Original Research

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Pseudomonas is a genus of aerobic, Gram-negative bacilli consisting of about 200 species. Pseudomonas aeruginosa (P aeruginosa) is the species most commonly associated with serious hospital-acquired infections and is commonly found in moist environments in hospitals, such as sinks, showers, and machinery/equipment. The symptoms of an infection by this bacterium are variable based on the site of infection and can manifest in various sites, such as the respiratory tract, urinary tract, ears, eyes, heart, skin, and soft tissue.¹ General risk factors for infection with P aeruginosa include immunosuppression, history of lung disease, hospitalization lasting at least 5 days, history of repeated antibiotic use within 90 days, and a history of pseudomonal colonization/infection.

Related: Antibiotic Therapy and Bacterial Resistance in Patients With Spinal Cord Injury

Pseudomonas aeruginosa is a challenging organism to manage, as it is inherently resistant to many antibiotics. Furthermore, antibiotics effective against infections caused by P aeruginosa often require specific regimens as a result of the high minimum inhibitory concentration (MIC) of the organism. Two specific strategies that have been analyzed for proper coverage of P aeruginosa include the use of higher than usual doses and extended infusions. Due to significant challenges associated with obtaining patient outcomes data in human clinical trials, researchers often use Monte Carlo simulations, which are computational algorithms that simulate the variables of a study (ie, patient demographics) to be as real as possible to accurately predict therapeutic responses in patients.

Analyzing pharmacokinetic (PK) and pharmacodynamic (PD) indexes is valuable for determining therapeutic efficacy, as these indexes consider both the antibiotic dose/concentration and its effect over time in relation to response to therapy. The free-drug area under the concentration time curve (fAUC/MIC) ratio is a PK/PD value commonly used to describe the free-drug concentration over 24 hours that is above the MIC.² The fAUC is dependent on creatinine clearance (CrCl) and, therefore, is specific to each patient. A threshold value for the fAUC/MIC is determined for an antibiotic, and a therapeutic regimen is dosed accordingly to assure fAUC/MIC attainment above the minimum threshold. The probability of target attainment (PTA), which is the probability that the threshold value of a PD index is achieved at a certain MIC, and the probability of cure (POC) for a given antibiotic regimen are used to determine the efficacy of an antibiotic in Monte Carlo simulations.²

Related: Bacteremia From an Unlikely Source

A study by Zelenitsky and colleagues evaluated the efficacy of 3 ciprofloxacin dosing regimens using Monte Carlo simulations (400 mg IV every 12 hours [standard dose], 400 mg IV every 8 hours [high dose], and a PD-targeted regimen dosed to attain an fAUC/MIC value > 86).³ An fAUC/MIC value of 86 was previously determined to predict cure rates of at least 90%.⁴ The Clinical and Laboratory Standards Institute defines a P aeruginosa MIC of ≤ 1 μg/mL to be susceptible and an MIC of ≥ 4 μg/mL to be resistant to ciprofloxacin.⁵

The researchers determined PTA and POC values for each regimen based on various MICs. The in vitro laboratory simulations revealed the PTA and POC values approached 100% for all 3 regimens when the MIC was 0.125 μg/mL. However, when the MIC was 1 μg/mL, the PTA for the standard and high dose was 0%, and the PD-targeted regimen was 40%. The POC was 27%, 40%, and 72% for the standard dose, high dose, and the PD-targeted regimen, respectively. Although the PD-targeted regimen was the most efficacious, it took doses exceeding 1,300 mg and 1,800 mg daily to achieve similar results. In addition, PD-targeted regimens are not practical for dosing due to patient variability in CrCl. From these simulations, it was concluded that the high dose of ciprofloxacin 400 mg IV every 8 hours should be recommended for treating Pseudomonas infections in patients with normal renal function.

Related: Antimicrobial Stewardship in an Outpatient Parenteral Antibiotic Therapy Program

In another study by Lodise and colleagues, researchers examined the clinical implications of an extended-infusion dosing strategy for piperacillin-tazobactam in the critically ill.⁶ The 2 piperacillin- tazobactam regimens evaluated were 3.375 g IV over 30 minutes given every 4 or 6 hours and 3.375 g IV over 4 hours given every 8 hours. The 14-day mortality rate in critically ill patients who received the extended- and intermittent-infusion regimens was 12.2% and 31.6%, respectively (P = .04). Additionally, patients receiving the extended-infusion regimen had a decreased in-house length of stay compared with the intermittent-infusion group (21 vs 38 days, P = .02). Despite having a lower drug concentration peak, the extended-infusion regimen maintains steady drug concentrations above the MIC for a greater period, resulting in prolonged therapeutic efficacy. Other antibiotics (cefepime⁷ and ceftazidime⁸) have been studied by using the same methodology of comparing intermittent and extended infusions and have had similar results.

Given the management challenges associated with P aeruginosa infections, it is important for clinicians to recognize patients who may have or be at risk of infection with P aeruginosa and use appropriate dosing regimens to effectively manage infections and improve patient outcomes.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.