Clinical Inquiries

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

Evidence summary

There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).¹

A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.²

MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.

When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).³

Recommendations from others

We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.

Evidence summary

There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).¹

A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.²

MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.

When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).³

Recommendations from others

We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.

Evidence summary

There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).¹

A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.²

MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.

When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).³

Recommendations from others

We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.

Evidence summary

Several large population-based case series have tried to define the incidence of isoniazid-induced hepatitis and fatal hepatitis. Because these series differed in patient selection, diagnostic criteria for hepatitis, and toxicity monitoring strategies, and because their data span decades, they provide limited insight. Data from 6 large case series^1,3-7 and 1 pooled compilation of published and unpublished reports⁸ are summarized in the Table.

Two studies^1,2 that defined hepatitis as asymptomatic liver function test elevation (>5 times normal) on monthly screening found a 6% to 6.4% incidence of hepatitis, a rate 10 to 60 times higher than 4 case series^3-6 that relied on symptom-based monitoring. A pooled analysis of more than 200,000 patients receiving isoniazid prophylaxis and monitored according to 1983 American Thoracic Society guidelines reported an intermediate hepatitis rate (1.2%) and only 2 deaths.⁸ Mortality from isoniazid hepatitis is rare, whichever monitoring strategy is selected. Some deaths attributed to isoniazid prophylaxis may also have had other contributing causes, such as unrecognized hepatitis C; most cases and deaths reported in these large series occurred before testing for hepatitis C became available in 1991.

Symptom-based monitoring strategies require stopping isoniazid promptly if symptoms of hepatotoxicity develop. In a series of 62 fatal cases of probable or possible isoniazid hepatitis, 42% had been monitored at least monthly for symptoms, and 38% stopped isoniazid within 1 week of symptom onset.⁹ Seven of the 8 patients receiving a liver transplant following the development of fulminant, isoniazid-related hepatitis continued to take the drug for a least 10 days after onset of symptoms of hepatotoxicity.¹⁰

Several series report increasing hepatitis risk with advancing age.^1,3,5,6 In 1 series,³ rates were 3/1000 in those aged 20 to 34 years, 12/1000 in those aged 35 to 49 years, 23/1000 in those aged 50 to 64 years, and 8/1000 after age 65.

TABLE
INH hepatitis incidence and mortality rates: summary of the largest case series

Recommendations From Others

The Centers for Disease Control and Prevention (CDC) and the American Thoracic Society joint guidelines for the treatment of latent TB infection state that baseline laboratory testing is not routinely indicated, even for persons aged >35 years, but may be considered for patients who are taking other hepatotoxic medications or have chronic medical conditions.¹¹

Baseline measurements of bilirubin and aspartate transaminase (AST) or alanine transaminase (ALT) along with monthly liver function test monitoring are recommended for patients with pre-existing liver disease, patients at risk for chronic liver disease, patients with HIV infection, pregnant or postpartum women, and regular users of alcohol. All patients should be evaluated at least monthly for symptoms of hepatitis, and liver function tests should also be obtained for patients with symptoms compatible with hepatotoxicity. The guideline suggests that isoniazid be stopped if liver function tests exceed 5 times the upper limits of normal, or 3 times the upper limits of normal if the patient is symptomatic. The Canadian Tuberculosis Standards (5th ed, 2000) recommend baseline AST before isoniazid preventive therapy is started, and regular monitoring in those with pre-existing liver disease, a history of ethanol abuse, or age ≥35 years.¹²

Evidence summary

Several large population-based case series have tried to define the incidence of isoniazid-induced hepatitis and fatal hepatitis. Because these series differed in patient selection, diagnostic criteria for hepatitis, and toxicity monitoring strategies, and because their data span decades, they provide limited insight. Data from 6 large case series^1,3-7 and 1 pooled compilation of published and unpublished reports⁸ are summarized in the Table.

Two studies^1,2 that defined hepatitis as asymptomatic liver function test elevation (>5 times normal) on monthly screening found a 6% to 6.4% incidence of hepatitis, a rate 10 to 60 times higher than 4 case series^3-6 that relied on symptom-based monitoring. A pooled analysis of more than 200,000 patients receiving isoniazid prophylaxis and monitored according to 1983 American Thoracic Society guidelines reported an intermediate hepatitis rate (1.2%) and only 2 deaths.⁸ Mortality from isoniazid hepatitis is rare, whichever monitoring strategy is selected. Some deaths attributed to isoniazid prophylaxis may also have had other contributing causes, such as unrecognized hepatitis C; most cases and deaths reported in these large series occurred before testing for hepatitis C became available in 1991.

Symptom-based monitoring strategies require stopping isoniazid promptly if symptoms of hepatotoxicity develop. In a series of 62 fatal cases of probable or possible isoniazid hepatitis, 42% had been monitored at least monthly for symptoms, and 38% stopped isoniazid within 1 week of symptom onset.⁹ Seven of the 8 patients receiving a liver transplant following the development of fulminant, isoniazid-related hepatitis continued to take the drug for a least 10 days after onset of symptoms of hepatotoxicity.¹⁰

Several series report increasing hepatitis risk with advancing age.^1,3,5,6 In 1 series,³ rates were 3/1000 in those aged 20 to 34 years, 12/1000 in those aged 35 to 49 years, 23/1000 in those aged 50 to 64 years, and 8/1000 after age 65.

TABLE
INH hepatitis incidence and mortality rates: summary of the largest case series

Recommendations From Others

The Centers for Disease Control and Prevention (CDC) and the American Thoracic Society joint guidelines for the treatment of latent TB infection state that baseline laboratory testing is not routinely indicated, even for persons aged >35 years, but may be considered for patients who are taking other hepatotoxic medications or have chronic medical conditions.¹¹

Baseline measurements of bilirubin and aspartate transaminase (AST) or alanine transaminase (ALT) along with monthly liver function test monitoring are recommended for patients with pre-existing liver disease, patients at risk for chronic liver disease, patients with HIV infection, pregnant or postpartum women, and regular users of alcohol. All patients should be evaluated at least monthly for symptoms of hepatitis, and liver function tests should also be obtained for patients with symptoms compatible with hepatotoxicity. The guideline suggests that isoniazid be stopped if liver function tests exceed 5 times the upper limits of normal, or 3 times the upper limits of normal if the patient is symptomatic. The Canadian Tuberculosis Standards (5th ed, 2000) recommend baseline AST before isoniazid preventive therapy is started, and regular monitoring in those with pre-existing liver disease, a history of ethanol abuse, or age ≥35 years.¹²

Evidence summary

Several large population-based case series have tried to define the incidence of isoniazid-induced hepatitis and fatal hepatitis. Because these series differed in patient selection, diagnostic criteria for hepatitis, and toxicity monitoring strategies, and because their data span decades, they provide limited insight. Data from 6 large case series^1,3-7 and 1 pooled compilation of published and unpublished reports⁸ are summarized in the Table.

Two studies^1,2 that defined hepatitis as asymptomatic liver function test elevation (>5 times normal) on monthly screening found a 6% to 6.4% incidence of hepatitis, a rate 10 to 60 times higher than 4 case series^3-6 that relied on symptom-based monitoring. A pooled analysis of more than 200,000 patients receiving isoniazid prophylaxis and monitored according to 1983 American Thoracic Society guidelines reported an intermediate hepatitis rate (1.2%) and only 2 deaths.⁸ Mortality from isoniazid hepatitis is rare, whichever monitoring strategy is selected. Some deaths attributed to isoniazid prophylaxis may also have had other contributing causes, such as unrecognized hepatitis C; most cases and deaths reported in these large series occurred before testing for hepatitis C became available in 1991.

Symptom-based monitoring strategies require stopping isoniazid promptly if symptoms of hepatotoxicity develop. In a series of 62 fatal cases of probable or possible isoniazid hepatitis, 42% had been monitored at least monthly for symptoms, and 38% stopped isoniazid within 1 week of symptom onset.⁹ Seven of the 8 patients receiving a liver transplant following the development of fulminant, isoniazid-related hepatitis continued to take the drug for a least 10 days after onset of symptoms of hepatotoxicity.¹⁰

Several series report increasing hepatitis risk with advancing age.^1,3,5,6 In 1 series,³ rates were 3/1000 in those aged 20 to 34 years, 12/1000 in those aged 35 to 49 years, 23/1000 in those aged 50 to 64 years, and 8/1000 after age 65.

TABLE
INH hepatitis incidence and mortality rates: summary of the largest case series

Recommendations From Others

The Centers for Disease Control and Prevention (CDC) and the American Thoracic Society joint guidelines for the treatment of latent TB infection state that baseline laboratory testing is not routinely indicated, even for persons aged >35 years, but may be considered for patients who are taking other hepatotoxic medications or have chronic medical conditions.¹¹

Baseline measurements of bilirubin and aspartate transaminase (AST) or alanine transaminase (ALT) along with monthly liver function test monitoring are recommended for patients with pre-existing liver disease, patients at risk for chronic liver disease, patients with HIV infection, pregnant or postpartum women, and regular users of alcohol. All patients should be evaluated at least monthly for symptoms of hepatitis, and liver function tests should also be obtained for patients with symptoms compatible with hepatotoxicity. The guideline suggests that isoniazid be stopped if liver function tests exceed 5 times the upper limits of normal, or 3 times the upper limits of normal if the patient is symptomatic. The Canadian Tuberculosis Standards (5th ed, 2000) recommend baseline AST before isoniazid preventive therapy is started, and regular monitoring in those with pre-existing liver disease, a history of ethanol abuse, or age ≥35 years.¹²

Evidence summary

Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.¹ In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).^2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.²

A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B₆ and B₁₂, reduces plasma homocysteine levels.⁴ However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.⁵

Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.⁶ In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.⁶ All patients in this study were on statin therapy prior to initiation of folate supplementation.

The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B₆ and 400 μg of vitamin B₁₂ for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).⁷ There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).

Recommendations from others

The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B₁₂ (2.4 μg), and B₆ (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.⁸ Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.⁸

The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.² Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B₁₂, and B₆.²

Evidence summary

Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.¹ In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).^2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.²

A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B₆ and B₁₂, reduces plasma homocysteine levels.⁴ However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.⁵

Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.⁶ In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.⁶ All patients in this study were on statin therapy prior to initiation of folate supplementation.

The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B₆ and 400 μg of vitamin B₁₂ for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).⁷ There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).

Recommendations from others

The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B₁₂ (2.4 μg), and B₆ (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.⁸ Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.⁸

The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.² Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B₁₂, and B₆.²

Evidence summary

Hyperhomocysteinemia is defined as a fasting plasma homocysteine level 15 μmol/L, although levels >10 μmol/L appear to have detrimental effects on risk profiles for CAD and arteriosclerosis.¹ In 22 of 27 retrospective case-control studies, patients with CAD had significantly higher plasma homocysteine levels than control subjects (odds ratio [OR]=1.2–10.9, after adjustment for other CAD risk factors).^2,3 However, only 4 of 7 prospective nested case-control trials showed a correlation between elevated homocysteine and myocardial infarction (MI) and coronary death.²

A meta-analysis of 12 randomized controlled trials found that folate supplementation, with vitamin B₆ and B₁₂, reduces plasma homocysteine levels.⁴ However, the long-term clinical cons quences of these interventions are unknown. At doses of 1 gm/d folate has no known side-effects.⁵

Two randomized, placebo-controlled trials of folate reporting clinical endpoints have been completed. One study analyzed folate supplementation in a patient population with known, stable CAD and found no difference in clinical endpoints at 24 months.⁶ In this study, 593 patients were randomized to receive either 0.5 mg/d of folic acid or placebo. The primary study endpoint was a composite of events including: overall mortality, sudden death, MI, stroke, and major vascular surgery. The study was powered to detect a 50% reduction in clinical events based on existing observational data in populations with CAD. An event rate of 15% for the 2-year interval was assumed.⁶ All patients in this study were on statin therapy prior to initiation of folate supplementation.

The second study analyzed folate supplementation in 553 post-PCI patients. Patients were treated with 1 mg of folate plus 10 mg of vitamin B₆ and 400 μg of vitamin B₁₂ for 6 months after the PCI. After a mean follow-up of 11 months, the rate of restenosis requiring revascularization was lower in the vitamin-treated study arm (9.9% vs 16% restenosis rate; relative risk [RR]=0.62; 95% confidence interval [CI], 0.40–0.97; number needed to treat=16).⁷ There was also a nonsignificant trend toward fewer deaths and MIs in the treated arm at both 6 and 12 months after intervention (death: 1.5% vs 2.8%; RR=0.54; 95% CI, 0.016–1.7; MI: 2.6% vs 4.3%; RR=0.60; 95% CI, 0.24–1.51). Statin use was similar in both control (71%) and treatment groups (69%).

Recommendations from others

The American Heart Association and American College of Cardiology do not recommend the routine use of high-dose folic acid or B-vitamin supplements for the primary or secondary prevention of cardiovascular events. The AHA recommendation is to meet recommended daily allowances of folate (400 μg), B₁₂ (2.4 μg), and B₆ (1.7 mg) primarily through a balanced diet, with use of supplements if diet alone does not meet the above requirements.⁸ Since 1998, wheat flour has been supplemented with folate, adding an estimated 100 μg/day to the average American diet.⁸

The Canadian Task Force on Preventive Health Care (CTFPHC) finds insufficient evidence to advocate screening for hyperhomocysteinemia and rely on expert opinion to advocate treatment in select, high-risk populations.² Currently, the CTFPHC advocates meeting the recommended daily allowance of folate, B₁₂, and B₆.²

Evidence summary

Acetaminophen has a different mechanism of action from other antipyretics. It halts the production of prostaglandin in the brain but not in the periphery, solely lowering fever. Aspirin and other nonsteroidal anti-inflammatory agents inhibit both central and peripheral cyclooxygenase and may cause multiple effects in addition to temperature reduction. Clinical outcome studies of their antipyretic effects are inconclusive.¹

A randomized controlled trial involving 60 volunteers given intranasal rhinovirus type 2 monitored the effect of aspirin, acetaminophen, ibuprofen, or placebo on virus shedding, immune response, and clinical status. There was no difference in duration of illness. There was a trend toward longer duration of virus shedding in the aspirin and acetaminophen groups, but serum neutralizing antibody response was suppressed (P<.05 vs placebo). Aspirin and acetaminophen worsened symptoms of turbinate edema and nasal obstruction (P<.05 vs placebo).²

In 2 double-blind trials, 45 adults infected with rhinovirus were given aspirin or placebo for 5 days, beginning on the day after viral exposure (as opposed to the typical use in response to symptoms). Aspirin treatment improved symptoms of conjunctivitis significantly, but did not change the duration of illness. Other symptoms (headache, sneezing, chills, malaise, nasal discharge) were not significantly different. Aspirin increased the amount of viral shedding by 36% in 1 trial and 17% in the other (P<.01), potentially increasing risk of spread.³

In a randomized controlled trial evaluating antipyretic effects on the duration or severity of childhood varicella, 31 children received placebo and 37 received acetaminophen for 4 days. There was no difference in itching, appetite, activity, or overall condition between the 2 groups. Children treated with acetaminophen took 1.1 days longer to total scabbing (P<.05), although the number of days until the appearance of the last new vesicle and the time to total healing were unchanged. The duration of viral shedding was not measured, but it is possible that the delay in healing of lesions would prolong viral shedding as well.⁴

A retrospective observational study of 54 volunteers demonstrated prolonged illness in subjects infected with influenza A that received antipyretic therapy. Patients who got antipyretics were sick 3.5 days longer than those who did not (8.8 ± 2.3 days vs 5.3 ± 3.0 days; P<.001). Only patients with temperatures >38.9°C on 2 readings 6 hours apart received antipyretics, indicating that the longer course correlated with greater severity of illness as well as with antipyretic use.

In the same study, antipyretics were associated with a trend towards prolonged duration of illness in a group of 21 patients infected with S sonnei (4.6 ± 2.1 days with antipyretics vs 1.9 ± 1.6 days without; P=not significant).⁵

A Cochrane review examined 3 trials of acetaminophen vs placebo for fever in 128 adults and children with P falciparum malaria. Although fever clearance varied between the trials, the malaria cure rate was similar in all, and the review concluded that data were insufficient to evaluate an effect on parasitemia.⁶

Recommendations from others

We found no recommendations regarding the use of antipyretics and their effect on the duration of febrile illness.

Evidence summary

Acetaminophen has a different mechanism of action from other antipyretics. It halts the production of prostaglandin in the brain but not in the periphery, solely lowering fever. Aspirin and other nonsteroidal anti-inflammatory agents inhibit both central and peripheral cyclooxygenase and may cause multiple effects in addition to temperature reduction. Clinical outcome studies of their antipyretic effects are inconclusive.¹

A randomized controlled trial involving 60 volunteers given intranasal rhinovirus type 2 monitored the effect of aspirin, acetaminophen, ibuprofen, or placebo on virus shedding, immune response, and clinical status. There was no difference in duration of illness. There was a trend toward longer duration of virus shedding in the aspirin and acetaminophen groups, but serum neutralizing antibody response was suppressed (P<.05 vs placebo). Aspirin and acetaminophen worsened symptoms of turbinate edema and nasal obstruction (P<.05 vs placebo).²

In 2 double-blind trials, 45 adults infected with rhinovirus were given aspirin or placebo for 5 days, beginning on the day after viral exposure (as opposed to the typical use in response to symptoms). Aspirin treatment improved symptoms of conjunctivitis significantly, but did not change the duration of illness. Other symptoms (headache, sneezing, chills, malaise, nasal discharge) were not significantly different. Aspirin increased the amount of viral shedding by 36% in 1 trial and 17% in the other (P<.01), potentially increasing risk of spread.³

In a randomized controlled trial evaluating antipyretic effects on the duration or severity of childhood varicella, 31 children received placebo and 37 received acetaminophen for 4 days. There was no difference in itching, appetite, activity, or overall condition between the 2 groups. Children treated with acetaminophen took 1.1 days longer to total scabbing (P<.05), although the number of days until the appearance of the last new vesicle and the time to total healing were unchanged. The duration of viral shedding was not measured, but it is possible that the delay in healing of lesions would prolong viral shedding as well.⁴

A retrospective observational study of 54 volunteers demonstrated prolonged illness in subjects infected with influenza A that received antipyretic therapy. Patients who got antipyretics were sick 3.5 days longer than those who did not (8.8 ± 2.3 days vs 5.3 ± 3.0 days; P<.001). Only patients with temperatures >38.9°C on 2 readings 6 hours apart received antipyretics, indicating that the longer course correlated with greater severity of illness as well as with antipyretic use.

In the same study, antipyretics were associated with a trend towards prolonged duration of illness in a group of 21 patients infected with S sonnei (4.6 ± 2.1 days with antipyretics vs 1.9 ± 1.6 days without; P=not significant).⁵

A Cochrane review examined 3 trials of acetaminophen vs placebo for fever in 128 adults and children with P falciparum malaria. Although fever clearance varied between the trials, the malaria cure rate was similar in all, and the review concluded that data were insufficient to evaluate an effect on parasitemia.⁶

Recommendations from others

We found no recommendations regarding the use of antipyretics and their effect on the duration of febrile illness.

Evidence summary

Acetaminophen has a different mechanism of action from other antipyretics. It halts the production of prostaglandin in the brain but not in the periphery, solely lowering fever. Aspirin and other nonsteroidal anti-inflammatory agents inhibit both central and peripheral cyclooxygenase and may cause multiple effects in addition to temperature reduction. Clinical outcome studies of their antipyretic effects are inconclusive.¹

A randomized controlled trial involving 60 volunteers given intranasal rhinovirus type 2 monitored the effect of aspirin, acetaminophen, ibuprofen, or placebo on virus shedding, immune response, and clinical status. There was no difference in duration of illness. There was a trend toward longer duration of virus shedding in the aspirin and acetaminophen groups, but serum neutralizing antibody response was suppressed (P<.05 vs placebo). Aspirin and acetaminophen worsened symptoms of turbinate edema and nasal obstruction (P<.05 vs placebo).²

In 2 double-blind trials, 45 adults infected with rhinovirus were given aspirin or placebo for 5 days, beginning on the day after viral exposure (as opposed to the typical use in response to symptoms). Aspirin treatment improved symptoms of conjunctivitis significantly, but did not change the duration of illness. Other symptoms (headache, sneezing, chills, malaise, nasal discharge) were not significantly different. Aspirin increased the amount of viral shedding by 36% in 1 trial and 17% in the other (P<.01), potentially increasing risk of spread.³

In a randomized controlled trial evaluating antipyretic effects on the duration or severity of childhood varicella, 31 children received placebo and 37 received acetaminophen for 4 days. There was no difference in itching, appetite, activity, or overall condition between the 2 groups. Children treated with acetaminophen took 1.1 days longer to total scabbing (P<.05), although the number of days until the appearance of the last new vesicle and the time to total healing were unchanged. The duration of viral shedding was not measured, but it is possible that the delay in healing of lesions would prolong viral shedding as well.⁴

A retrospective observational study of 54 volunteers demonstrated prolonged illness in subjects infected with influenza A that received antipyretic therapy. Patients who got antipyretics were sick 3.5 days longer than those who did not (8.8 ± 2.3 days vs 5.3 ± 3.0 days; P<.001). Only patients with temperatures >38.9°C on 2 readings 6 hours apart received antipyretics, indicating that the longer course correlated with greater severity of illness as well as with antipyretic use.

In the same study, antipyretics were associated with a trend towards prolonged duration of illness in a group of 21 patients infected with S sonnei (4.6 ± 2.1 days with antipyretics vs 1.9 ± 1.6 days without; P=not significant).⁵

A Cochrane review examined 3 trials of acetaminophen vs placebo for fever in 128 adults and children with P falciparum malaria. Although fever clearance varied between the trials, the malaria cure rate was similar in all, and the review concluded that data were insufficient to evaluate an effect on parasitemia.⁶

Recommendations from others

We found no recommendations regarding the use of antipyretics and their effect on the duration of febrile illness.

Evidence summary

A Cochrane review of 10 randomized controlled trials comparing nebulizers with MDI/S, both in adults and in children aged >2 years, showed a substantial trend towards improvement in hospital admission rates with MDI/S use. Sample size for each study was small, ranging from 18 to 152 patients, with a total sample size of 880 children and 444 adults.

The relative risk of admission for MDI/S vs nebulizer for children was 0.65 (95% confidence interval, 0.4–1.06). Secondary outcomes were equivalent or slightly improved, including duration in the emergency department, changes in respiratory rate, blood gases, pulse, tremor, symptoms score, lung function, and use of steroids. Patients with life-threatening asthma (for example, those considered for ventilation) or other chronic illnesses were excluded.¹

All but 1 of these studies were set in the emergency department and all involved the use of one of a variety of spacers with the MDI, such as the Aerochamber or Inspirease. Whether these efficacy studies can be translated into daily outpatient clinical practice remains unclear. Emergency departments typically have higher staffing levels, and study subjects and their parents may have received more MDI/S training than is practical in many office settings.

While most of the data were for children aged 2 years and older, 1 study published after the Cochrane review did show a lower admission rate in 85 patients who were 2 to 24 months in the MDI/S group.² Controlling for the initial Pulmonary Index score, children using an MDI and Aerochamber spacer were admitted less often (5% vs 20%, number needed to treat=7; P=.05) than children using nebulizers. Since the results of this single small trial are the only data available for this younger age group, using MDI/S instead of nebulizers should be done with caution for children aged <2 years.

Another randomized controlled trial of 152 patients found no difference in primary outcomes of asthma severity score, oxygen saturation, and percent predicted peak expiratory flow rate (PEFR). Several secondary outcomes slightly favored MDI/S: number of treatments given, whether steroids were used, change in heart rate, side effects, rate of hospital admission, and treatment time in the emergency department.³

A smaller double-blinded randomized controlled trial of 33 children aged 6 to 14 years showed no difference in MDI/S vs nebulizer, as measured by clinical score, respiratory rate, oxygen saturation, and forced expiratory volume at 1 second (FEV₁).⁴ The researchers calculated the study had 90% power to detect a clinically meaningful difference in FEV₁ of 12% of the predicted value between the groups.

Other review articles reach the same conclusion. One article reviewed the literature from 1980 to 1996 and examined 17 prospective clinical trials. Outcomes measured included pulmonary function measures and clinical scores. The researchers recommended that MDI/S be used due to clinical benefit, safety, lower cost, personnel time, and speed and ease of administration.⁵

A review article from the British literature examined 3 randomized controlled trials involving 51 patients and found no superiority of nebulizer vs MDI/S.⁶ A similar review article examined 14 randomized controlled trials for beta-agonist delivery for patients aged 5 to 15 with stable asthma. They found no obvious benefit of 1 type of device over another, including nebulizer, MDI/S, and dry powder inhalers.⁷ These last 2 articles claimed to be systematic reviews, although they do not clearly state their search methodology.

Researchers used a wide variety of spacers in all aforementioned studies; accordingly, one cannot be recommended as superior to others. The degree of teaching given to parents and children about MDI/S use was not described in any of the trials.

FIGURE
MDI with spacer is beneficial when used properly

Recommendations from others

Guidelines from the Global Health Initiative for Asthma, a collaboration of the National Heart, Lung and Blood Institute and the World Health Organization, recommend MDI/S for children with asthma due to increased efficacy and decreased cost (revised in 2002). Specifically, they recommend a spacer with a face mask for infants and preschool children, a mouthpiece and spacer for children aged 4 to 6 years, and a dry powder inhaler or breath-activated device from age 6 onwards.⁸ Cincinnati Children’s Hospital’s evidence-based guidelines from 1998 also recommend MDI/S for children aged >1 year with acute asthma exacerbations.⁹ This guideline suggests using 4 to 8 puffs from a 90 μg albuterol MDI at 1- to 2-minute intervals every 20 minutes for 1 hour, then every 1 to 4 hours subsequently.

Evidence summary

A Cochrane review of 10 randomized controlled trials comparing nebulizers with MDI/S, both in adults and in children aged >2 years, showed a substantial trend towards improvement in hospital admission rates with MDI/S use. Sample size for each study was small, ranging from 18 to 152 patients, with a total sample size of 880 children and 444 adults.

The relative risk of admission for MDI/S vs nebulizer for children was 0.65 (95% confidence interval, 0.4–1.06). Secondary outcomes were equivalent or slightly improved, including duration in the emergency department, changes in respiratory rate, blood gases, pulse, tremor, symptoms score, lung function, and use of steroids. Patients with life-threatening asthma (for example, those considered for ventilation) or other chronic illnesses were excluded.¹

All but 1 of these studies were set in the emergency department and all involved the use of one of a variety of spacers with the MDI, such as the Aerochamber or Inspirease. Whether these efficacy studies can be translated into daily outpatient clinical practice remains unclear. Emergency departments typically have higher staffing levels, and study subjects and their parents may have received more MDI/S training than is practical in many office settings.

While most of the data were for children aged 2 years and older, 1 study published after the Cochrane review did show a lower admission rate in 85 patients who were 2 to 24 months in the MDI/S group.² Controlling for the initial Pulmonary Index score, children using an MDI and Aerochamber spacer were admitted less often (5% vs 20%, number needed to treat=7; P=.05) than children using nebulizers. Since the results of this single small trial are the only data available for this younger age group, using MDI/S instead of nebulizers should be done with caution for children aged <2 years.

Another randomized controlled trial of 152 patients found no difference in primary outcomes of asthma severity score, oxygen saturation, and percent predicted peak expiratory flow rate (PEFR). Several secondary outcomes slightly favored MDI/S: number of treatments given, whether steroids were used, change in heart rate, side effects, rate of hospital admission, and treatment time in the emergency department.³

A smaller double-blinded randomized controlled trial of 33 children aged 6 to 14 years showed no difference in MDI/S vs nebulizer, as measured by clinical score, respiratory rate, oxygen saturation, and forced expiratory volume at 1 second (FEV₁).⁴ The researchers calculated the study had 90% power to detect a clinically meaningful difference in FEV₁ of 12% of the predicted value between the groups.

Other review articles reach the same conclusion. One article reviewed the literature from 1980 to 1996 and examined 17 prospective clinical trials. Outcomes measured included pulmonary function measures and clinical scores. The researchers recommended that MDI/S be used due to clinical benefit, safety, lower cost, personnel time, and speed and ease of administration.⁵

A review article from the British literature examined 3 randomized controlled trials involving 51 patients and found no superiority of nebulizer vs MDI/S.⁶ A similar review article examined 14 randomized controlled trials for beta-agonist delivery for patients aged 5 to 15 with stable asthma. They found no obvious benefit of 1 type of device over another, including nebulizer, MDI/S, and dry powder inhalers.⁷ These last 2 articles claimed to be systematic reviews, although they do not clearly state their search methodology.

Researchers used a wide variety of spacers in all aforementioned studies; accordingly, one cannot be recommended as superior to others. The degree of teaching given to parents and children about MDI/S use was not described in any of the trials.

FIGURE
MDI with spacer is beneficial when used properly

Recommendations from others

Guidelines from the Global Health Initiative for Asthma, a collaboration of the National Heart, Lung and Blood Institute and the World Health Organization, recommend MDI/S for children with asthma due to increased efficacy and decreased cost (revised in 2002). Specifically, they recommend a spacer with a face mask for infants and preschool children, a mouthpiece and spacer for children aged 4 to 6 years, and a dry powder inhaler or breath-activated device from age 6 onwards.⁸ Cincinnati Children’s Hospital’s evidence-based guidelines from 1998 also recommend MDI/S for children aged >1 year with acute asthma exacerbations.⁹ This guideline suggests using 4 to 8 puffs from a 90 μg albuterol MDI at 1- to 2-minute intervals every 20 minutes for 1 hour, then every 1 to 4 hours subsequently.

Evidence summary

A Cochrane review of 10 randomized controlled trials comparing nebulizers with MDI/S, both in adults and in children aged >2 years, showed a substantial trend towards improvement in hospital admission rates with MDI/S use. Sample size for each study was small, ranging from 18 to 152 patients, with a total sample size of 880 children and 444 adults.

The relative risk of admission for MDI/S vs nebulizer for children was 0.65 (95% confidence interval, 0.4–1.06). Secondary outcomes were equivalent or slightly improved, including duration in the emergency department, changes in respiratory rate, blood gases, pulse, tremor, symptoms score, lung function, and use of steroids. Patients with life-threatening asthma (for example, those considered for ventilation) or other chronic illnesses were excluded.¹

All but 1 of these studies were set in the emergency department and all involved the use of one of a variety of spacers with the MDI, such as the Aerochamber or Inspirease. Whether these efficacy studies can be translated into daily outpatient clinical practice remains unclear. Emergency departments typically have higher staffing levels, and study subjects and their parents may have received more MDI/S training than is practical in many office settings.

While most of the data were for children aged 2 years and older, 1 study published after the Cochrane review did show a lower admission rate in 85 patients who were 2 to 24 months in the MDI/S group.² Controlling for the initial Pulmonary Index score, children using an MDI and Aerochamber spacer were admitted less often (5% vs 20%, number needed to treat=7; P=.05) than children using nebulizers. Since the results of this single small trial are the only data available for this younger age group, using MDI/S instead of nebulizers should be done with caution for children aged <2 years.

Another randomized controlled trial of 152 patients found no difference in primary outcomes of asthma severity score, oxygen saturation, and percent predicted peak expiratory flow rate (PEFR). Several secondary outcomes slightly favored MDI/S: number of treatments given, whether steroids were used, change in heart rate, side effects, rate of hospital admission, and treatment time in the emergency department.³

A smaller double-blinded randomized controlled trial of 33 children aged 6 to 14 years showed no difference in MDI/S vs nebulizer, as measured by clinical score, respiratory rate, oxygen saturation, and forced expiratory volume at 1 second (FEV₁).⁴ The researchers calculated the study had 90% power to detect a clinically meaningful difference in FEV₁ of 12% of the predicted value between the groups.

Other review articles reach the same conclusion. One article reviewed the literature from 1980 to 1996 and examined 17 prospective clinical trials. Outcomes measured included pulmonary function measures and clinical scores. The researchers recommended that MDI/S be used due to clinical benefit, safety, lower cost, personnel time, and speed and ease of administration.⁵

A review article from the British literature examined 3 randomized controlled trials involving 51 patients and found no superiority of nebulizer vs MDI/S.⁶ A similar review article examined 14 randomized controlled trials for beta-agonist delivery for patients aged 5 to 15 with stable asthma. They found no obvious benefit of 1 type of device over another, including nebulizer, MDI/S, and dry powder inhalers.⁷ These last 2 articles claimed to be systematic reviews, although they do not clearly state their search methodology.

Researchers used a wide variety of spacers in all aforementioned studies; accordingly, one cannot be recommended as superior to others. The degree of teaching given to parents and children about MDI/S use was not described in any of the trials.

FIGURE
MDI with spacer is beneficial when used properly

Recommendations from others

Guidelines from the Global Health Initiative for Asthma, a collaboration of the National Heart, Lung and Blood Institute and the World Health Organization, recommend MDI/S for children with asthma due to increased efficacy and decreased cost (revised in 2002). Specifically, they recommend a spacer with a face mask for infants and preschool children, a mouthpiece and spacer for children aged 4 to 6 years, and a dry powder inhaler or breath-activated device from age 6 onwards.⁸ Cincinnati Children’s Hospital’s evidence-based guidelines from 1998 also recommend MDI/S for children aged >1 year with acute asthma exacerbations.⁹ This guideline suggests using 4 to 8 puffs from a 90 μg albuterol MDI at 1- to 2-minute intervals every 20 minutes for 1 hour, then every 1 to 4 hours subsequently.

Evidence summary

Three systematic reviews addressing the efficacy of systemic corticosteroids in managing acute exacerbations of COPD found consistent, good-quality evidence supporting short courses of systemic steroids. The improvement in outcomes included decreases in airflow obstruction, treatment failure, and length of hospital stay.^1-3

The optimal initial doses of systemic corticosteroids to achieve these benefits are uncertain. Variable study designs limit combining study results into a dose-response curve, and there are no comparative trials of high- vs low-dose regimens. A panel consensus judgment from a collaboration of the National Heart, Lung, and Blood Institute and the World Health Organization recommended 30–40 mg of oral prednisone daily for 10 to 14 days.⁴

A Cochrane systematic review analyzed 7 randomized, placebo-controlled trials of systemic steroids for acute exacerbations of COPD.¹ While most of the studies reporting symptom outcomes used disparate methods of measurement, 2 small studies^5,6 reported changes in quality of life using validated visual analogue scales. This allowed their results to be combined into a summary estimate of the effect of corticosteroids compared with placebo. Combining the visual analogue scales using a standardized mean difference showed a significant improvement of this summary quality of life measure in the steroid-treated group.

Other small randomized controlled trials of systemic steroids¹ demonstrated trends towards improvement in symptom outcomes. A Taiwanese study randomized 138 patients presenting to an emergency department to treatment with 100 mg intravenous hydrocortisone or placebo within 15 minutes of arrival.¹ Using a 6-point scale, patients gave self-assessments of the severity of their attack on arrival and at 6 hours. Compared with placebo, the steroid group showed a 6-hour improvement of uncertain significance.

Similarly, a British trial of 30 mg prednisone vs placebo in 56 inpatients with acute exacerbations of COPD measured a daily composite symptom score based on 7 pulmonary and functional symptoms.⁸ There was a nonsignificant trend towards greater improvement in the steroid-treated group.

Finally, a multicenter, 3-armed, placebo-controlled, double-blinded, parallel design study enrolled 199 COPD inpatients, who were randomized to oral prednisone, inhaled budesonide, or placebo treatment groups.⁹ Dyspnea was assessed using a validated, modified Borg scale every 12 hours for 72 hours. The reduction in the modified Borg scale rating was of comparable magnitude in the 3 groups, but again there was a nonsignificant greater reduction in the systemic steroid group compared with both the placebo and inhaled budesonide groups. Power calculations were not provided, so it is unclear whether sample size in this study was sufficient to detect important differences in outcomes.

Three randomized controlled trials prospectively measured adverse events rates of systemic steroids in acute exacerbations of COPD.^9-11 Hyperglycemia or glycosuria was more common in the steroid-treated groups. The SCCOPE study, the largest of the 3 trials, found hyperglycemia requiring treatment occurred in a greater proportion of the steroid-treated group than placebo (15% vs 4%; P=.002; number needed to harm=9).

Recommendations from others

A recent review provides a concise summary of practice guidelines for the management of acute exacerbations of COPD from widely recognized professional societies.¹² Systemic steroids are endorsed in the evidence-based systematic review guidelines from the American College of Chest Physicians–American Society of Internal Medicine, along with the National Heart, Lung, and Blood Institute with the World Health Organization cosponsored Global Initiative for Chronic Obstructive Lung Disease (GOLD), and the consensus guidelines of the American Thoracic Society.¹³

Evidence summary

Three systematic reviews addressing the efficacy of systemic corticosteroids in managing acute exacerbations of COPD found consistent, good-quality evidence supporting short courses of systemic steroids. The improvement in outcomes included decreases in airflow obstruction, treatment failure, and length of hospital stay.^1-3

The optimal initial doses of systemic corticosteroids to achieve these benefits are uncertain. Variable study designs limit combining study results into a dose-response curve, and there are no comparative trials of high- vs low-dose regimens. A panel consensus judgment from a collaboration of the National Heart, Lung, and Blood Institute and the World Health Organization recommended 30–40 mg of oral prednisone daily for 10 to 14 days.⁴

A Cochrane systematic review analyzed 7 randomized, placebo-controlled trials of systemic steroids for acute exacerbations of COPD.¹ While most of the studies reporting symptom outcomes used disparate methods of measurement, 2 small studies^5,6 reported changes in quality of life using validated visual analogue scales. This allowed their results to be combined into a summary estimate of the effect of corticosteroids compared with placebo. Combining the visual analogue scales using a standardized mean difference showed a significant improvement of this summary quality of life measure in the steroid-treated group.

Other small randomized controlled trials of systemic steroids¹ demonstrated trends towards improvement in symptom outcomes. A Taiwanese study randomized 138 patients presenting to an emergency department to treatment with 100 mg intravenous hydrocortisone or placebo within 15 minutes of arrival.¹ Using a 6-point scale, patients gave self-assessments of the severity of their attack on arrival and at 6 hours. Compared with placebo, the steroid group showed a 6-hour improvement of uncertain significance.

Similarly, a British trial of 30 mg prednisone vs placebo in 56 inpatients with acute exacerbations of COPD measured a daily composite symptom score based on 7 pulmonary and functional symptoms.⁸ There was a nonsignificant trend towards greater improvement in the steroid-treated group.

Finally, a multicenter, 3-armed, placebo-controlled, double-blinded, parallel design study enrolled 199 COPD inpatients, who were randomized to oral prednisone, inhaled budesonide, or placebo treatment groups.⁹ Dyspnea was assessed using a validated, modified Borg scale every 12 hours for 72 hours. The reduction in the modified Borg scale rating was of comparable magnitude in the 3 groups, but again there was a nonsignificant greater reduction in the systemic steroid group compared with both the placebo and inhaled budesonide groups. Power calculations were not provided, so it is unclear whether sample size in this study was sufficient to detect important differences in outcomes.

Three randomized controlled trials prospectively measured adverse events rates of systemic steroids in acute exacerbations of COPD.^9-11 Hyperglycemia or glycosuria was more common in the steroid-treated groups. The SCCOPE study, the largest of the 3 trials, found hyperglycemia requiring treatment occurred in a greater proportion of the steroid-treated group than placebo (15% vs 4%; P=.002; number needed to harm=9).

Recommendations from others

A recent review provides a concise summary of practice guidelines for the management of acute exacerbations of COPD from widely recognized professional societies.¹² Systemic steroids are endorsed in the evidence-based systematic review guidelines from the American College of Chest Physicians–American Society of Internal Medicine, along with the National Heart, Lung, and Blood Institute with the World Health Organization cosponsored Global Initiative for Chronic Obstructive Lung Disease (GOLD), and the consensus guidelines of the American Thoracic Society.¹³

Evidence summary

Three systematic reviews addressing the efficacy of systemic corticosteroids in managing acute exacerbations of COPD found consistent, good-quality evidence supporting short courses of systemic steroids. The improvement in outcomes included decreases in airflow obstruction, treatment failure, and length of hospital stay.^1-3

The optimal initial doses of systemic corticosteroids to achieve these benefits are uncertain. Variable study designs limit combining study results into a dose-response curve, and there are no comparative trials of high- vs low-dose regimens. A panel consensus judgment from a collaboration of the National Heart, Lung, and Blood Institute and the World Health Organization recommended 30–40 mg of oral prednisone daily for 10 to 14 days.⁴

A Cochrane systematic review analyzed 7 randomized, placebo-controlled trials of systemic steroids for acute exacerbations of COPD.¹ While most of the studies reporting symptom outcomes used disparate methods of measurement, 2 small studies^5,6 reported changes in quality of life using validated visual analogue scales. This allowed their results to be combined into a summary estimate of the effect of corticosteroids compared with placebo. Combining the visual analogue scales using a standardized mean difference showed a significant improvement of this summary quality of life measure in the steroid-treated group.

Other small randomized controlled trials of systemic steroids¹ demonstrated trends towards improvement in symptom outcomes. A Taiwanese study randomized 138 patients presenting to an emergency department to treatment with 100 mg intravenous hydrocortisone or placebo within 15 minutes of arrival.¹ Using a 6-point scale, patients gave self-assessments of the severity of their attack on arrival and at 6 hours. Compared with placebo, the steroid group showed a 6-hour improvement of uncertain significance.

Similarly, a British trial of 30 mg prednisone vs placebo in 56 inpatients with acute exacerbations of COPD measured a daily composite symptom score based on 7 pulmonary and functional symptoms.⁸ There was a nonsignificant trend towards greater improvement in the steroid-treated group.

Finally, a multicenter, 3-armed, placebo-controlled, double-blinded, parallel design study enrolled 199 COPD inpatients, who were randomized to oral prednisone, inhaled budesonide, or placebo treatment groups.⁹ Dyspnea was assessed using a validated, modified Borg scale every 12 hours for 72 hours. The reduction in the modified Borg scale rating was of comparable magnitude in the 3 groups, but again there was a nonsignificant greater reduction in the systemic steroid group compared with both the placebo and inhaled budesonide groups. Power calculations were not provided, so it is unclear whether sample size in this study was sufficient to detect important differences in outcomes.

Three randomized controlled trials prospectively measured adverse events rates of systemic steroids in acute exacerbations of COPD.^9-11 Hyperglycemia or glycosuria was more common in the steroid-treated groups. The SCCOPE study, the largest of the 3 trials, found hyperglycemia requiring treatment occurred in a greater proportion of the steroid-treated group than placebo (15% vs 4%; P=.002; number needed to harm=9).

Recommendations from others

A recent review provides a concise summary of practice guidelines for the management of acute exacerbations of COPD from widely recognized professional societies.¹² Systemic steroids are endorsed in the evidence-based systematic review guidelines from the American College of Chest Physicians–American Society of Internal Medicine, along with the National Heart, Lung, and Blood Institute with the World Health Organization cosponsored Global Initiative for Chronic Obstructive Lung Disease (GOLD), and the consensus guidelines of the American Thoracic Society.¹³

Evidence summary

Zolpidem and zaleplon

Zolpidem and zaleplon differ structurally from benzodiazepines but act at the benzodiazepine receptor.¹ Due to their rapid absorption and short half-lives, they are particularly helpful for patients who have trouble falling asleep.² They have been shown to decrease sleep latency, increase total sleep time, and increase sleep efficiency without disturbing sleep architecture or adversely affecting memory.¹

Comparative studies in the elderly have demonstrated that zolpidem is as effective as triazolam,³ and that zaleplon is more effective than placebo at decreasing sleep latency and improving sleep quality.⁴ Tolerance, withdrawal symptoms, or rebound insomnia occur less frequently than with benzodi-azepines,¹ but zolpidem increased risk of hip fracture in a case control study (adjusted odds ratio=1.95, 95% confidence interval, 1.09–3.51).⁵

Side effects of zolpidem and zaleplon are considered dose-related, and a lower dose of 5 mg is recommended for older patients.² Efficacy of intermittent use of zolpidem has been demonstrated in clinical studies,¹ a practice that could potentially decrease risk of side effects. Overall, if a hypnotic is desired for an older adult, zolpidem and zaleplon are preferred because of their improved side-effect profiles compared with older hypnotics such as benzodiazepines, chloral hydrate, over-the-counter sleep aids, and antidepressants (see Table ).

TABLE 1
Adverse effects of hypnotics in the elderly

Benzodiazepines

Benzodiazepines have been used since the 1960s for their hypnotic, anxiolytic, anticonvulsant, muscle-relaxing, and amnesic properties. A recent meta-analysis showed that benzodiazepines improve sleep latency by only 4.2 minutes compared with placebo.⁶ Although benzodiazepines increase sleep time and efficiency, patients quickly develop tolerance to the hypnotic effects.⁷ Additional problems associated with benzodiazepines include dependence, rebound insomnia, residual sedation, falls, hip fractures, and detrimental effects on sleep architecture.⁷

Chloral hydrate

Chloral hydrate has a narrow therapeutic index and is not recommended for the treatment of insomnia.⁸ Tolerance to its effects develops after only 2 weeks of use, and drug interactions with warfarin can occur.²

Over-the-counter sleep aids

Most over-the-counter sleep aids contain diphen-hydramine, a long-acting antihistamine that is considered less effective than benzodiazepines. The anticholinergic properties of antihistamines can result in cognitive changes and urinary retention in the elderly.⁸ Melatonin and valerian are “natural” hypnotics that are available without a prescription,⁹ but their safety and efficacy are not regulated by the FDA.⁸

Antidepressants

Antidepressants with sedative effects, such as tricyclic antidepressants and trazodone, have been used for insomnia, but minimal data support the efficacy or safety of this approach.⁸ Tricyclic antidepressants may exacerbate restless legs syndrome and periodic limb movement disorder,⁸ cause anticholinergic side effects, worsen chronic heart failure, and cause ortho-static hypotension and falls.² Although tra-zodone is not a tricyclic antidepressant, it can cause dry mouth, orthostatic hypotension, and (rarely) priapism.²

Recommendations from others

A Canadian consensus statement published in 2003 supports the use of non-benzodiazepines such as zolpidem and zaleplon due to improved tolerability, and less withdrawal and abuse potential compared with benzodiazepines.⁷ The National Heart, Lung and Blood Institute Working Group on Insomnia recommends the use of short-acting hypnotics for short-term management of insomnia, but does not differentiate between short-acting benzodiazepines and the newer hypnotics such as zolpidem and zale-plon.⁸ Geriatric experts recommend that long-acting benzodiazepines, barbiturates, and amitriptyline be avoided in the elderly due to the risk of adverse drug events.¹⁰

Evidence summary

Zolpidem and zaleplon

Zolpidem and zaleplon differ structurally from benzodiazepines but act at the benzodiazepine receptor.¹ Due to their rapid absorption and short half-lives, they are particularly helpful for patients who have trouble falling asleep.² They have been shown to decrease sleep latency, increase total sleep time, and increase sleep efficiency without disturbing sleep architecture or adversely affecting memory.¹

Comparative studies in the elderly have demonstrated that zolpidem is as effective as triazolam,³ and that zaleplon is more effective than placebo at decreasing sleep latency and improving sleep quality.⁴ Tolerance, withdrawal symptoms, or rebound insomnia occur less frequently than with benzodi-azepines,¹ but zolpidem increased risk of hip fracture in a case control study (adjusted odds ratio=1.95, 95% confidence interval, 1.09–3.51).⁵

Side effects of zolpidem and zaleplon are considered dose-related, and a lower dose of 5 mg is recommended for older patients.² Efficacy of intermittent use of zolpidem has been demonstrated in clinical studies,¹ a practice that could potentially decrease risk of side effects. Overall, if a hypnotic is desired for an older adult, zolpidem and zaleplon are preferred because of their improved side-effect profiles compared with older hypnotics such as benzodiazepines, chloral hydrate, over-the-counter sleep aids, and antidepressants (see Table ).

TABLE 1
Adverse effects of hypnotics in the elderly

Benzodiazepines

Benzodiazepines have been used since the 1960s for their hypnotic, anxiolytic, anticonvulsant, muscle-relaxing, and amnesic properties. A recent meta-analysis showed that benzodiazepines improve sleep latency by only 4.2 minutes compared with placebo.⁶ Although benzodiazepines increase sleep time and efficiency, patients quickly develop tolerance to the hypnotic effects.⁷ Additional problems associated with benzodiazepines include dependence, rebound insomnia, residual sedation, falls, hip fractures, and detrimental effects on sleep architecture.⁷

Chloral hydrate

Chloral hydrate has a narrow therapeutic index and is not recommended for the treatment of insomnia.⁸ Tolerance to its effects develops after only 2 weeks of use, and drug interactions with warfarin can occur.²

Over-the-counter sleep aids

Most over-the-counter sleep aids contain diphen-hydramine, a long-acting antihistamine that is considered less effective than benzodiazepines. The anticholinergic properties of antihistamines can result in cognitive changes and urinary retention in the elderly.⁸ Melatonin and valerian are “natural” hypnotics that are available without a prescription,⁹ but their safety and efficacy are not regulated by the FDA.⁸

Antidepressants

Antidepressants with sedative effects, such as tricyclic antidepressants and trazodone, have been used for insomnia, but minimal data support the efficacy or safety of this approach.⁸ Tricyclic antidepressants may exacerbate restless legs syndrome and periodic limb movement disorder,⁸ cause anticholinergic side effects, worsen chronic heart failure, and cause ortho-static hypotension and falls.² Although tra-zodone is not a tricyclic antidepressant, it can cause dry mouth, orthostatic hypotension, and (rarely) priapism.²

Recommendations from others

A Canadian consensus statement published in 2003 supports the use of non-benzodiazepines such as zolpidem and zaleplon due to improved tolerability, and less withdrawal and abuse potential compared with benzodiazepines.⁷ The National Heart, Lung and Blood Institute Working Group on Insomnia recommends the use of short-acting hypnotics for short-term management of insomnia, but does not differentiate between short-acting benzodiazepines and the newer hypnotics such as zolpidem and zale-plon.⁸ Geriatric experts recommend that long-acting benzodiazepines, barbiturates, and amitriptyline be avoided in the elderly due to the risk of adverse drug events.¹⁰

Evidence summary

Zolpidem and zaleplon

Zolpidem and zaleplon differ structurally from benzodiazepines but act at the benzodiazepine receptor.¹ Due to their rapid absorption and short half-lives, they are particularly helpful for patients who have trouble falling asleep.² They have been shown to decrease sleep latency, increase total sleep time, and increase sleep efficiency without disturbing sleep architecture or adversely affecting memory.¹

Comparative studies in the elderly have demonstrated that zolpidem is as effective as triazolam,³ and that zaleplon is more effective than placebo at decreasing sleep latency and improving sleep quality.⁴ Tolerance, withdrawal symptoms, or rebound insomnia occur less frequently than with benzodi-azepines,¹ but zolpidem increased risk of hip fracture in a case control study (adjusted odds ratio=1.95, 95% confidence interval, 1.09–3.51).⁵

Side effects of zolpidem and zaleplon are considered dose-related, and a lower dose of 5 mg is recommended for older patients.² Efficacy of intermittent use of zolpidem has been demonstrated in clinical studies,¹ a practice that could potentially decrease risk of side effects. Overall, if a hypnotic is desired for an older adult, zolpidem and zaleplon are preferred because of their improved side-effect profiles compared with older hypnotics such as benzodiazepines, chloral hydrate, over-the-counter sleep aids, and antidepressants (see Table ).

TABLE 1
Adverse effects of hypnotics in the elderly

Benzodiazepines

Benzodiazepines have been used since the 1960s for their hypnotic, anxiolytic, anticonvulsant, muscle-relaxing, and amnesic properties. A recent meta-analysis showed that benzodiazepines improve sleep latency by only 4.2 minutes compared with placebo.⁶ Although benzodiazepines increase sleep time and efficiency, patients quickly develop tolerance to the hypnotic effects.⁷ Additional problems associated with benzodiazepines include dependence, rebound insomnia, residual sedation, falls, hip fractures, and detrimental effects on sleep architecture.⁷

Chloral hydrate

Chloral hydrate has a narrow therapeutic index and is not recommended for the treatment of insomnia.⁸ Tolerance to its effects develops after only 2 weeks of use, and drug interactions with warfarin can occur.²

Over-the-counter sleep aids

Most over-the-counter sleep aids contain diphen-hydramine, a long-acting antihistamine that is considered less effective than benzodiazepines. The anticholinergic properties of antihistamines can result in cognitive changes and urinary retention in the elderly.⁸ Melatonin and valerian are “natural” hypnotics that are available without a prescription,⁹ but their safety and efficacy are not regulated by the FDA.⁸

Antidepressants

Antidepressants with sedative effects, such as tricyclic antidepressants and trazodone, have been used for insomnia, but minimal data support the efficacy or safety of this approach.⁸ Tricyclic antidepressants may exacerbate restless legs syndrome and periodic limb movement disorder,⁸ cause anticholinergic side effects, worsen chronic heart failure, and cause ortho-static hypotension and falls.² Although tra-zodone is not a tricyclic antidepressant, it can cause dry mouth, orthostatic hypotension, and (rarely) priapism.²

Recommendations from others

A Canadian consensus statement published in 2003 supports the use of non-benzodiazepines such as zolpidem and zaleplon due to improved tolerability, and less withdrawal and abuse potential compared with benzodiazepines.⁷ The National Heart, Lung and Blood Institute Working Group on Insomnia recommends the use of short-acting hypnotics for short-term management of insomnia, but does not differentiate between short-acting benzodiazepines and the newer hypnotics such as zolpidem and zale-plon.⁸ Geriatric experts recommend that long-acting benzodiazepines, barbiturates, and amitriptyline be avoided in the elderly due to the risk of adverse drug events.¹⁰

Evidence summary

There is little evidence that statins cause myopathy. Synthesis is difficult because definitions of myopathy types differ among investigators. Proposed clinical syndrome definitions are myalgia (muscle weakness or ache with normal creatine kinase), myositis (symptoms with increased creatine kinase), and rhabdomyolysis (symptoms, markedly elevated creatine kinase, and renal insufficiency) as subsets of the more general term myopathy.¹ The Table summarizes myopathy data from 30 statin trials analyzed in a recent systematic review, showing similar myopathy rates in statin and placebo patients.² There may be a lower myopathy rate in these trials than in routine clinical practice because of stricter exclusion criteria and more intense monitoring.

A large well-done British epidemiologic cohort study (n=96,193) found an increased rate of myopathy (broadly defined, not requiring creatine kinase elevation) among patients taking statins, with an absolute rate difference of 1 per 10,000 person-years.³ A small study of 21 patients on statins with muscle symptoms but normal creatine kinases described 4 patients who were able to distinguish statins from placebo, with objective reversible weakness and abnormal muscle biopsies.⁴ Postmarket voluntary clinician reports point to statin myopathy in this and other countries;^5-7 these include 3339 rhabdomyolysis FDA reports (1990 to March 2002).²

Though some assert differential myopathy rates among statins based on cell research, case reports, or differences in metabolic clearance, no studies directly compare clinical myopathy rates among statins. There is no good evidence of a differential myopathy risk among statins currently available in the US.^1-2 Cerivastatin, however, was withdrawn from the US market because of a fatal rhabdomyolysis rate 16 to 80 times higher than other statins based on FDA reports using a denominator of prescription volume (3.16 fatal cases/million prescriptions vs 0.15 for the statin class as a whole).⁶

It is unknown whether previous myopathy, however defined, increases the risk of future myopathy with statin rechallenge. A tabular analysis of 74 published case reports of statin-associated rhabdomyolysis from a MEDLINE search covering 1985 to 2000 reported that in most cases the statin was safely restarted after stopping presumed interactive drugs (exact numbers not reported).⁸ In the AFCAPS/TexCAPS trial, 20 of 21 statin patients (out of a study population of 3304) who had elevated creatine kinase (>10 times the upper limits of normal) recovered with continued lovastatin treatment, while the other patient resumed treatment after a brief interruption without further elevations.⁹ The EXCEL trial (n=8245) of various lovastatin dosages included routine creatine kinase tests every 6 weeks for 48 weeks. Five lovastatin patients had muscle symptoms with creatine kinases >10 times the upper limits of normal, and in the 2 who continued treatment, symptoms and creatine kinase became normal.¹⁰ Of note, creatine kinase elevation of any kind at least once during 48 weeks occurred in 28.9% of placebo patients, arguing against routine creatine kinase screening in statin patients.

Case studies suggest an increased myopathy risk when statins are given with various medications, including fibrates, cyclosporine, azole antifungals, warfarin, nefazodone, and macrolide antibiotics.^4,6,8 Pravastatin and fluvastatin, which are not metabolized by the P450 CYP3A4 pathway, may be safer to use because of fewer drug interactions.^2,8 Likewise, certain comorbid states such as hypothyroidism, renal insufficiency (especially in patients with diabetes), recent trauma, and perioperative periods, as well as advanced age, small body frame, and multiple medications may increase statin myopathy risk.^1,2,7,8

TABLE
Pooled myopathy data from 30 randomized controlled statin trials

Recommendations from others

A 2002 Clinical Advisory, jointly issued by the American College of Cardiology, the American Heart Association, and the National Heart, Lung and Blood Institute, asserted that statins carry a small but definite myopathy risk.¹ It recommended against routine creatine kinase tests, reserving them for patients who develop muscle symptoms. It also recommended stopping statins when muscle symptoms with creatine kinase elevations >10 times the upper limits of normal occur, with consideration of restarting statins later at a lower dose if symptoms and elevated creatine kinase resolve. Careful monitoring of patients at higher risk of statin myopathy is also recommended.

Evidence summary

There is little evidence that statins cause myopathy. Synthesis is difficult because definitions of myopathy types differ among investigators. Proposed clinical syndrome definitions are myalgia (muscle weakness or ache with normal creatine kinase), myositis (symptoms with increased creatine kinase), and rhabdomyolysis (symptoms, markedly elevated creatine kinase, and renal insufficiency) as subsets of the more general term myopathy.¹ The Table summarizes myopathy data from 30 statin trials analyzed in a recent systematic review, showing similar myopathy rates in statin and placebo patients.² There may be a lower myopathy rate in these trials than in routine clinical practice because of stricter exclusion criteria and more intense monitoring.

A large well-done British epidemiologic cohort study (n=96,193) found an increased rate of myopathy (broadly defined, not requiring creatine kinase elevation) among patients taking statins, with an absolute rate difference of 1 per 10,000 person-years.³ A small study of 21 patients on statins with muscle symptoms but normal creatine kinases described 4 patients who were able to distinguish statins from placebo, with objective reversible weakness and abnormal muscle biopsies.⁴ Postmarket voluntary clinician reports point to statin myopathy in this and other countries;^5-7 these include 3339 rhabdomyolysis FDA reports (1990 to March 2002).²

Though some assert differential myopathy rates among statins based on cell research, case reports, or differences in metabolic clearance, no studies directly compare clinical myopathy rates among statins. There is no good evidence of a differential myopathy risk among statins currently available in the US.^1-2 Cerivastatin, however, was withdrawn from the US market because of a fatal rhabdomyolysis rate 16 to 80 times higher than other statins based on FDA reports using a denominator of prescription volume (3.16 fatal cases/million prescriptions vs 0.15 for the statin class as a whole).⁶

It is unknown whether previous myopathy, however defined, increases the risk of future myopathy with statin rechallenge. A tabular analysis of 74 published case reports of statin-associated rhabdomyolysis from a MEDLINE search covering 1985 to 2000 reported that in most cases the statin was safely restarted after stopping presumed interactive drugs (exact numbers not reported).⁸ In the AFCAPS/TexCAPS trial, 20 of 21 statin patients (out of a study population of 3304) who had elevated creatine kinase (>10 times the upper limits of normal) recovered with continued lovastatin treatment, while the other patient resumed treatment after a brief interruption without further elevations.⁹ The EXCEL trial (n=8245) of various lovastatin dosages included routine creatine kinase tests every 6 weeks for 48 weeks. Five lovastatin patients had muscle symptoms with creatine kinases >10 times the upper limits of normal, and in the 2 who continued treatment, symptoms and creatine kinase became normal.¹⁰ Of note, creatine kinase elevation of any kind at least once during 48 weeks occurred in 28.9% of placebo patients, arguing against routine creatine kinase screening in statin patients.

Case studies suggest an increased myopathy risk when statins are given with various medications, including fibrates, cyclosporine, azole antifungals, warfarin, nefazodone, and macrolide antibiotics.^4,6,8 Pravastatin and fluvastatin, which are not metabolized by the P450 CYP3A4 pathway, may be safer to use because of fewer drug interactions.^2,8 Likewise, certain comorbid states such as hypothyroidism, renal insufficiency (especially in patients with diabetes), recent trauma, and perioperative periods, as well as advanced age, small body frame, and multiple medications may increase statin myopathy risk.^1,2,7,8

TABLE
Pooled myopathy data from 30 randomized controlled statin trials

Recommendations from others

A 2002 Clinical Advisory, jointly issued by the American College of Cardiology, the American Heart Association, and the National Heart, Lung and Blood Institute, asserted that statins carry a small but definite myopathy risk.¹ It recommended against routine creatine kinase tests, reserving them for patients who develop muscle symptoms. It also recommended stopping statins when muscle symptoms with creatine kinase elevations >10 times the upper limits of normal occur, with consideration of restarting statins later at a lower dose if symptoms and elevated creatine kinase resolve. Careful monitoring of patients at higher risk of statin myopathy is also recommended.

Evidence summary

There is little evidence that statins cause myopathy. Synthesis is difficult because definitions of myopathy types differ among investigators. Proposed clinical syndrome definitions are myalgia (muscle weakness or ache with normal creatine kinase), myositis (symptoms with increased creatine kinase), and rhabdomyolysis (symptoms, markedly elevated creatine kinase, and renal insufficiency) as subsets of the more general term myopathy.¹ The Table summarizes myopathy data from 30 statin trials analyzed in a recent systematic review, showing similar myopathy rates in statin and placebo patients.² There may be a lower myopathy rate in these trials than in routine clinical practice because of stricter exclusion criteria and more intense monitoring.

A large well-done British epidemiologic cohort study (n=96,193) found an increased rate of myopathy (broadly defined, not requiring creatine kinase elevation) among patients taking statins, with an absolute rate difference of 1 per 10,000 person-years.³ A small study of 21 patients on statins with muscle symptoms but normal creatine kinases described 4 patients who were able to distinguish statins from placebo, with objective reversible weakness and abnormal muscle biopsies.⁴ Postmarket voluntary clinician reports point to statin myopathy in this and other countries;^5-7 these include 3339 rhabdomyolysis FDA reports (1990 to March 2002).²

Though some assert differential myopathy rates among statins based on cell research, case reports, or differences in metabolic clearance, no studies directly compare clinical myopathy rates among statins. There is no good evidence of a differential myopathy risk among statins currently available in the US.^1-2 Cerivastatin, however, was withdrawn from the US market because of a fatal rhabdomyolysis rate 16 to 80 times higher than other statins based on FDA reports using a denominator of prescription volume (3.16 fatal cases/million prescriptions vs 0.15 for the statin class as a whole).⁶

It is unknown whether previous myopathy, however defined, increases the risk of future myopathy with statin rechallenge. A tabular analysis of 74 published case reports of statin-associated rhabdomyolysis from a MEDLINE search covering 1985 to 2000 reported that in most cases the statin was safely restarted after stopping presumed interactive drugs (exact numbers not reported).⁸ In the AFCAPS/TexCAPS trial, 20 of 21 statin patients (out of a study population of 3304) who had elevated creatine kinase (>10 times the upper limits of normal) recovered with continued lovastatin treatment, while the other patient resumed treatment after a brief interruption without further elevations.⁹ The EXCEL trial (n=8245) of various lovastatin dosages included routine creatine kinase tests every 6 weeks for 48 weeks. Five lovastatin patients had muscle symptoms with creatine kinases >10 times the upper limits of normal, and in the 2 who continued treatment, symptoms and creatine kinase became normal.¹⁰ Of note, creatine kinase elevation of any kind at least once during 48 weeks occurred in 28.9% of placebo patients, arguing against routine creatine kinase screening in statin patients.

Case studies suggest an increased myopathy risk when statins are given with various medications, including fibrates, cyclosporine, azole antifungals, warfarin, nefazodone, and macrolide antibiotics.^4,6,8 Pravastatin and fluvastatin, which are not metabolized by the P450 CYP3A4 pathway, may be safer to use because of fewer drug interactions.^2,8 Likewise, certain comorbid states such as hypothyroidism, renal insufficiency (especially in patients with diabetes), recent trauma, and perioperative periods, as well as advanced age, small body frame, and multiple medications may increase statin myopathy risk.^1,2,7,8

TABLE
Pooled myopathy data from 30 randomized controlled statin trials

Recommendations from others

A 2002 Clinical Advisory, jointly issued by the American College of Cardiology, the American Heart Association, and the National Heart, Lung and Blood Institute, asserted that statins carry a small but definite myopathy risk.¹ It recommended against routine creatine kinase tests, reserving them for patients who develop muscle symptoms. It also recommended stopping statins when muscle symptoms with creatine kinase elevations >10 times the upper limits of normal occur, with consideration of restarting statins later at a lower dose if symptoms and elevated creatine kinase resolve. Careful monitoring of patients at higher risk of statin myopathy is also recommended.

FIGURE 1
Cause of BPPVE

FIGURE 2
Pley maneuver for BPPV

BPPV is characterized by brief, self-limited episodes of vertigo, provoked by typical position changes. This condition may result from free-floating debris in the endolymph of the posterior semicircular canal. This debris moves with position change, causing an abnormal perception of movement and classic symptoms of vertigo. Dix-Hallpike testing aids in the diagnosis, but treatment is often prescribed empirically.¹

The most widely studied treatments for BPPV are the single-treatment repositioning techniques, such as the Epley maneuver.²A Cochrane review of treatments for BPPV yielded 11 trials, of which 9 were excluded due to a high risk of bias.³ The 2 remaining trials compared the Epley maneuver with a sham procedure among 86 patients referred to specialty care.^4,5 Outcomes included conversion of the Dix-Hallpike test from positive to negative, as well as resolution of symptoms by patient report. Assessment occurred 1–4 weeks following the intervention in the 2 trials.^4,5 Pooled data yielded odds ratios in favor of treatment for both objective testing (OR=5.67; 95% confidence interval [CI], 2.21–14.56) and symptom resolution (OR=4.92; 95% CI, 1.84–13.16), with no adverse outcomes reported.³We found no trials comparing the Epley maneuver with either vestibular habituation therapy or surgical management of BPPV.

There is no direct evidence for vestibular rehabilitation in BPPV. In a trial of vestibular rehabilitation for prolonged, undifferentiated dizziness, patients were randomized to usual care (n=76) or treatment with two 30-minute home education sessions at baseline and 6 weeks (n=67). A nurse, who had received 2 weeks of training, led the sessions, which included basic education on the vestibular system, causes of dizziness, and the rationale for exercise therapy. The nurse then taught the patients 8 sets of standard head and body movements to be performed twice daily. At 6 months, 69% of the treatment group vs 37% of the control group reported subjective improvement (OR=3.8 at 6 months; 95% CI, 1.6–8.7).⁶

Lorazepam and diazepam had no effect in 1 small randomized controlled trial.⁷ In this study, 25 BPPV patients from specialty clinics were randomized to placebo, diazepam 5 mg, or lorazepam 1 mg 3 times daily for 4 weeks. Patients reported dizziness on a 10-point scale at baseline and after 4 weeks of therapy. Nystagmus severity was also assessed using a 10-point scale at baseline and within 2 days following completion of treatment. The authors found no significant difference between the treatment and placebo arms; however, the study may have been underpowered to detect a clinically significant difference.

Recommendations from others

The Vestibular Disorders Association recommends the Epley maneuver as first-line treatment for BPPV, as does the Mayo Clinic.^8,9 The National Institute on Deafness and Other Communication Disorders suggests that vestibular rehabilitation may be useful as a treatment for dizziness depending on the cause.¹⁰

FIGURE 1
Cause of BPPVE

FIGURE 2
Pley maneuver for BPPV

BPPV is characterized by brief, self-limited episodes of vertigo, provoked by typical position changes. This condition may result from free-floating debris in the endolymph of the posterior semicircular canal. This debris moves with position change, causing an abnormal perception of movement and classic symptoms of vertigo. Dix-Hallpike testing aids in the diagnosis, but treatment is often prescribed empirically.¹

The most widely studied treatments for BPPV are the single-treatment repositioning techniques, such as the Epley maneuver.²A Cochrane review of treatments for BPPV yielded 11 trials, of which 9 were excluded due to a high risk of bias.³ The 2 remaining trials compared the Epley maneuver with a sham procedure among 86 patients referred to specialty care.^4,5 Outcomes included conversion of the Dix-Hallpike test from positive to negative, as well as resolution of symptoms by patient report. Assessment occurred 1–4 weeks following the intervention in the 2 trials.^4,5 Pooled data yielded odds ratios in favor of treatment for both objective testing (OR=5.67; 95% confidence interval [CI], 2.21–14.56) and symptom resolution (OR=4.92; 95% CI, 1.84–13.16), with no adverse outcomes reported.³We found no trials comparing the Epley maneuver with either vestibular habituation therapy or surgical management of BPPV.

There is no direct evidence for vestibular rehabilitation in BPPV. In a trial of vestibular rehabilitation for prolonged, undifferentiated dizziness, patients were randomized to usual care (n=76) or treatment with two 30-minute home education sessions at baseline and 6 weeks (n=67). A nurse, who had received 2 weeks of training, led the sessions, which included basic education on the vestibular system, causes of dizziness, and the rationale for exercise therapy. The nurse then taught the patients 8 sets of standard head and body movements to be performed twice daily. At 6 months, 69% of the treatment group vs 37% of the control group reported subjective improvement (OR=3.8 at 6 months; 95% CI, 1.6–8.7).⁶

Lorazepam and diazepam had no effect in 1 small randomized controlled trial.⁷ In this study, 25 BPPV patients from specialty clinics were randomized to placebo, diazepam 5 mg, or lorazepam 1 mg 3 times daily for 4 weeks. Patients reported dizziness on a 10-point scale at baseline and after 4 weeks of therapy. Nystagmus severity was also assessed using a 10-point scale at baseline and within 2 days following completion of treatment. The authors found no significant difference between the treatment and placebo arms; however, the study may have been underpowered to detect a clinically significant difference.

Recommendations from others

The Vestibular Disorders Association recommends the Epley maneuver as first-line treatment for BPPV, as does the Mayo Clinic.^8,9 The National Institute on Deafness and Other Communication Disorders suggests that vestibular rehabilitation may be useful as a treatment for dizziness depending on the cause.¹⁰

FIGURE 1
Cause of BPPVE

FIGURE 2
Pley maneuver for BPPV

BPPV is characterized by brief, self-limited episodes of vertigo, provoked by typical position changes. This condition may result from free-floating debris in the endolymph of the posterior semicircular canal. This debris moves with position change, causing an abnormal perception of movement and classic symptoms of vertigo. Dix-Hallpike testing aids in the diagnosis, but treatment is often prescribed empirically.¹

The most widely studied treatments for BPPV are the single-treatment repositioning techniques, such as the Epley maneuver.²A Cochrane review of treatments for BPPV yielded 11 trials, of which 9 were excluded due to a high risk of bias.³ The 2 remaining trials compared the Epley maneuver with a sham procedure among 86 patients referred to specialty care.^4,5 Outcomes included conversion of the Dix-Hallpike test from positive to negative, as well as resolution of symptoms by patient report. Assessment occurred 1–4 weeks following the intervention in the 2 trials.^4,5 Pooled data yielded odds ratios in favor of treatment for both objective testing (OR=5.67; 95% confidence interval [CI], 2.21–14.56) and symptom resolution (OR=4.92; 95% CI, 1.84–13.16), with no adverse outcomes reported.³We found no trials comparing the Epley maneuver with either vestibular habituation therapy or surgical management of BPPV.

There is no direct evidence for vestibular rehabilitation in BPPV. In a trial of vestibular rehabilitation for prolonged, undifferentiated dizziness, patients were randomized to usual care (n=76) or treatment with two 30-minute home education sessions at baseline and 6 weeks (n=67). A nurse, who had received 2 weeks of training, led the sessions, which included basic education on the vestibular system, causes of dizziness, and the rationale for exercise therapy. The nurse then taught the patients 8 sets of standard head and body movements to be performed twice daily. At 6 months, 69% of the treatment group vs 37% of the control group reported subjective improvement (OR=3.8 at 6 months; 95% CI, 1.6–8.7).⁶

Lorazepam and diazepam had no effect in 1 small randomized controlled trial.⁷ In this study, 25 BPPV patients from specialty clinics were randomized to placebo, diazepam 5 mg, or lorazepam 1 mg 3 times daily for 4 weeks. Patients reported dizziness on a 10-point scale at baseline and after 4 weeks of therapy. Nystagmus severity was also assessed using a 10-point scale at baseline and within 2 days following completion of treatment. The authors found no significant difference between the treatment and placebo arms; however, the study may have been underpowered to detect a clinically significant difference.

Recommendations from others

The Vestibular Disorders Association recommends the Epley maneuver as first-line treatment for BPPV, as does the Mayo Clinic.^8,9 The National Institute on Deafness and Other Communication Disorders suggests that vestibular rehabilitation may be useful as a treatment for dizziness depending on the cause.¹⁰