  • Confounding psychosocial issues are often contributory, important, and relevant.
  • A careful, informed history and physical examination are invaluable; diagnostic studies, however technologically sophisticated, are never a substitute.
  • Defer diagnostic studies for specific indications.
  • Refer patients only if they have underlying disease or progressive neurologic dysfunction, or if they do not respond to conservative management.
  • Encouragement of activity is benign and perhaps salutary for back pain and is desirable for general physical and mental health; there is only scant evidence to support bed rest.3
  • Few if any treatments have been proven effective for low back pain.
  • Talking to the patient and explaining the issues involved are critical to successful management.4

INITIAL CONSIDERATIONS WHEN EVALUATING A PATIENT

When encountering a patient with back pain, the initial consideration is whether the symptoms are regional—ie, local, mechanical, and musculoskeletal—or if they reflect a systemic disease. It is also important to look for evidence of social or psychological distress that may amplify, prolong, or confound the pain or the patient’s perception of it.

What are the clues to a systemic process?

Red flags of a serious, systemic cause of low back pain are presented in Table 1. Other symptoms that may indicate a systemic cause include night pain (also seen with disk disease and neurocompression), pain with recumbency (malignancy), back pain with morning stiffness lasting for more than 1 hour (spondyloarthropathy), cauda equina syndrome (overflow incontinence, saddle anesthesia, and paraparesis), and other systemic and constitutional symptoms.

Does the patient have a regional low back syndrome?

Regional low back syndromes account for 90% of the causes of low back pain. They are usually mechanical in origin.

Regional back pain is due to overuse of a normal mechanical structure (muscle strain, “lumbago”) or is secondary to trauma, deformity, or degeneration of an anatomical structure (herniated nucleus pulposus, fracture, and spondyloarthropathy, including facet joint arthritis). Chronic regional back syndromes include osteoarthritis of the spine (ie, spondylosis), spinal stenosis, and facet joint arthropathy.

Characteristically, mechanical disorders are exacerbated by certain physical activities, such as lifting, and are relieved by others, such as assuming a supine position.

 

 

Does the patient have sciatica or another nerve root compression syndrome?

The obvious manifestation of nerve root irritation is usually sciatica, a sharp or burning pain radiating down the posterior or lateral aspect of the leg usually to the foot or the ankle and often associated with numbness or paresthesias. The pain is sometimes aggravated by coughing, sneezing, or the Valsalva maneuver. It is most commonly seen in lumbar disk herniation, cauda equina syndrome, and spinal stenosis.

Might the patient have spinal stenosis?

More than 20% of people over age 60 have radiographic evidence of lumbar spinal canal stenosis, even if they have no symptoms.5 For this reason, the diagnosis of spinal stenosis as a cause of low back pain must be based on the history and physical examination.

The classic history of spinal stenosis is that of neurogenic claudication (“pseudoclaudication”), which is pain that occurs in the legs after walking or prolonged standing and is relieved with sitting. It may sometimes be associated with a varying and transient neurologic deficit. Lumbar flexion increases and lumbar extension decreases the cross-sectional area of the spinal canal—hence, the relief of symptoms of spinal stenosis on stooping or bending forward. Pain is commonly perceived in the back, buttock, or thigh and is elicited by prolonged lumbar extension.

On neurologic examination, about 50% of patients with spinal stenosis have a deficit in vibratory sensibility, temperature sensitivity, or muscle strength. The nerve root involved is most commonly L5, followed by S1 and L4.

Many patients have balance disturbance (wide-based gait or Romberg sign), particularly later in the course of the disorder, with normal cerebellar signs (“pseudocerebellar” presentation).

Patients with bilateral hip osteoarthritis may present with similar symptoms of buttock or thigh pain, which can be distinguished with the above clinical examination. Rotation of the hip is painful in osteoarthritis but not in spinal stenosis. If both conditions overlap, injection of a steroid or lidocaine in the painful hip should decrease the pain associated with hip osteoarthritis.

Does the patient have evidence of neurologic compromise?

Assessment of neurologic compromise requires a thorough history for evidence of muscle weakness, gait disturbances, paresthesias, numbness, radicular pain, and bowel or bladder disturbances. The neurologic examination includes testing muscle strength, evaluating sensation and reflexes (Table 2), and analyzing the gait.

Muscle strength is tested by examining the:

  • L2 nerve root (which supplies the iliopsoas muscle and is tested by hip flexion)
  • L3 nerve root (quadriceps, tested by knee extension)
  • L4 nerve root (tibialis anterior, assessed by evaluating ankle dorsiflexion and inversion at the subtalar joint)
  • L5 nerve root (extensor hallucis longus and extensor digitorum longus, tested by asking the patient to dorsiflex the great toe, then the other toes)
  • S1 nerve root (flexor hallucis longus, flexor digitorum longus, and tendoachilles, tested by asking the patient to plantar-flex the great toe, then the other toes, and then the ankle).

The patient is also asked to walk a few steps on the toes and then on the heels. Inability to toe-walk indicates S1 nerve root involvement; inability to heel-walk may indicate L4 or L5 involvement. If the patient cannot heelwalk, ask him or her to squat; inability to do so indicates L4 problems.6

Radiculopathy. Detecting and locating the cause of radiculopathy may be helpful. In L3–L4 disk herniation, there is pain and paresthesia with numbness and hypalgesia in the anteromedial thigh and the knee. In L4–L5 disk herniation, there is usually involvement of the exiting L5 nerve root, which presents as numbness or paresthesias in the anterolateral calf, great toe, first web space, and medial foot. In L5-S1 disk herniation, the S1 nerve root is involved, presenting as numbness and hypalgesia in the fifth toe, lateral aspect of the foot, sole, and posterolateral calf and thigh.

Reflexes. Exaggerated or decreased reflexes do not always indicate a neurologic abnormality, but reflex asymmetry is significant. The knee-jerk reflex is diminished in L3–L4 nerve root involvement, and the ankle-jerk reflex is diminished with S1 nerve root involvement. The Babinski sign indicates pyramidal tract involvement.

Gait. Observe the patient’s gait as he or she rises and moves to the examining table, to determine whether it is shortened, asymmetrical, or antalgic.7 Also note any foot drop, which may indicate a potentially serious problem (L5 radiculopathy).

What is an adequate examination of the back?

A good back examination can elicit important information about the cause and the extent of back pain. It includes inspection, palpation, and range of movement of the spine along with a detailed neurologic examination.

Inspect it for any deformities, scoliosis, asymmetry, paraspinal muscle spasm, unusual hair growth, listing to one side, decrease or increase in lumbar lordosis, or muscle atrophy or fasciculation.

Palpate it for paraspinal muscle spasm, warmth, and localized bone pain.

Move it. The normal ranges of motion of the lumbar spine are 15 degrees of extension, 40 degrees of flexion, 30 degrees of lateral bending, and 40 degrees of lateral rotation to each side.

Assess it. This includes estimating the tone and nutrition of the muscles, testing their strength (Table 2), examining vibratory or proprioception and pinprick sensation in each dermatome (see below), testing the Achilles and patellar reflexes, and looking for the Babinski sign and clonus. In addition, perform the straight-leg-raising and the cross-straightleg-raising tests, which are positive in most patients with lower lumbar disk herniations.

The femoral stretch test is usually positive in upper lumbar disk herniations (L2–L3, L3– L4). It is performed with the patient in the prone position, with the knee being gradually flexed from full extension. Pain radiating along the anterior aspect of the thigh indicates a positive test.

The examination of the spine must be supplemented with examination of the hip and sacroiliac joints, since back pain may be a referred symptom from any pathology affecting these joints.

 

 

When should patients be referred to a specialist?

Patients should be referred to a neurologist, neurosurgeon, orthopedist, or other specialist if they have cauda equina syndrome; severe or progressive neurologic deficits; infections, tumors, or fractures compressing the spinal cord; or, perhaps, no response to conservative therapy for 4 to 6 weeks for patients with a herniated lumbar disk or 8 to 12 weeks for those with spinal stenosis.

If there is profound motor involvement at the time of the initial evaluation, patients must be promptly given systemic corticosteroids such as methylprednisolone (Medrol) or dexamethasone (Decadron) to decrease spinal cord edema.

Are there signs of psychological distress?

Psychosocial factors can significantly affect pain and functional disability in patients who have low back pain.8,9 These are known as “yellow flags” and are better predictors of treatment outcome than physical factors. 10 Anatomically inappropriate signs may be helpful in identifying psychological distress as a result of or as an amplifier of low back symptoms.

Waddell et al11 proposed five categories of these nonorganic signs. These are:

  • Inappropriate tenderness that is superficial or widespread
  • Pain on simulated axial loading by pressing on the top of the head or simulated spine rotation
  • Distraction signs such as inconsistent performance between straight-leg-raising in the seated position vs the supine position
  • Regional disturbances in strength and sensation that do not correspond with nerve root innervation patterns
  • Overreaction during the physical examination.

The occurrence of any one of the signs is of limited value, but positive findings in three of the five categories suggest psychological distress.11

Which diagnostic studies are useful, cost-effective, and supported by evidence?

Since most abnormalities found on imaging studies are nonspecific, such studies are not necessary during the initial evaluation of acute low back pain unless there are red flags that suggest a more ominous source of pain.

Routine plain lumbosacral spine radiographs with anteroposterior and lateral views may be appropriate initially if the patient has risk factors for vertebral fractures (Table 1), or if the patient does not improve after a course of conservative treatment (usually 4–6 weeks).

Magnetic resonance imaging (MRI) is the preferred test if one suspects a tumor, infection, disk pathology, or spinal stenosis.

Computed tomography (CT) shows bony details better than MRI does. Hence, it is preferred when one needs to evaluate bony details (fractures, scoliosis) and when there are contraindications to MRI, as in patients with metal implant devices and those who are claustrophobic (although now there are “open system” MRI machines, in which the feeling of claustrophobia is much less).

MRI and CT should not be ordered routinely, but only for specific indications to answer specific questions, when specific findings would indicate specific treatment.

In most cases, contrast is not needed for CT or MRI to rule out common causes of low back pain, except in cases of suspected intraspinal tumor. Patients with compromised renal function who need contrast for CT need to be hydrated before the scan to lower the risk of contrast-induced nephropathy. These patients are also at higher risk of nephrogenic fibrosing dermopathy when they receive gadolinium contrast for MRI.

Bone scans can be used to look for infections or fractures not noted on plain radiography. However, MRI provides similar or better diagnostic accuracy without radiation.

Electrodiagnostic studies may be used in patients with radiculopathy when clinical examination suggests multilevel root lesions, when symptoms do not match imaging studies, and when patients have breakaway weakness (fluctuating levels of strength in one or more muscle groups).

Other useful diagnostic and laboratory studies may include the erythrocyte sedimentation rate to screen for malignancy and infection when these are suspected, blood culture for osteomyelitis, and bone aspiration and biopsy for histopathologic diagnosis of infection, malignancy, or other lesions.

WHICH TREATMENTS ARE SUPPORTED BY ROBUST EVIDENCE?

The primary treatment of low back pain should be conservative care, reassurance, and education, allowing patients to improve on their own and helping them cope with their predicament.

Limited bed rest. While 2 or 3 days of limited bed rest may help improve symptoms in patients who have acute radiculopathy, several studies have shown that long periods of bed rest are not beneficial for acute or subacute low back pain.12 Encouraging activity modification allows patients with nonspecific back pain or radicular symptoms to remain active while avoiding activities that may aggravate pain and is shown to lead to a more rapid recovery than bed rest.13,14 The most common situations to avoid are prolonged sitting or standing.15 Low-stress aerobic activities, especially walking, are the best early activities.15

Exercise is one of the only evidence-based, effective treatments for chronic low back pain.16 The most commonly prescribed exercises are aimed at retraining the multifidus (a back muscle) and transversus abdominis (a deep abdominal muscle), supplemented with exercises for the pelvic floor and breathing control.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Tylenol) are the drugs of choice for pain control in acute back pain17,18 and are as effective as muscle relaxants or opioids.

Muscle relaxants and opioids offer few advantages over NSAIDs and acetaminophen, except when there is severe muscle spasm associated with the back pain or if acetaminophen or NSAIDs do not relieve the pain. Muscle relaxants and opioids are both associated with more severe adverse effects. If prescribed, they should be used for a short, clearly defined period (1 to 2 weeks).19

Epidural corticosteroids, when used for sciatica, give mild to moderate short-term improvement in leg pain and sensory deficit but no significant long-term functional benefit or reduction in the need for surgery.20

Surgery may be considered in cases of cauda equina syndrome, which is a surgical emergency; severe or progressive neurologic deficit; infections, tumors, and fractures compressing the spinal cord; mechanical instability of the back; and, perhaps, intractable pain (leg pain equal to or greater than back pain) with a positive straight-leg-raising test and no response to conservative therapy.

The term “instability” implies an abnormal motion under physiologic loads. Lumbar instability is defined as translation of more than 4 mm or 10 degrees of angular motion between flexion and extension on an upright lateral radiograph.

Although Weinstein et al21 showed that patients with spinal stenosis who underwent surgery showed significantly more improvement in all primary outcomes than did patients treated nonsurgically, many patients can be effectively treated without surgery.

 

 

WHAT SHOULD BE REMEMBERED ABOUT LOW BACK PAIN?

Low back pain is a common and costly medical condition with only a weak correlation between symptoms and pathologic changes, resulting in a lack of objective clinical findings on which a definitive diagnosis can be based.22 Most back pain has no recognizable cause and is usually regional and musculoskeletal. Back pain as a result of an underlying systemic disease is rare and needs to be excluded by a good history and physical examination. Diagnostic studies are best reserved for specific indications.

Referral to a specialist is warranted when the patient is not responding to conservative treatment, when a progressive neurologic deficit or cauda equina syndrome is noted or suspected, or when the patient has an underlying malignancy, infection, fracture, or spinal instability.

Bed rest is best avoided, and activity within the limits of pain is encouraged. NSAIDs and acetaminophen are usually the drugs of choice for controlling acute low back pain.

Ultimately, the goal for clinicians is to identify serious conditions and to prevent the back pain from becoming chronic pain by promptly identifying the various risk factors.

References
  1. Hadler NM. Low back pain. In:Koopman WJ, editor. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lipincott Williams and Wilkins; 2001:2026–2041.
  2. Martin BI, Deyo RA, Mirza SK, et al. Expenditures and health status among adults with back and neck problems. JAMA 2008; 299:656–664.
  3. NASS Task Force on clinical guidelines. Phase III clinical guidelines for multidisciplinary spine care specialists. Unremitting low back pain. 1st ed. Burr Ridge, IL: North American Spine Society; 2000.
  4. Cailliet R. Low back pain. In: Soft Tissue Pain and Disability. 3rd ed. Philadelphia, PA: FA Davis; 1996:101–170.
  5. Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331:69–73.
  6. A gency for Health Care Policy and Research. Acute low back pain problems in adults: assessment and treatment. http://www.chirobase.org/07Strategy/AHCPR/ahcprclinician.html. Accessed March 2009.
  7. Cohen R, Chopra P, Upshur C. Primary care work-up of acute and chronic symptoms. Geriatrics 2001; 56:26–37.
  8. Pincus T, Burton AK, Vogel S, Field AP. A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine 2002; 27:E109–E120.
  9. Carragee EJ. Clinical practice: persistent low back pain. N Engl J Med 2005; 352:1891–1898.
  10. Pincus T, Vlaeyen JW, Kendall NA, Von Korff MR, Kalauokalani DA, Reis S. Cognitive-behavioral therapy and psychosocial factors in low back pain: directions for the future. Spine 2002; 27:E133–E138.
  11. Waddell G, McCulloch JA, Kummel E, Venner RM. Nonorganic physical signs in low back pain. Spine 1980; 5:117–125.
  12. Hagen KB, Hilde G, Jamtvedt G, Winnem M. Bed rest for acute low-back pain and sciatica. Cochrane Database Syst Rev 2004; 4:CD001254.
  13. Patel AT, Ogle AA. Diagnosis and management of acute low back pain. Am Fam Physician 2000; 61:1779–1790.
  14. Grotle M, Brox JI, Glomsrød B, Lønn JH, Vøllestad NK. Prognostic factors in first-time care seekers due to acute low back pain. Eur J Pain 2007; 11:290–298.
  15. Atlas SJ, Deyo RA. Evaluating and managing acute low back pain in the primary care setting. J Gen Intern Med 2001; 16:120–131.
  16. Maher CG. Effective physical treatment for low back pain. Orthop Clin North Am 2004; 35:57–64.
  17. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007; 147:478–491.
  18. Chou R, Huffman LHAmerican Pain Society. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007; 147:505–514.
  19. Cherkin DC, Wheeler KJ, Barlow W, Deyo RA. Medication use for low back pain in primary care. Spine 1998; 23:607–614.
  20. Carette S, Leclaire R, Marcoux S, et al. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med 1997; 336:1634–1640.
  21. Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical versus non-surgical therapy for lumbar spinal stenosis. N Engl J Med 2008; 358:794–810.
  22. Deyo RA, Rainville J, Kent DL. What can the history and physical examination tell us about low back pain? JAMA 1992; 268:760–765.
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Samir D. Bhangle, MD
Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Sunil Sapru, MD
Assistant Professor and Assistant Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Richard S. Panush, MD, MACP, MACR
Professor, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; Chair and Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Address: Richard S. Panush, MD, Department of Medicine, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, NJ 07039; e-mail [email protected]

Issue
Cleveland Clinic Journal of Medicine - 76(7)
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Cleveland Clinic Journal of Medicine
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Neurology
Drug Therapy
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Samir D. Bhangle, MD
Sunil Sapru, MD
Richard S. Panush, MD, MACP, MACR
Author(s)
Samir D. Bhangle, MD
Sunil Sapru, MD
Richard S. Panush, MD, MACP, MACR
Author and Disclosure Information

Samir D. Bhangle, MD
Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Sunil Sapru, MD
Assistant Professor and Assistant Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Richard S. Panush, MD, MACP, MACR
Professor, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; Chair and Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Address: Richard S. Panush, MD, Department of Medicine, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, NJ 07039; e-mail [email protected]

Author and Disclosure Information

Samir D. Bhangle, MD
Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Sunil Sapru, MD
Assistant Professor and Assistant Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Richard S. Panush, MD, MACP, MACR
Professor, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; Chair and Program Director, Department of Medicine, Saint Barnabas Medical Center, Livingston, NJ

Address: Richard S. Panush, MD, Department of Medicine, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, NJ 07039; e-mail [email protected]

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Low back pain should be understood as a remittent, intermittent predicament of life. Its cause is indeterminate, but its course is predictable. Its link to work-related injury is tenuous and confounded by psychosocial issues, including workers’ compensation. It challenges function, compromises performance, and calls for empathy and understanding.1

In this brief paper, we offer a simple approach to one of the most common human afflictions, based on principles and evidence.

WHY IS BACK PAIN IMPORTANT?

Low back pain is common and affects people of all ages. It is second only to the common cold as the most common affliction of mankind, and it is among the leading complaints bringing patients to physicians’ offices. Its lifetime prevalence exceeds 70% in most industrialized countries, with an annual incidence of 15% to 20% in the United States.

Its social and economic impact is substantial. It is the most frequent cause of disability for people under age 45. In 2005, the mean age- and sex-adjusted medical expenditure among respondents with spine problems was $6,096 vs $3,516 in those without spine problems, and it had increased by 65% (adjusted for inflation) from 1997 to 2005.2

WHAT ARE THE GOALS AND PRINCIPLES OF MANAGING LOW BACK PAIN?

The goals of management for patients with low back pain are to:

  • Decrease the pain
  • Restore mobility
  • Hasten recovery so the patient can resume normal daily activities as soon as possible
  • Prevent development of a chronic recurrent condition: low back pain is considered acute when it persists for less than 6 weeks, subacute between 6 weeks and 3 months, and chronic when it lasts longer than 3 months
  • Restore and preserve physical and financial independence and comfort.

Principles of management

  • Most back pain has no recognizable cause and is therefore termed “mechanical” or “musculoskeletal.”
  • Underlying systemic disease is rare.
  • Most episodes of back pain are unpreventable.
  • Confounding psychosocial issues are often contributory, important, and relevant.
  • A careful, informed history and physical examination are invaluable; diagnostic studies, however technologically sophisticated, are never a substitute.
  • Defer diagnostic studies for specific indications.
  • Refer patients only if they have underlying disease or progressive neurologic dysfunction, or if they do not respond to conservative management.
  • Encouragement of activity is benign and perhaps salutary for back pain and is desirable for general physical and mental health; there is only scant evidence to support bed rest.3
  • Few if any treatments have been proven effective for low back pain.
  • Talking to the patient and explaining the issues involved are critical to successful management.4

INITIAL CONSIDERATIONS WHEN EVALUATING A PATIENT

When encountering a patient with back pain, the initial consideration is whether the symptoms are regional—ie, local, mechanical, and musculoskeletal—or if they reflect a systemic disease. It is also important to look for evidence of social or psychological distress that may amplify, prolong, or confound the pain or the patient’s perception of it.

What are the clues to a systemic process?

Red flags of a serious, systemic cause of low back pain are presented in Table 1. Other symptoms that may indicate a systemic cause include night pain (also seen with disk disease and neurocompression), pain with recumbency (malignancy), back pain with morning stiffness lasting for more than 1 hour (spondyloarthropathy), cauda equina syndrome (overflow incontinence, saddle anesthesia, and paraparesis), and other systemic and constitutional symptoms.

Does the patient have a regional low back syndrome?

Regional low back syndromes account for 90% of the causes of low back pain. They are usually mechanical in origin.

Regional back pain is due to overuse of a normal mechanical structure (muscle strain, “lumbago”) or is secondary to trauma, deformity, or degeneration of an anatomical structure (herniated nucleus pulposus, fracture, and spondyloarthropathy, including facet joint arthritis). Chronic regional back syndromes include osteoarthritis of the spine (ie, spondylosis), spinal stenosis, and facet joint arthropathy.

Characteristically, mechanical disorders are exacerbated by certain physical activities, such as lifting, and are relieved by others, such as assuming a supine position.

 

 

Does the patient have sciatica or another nerve root compression syndrome?

The obvious manifestation of nerve root irritation is usually sciatica, a sharp or burning pain radiating down the posterior or lateral aspect of the leg usually to the foot or the ankle and often associated with numbness or paresthesias. The pain is sometimes aggravated by coughing, sneezing, or the Valsalva maneuver. It is most commonly seen in lumbar disk herniation, cauda equina syndrome, and spinal stenosis.

Might the patient have spinal stenosis?

More than 20% of people over age 60 have radiographic evidence of lumbar spinal canal stenosis, even if they have no symptoms.5 For this reason, the diagnosis of spinal stenosis as a cause of low back pain must be based on the history and physical examination.

The classic history of spinal stenosis is that of neurogenic claudication (“pseudoclaudication”), which is pain that occurs in the legs after walking or prolonged standing and is relieved with sitting. It may sometimes be associated with a varying and transient neurologic deficit. Lumbar flexion increases and lumbar extension decreases the cross-sectional area of the spinal canal—hence, the relief of symptoms of spinal stenosis on stooping or bending forward. Pain is commonly perceived in the back, buttock, or thigh and is elicited by prolonged lumbar extension.

On neurologic examination, about 50% of patients with spinal stenosis have a deficit in vibratory sensibility, temperature sensitivity, or muscle strength. The nerve root involved is most commonly L5, followed by S1 and L4.

Many patients have balance disturbance (wide-based gait or Romberg sign), particularly later in the course of the disorder, with normal cerebellar signs (“pseudocerebellar” presentation).

Patients with bilateral hip osteoarthritis may present with similar symptoms of buttock or thigh pain, which can be distinguished with the above clinical examination. Rotation of the hip is painful in osteoarthritis but not in spinal stenosis. If both conditions overlap, injection of a steroid or lidocaine in the painful hip should decrease the pain associated with hip osteoarthritis.

Does the patient have evidence of neurologic compromise?

Assessment of neurologic compromise requires a thorough history for evidence of muscle weakness, gait disturbances, paresthesias, numbness, radicular pain, and bowel or bladder disturbances. The neurologic examination includes testing muscle strength, evaluating sensation and reflexes (Table 2), and analyzing the gait.

Muscle strength is tested by examining the:

  • L2 nerve root (which supplies the iliopsoas muscle and is tested by hip flexion)
  • L3 nerve root (quadriceps, tested by knee extension)
  • L4 nerve root (tibialis anterior, assessed by evaluating ankle dorsiflexion and inversion at the subtalar joint)
  • L5 nerve root (extensor hallucis longus and extensor digitorum longus, tested by asking the patient to dorsiflex the great toe, then the other toes)
  • S1 nerve root (flexor hallucis longus, flexor digitorum longus, and tendoachilles, tested by asking the patient to plantar-flex the great toe, then the other toes, and then the ankle).

The patient is also asked to walk a few steps on the toes and then on the heels. Inability to toe-walk indicates S1 nerve root involvement; inability to heel-walk may indicate L4 or L5 involvement. If the patient cannot heelwalk, ask him or her to squat; inability to do so indicates L4 problems.6

Radiculopathy. Detecting and locating the cause of radiculopathy may be helpful. In L3–L4 disk herniation, there is pain and paresthesia with numbness and hypalgesia in the anteromedial thigh and the knee. In L4–L5 disk herniation, there is usually involvement of the exiting L5 nerve root, which presents as numbness or paresthesias in the anterolateral calf, great toe, first web space, and medial foot. In L5-S1 disk herniation, the S1 nerve root is involved, presenting as numbness and hypalgesia in the fifth toe, lateral aspect of the foot, sole, and posterolateral calf and thigh.

Reflexes. Exaggerated or decreased reflexes do not always indicate a neurologic abnormality, but reflex asymmetry is significant. The knee-jerk reflex is diminished in L3–L4 nerve root involvement, and the ankle-jerk reflex is diminished with S1 nerve root involvement. The Babinski sign indicates pyramidal tract involvement.

Gait. Observe the patient’s gait as he or she rises and moves to the examining table, to determine whether it is shortened, asymmetrical, or antalgic.7 Also note any foot drop, which may indicate a potentially serious problem (L5 radiculopathy).

What is an adequate examination of the back?

A good back examination can elicit important information about the cause and the extent of back pain. It includes inspection, palpation, and range of movement of the spine along with a detailed neurologic examination.

Inspect it for any deformities, scoliosis, asymmetry, paraspinal muscle spasm, unusual hair growth, listing to one side, decrease or increase in lumbar lordosis, or muscle atrophy or fasciculation.

Palpate it for paraspinal muscle spasm, warmth, and localized bone pain.

Move it. The normal ranges of motion of the lumbar spine are 15 degrees of extension, 40 degrees of flexion, 30 degrees of lateral bending, and 40 degrees of lateral rotation to each side.

Assess it. This includes estimating the tone and nutrition of the muscles, testing their strength (Table 2), examining vibratory or proprioception and pinprick sensation in each dermatome (see below), testing the Achilles and patellar reflexes, and looking for the Babinski sign and clonus. In addition, perform the straight-leg-raising and the cross-straightleg-raising tests, which are positive in most patients with lower lumbar disk herniations.

The femoral stretch test is usually positive in upper lumbar disk herniations (L2–L3, L3– L4). It is performed with the patient in the prone position, with the knee being gradually flexed from full extension. Pain radiating along the anterior aspect of the thigh indicates a positive test.

The examination of the spine must be supplemented with examination of the hip and sacroiliac joints, since back pain may be a referred symptom from any pathology affecting these joints.

 

 

When should patients be referred to a specialist?

Patients should be referred to a neurologist, neurosurgeon, orthopedist, or other specialist if they have cauda equina syndrome; severe or progressive neurologic deficits; infections, tumors, or fractures compressing the spinal cord; or, perhaps, no response to conservative therapy for 4 to 6 weeks for patients with a herniated lumbar disk or 8 to 12 weeks for those with spinal stenosis.

If there is profound motor involvement at the time of the initial evaluation, patients must be promptly given systemic corticosteroids such as methylprednisolone (Medrol) or dexamethasone (Decadron) to decrease spinal cord edema.

Are there signs of psychological distress?

Psychosocial factors can significantly affect pain and functional disability in patients who have low back pain.8,9 These are known as “yellow flags” and are better predictors of treatment outcome than physical factors. 10 Anatomically inappropriate signs may be helpful in identifying psychological distress as a result of or as an amplifier of low back symptoms.

Waddell et al11 proposed five categories of these nonorganic signs. These are:

  • Inappropriate tenderness that is superficial or widespread
  • Pain on simulated axial loading by pressing on the top of the head or simulated spine rotation
  • Distraction signs such as inconsistent performance between straight-leg-raising in the seated position vs the supine position
  • Regional disturbances in strength and sensation that do not correspond with nerve root innervation patterns
  • Overreaction during the physical examination.

The occurrence of any one of the signs is of limited value, but positive findings in three of the five categories suggest psychological distress.11

Which diagnostic studies are useful, cost-effective, and supported by evidence?

Since most abnormalities found on imaging studies are nonspecific, such studies are not necessary during the initial evaluation of acute low back pain unless there are red flags that suggest a more ominous source of pain.

Routine plain lumbosacral spine radiographs with anteroposterior and lateral views may be appropriate initially if the patient has risk factors for vertebral fractures (Table 1), or if the patient does not improve after a course of conservative treatment (usually 4–6 weeks).

Magnetic resonance imaging (MRI) is the preferred test if one suspects a tumor, infection, disk pathology, or spinal stenosis.

Computed tomography (CT) shows bony details better than MRI does. Hence, it is preferred when one needs to evaluate bony details (fractures, scoliosis) and when there are contraindications to MRI, as in patients with metal implant devices and those who are claustrophobic (although now there are “open system” MRI machines, in which the feeling of claustrophobia is much less).

MRI and CT should not be ordered routinely, but only for specific indications to answer specific questions, when specific findings would indicate specific treatment.

In most cases, contrast is not needed for CT or MRI to rule out common causes of low back pain, except in cases of suspected intraspinal tumor. Patients with compromised renal function who need contrast for CT need to be hydrated before the scan to lower the risk of contrast-induced nephropathy. These patients are also at higher risk of nephrogenic fibrosing dermopathy when they receive gadolinium contrast for MRI.

Bone scans can be used to look for infections or fractures not noted on plain radiography. However, MRI provides similar or better diagnostic accuracy without radiation.

Electrodiagnostic studies may be used in patients with radiculopathy when clinical examination suggests multilevel root lesions, when symptoms do not match imaging studies, and when patients have breakaway weakness (fluctuating levels of strength in one or more muscle groups).

Other useful diagnostic and laboratory studies may include the erythrocyte sedimentation rate to screen for malignancy and infection when these are suspected, blood culture for osteomyelitis, and bone aspiration and biopsy for histopathologic diagnosis of infection, malignancy, or other lesions.

WHICH TREATMENTS ARE SUPPORTED BY ROBUST EVIDENCE?

The primary treatment of low back pain should be conservative care, reassurance, and education, allowing patients to improve on their own and helping them cope with their predicament.

Limited bed rest. While 2 or 3 days of limited bed rest may help improve symptoms in patients who have acute radiculopathy, several studies have shown that long periods of bed rest are not beneficial for acute or subacute low back pain.12 Encouraging activity modification allows patients with nonspecific back pain or radicular symptoms to remain active while avoiding activities that may aggravate pain and is shown to lead to a more rapid recovery than bed rest.13,14 The most common situations to avoid are prolonged sitting or standing.15 Low-stress aerobic activities, especially walking, are the best early activities.15

Exercise is one of the only evidence-based, effective treatments for chronic low back pain.16 The most commonly prescribed exercises are aimed at retraining the multifidus (a back muscle) and transversus abdominis (a deep abdominal muscle), supplemented with exercises for the pelvic floor and breathing control.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Tylenol) are the drugs of choice for pain control in acute back pain17,18 and are as effective as muscle relaxants or opioids.

Muscle relaxants and opioids offer few advantages over NSAIDs and acetaminophen, except when there is severe muscle spasm associated with the back pain or if acetaminophen or NSAIDs do not relieve the pain. Muscle relaxants and opioids are both associated with more severe adverse effects. If prescribed, they should be used for a short, clearly defined period (1 to 2 weeks).19

Epidural corticosteroids, when used for sciatica, give mild to moderate short-term improvement in leg pain and sensory deficit but no significant long-term functional benefit or reduction in the need for surgery.20

Surgery may be considered in cases of cauda equina syndrome, which is a surgical emergency; severe or progressive neurologic deficit; infections, tumors, and fractures compressing the spinal cord; mechanical instability of the back; and, perhaps, intractable pain (leg pain equal to or greater than back pain) with a positive straight-leg-raising test and no response to conservative therapy.

The term “instability” implies an abnormal motion under physiologic loads. Lumbar instability is defined as translation of more than 4 mm or 10 degrees of angular motion between flexion and extension on an upright lateral radiograph.

Although Weinstein et al21 showed that patients with spinal stenosis who underwent surgery showed significantly more improvement in all primary outcomes than did patients treated nonsurgically, many patients can be effectively treated without surgery.

 

 

WHAT SHOULD BE REMEMBERED ABOUT LOW BACK PAIN?

Low back pain is a common and costly medical condition with only a weak correlation between symptoms and pathologic changes, resulting in a lack of objective clinical findings on which a definitive diagnosis can be based.22 Most back pain has no recognizable cause and is usually regional and musculoskeletal. Back pain as a result of an underlying systemic disease is rare and needs to be excluded by a good history and physical examination. Diagnostic studies are best reserved for specific indications.

Referral to a specialist is warranted when the patient is not responding to conservative treatment, when a progressive neurologic deficit or cauda equina syndrome is noted or suspected, or when the patient has an underlying malignancy, infection, fracture, or spinal instability.

Bed rest is best avoided, and activity within the limits of pain is encouraged. NSAIDs and acetaminophen are usually the drugs of choice for controlling acute low back pain.

Ultimately, the goal for clinicians is to identify serious conditions and to prevent the back pain from becoming chronic pain by promptly identifying the various risk factors.

Low back pain should be understood as a remittent, intermittent predicament of life. Its cause is indeterminate, but its course is predictable. Its link to work-related injury is tenuous and confounded by psychosocial issues, including workers’ compensation. It challenges function, compromises performance, and calls for empathy and understanding.1

In this brief paper, we offer a simple approach to one of the most common human afflictions, based on principles and evidence.

WHY IS BACK PAIN IMPORTANT?

Low back pain is common and affects people of all ages. It is second only to the common cold as the most common affliction of mankind, and it is among the leading complaints bringing patients to physicians’ offices. Its lifetime prevalence exceeds 70% in most industrialized countries, with an annual incidence of 15% to 20% in the United States.

Its social and economic impact is substantial. It is the most frequent cause of disability for people under age 45. In 2005, the mean age- and sex-adjusted medical expenditure among respondents with spine problems was $6,096 vs $3,516 in those without spine problems, and it had increased by 65% (adjusted for inflation) from 1997 to 2005.2

WHAT ARE THE GOALS AND PRINCIPLES OF MANAGING LOW BACK PAIN?

The goals of management for patients with low back pain are to:

  • Decrease the pain
  • Restore mobility
  • Hasten recovery so the patient can resume normal daily activities as soon as possible
  • Prevent development of a chronic recurrent condition: low back pain is considered acute when it persists for less than 6 weeks, subacute between 6 weeks and 3 months, and chronic when it lasts longer than 3 months
  • Restore and preserve physical and financial independence and comfort.

Principles of management

  • Most back pain has no recognizable cause and is therefore termed “mechanical” or “musculoskeletal.”
  • Underlying systemic disease is rare.
  • Most episodes of back pain are unpreventable.
  • Confounding psychosocial issues are often contributory, important, and relevant.
  • A careful, informed history and physical examination are invaluable; diagnostic studies, however technologically sophisticated, are never a substitute.
  • Defer diagnostic studies for specific indications.
  • Refer patients only if they have underlying disease or progressive neurologic dysfunction, or if they do not respond to conservative management.
  • Encouragement of activity is benign and perhaps salutary for back pain and is desirable for general physical and mental health; there is only scant evidence to support bed rest.3
  • Few if any treatments have been proven effective for low back pain.
  • Talking to the patient and explaining the issues involved are critical to successful management.4

INITIAL CONSIDERATIONS WHEN EVALUATING A PATIENT

When encountering a patient with back pain, the initial consideration is whether the symptoms are regional—ie, local, mechanical, and musculoskeletal—or if they reflect a systemic disease. It is also important to look for evidence of social or psychological distress that may amplify, prolong, or confound the pain or the patient’s perception of it.

What are the clues to a systemic process?

Red flags of a serious, systemic cause of low back pain are presented in Table 1. Other symptoms that may indicate a systemic cause include night pain (also seen with disk disease and neurocompression), pain with recumbency (malignancy), back pain with morning stiffness lasting for more than 1 hour (spondyloarthropathy), cauda equina syndrome (overflow incontinence, saddle anesthesia, and paraparesis), and other systemic and constitutional symptoms.

Does the patient have a regional low back syndrome?

Regional low back syndromes account for 90% of the causes of low back pain. They are usually mechanical in origin.

Regional back pain is due to overuse of a normal mechanical structure (muscle strain, “lumbago”) or is secondary to trauma, deformity, or degeneration of an anatomical structure (herniated nucleus pulposus, fracture, and spondyloarthropathy, including facet joint arthritis). Chronic regional back syndromes include osteoarthritis of the spine (ie, spondylosis), spinal stenosis, and facet joint arthropathy.

Characteristically, mechanical disorders are exacerbated by certain physical activities, such as lifting, and are relieved by others, such as assuming a supine position.

 

 

Does the patient have sciatica or another nerve root compression syndrome?

The obvious manifestation of nerve root irritation is usually sciatica, a sharp or burning pain radiating down the posterior or lateral aspect of the leg usually to the foot or the ankle and often associated with numbness or paresthesias. The pain is sometimes aggravated by coughing, sneezing, or the Valsalva maneuver. It is most commonly seen in lumbar disk herniation, cauda equina syndrome, and spinal stenosis.

Might the patient have spinal stenosis?

More than 20% of people over age 60 have radiographic evidence of lumbar spinal canal stenosis, even if they have no symptoms.5 For this reason, the diagnosis of spinal stenosis as a cause of low back pain must be based on the history and physical examination.

The classic history of spinal stenosis is that of neurogenic claudication (“pseudoclaudication”), which is pain that occurs in the legs after walking or prolonged standing and is relieved with sitting. It may sometimes be associated with a varying and transient neurologic deficit. Lumbar flexion increases and lumbar extension decreases the cross-sectional area of the spinal canal—hence, the relief of symptoms of spinal stenosis on stooping or bending forward. Pain is commonly perceived in the back, buttock, or thigh and is elicited by prolonged lumbar extension.

On neurologic examination, about 50% of patients with spinal stenosis have a deficit in vibratory sensibility, temperature sensitivity, or muscle strength. The nerve root involved is most commonly L5, followed by S1 and L4.

Many patients have balance disturbance (wide-based gait or Romberg sign), particularly later in the course of the disorder, with normal cerebellar signs (“pseudocerebellar” presentation).

Patients with bilateral hip osteoarthritis may present with similar symptoms of buttock or thigh pain, which can be distinguished with the above clinical examination. Rotation of the hip is painful in osteoarthritis but not in spinal stenosis. If both conditions overlap, injection of a steroid or lidocaine in the painful hip should decrease the pain associated with hip osteoarthritis.

Does the patient have evidence of neurologic compromise?

Assessment of neurologic compromise requires a thorough history for evidence of muscle weakness, gait disturbances, paresthesias, numbness, radicular pain, and bowel or bladder disturbances. The neurologic examination includes testing muscle strength, evaluating sensation and reflexes (Table 2), and analyzing the gait.

Muscle strength is tested by examining the:

  • L2 nerve root (which supplies the iliopsoas muscle and is tested by hip flexion)
  • L3 nerve root (quadriceps, tested by knee extension)
  • L4 nerve root (tibialis anterior, assessed by evaluating ankle dorsiflexion and inversion at the subtalar joint)
  • L5 nerve root (extensor hallucis longus and extensor digitorum longus, tested by asking the patient to dorsiflex the great toe, then the other toes)
  • S1 nerve root (flexor hallucis longus, flexor digitorum longus, and tendoachilles, tested by asking the patient to plantar-flex the great toe, then the other toes, and then the ankle).

The patient is also asked to walk a few steps on the toes and then on the heels. Inability to toe-walk indicates S1 nerve root involvement; inability to heel-walk may indicate L4 or L5 involvement. If the patient cannot heelwalk, ask him or her to squat; inability to do so indicates L4 problems.6

Radiculopathy. Detecting and locating the cause of radiculopathy may be helpful. In L3–L4 disk herniation, there is pain and paresthesia with numbness and hypalgesia in the anteromedial thigh and the knee. In L4–L5 disk herniation, there is usually involvement of the exiting L5 nerve root, which presents as numbness or paresthesias in the anterolateral calf, great toe, first web space, and medial foot. In L5-S1 disk herniation, the S1 nerve root is involved, presenting as numbness and hypalgesia in the fifth toe, lateral aspect of the foot, sole, and posterolateral calf and thigh.

Reflexes. Exaggerated or decreased reflexes do not always indicate a neurologic abnormality, but reflex asymmetry is significant. The knee-jerk reflex is diminished in L3–L4 nerve root involvement, and the ankle-jerk reflex is diminished with S1 nerve root involvement. The Babinski sign indicates pyramidal tract involvement.

Gait. Observe the patient’s gait as he or she rises and moves to the examining table, to determine whether it is shortened, asymmetrical, or antalgic.7 Also note any foot drop, which may indicate a potentially serious problem (L5 radiculopathy).

What is an adequate examination of the back?

A good back examination can elicit important information about the cause and the extent of back pain. It includes inspection, palpation, and range of movement of the spine along with a detailed neurologic examination.

Inspect it for any deformities, scoliosis, asymmetry, paraspinal muscle spasm, unusual hair growth, listing to one side, decrease or increase in lumbar lordosis, or muscle atrophy or fasciculation.

Palpate it for paraspinal muscle spasm, warmth, and localized bone pain.

Move it. The normal ranges of motion of the lumbar spine are 15 degrees of extension, 40 degrees of flexion, 30 degrees of lateral bending, and 40 degrees of lateral rotation to each side.

Assess it. This includes estimating the tone and nutrition of the muscles, testing their strength (Table 2), examining vibratory or proprioception and pinprick sensation in each dermatome (see below), testing the Achilles and patellar reflexes, and looking for the Babinski sign and clonus. In addition, perform the straight-leg-raising and the cross-straightleg-raising tests, which are positive in most patients with lower lumbar disk herniations.

The femoral stretch test is usually positive in upper lumbar disk herniations (L2–L3, L3– L4). It is performed with the patient in the prone position, with the knee being gradually flexed from full extension. Pain radiating along the anterior aspect of the thigh indicates a positive test.

The examination of the spine must be supplemented with examination of the hip and sacroiliac joints, since back pain may be a referred symptom from any pathology affecting these joints.

 

 

When should patients be referred to a specialist?

Patients should be referred to a neurologist, neurosurgeon, orthopedist, or other specialist if they have cauda equina syndrome; severe or progressive neurologic deficits; infections, tumors, or fractures compressing the spinal cord; or, perhaps, no response to conservative therapy for 4 to 6 weeks for patients with a herniated lumbar disk or 8 to 12 weeks for those with spinal stenosis.

If there is profound motor involvement at the time of the initial evaluation, patients must be promptly given systemic corticosteroids such as methylprednisolone (Medrol) or dexamethasone (Decadron) to decrease spinal cord edema.

Are there signs of psychological distress?

Psychosocial factors can significantly affect pain and functional disability in patients who have low back pain.8,9 These are known as “yellow flags” and are better predictors of treatment outcome than physical factors. 10 Anatomically inappropriate signs may be helpful in identifying psychological distress as a result of or as an amplifier of low back symptoms.

Waddell et al11 proposed five categories of these nonorganic signs. These are:

  • Inappropriate tenderness that is superficial or widespread
  • Pain on simulated axial loading by pressing on the top of the head or simulated spine rotation
  • Distraction signs such as inconsistent performance between straight-leg-raising in the seated position vs the supine position
  • Regional disturbances in strength and sensation that do not correspond with nerve root innervation patterns
  • Overreaction during the physical examination.

The occurrence of any one of the signs is of limited value, but positive findings in three of the five categories suggest psychological distress.11

Which diagnostic studies are useful, cost-effective, and supported by evidence?

Since most abnormalities found on imaging studies are nonspecific, such studies are not necessary during the initial evaluation of acute low back pain unless there are red flags that suggest a more ominous source of pain.

Routine plain lumbosacral spine radiographs with anteroposterior and lateral views may be appropriate initially if the patient has risk factors for vertebral fractures (Table 1), or if the patient does not improve after a course of conservative treatment (usually 4–6 weeks).

Magnetic resonance imaging (MRI) is the preferred test if one suspects a tumor, infection, disk pathology, or spinal stenosis.

Computed tomography (CT) shows bony details better than MRI does. Hence, it is preferred when one needs to evaluate bony details (fractures, scoliosis) and when there are contraindications to MRI, as in patients with metal implant devices and those who are claustrophobic (although now there are “open system” MRI machines, in which the feeling of claustrophobia is much less).

MRI and CT should not be ordered routinely, but only for specific indications to answer specific questions, when specific findings would indicate specific treatment.

In most cases, contrast is not needed for CT or MRI to rule out common causes of low back pain, except in cases of suspected intraspinal tumor. Patients with compromised renal function who need contrast for CT need to be hydrated before the scan to lower the risk of contrast-induced nephropathy. These patients are also at higher risk of nephrogenic fibrosing dermopathy when they receive gadolinium contrast for MRI.

Bone scans can be used to look for infections or fractures not noted on plain radiography. However, MRI provides similar or better diagnostic accuracy without radiation.

Electrodiagnostic studies may be used in patients with radiculopathy when clinical examination suggests multilevel root lesions, when symptoms do not match imaging studies, and when patients have breakaway weakness (fluctuating levels of strength in one or more muscle groups).

Other useful diagnostic and laboratory studies may include the erythrocyte sedimentation rate to screen for malignancy and infection when these are suspected, blood culture for osteomyelitis, and bone aspiration and biopsy for histopathologic diagnosis of infection, malignancy, or other lesions.

WHICH TREATMENTS ARE SUPPORTED BY ROBUST EVIDENCE?

The primary treatment of low back pain should be conservative care, reassurance, and education, allowing patients to improve on their own and helping them cope with their predicament.

Limited bed rest. While 2 or 3 days of limited bed rest may help improve symptoms in patients who have acute radiculopathy, several studies have shown that long periods of bed rest are not beneficial for acute or subacute low back pain.12 Encouraging activity modification allows patients with nonspecific back pain or radicular symptoms to remain active while avoiding activities that may aggravate pain and is shown to lead to a more rapid recovery than bed rest.13,14 The most common situations to avoid are prolonged sitting or standing.15 Low-stress aerobic activities, especially walking, are the best early activities.15

Exercise is one of the only evidence-based, effective treatments for chronic low back pain.16 The most commonly prescribed exercises are aimed at retraining the multifidus (a back muscle) and transversus abdominis (a deep abdominal muscle), supplemented with exercises for the pelvic floor and breathing control.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Tylenol) are the drugs of choice for pain control in acute back pain17,18 and are as effective as muscle relaxants or opioids.

Muscle relaxants and opioids offer few advantages over NSAIDs and acetaminophen, except when there is severe muscle spasm associated with the back pain or if acetaminophen or NSAIDs do not relieve the pain. Muscle relaxants and opioids are both associated with more severe adverse effects. If prescribed, they should be used for a short, clearly defined period (1 to 2 weeks).19

Epidural corticosteroids, when used for sciatica, give mild to moderate short-term improvement in leg pain and sensory deficit but no significant long-term functional benefit or reduction in the need for surgery.20

Surgery may be considered in cases of cauda equina syndrome, which is a surgical emergency; severe or progressive neurologic deficit; infections, tumors, and fractures compressing the spinal cord; mechanical instability of the back; and, perhaps, intractable pain (leg pain equal to or greater than back pain) with a positive straight-leg-raising test and no response to conservative therapy.

The term “instability” implies an abnormal motion under physiologic loads. Lumbar instability is defined as translation of more than 4 mm or 10 degrees of angular motion between flexion and extension on an upright lateral radiograph.

Although Weinstein et al21 showed that patients with spinal stenosis who underwent surgery showed significantly more improvement in all primary outcomes than did patients treated nonsurgically, many patients can be effectively treated without surgery.

 

 

WHAT SHOULD BE REMEMBERED ABOUT LOW BACK PAIN?

Low back pain is a common and costly medical condition with only a weak correlation between symptoms and pathologic changes, resulting in a lack of objective clinical findings on which a definitive diagnosis can be based.22 Most back pain has no recognizable cause and is usually regional and musculoskeletal. Back pain as a result of an underlying systemic disease is rare and needs to be excluded by a good history and physical examination. Diagnostic studies are best reserved for specific indications.

Referral to a specialist is warranted when the patient is not responding to conservative treatment, when a progressive neurologic deficit or cauda equina syndrome is noted or suspected, or when the patient has an underlying malignancy, infection, fracture, or spinal instability.

Bed rest is best avoided, and activity within the limits of pain is encouraged. NSAIDs and acetaminophen are usually the drugs of choice for controlling acute low back pain.

Ultimately, the goal for clinicians is to identify serious conditions and to prevent the back pain from becoming chronic pain by promptly identifying the various risk factors.

References
  1. Hadler NM. Low back pain. In:Koopman WJ, editor. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lipincott Williams and Wilkins; 2001:2026–2041.
  2. Martin BI, Deyo RA, Mirza SK, et al. Expenditures and health status among adults with back and neck problems. JAMA 2008; 299:656–664.
  3. NASS Task Force on clinical guidelines. Phase III clinical guidelines for multidisciplinary spine care specialists. Unremitting low back pain. 1st ed. Burr Ridge, IL: North American Spine Society; 2000.
  4. Cailliet R. Low back pain. In: Soft Tissue Pain and Disability. 3rd ed. Philadelphia, PA: FA Davis; 1996:101–170.
  5. Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331:69–73.
  6. A gency for Health Care Policy and Research. Acute low back pain problems in adults: assessment and treatment. http://www.chirobase.org/07Strategy/AHCPR/ahcprclinician.html. Accessed March 2009.
  7. Cohen R, Chopra P, Upshur C. Primary care work-up of acute and chronic symptoms. Geriatrics 2001; 56:26–37.
  8. Pincus T, Burton AK, Vogel S, Field AP. A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine 2002; 27:E109–E120.
  9. Carragee EJ. Clinical practice: persistent low back pain. N Engl J Med 2005; 352:1891–1898.
  10. Pincus T, Vlaeyen JW, Kendall NA, Von Korff MR, Kalauokalani DA, Reis S. Cognitive-behavioral therapy and psychosocial factors in low back pain: directions for the future. Spine 2002; 27:E133–E138.
  11. Waddell G, McCulloch JA, Kummel E, Venner RM. Nonorganic physical signs in low back pain. Spine 1980; 5:117–125.
  12. Hagen KB, Hilde G, Jamtvedt G, Winnem M. Bed rest for acute low-back pain and sciatica. Cochrane Database Syst Rev 2004; 4:CD001254.
  13. Patel AT, Ogle AA. Diagnosis and management of acute low back pain. Am Fam Physician 2000; 61:1779–1790.
  14. Grotle M, Brox JI, Glomsrød B, Lønn JH, Vøllestad NK. Prognostic factors in first-time care seekers due to acute low back pain. Eur J Pain 2007; 11:290–298.
  15. Atlas SJ, Deyo RA. Evaluating and managing acute low back pain in the primary care setting. J Gen Intern Med 2001; 16:120–131.
  16. Maher CG. Effective physical treatment for low back pain. Orthop Clin North Am 2004; 35:57–64.
  17. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007; 147:478–491.
  18. Chou R, Huffman LHAmerican Pain Society. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007; 147:505–514.
  19. Cherkin DC, Wheeler KJ, Barlow W, Deyo RA. Medication use for low back pain in primary care. Spine 1998; 23:607–614.
  20. Carette S, Leclaire R, Marcoux S, et al. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med 1997; 336:1634–1640.
  21. Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical versus non-surgical therapy for lumbar spinal stenosis. N Engl J Med 2008; 358:794–810.
  22. Deyo RA, Rainville J, Kent DL. What can the history and physical examination tell us about low back pain? JAMA 1992; 268:760–765.
References
  1. Hadler NM. Low back pain. In:Koopman WJ, editor. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lipincott Williams and Wilkins; 2001:2026–2041.
  2. Martin BI, Deyo RA, Mirza SK, et al. Expenditures and health status among adults with back and neck problems. JAMA 2008; 299:656–664.
  3. NASS Task Force on clinical guidelines. Phase III clinical guidelines for multidisciplinary spine care specialists. Unremitting low back pain. 1st ed. Burr Ridge, IL: North American Spine Society; 2000.
  4. Cailliet R. Low back pain. In: Soft Tissue Pain and Disability. 3rd ed. Philadelphia, PA: FA Davis; 1996:101–170.
  5. Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331:69–73.
  6. A gency for Health Care Policy and Research. Acute low back pain problems in adults: assessment and treatment. http://www.chirobase.org/07Strategy/AHCPR/ahcprclinician.html. Accessed March 2009.
  7. Cohen R, Chopra P, Upshur C. Primary care work-up of acute and chronic symptoms. Geriatrics 2001; 56:26–37.
  8. Pincus T, Burton AK, Vogel S, Field AP. A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine 2002; 27:E109–E120.
  9. Carragee EJ. Clinical practice: persistent low back pain. N Engl J Med 2005; 352:1891–1898.
  10. Pincus T, Vlaeyen JW, Kendall NA, Von Korff MR, Kalauokalani DA, Reis S. Cognitive-behavioral therapy and psychosocial factors in low back pain: directions for the future. Spine 2002; 27:E133–E138.
  11. Waddell G, McCulloch JA, Kummel E, Venner RM. Nonorganic physical signs in low back pain. Spine 1980; 5:117–125.
  12. Hagen KB, Hilde G, Jamtvedt G, Winnem M. Bed rest for acute low-back pain and sciatica. Cochrane Database Syst Rev 2004; 4:CD001254.
  13. Patel AT, Ogle AA. Diagnosis and management of acute low back pain. Am Fam Physician 2000; 61:1779–1790.
  14. Grotle M, Brox JI, Glomsrød B, Lønn JH, Vøllestad NK. Prognostic factors in first-time care seekers due to acute low back pain. Eur J Pain 2007; 11:290–298.
  15. Atlas SJ, Deyo RA. Evaluating and managing acute low back pain in the primary care setting. J Gen Intern Med 2001; 16:120–131.
  16. Maher CG. Effective physical treatment for low back pain. Orthop Clin North Am 2004; 35:57–64.
  17. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007; 147:478–491.
  18. Chou R, Huffman LHAmerican Pain Society. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007; 147:505–514.
  19. Cherkin DC, Wheeler KJ, Barlow W, Deyo RA. Medication use for low back pain in primary care. Spine 1998; 23:607–614.
  20. Carette S, Leclaire R, Marcoux S, et al. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med 1997; 336:1634–1640.
  21. Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical versus non-surgical therapy for lumbar spinal stenosis. N Engl J Med 2008; 358:794–810.
  22. Deyo RA, Rainville J, Kent DL. What can the history and physical examination tell us about low back pain? JAMA 1992; 268:760–765.
Issue
Cleveland Clinic Journal of Medicine - 76(7)
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Cleveland Clinic Journal of Medicine - 76(7)
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393-399
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Back pain made simple: An approach based on principles and evidence
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KEY POINTS

  • Most back pain has no recognizable cause and is therefore termed “mechanical” or “musculoskeletal.” Underlying systemic disease is rare.
  • Most episodes of back pain are not preventable.
  • Confounding psychosocial issues are common.
  • A careful, informed history and physical examination are invaluable; diagnostic studies, however sophisticated, are never a substitute. Defer them for specific indications.
  • Refer patients only if they have underlying disease or progressive neurologic dysfunction or do not respond to conservative management.
  • Encouragement of activity is benign and perhaps salutary for back pain and is desirable for general physical and mental health. Evidence to support bed rest is scant.
  • Few if any treatments have been proven effective for low back pain.
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What is the role of probiotics in the treatment of acute Clostridium difficile-associated diarrhea?

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What is the role of probiotics in the treatment of acute Clostridium difficile-associated diarrhea?
Author(s)
Kennon Miller, MD
Thomas Fraser, MD

Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.1,2 Six trials of various probiotics were included in a 2006 meta-analysis.3 Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.6

McFarland et al4 gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.4

Surawicz et al5 gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

 

 

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.12

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

References
  1. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005; 173:167–170.
  2. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008;CD004611.
  3. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101:812–822.
  4. McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271:1913–1918.
  5. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31:1012–1017.
  6. Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999; 67:302–307.
  7. Huff BA. Caveat emptor. “Probiotics” might not be what they seem. Can Fam Physician 2004; 50:583–587.
  8. Coeuret V, Gueguen M, Vernoux J. Numbers and strains of lactobacilli in some probiotic products. Int J Food Microbiol 2004; 97:147–156.
  9. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005; 115;178–181.
  10. Lherm T, Monet C, Nougière B, et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002; 28:797–801.
  11. Salminen MK, Rautelin H, Tynkkynen S, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004; 38:62–69.
  12. Merrigan MM, Sambol SP, Johnson S, Gerding DN. Prevention of fatal Clostridium difficile-associated disease during continuous administration of clindamycin in hamsters. J Infect Dis 2003; 188:1922–1927.
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Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.1,2 Six trials of various probiotics were included in a 2006 meta-analysis.3 Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.6

McFarland et al4 gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.4

Surawicz et al5 gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

 

 

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.12

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.1,2 Six trials of various probiotics were included in a 2006 meta-analysis.3 Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.6

McFarland et al4 gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.4

Surawicz et al5 gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

 

 

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.12

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

References
  1. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005; 173:167–170.
  2. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008;CD004611.
  3. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101:812–822.
  4. McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271:1913–1918.
  5. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31:1012–1017.
  6. Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999; 67:302–307.
  7. Huff BA. Caveat emptor. “Probiotics” might not be what they seem. Can Fam Physician 2004; 50:583–587.
  8. Coeuret V, Gueguen M, Vernoux J. Numbers and strains of lactobacilli in some probiotic products. Int J Food Microbiol 2004; 97:147–156.
  9. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005; 115;178–181.
  10. Lherm T, Monet C, Nougière B, et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002; 28:797–801.
  11. Salminen MK, Rautelin H, Tynkkynen S, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004; 38:62–69.
  12. Merrigan MM, Sambol SP, Johnson S, Gerding DN. Prevention of fatal Clostridium difficile-associated disease during continuous administration of clindamycin in hamsters. J Infect Dis 2003; 188:1922–1927.
References
  1. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005; 173:167–170.
  2. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008;CD004611.
  3. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101:812–822.
  4. McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271:1913–1918.
  5. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31:1012–1017.
  6. Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999; 67:302–307.
  7. Huff BA. Caveat emptor. “Probiotics” might not be what they seem. Can Fam Physician 2004; 50:583–587.
  8. Coeuret V, Gueguen M, Vernoux J. Numbers and strains of lactobacilli in some probiotic products. Int J Food Microbiol 2004; 97:147–156.
  9. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005; 115;178–181.
  10. Lherm T, Monet C, Nougière B, et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002; 28:797–801.
  11. Salminen MK, Rautelin H, Tynkkynen S, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004; 38:62–69.
  12. Merrigan MM, Sambol SP, Johnson S, Gerding DN. Prevention of fatal Clostridium difficile-associated disease during continuous administration of clindamycin in hamsters. J Infect Dis 2003; 188:1922–1927.
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The blade, the flea, and the colon

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We see our patients and their medical problems through lenses colored by our experiences. As internists, we pride ourselves on our reflective skills and our ability to draw on our understanding of pathophysiologic principles in therapeutic decision-making. But we, and our surgical colleagues, recognize our limitations as we deal with acute disease. We internists cogitate and temporize, and we are sometimes called “fleas” because of our attention to minuscule detail. Surgeons, on the other hand, get to act, working in the moment of acuity to bring resolution and, hopefully, prevent chronic disease from taking hold. The professional roles are cast, and we play our parts as expected—except in cases of ischemic colitis.

As Elder et al point out in this issue of the Journal, the management of ischemic colitis presents an interesting clinical paradox: the internist makes the diagnosis of potentially life-threatening impending tissue necrosis, while the surgeon, consulted to act, tends to be a cheerleader for temperate observation.

Ischemic colitis may account for 1 in 1,000 hospitalizations. Many patients present with a combination of focal lower abdominal pain and some bloody diarrhea. The examiner often localizes the tender colon either by anterior palpation or by rectal examination, unlike the scenario of life-threatening small bowel ischemia, in which severe pain may be accompanied by a fairly “benign” examination.

Some cases of ischemic colitis require resection of a gangrenous colon or become chronic and lead to the development of a stricture. But far more often the ischemic episode resolves after several days of watchful waiting. The typical but not specific endoscopic findings and the thumb-printing and thickening seen on radiographic imaging resolve.

Whatever the assumed cause (a specific one is often not found), ischemic colitis gives the internist and the surgeon a chance to commiserate on the power of informed watchful waiting.

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Related Articles
Clinical approach to colonic ischemia

We see our patients and their medical problems through lenses colored by our experiences. As internists, we pride ourselves on our reflective skills and our ability to draw on our understanding of pathophysiologic principles in therapeutic decision-making. But we, and our surgical colleagues, recognize our limitations as we deal with acute disease. We internists cogitate and temporize, and we are sometimes called “fleas” because of our attention to minuscule detail. Surgeons, on the other hand, get to act, working in the moment of acuity to bring resolution and, hopefully, prevent chronic disease from taking hold. The professional roles are cast, and we play our parts as expected—except in cases of ischemic colitis.

As Elder et al point out in this issue of the Journal, the management of ischemic colitis presents an interesting clinical paradox: the internist makes the diagnosis of potentially life-threatening impending tissue necrosis, while the surgeon, consulted to act, tends to be a cheerleader for temperate observation.

Ischemic colitis may account for 1 in 1,000 hospitalizations. Many patients present with a combination of focal lower abdominal pain and some bloody diarrhea. The examiner often localizes the tender colon either by anterior palpation or by rectal examination, unlike the scenario of life-threatening small bowel ischemia, in which severe pain may be accompanied by a fairly “benign” examination.

Some cases of ischemic colitis require resection of a gangrenous colon or become chronic and lead to the development of a stricture. But far more often the ischemic episode resolves after several days of watchful waiting. The typical but not specific endoscopic findings and the thumb-printing and thickening seen on radiographic imaging resolve.

Whatever the assumed cause (a specific one is often not found), ischemic colitis gives the internist and the surgeon a chance to commiserate on the power of informed watchful waiting.

We see our patients and their medical problems through lenses colored by our experiences. As internists, we pride ourselves on our reflective skills and our ability to draw on our understanding of pathophysiologic principles in therapeutic decision-making. But we, and our surgical colleagues, recognize our limitations as we deal with acute disease. We internists cogitate and temporize, and we are sometimes called “fleas” because of our attention to minuscule detail. Surgeons, on the other hand, get to act, working in the moment of acuity to bring resolution and, hopefully, prevent chronic disease from taking hold. The professional roles are cast, and we play our parts as expected—except in cases of ischemic colitis.

As Elder et al point out in this issue of the Journal, the management of ischemic colitis presents an interesting clinical paradox: the internist makes the diagnosis of potentially life-threatening impending tissue necrosis, while the surgeon, consulted to act, tends to be a cheerleader for temperate observation.

Ischemic colitis may account for 1 in 1,000 hospitalizations. Many patients present with a combination of focal lower abdominal pain and some bloody diarrhea. The examiner often localizes the tender colon either by anterior palpation or by rectal examination, unlike the scenario of life-threatening small bowel ischemia, in which severe pain may be accompanied by a fairly “benign” examination.

Some cases of ischemic colitis require resection of a gangrenous colon or become chronic and lead to the development of a stricture. But far more often the ischemic episode resolves after several days of watchful waiting. The typical but not specific endoscopic findings and the thumb-printing and thickening seen on radiographic imaging resolve.

Whatever the assumed cause (a specific one is often not found), ischemic colitis gives the internist and the surgeon a chance to commiserate on the power of informed watchful waiting.

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Clinical approach to colonic ischemia

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Clinical approach to colonic ischemia
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Kareem Elder, MD
Bret A. Lashner, MD
Firas Al Solaiman, MD

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia1 and is responsible for an estimated 1 in 2,000 hospital admissions.2

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.
Figure 1. The arteries supplying the large intestine. In spite of an extensive network of collateral arteries, the watershed areas between major arteries are vulnerable to hypoperfusion.
During systemic hypotension, ischemic injury most often occurs at “watershed” areas, where the collateral arteries are small and narrow. These involve the terminal branches of the superior mesenteric artery supplying the splenic flexure and those of the inferior mesenteric artery supplying the rectosigmoid junction. (Figure 1).3,4 Although any area of the colon can be affected, approximately 75% of cases involve the left colon, and nearly 25% involve the splenic flexure.5

MANY POSSIBLE CAUSES AND FACTORS

Colonic ischemia is caused by a diminution of the colonic blood supply that is so severe that metabolic demands are not met. This diminution is most often the result of a decrease in systemic perfusion or an anatomic occlusion. Although it can be associated with many medical and surgical conditions (Table 1), a specific cause cannot be determined in most cases.

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.6 Binns and Isaacson7 suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.8

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al9 found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell10 found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.11

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).16

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al27 reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al20 reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

  • Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.30 It was later reinstated, with some restrictions.
  • Digitalis
  • Diuretics
  • Estrogens
  • Danazol (Danocrine)
  • Nonsteroidal anti-inflammatory drugs
  • Tegaserod (Zelnorm)
  • Paclitaxel (Abraxane)
  • Carboplatin (Paraplatin)
  • Sumatriptan (Imitrex)
  • Simvastatin (Zocor)
  • Interferon-ribavirin31
  • Pseudoephedrine (eg, Sudafed).32

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.33

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.36

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.37 This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.38

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).39

 

 

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

  • Rapid onset of mild abdominal pain
  • Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
  • Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.40

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.4

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.41 In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation42:

  • Reversible colonopathy (submucosal or intramural hemorrhage)
  • Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al43)
  • Chronic colitis (19% of cases)
  • Stricture (13%)
  • Gangrene (19%)
  • Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.44

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).45

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. 46

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 109/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.48

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.49,50

Figure 2. Mildly active ischemic colitis with a large superficial ulcer in the watershed area of the splenic flexure.
In early and mild disease (Figure 2), the mucosa is pale and edematous with petechiae, and the single-stripe sign is present.

Figure 3. Severely active ischemic colitis with extensive ulceration and submucosal hemorrhage distributed segmentally in the distal transverse colon and descending colon.
As ischemia progresses, hemorrhagic nodules appear (visible as “thumbprinting” on barium enema radiographs), usually in the company of erythematous mucosa with dispersed ulcerations and submucosal hemorrhage (Figure 3). Severe ischemia causing gangrene usually manifests as cyanotic mucosal nodules and hemorrhagic ulcerations.51–53

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.54,55

 

 

Imaging studies are not specific

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.56 However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.9 A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.
Figure 4. Management of colonic ischemia.
Conservative therapy with intravenous fluids, hemodynamic stabilization, discontinuation or avoidance of vasoconstrictive agents, bowel rest, and empiric antibiotics is effective in most cases (Figure 4).

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.42 Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.57 However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.58 Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.40

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  23. Verger P, Blanc C, Feydy P, Boey S. Ischemic colitis caused by protein S deficiency. Presse Med 1996; 25:1350.
  24. Ludwig D, Stahl M, David-Walek T, et al. Ischemic colitis, pulmonary embolism, and atrial thrombosis in a patient with inherited resistance to activated protein C. Dig Dis Sci 1998; 43:1362–1367.
  25. Yee NS, Guerry D, Lichtenstein GR. Ischemic colitis associated with factor V Leiden mutation. Ann Intern Med 2000; 132:595–596.
  26. Balian A, Veyradier A, Naveau S, et al. Prothrombin 20210G/A mutation in two patients with mesenteric ischemia. Dig Dis Sci 1999; 44:1910–1913.
  27. Arnott ID, Ghosh S, Ferguson A. The spectrum of ischaemic colitis. Eur J Gastroenterol Hepatol 1999; 11:295–303.
  28. Chin BW, Greenberg D, Wilson RB, Meredith CG. A case of ischemic colitis associated with factor V Leiden mutation: successful treatment with anticoagulation. Gastrointest Endosc 2007; 66:416–418.
  29. Heyn J, Buhmann S, Ladurner R, et al. Recurrent ischemic colitis in a patient with Leiden factor V mutation and systemic lupus erythematosus with antiphospholipid syndrome. Eur J Med Res 2008; 13:182–184.
  30. Chang L, Chey WD, Harris L, Olden K, Surawicz C, Schoenfeld P. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol 2006; 101:1069–1079.
  31. Punnam SR, Pothula VR, Gourineni N, Punnam A, Ranganathan V. Interferon-ribavirin-associated ischemic colitis. J Clin Gastroenterol 2008; 42:323–325.
  32. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. Am J Gastroenterol 1999; 94:2430–2434.
  33. Kingsley DD, Schermer CR, Jamal MM. Rare complications of endoscopic retrograde cholangiopancreatography: two case reports. JSLS 2001; 5:171–173.
  34. Boley SJ, Agrawal GP, Warren AR, et al. Pathophysiologic effects of bowel distension on intestinal blood flow. Am J Surg 1969; 117:228–234.
  35. Reinus JF, Brandt LJ, Boley SJ. Ischemic diseases of the bowel. Gastroenterol Clin North Am 1990; 19:319–343.
  36. Moses FM. Exercise-associated intestinal ischemia. Curr Sports Med Rep 2005; 4:91–95.
  37. Rosenblum JD, Boyle CM, Schwartz LB. The mesenteric circulation. Anatomy and physiology. Surg Clin North Am 1997; 77:289–306.
  38. Haglund U, Bulkley GB, Granger DN. On the pathophysiology of intestinal ischemic injury. Clinical review. Acta Chir Scand 1987; 153:321–324.
  39. Kim MK, Cho YS, Kim HK, Kim JS, Kim SS, Chae HS. Transient ischemic colitis after a pit viper bite (Agkistrodon blomhoffii brevicaudus). J Clin Gastroenterol 2008; 42:111–112.
  40. Cappell MS. Intestinal (mesenteric) vasculopathy. II. Ischemic colitis and chronic mesenteric ischemia. Gastroenterol Clin North Am 1998; 27:827–860.
  41. Greenwald DA, Brandt LJ. Colonic ischemia. J Clin Gastroenterol 1998; 27:122–128.
  42. Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology 2000; 118:954–968.
  43. Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of the intestines. Curr Probl Surg 1978; 15:1–85.
  44. Schuler JG, Hudlin MM. Cecal necrosis: infrequent variant of ischemic colitis. Report of five cases. Dis Colon Rectum 2000; 43:708–712.
  45. Sotiriadis J, Brandt LJ, Behin DS, Southern WN. Ischemic colitis has a worse prognosis when isolated to the right side of the colon. Am J Gastroenterol 2007; 102:2247–2252.
  46. Park CJ, Jang MK, Shin WG, et al. Can we predict the development of ischemic colitis among patients with lower abdominal pain? Dis Colon Rectum 2007; 50:232–238.
  47. Su C, Brandt LJ, Sigal SH, et al. The immunohistological diagnosis of E. coli 0157:H7 colitis: possible association with colonic ischemia. Am J Gastroenterol 1998; 93:1055–1059.
  48. Scowcroft CW, Sanowski RA, Kozarek RA. Colonoscopy in ischemic colitis. Gastrointest Endosc 1981; 27:156–161.
  49. Rogers AI, David S. Intestinal blood flow and diseases of vascular impairment. In: Haubrich WS, Schaffner F, Berk JE, editors. Gastroenterology. 5th ed. Philadelphia: WB Saunders; 1995:1212–1234.
  50. Zuckerman GR, Prakash C, Merriman RB, Sawhney MS, DeSchryver-Kecskemeti K, Clouse RE. The colon single-stripe sign and its relationship to ischemic colitis. Am J Gastroenterol 2003; 98:2018–2022.
  51. Green BT, Tendler DA. Ischemic colitis: a clinical review. South Med J 2005; 98:217–222.
  52. Baixauli J, Kiran RP, Delaney CP. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–930.
  53. Habu Y, Tahashi Y, Kiyota K, et al. Reevaluation of clinical features of ischemic colitis: analysis of 68 consecutive cases diagnosed by early colonoscopy. Scand J Gastroenterol 1996; 31:881–886.
  54. Mitsudo S, Brandt LJ. Pathology of intestinal ischemia. Surg Clin North Am 1992; 72:43–63.
  55. Price AB. Ischaemic colitis. Curr Top Pathol 1990; 81:229–246.
  56. Balthazar EJ, Yen BC, Gordon RB. Ischemic colitis: CT evaluation of 54 cases. Radiology 1999; 211:381–388.
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  59. Oz MC, Forde KA. Endoscopic alternatives in the management of colonic strictures. Surgery 1990; 108:513–519.
  60. Profili S, Bifulco V, Meloni GB, Demelas L, Niolu P, Manzoni MA. A case of ischemic stenosis of the colon-sigmoid treated with self-expandable uncoated metallic prosthesis. Radiol Med 1996; 91:665–667.
  61. Brandt LJ, Boley SJ. Colonic ischemia. Surg Clin North Am 1992; 72:203–229.
  62. Boley SJ. 1989 David H. Sun lecture. Colonic ischemia—25 years later. Am J Gastroenterol 1990; 85:931–934.
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Firas Al Solaiman, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Firas Al Solaiman, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Address: Firas Al Solaiman, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Related Articles
The blade, the flea, and the colon

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia1 and is responsible for an estimated 1 in 2,000 hospital admissions.2

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.
Figure 1. The arteries supplying the large intestine. In spite of an extensive network of collateral arteries, the watershed areas between major arteries are vulnerable to hypoperfusion.
During systemic hypotension, ischemic injury most often occurs at “watershed” areas, where the collateral arteries are small and narrow. These involve the terminal branches of the superior mesenteric artery supplying the splenic flexure and those of the inferior mesenteric artery supplying the rectosigmoid junction. (Figure 1).3,4 Although any area of the colon can be affected, approximately 75% of cases involve the left colon, and nearly 25% involve the splenic flexure.5

MANY POSSIBLE CAUSES AND FACTORS

Colonic ischemia is caused by a diminution of the colonic blood supply that is so severe that metabolic demands are not met. This diminution is most often the result of a decrease in systemic perfusion or an anatomic occlusion. Although it can be associated with many medical and surgical conditions (Table 1), a specific cause cannot be determined in most cases.

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.6 Binns and Isaacson7 suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.8

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al9 found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell10 found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.11

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).16

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al27 reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al20 reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

  • Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.30 It was later reinstated, with some restrictions.
  • Digitalis
  • Diuretics
  • Estrogens
  • Danazol (Danocrine)
  • Nonsteroidal anti-inflammatory drugs
  • Tegaserod (Zelnorm)
  • Paclitaxel (Abraxane)
  • Carboplatin (Paraplatin)
  • Sumatriptan (Imitrex)
  • Simvastatin (Zocor)
  • Interferon-ribavirin31
  • Pseudoephedrine (eg, Sudafed).32

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.33

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.36

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.37 This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.38

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).39

 

 

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

  • Rapid onset of mild abdominal pain
  • Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
  • Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.40

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.4

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.41 In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation42:

  • Reversible colonopathy (submucosal or intramural hemorrhage)
  • Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al43)
  • Chronic colitis (19% of cases)
  • Stricture (13%)
  • Gangrene (19%)
  • Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.44

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).45

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. 46

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 109/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.48

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.49,50

Figure 2. Mildly active ischemic colitis with a large superficial ulcer in the watershed area of the splenic flexure.
In early and mild disease (Figure 2), the mucosa is pale and edematous with petechiae, and the single-stripe sign is present.

Figure 3. Severely active ischemic colitis with extensive ulceration and submucosal hemorrhage distributed segmentally in the distal transverse colon and descending colon.
As ischemia progresses, hemorrhagic nodules appear (visible as “thumbprinting” on barium enema radiographs), usually in the company of erythematous mucosa with dispersed ulcerations and submucosal hemorrhage (Figure 3). Severe ischemia causing gangrene usually manifests as cyanotic mucosal nodules and hemorrhagic ulcerations.51–53

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.54,55

 

 

Imaging studies are not specific

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.56 However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.9 A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.
Figure 4. Management of colonic ischemia.
Conservative therapy with intravenous fluids, hemodynamic stabilization, discontinuation or avoidance of vasoconstrictive agents, bowel rest, and empiric antibiotics is effective in most cases (Figure 4).

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.42 Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.57 However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.58 Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.40

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia1 and is responsible for an estimated 1 in 2,000 hospital admissions.2

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.
Figure 1. The arteries supplying the large intestine. In spite of an extensive network of collateral arteries, the watershed areas between major arteries are vulnerable to hypoperfusion.
During systemic hypotension, ischemic injury most often occurs at “watershed” areas, where the collateral arteries are small and narrow. These involve the terminal branches of the superior mesenteric artery supplying the splenic flexure and those of the inferior mesenteric artery supplying the rectosigmoid junction. (Figure 1).3,4 Although any area of the colon can be affected, approximately 75% of cases involve the left colon, and nearly 25% involve the splenic flexure.5

MANY POSSIBLE CAUSES AND FACTORS

Colonic ischemia is caused by a diminution of the colonic blood supply that is so severe that metabolic demands are not met. This diminution is most often the result of a decrease in systemic perfusion or an anatomic occlusion. Although it can be associated with many medical and surgical conditions (Table 1), a specific cause cannot be determined in most cases.

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.6 Binns and Isaacson7 suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.8

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al9 found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell10 found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.11

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).16

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al27 reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al20 reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

  • Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.30 It was later reinstated, with some restrictions.
  • Digitalis
  • Diuretics
  • Estrogens
  • Danazol (Danocrine)
  • Nonsteroidal anti-inflammatory drugs
  • Tegaserod (Zelnorm)
  • Paclitaxel (Abraxane)
  • Carboplatin (Paraplatin)
  • Sumatriptan (Imitrex)
  • Simvastatin (Zocor)
  • Interferon-ribavirin31
  • Pseudoephedrine (eg, Sudafed).32

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.33

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.36

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.37 This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.38

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).39

 

 

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

  • Rapid onset of mild abdominal pain
  • Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
  • Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.40

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.4

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.41 In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation42:

  • Reversible colonopathy (submucosal or intramural hemorrhage)
  • Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al43)
  • Chronic colitis (19% of cases)
  • Stricture (13%)
  • Gangrene (19%)
  • Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.44

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).45

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. 46

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 109/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.48

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.49,50

Figure 2. Mildly active ischemic colitis with a large superficial ulcer in the watershed area of the splenic flexure.
In early and mild disease (Figure 2), the mucosa is pale and edematous with petechiae, and the single-stripe sign is present.

Figure 3. Severely active ischemic colitis with extensive ulceration and submucosal hemorrhage distributed segmentally in the distal transverse colon and descending colon.
As ischemia progresses, hemorrhagic nodules appear (visible as “thumbprinting” on barium enema radiographs), usually in the company of erythematous mucosa with dispersed ulcerations and submucosal hemorrhage (Figure 3). Severe ischemia causing gangrene usually manifests as cyanotic mucosal nodules and hemorrhagic ulcerations.51–53

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.54,55

 

 

Imaging studies are not specific

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.56 However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.9 A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.
Figure 4. Management of colonic ischemia.
Conservative therapy with intravenous fluids, hemodynamic stabilization, discontinuation or avoidance of vasoconstrictive agents, bowel rest, and empiric antibiotics is effective in most cases (Figure 4).

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.42 Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.57 However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.58 Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.40

References
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  21. Midian-Singh R, Polen A, Durishin C, Crock RD, Whittier FC, Fahmy N. Ischemic colitis revisited: a prospective study identifying hypercoagulability as a risk factor. South Med J 2004; 97:120–123.
  22. Blanc P, Bories P, Donadio D, et al. Ischemic colitis and recurrent venous thrombosis caused by familial protein S deficiency. Gastroenterol Clin Biol 1989; 13:945.
  23. Verger P, Blanc C, Feydy P, Boey S. Ischemic colitis caused by protein S deficiency. Presse Med 1996; 25:1350.
  24. Ludwig D, Stahl M, David-Walek T, et al. Ischemic colitis, pulmonary embolism, and atrial thrombosis in a patient with inherited resistance to activated protein C. Dig Dis Sci 1998; 43:1362–1367.
  25. Yee NS, Guerry D, Lichtenstein GR. Ischemic colitis associated with factor V Leiden mutation. Ann Intern Med 2000; 132:595–596.
  26. Balian A, Veyradier A, Naveau S, et al. Prothrombin 20210G/A mutation in two patients with mesenteric ischemia. Dig Dis Sci 1999; 44:1910–1913.
  27. Arnott ID, Ghosh S, Ferguson A. The spectrum of ischaemic colitis. Eur J Gastroenterol Hepatol 1999; 11:295–303.
  28. Chin BW, Greenberg D, Wilson RB, Meredith CG. A case of ischemic colitis associated with factor V Leiden mutation: successful treatment with anticoagulation. Gastrointest Endosc 2007; 66:416–418.
  29. Heyn J, Buhmann S, Ladurner R, et al. Recurrent ischemic colitis in a patient with Leiden factor V mutation and systemic lupus erythematosus with antiphospholipid syndrome. Eur J Med Res 2008; 13:182–184.
  30. Chang L, Chey WD, Harris L, Olden K, Surawicz C, Schoenfeld P. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol 2006; 101:1069–1079.
  31. Punnam SR, Pothula VR, Gourineni N, Punnam A, Ranganathan V. Interferon-ribavirin-associated ischemic colitis. J Clin Gastroenterol 2008; 42:323–325.
  32. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. Am J Gastroenterol 1999; 94:2430–2434.
  33. Kingsley DD, Schermer CR, Jamal MM. Rare complications of endoscopic retrograde cholangiopancreatography: two case reports. JSLS 2001; 5:171–173.
  34. Boley SJ, Agrawal GP, Warren AR, et al. Pathophysiologic effects of bowel distension on intestinal blood flow. Am J Surg 1969; 117:228–234.
  35. Reinus JF, Brandt LJ, Boley SJ. Ischemic diseases of the bowel. Gastroenterol Clin North Am 1990; 19:319–343.
  36. Moses FM. Exercise-associated intestinal ischemia. Curr Sports Med Rep 2005; 4:91–95.
  37. Rosenblum JD, Boyle CM, Schwartz LB. The mesenteric circulation. Anatomy and physiology. Surg Clin North Am 1997; 77:289–306.
  38. Haglund U, Bulkley GB, Granger DN. On the pathophysiology of intestinal ischemic injury. Clinical review. Acta Chir Scand 1987; 153:321–324.
  39. Kim MK, Cho YS, Kim HK, Kim JS, Kim SS, Chae HS. Transient ischemic colitis after a pit viper bite (Agkistrodon blomhoffii brevicaudus). J Clin Gastroenterol 2008; 42:111–112.
  40. Cappell MS. Intestinal (mesenteric) vasculopathy. II. Ischemic colitis and chronic mesenteric ischemia. Gastroenterol Clin North Am 1998; 27:827–860.
  41. Greenwald DA, Brandt LJ. Colonic ischemia. J Clin Gastroenterol 1998; 27:122–128.
  42. Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology 2000; 118:954–968.
  43. Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of the intestines. Curr Probl Surg 1978; 15:1–85.
  44. Schuler JG, Hudlin MM. Cecal necrosis: infrequent variant of ischemic colitis. Report of five cases. Dis Colon Rectum 2000; 43:708–712.
  45. Sotiriadis J, Brandt LJ, Behin DS, Southern WN. Ischemic colitis has a worse prognosis when isolated to the right side of the colon. Am J Gastroenterol 2007; 102:2247–2252.
  46. Park CJ, Jang MK, Shin WG, et al. Can we predict the development of ischemic colitis among patients with lower abdominal pain? Dis Colon Rectum 2007; 50:232–238.
  47. Su C, Brandt LJ, Sigal SH, et al. The immunohistological diagnosis of E. coli 0157:H7 colitis: possible association with colonic ischemia. Am J Gastroenterol 1998; 93:1055–1059.
  48. Scowcroft CW, Sanowski RA, Kozarek RA. Colonoscopy in ischemic colitis. Gastrointest Endosc 1981; 27:156–161.
  49. Rogers AI, David S. Intestinal blood flow and diseases of vascular impairment. In: Haubrich WS, Schaffner F, Berk JE, editors. Gastroenterology. 5th ed. Philadelphia: WB Saunders; 1995:1212–1234.
  50. Zuckerman GR, Prakash C, Merriman RB, Sawhney MS, DeSchryver-Kecskemeti K, Clouse RE. The colon single-stripe sign and its relationship to ischemic colitis. Am J Gastroenterol 2003; 98:2018–2022.
  51. Green BT, Tendler DA. Ischemic colitis: a clinical review. South Med J 2005; 98:217–222.
  52. Baixauli J, Kiran RP, Delaney CP. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–930.
  53. Habu Y, Tahashi Y, Kiyota K, et al. Reevaluation of clinical features of ischemic colitis: analysis of 68 consecutive cases diagnosed by early colonoscopy. Scand J Gastroenterol 1996; 31:881–886.
  54. Mitsudo S, Brandt LJ. Pathology of intestinal ischemia. Surg Clin North Am 1992; 72:43–63.
  55. Price AB. Ischaemic colitis. Curr Top Pathol 1990; 81:229–246.
  56. Balthazar EJ, Yen BC, Gordon RB. Ischemic colitis: CT evaluation of 54 cases. Radiology 1999; 211:381–388.
  57. Mosdell DM, Doberneck RC. Morbidity and mortality of ostomy closure. Am J Surg 1991; 162:633–636.
  58. Iqbal T, Zarin M, Iqbal A, et al. Results of primary closure in the management of gangrenous and viable sigmoid volvulus. Pak J Surg 2007; 23:118–121.
  59. Oz MC, Forde KA. Endoscopic alternatives in the management of colonic strictures. Surgery 1990; 108:513–519.
  60. Profili S, Bifulco V, Meloni GB, Demelas L, Niolu P, Manzoni MA. A case of ischemic stenosis of the colon-sigmoid treated with self-expandable uncoated metallic prosthesis. Radiol Med 1996; 91:665–667.
  61. Brandt LJ, Boley SJ. Colonic ischemia. Surg Clin North Am 1992; 72:203–229.
  62. Boley SJ. 1989 David H. Sun lecture. Colonic ischemia—25 years later. Am J Gastroenterol 1990; 85:931–934.
References
  1. Higgins PD, Davis KJ, Laine L. Systematic review: the epidemiology of ischaemic colitis. Aliment Pharmacol Ther 2004; 19:729–738.
  2. Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 7th ed. Philadelphia, PA: Saunders; 2002.
  3. Gandhi SK, Hanson MM, Vernava AM, Kaminski DL, Longo WE. Ischemic colitis. Dis Colon Rectum 1996; 39:88–100.
  4. Greenwald DA, Brandt LJ, Reinus JF. Ischemic bowel disease in the elderly. Gastroenterol Clin North Am 2001; 30:445–473.
  5. Reeders JW, Tytgat GN, Rosenbusch G, et al. Ischaemic colitis. The Hague: Martinus Nijhoff, 1984;17.
  6. Brandt L, Boley S, Goldberg L, Mitsudo S, Berman A. Colitis in the elderly. A reappraisal. Am J Gastroenterol 1981; 76:239–245.
  7. Binns JC, Isaacson P. Age-related changes in the colonic blood supply: their relevance to ischaemic colitis. Gut 1978; 19:384–390.
  8. Zimmerman BJ, Granger DN. Reperfusion injury. Surg Clin North Am 1992; 72:65–83.
  9. Hourmand-Ollivier I, Bouin M, Saloux E, et al. Cardiac sources of embolism should be routinely screened in ischemic colitis. Am J Gastroenterol 2003; 98:1573–1577.
  10. Cappell MS. Safety and efficacy of colonoscopy after myocardial infarction: an analysis of 100 study patients and 100 control patients at two tertiary cardiac referral hospitals. Gastrointest Endosc 2004; 60:901–909.
  11. Cappell MS, Mahajan D, Kurupath V. Characterization of ischemic colitis associated with myocardial infarction: an analysis of 23 patients. Am J Med 2006; 119:527.e1–e9.
  12. Hagihara PF, Ernst CB, Griffen WO. Incidence of ischemic colitis following abdominal aortic reconstruction. Surg Gynecol Obstet 1979; 149:571–573.
  13. Brewster DC, Franklin DP, Cambria RP, et al. Intestinal ischemia complicating abdominal aortic surgery. Surgery 1991; 109:447–454.
  14. Piotrowski JJ, Ripepi AJ, Yuhas JP, Alexander JJ, Brandt CP. Colonic ischemia: the Achilles heel of ruptured aortic aneurysm repair. Am Surg 1996; 62:557–560.
  15. Ernst CB. Colonic ischemia following aortic reconstruction. In: Rutherford RB, editor. Vascular Surgery. 4th ed. Philadelphia, PA: WB Saunders; 1995:1312–1320.
  16. Geroghty PS, Sanchez LA, Rubin BG, et al. Overt ischemic colitis after endovascular repair of aortoiliac aneurysm. J Vasc Surg 2004; 40:413–418.
  17. Klestzick HN, McPhedran P, Cipolla D, Berry WA, DiCorato M, Denowitz J. The antiphospholipid syndrome and ischemic colitis. Gastroenterologist 1995; 3:249–256.
  18. Knot EA, ten Cate JW, Bruin T, Iburg AH, Tytgat GN. Antithrombin III metabolism in two colitis patients with acquired antithrombin III deficiency. Gastroenterology 1985; 89:421–425.
  19. Maloisel F. Role of coagulation disorders in mesenteric ischemia. J Chir (Paris) 1996; 133:442–447.
  20. Koutroubakis IE, Sfiridaki A, Theodoropoulou A, Kouroumalis EA. Role of acquired and hereditary thrombotic risk factors in colon ischemia of ambulatory patients. Gastroenterology 2001; 121:561–565.
  21. Midian-Singh R, Polen A, Durishin C, Crock RD, Whittier FC, Fahmy N. Ischemic colitis revisited: a prospective study identifying hypercoagulability as a risk factor. South Med J 2004; 97:120–123.
  22. Blanc P, Bories P, Donadio D, et al. Ischemic colitis and recurrent venous thrombosis caused by familial protein S deficiency. Gastroenterol Clin Biol 1989; 13:945.
  23. Verger P, Blanc C, Feydy P, Boey S. Ischemic colitis caused by protein S deficiency. Presse Med 1996; 25:1350.
  24. Ludwig D, Stahl M, David-Walek T, et al. Ischemic colitis, pulmonary embolism, and atrial thrombosis in a patient with inherited resistance to activated protein C. Dig Dis Sci 1998; 43:1362–1367.
  25. Yee NS, Guerry D, Lichtenstein GR. Ischemic colitis associated with factor V Leiden mutation. Ann Intern Med 2000; 132:595–596.
  26. Balian A, Veyradier A, Naveau S, et al. Prothrombin 20210G/A mutation in two patients with mesenteric ischemia. Dig Dis Sci 1999; 44:1910–1913.
  27. Arnott ID, Ghosh S, Ferguson A. The spectrum of ischaemic colitis. Eur J Gastroenterol Hepatol 1999; 11:295–303.
  28. Chin BW, Greenberg D, Wilson RB, Meredith CG. A case of ischemic colitis associated with factor V Leiden mutation: successful treatment with anticoagulation. Gastrointest Endosc 2007; 66:416–418.
  29. Heyn J, Buhmann S, Ladurner R, et al. Recurrent ischemic colitis in a patient with Leiden factor V mutation and systemic lupus erythematosus with antiphospholipid syndrome. Eur J Med Res 2008; 13:182–184.
  30. Chang L, Chey WD, Harris L, Olden K, Surawicz C, Schoenfeld P. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol 2006; 101:1069–1079.
  31. Punnam SR, Pothula VR, Gourineni N, Punnam A, Ranganathan V. Interferon-ribavirin-associated ischemic colitis. J Clin Gastroenterol 2008; 42:323–325.
  32. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. Am J Gastroenterol 1999; 94:2430–2434.
  33. Kingsley DD, Schermer CR, Jamal MM. Rare complications of endoscopic retrograde cholangiopancreatography: two case reports. JSLS 2001; 5:171–173.
  34. Boley SJ, Agrawal GP, Warren AR, et al. Pathophysiologic effects of bowel distension on intestinal blood flow. Am J Surg 1969; 117:228–234.
  35. Reinus JF, Brandt LJ, Boley SJ. Ischemic diseases of the bowel. Gastroenterol Clin North Am 1990; 19:319–343.
  36. Moses FM. Exercise-associated intestinal ischemia. Curr Sports Med Rep 2005; 4:91–95.
  37. Rosenblum JD, Boyle CM, Schwartz LB. The mesenteric circulation. Anatomy and physiology. Surg Clin North Am 1997; 77:289–306.
  38. Haglund U, Bulkley GB, Granger DN. On the pathophysiology of intestinal ischemic injury. Clinical review. Acta Chir Scand 1987; 153:321–324.
  39. Kim MK, Cho YS, Kim HK, Kim JS, Kim SS, Chae HS. Transient ischemic colitis after a pit viper bite (Agkistrodon blomhoffii brevicaudus). J Clin Gastroenterol 2008; 42:111–112.
  40. Cappell MS. Intestinal (mesenteric) vasculopathy. II. Ischemic colitis and chronic mesenteric ischemia. Gastroenterol Clin North Am 1998; 27:827–860.
  41. Greenwald DA, Brandt LJ. Colonic ischemia. J Clin Gastroenterol 1998; 27:122–128.
  42. Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology 2000; 118:954–968.
  43. Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of the intestines. Curr Probl Surg 1978; 15:1–85.
  44. Schuler JG, Hudlin MM. Cecal necrosis: infrequent variant of ischemic colitis. Report of five cases. Dis Colon Rectum 2000; 43:708–712.
  45. Sotiriadis J, Brandt LJ, Behin DS, Southern WN. Ischemic colitis has a worse prognosis when isolated to the right side of the colon. Am J Gastroenterol 2007; 102:2247–2252.
  46. Park CJ, Jang MK, Shin WG, et al. Can we predict the development of ischemic colitis among patients with lower abdominal pain? Dis Colon Rectum 2007; 50:232–238.
  47. Su C, Brandt LJ, Sigal SH, et al. The immunohistological diagnosis of E. coli 0157:H7 colitis: possible association with colonic ischemia. Am J Gastroenterol 1998; 93:1055–1059.
  48. Scowcroft CW, Sanowski RA, Kozarek RA. Colonoscopy in ischemic colitis. Gastrointest Endosc 1981; 27:156–161.
  49. Rogers AI, David S. Intestinal blood flow and diseases of vascular impairment. In: Haubrich WS, Schaffner F, Berk JE, editors. Gastroenterology. 5th ed. Philadelphia: WB Saunders; 1995:1212–1234.
  50. Zuckerman GR, Prakash C, Merriman RB, Sawhney MS, DeSchryver-Kecskemeti K, Clouse RE. The colon single-stripe sign and its relationship to ischemic colitis. Am J Gastroenterol 2003; 98:2018–2022.
  51. Green BT, Tendler DA. Ischemic colitis: a clinical review. South Med J 2005; 98:217–222.
  52. Baixauli J, Kiran RP, Delaney CP. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–930.
  53. Habu Y, Tahashi Y, Kiyota K, et al. Reevaluation of clinical features of ischemic colitis: analysis of 68 consecutive cases diagnosed by early colonoscopy. Scand J Gastroenterol 1996; 31:881–886.
  54. Mitsudo S, Brandt LJ. Pathology of intestinal ischemia. Surg Clin North Am 1992; 72:43–63.
  55. Price AB. Ischaemic colitis. Curr Top Pathol 1990; 81:229–246.
  56. Balthazar EJ, Yen BC, Gordon RB. Ischemic colitis: CT evaluation of 54 cases. Radiology 1999; 211:381–388.
  57. Mosdell DM, Doberneck RC. Morbidity and mortality of ostomy closure. Am J Surg 1991; 162:633–636.
  58. Iqbal T, Zarin M, Iqbal A, et al. Results of primary closure in the management of gangrenous and viable sigmoid volvulus. Pak J Surg 2007; 23:118–121.
  59. Oz MC, Forde KA. Endoscopic alternatives in the management of colonic strictures. Surgery 1990; 108:513–519.
  60. Profili S, Bifulco V, Meloni GB, Demelas L, Niolu P, Manzoni MA. A case of ischemic stenosis of the colon-sigmoid treated with self-expandable uncoated metallic prosthesis. Radiol Med 1996; 91:665–667.
  61. Brandt LJ, Boley SJ. Colonic ischemia. Surg Clin North Am 1992; 72:203–229.
  62. Boley SJ. 1989 David H. Sun lecture. Colonic ischemia—25 years later. Am J Gastroenterol 1990; 85:931–934.
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KEY POINTS

  • The incidence of colonic ischemia is difficult to ascertain, as most cases are transient and either not reported or misdiagnosed.
  • Most cases are in the elderly.
  • The clinical presentation is not specific, as other conditions also present with abdominal pain and hematochezia.
  • The most common mechanisms are hypotension and hypovolemia caused by dehydration or bleeding that results in systemic hypoperfusion.
  • Endoscopy has become the diagnostic procedure of choice.
  • Although most patients can be treated conservatively with intravenous fluids, bowel rest, and antibiotics, some develop peritonitis or clinically deteriorate and require surgery.
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In reply: Radiologic workup of a palpable breast mass

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The authors thank Dr. Keller for his readership. (On a personal note, Dr. Chellman-Jeffers spent her childhood in the Los Angeles area near his practice.) Dr. Keller brings up several interesting points regarding breast MRI, a subject that fills entire subspecialty textbooks.

On the subject of a palpable abnormality, a breast MRI’s field of view encompasses the entire breast, and although breast MRI is quite sensitive, it is known to have a lower specificity than other modalities.1 This means that more findings—which may or may not be related to the actual palpable abnormality—will lead to more studies and more biopsies, with proportionately fewer cancers found.

As for regions of tissue coverage with mammography, the axillary tail is actually more consistently imaged with mammography and ultrasonography than with MRI because of the cardiac pulsation artifact in the plane of the heart, as well as the breastcoil image centering on the breast. MRI-guided biopsy in the axilla is also generally not possible. These limitations are typical for breast MRI equipment. The expense of breast MRI is indeed considerable, but cost is not the main reason for the preference of other modalities.

In contrast, targeted ultrasonography is exquisitely suited to specifically image a palpable abnormality. With its small field of view (4 cm and smaller), a very high percentage of palpable masses can be seen. It is also more personal and comfortable and can be patient-directed. You can ask the patient to physically show you what is being felt and then scan it in real time. Needle biopsy can then be performed, often during the same visit (at many facilities), using ultrasonography as a real-time guidance tool in any location within the breast, including the axilla.

In the algorithm implied by your question, the patient feels a lump and has a negative diagnostic mammogram (including specific, problem-directed views) and targeted ultrasonography, which, again, is more focused than MRI and more capable of imaging the axilla or areas out of the breast coil for this purpose. Then, based on clinical suspicion or patient anxiety, these two very good tests are disregarded or not believed. At this point, the patient should be seen by a specialist, usually a surgeon, for evaluation for palpation-guided biopsy. It is true that some palpable masses are not identified by mammography and ultrasonography. But it is also true that MRI does not find every cancer, and it can find many more lesions that are not cancerous and that have a dubious relation to the original area of concern. This can easily turn into the proverbial wild-goose chase. No matter the outcome of the MRI, the patient still needs to be seen by a surgeon.

Our two major indications for breast MRI are currently in the preoperative extent-of-disease workup for known breast cancer and as an additional screening examination for high-risk patients (lifetime risk greater than 20%–25% by BRCAPRO, Gail, or other model method per the 2007 American Cancer Society guidelines2). We always require a comparative review of mammography in the completed interpretation of breast MRI and, as such, do not consider MRI a viable (or statistically proven) substitute for screening mammography for patients with sensitive breasts. Breast MRI is in fact more physically challenging for most patients than mammography, because the patient needs to remain motionless in a prone position in an enclosed space for an extended period of time (our protocol is 17 minutes). Gadolinium contrast must also be given, which requires renal function laboratory tests and intravenous access. The study must also be scheduled in all premenopausal patients in the postmenstrual phase of her cycle (around days 7–14) to avoid diffuse hormonally related enhancement and to minimize false-positive results.

References
  1. Orel S. Who should have breast magnetic resonance imaging evaluation? J Clin Oncol 2008; 26:703–711.
  2. Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography, CA Cancer J Clin 2007; 57:75–89. Erratum in: CA Cancer J Clin 2007; 57:185.
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Radiologic workup of a palpable breast mass
The radiologic workup of a palpable breast mass

The authors thank Dr. Keller for his readership. (On a personal note, Dr. Chellman-Jeffers spent her childhood in the Los Angeles area near his practice.) Dr. Keller brings up several interesting points regarding breast MRI, a subject that fills entire subspecialty textbooks.

On the subject of a palpable abnormality, a breast MRI’s field of view encompasses the entire breast, and although breast MRI is quite sensitive, it is known to have a lower specificity than other modalities.1 This means that more findings—which may or may not be related to the actual palpable abnormality—will lead to more studies and more biopsies, with proportionately fewer cancers found.

As for regions of tissue coverage with mammography, the axillary tail is actually more consistently imaged with mammography and ultrasonography than with MRI because of the cardiac pulsation artifact in the plane of the heart, as well as the breastcoil image centering on the breast. MRI-guided biopsy in the axilla is also generally not possible. These limitations are typical for breast MRI equipment. The expense of breast MRI is indeed considerable, but cost is not the main reason for the preference of other modalities.

In contrast, targeted ultrasonography is exquisitely suited to specifically image a palpable abnormality. With its small field of view (4 cm and smaller), a very high percentage of palpable masses can be seen. It is also more personal and comfortable and can be patient-directed. You can ask the patient to physically show you what is being felt and then scan it in real time. Needle biopsy can then be performed, often during the same visit (at many facilities), using ultrasonography as a real-time guidance tool in any location within the breast, including the axilla.

In the algorithm implied by your question, the patient feels a lump and has a negative diagnostic mammogram (including specific, problem-directed views) and targeted ultrasonography, which, again, is more focused than MRI and more capable of imaging the axilla or areas out of the breast coil for this purpose. Then, based on clinical suspicion or patient anxiety, these two very good tests are disregarded or not believed. At this point, the patient should be seen by a specialist, usually a surgeon, for evaluation for palpation-guided biopsy. It is true that some palpable masses are not identified by mammography and ultrasonography. But it is also true that MRI does not find every cancer, and it can find many more lesions that are not cancerous and that have a dubious relation to the original area of concern. This can easily turn into the proverbial wild-goose chase. No matter the outcome of the MRI, the patient still needs to be seen by a surgeon.

Our two major indications for breast MRI are currently in the preoperative extent-of-disease workup for known breast cancer and as an additional screening examination for high-risk patients (lifetime risk greater than 20%–25% by BRCAPRO, Gail, or other model method per the 2007 American Cancer Society guidelines2). We always require a comparative review of mammography in the completed interpretation of breast MRI and, as such, do not consider MRI a viable (or statistically proven) substitute for screening mammography for patients with sensitive breasts. Breast MRI is in fact more physically challenging for most patients than mammography, because the patient needs to remain motionless in a prone position in an enclosed space for an extended period of time (our protocol is 17 minutes). Gadolinium contrast must also be given, which requires renal function laboratory tests and intravenous access. The study must also be scheduled in all premenopausal patients in the postmenstrual phase of her cycle (around days 7–14) to avoid diffuse hormonally related enhancement and to minimize false-positive results.

The authors thank Dr. Keller for his readership. (On a personal note, Dr. Chellman-Jeffers spent her childhood in the Los Angeles area near his practice.) Dr. Keller brings up several interesting points regarding breast MRI, a subject that fills entire subspecialty textbooks.

On the subject of a palpable abnormality, a breast MRI’s field of view encompasses the entire breast, and although breast MRI is quite sensitive, it is known to have a lower specificity than other modalities.1 This means that more findings—which may or may not be related to the actual palpable abnormality—will lead to more studies and more biopsies, with proportionately fewer cancers found.

As for regions of tissue coverage with mammography, the axillary tail is actually more consistently imaged with mammography and ultrasonography than with MRI because of the cardiac pulsation artifact in the plane of the heart, as well as the breastcoil image centering on the breast. MRI-guided biopsy in the axilla is also generally not possible. These limitations are typical for breast MRI equipment. The expense of breast MRI is indeed considerable, but cost is not the main reason for the preference of other modalities.

In contrast, targeted ultrasonography is exquisitely suited to specifically image a palpable abnormality. With its small field of view (4 cm and smaller), a very high percentage of palpable masses can be seen. It is also more personal and comfortable and can be patient-directed. You can ask the patient to physically show you what is being felt and then scan it in real time. Needle biopsy can then be performed, often during the same visit (at many facilities), using ultrasonography as a real-time guidance tool in any location within the breast, including the axilla.

In the algorithm implied by your question, the patient feels a lump and has a negative diagnostic mammogram (including specific, problem-directed views) and targeted ultrasonography, which, again, is more focused than MRI and more capable of imaging the axilla or areas out of the breast coil for this purpose. Then, based on clinical suspicion or patient anxiety, these two very good tests are disregarded or not believed. At this point, the patient should be seen by a specialist, usually a surgeon, for evaluation for palpation-guided biopsy. It is true that some palpable masses are not identified by mammography and ultrasonography. But it is also true that MRI does not find every cancer, and it can find many more lesions that are not cancerous and that have a dubious relation to the original area of concern. This can easily turn into the proverbial wild-goose chase. No matter the outcome of the MRI, the patient still needs to be seen by a surgeon.

Our two major indications for breast MRI are currently in the preoperative extent-of-disease workup for known breast cancer and as an additional screening examination for high-risk patients (lifetime risk greater than 20%–25% by BRCAPRO, Gail, or other model method per the 2007 American Cancer Society guidelines2). We always require a comparative review of mammography in the completed interpretation of breast MRI and, as such, do not consider MRI a viable (or statistically proven) substitute for screening mammography for patients with sensitive breasts. Breast MRI is in fact more physically challenging for most patients than mammography, because the patient needs to remain motionless in a prone position in an enclosed space for an extended period of time (our protocol is 17 minutes). Gadolinium contrast must also be given, which requires renal function laboratory tests and intravenous access. The study must also be scheduled in all premenopausal patients in the postmenstrual phase of her cycle (around days 7–14) to avoid diffuse hormonally related enhancement and to minimize false-positive results.

References
  1. Orel S. Who should have breast magnetic resonance imaging evaluation? J Clin Oncol 2008; 26:703–711.
  2. Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography, CA Cancer J Clin 2007; 57:75–89. Erratum in: CA Cancer J Clin 2007; 57:185.
References
  1. Orel S. Who should have breast magnetic resonance imaging evaluation? J Clin Oncol 2008; 26:703–711.
  2. Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography, CA Cancer J Clin 2007; 57:75–89. Erratum in: CA Cancer J Clin 2007; 57:185.
Issue
Cleveland Clinic Journal of Medicine - 76(7)
Issue
Cleveland Clinic Journal of Medicine - 76(7)
Page Number
385-389
Page Number
385-389
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Imaging
Women's Health
Article Type
Article
Display Headline
In reply: Radiologic workup of a palpable breast mass
Display Headline
In reply: Radiologic workup of a palpable breast mass
Sections
Letters To The Editor
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Alternative CME
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