Clinical Question:
Does oral decontamination reduce pneumonia in mechanically ventilated patients?

Bottom Line:
Oral decontamination with antiseptics reduces ventilator-associated pneumonia (VAP). Decontamination with antibiotics, however, did not reduce VAP, and neither approach had an effect on mortality. (LOE = 1a)

Reference:
Chan EY, Ruest A, Meade MO, Cook DJ. Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis. BMJ 2007;334:889.

Study Design:
Meta-analysis (other)

Synopsis:
The investigators evaluated the effect of oral decontamination on the incidence of ventilator associated pneumonia and mortality in mechanically ventilated adults. They did a systematic review and meta-analysis from Medline, Embase, CINAHL, the Cochrane Library, trials registers, reference lists, conference proceedings, and investigators in the specialty. Two independent reviewers screened studies for inclusion, assessed trial quality, and extracted data. Eligible trials were randomised controlled trials enrolling mechanically ventilated adults that compared the effects of daily oral application of antibiotics or antiseptics with no prophylaxis. Eleven trials totalling 3242 patients met the inclusion criteria. Among four trials with 1098 patients, oral application of antibiotics did not significantly reduce the incidence of ventilator associated pneumonia (relative risk 0.69, 95% confidence interval 0.41 to 1.18). In seven trials with 2144 patients, however, oral application of antiseptics significantly reduced the incidence of ventilator associated pneumonia (0.56, 0.39 to 0.81). When the results of the 11 trials were pooled, rates of ventilator associated pneumonia were lower among patients receiving either method of oral decontamination (0.61, 0.45 to 0.82). Mortality was not influenced by prophylaxis with either antibiotics (0.94, 0.73 to 1.21) or antiseptics (0.96, 0.69 to 1.33) nor was duration of mechanical ventilation or stay in the intensive care unit.

Clinical Question:
Are there good alternatives to the twice-daily inhaled corticosteroids in patients with mild persistent asthma?

Bottom Line:
Patients with asthma that is well controlled with the use of twice-daily inhaled fluticasone can be switched to once-daily fluticasone plus salmeterol without increased rates of treatment failure. A switch to montelukast results in an increased rate of treatment failure and decreased asthma control; however, patients taking montelukast remained free of symptoms on 78.7% of treatment days.

Reference:
American Lung Association Asthma Clinical Research Centers, Peters SP, Anthonisen N, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027-2039.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The standard recommendation for patients with mild persistent asthma is to control symptoms and prevent exacerbations by using inhaled corticosteroids, usually twice daily. However, compliance is an issue, particularly for patients whose symptoms are usually mild, and many patients just don’t like inhalers. In this study, patients older than 6 years who met criteria for mild persistent asthma were initially given open-label treatment with fluticasone propionate (Flovent) 100 mcg twice daily for 4 to 6 weeks. If their symptoms were well controlled, the 500 patients were then randomized to 1 of 3 treatment groups: (1) montelukast 5 mg to 10 mg at bedtime, (2) fluticasone 100 mcg twice daily, or (3) fluticasone 100 mcg plus salmeterol 50 mcg at bedtime. Groups were balanced at the start of the study, with each group including approximately 25 children aged 6 years to 15 years and approximately 140 patients older than 15 years. Although allocation concealment was not described, analysis was by intention to treat and outcome assessors appear to have been masked to treatment assignment. Patients were followed up for 16 weeks.

The primary outcome was the time to treatment failure, defined as an urgent medical consultation or hospitalization, the need for systemic corticosteroids, or a significant decrease in the FEV1 or peak expiratory flow rate; needing 10 or more puffs per day of rescue beta-agonist; physician discontinuation because of safety reasons; or refusal to continue. There was no difference in treatment failure rates between groups 2 and 3 (20%), but the failure rate was higher in the group taking montelukast (30.3%). However, most of the “failures” were based on physiologic measures of lung function. If you only look at failures based on patient-oriented outcomes the difference between groups largely disappears: 10.7% for fluticasone twice daily, 11.1% for fluticasone plus salmeterol, and 13.3% for montelukast. Minor adverse events were similar between groups, but fewer patients in the montelukast group developed an upper respiratory infection (26.7% for montelukast compared with 38% in the other 2 groups; number needed to treat to harm = 9; 95% CI, 5 – 71). They also developed fewer viral respiratory infections (7.3% vs 14% to 15%).

Clinical Question:
Do inhaled corticosteroids really have to be taken daily by patients with mild persistent asthma?

Bottom Line:
In patients with mild asthma, the symptom-driven use of inhaled beclomethasone (250 microg) and albuterol (100 microg) in a single inhaler is as effective as regular use of inhaled beclomethasone (250 microg twice daily) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid.

Reference:
Papi A, Canonica GW, Maestrelli P, et al, for the BEST Study Group. Rescue use of beclometasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:2040-2052.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. The authors investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol (also known as salbutamol) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol. They conducted a 6-month, double-blind, double-dummy, randomized, parallel-group trial. After a 4-week run-in, patients with mild asthma were randomly assigned to receive one of four inhaled treatments: placebo twice daily plus 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler as needed (as-needed combination therapy); placebo twice daily plus 100 microg of albuterol as needed (as-needed albuterol therapy); 250 microg of beclomethasone twice daily and 100 microg of albuterol as needed (regular beclomethasone therapy); or 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler twice daily plus 100 microg of albuterol as needed (regular combination therapy). The primary outcome was the morning peak expiratory flow rate. In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters (88.36% of the predicted value), the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher (P=0.04) and the number of exacerbations during the 6-month treatment was lower (P=0.002) in the as-needed combination therapy group than in the as-needed albuterol therapy group, but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy. The cumulative dose of inhaled beclomethasone was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy (P<0.001 for both comparisons).

Clinical Question:
Does prolonged methylprednisolone administered to patients with ARDS reduce lung injury and improve patient outcomes?

Bottom Line:
Methylprednisolone initiated early in the course of acute respiratory distress syndrome (ARDS) reduces the duration of mechanical ventilation and mortality in the intensive care unit (ICU).

Reference:
Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized trial. Chest 2007;131:954-963.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors determined the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe Acute Respiratory Distress Syndrome (ARDS). Randomized, double-blind, placebo-controlled trial was done. They did at ICUs of five hospitals in Memphis. Ninety-one patients with severe early ARDS (

Clinical Question:
Does thermoplasty improve asthma symptoms in adults?

Bottom Line:
In adults with moderate to severe asthma, a series of 3 bronchoscopic thermoplasty treatments causes a short-term increase in symptoms but a long-term (1 year) decrease in mild exacerbations and reduces the need for long-acting beta agonists. It will be very tempting for physicians to broaden the indications for this treatment, but we should resist the temptation, and remember that patients not only did worse in the short-term but that there was no significant change in severe exacerbations. (LOE = 1b)

Reference:
Cox G, Thomson NC, Rubin AS, et al, for the AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327-1337.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Asthma is caused in part by contraction of smooth muscle in the airway, so perhaps reducing the mass of smooth muscle by controlled thermal injury (thermoplasty) will improve symptoms. In this study, patients with moderate or severe persistent asthma were recruited. All required maintenance therapy with at least 200 mcg per day of beclomethasone (or its equivalent) and at least 100 mcg per day of salmeterol (Serevent). All had an FEV1 of between 60% and 85% of predicted and airway hyper-responsiveness based on methacholine testing, and only patients with worsening of control after the discontinuation of the long-acting beta2-adrenergic agonist (LABA) were included in the study. Patients initially underwent a run-in period with 2 weeks of inhaled corticosteroid and LABA, followed by 2 weeks of corticosteroid alone. Patients were then randomized to receive thermoplasty (3 times over a 6-week to 9-week period) or usual care. All patients received the inhaled corticosteroid and LABA, but the latter was then withdrawn 2 weeks prior to the outcome assessment at 3, 6, and 12 months of follow-up. After each LABA withdrawal, it was restarted if necessary. There were a total of 109 patients in the study, of whom 44% were men; the mean age was 40 years. Analysis was by intention to treat.

The primary outcome was the number of mild exacerbations, defined as 2 consecutive days with one of the following: a 20% reduction in peak expiratory flow; requiring more than 3 additional puffs of beta agonist; or nocturnal awakening caused by asthma symptoms. This outcome was only measured during the 2 weeks during which the LABA was withdrawn at 3, 6, and 12 months. After 12 months, the mean number of mild exacerbations had declined from 0.35 to 0.18 per week in the thermoplasty group and increased from 0.28 to 0.31 per week in the control group (P = .03). The change from baseline was also statistically significant in favor of thermoplasty at 3 months, but interestingly not at 6 months. Extrapolated to a full year, this would amount to approximately 8 fewer mild exacerbations. There was no significant difference in severe exacerbations, although the total number was small and the study was probably underpowered for this outcome. There were statistically significant improvements in the symptom score and asthma control quality score, but they were of questionable clinical significance. The treatment was not without adverse effects: a large percentage of patients had dyspnea, wheezing, cough, chest pain, nighttime awakening, and productive cough in the weeks after the procedure.

Clinical Question:
Does morphine decrease chronic, intractable cough?

Bottom Line:
Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily

Reference:
Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med 2007;175:312-315.

Study Design:
Cross-over trial (randomized)

Synopsis:
Cough is the most common complaint for which medical attention is sought, and chronic cough can be both physically and mentally debilitating. There is currently no evidence supporting the use of antitussives in chronic treatment-resistant cough. The authors tested the hypothesis that morphine sulfate in the dose of 5 mg twice daily would bring about a reduction in cough frequency and severity in patients failing to respond to specific measures. Patients recruited from the Hull Cough Clinic were enrolled into a randomized double-blind placebo-controlled study using 4 weeks of slow-release morphine sulfate and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to 10 mg twice daily. Cough was assessed using the Leicester Cough Questionnaire, daily symptom diary, and citric acid cough challenge. Twenty-seven patients completed the core study. A significant improvement of 3.2 points over baseline was noted on the Leicester Cough Questionnaire (p < 0.01). A rapid and highly significant reduction by 40% in daily cough scores was noted among patients on slow-release morphine sulfate (p < 0.01). Objective testing of the cough reflex using citric acid cough challenge tests did not show any significant changes. Eighteen patients continued into the extension study. Two-thirds of these patients opted to increase the morphine to 10 mg twice daily. At the end of 3 months, there was a similar improvement in cough between the 5- and 10-mg groups.

Clinical Question:
Does montelukast given early in an acute asthma attack in children with intermittent asthma reduce the severity of the attack?

Bottom Line:
Montelukast (Singulair) when given at the first sign of an exacerbation or an upper respiratory infection was slightly better than placebo in reducing health care use and improving symptoms in children with intermittent asthma with 3 to 6 significant exacerbations per year. These children were not taking controller medications. We don’t know if montelukast is better than steroids, or if this approach is effective in children who are taking controller medications.

Reference:
Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-329.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
In children, intermittent asthma is the most common pattern and is responsible for the majority of exacerbations. Montelukast has a rapid onset of action and may be effective if used intermittently. The authors determined whether a short course of montelukast in children with intermittent asthma would modify the severity of an asthma episode. Children, aged 2-14 years with intermittent asthma participated in this multicenter, randomized, double-blind, placebo-controlled clinical trial over a 12-month period. Treatment with montelukast or placebo was initiated by parents at the onset of each upper respiratory tract infection or asthma symptoms and continued for a minimum of 7 days or until symptoms had resolved for 48 hours. A total of 220 children were randomized, 107 to montelukast and 113 to placebo. There were 681 treated episodes (345 montelukast, 336 placebo) provided by 202 patients. The montelukast group had 163 unscheduled health care resource utilizations for asthma compared with 228 in the placebo group (odds ratio, 0.65; 95% confidence interval, 0.47-0.89). There was a nonsignificant reduction in specialist attendances and hospitalizations, duration of episode, and beta-agonist and prednisolone use. Symptoms were reduced by 14% and nights awakened by 8.6% (p = 0.043), and days off from school or childcare by 37% and parent time off from work by 33% (p < 0.0001 for both).

Clinical Question:
Does choosing an initial antibiotic that doesn’t have in vitro activity against the particular strain of pneumococcus affect clinical outcome?

Bottom Line:
The initial discordant treatment with beta-lactam antibiotics was not associated with a statistically significant Increase in mortality or clinical or bacteriological failure of therapy for pneumococcal pneumonia. In limited research, it appears that initial choice of antibiotic for pneumococcal pneumonia is not important. Patients get better even when the bacteria are resistant to the antibiotic.

Reference:
Falagas ME, Siempos II, Bliziotis IA, Panos GZ. Impact of initial discordant treatment with beta-lactam antibiotics on clinical outcomes in adults with pneumococcal pneumonia: a systematic review. Mayo Clin Proc 2006;81:1567-1574.

Study Design:
Meta-analysis (other)

Synopsis:
The authors systematically examine the available evidence regarding the effect of initial discordant therapy with beta-lactam antibiotics on mortality, clinical success, and bacteriological eradication in patients with pneumococcal pneumonia. They analyzed prospective studies that compared the clinical effectiveness of concordant (active in vitro) beta-lactam monotherapy with discordant (inactive in vitro) monotherapy with the same beta-lactam in patients with pneumococcal pneumonia. Relevant studies were identified from searches of the PubMed database (1950 to November 2005) and references from articles. Outcomes between groups of patients who received concordant and discordant treatment were compared by simple pooling of data and by estimation of pooled odds ratios or risk difference (RD), when applicable. Six prospective studies were included in the analysis. No statistically significant difference was found in mortality of patients treated with beta-Iactam concordant and discordant therapy (51/275 [19%] vs 9/42 [21%]; P = .66; data from 6 studies; RD, -0.05; 95% confidence interval [CI], -0.23 to 0.12; data from 5 studies). In addition, no statistically significant difference was found regarding clinical success (37/42 [88%] vs 5/6 [83%]; P = .57; odds ratio, 2.57; 95% CI, 0.46 to 14.34; RD, 0.07; 95% CI, -0.36 to 0.50; data from 3 studies) or bacteriological success (24/30 [80%] vs 3/3 [100%]; P = .99; and RD, -0.18; 95% CI, -0.79 to 0.42; data from 2 studies) between concordant and discordant therapy.

Clinical Question:
Can patients with severe pneumonia be switched to oral therapy after 3 days if clinically stable?

Bottom Line:
Early switch from intravenous to oral antibiotics in patients with severe community acquired pneumonia is safe and decreases length of hospital stay by 2 days. Mortality and cure rates will be the same, and hospital stays may be shorter.

Reference:
Oosterheert JJ, Bonten MJ, Schneider MM, et al. Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial. BMJ 2006;333:1193.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Rather than the usual 7 days of IV treatment, a switch to oral antibiotic treatment after 3 days has been shown to produce similar outcomes while decreasing length of stay in patients hospitalized with community-acquired pneumonia. The authors compared the effectiveness of an early switch to oral antibiotics with the standard 7 day course of intravenous antibiotics in severe community acquired pneumonia. They did a multicentre randomised controlled trial to a five teaching hospitals and 2 university medical centres in the Netherlands. Participants are 302 patients in non-intensive care wards with severe community acquired pneumonia. 265 patients fulfilled the study requirements. Three days of treatment with intravenous antibiotics followed, when clinically stable, by oral antibiotics or by 7 days of intravenous antibiotics. Clinical cure and length of hospital stay are observed, 302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval -3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, -7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively.

Clinical Question:
Is montelukast an effective treatment for allergic rhinitis?

Bottom Line:
Montelukast (Singulair) does have a role to play in the management of patients with allergic rhinitis. Its effects are not as great as those of antihistamines and small compared with topical corticosteroids and it should, therefore, remain a second line agent. When used, consideration should be given to using montelukast in combination with an antihistamine.

High quality evidence remains sparse for the use of montelukast in patients with perennial rhinitis and active asthma. Little evidence exists for the use of montelukast in nasal polyposis. These are areas that require further research, particularly in the UK, where licensing arrangements currently restrict the use of montelukast in these patients.

Reference:
Grainger J, Drake-Lee A. Montelukast in allergic rhinitis: a systematic review and meta-analysis. Clin Otolaryngol 2006;31:360-367.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Montelukast is a leukotriene inhibitor that has become a standard treatment for allergic rhinitis. In this systematic review, the authors did a comprehensive search of the literature and identified 20 randomized controlled trials with blinded outcome assessment of montelukast for the treatment of allergic rhinitis in adults. Twelve studies compared montelukast with placebo, 6 with an antihistamine, and 4 with a topical nasal corticosteroid. Fifteen were parallel group studies with between 38 and 1992 patients; 5 were cross-over studies with between 12 and 37 patients. Montelukast produced a consistent, statistically significant 3.4% decrease in nasal symptom scores. However, a 10% to 15% decrease is considered the minimum clinically significant improvement. The improvement was slightly greater (4.4%) for the subgroup of patients with asthma. Results were similar for those studies that used the same outcome measure (the Rhinosinusitis Quality of Life Questionnaire). Comparisons with fexofenadine 180 mg (Allegra, 1 study) or loratadine 10 mg (Claritin, 5 studies) found a 3% greater improvement in nasal symptom scores for the antihistamine groups compared with montelukast. Topical nasal corticosteroids were also significantly more effective than montelukast (8.4% greater improvement; 95% CI, 6% to 11%). Montelukast plus antihistamine was similarly effective to nasal corticosteroid in 2 studies.