Clinical Inquiries

Evidence summary

Clinicians expecting results similar to a randomized clinical trial should use treatment regimes based on those used in the trial. The Air Force/Texas Coronary Atherosclerosis Prevention Study was the only primary prevention randomized controlled trial that titrated the dose of medication (either 20 mg or 40 mg of lovastatin daily) to reach a LDL-C of 110 mg/dL² or lower. Titration was done after 3 months of therapy. All other studies used a fixed dose of medication without regard to the lipid levels obtained (cholestyramine 24 g/day,⁴ gemfibrozil 600 mg twice daily,⁵ clofibrate 1.6g/day,⁶ and pravastatin 40 mg/day¹). There have been no trials that test different strategies for monitoring lipid levels.

The Munster Heart Study (PROCAM)⁷ demonstrated that “the ranking of continuous risk factors in terms of predicting major coronary events was LDL-C, total cholesterol (TC), high-density lipoprotein (HDL-C), triglycerides (TG)….” Grover and colleagues⁸ found that the TC/HDL-C and the LDL-C/HDL-C ratios both performed better than the TC in predicting heart disease mortality. The Framingham Study⁹ confirmed the usefulness of TC and HDL-C in assessing risk. None of the studies gave guidance on what to monitor while a patient is on treatment.

Recommendations from others

The National Cholesterol Education Program (NCEP)¹⁰ recommends that LDL-C be monitored every 6 weeks after the initiation of treatment. After the goal LDL-C is attained, measurement every 4 to 6 months is adequate.

Evidence summary

Clinicians expecting results similar to a randomized clinical trial should use treatment regimes based on those used in the trial. The Air Force/Texas Coronary Atherosclerosis Prevention Study was the only primary prevention randomized controlled trial that titrated the dose of medication (either 20 mg or 40 mg of lovastatin daily) to reach a LDL-C of 110 mg/dL² or lower. Titration was done after 3 months of therapy. All other studies used a fixed dose of medication without regard to the lipid levels obtained (cholestyramine 24 g/day,⁴ gemfibrozil 600 mg twice daily,⁵ clofibrate 1.6g/day,⁶ and pravastatin 40 mg/day¹). There have been no trials that test different strategies for monitoring lipid levels.

The Munster Heart Study (PROCAM)⁷ demonstrated that “the ranking of continuous risk factors in terms of predicting major coronary events was LDL-C, total cholesterol (TC), high-density lipoprotein (HDL-C), triglycerides (TG)….” Grover and colleagues⁸ found that the TC/HDL-C and the LDL-C/HDL-C ratios both performed better than the TC in predicting heart disease mortality. The Framingham Study⁹ confirmed the usefulness of TC and HDL-C in assessing risk. None of the studies gave guidance on what to monitor while a patient is on treatment.

Recommendations from others

The National Cholesterol Education Program (NCEP)¹⁰ recommends that LDL-C be monitored every 6 weeks after the initiation of treatment. After the goal LDL-C is attained, measurement every 4 to 6 months is adequate.

Evidence summary

Clinicians expecting results similar to a randomized clinical trial should use treatment regimes based on those used in the trial. The Air Force/Texas Coronary Atherosclerosis Prevention Study was the only primary prevention randomized controlled trial that titrated the dose of medication (either 20 mg or 40 mg of lovastatin daily) to reach a LDL-C of 110 mg/dL² or lower. Titration was done after 3 months of therapy. All other studies used a fixed dose of medication without regard to the lipid levels obtained (cholestyramine 24 g/day,⁴ gemfibrozil 600 mg twice daily,⁵ clofibrate 1.6g/day,⁶ and pravastatin 40 mg/day¹). There have been no trials that test different strategies for monitoring lipid levels.

The Munster Heart Study (PROCAM)⁷ demonstrated that “the ranking of continuous risk factors in terms of predicting major coronary events was LDL-C, total cholesterol (TC), high-density lipoprotein (HDL-C), triglycerides (TG)….” Grover and colleagues⁸ found that the TC/HDL-C and the LDL-C/HDL-C ratios both performed better than the TC in predicting heart disease mortality. The Framingham Study⁹ confirmed the usefulness of TC and HDL-C in assessing risk. None of the studies gave guidance on what to monitor while a patient is on treatment.

Recommendations from others

The National Cholesterol Education Program (NCEP)¹⁰ recommends that LDL-C be monitored every 6 weeks after the initiation of treatment. After the goal LDL-C is attained, measurement every 4 to 6 months is adequate.

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Evidence summary

The current expert recommendations are apparently based on the 0.5% to 3% occurrence of a persistent elevation in aminotransferases (greater than 3 times the upper limit of normal occurring on 2 or more occasions) noted in clinical studies of statins. The incidence of this asymptomatic abnormality increases in a dose-dependent fashion and usually occurs within the first 3 months of therapy. A decreased dose or discontinuation of statin therapy typically results in normalization of aminotransferase values. Yet at least 2 placebo-controlled randomized trials demonstrated no significant difference in the incidence of persistently elevated aminotransferases between statin and placebo treatment.^1,2 Since there has been no study of the natural history and prognosis of persistently elevated aminotransferase values secondary to statin therapy, it is impossible to accurately estimate the need or value of screening for this complication. Gemfibrozil only rarely causes persistently elevated aminotransferase levels.

Myopathy, defined as generalized myalgia with a serum creatine kinase (CK) level greater than 10 times the upper limit of normal is rare (<0.1%), but less so when the statins are used concomitantly with medications such as gemfibrozil, nicotinic acid, antifungal azoles, macrolide antibiotics, and cyclosporine. The myalgia and CK elevation typically resolves after prompt discontinuation from treatment; several fatal cases of rhabdomyolysis, however, have been reported. Remaining alert for the symptoms of myopathy appears to be the best approach to minimize morbidity. The routine determination of serum CK during either statin or gemfibrozil monotherapy is not recommended.

Recommendations from others

For each of the currently approved statins, the US Food and Drug Administration approved labeling information generally includes liver function testing before, and at 12 weeks following, the initiation of therapy, and at any elevation of dose and periodically thereafter. Periodic liver function monitoring is also recommended for treatment with the fibric acid derivative gemfibrozil.

The Washington Manual of Medical Therapeutics³ recommends liver function testing every 6 weeks for the first 3 months, then every 6 months afterward. The National Cholesterol Education Program guidelines do not address the appropriateness or frequency of liver function testing.⁴

Evidence Summary

Several case series have demonstrated that occult coronary heart disease (CHD) can be identified by screening asymptomatic adults with an EST, some of whom will ultimately experience CHD death. The best estimates of sensitivity and specificity of the EST for identifying occult CHD are 45% and 85%, respectively.¹ The sensitivity for detection of risk for cardiac death is lower; sensitivities between 27%2 and 61%³ have been reported. In a population with a low risk of CHD death, the positive predictive value (percent with a positive test who actually have CHD) will be low.

Patients and clinicians might be more likely to address risk factors for cardiovascular disease in patients with silent ischemia. However, it has never been shown that early intervention of known ischemia during its asymptomatic phase improves CHD outcome.

Limiting screening to those at high risk for CHD would improve the predictive value of a positive test. One study⁵ of middle-aged asymptomatic men and recorded the presence of a first-degree relative with heart disease, systolic blood pressure of 140 mm Hg or greater, smoking, or total cholesterol higher than 250 mg per dL. Men with any of these risk factors had significantly higher CHD event incidence if they had 2 or more EST abnormalities than those with less than 2 EST abnormalities. The authors concluded that routine screening of asymptomatic men without these risk factors was not warranted, but the uncertain efficacy of earlier intervention remains.

Screening individuals in occupations that can affect public safety, such as airline pilots, would identify some individuals at risk for sudden cardiac death, though the population impact of this would be miniscule. Screening individuals who will be engaging in strenuous physical activity would also be effective at detecting at least some people who are at risk of sudden death. However, only 2% of cardiac deaths occur during exercise,² and it again is not clear that early intervention improves outcome.

Recommendations from others

The United States Preventive Services Task Force found insufficient evidence to recommend for or against the use of screening EST in middle-aged individuals.² The American Heart Association and the American College of Cardiology advise against routine screening of asymptomatic men or women but suggested that there might be value in screening individuals who plan to start a vigorous exercise program, who are involved in occupations in which impairment might have an impact on public safety, or who are at high risk for CHD due to other diseases.⁶ The American College of Sports Medicine, in a joint opinion with the American Heart Association, recommends a screening EST for men older than of 45 years who are about to embark on a vigorous exercise program.⁷

Evidence Summary

Several case series have demonstrated that occult coronary heart disease (CHD) can be identified by screening asymptomatic adults with an EST, some of whom will ultimately experience CHD death. The best estimates of sensitivity and specificity of the EST for identifying occult CHD are 45% and 85%, respectively.¹ The sensitivity for detection of risk for cardiac death is lower; sensitivities between 27%2 and 61%³ have been reported. In a population with a low risk of CHD death, the positive predictive value (percent with a positive test who actually have CHD) will be low.

Patients and clinicians might be more likely to address risk factors for cardiovascular disease in patients with silent ischemia. However, it has never been shown that early intervention of known ischemia during its asymptomatic phase improves CHD outcome.

Limiting screening to those at high risk for CHD would improve the predictive value of a positive test. One study⁵ of middle-aged asymptomatic men and recorded the presence of a first-degree relative with heart disease, systolic blood pressure of 140 mm Hg or greater, smoking, or total cholesterol higher than 250 mg per dL. Men with any of these risk factors had significantly higher CHD event incidence if they had 2 or more EST abnormalities than those with less than 2 EST abnormalities. The authors concluded that routine screening of asymptomatic men without these risk factors was not warranted, but the uncertain efficacy of earlier intervention remains.

Screening individuals in occupations that can affect public safety, such as airline pilots, would identify some individuals at risk for sudden cardiac death, though the population impact of this would be miniscule. Screening individuals who will be engaging in strenuous physical activity would also be effective at detecting at least some people who are at risk of sudden death. However, only 2% of cardiac deaths occur during exercise,² and it again is not clear that early intervention improves outcome.

Recommendations from others

The United States Preventive Services Task Force found insufficient evidence to recommend for or against the use of screening EST in middle-aged individuals.² The American Heart Association and the American College of Cardiology advise against routine screening of asymptomatic men or women but suggested that there might be value in screening individuals who plan to start a vigorous exercise program, who are involved in occupations in which impairment might have an impact on public safety, or who are at high risk for CHD due to other diseases.⁶ The American College of Sports Medicine, in a joint opinion with the American Heart Association, recommends a screening EST for men older than of 45 years who are about to embark on a vigorous exercise program.⁷

Evidence Summary

Several case series have demonstrated that occult coronary heart disease (CHD) can be identified by screening asymptomatic adults with an EST, some of whom will ultimately experience CHD death. The best estimates of sensitivity and specificity of the EST for identifying occult CHD are 45% and 85%, respectively.¹ The sensitivity for detection of risk for cardiac death is lower; sensitivities between 27%2 and 61%³ have been reported. In a population with a low risk of CHD death, the positive predictive value (percent with a positive test who actually have CHD) will be low.

Patients and clinicians might be more likely to address risk factors for cardiovascular disease in patients with silent ischemia. However, it has never been shown that early intervention of known ischemia during its asymptomatic phase improves CHD outcome.

Limiting screening to those at high risk for CHD would improve the predictive value of a positive test. One study⁵ of middle-aged asymptomatic men and recorded the presence of a first-degree relative with heart disease, systolic blood pressure of 140 mm Hg or greater, smoking, or total cholesterol higher than 250 mg per dL. Men with any of these risk factors had significantly higher CHD event incidence if they had 2 or more EST abnormalities than those with less than 2 EST abnormalities. The authors concluded that routine screening of asymptomatic men without these risk factors was not warranted, but the uncertain efficacy of earlier intervention remains.

Screening individuals in occupations that can affect public safety, such as airline pilots, would identify some individuals at risk for sudden cardiac death, though the population impact of this would be miniscule. Screening individuals who will be engaging in strenuous physical activity would also be effective at detecting at least some people who are at risk of sudden death. However, only 2% of cardiac deaths occur during exercise,² and it again is not clear that early intervention improves outcome.

Recommendations from others

The United States Preventive Services Task Force found insufficient evidence to recommend for or against the use of screening EST in middle-aged individuals.² The American Heart Association and the American College of Cardiology advise against routine screening of asymptomatic men or women but suggested that there might be value in screening individuals who plan to start a vigorous exercise program, who are involved in occupations in which impairment might have an impact on public safety, or who are at high risk for CHD due to other diseases.⁶ The American College of Sports Medicine, in a joint opinion with the American Heart Association, recommends a screening EST for men older than of 45 years who are about to embark on a vigorous exercise program.⁷

Evidence Summary

Vaginal bleeding can be a sign of endometrial hyperplasia or cancer. Fifty-year-old perimenopausal women with an intact uterus have a 5% prevalence of hyperplasia1,² and a 2% to 3% risk of endometrial cancer in their lifetime.² HRT causes irregular bleeding for 8% to 60% of these women at 6 months and 4% to 30% at 12 months.^3,4 Roughly half of those bleeding at 6 months are no longer bleeding at a year.^3-5 Bleeding may be reduced by using lower-dose combinations, sequential hormones in perimenopausal women, and continuous regimens in women more than 3 years after menopause.^1,3,5

Any woman taking HRT who has irregular bleeding after a year should have a Pap test, since cervical abnormalities are not uncommon.⁶ Although HRT increases average endometrial thickness (at least initially),^6,7 TVUS showing an endometrial stripe of 5 mm or greater is more than 90% sensitive in detecting endometrial disease (cancer, complex hyperplasia, polyps).⁷ Approximately 3% of endometrial stripes are unmeasurable by TVUS and should be treated as abnormal. TVUS also shows many structural abnormalities, including those outside of the endometrium. A negative TVUS using the 5-mm criterion is associated with a 0.6% to 1% chance of endometrial cancer.^6,7

Abnormal sonograms or persistent unexpected bleeding after a normal sonogram requires further evaluation. Endometrial biopsy is a straightforward office procedure, and is as sensitive as dilatation and curretage.⁴ It fails (eg, from cervical stenosis) or is nondiagnostic in 2% to 28% of attempts.⁷ Hysteroscopy is also accurate but sometimes requires paracervical and general anesthesia. It also requires additional training and equipment. Zero percent to 12% of attempts fail (failures are less common in patients taking HRT), and the false-negative rate is roughly 3%.⁴

Recommendations from others

The American Association of Clinical Endocrinologists states in its menopause management guideline: “Unexpected uterine bleeding or spotting during HRT is common and is managed by appropriate changes in therapy, not by discontinuation of HRT…. Nevertheless, monitoring of the endometrium by transvaginal ultrasound study or endometrial biopsy is indicated, especially in women who have an abnormal bleeding pattern.”⁸

Special thanks to Kate Rose and Joellynn I. Wilner for their library assistance.

Evidence Summary

Vaginal bleeding can be a sign of endometrial hyperplasia or cancer. Fifty-year-old perimenopausal women with an intact uterus have a 5% prevalence of hyperplasia1,² and a 2% to 3% risk of endometrial cancer in their lifetime.² HRT causes irregular bleeding for 8% to 60% of these women at 6 months and 4% to 30% at 12 months.^3,4 Roughly half of those bleeding at 6 months are no longer bleeding at a year.^3-5 Bleeding may be reduced by using lower-dose combinations, sequential hormones in perimenopausal women, and continuous regimens in women more than 3 years after menopause.^1,3,5

Any woman taking HRT who has irregular bleeding after a year should have a Pap test, since cervical abnormalities are not uncommon.⁶ Although HRT increases average endometrial thickness (at least initially),^6,7 TVUS showing an endometrial stripe of 5 mm or greater is more than 90% sensitive in detecting endometrial disease (cancer, complex hyperplasia, polyps).⁷ Approximately 3% of endometrial stripes are unmeasurable by TVUS and should be treated as abnormal. TVUS also shows many structural abnormalities, including those outside of the endometrium. A negative TVUS using the 5-mm criterion is associated with a 0.6% to 1% chance of endometrial cancer.^6,7

Abnormal sonograms or persistent unexpected bleeding after a normal sonogram requires further evaluation. Endometrial biopsy is a straightforward office procedure, and is as sensitive as dilatation and curretage.⁴ It fails (eg, from cervical stenosis) or is nondiagnostic in 2% to 28% of attempts.⁷ Hysteroscopy is also accurate but sometimes requires paracervical and general anesthesia. It also requires additional training and equipment. Zero percent to 12% of attempts fail (failures are less common in patients taking HRT), and the false-negative rate is roughly 3%.⁴

Recommendations from others

The American Association of Clinical Endocrinologists states in its menopause management guideline: “Unexpected uterine bleeding or spotting during HRT is common and is managed by appropriate changes in therapy, not by discontinuation of HRT…. Nevertheless, monitoring of the endometrium by transvaginal ultrasound study or endometrial biopsy is indicated, especially in women who have an abnormal bleeding pattern.”⁸

Special thanks to Kate Rose and Joellynn I. Wilner for their library assistance.

Evidence Summary

Vaginal bleeding can be a sign of endometrial hyperplasia or cancer. Fifty-year-old perimenopausal women with an intact uterus have a 5% prevalence of hyperplasia1,² and a 2% to 3% risk of endometrial cancer in their lifetime.² HRT causes irregular bleeding for 8% to 60% of these women at 6 months and 4% to 30% at 12 months.^3,4 Roughly half of those bleeding at 6 months are no longer bleeding at a year.^3-5 Bleeding may be reduced by using lower-dose combinations, sequential hormones in perimenopausal women, and continuous regimens in women more than 3 years after menopause.^1,3,5

Any woman taking HRT who has irregular bleeding after a year should have a Pap test, since cervical abnormalities are not uncommon.⁶ Although HRT increases average endometrial thickness (at least initially),^6,7 TVUS showing an endometrial stripe of 5 mm or greater is more than 90% sensitive in detecting endometrial disease (cancer, complex hyperplasia, polyps).⁷ Approximately 3% of endometrial stripes are unmeasurable by TVUS and should be treated as abnormal. TVUS also shows many structural abnormalities, including those outside of the endometrium. A negative TVUS using the 5-mm criterion is associated with a 0.6% to 1% chance of endometrial cancer.^6,7

Abnormal sonograms or persistent unexpected bleeding after a normal sonogram requires further evaluation. Endometrial biopsy is a straightforward office procedure, and is as sensitive as dilatation and curretage.⁴ It fails (eg, from cervical stenosis) or is nondiagnostic in 2% to 28% of attempts.⁷ Hysteroscopy is also accurate but sometimes requires paracervical and general anesthesia. It also requires additional training and equipment. Zero percent to 12% of attempts fail (failures are less common in patients taking HRT), and the false-negative rate is roughly 3%.⁴

Recommendations from others

The American Association of Clinical Endocrinologists states in its menopause management guideline: “Unexpected uterine bleeding or spotting during HRT is common and is managed by appropriate changes in therapy, not by discontinuation of HRT…. Nevertheless, monitoring of the endometrium by transvaginal ultrasound study or endometrial biopsy is indicated, especially in women who have an abnormal bleeding pattern.”⁸

Special thanks to Kate Rose and Joellynn I. Wilner for their library assistance.

Evidence summary

Several large randomized controlled trials, have demonstrated that control of hypertension in patients with diabetes prevents development or progression of nephropathy, retinopathy, and cardiovascular conditions.^1-5 On the basis of these results, the American Diabetes Association (ADA) has lowered the recommended target blood pressure in patients with diabetes to 130 over 80. ACE inhibitors are superior to calcium channel blockers (CCBs) in preventing cardiovascular outcomes in patients with diabetes.^6,7 It is not clear if this is due to beneficial effects of ACE inhibitors or adverse effects of CCBs. There is no evidence that ACE inhibitors are superior to b-blockers or diuretics in preventing cardiovascular outcomes at similar levels of blood pressure reduction.²

Cardiovascular disease (CVD) accounts for 60% to 75% of all deaths in patients with diabetes. Those patients with diabetes who do not have clinical evidence of CVD have a similar mortality rate from CVD as patients who do not have diabetes but do have known CVD.⁸ The Heart Outcomes Prevention Evaluation (HOPE) study and the MICRO-HOPE substudy added a low dose of ramipril to the current regimen in patients with diabetes who are older than 55 years and have additional risk factors,⁸ which lowered the risk of death, cardiovascular events, and nephropathy by 24% to 25% each. The cardiovascular effect was greater than that attributed to the decrease in blood pressure. It is not possible to generalize from this study the effects on risk reduction of treatment of nonhypertensive or lower-risk patients with diabetes.

ACE inhibitors also have been demonstrated to slow the progression of diabetic nephropathy in patients with type 1 diabetes⁹ and may slow the progression of microalbuminuria in those with type 2 diabetes, even in the absence of hypertension.¹⁰

Recommendations from others

The American Association of Clinical Endocrinologists; the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; the ADA; and Conn’s Current Therapy all support ACE inhibitors in hypertensive or microalbuminuric patients with diabetes.^5,11 No published recommendations were found supporting ACE inhibitors in normotensive patients with diabetes who do not have microalbuminuria.

Evidence summary

Several large randomized controlled trials, have demonstrated that control of hypertension in patients with diabetes prevents development or progression of nephropathy, retinopathy, and cardiovascular conditions.^1-5 On the basis of these results, the American Diabetes Association (ADA) has lowered the recommended target blood pressure in patients with diabetes to 130 over 80. ACE inhibitors are superior to calcium channel blockers (CCBs) in preventing cardiovascular outcomes in patients with diabetes.^6,7 It is not clear if this is due to beneficial effects of ACE inhibitors or adverse effects of CCBs. There is no evidence that ACE inhibitors are superior to b-blockers or diuretics in preventing cardiovascular outcomes at similar levels of blood pressure reduction.²

Cardiovascular disease (CVD) accounts for 60% to 75% of all deaths in patients with diabetes. Those patients with diabetes who do not have clinical evidence of CVD have a similar mortality rate from CVD as patients who do not have diabetes but do have known CVD.⁸ The Heart Outcomes Prevention Evaluation (HOPE) study and the MICRO-HOPE substudy added a low dose of ramipril to the current regimen in patients with diabetes who are older than 55 years and have additional risk factors,⁸ which lowered the risk of death, cardiovascular events, and nephropathy by 24% to 25% each. The cardiovascular effect was greater than that attributed to the decrease in blood pressure. It is not possible to generalize from this study the effects on risk reduction of treatment of nonhypertensive or lower-risk patients with diabetes.

ACE inhibitors also have been demonstrated to slow the progression of diabetic nephropathy in patients with type 1 diabetes⁹ and may slow the progression of microalbuminuria in those with type 2 diabetes, even in the absence of hypertension.¹⁰

Recommendations from others

The American Association of Clinical Endocrinologists; the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; the ADA; and Conn’s Current Therapy all support ACE inhibitors in hypertensive or microalbuminuric patients with diabetes.^5,11 No published recommendations were found supporting ACE inhibitors in normotensive patients with diabetes who do not have microalbuminuria.

Evidence summary

Several large randomized controlled trials, have demonstrated that control of hypertension in patients with diabetes prevents development or progression of nephropathy, retinopathy, and cardiovascular conditions.^1-5 On the basis of these results, the American Diabetes Association (ADA) has lowered the recommended target blood pressure in patients with diabetes to 130 over 80. ACE inhibitors are superior to calcium channel blockers (CCBs) in preventing cardiovascular outcomes in patients with diabetes.^6,7 It is not clear if this is due to beneficial effects of ACE inhibitors or adverse effects of CCBs. There is no evidence that ACE inhibitors are superior to b-blockers or diuretics in preventing cardiovascular outcomes at similar levels of blood pressure reduction.²

Cardiovascular disease (CVD) accounts for 60% to 75% of all deaths in patients with diabetes. Those patients with diabetes who do not have clinical evidence of CVD have a similar mortality rate from CVD as patients who do not have diabetes but do have known CVD.⁸ The Heart Outcomes Prevention Evaluation (HOPE) study and the MICRO-HOPE substudy added a low dose of ramipril to the current regimen in patients with diabetes who are older than 55 years and have additional risk factors,⁸ which lowered the risk of death, cardiovascular events, and nephropathy by 24% to 25% each. The cardiovascular effect was greater than that attributed to the decrease in blood pressure. It is not possible to generalize from this study the effects on risk reduction of treatment of nonhypertensive or lower-risk patients with diabetes.

ACE inhibitors also have been demonstrated to slow the progression of diabetic nephropathy in patients with type 1 diabetes⁹ and may slow the progression of microalbuminuria in those with type 2 diabetes, even in the absence of hypertension.¹⁰

Recommendations from others

The American Association of Clinical Endocrinologists; the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; the ADA; and Conn’s Current Therapy all support ACE inhibitors in hypertensive or microalbuminuric patients with diabetes.^5,11 No published recommendations were found supporting ACE inhibitors in normotensive patients with diabetes who do not have microalbuminuria.

Evidence summary

The definition of macrosomia is fetal weight of 4000 to 4500 g or greater, regardless of gestational age. This differs from “large for gestational age,” which is a birth weight greater than 90th percentile for a given gestational age. Ten percent of all US live born infants weigh more than 4000 g, and 1.5% weigh more than 4500 g.¹ Detection of fetal macrosomia is difficult, because there are no reliable methods for determining EFW. Ultrasound estimate of fetal weight may be less accurate than estimates by multiparous patients and clinicians using Leopold maneuvers.² Ultrasound prediction of EFW in babies 4500 g or larger can be off by as much as 13%.¹ The purpose of induction for fetal macrosomia would be to prevent maternal and neonatal morbidities. However, studies have shown that the incidence of cesarean and instrumented deliveries was not decreased, and perinatal morbidity was not changed.³ To date, there are only 2 randomized controlled trials comparing expectant management with induction of labor for suspected fetal macrosomia.

Gonen and colleagues⁴ followed 273 women at 38 weeks or more with ultrasound-determined fetal weights between 4000 and 4500 g. Women were excluded if they had diabetes, noncephalic presentations, a previous cesarean delivery, or other indications for induction. The induction group received either prostaglandin or pitocin for induction, depending on cervical status. Patients in the expectant management group were induced at 42 weeks. There was no change in cesarean delivery rate or in neonatal morbidity.

Tey and coworkers⁵ randomized 40 women who did not have diabetes at 37 to 42 weeks with EFWs between 4000 and 4500 g to induction versus expectant management. Induction was performed with prostaglandin if the cervix was unfavorable (Bishop score <6), followed by pitocin. Women were excluded if there was an indication for delivery at the time of enrollment. There was no statistical difference in the cesarean delivery rate or incidence of shoulder dystocia between the 2 groups.

Recommendations from others

An American College of Obstetrics and Gynecology Practice Bulletin states the position that there is no role for induction of labor in term women with suspected fetal macrosomia. This recommendation is based on the difficulty of accurate assessment of fetal weight and additional case-control evidence suggesting that induction increases the risk of cesarean delivery without improving maternal or fetal outcomes.

Evidence summary

The definition of macrosomia is fetal weight of 4000 to 4500 g or greater, regardless of gestational age. This differs from “large for gestational age,” which is a birth weight greater than 90th percentile for a given gestational age. Ten percent of all US live born infants weigh more than 4000 g, and 1.5% weigh more than 4500 g.¹ Detection of fetal macrosomia is difficult, because there are no reliable methods for determining EFW. Ultrasound estimate of fetal weight may be less accurate than estimates by multiparous patients and clinicians using Leopold maneuvers.² Ultrasound prediction of EFW in babies 4500 g or larger can be off by as much as 13%.¹ The purpose of induction for fetal macrosomia would be to prevent maternal and neonatal morbidities. However, studies have shown that the incidence of cesarean and instrumented deliveries was not decreased, and perinatal morbidity was not changed.³ To date, there are only 2 randomized controlled trials comparing expectant management with induction of labor for suspected fetal macrosomia.

Gonen and colleagues⁴ followed 273 women at 38 weeks or more with ultrasound-determined fetal weights between 4000 and 4500 g. Women were excluded if they had diabetes, noncephalic presentations, a previous cesarean delivery, or other indications for induction. The induction group received either prostaglandin or pitocin for induction, depending on cervical status. Patients in the expectant management group were induced at 42 weeks. There was no change in cesarean delivery rate or in neonatal morbidity.

Tey and coworkers⁵ randomized 40 women who did not have diabetes at 37 to 42 weeks with EFWs between 4000 and 4500 g to induction versus expectant management. Induction was performed with prostaglandin if the cervix was unfavorable (Bishop score <6), followed by pitocin. Women were excluded if there was an indication for delivery at the time of enrollment. There was no statistical difference in the cesarean delivery rate or incidence of shoulder dystocia between the 2 groups.

Recommendations from others

An American College of Obstetrics and Gynecology Practice Bulletin states the position that there is no role for induction of labor in term women with suspected fetal macrosomia. This recommendation is based on the difficulty of accurate assessment of fetal weight and additional case-control evidence suggesting that induction increases the risk of cesarean delivery without improving maternal or fetal outcomes.

Evidence summary

The definition of macrosomia is fetal weight of 4000 to 4500 g or greater, regardless of gestational age. This differs from “large for gestational age,” which is a birth weight greater than 90th percentile for a given gestational age. Ten percent of all US live born infants weigh more than 4000 g, and 1.5% weigh more than 4500 g.¹ Detection of fetal macrosomia is difficult, because there are no reliable methods for determining EFW. Ultrasound estimate of fetal weight may be less accurate than estimates by multiparous patients and clinicians using Leopold maneuvers.² Ultrasound prediction of EFW in babies 4500 g or larger can be off by as much as 13%.¹ The purpose of induction for fetal macrosomia would be to prevent maternal and neonatal morbidities. However, studies have shown that the incidence of cesarean and instrumented deliveries was not decreased, and perinatal morbidity was not changed.³ To date, there are only 2 randomized controlled trials comparing expectant management with induction of labor for suspected fetal macrosomia.

Gonen and colleagues⁴ followed 273 women at 38 weeks or more with ultrasound-determined fetal weights between 4000 and 4500 g. Women were excluded if they had diabetes, noncephalic presentations, a previous cesarean delivery, or other indications for induction. The induction group received either prostaglandin or pitocin for induction, depending on cervical status. Patients in the expectant management group were induced at 42 weeks. There was no change in cesarean delivery rate or in neonatal morbidity.

Tey and coworkers⁵ randomized 40 women who did not have diabetes at 37 to 42 weeks with EFWs between 4000 and 4500 g to induction versus expectant management. Induction was performed with prostaglandin if the cervix was unfavorable (Bishop score <6), followed by pitocin. Women were excluded if there was an indication for delivery at the time of enrollment. There was no statistical difference in the cesarean delivery rate or incidence of shoulder dystocia between the 2 groups.

Recommendations from others

An American College of Obstetrics and Gynecology Practice Bulletin states the position that there is no role for induction of labor in term women with suspected fetal macrosomia. This recommendation is based on the difficulty of accurate assessment of fetal weight and additional case-control evidence suggesting that induction increases the risk of cesarean delivery without improving maternal or fetal outcomes.

Evidence summary

A total of 701 patients referred for EGD by gastroenterologists for GERD symptoms yielded 77 cases of Barrett’s esophagus. Compared with patients without Barrett’s esophagus, patients with the condition were more likely to have symptoms greater than 1 year: 1 to 5 years (OR=3.0 [95% confidence interval (CI), 1.2-8.0]), 5 to 10 years [OR=5.1 (95% CI, 1.2-14.7)], more than 10 years [OR=6.4 (95% CI, 2.4-17.10)].¹

A case control study conducted at Duke University compared 79 patients with Barrett’s esophagus with 2 control groups: patients undergoing endoscopy for GERD symptoms and patients undergoing endoscopy for other indications. Patients with Barrett’s esophagus developed symptoms at an earlier age (mean age = 35.3 years ± 16 years compared with 43.7 years ± 13 years and 42.7 years ± 13 years, respectively) and had a longer duration of symptoms (mean duration = 16.36 years [range = 1-63 years] compared with 11.81 years [range = 1-55 years] and 13.03 years [range = 1-53 years]) than patients without Barrett’s esophagus.

A Swedish case-controlled study compared 189 cases of esophageal adenocarcinoma and 167 cases of squamous cell carcinoma with 820 control subjects recruited from the general population. Patients with esophageal adenocarcinoma were 7.7 times more likely to report symptoms of GERD at least once weekly 5 years before their diagnosis with adenocarcinoma. Other ORs are as follows: symptoms once per week (5.1), symptoms more than 3 times per week (16.7), nocturnal symptoms at least once per week (10.8), and duration more than 20 years (16.4).³ Also, obesity was a risk factor for esophageal adenocarcinoma in this population. Patients with a body mass index (BMI) greater than 30 had increased risk of adenocarcinoma compared with patients with a BMI less than 25 (OR=16.2; 95% CI, 6.3-41.4).⁴ These authors calculated numbers of endoscopies needed to detect 1 case of esophageal adenocarcinoma. Among Swedish men aged 50 to 79 years with symptoms at least 1 time per week and BMI greater than 30, 594 endoscopies (95% CI, 385-972) are needed to find 1 case of esophageal adenocarcinoma.⁵ These authors estimate incidence of adenocarcinoma using population-wide surveillance data.

There is no current evidence that evaluation of GERD patients with EGD improves outcomes, although 2 retrospective studies have shown improved outcomes for patients with Barrett’s esophagus undergoing surveillance endoscopy compared with those without surveillance.^6,7

Recommendations from others

The American College of Gastroenterology recommends EGD for GERD patients who do not respond to therapy, experience alarm symptoms, who have chronic symptoms and are at risk for Barrett’s esophagus, and need continuous chronic therapy.⁸

The Alberta (Canada) clinical practice guideline recommends EGD for GERD patients with alarm symptoms or failure to respond to 4 to 8 weeks of therapy with a proton pump inhibitor.⁹

Evidence summary

A total of 701 patients referred for EGD by gastroenterologists for GERD symptoms yielded 77 cases of Barrett’s esophagus. Compared with patients without Barrett’s esophagus, patients with the condition were more likely to have symptoms greater than 1 year: 1 to 5 years (OR=3.0 [95% confidence interval (CI), 1.2-8.0]), 5 to 10 years [OR=5.1 (95% CI, 1.2-14.7)], more than 10 years [OR=6.4 (95% CI, 2.4-17.10)].¹

A case control study conducted at Duke University compared 79 patients with Barrett’s esophagus with 2 control groups: patients undergoing endoscopy for GERD symptoms and patients undergoing endoscopy for other indications. Patients with Barrett’s esophagus developed symptoms at an earlier age (mean age = 35.3 years ± 16 years compared with 43.7 years ± 13 years and 42.7 years ± 13 years, respectively) and had a longer duration of symptoms (mean duration = 16.36 years [range = 1-63 years] compared with 11.81 years [range = 1-55 years] and 13.03 years [range = 1-53 years]) than patients without Barrett’s esophagus.

A Swedish case-controlled study compared 189 cases of esophageal adenocarcinoma and 167 cases of squamous cell carcinoma with 820 control subjects recruited from the general population. Patients with esophageal adenocarcinoma were 7.7 times more likely to report symptoms of GERD at least once weekly 5 years before their diagnosis with adenocarcinoma. Other ORs are as follows: symptoms once per week (5.1), symptoms more than 3 times per week (16.7), nocturnal symptoms at least once per week (10.8), and duration more than 20 years (16.4).³ Also, obesity was a risk factor for esophageal adenocarcinoma in this population. Patients with a body mass index (BMI) greater than 30 had increased risk of adenocarcinoma compared with patients with a BMI less than 25 (OR=16.2; 95% CI, 6.3-41.4).⁴ These authors calculated numbers of endoscopies needed to detect 1 case of esophageal adenocarcinoma. Among Swedish men aged 50 to 79 years with symptoms at least 1 time per week and BMI greater than 30, 594 endoscopies (95% CI, 385-972) are needed to find 1 case of esophageal adenocarcinoma.⁵ These authors estimate incidence of adenocarcinoma using population-wide surveillance data.

There is no current evidence that evaluation of GERD patients with EGD improves outcomes, although 2 retrospective studies have shown improved outcomes for patients with Barrett’s esophagus undergoing surveillance endoscopy compared with those without surveillance.^6,7

Recommendations from others

The American College of Gastroenterology recommends EGD for GERD patients who do not respond to therapy, experience alarm symptoms, who have chronic symptoms and are at risk for Barrett’s esophagus, and need continuous chronic therapy.⁸

The Alberta (Canada) clinical practice guideline recommends EGD for GERD patients with alarm symptoms or failure to respond to 4 to 8 weeks of therapy with a proton pump inhibitor.⁹

Evidence summary

A total of 701 patients referred for EGD by gastroenterologists for GERD symptoms yielded 77 cases of Barrett’s esophagus. Compared with patients without Barrett’s esophagus, patients with the condition were more likely to have symptoms greater than 1 year: 1 to 5 years (OR=3.0 [95% confidence interval (CI), 1.2-8.0]), 5 to 10 years [OR=5.1 (95% CI, 1.2-14.7)], more than 10 years [OR=6.4 (95% CI, 2.4-17.10)].¹

A case control study conducted at Duke University compared 79 patients with Barrett’s esophagus with 2 control groups: patients undergoing endoscopy for GERD symptoms and patients undergoing endoscopy for other indications. Patients with Barrett’s esophagus developed symptoms at an earlier age (mean age = 35.3 years ± 16 years compared with 43.7 years ± 13 years and 42.7 years ± 13 years, respectively) and had a longer duration of symptoms (mean duration = 16.36 years [range = 1-63 years] compared with 11.81 years [range = 1-55 years] and 13.03 years [range = 1-53 years]) than patients without Barrett’s esophagus.

A Swedish case-controlled study compared 189 cases of esophageal adenocarcinoma and 167 cases of squamous cell carcinoma with 820 control subjects recruited from the general population. Patients with esophageal adenocarcinoma were 7.7 times more likely to report symptoms of GERD at least once weekly 5 years before their diagnosis with adenocarcinoma. Other ORs are as follows: symptoms once per week (5.1), symptoms more than 3 times per week (16.7), nocturnal symptoms at least once per week (10.8), and duration more than 20 years (16.4).³ Also, obesity was a risk factor for esophageal adenocarcinoma in this population. Patients with a body mass index (BMI) greater than 30 had increased risk of adenocarcinoma compared with patients with a BMI less than 25 (OR=16.2; 95% CI, 6.3-41.4).⁴ These authors calculated numbers of endoscopies needed to detect 1 case of esophageal adenocarcinoma. Among Swedish men aged 50 to 79 years with symptoms at least 1 time per week and BMI greater than 30, 594 endoscopies (95% CI, 385-972) are needed to find 1 case of esophageal adenocarcinoma.⁵ These authors estimate incidence of adenocarcinoma using population-wide surveillance data.

There is no current evidence that evaluation of GERD patients with EGD improves outcomes, although 2 retrospective studies have shown improved outcomes for patients with Barrett’s esophagus undergoing surveillance endoscopy compared with those without surveillance.^6,7

Recommendations from others

The American College of Gastroenterology recommends EGD for GERD patients who do not respond to therapy, experience alarm symptoms, who have chronic symptoms and are at risk for Barrett’s esophagus, and need continuous chronic therapy.⁸

The Alberta (Canada) clinical practice guideline recommends EGD for GERD patients with alarm symptoms or failure to respond to 4 to 8 weeks of therapy with a proton pump inhibitor.⁹

Evidence summary

Several studies demonstrating the accuracy of helical CT have been published recently.^1-3 The most convincing are 2 prospective studies done in emergency departments in Belgium and Australia.^1,2 Both compared helical CT with intravenous pyelography (IVP) and used the gold standard of recovery and direct visualization of a stone. The Australian study enrolled 40 consecutive patients; the Belgian study enrolled 53 of 70 consecutive patients. In these 2 studies, helical CT correctly identified every instance of urinary tract stones. In contrast, IVP failed to detect stones in a third of the patients with stones, and 44% of the negative readings were false-negatives. Both tests did well in reporting negative results for those patients without stones (specificity = 97% for both tests). In terms of likelihood ratios, helical CT and IVP had positive likelihood ratios of 29 and 19, respectively, and negative likelihood ratios of 0 and 0.36 (a lower negative likelihood ratio is better). In other words, helical CT appears to be far superior to IVP in ruling out the presence of urinary tract stones. As an additional comparison, another study found that urine dipstick testing for hematuria yielded positive likelihood ratios of 1.25 and a negative likelihood ratio of 0.55.⁴ The accuracy of ultrasonography appears to fall somewhere in between hematuria testing and IVP.⁵ The Table shows an overall comparison of these diagnostic tests.

In addition to its better accuracy, several studies discuss the better safety profile and decreased diagnostic time of helical CT than IVP.^6-8 The risk of contrast reaction during IVP is between 5% and 10%, with a mortality of approximately 1 in 40,000. Helical CT (when evaluating for stones) does not use contrast, although the radiation exposure is approximately twice that of IVP.⁶ The costs of helical CT and IVP are comparable, and helical CT becomes more cost effective when the shorter time to discharge with a definitive diagnosis is considered.^7,8 Several authors also cite instances when helical CT uncovered a nonurinary cause for patients’ symptoms that IVP would have missed.^8,9

Access to helical CT is improving throughout the United States, and individual radiologists can become quickly skilled at helical CT interpretation.¹⁰ Physicians should confirm that their local radiologists are comfortable with helical CT readings before incorporating this into their diagnostic routines.

Recommendations from others

Several urology and radiology departments have published reviews lately supporting the use of helical CT over other diagnostic testing for urinary tract stones.^9,11 No official recommendations from professional organizations were found.

Evidence summary

Several studies demonstrating the accuracy of helical CT have been published recently.^1-3 The most convincing are 2 prospective studies done in emergency departments in Belgium and Australia.^1,2 Both compared helical CT with intravenous pyelography (IVP) and used the gold standard of recovery and direct visualization of a stone. The Australian study enrolled 40 consecutive patients; the Belgian study enrolled 53 of 70 consecutive patients. In these 2 studies, helical CT correctly identified every instance of urinary tract stones. In contrast, IVP failed to detect stones in a third of the patients with stones, and 44% of the negative readings were false-negatives. Both tests did well in reporting negative results for those patients without stones (specificity = 97% for both tests). In terms of likelihood ratios, helical CT and IVP had positive likelihood ratios of 29 and 19, respectively, and negative likelihood ratios of 0 and 0.36 (a lower negative likelihood ratio is better). In other words, helical CT appears to be far superior to IVP in ruling out the presence of urinary tract stones. As an additional comparison, another study found that urine dipstick testing for hematuria yielded positive likelihood ratios of 1.25 and a negative likelihood ratio of 0.55.⁴ The accuracy of ultrasonography appears to fall somewhere in between hematuria testing and IVP.⁵ The Table shows an overall comparison of these diagnostic tests.

In addition to its better accuracy, several studies discuss the better safety profile and decreased diagnostic time of helical CT than IVP.^6-8 The risk of contrast reaction during IVP is between 5% and 10%, with a mortality of approximately 1 in 40,000. Helical CT (when evaluating for stones) does not use contrast, although the radiation exposure is approximately twice that of IVP.⁶ The costs of helical CT and IVP are comparable, and helical CT becomes more cost effective when the shorter time to discharge with a definitive diagnosis is considered.^7,8 Several authors also cite instances when helical CT uncovered a nonurinary cause for patients’ symptoms that IVP would have missed.^8,9

Access to helical CT is improving throughout the United States, and individual radiologists can become quickly skilled at helical CT interpretation.¹⁰ Physicians should confirm that their local radiologists are comfortable with helical CT readings before incorporating this into their diagnostic routines.

Recommendations from others

Several urology and radiology departments have published reviews lately supporting the use of helical CT over other diagnostic testing for urinary tract stones.^9,11 No official recommendations from professional organizations were found.

Evidence summary

Several studies demonstrating the accuracy of helical CT have been published recently.^1-3 The most convincing are 2 prospective studies done in emergency departments in Belgium and Australia.^1,2 Both compared helical CT with intravenous pyelography (IVP) and used the gold standard of recovery and direct visualization of a stone. The Australian study enrolled 40 consecutive patients; the Belgian study enrolled 53 of 70 consecutive patients. In these 2 studies, helical CT correctly identified every instance of urinary tract stones. In contrast, IVP failed to detect stones in a third of the patients with stones, and 44% of the negative readings were false-negatives. Both tests did well in reporting negative results for those patients without stones (specificity = 97% for both tests). In terms of likelihood ratios, helical CT and IVP had positive likelihood ratios of 29 and 19, respectively, and negative likelihood ratios of 0 and 0.36 (a lower negative likelihood ratio is better). In other words, helical CT appears to be far superior to IVP in ruling out the presence of urinary tract stones. As an additional comparison, another study found that urine dipstick testing for hematuria yielded positive likelihood ratios of 1.25 and a negative likelihood ratio of 0.55.⁴ The accuracy of ultrasonography appears to fall somewhere in between hematuria testing and IVP.⁵ The Table shows an overall comparison of these diagnostic tests.

In addition to its better accuracy, several studies discuss the better safety profile and decreased diagnostic time of helical CT than IVP.^6-8 The risk of contrast reaction during IVP is between 5% and 10%, with a mortality of approximately 1 in 40,000. Helical CT (when evaluating for stones) does not use contrast, although the radiation exposure is approximately twice that of IVP.⁶ The costs of helical CT and IVP are comparable, and helical CT becomes more cost effective when the shorter time to discharge with a definitive diagnosis is considered.^7,8 Several authors also cite instances when helical CT uncovered a nonurinary cause for patients’ symptoms that IVP would have missed.^8,9

Access to helical CT is improving throughout the United States, and individual radiologists can become quickly skilled at helical CT interpretation.¹⁰ Physicians should confirm that their local radiologists are comfortable with helical CT readings before incorporating this into their diagnostic routines.

Recommendations from others

Several urology and radiology departments have published reviews lately supporting the use of helical CT over other diagnostic testing for urinary tract stones.^9,11 No official recommendations from professional organizations were found.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.

Evidence summary

Reflux of gastric contents into the esophagus (both regurgitant [into the mouth] and nonregurgitant) is a normal physiologic event. The incidence of regurgitation is similar in breast-fed and formula-fed infants, occurring in up to 67% of 4-month-olds. In the majority of infants, regurgitation is uncomplicated and self-limited, resolving spontaneously by 6 to 12 months of age,^5,6 with 21% of 6- to 7-month-old infants and 5% of 10- to 12- month old infants experiencing regurgitant reflux.⁶ In less than 3% of infants, reflux is severe enough to result in clinically significant GERD.⁵ GERD is suggested by persistent irritability, sleep disturbance, abnormal posturing, hematemesis, excessive crying, respiratory symptoms, and failure to thrive.⁷

True allergy to cow’s milk or soy-based formulas likely occurs in less than 2% of infants,⁸ but is unlikely to present with vomiting as the only symptom. Temporary carbohydrate intolerance may occur with gastroenteritis, malnutrition, or in preterm infants, but otherwise is rare in infancy.⁹ Controlled trials have demonstrated no difference in colic, spitting-up, vomiting, fussiness, cramps, flatus, or stools frequency between iron-fortified and nonfortified formulas.^1,2

Retrospective surveys studying outcomes associated with formula change reveal that approximately one third of infants experience a formula change,³ but the retrospective nature of these studies, lack of blinding and control groups, and selflimiting nature of regurgitation makes interpretation of these studies difficult.

In infants with GERD, formula thickening has numerous benefits, including reductions in frequency of regurgitation, total volume of emesis, and time spent crying by one third, and an increase in time spent sleeping by 18% per 90-minute postprandial period. Formula thickening also increases the frequency of postprandial cough, but the clinical significance of this is unclear. Aspiration was not observed on scintigraphic examination following thickened feedings.⁴

Dry rice cereal (one tablespoon per ounce of formula) is a common thickener with excellent digestibility, but increases the caloric density of formula and can cause constipation. Thickened formulas also require enlarged nipple holes to feed, potentially resulting in greater ingestion of air or formula, which can favor regurgitation. Commercially available pre-thickened formulas are nutritionally balanced, convenient, well tolerated, and do not require enlarged nipple holes to feed.⁵

Increased frequency of feedings with smaller volumes has not been proved efficacious, is difficult to implement, and may create distress in a hungry infant. In overfed infants, or infants fed large volumes at infrequent intervals, feeding volume or feeding interval should be reduced. There is no benefit to head-elevated prone versus flat-prone positioning.

Recommendations from others

The European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend parental reassurance and formula thickening as first-line therapy for the management of infants with uncomplicated regurgitation.⁵ Flat-prone positioning, further evaluation, or a trial of H2 blockers may be considered in infants not responding to first-line therapy.