Steroids Have No Benefit for Bronchiolitis

A multicenter trial shows no benefit over placebo.
Bronchiolitis is the most common reason for hospitalization of infants in the U.S., and the possible role for steroid treatment has been hotly debated. To assess the efficacy of dexamethasone, researchers conducted a randomized, double-blind, placebo-controlled trial in infants aged 2 to 12 months at 20 emergency departments during three respiratory virus seasons. Inclusion criteria included first episode of wheezing and an ED diagnosis of moderate-to-severe bronchiolitis (defined as a Respiratory Distress Assessment Instrument [RDAI] score 6).
Of 8686 infants screened, 93% were excluded because of prior wheezing (41% of excluded cases), an RDAI score <6 (25%), or other reasons. Overall, 600 infants were randomized to receive either a single dose of dexamethasone (1 mg/kg up to a maximum of 12 mg) or placebo. All other care was at the discretion of the attending physician. Most patients received bronchodilators.
There were no differences between the dexamethasone and placebo groups in admission rates (the primary outcome), respiratory status 4 hours after treatment, hospital length of stay, or readmission rates. The findings remained the same in infants who were positive or negative for respiratory syncytial virus and in those with and without eczema or a family history of asthma.
Comment: This properly sized, well-designed study should end the use of steroids in children with bronchiolitis. If steroids did have an effect, the inclusion of only patients with moderate-to-severe disease should have favored them by eliminating the mild cases from which recovery is virtually ensured, regardless of treatment. Similarly, the exclusion of patients with prior episodes of wheezing, which might represent asthma, makes this a clean decision: First episode of wheezing means no steroids, period.
— J. Stephen Bohan, MD, MS, FACP, FACEP
Published in Journal Watch Emergency Medicine July 25, 2007
Citation(s):
Corneli HM et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med 2007 Jul 26; 357:331-9.

Antibiotic Prophylaxis Does Not Lower Rate of Recurrent UTI in Children

In fact, prophylaxis is associated with increased risk for resistant urinary tract infection.

The 1999 American Academy of Pediatrics practice guideline recommends that children with a first urinary tract infection (UTI) undergo imaging to determine the presence and grade of vesicoureteral reflux, which is found in 30% to 40% of children with UTI. The guideline recommends that children with vesicoureteral reflux be given daily antibiotic prophylaxis to suppress recurrent UTI and, theoretically, to prevent renal scarring, but there is scant scientific support for this stance. Therefore, investigators sought to identify risk factors for recurrent UTI and resistant UTI and to assess the value of antibiotic prophylaxis against recurrent UTI in a cohort study of children 6 years or younger.

Among nearly 75,000 children seen at 27 primary care pediatric practices from 2001 to 2006, the incidence of first UTI was 0.7%, the rate of recurrent UTI was 12%, and the cumulative incidence of UTI was 4.2% per person-year. Factors that increased the risk for recurrent UTI were white race (hazard ratio, 1.97); age 3–4 years (HR, 2.75); age 4–5 years (HR, 2.47); and grade 4–5 vesicoureteral reflux (HR, 4.38). Antibiotic prophylaxis was not associated with lower risk of recurrent UTI (HR, 1.01) but was a risk factor for antibiotic resistance among children with recurrent UTI (HR, 7.50).

Comment: This is the first large cohort study to determine the incidence of and risk factors for recurrent UTI in children. The noteworthy discovery that antibiotic prophylaxis does not help prevent recurrent UTI and that, in fact, it leads to an increase in resistant strains in recurrent UTI episodes strikes down conventional dogma. For children 6 years old with primary or recurrent UTI, treat the primary disease, but do not initiate or recommend daily antibiotic prophylaxis.

— John A. Marx, MD, FAAEM, FACEP

Published in Journal Watch Emergency Medicine July 27, 2007

Citation(s):
Conway PH et al. Recurrent urinary tract infections in children: Risk factors and association with prophylactic antimicrobials. JAMA 2007 Jul 11; 298:179-86.

VA Hospital Dramatically Lowers Its MRSA Rate

A Veterans Affairs hospital that screens all new patients for methicillin-resistant S. aureus (MRSA) cut infections to 17 cases from an average of 60 in previous years, according to the New York Times.

The paper quotes the hospital's chief of staff as saying that the entire program — added personnel, screening, using disposable blood pressure cuffs, isolating MRSA carriers, leaving a stethoscope in each room — costs about $500,000 while saving some $900,000 annually in treatment costs. Estimated U.S. costs for treating these infections run up to $30 billion annually.

The article quotes an infection-control advocate who criticizes the CDC's 2006 guidelines for infection control as "lax" and giving hospitals "an excuse to do too little."

CDC's 2006 guidelines on multidrug-resistant organisms (Free PDF)

Guidelines for managing RA

full article (pdf)

Nonfasting Trigylceride Levels Seem Better at Defining Risk for Heart Disease

Two studies measuring triglycerides in the nonfasting state show a strong association between elevated levels and risk for cardiovascular disease or death. Both appear in today's JAMA.

One study, using a population sample from Copenhagen, followed nearly 14,000 men and women for an average of 26 years. Researchers found that the risk for MI, ischemic heart disease, or death increased with increasing levels of nonfasting triglycerides, especially among women.

Another study, performed within the Women's Health Initiative, followed some 26,500 women for a median of 11 years and compared the effects of fasting versus nonfasting triglycerides on risk for cardiovascular events. When measured in the nonfasting state (especially 2 to 4 hours postprandially), triglyceride levels showed a strong, independent association with future risk, which persisted in fully adjusted analyses. Fasting levels, according to the authors, "showed little independent association with cardiovascular events."

According to an editorialist, the results "suggest that using 2- to 4-hour postprandial triglyceride measurements may be more predictive [of risk] than LDL-C."

Polyethylene Glycol for Chronic Constipation

Six months of treatment provided significant symptom relief, compared with placebo.

Polyethylene glycol (PEG) 3350 (MiraLax and others) is an osmotic laxative approved for short-term treatment of constipation. In this multicenter industry-sponsored study, researchers assessed the use of PEG for longer-term treatment of constipation.

The study included 304 patients (mean age, 53; 85% women) with chronic constipation, as defined by standardized criteria; the mean duration of constipation was 23 years. The patients were randomized to receive either once-daily PEG (a 17-g packet mixed with 8 oz of liquid) or placebo. During 6 months of treatment, the primary efficacy endpoint (at least 3 satisfactory bowel movements per week, without use of rescue laxative, for at least half of treatment weeks) was reached by 52% of PEG recipients and 11% of placebo recipients — a highly significant difference. Nearly all secondary endpoints also favored the PEG group decisively. Side effects included abdominal distention and diarrhea; no clinically significant laboratory abnormalities were noted.

Comment: Polyethylene glycol, prescribed for up to 6 months at the dose used in this trial, appears to be safe and reasonably effective for adults with chronic constipation. Note that the patients in this trial were generally healthy, had no evidence of organic bowel disorders, and were not taking medications known to cause constipation.

— Allan S. Brett, MD

Published in Journal Watch General Medicine July 12, 2007

Citation(s):
DiPalma JA et al. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007 Jul; 102:1436-4

Enoxaparin vs. Heparin: The PREVAIL Study

The jury is still out but may favor enoxaparin.

In this manufacturer-sponsored, open-label, international trial, researchers compared the effectiveness and safety of enoxaparin (low-molecular-weight heparin) and of unfractionated heparin in reducing the overall number of venous-thromboembolism (VTE) events after acute ischemic stroke. The authors randomized 1762 patients within 48 hours of an acute ischemic stroke to receive either enoxaparin (40 mg once daily) or unfractionated heparin (5000 U every 12 hours) for a mean of 10 days. Patients underwent ultrasound, venography, or both. Pulmonary embolism, if suspected, was evaluated by ventilation perfusion scan, helical CT, or angiography.

The analysis included 76% of the patients. Compared with unfractionated heparin, enoxaparin conferred a 43% reduction in overall number of VTE events up to day 14 that was maintained at 30, 60, and 90 days and was independent of stroke severity (NIHSS score of <14 vs. 14). However, the number of symptomatic VTE events did not differ between the treatment groups, and mortality rates were similar. The number of intracranial bleeding events was similar in both groups, and extracranial events (mainly gastrointestinal bleeding) were slightly more common in the enoxaparin group.

Comment: This was the largest prospective study of its kind. Despite some limitations, this study’s many strengths include its strong statistical power and long-term follow-up. The findings may justify the routine use of enoxaparin, although cost was not addressed and the number of symptomatic events was similar regardless of treatment. These limitations indicate that a more thorough cost-effectiveness analysis is needed before enoxaparin is adopted as the standard of care.

— Flavia Nelson, MD, and James Grotta, MD

Dr. Nelson is Assistant Professor of Neurology, Board Certified Internist, The University of Texas Houston Medical School, and Assistant Director, MRI Analysis Center, Multiple Sclerosis Research Group, The University of Texas Health Science Center at Houston. Dr. Grotta is Professor and Chair, Department of Neurology, The University of Texas Houston Medical School, and Director of Vascular Neurology, The University of Texas Health Science Center at Houston.

Published in Journal Watch Neurology June 26, 2007

Citation(s):
Sherman DG et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): An open-label randomised comparison. Lancet 2007 Apr 21; 369:1347-55.

New Drug Approved for Pulmonary Arterial Hypertension

The FDA has approved the endothelin-receptor antagonist Letairis (ambrisentan) for the treatment of pulmonary arterial hypertension.

In clinical trials, the once-daily pill effectively delayed worsening of the condition.

The FDA notes that Letairis may cause birth defects and should not be used during pregnancy.

fda announcement

Methimazole vs. Propylthiouracil for Hyperthyroidism

Methimazole was superior overall, and lower doses seemed sufficient for patients with mild-to-moderate hyperthyroidism.

Both methimazole and propylthiouracil (PTU) are used to treat hyperthyroidism. To compare these drugs, Japanese researchers randomized 396 patients with Graves hyperthyroidism to receive 15 mg of methimazole once daily, 30 mg of methimazole daily (given as 15 mg twice daily), or 100 mg of PTU three times daily.

At each of three time points (4, 8, and 12 weeks), the proportion of patients with normalized free thyroxine (T4) levels was higher in the 30-mg methimazole group than in the other two groups. The differences were of borderline statistical significance at 4 and 8 weeks but significant at 12 weeks (normal free T4 achieved in 97%, 86%, and 78% of patients in the 30-mg methimazole, 15-mg methimazole, and PTU groups, respectively). In patients with mild or moderate hyperthyroidism, normal free T4 was achieved at similar rates in the three groups. However, in patients with severe hyperthyroidism (i.e., free T4 7 ng/dL), higher-dose methimazole was more effective than lower-dose methimazole or PTU. Transaminase elevations and leukopenia occurred less commonly with both doses of methimazole than with PTU. Rash was less common with lower-dose methimazole than with higher-dose methimazole or PTU.

Comment: Based on these results, the authors favor methimazole — at doses of 15 mg/day for those with mild-to-moderate hyperthyroidism, and 30 mg/day for those with severe hyperthyroidism. Because other studies have reached similar conclusions, most U.S. experts already favor methimazole. One exception is that PTU is recommended during pregnancy.

— Allan S. Brett, MD

Published in Journal Watch General Medicine June 19, 2007

Citation(s):
Nakamura H et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007 Jun; 92:2157-62.

Sequential Therapy for H. pylori Eradication

In this study, sequential therapy was more efficacious than simultaneous therapy, but the mechanism underlying its success remains unexplained.
Standard triple therapy for Helicobacter pylori infection consists of a proton-pump inhibitor and two antibiotics, administered simultaneously. Increasing resistance to two commonly used antibiotics, metronidazole and clarithromycin, has decreased the efficacy of this approach to less than 80% in North America and Europe. Small studies have suggested that sequential, rather than simultaneous, antibiotic therapy might improve eradication rates. Researchers explored this possibility in a double-blind study that involved 300 adults in Italy with dyspepsia or peptic ulcers.
Participants were evaluated by endoscopy (with biopsies for histologic evaluation, culture, and urease testing) and by urea breath testing to confirm H. pylori infection. They then were randomized to receive standard therapy twice daily for 10 days (pantoprazole [40 mg], amoxicillin [1 g], and clarithromycin [500 mg]) or sequential therapy (pantoprazole [40 mg], amoxicillin [1 g], and placebo twice daily for 5 days, followed by pantoprazole [40 mg], clarithromycin [500 mg], and tinidazole [500 mg] twice daily for 5 days). Follow-up breath testing was performed at 4 and 8 weeks after completion of therapy. Eradication was defined as negative results on both tests.
Per-protocol analysis revealed eradication rates of 93% for sequential therapy and 79% for standard therapy (P=0.001). Among patients with clarithromycin-resistant H. pylori strains, eradication rates were higher with sequential than with standard therapy (89% vs. 29%; P=0.003), but, among those with metronidazole-resistant strains, rates were similar in the two treatment arms (97% vs. 91%). Among patients with strains that were resistant to both clarithromycin and metronidazole, none of four sequential-therapy recipients, versus two of seven standard-therapy recipients, achieved eradication. Side effects were mild and similar between groups. The authors concluded that sequential therapy might be more effective than standard triple therapy and should be considered as a possible first-line therapy for patients with H. pylori infection.
Comment: These results provide important information about how to address the dropping success rates for H. pylori eradication therapy in North America and Europe. The mechanism underlying sequential therapy’s superiority in this trial remains unclear. Initial therapy with amoxicillin might increase the efficacy of clarithromycin in the second phase of treatment; however, the results also could be due to the addition of a new drug, tinidazole, to the standard regimen. Additional studies should be performed to clarify the mechanism and generalizability of this effect.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)
Published in Journal Watch Gastroenterology June 15, 2007
Citation(s):
Vaira D et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: A randomized trial. Ann Intern Med 2007 Apr 17; 146:556-63.

Low Dose Hormone Replacement Options

PDF list of products

NY Times article

Aspirin Reduces Risk for Preeclampsia, but Who Should Be Treated?

A meta-analysis found a significant decrease in the rate of preeclampsia, but the benefits of treatment are small and the risks unclear.

The poorly understood etiology of preeclampsia seems to involve inflammation, placental damage, prostaglandin imbalance, and activation of platelets and the clotting system. Some early trials suggested that antiplatelet agents might prevent or delay preeclampsia, but subsequent larger studies suggested that the benefits were modest at best. Investigators have now combined unpublished individual patient data from 31 primary-prevention trials in which more than 32,000 pregnant women at risk for preeclampsia were randomized to receive one or more antiplatelet agents (primarily aspirin), a placebo, or no treatment.

Antiplatelet agents were associated with a 9% to 10% reduction in relative risk for each of four major outcomes (preeclampsia, delivery before 34 weeks’ gestation, stillbirth or infant death before hospital discharge, and small infant for gestational age) and a composite outcome including all of the above plus maternal death. Only the reductions in preeclampsia, preterm delivery, and the composite outcome were statistically significant. The groups did not differ significantly in any other maternal outcomes, including potential adverse effects of antiplatelet therapy (e.g., perinatal hemorrhage). Need for assisted ventilation was a significant 21% lower among infants whose mothers received antiplatelet agents. Outcomes did not differ significantly by dose of aspirin or timing of treatment, or in any prespecified subgroup of women.

Comment: This meta-analysis was strengthened by returning to individual patient data and standardizing outcome definitions. But the potential long-term risks of antiplatelet therapy remain unclear, and even this large study was unable to identify a high-risk subgroup in which the benefit of treatment is substantial. Editorialists suggest that risks and benefits be weighed for each individual patient.

— Bruce Soloway, MD

Published in Journal Watch General Medicine June 26, 2007

Citation(s):
Askie LM et al. Antiplatelet agents for prevention of pre-eclampsia: A meta-analysis of individual patient data. Lancet 2007 May 26; 369:1791-8.
[Medline abstract] (Free)
Roberts JM and Catov JM. Aspirin for pre-eclampsia: Compelling data on benefit and risk. Lancet 2007 May 26; 369:1765-6.

Do SSRIs Cause Birth Defects?

Two large case-control studies indicate a few very small increases in risks for particular defects.
Earlier studies reported that use of selective serotonin reuptake inhibitors (SSRIs) —especially paroxetine — during early pregnancy increases the incidence of cardiovascular birth defects markedly. Now, two large ongoing case-control studies challenge these findings.
Investigators from the U.S. and Canada identified 9622 infants with major birth defects, and 4092 controls without such defects, born between 1997 and 2002. No significant association was found between SSRI use in early pregnancy and congenital heart defects. However, there were small absolute increases in risks for anencephaly, craniosynostosis, and omphalocele with SSRI use, and all these risks — as well as the risk for ventricular outflow tract lesions — were increased most with paroxetine.
In a second study, funded in part by the manufacturer of paroxetine, 9849 infants with birth defects were compared with 5860 control infants born in five centers in the U.S. and Canada between 1993 and 2005. Use of SSRIs in early pregnancy was not associated with heart defects in general, but there was an increased risk for right ventricular outflow tract lesions with paroxetine and an increased risk for septal defects with sertraline. No evidence of increased risk was found for any other birth defects with paroxetine.
Comment: As an editorialist notes, these studies dispel the belief that SSRIs are major causes of birth defects. The absolute risk for right ventricular outflow tract lesions in the infant of a mother who uses paroxetine during pregnancy is likely less than 1%, and the risk for any congenital heart defect is unlikely to exceed 2%. These small risks must be weighed against the risks associated with discontinuing an SSRI during pregnancy.
— Robert W. Rebar, MD
Published in Journal Watch General Medicine June 27, 2007
Citation(s):
Alwan S et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007 Jun 28; 356:2684-92.
Original article (Subscription may be required)
Medline abstract (Free)
Louik C et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007 Jun 28; 356:2675-83.
Original article (Subscription may be required)
Medline abstract (Free)
Greene MF. Teratogenicity of SSRIs — Serious concern or much ado about little? N Engl J Med 2007 Jun 28; 356:2732-3.
Original article (Subscription may be required)
Medline abstract (Free)

Probiotic Drink Helps Reduce Antibiotic-Associated Diarrhea

Consuming a probiotic drink containing Lactobacillus may help older hospitalized patients avoid antibiotic-associated diarrhea, according to a study published online in the British Medical Journal.

In the manufacturer-supported study, 135 hospitalized patients older than 50 who were prescribed antibiotics were randomized to consume a probiotic yogurt drink or a placebo milkshake. The drinks were consumed twice a day concurrent with antibiotic treatment and for a week afterward.

Significantly fewer intervention patients than controls developed antibiotic-associated diarrhea (12% vs. 34%). The number needed to treat (NNT) to prevent one case of antibiotic-associated diarrhea was 5. The NNT to prevent one case of C. difficile-associated diarrhea was 6.

The authors estimate that it would cost $120 to prevent one case of C. difficile-associated diarrhea, whereas it costs an average of $3700 to treat a case in the U.S. They conclude that the drink "has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50."

original article BMJ

Is Liquid-Based Cervical Cytology Better Than Conventional?

No improvement was found in detecting grade 2 or 3 cervical intraepithelial neoplasia.

Although liquid-based cervical cytology has become a standard technique for cervical cancer screening, evidence that it is better than conventional cytology is meager. To compare the two methods, Italian investigators randomized more than 45,000 women (age range, 25–60) presenting for Pap smears to undergo screening using either conventional or liquid-based cytology.

In an intention-to-screen analysis, the proportion of women who had at least one technically unsatisfactory or uninterpretable cytology result was significantly lower in the liquid-based cytology group; this reduction was greater in women aged 25 to 34 than in older women. No significant increase in sensitivity for grade 2 or higher cervical intraepithelial neoplasia was found, and the positive predictive value was significantly lower for liquid-based cytology regardless of the cutoff point used to refer women for colposcopy and biopsy to document cervical dysplasia. Liquid-based cytology was significantly more sensitive in detecting grade 1 or higher cervical intraepithelial neoplasia.

Comment: Although liquid-based cytology was more sensitive than conventional cytology in detecting mild cervical abnormalities, it was not better at detecting serious lesions. Yet, most insurers in the U.S. pay for the more expensive liquid-based cytology. It is more important to obtain Pap smears than to be concerned about the method used to prepare them.

— Robert W. Rebar, MD

Published in Journal Watch General Medicine June 12, 2007

Citation(s):
Ronco G et al. Accuracy of liquid based versus conventional cytology: Overall results of new technologies for cervical cancer screening randomised controlled trial. BMJ 2007 May 21; [e-pub ahead of print]. (http://dx.doi.org/10.1136/bmj.39196.740995.BE)

Lancet Editorial Supports Ovarian Cancer Consensus Statement


A Lancet editorial supports the new ovarian cancer screening consensus statement that women who experience bloating, pelvic/abdominal pain, difficulty eating or feeling full quickly, or frequent or urgent urination for more than a couple of weeks should see their doctor, as these may be early symptoms of the disease.

While acknowledging that "such symptoms are ... associated with many other diseases and conditions, and for every ovarian cancer detected, many false positives might also result," the editorial points to recent research indicating that these symptoms are more severe and frequent in ovarian cancer.

Having also noted that the statement provides no guidance to physicians and that there's no evidence that use of these symptoms for screening will reduce mortality, the editorial concludes that it is a "move in the right direction" and that "its chief contribution might be to improve communication between women and their doctors."
ovarian cancer website for patients

ovarian cancer website for patients

http://www.wcn.org/interior.cfm?diseaseid=8&featureid=1

Effect of Soy Intake on Blood Pressure and Lipids

In hypertensive women who added soy to their diets, blood pressure decreased.

Dietary soy is one of several factors that might explain the lower incidence of coronary heart disease in Asian countries than in Western countries. In a randomized, crossover trial, 60 healthy postmenopausal women followed the National Cholesterol Education Program (NCEP) diet or the NCEP diet with 25 g of soy protein supplied as one half cup of unsalted soy nuts (i.e., roasted soy beans) daily while maintaining an equivalent total protein content. Each phase was continued for 8 weeks, and researchers assessed the effect of the diets upon lipids and blood pressure (BP). Patients with systolic BP 165 mm Hg or diastolic BP of 100 mm Hg were excluded from the trial.

Mean BP was lower with soy than without, both among hypertensive women (137/82 vs. 152/88 mm Hg) and normotensive women (110/67 vs. 116/69 mm Hg). The soy diet was significantly lower in total and saturated fat than the control diet. Nonetheless, among normotensive women, total, LDL, and HDL cholesterol levels did not differ across diets. Among hypertensive women, LDL decreased by 11%; total and HDL cholesterol levels did not differ significantly.

Comment: In this small randomized crossover trial, adding soy protein to a diet showed impressive reductions in blood pressure; the magnitude of this effect was surprising and certainly requires confirmation. In contrast, the effect upon lipids was limited.

— Jamaluddin Moloo, MD, MPH

Published in Journal Watch General Medicine June 14, 2007

Citation(s):
Welty FK et al. Effect of soy nuts on blood pressure and lipid levels in hypertensive, prehypertensive, and normotensive postmenopausal women. Arch Intern Med 2007 May 28; 167:1060-7.