Clinical Inquiries

Evidence summary

Evidence is summarized in the Table. Evaluation of an infant with diarrhea usually requires only a thorough history and physical exam. While no clinical trials have tested the impact of blood or stool testing on patient outcome, a recent systematic review suggested the only blood test reliable for ruling out dehydration is a serum bicarbonate greater than 15 to 17 mEq/L.¹ Consensus reports have suggested laboratory studies are unnecessary unless dehydration is severe or IV fluids are required; stool cultures are necessary only for bloody or prolonged diarrhea, systemically ill infants, suspected food poisoning, or recent travel abroad.^2,3

Effective management of infant diarrhea is based on the degree of dehydration, which can be estimated by percent body weight loss—the difference between the baseline and acute weights, divided by the baseline weight.³ If the baseline weight is not known, prolonged capillary refill time, abnormal skin turgor, and abnormal respiratory pattern are more reliable indicators of dehydration; other physical findings are less precise.¹

Infants with diarrhea who are not dehydrated should continue age-appropriate nutrition.⁴ For infants with mild to moderate dehydration, however, rehydration using oral rehydrating solution is the initial therapy, followed by continued hydration to replace ongoing losses.^2,3 A meta-analysis of randomized controlled trials (RCTs) in developed countries demonstrated equivalent efficacy of oral fluids compared with IV fluids, with an overall failure rate of only 3.6% for infants and children treated with oral rehydrating solution (95% confidence interval [CI], 1.4–5.8). There was no significant difference between oral rehydrating solution of varying sodium concentrations, and no increased risk of hypernatremia or hyponatremia compared with the IV treatment arm.⁵ Continued breastfeeding during the rehydrating phase significantly reduced dehydration (based on case control studies; odds ratio [OR]=5.23; 95% CI, 1.37–19.99; P=.016, limited by sample size).^3,6 Breastfeeding also significantly reduced the number of diarrheal stools (found in a small-scale RCT).⁷ For obtunded or severely dehydrated infants, or those with an ileus or persistent vomiting, expert opinion suggested IV fluids.^2,4

In a systematic review of RCTs comparing lower-concentration oral rehydrating solution with standard World Health Organization solution, lower-concentration solution showed superior efficacy. These resulted in fewer unscheduled infusions of IV fluids (OR=0.59; 95% CI, 0.45–0.79) and less stool output without increasing the incidence of hyponatremia.⁸

Unrestricted diets may reduce the duration of diarrhea compared with oral or IV fluids alone, and age-appropriate diets should be resumed immediately after hydration (based on a review of variable-quality RCTs and prospective trials or case series).² No studies supported the effectiveness of BRAT (bananas, rice cereal, applesauce, toast) diets over the infant’s usual diet.^2,4 A meta-analysis of variable-quality RCTs demonstrated no significant difference in stool frequency between lactose-containing and lactose-free diets.⁹ Comparisons of undiluted lactose-milk with diluted milk or delayed reintroduction of milk revealed no significant differences in treatment failure or duration of diarrhea, although stool output increased slightly with the undiluted diet. However, undiluted milk was superior for restoring body weight.⁹

Multiple RCTs showed that Lactobacillus supplementation shortened the duration of diarrhea for infants and young children^10,11 and reduced the risk of diarrhea persisting more than 3 days (relative risk [RR]=0.43; 95% CI, 0.34–0.53; P<.001; number needed to treat [NNT]=4).¹¹ This probiotic can be reconstituted in oral rehydrating solution and administered 1 to 8 times daily, depending on the formulation.

Antidiarrheal agents are not recommended (based on limited reviews and consensus reports).^2-4,12

TABLE
Evaluative strategies and therapeutic interventions for infant diarrhea

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends oral rehydrating solution for mild to moderate dehydration, and boluses of normal saline or Lactated Ringer’s (20 cc/kg) for severe dehydration. For frail or malnourished infants, boluses of 10 cc/kg should be given until hydrated.

The CDC also recommended against nutrition containing simple sugars (soft drinks, juice, gelatin desserts) due to high osmotic loads, but noted that diets containing some fats may have a beneficial effect on intestinal motility. They also recommended age-appropriate use of complex carbohydrates, meats, yogurt, fruits and vegetables. Zinc supplementation may also be beneficial (SOR: C).¹²

Evidence summary

Evidence is summarized in the Table. Evaluation of an infant with diarrhea usually requires only a thorough history and physical exam. While no clinical trials have tested the impact of blood or stool testing on patient outcome, a recent systematic review suggested the only blood test reliable for ruling out dehydration is a serum bicarbonate greater than 15 to 17 mEq/L.¹ Consensus reports have suggested laboratory studies are unnecessary unless dehydration is severe or IV fluids are required; stool cultures are necessary only for bloody or prolonged diarrhea, systemically ill infants, suspected food poisoning, or recent travel abroad.^2,3

Effective management of infant diarrhea is based on the degree of dehydration, which can be estimated by percent body weight loss—the difference between the baseline and acute weights, divided by the baseline weight.³ If the baseline weight is not known, prolonged capillary refill time, abnormal skin turgor, and abnormal respiratory pattern are more reliable indicators of dehydration; other physical findings are less precise.¹

Infants with diarrhea who are not dehydrated should continue age-appropriate nutrition.⁴ For infants with mild to moderate dehydration, however, rehydration using oral rehydrating solution is the initial therapy, followed by continued hydration to replace ongoing losses.^2,3 A meta-analysis of randomized controlled trials (RCTs) in developed countries demonstrated equivalent efficacy of oral fluids compared with IV fluids, with an overall failure rate of only 3.6% for infants and children treated with oral rehydrating solution (95% confidence interval [CI], 1.4–5.8). There was no significant difference between oral rehydrating solution of varying sodium concentrations, and no increased risk of hypernatremia or hyponatremia compared with the IV treatment arm.⁵ Continued breastfeeding during the rehydrating phase significantly reduced dehydration (based on case control studies; odds ratio [OR]=5.23; 95% CI, 1.37–19.99; P=.016, limited by sample size).^3,6 Breastfeeding also significantly reduced the number of diarrheal stools (found in a small-scale RCT).⁷ For obtunded or severely dehydrated infants, or those with an ileus or persistent vomiting, expert opinion suggested IV fluids.^2,4

In a systematic review of RCTs comparing lower-concentration oral rehydrating solution with standard World Health Organization solution, lower-concentration solution showed superior efficacy. These resulted in fewer unscheduled infusions of IV fluids (OR=0.59; 95% CI, 0.45–0.79) and less stool output without increasing the incidence of hyponatremia.⁸

Unrestricted diets may reduce the duration of diarrhea compared with oral or IV fluids alone, and age-appropriate diets should be resumed immediately after hydration (based on a review of variable-quality RCTs and prospective trials or case series).² No studies supported the effectiveness of BRAT (bananas, rice cereal, applesauce, toast) diets over the infant’s usual diet.^2,4 A meta-analysis of variable-quality RCTs demonstrated no significant difference in stool frequency between lactose-containing and lactose-free diets.⁹ Comparisons of undiluted lactose-milk with diluted milk or delayed reintroduction of milk revealed no significant differences in treatment failure or duration of diarrhea, although stool output increased slightly with the undiluted diet. However, undiluted milk was superior for restoring body weight.⁹

Multiple RCTs showed that Lactobacillus supplementation shortened the duration of diarrhea for infants and young children^10,11 and reduced the risk of diarrhea persisting more than 3 days (relative risk [RR]=0.43; 95% CI, 0.34–0.53; P<.001; number needed to treat [NNT]=4).¹¹ This probiotic can be reconstituted in oral rehydrating solution and administered 1 to 8 times daily, depending on the formulation.

Antidiarrheal agents are not recommended (based on limited reviews and consensus reports).^2-4,12

TABLE
Evaluative strategies and therapeutic interventions for infant diarrhea

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends oral rehydrating solution for mild to moderate dehydration, and boluses of normal saline or Lactated Ringer’s (20 cc/kg) for severe dehydration. For frail or malnourished infants, boluses of 10 cc/kg should be given until hydrated.

The CDC also recommended against nutrition containing simple sugars (soft drinks, juice, gelatin desserts) due to high osmotic loads, but noted that diets containing some fats may have a beneficial effect on intestinal motility. They also recommended age-appropriate use of complex carbohydrates, meats, yogurt, fruits and vegetables. Zinc supplementation may also be beneficial (SOR: C).¹²

Evidence summary

Evidence is summarized in the Table. Evaluation of an infant with diarrhea usually requires only a thorough history and physical exam. While no clinical trials have tested the impact of blood or stool testing on patient outcome, a recent systematic review suggested the only blood test reliable for ruling out dehydration is a serum bicarbonate greater than 15 to 17 mEq/L.¹ Consensus reports have suggested laboratory studies are unnecessary unless dehydration is severe or IV fluids are required; stool cultures are necessary only for bloody or prolonged diarrhea, systemically ill infants, suspected food poisoning, or recent travel abroad.^2,3

Effective management of infant diarrhea is based on the degree of dehydration, which can be estimated by percent body weight loss—the difference between the baseline and acute weights, divided by the baseline weight.³ If the baseline weight is not known, prolonged capillary refill time, abnormal skin turgor, and abnormal respiratory pattern are more reliable indicators of dehydration; other physical findings are less precise.¹

Infants with diarrhea who are not dehydrated should continue age-appropriate nutrition.⁴ For infants with mild to moderate dehydration, however, rehydration using oral rehydrating solution is the initial therapy, followed by continued hydration to replace ongoing losses.^2,3 A meta-analysis of randomized controlled trials (RCTs) in developed countries demonstrated equivalent efficacy of oral fluids compared with IV fluids, with an overall failure rate of only 3.6% for infants and children treated with oral rehydrating solution (95% confidence interval [CI], 1.4–5.8). There was no significant difference between oral rehydrating solution of varying sodium concentrations, and no increased risk of hypernatremia or hyponatremia compared with the IV treatment arm.⁵ Continued breastfeeding during the rehydrating phase significantly reduced dehydration (based on case control studies; odds ratio [OR]=5.23; 95% CI, 1.37–19.99; P=.016, limited by sample size).^3,6 Breastfeeding also significantly reduced the number of diarrheal stools (found in a small-scale RCT).⁷ For obtunded or severely dehydrated infants, or those with an ileus or persistent vomiting, expert opinion suggested IV fluids.^2,4

In a systematic review of RCTs comparing lower-concentration oral rehydrating solution with standard World Health Organization solution, lower-concentration solution showed superior efficacy. These resulted in fewer unscheduled infusions of IV fluids (OR=0.59; 95% CI, 0.45–0.79) and less stool output without increasing the incidence of hyponatremia.⁸

Unrestricted diets may reduce the duration of diarrhea compared with oral or IV fluids alone, and age-appropriate diets should be resumed immediately after hydration (based on a review of variable-quality RCTs and prospective trials or case series).² No studies supported the effectiveness of BRAT (bananas, rice cereal, applesauce, toast) diets over the infant’s usual diet.^2,4 A meta-analysis of variable-quality RCTs demonstrated no significant difference in stool frequency between lactose-containing and lactose-free diets.⁹ Comparisons of undiluted lactose-milk with diluted milk or delayed reintroduction of milk revealed no significant differences in treatment failure or duration of diarrhea, although stool output increased slightly with the undiluted diet. However, undiluted milk was superior for restoring body weight.⁹

Multiple RCTs showed that Lactobacillus supplementation shortened the duration of diarrhea for infants and young children^10,11 and reduced the risk of diarrhea persisting more than 3 days (relative risk [RR]=0.43; 95% CI, 0.34–0.53; P<.001; number needed to treat [NNT]=4).¹¹ This probiotic can be reconstituted in oral rehydrating solution and administered 1 to 8 times daily, depending on the formulation.

Antidiarrheal agents are not recommended (based on limited reviews and consensus reports).^2-4,12

TABLE
Evaluative strategies and therapeutic interventions for infant diarrhea

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends oral rehydrating solution for mild to moderate dehydration, and boluses of normal saline or Lactated Ringer’s (20 cc/kg) for severe dehydration. For frail or malnourished infants, boluses of 10 cc/kg should be given until hydrated.

The CDC also recommended against nutrition containing simple sugars (soft drinks, juice, gelatin desserts) due to high osmotic loads, but noted that diets containing some fats may have a beneficial effect on intestinal motility. They also recommended age-appropriate use of complex carbohydrates, meats, yogurt, fruits and vegetables. Zinc supplementation may also be beneficial (SOR: C).¹²

Evidence summary

Overuse of antibiotics is already a problem in nursing homes. A large portion of bacterial pneumonia in the nursing home population results from aspiration of oropharyngeal bacteria, which is more likely to be drug-resistant if the resident has been on antibiotics.¹ We found no studies that testing antibacterial agents for prevention of pneumonia in nursing home patients. However, 3 measures are clearly helpful in preventing pneumonia in nursing home patients:

1. Influenza vaccination of residents: A meta-analysis of 20 cohort studies showed a 53% efficacy (95% confidence interval [CI], 35–66)—defined as 1 minus the odds ratio—for influenza immunization in preventing pneumonia.²
2. Influenza vaccination of caregivers: A cluster randomized trial in British long-term care facilities demonstrated that influenza vaccination of health care workers (61% of 1078 workers) reduced the total nursing home mortality rate (odds ratio [OR]=0.56 [95% CI, 0.4–0.8]) for a drop in mortality rate from 17% to 10% (number needed to treat [NNT]=14.3).³
3. Pneumococcal vaccination of residents: This evidence was reviewed in a prior Clinical Inquiry.⁴ The evidence comes primarily from 2 clinical trials in which the NNT to prevent 1 episode of pneumonia was about 35.

Two other proposed interventions require further study to evaluate their role in prophylaxis. Antiviral prophylaxis to prevent pneumonia during nursing home outbreaks of influenza has not been evaluated in controlled trials. Observational studies strongly suggest that amantadine, rimantadine, and oseltamivir are all effective in reducing spread of influenza during outbreaks in nursing homes (Table). Oseltamivir acts against influenza B as well as A and has fewer side effects, but it is more expensive.^5,6 Presumably, decreasing the rate of influenza also reduces the rate of subsequent pneumonia.

Oral hygiene programs for nursing home residents may also reduce pneumonia. In a single study, 366 patients in 11 Japanese nursing homes were divided into controls (self-care) and those treated with rigorous oral care (by staff). The intervention group had a relative risk of 0.6 (95% CI, 0.36–0.99; NNT=12.5) for pneumonia over a 2-year period.⁷ The NNT for preventing a death by pneumonia was 11 (P<.01). This intriguing result merits follow up in larger groups in US nursing homes to see if this approach is feasible.

TABLE
Available treatment and prophylactic regimens for influenza

Recommendations from others

There are no recommendations about the use of antibiotic prophylaxis for pneumonia in either the nursing home or in the outpatient settings; however, there are clear recommendations against the overuse of antibiotics.⁸

The CDC Advisory Committee on Immunization Practices (ACIP) recommends:

• annual influenza vaccine for persons residing in nursing homes⁹
• annual influenza vaccine for health care workers in long-term care facilities⁹
• pneumococcal vaccine for persons residing in a nursing home (the schedule for an immunocompetent adult is a single dose, followed by a booster after age 65 if the first dose was before age 65, or after 5 years for persons <65 years with compromised immune status)¹⁰
• chemoprophylaxis for influenza outbreaks in nursing homes.¹¹

Evidence summary

Overuse of antibiotics is already a problem in nursing homes. A large portion of bacterial pneumonia in the nursing home population results from aspiration of oropharyngeal bacteria, which is more likely to be drug-resistant if the resident has been on antibiotics.¹ We found no studies that testing antibacterial agents for prevention of pneumonia in nursing home patients. However, 3 measures are clearly helpful in preventing pneumonia in nursing home patients:

1. Influenza vaccination of residents: A meta-analysis of 20 cohort studies showed a 53% efficacy (95% confidence interval [CI], 35–66)—defined as 1 minus the odds ratio—for influenza immunization in preventing pneumonia.²
2. Influenza vaccination of caregivers: A cluster randomized trial in British long-term care facilities demonstrated that influenza vaccination of health care workers (61% of 1078 workers) reduced the total nursing home mortality rate (odds ratio [OR]=0.56 [95% CI, 0.4–0.8]) for a drop in mortality rate from 17% to 10% (number needed to treat [NNT]=14.3).³
3. Pneumococcal vaccination of residents: This evidence was reviewed in a prior Clinical Inquiry.⁴ The evidence comes primarily from 2 clinical trials in which the NNT to prevent 1 episode of pneumonia was about 35.

Two other proposed interventions require further study to evaluate their role in prophylaxis. Antiviral prophylaxis to prevent pneumonia during nursing home outbreaks of influenza has not been evaluated in controlled trials. Observational studies strongly suggest that amantadine, rimantadine, and oseltamivir are all effective in reducing spread of influenza during outbreaks in nursing homes (Table). Oseltamivir acts against influenza B as well as A and has fewer side effects, but it is more expensive.^5,6 Presumably, decreasing the rate of influenza also reduces the rate of subsequent pneumonia.

Oral hygiene programs for nursing home residents may also reduce pneumonia. In a single study, 366 patients in 11 Japanese nursing homes were divided into controls (self-care) and those treated with rigorous oral care (by staff). The intervention group had a relative risk of 0.6 (95% CI, 0.36–0.99; NNT=12.5) for pneumonia over a 2-year period.⁷ The NNT for preventing a death by pneumonia was 11 (P<.01). This intriguing result merits follow up in larger groups in US nursing homes to see if this approach is feasible.

TABLE
Available treatment and prophylactic regimens for influenza

Recommendations from others

There are no recommendations about the use of antibiotic prophylaxis for pneumonia in either the nursing home or in the outpatient settings; however, there are clear recommendations against the overuse of antibiotics.⁸

The CDC Advisory Committee on Immunization Practices (ACIP) recommends:

• annual influenza vaccine for persons residing in nursing homes⁹
• annual influenza vaccine for health care workers in long-term care facilities⁹
• pneumococcal vaccine for persons residing in a nursing home (the schedule for an immunocompetent adult is a single dose, followed by a booster after age 65 if the first dose was before age 65, or after 5 years for persons <65 years with compromised immune status)¹⁰
• chemoprophylaxis for influenza outbreaks in nursing homes.¹¹

Evidence summary

Overuse of antibiotics is already a problem in nursing homes. A large portion of bacterial pneumonia in the nursing home population results from aspiration of oropharyngeal bacteria, which is more likely to be drug-resistant if the resident has been on antibiotics.¹ We found no studies that testing antibacterial agents for prevention of pneumonia in nursing home patients. However, 3 measures are clearly helpful in preventing pneumonia in nursing home patients:

1. Influenza vaccination of residents: A meta-analysis of 20 cohort studies showed a 53% efficacy (95% confidence interval [CI], 35–66)—defined as 1 minus the odds ratio—for influenza immunization in preventing pneumonia.²
2. Influenza vaccination of caregivers: A cluster randomized trial in British long-term care facilities demonstrated that influenza vaccination of health care workers (61% of 1078 workers) reduced the total nursing home mortality rate (odds ratio [OR]=0.56 [95% CI, 0.4–0.8]) for a drop in mortality rate from 17% to 10% (number needed to treat [NNT]=14.3).³
3. Pneumococcal vaccination of residents: This evidence was reviewed in a prior Clinical Inquiry.⁴ The evidence comes primarily from 2 clinical trials in which the NNT to prevent 1 episode of pneumonia was about 35.

Two other proposed interventions require further study to evaluate their role in prophylaxis. Antiviral prophylaxis to prevent pneumonia during nursing home outbreaks of influenza has not been evaluated in controlled trials. Observational studies strongly suggest that amantadine, rimantadine, and oseltamivir are all effective in reducing spread of influenza during outbreaks in nursing homes (Table). Oseltamivir acts against influenza B as well as A and has fewer side effects, but it is more expensive.^5,6 Presumably, decreasing the rate of influenza also reduces the rate of subsequent pneumonia.

Oral hygiene programs for nursing home residents may also reduce pneumonia. In a single study, 366 patients in 11 Japanese nursing homes were divided into controls (self-care) and those treated with rigorous oral care (by staff). The intervention group had a relative risk of 0.6 (95% CI, 0.36–0.99; NNT=12.5) for pneumonia over a 2-year period.⁷ The NNT for preventing a death by pneumonia was 11 (P<.01). This intriguing result merits follow up in larger groups in US nursing homes to see if this approach is feasible.

TABLE
Available treatment and prophylactic regimens for influenza

Recommendations from others

There are no recommendations about the use of antibiotic prophylaxis for pneumonia in either the nursing home or in the outpatient settings; however, there are clear recommendations against the overuse of antibiotics.⁸

The CDC Advisory Committee on Immunization Practices (ACIP) recommends:

• annual influenza vaccine for persons residing in nursing homes⁹
• annual influenza vaccine for health care workers in long-term care facilities⁹
• pneumococcal vaccine for persons residing in a nursing home (the schedule for an immunocompetent adult is a single dose, followed by a booster after age 65 if the first dose was before age 65, or after 5 years for persons <65 years with compromised immune status)¹⁰
• chemoprophylaxis for influenza outbreaks in nursing homes.¹¹

Evidence summary

Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.^1,2

Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.³ A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.⁴

The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.^{5 7 P}atients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.⁷ Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.^1,2

The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.⁸ The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.^8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.¹⁰ The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.¹¹

Recommendations from others

The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.¹² It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.

UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.¹ . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”²

Evidence summary

Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.^1,2

Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.³ A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.⁴

The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.^{5 7 P}atients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.⁷ Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.^1,2

The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.⁸ The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.^8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.¹⁰ The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.¹¹

Recommendations from others

The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.¹² It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.

UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.¹ . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”²

Evidence summary

Initial thyroid replacement with synthetic LT4 is recommended because LT4 is safe, effective, reliably relieves symptoms, and normalizes lab tests for hypothyroid patients.^1,2

Two recent randomized trials comparing LT4 alone or LT4 and LT3 together for a total of 86 adult hypothyroid patients found similar outcomes. One study, which enrolled patients with hypothy-roidism and mild depressive symptoms, assessed scores on the Symptom Check-List-90, the Comprehensive Epidemiological Screens for Depression, and the Medical Outcomes Study health status questionnaire at baseline and multiple times over the duration of the study. For these outcomes, no differences were found between the LT4 alone and combination LT4-LT3 treatment groups within 90% confidence intervals.³ A second study assessed changes in body weight, lipid profile, hypothyroid-specific health-related quality-of-life scores, and 13 neuropsychological measures pre- and posttreatment. This study detected no difference in body weight and serum lipids at baseline and after treatment. The hypothyroid-specific health-related quality-of-life scores similarly improved for both treatment groups. Twelve of 13 neuropsychological tests demonstrated no differences between treatment groups; the Grooved Peg Board Test of manual dexterity and fine visual-motor coordination demonstrated a slight improvement for the LT4 alone treatment group.⁴

The initial dose of LT4 can be based on the age and health status of the patient. The mean replacement dose of LT4 is 1.6 μg/kg/d for healthy patients aged ≤60 years.^{5 7 P}atients aged >60 years should be started on 25 to 50 μg daily. An uncontrolled cohort study of 84 patients found that for patients aged >60 years, 25- to 50-μg doses of LT4 resulted in similar serum thyrotropin (TSH) levels as the higher (1.6 μg/kg/d) doses required for younger patients.⁷ Based on expert opinion, patients of any age with heart disease should be given lower doses of 12.5 to 25 μg daily as initial treatment.^1,2

The choice of the LT4 preparation continues to be debated. In 1997, a bioequivalence study compared 2 generic brands to 2 name brands by having 22 women with hypothyroidism, who were euthyroid on replacement medication, take each preparation for 6 weeks.⁸ The area under the curve, peak serum concentration, and time to peak concentration for 3 indexes of thyroid function (thyroxine, triiodothyronine, and free T4 index) were not significantly different and met the FDA criterion for relative bioequivalence. However, they did not examine therapeutic equivalence and from a clinical perspective, some researchers and pharmaceutical companies felt that the authors could not comment on whether the products were interchangeable.^8,9 The FDA now requires thyroxine bioavailability and bioequivalence studies to evaluate product substitution.¹⁰ The FDA lists Levothyroxine Sodium (Mylan) to be therapeutically equivalent and therefore interchangeable with Unithroid.¹¹

Recommendations from others

The American Association of Clinical Endocrinologists Thyroid Task Force recommends the use of a high-quality brand preparation of LT4 rather than desiccated thyroid hormone, combinations of thyroid hormones, or LT3.¹² It recommends a mean replacement dosage of LT4 of 1.6 μg/kg of body weight per day with initial dose ranging from 12.5 μg daily to a full replacement dosage based on the age, weight, and cardiac status of the patient.

UpToDate states that although LT4 products are standardized, subtle differences between preparations exist, and products should be interchanged only with sufficient monitoring after the change. In addition, they recommend generally avoiding generics because the pharmacy may interchange products without physicians being aware.¹ . The Physicians’ Information and Education Resource from the American College of Physicians states “Name-brand LT4 products provide more consistent potency than generic preparations. The cost of brand-name LT4 products is only slightly more than that of generic preparations.”²

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

Osteoarthritis, also known as degenerative joint disease, is the most prevalent form of arthritis in the United States.³ For the elderly, it is a common cause of pain and disability, affecting patients’ ability to perform activities of daily living. Common causes of osteoarthritis include past and present biomechanical stresses affecting the articular cartilage, sub-chondral bone changes, and biochemical changes in the articular cartilage and synovial membrane.³

Treatment of patients with osteoarthritis of the knee should be individualized to the severity of symptoms for each patient. A treatment plan can include patient education, physical and occupational therapy, non-opioid oral and topical agents, NSAIDs, intra-articular corticosteroid injections, viscosupplementation injections, arthroscopic lavage, and total knee replacements.

Our knowledge of the long-term safety and efficacy of intra-articular knee corticosteroid injection is based on limited data. In a randomized, double-blind, placebo-controlled crossover study, investigators randomized 59 patients aged 51 to 89 years to receive either an intra-articular injection of 1 mL of 40 mg methylprednisolone or 1 mL of 0.9% saline. After 3 weeks, patients receiving steroid injection had a minimal change in baseline visual analogue score for pain compared with those receiving saline (median change: –2.0 mm vs 0 mm on a 100-mm scale).⁴

A randomized, single-blinded study involving 84 patients demonstrated significant self-report-ed “overall improvement” for patients given intra-articular triamcinolone hexacetonide (78%) compared with placebo (49%) after 1 week (P<.05).⁵ It also confirmed reports that visual analogue score for pain and distance walked in 1 minute improves significantly for both steroid- and placebo-treated groups up to 6 weeks. Only the steroid-treated patients exhibited improved walking distance at 1 week compared with baseline (P<.001).

A recent randomized, double-blind, placebo-controlled trial studied the long-term safety and efficacy of treatment of knee osteoarthritis with repeated steroid injections.⁶ These investigators studied 66 patients aged 40 to 80 years recruited from rheumatology clinics. One half (n=33) received injections of triamcinolone acetonide 40 mg, and the other half received saline injections every 3 months for 2 years. At 1- and 2-year interval follow-ups, no statistically significant difference was seen between the 2 groups in loss of joint space and no progression of degenerative disease, as demonstrated by measurements of joint space widths by standardized fluoroscopically guided radiographs. Although the primary outcome measure of this study was to assess radiologic joint space narrowing with repeated injections, knee pain and stiffness appeared to improve after 2 years, although these results were not well quantified.

A limitation of most studies testing intraarticular therapy has been sample size. Combining studies may allow the ability to detect levels of pain relief not found in individual studies. A recent meta-analysis of 6 randomized controlled trials using intra-articular corticosteroid knee injections found short-term relief of pain for 2 weeks (relative risk [RR]=1.66; 95% confidence interval [CI], 1.37–2.01).⁷ The number needed to treat (NNT) range for these studies is 1.3 to 3.5. Two additional studies included in this study using higher-dose steroids (prednisone equivalent dose of 37.5 to 80 mg), with or without joint lavage, assessed improvement at 16 to 24 weeks. Although neither individual study showed statistically significant differences, the pooled data from the 2 studies favored symptom improvement at 16 to 24 weeks (RR=2.09; 95% CI, 1.2–3.7; NNT=4.4).⁷

Recommendations from others

Guidelines for the treatment of knee osteoarthritis were outlined by a task force for the European League Against Rheumatism (EULAR) Standing Committee for Clinical Trials. The task force recommended intra-articular steroid injection for acute exacerbation of knee pain. This task force performed an evidence-based review and concluded at least 1 randomized control trial recommended intraarticular steroid for patients with osteoarthritis. It was noted that intra-articular steroid injections were effective for only short-term pain relief and that there are no predictors of success of treatment, such as the presence or absence of such factors as joint effusion, degree of radio-logic change, age, or obesity.²

The American College of Rheumatology Subcommittee on Osteoarthritis Guidelines developed both nonpharmacological and pharmacological recommendations for the treatment of osteoarthritis of the knee.⁸ These recommendations include: use of intra-articular steroid injection for patients with acute exacerbations who had evidence for joint inflammation, and joint aspiration accompanying the intra-articular injection for “short-term relief.”

Evidence summary

Osteoarthritis, also known as degenerative joint disease, is the most prevalent form of arthritis in the United States.³ For the elderly, it is a common cause of pain and disability, affecting patients’ ability to perform activities of daily living. Common causes of osteoarthritis include past and present biomechanical stresses affecting the articular cartilage, sub-chondral bone changes, and biochemical changes in the articular cartilage and synovial membrane.³

Treatment of patients with osteoarthritis of the knee should be individualized to the severity of symptoms for each patient. A treatment plan can include patient education, physical and occupational therapy, non-opioid oral and topical agents, NSAIDs, intra-articular corticosteroid injections, viscosupplementation injections, arthroscopic lavage, and total knee replacements.

Our knowledge of the long-term safety and efficacy of intra-articular knee corticosteroid injection is based on limited data. In a randomized, double-blind, placebo-controlled crossover study, investigators randomized 59 patients aged 51 to 89 years to receive either an intra-articular injection of 1 mL of 40 mg methylprednisolone or 1 mL of 0.9% saline. After 3 weeks, patients receiving steroid injection had a minimal change in baseline visual analogue score for pain compared with those receiving saline (median change: –2.0 mm vs 0 mm on a 100-mm scale).⁴

A randomized, single-blinded study involving 84 patients demonstrated significant self-report-ed “overall improvement” for patients given intra-articular triamcinolone hexacetonide (78%) compared with placebo (49%) after 1 week (P<.05).⁵ It also confirmed reports that visual analogue score for pain and distance walked in 1 minute improves significantly for both steroid- and placebo-treated groups up to 6 weeks. Only the steroid-treated patients exhibited improved walking distance at 1 week compared with baseline (P<.001).

A recent randomized, double-blind, placebo-controlled trial studied the long-term safety and efficacy of treatment of knee osteoarthritis with repeated steroid injections.⁶ These investigators studied 66 patients aged 40 to 80 years recruited from rheumatology clinics. One half (n=33) received injections of triamcinolone acetonide 40 mg, and the other half received saline injections every 3 months for 2 years. At 1- and 2-year interval follow-ups, no statistically significant difference was seen between the 2 groups in loss of joint space and no progression of degenerative disease, as demonstrated by measurements of joint space widths by standardized fluoroscopically guided radiographs. Although the primary outcome measure of this study was to assess radiologic joint space narrowing with repeated injections, knee pain and stiffness appeared to improve after 2 years, although these results were not well quantified.

A limitation of most studies testing intraarticular therapy has been sample size. Combining studies may allow the ability to detect levels of pain relief not found in individual studies. A recent meta-analysis of 6 randomized controlled trials using intra-articular corticosteroid knee injections found short-term relief of pain for 2 weeks (relative risk [RR]=1.66; 95% confidence interval [CI], 1.37–2.01).⁷ The number needed to treat (NNT) range for these studies is 1.3 to 3.5. Two additional studies included in this study using higher-dose steroids (prednisone equivalent dose of 37.5 to 80 mg), with or without joint lavage, assessed improvement at 16 to 24 weeks. Although neither individual study showed statistically significant differences, the pooled data from the 2 studies favored symptom improvement at 16 to 24 weeks (RR=2.09; 95% CI, 1.2–3.7; NNT=4.4).⁷

Recommendations from others

Guidelines for the treatment of knee osteoarthritis were outlined by a task force for the European League Against Rheumatism (EULAR) Standing Committee for Clinical Trials. The task force recommended intra-articular steroid injection for acute exacerbation of knee pain. This task force performed an evidence-based review and concluded at least 1 randomized control trial recommended intraarticular steroid for patients with osteoarthritis. It was noted that intra-articular steroid injections were effective for only short-term pain relief and that there are no predictors of success of treatment, such as the presence or absence of such factors as joint effusion, degree of radio-logic change, age, or obesity.²

The American College of Rheumatology Subcommittee on Osteoarthritis Guidelines developed both nonpharmacological and pharmacological recommendations for the treatment of osteoarthritis of the knee.⁸ These recommendations include: use of intra-articular steroid injection for patients with acute exacerbations who had evidence for joint inflammation, and joint aspiration accompanying the intra-articular injection for “short-term relief.”

Evidence summary

Osteoarthritis, also known as degenerative joint disease, is the most prevalent form of arthritis in the United States.³ For the elderly, it is a common cause of pain and disability, affecting patients’ ability to perform activities of daily living. Common causes of osteoarthritis include past and present biomechanical stresses affecting the articular cartilage, sub-chondral bone changes, and biochemical changes in the articular cartilage and synovial membrane.³

Treatment of patients with osteoarthritis of the knee should be individualized to the severity of symptoms for each patient. A treatment plan can include patient education, physical and occupational therapy, non-opioid oral and topical agents, NSAIDs, intra-articular corticosteroid injections, viscosupplementation injections, arthroscopic lavage, and total knee replacements.

Our knowledge of the long-term safety and efficacy of intra-articular knee corticosteroid injection is based on limited data. In a randomized, double-blind, placebo-controlled crossover study, investigators randomized 59 patients aged 51 to 89 years to receive either an intra-articular injection of 1 mL of 40 mg methylprednisolone or 1 mL of 0.9% saline. After 3 weeks, patients receiving steroid injection had a minimal change in baseline visual analogue score for pain compared with those receiving saline (median change: –2.0 mm vs 0 mm on a 100-mm scale).⁴

A randomized, single-blinded study involving 84 patients demonstrated significant self-report-ed “overall improvement” for patients given intra-articular triamcinolone hexacetonide (78%) compared with placebo (49%) after 1 week (P<.05).⁵ It also confirmed reports that visual analogue score for pain and distance walked in 1 minute improves significantly for both steroid- and placebo-treated groups up to 6 weeks. Only the steroid-treated patients exhibited improved walking distance at 1 week compared with baseline (P<.001).

A recent randomized, double-blind, placebo-controlled trial studied the long-term safety and efficacy of treatment of knee osteoarthritis with repeated steroid injections.⁶ These investigators studied 66 patients aged 40 to 80 years recruited from rheumatology clinics. One half (n=33) received injections of triamcinolone acetonide 40 mg, and the other half received saline injections every 3 months for 2 years. At 1- and 2-year interval follow-ups, no statistically significant difference was seen between the 2 groups in loss of joint space and no progression of degenerative disease, as demonstrated by measurements of joint space widths by standardized fluoroscopically guided radiographs. Although the primary outcome measure of this study was to assess radiologic joint space narrowing with repeated injections, knee pain and stiffness appeared to improve after 2 years, although these results were not well quantified.

A limitation of most studies testing intraarticular therapy has been sample size. Combining studies may allow the ability to detect levels of pain relief not found in individual studies. A recent meta-analysis of 6 randomized controlled trials using intra-articular corticosteroid knee injections found short-term relief of pain for 2 weeks (relative risk [RR]=1.66; 95% confidence interval [CI], 1.37–2.01).⁷ The number needed to treat (NNT) range for these studies is 1.3 to 3.5. Two additional studies included in this study using higher-dose steroids (prednisone equivalent dose of 37.5 to 80 mg), with or without joint lavage, assessed improvement at 16 to 24 weeks. Although neither individual study showed statistically significant differences, the pooled data from the 2 studies favored symptom improvement at 16 to 24 weeks (RR=2.09; 95% CI, 1.2–3.7; NNT=4.4).⁷

Recommendations from others

Guidelines for the treatment of knee osteoarthritis were outlined by a task force for the European League Against Rheumatism (EULAR) Standing Committee for Clinical Trials. The task force recommended intra-articular steroid injection for acute exacerbation of knee pain. This task force performed an evidence-based review and concluded at least 1 randomized control trial recommended intraarticular steroid for patients with osteoarthritis. It was noted that intra-articular steroid injections were effective for only short-term pain relief and that there are no predictors of success of treatment, such as the presence or absence of such factors as joint effusion, degree of radio-logic change, age, or obesity.²

The American College of Rheumatology Subcommittee on Osteoarthritis Guidelines developed both nonpharmacological and pharmacological recommendations for the treatment of osteoarthritis of the knee.⁸ These recommendations include: use of intra-articular steroid injection for patients with acute exacerbations who had evidence for joint inflammation, and joint aspiration accompanying the intra-articular injection for “short-term relief.”

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

FIGURE 1
Bariatric surgical techniques for weight loss

Evidence summary

A systematic review comparing bariatric surgery with conventional medical therapy for obesity included 1 randomized controlled trial and the Swedish Obesity Study, a large cohort study with matched controls. Surgery produced 23 to 28 kg more weight loss at 2 years.¹ The study demonstrated 33% ± 10% weight loss for gastric bypass and 0% for medical therapy (not described) at 2 years,² and 25% ± 6% loss vs 0.9% gain at 8 years.³ Among bariatric surgical techniques, patients undergoing gastric bypass lost more weight than those with gastroplasty (using staples to partition the stomach, either horizontally or vertically ( Figure 1 ) (P=.057, not significant) or gastric banding (placing a constricting ring around the stomach) (P<.05) at 8 years.³

The same systematic review assessed multiple randomized controlled trials comparing gastric bypass with gastroplasty and found greater weight loss, fewer revisions, and more side effects from gastric bypass ( Figure 2 ).¹ Five trials comparing gastric bypass with horizontal gastroplasty demonstrated significantly greater weight loss from gastric bypass. Five other trials comparing weight loss from gastric bypass with vertical gastroplasty produced mixed results, with 3 trials favoring gastric bypass and 2 showing no difference.¹ Fewer patients required revision after gastric bypass (0%–4%) compared with vertical gastroplasty (9%) or horizontal gastroplasty (19%–40%). One included trial found that postoperative dumping syndrome (28% vs 0%, P<0.05) and heartburn (59% vs 32%, P<.05) were more common with gastric bypass than with gastroplasty.¹

Bariatric surgery, including gastric bypass, improves a variety of obesity-related comorbid conditions. Diabetes prevalence decreased among gastric bypass patients at 2 years (0.0% vs 4.7%, P<0.005) and 8 years (3.6% vs 18.5%, P<.0005) compared with those receiving medical therapy.^2,3 In a case series involving 154 diabetic gastric bypass patients, diabetes resolved for 83% by 1 year, and for 86% at 5 to 7 years.⁴ In several case series, most patients became euglycemic and discontinued insulin or oral agents.

In the Swedish Obesity Study, hypertriglyceridemia decreased postoperatively but hypercholesterolemia did not.⁵ In a case series, bariatric surgery reduced triglycerides (50%) as well as total cholesterol (15%) (P<.05 for both) at 6 months and significantly increased high-density lipoprotein cholesterol levels at 1 and 5 years.⁶

Bariatric surgery significantly lowered the incidence of hypertension at 2 years (3.2%) compared with conventional treatment (9.9%), but after 8 years this difference disappeared.^2,3,5 However, in multiple large case series with morbidly obese patients, hypertension resolved or improved. The largest study showed resolution of hypertension for 69% at 1 to 2 years (91% follow-up), 66% at 5 to 7 years (50% follow-up), and 51% at 10 to 12 years (37% follow-up).⁴

Bariatric surgery improved obstructive sleep apnea and obesity hypoventilation syndrome in 2 case series. In one, Epworth Sleepiness Scale scores, minimum O₂ saturation, and other measures improved significantly (P<.001) by 3 to 21 months after surgery.⁷

In another case series, menstrual irregularities decreased from 40.4% to 4.6% following surgery (P<.001) among women who lost 50% of their excess weight.⁸ The incidence of urinary stress incontinence also decreased significantly (61.2% to 11.6%, P<.001 in this study⁸ ). The Swedish Obesity Study found significant improvements in Health-Related Quality of Life scores at 2 years with surgery vs conventional treatment.⁹

Bariatric surgery, including gastric bypass, has significant postoperative morbidity and mortality. Thirteen percent of patients in the Swedish Obesity Study experienced peri-operative complications, including pulmonary symptoms (6.2%), abdominal infection (2.1%), wound complications (1.8%), bleeding (0.9%), thromboembolic events (0.8%), and other miscellaneous complications (4.8%). Postoperative complications required reoperation for 2.2% of surgical patients, and there were 4 postoperative deaths (0.2% of the operative patients; 3 due to leakage, and 1 due to a technical laparoscopic error).²

Nutritional and vitamin deficiencies are common following gastric bypass, including deficiencies of vitamin B12, iron, folate, and calcium. Lifelong nutritional supplementation is generally necessary following this procedure.¹⁰

FIGURE 2
Long-term weight loss with bariatric surgery

Recommendations from others

A 1991 National Institutes of Health consensus conference suggested consideration of obesity surgery for patients with a body-mass index ≥40, or ≥35 plus severe obesity-related medical comorbidities (such as severe sleep apnea, obesity hypoventilation syndrome, obesity-related cardiomyopathy, or severe diabetes) who have not been successfully treated with non-surgical attempts at weight reduction.

Selected patients should be well-informed and motivated, with acceptable operative risk. A multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise should evaluate patients who are candidates for surgery. An experienced surgeon, working in a clinical setting with adequate support for all aspects of management and assessment, should perform the surgery.

Lifelong medical surveillance is necessary after surgery, and patients should be selected who are likely to comply with this.¹¹

Evidence summary

Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA_1c=6%–8%) are associated with a threefold increase in fetal malformations.^1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA_1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).² One limitation of this study was that preconception care was not consistently defined among the included studies.

A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA_1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA_1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.³

When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).⁵ An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.

Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.⁶

Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.⁷

Recommendations from others

The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.⁸ For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.⁹

The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.¹⁰ The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.¹¹

Evidence summary

Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA_1c=6%–8%) are associated with a threefold increase in fetal malformations.^1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA_1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).² One limitation of this study was that preconception care was not consistently defined among the included studies.

A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA_1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA_1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.³

When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).⁵ An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.

Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.⁶

Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.⁷

Recommendations from others

The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.⁸ For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.⁹

The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.¹⁰ The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.¹¹

Evidence summary

Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA_1c=6%–8%) are associated with a threefold increase in fetal malformations.^1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA_1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).² One limitation of this study was that preconception care was not consistently defined among the included studies.

A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA_1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA_1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.³

When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).⁵ An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.

Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.⁶

Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.⁷

Recommendations from others

The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.⁸ For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.⁹

The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.¹⁰ The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.¹¹

Evidence summary

The majority of gout sufferers are uric acid undersecretors rather than overproducers; however, many patients will have a combination of these 2 processes, as well as caloric or purine overindulgence. Efforts to limit the frequency and intensity of gout attacks have focused on reducing the uric acid load or reducing the inflammatory response to intra-articular crystal deposition. Pharmacologic therapies include 1) uricosurics, such as probenecid, sulfinpyrazone and benzbromarone (used mostly in Europe), which increase the renal clearance of uric acid, 2) xanthine oxidase inhibitors such as allopurinol, which limit the formation of uric acid to yield a more water soluble chemical, and 3) anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. Obesity and insulin resistance are associated with elevated uric acid, suggesting that weight loss may also help reduce episodes of gout.

A double-blinded crossover study of 38 veteran men with recurrent gout found that the addition of daily colchicine to uricosurics reduced the frequency of attacks by nearly two thirds in 6 months of follow-up.¹ A cohort study of 208 men with confirmed gout who used either daily colchicine alone or colchicine with uricosurics for 2 to 10 years found marked improvements in attack frequency in both groups, yet there was no difference between the intervention groups.² An additional study followed 734 patients (including some of the subjects in the first cohort study) and reported similar outcomes.³

Allopurinol was studied in 46 patients using prophylactic colchicine with an average follow-up of 12 months.⁴ Attack rates were unchanged for the first several weeks followed by a decline in the attack rate and a regression of tophi. When allopurinol was added to uricosurics in 48 patients, tophi were reduced.⁵

An average weight loss of 7.7 kg had a beneficial effect on serum uric acid levels and gout attack rates in 13 nondiabetic men, who were placed on a carefully controlled 1600-calorie diet with 40% of calories from complex carbohydrates.⁶

In a small study, the addition of uricosurics did not reduce the gout attack rate in 14 patients with nontophaceous gout.⁷ Patients were followed over 12 to 15 months in a crossover study of colchicine and placebo versus colchicine and sulfinpyrazone. Although this study had limited power, a larger cohort study had similar findings over a longer follow-up period.³

We were unable to find any applicable studies of daily NSAID use, dietary purine control, or alcohol reduction for the secondary prevention of gout. A prospective study of primary gout involving 47,150 men followed over 12 years noted a relative risk (RR) of gout 1.41 (95% confidence interval [CI], 1.07–1.86) in the highest quintile of meat eaters, a RR of 1.51 (95% CI, 1.17–1.95) in the highest quintile of seafood eaters, and an inverse relationship of dairy intake with gout risk.⁸ Thiazide diuretics appear to increase the likelihood of a gout diagnosis and if used, could be discontinued, although no studies have investigated this intervention. Most of the gout studies were performed in the 1960s using simple cohort designs and limited statistical analysis; some used combinations of medications and variable dosing. Only allopurinol appears effective in resorbing tophi⁵ and may have greater utility for patients with severe tophaceous gout, in those intolerant to uricosurics, in gross overproduction of uric acid, for patients with uric acid stones, or for those with renal impairment.

Recommendations from others

An expert panel, recruited by the Agency for Healthcare Research and Quality, recently published a summary combining evidence and expert opinion, which suggested that colchicine is a good prophylactic therapy and that uric acid lowering drugs (allopurinol, probenecid, and sulfinpyrazone) are effective in decreasing attack frequency in those with more than 2 attacks per year.⁹ Weight loss and alcohol reduction were also encouraged. A Cochrane review of this topic is scheduled for completion in 2004.

Evidence summary

The majority of gout sufferers are uric acid undersecretors rather than overproducers; however, many patients will have a combination of these 2 processes, as well as caloric or purine overindulgence. Efforts to limit the frequency and intensity of gout attacks have focused on reducing the uric acid load or reducing the inflammatory response to intra-articular crystal deposition. Pharmacologic therapies include 1) uricosurics, such as probenecid, sulfinpyrazone and benzbromarone (used mostly in Europe), which increase the renal clearance of uric acid, 2) xanthine oxidase inhibitors such as allopurinol, which limit the formation of uric acid to yield a more water soluble chemical, and 3) anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. Obesity and insulin resistance are associated with elevated uric acid, suggesting that weight loss may also help reduce episodes of gout.

A double-blinded crossover study of 38 veteran men with recurrent gout found that the addition of daily colchicine to uricosurics reduced the frequency of attacks by nearly two thirds in 6 months of follow-up.¹ A cohort study of 208 men with confirmed gout who used either daily colchicine alone or colchicine with uricosurics for 2 to 10 years found marked improvements in attack frequency in both groups, yet there was no difference between the intervention groups.² An additional study followed 734 patients (including some of the subjects in the first cohort study) and reported similar outcomes.³

Allopurinol was studied in 46 patients using prophylactic colchicine with an average follow-up of 12 months.⁴ Attack rates were unchanged for the first several weeks followed by a decline in the attack rate and a regression of tophi. When allopurinol was added to uricosurics in 48 patients, tophi were reduced.⁵

An average weight loss of 7.7 kg had a beneficial effect on serum uric acid levels and gout attack rates in 13 nondiabetic men, who were placed on a carefully controlled 1600-calorie diet with 40% of calories from complex carbohydrates.⁶

In a small study, the addition of uricosurics did not reduce the gout attack rate in 14 patients with nontophaceous gout.⁷ Patients were followed over 12 to 15 months in a crossover study of colchicine and placebo versus colchicine and sulfinpyrazone. Although this study had limited power, a larger cohort study had similar findings over a longer follow-up period.³

We were unable to find any applicable studies of daily NSAID use, dietary purine control, or alcohol reduction for the secondary prevention of gout. A prospective study of primary gout involving 47,150 men followed over 12 years noted a relative risk (RR) of gout 1.41 (95% confidence interval [CI], 1.07–1.86) in the highest quintile of meat eaters, a RR of 1.51 (95% CI, 1.17–1.95) in the highest quintile of seafood eaters, and an inverse relationship of dairy intake with gout risk.⁸ Thiazide diuretics appear to increase the likelihood of a gout diagnosis and if used, could be discontinued, although no studies have investigated this intervention. Most of the gout studies were performed in the 1960s using simple cohort designs and limited statistical analysis; some used combinations of medications and variable dosing. Only allopurinol appears effective in resorbing tophi⁵ and may have greater utility for patients with severe tophaceous gout, in those intolerant to uricosurics, in gross overproduction of uric acid, for patients with uric acid stones, or for those with renal impairment.

Recommendations from others

An expert panel, recruited by the Agency for Healthcare Research and Quality, recently published a summary combining evidence and expert opinion, which suggested that colchicine is a good prophylactic therapy and that uric acid lowering drugs (allopurinol, probenecid, and sulfinpyrazone) are effective in decreasing attack frequency in those with more than 2 attacks per year.⁹ Weight loss and alcohol reduction were also encouraged. A Cochrane review of this topic is scheduled for completion in 2004.

Evidence summary

The majority of gout sufferers are uric acid undersecretors rather than overproducers; however, many patients will have a combination of these 2 processes, as well as caloric or purine overindulgence. Efforts to limit the frequency and intensity of gout attacks have focused on reducing the uric acid load or reducing the inflammatory response to intra-articular crystal deposition. Pharmacologic therapies include 1) uricosurics, such as probenecid, sulfinpyrazone and benzbromarone (used mostly in Europe), which increase the renal clearance of uric acid, 2) xanthine oxidase inhibitors such as allopurinol, which limit the formation of uric acid to yield a more water soluble chemical, and 3) anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. Obesity and insulin resistance are associated with elevated uric acid, suggesting that weight loss may also help reduce episodes of gout.

A double-blinded crossover study of 38 veteran men with recurrent gout found that the addition of daily colchicine to uricosurics reduced the frequency of attacks by nearly two thirds in 6 months of follow-up.¹ A cohort study of 208 men with confirmed gout who used either daily colchicine alone or colchicine with uricosurics for 2 to 10 years found marked improvements in attack frequency in both groups, yet there was no difference between the intervention groups.² An additional study followed 734 patients (including some of the subjects in the first cohort study) and reported similar outcomes.³

Allopurinol was studied in 46 patients using prophylactic colchicine with an average follow-up of 12 months.⁴ Attack rates were unchanged for the first several weeks followed by a decline in the attack rate and a regression of tophi. When allopurinol was added to uricosurics in 48 patients, tophi were reduced.⁵

An average weight loss of 7.7 kg had a beneficial effect on serum uric acid levels and gout attack rates in 13 nondiabetic men, who were placed on a carefully controlled 1600-calorie diet with 40% of calories from complex carbohydrates.⁶

In a small study, the addition of uricosurics did not reduce the gout attack rate in 14 patients with nontophaceous gout.⁷ Patients were followed over 12 to 15 months in a crossover study of colchicine and placebo versus colchicine and sulfinpyrazone. Although this study had limited power, a larger cohort study had similar findings over a longer follow-up period.³

We were unable to find any applicable studies of daily NSAID use, dietary purine control, or alcohol reduction for the secondary prevention of gout. A prospective study of primary gout involving 47,150 men followed over 12 years noted a relative risk (RR) of gout 1.41 (95% confidence interval [CI], 1.07–1.86) in the highest quintile of meat eaters, a RR of 1.51 (95% CI, 1.17–1.95) in the highest quintile of seafood eaters, and an inverse relationship of dairy intake with gout risk.⁸ Thiazide diuretics appear to increase the likelihood of a gout diagnosis and if used, could be discontinued, although no studies have investigated this intervention. Most of the gout studies were performed in the 1960s using simple cohort designs and limited statistical analysis; some used combinations of medications and variable dosing. Only allopurinol appears effective in resorbing tophi⁵ and may have greater utility for patients with severe tophaceous gout, in those intolerant to uricosurics, in gross overproduction of uric acid, for patients with uric acid stones, or for those with renal impairment.

Recommendations from others

An expert panel, recruited by the Agency for Healthcare Research and Quality, recently published a summary combining evidence and expert opinion, which suggested that colchicine is a good prophylactic therapy and that uric acid lowering drugs (allopurinol, probenecid, and sulfinpyrazone) are effective in decreasing attack frequency in those with more than 2 attacks per year.⁹ Weight loss and alcohol reduction were also encouraged. A Cochrane review of this topic is scheduled for completion in 2004.