Francine M. Ducharme

Should inhaled anticholinergics be added to β2 agonists for treating acute childhood and adolescent asthma? A systematic review

Abstract Objectives To estimate the therapeutic and adverse effects of addition of inhaled anticholinergics to β2 agonists in acute asthma in children and adolescents. Design Systematic review of randomised controlled trials of children and adolescents taking β2 agonists for acute asthma with or without the addition of inhaled anticholinergics. Main outcome measures Hospital admission, pulmonary function tests, number of nebulised treatments, relapse, and adverse effects. Results Of 37 identified trials, 10 were relevant and six of these were of high quality. The addition of a single dose of anticholinergic to β2 agonist did not reduce hospital admission (relative risk 0.93, 95% confidence interval 0.65 to 1.32). However, significant group differences in lung function supporting the combination treatment were observed 60 minutes (standardised mean difference −0.57, −0.93 to −0.21) and 120 minutes (−0.53, −0.90 to −0.17) after the dose of anticholinergic. In contrast, the addition of multiple doses of anticholinergics to β2 agonists, mainly in children and adolescents with severe exacerbations, reduced the risk of hospital admission by 30% (relative risk 0.72, 0.53 to 0.99). Eleven (95% confidence interval 5 to 250) children would need to be treated to avoid one admission. A parallel improvement in lung function (standardised mean difference −0.66, −0.95 to −0.37) was noted 60 minutes after the last combined inhalation. In the single study where anticholinergics were systematically added to every β2 agonist inhalation, irrespective of asthma severity, no group differences were observed for the few available outcomes. There was no increase in the amount of nausea, vomiting, or tremor in patients treated with anticholinergics. Conclusions Adding multiple doses of anticholinergics to β2 agonists seems safe, improves lung function, and may avoid hospital admission in 1 of 11 such treated patients. Although multiple doses should be preferred to single doses of anticholinergics, the available evidence only supports their use in school aged children and adolescents with severe asthma exacerbation.

Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence

Abstract Objectives: To examine the evidence for the efficacy and glucocorticoid sparing effect of oral anti-leukotrienes taken daily as add-on therapy to inhaled glucocorticoids in patients with asthma. Design: Systematic review of randomised controlled trials of children and adults with asthma comparing the addition of anti-leukotrienes or placebo to inhaled glucocorticoids. Main outcome measures: The rate of exacerbations of asthma requiring rescue systemic glucocorticoids when the intervention was compared to the same or double dose of inhaled glucocorticoids, and the glucocorticoid sparing effect when the intervention was aimed at tapering the glucocorticoid. Results: Of 376 citations, 13 were included: 12 in adult patients and one in children. The addition of licensed doses of anti-leukotrienes to inhaled glucocorticoids resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids (two trials; relative risk 0.61, 95% confidence interval 0.36 to 1.05). No trials comparing the use of anti-leukotrienes with double the dose of inhaled glucocorticoids could be pooled. The use of anti-leukotrienes resulted in no overall group difference in the lowest achieved dose of inhaled glucocorticoids (three trials; weighted mean difference −44.43 μg/day, −147.87 to 59.02: random effect model) but was associated with a reduction in withdrawals owing to poor asthma control (four trials; relative risk 0.56, 0.35 to 0.89). Conclusions: The addition of anti-leukotrienes to inhaled glucocorticoids may modestly improve asthma control compared with inhaled glucocorticoids alone but this strategy cannot be recommended as a substitute for increasing the dose of inhaled glucocorticoids. The addition of anti-leukotrienes is possibly associated with superior asthma control after tapering of glucocorticoids, but the glucocorticoids sparing effect cannot be quantified at present. What is already known on this topic Anti-leukotrienes are increasingly being used as add-on therapy to inhaled glucocorticoids No systematic review of randomised controlled trials has examined the evidence to support this treatment strategy What this study adds There is a shortage of relevant trials testing anti-leukotrienes at licensed doses as add-on therapy to inhaled glucocorticoids in patients, particularly children

Do Systemic Corticosteroids Effectively Treat Obstructive Sleep Apnea Secondary to Adenotonsillar Hypertrophy

To determine if pediatric obstructive sleep apnea syndrome (OSAS) caused by adenotonsillar hypertrophy (ATH) could be treated by a short course of systemic corticosteroids, we conducted an openlabel pilot study in which standardized assessments of symptomatology, OSAS severity, and adenotonsillar size were performed before and after a 5‐day course of oral prednisone, 1.1 ± 0.1(± SE) mg/kg per day. Outcome measures included symptom severity, adenotonsillar size, and polysomnographic measures of OSAS. Selection criteria included age from 1 to 12 years, ATH, symptomatology suggesting OSAS, an apnea/hypopnea index (AHI) ≥ 3/hour, and intent to perform adenotonsillectomy. Only one of nine children showed enough improvement to avoid adenotonsillectomy. Symptomatology did not improve after corticosteroid treatment but did after removal of tonsils and adenoids. Polysomnographic indices of OSAS severity did not improve after corticosteroid treatment. After corticosteroids, tonsillar size decreased in only two patients, adenoidal size was only marginally reduced, and the size of the nasopharyngeal airway was not significantly increased. These results suggest that a short course of prednisone is ineffective in treating pediatric OSAS caused by ATH.

Pulse oximetry: Accuracy of methods of interpreting graphic summaries

Although pulse oximetry has been used to determine the frequency and extent of hemoglobin desaturation during sleep, movement artifact can result in overestimation of desaturation unless valid desaturations can be identified accurately. Therefore, we determined the accuracy of pulmonologists and technicians interpretations of graphic displays of desaturation events, derived an objective method for interpreting such events, and validated the method on an independent data set. Eighty‐seven randomly selected desaturation events were classified as valid (58) or artifactual (29) based on cardiorespiratory recordings (gold standard) that included pulse waveform and respiratory inductive plethysmography signals. Using oximetry recordings (test method), nine pediatric pulmonologists and three respiratory technicians (“readers”) averaged 50 ± 11% (SD) accuracy for event classification. A single variable, the pulse amplitude modulation range (PAMR) prior to desaturation, performed better in discriminating valid from artifactual events with 76% accuracy (P < 0.05). Following a seminar on oximetry and the use of the PAMR method, the readers accuracy increased to 73 ± 2%. In an independent set of 73 apparent desaturation events (74% valid, 26% artifactual), the PAMR method of assessing oximetry graphs yielded 82% accuracy; transcutaneous oxygen tension records confirmed a drop in oxygenation during 49 of 54 (89%) valid desaturation events. In conclusion, the most accurate method (91%) of assessing desaturation events requires recording of the pulse and respiratory waveforms. However, a practical, easy‐to‐use method of interpreting pulse oximetry recordings achieved 76–82% accuracy, which constitutes a significant improvement from previous subjective interpretations. Pediatr Pulmonol. 1996; 21:121–131.

Clinical decisionmaking based on venous versus capillary blood gas values in the well-perfused child.

STUDY OBJECTIVEnIn children aged 1 month to 18 years, we sought to examine the correlation between venous and arterialized capillary blood gas values, and to determine whether the source of blood sample influenced the interpretation of the acid-base status and clinical management.nnnMETHODSnIn a cross-sectional study, venous and capillary blood gas values were simultaneously obtained in acutely ill well-perfused patients treated in a pediatric emergency department. Intraclass correlation coefficients for capillary and venous measured gas values were calculated. Crude agreement and intraobserver concordance were calculated for responses of 2 intensivists to the interpretation and clinical management questions, based on capillary and venous gas results.nnnRESULTSnIntraclass correlation coefficients for 78 capillary and venous paired measured gas values were.92 (pH), .80 (PCO 2 ), and .67 (PO 2 ). The alpha of concordance values between capillary and venous blood gas values, with 95% confidence intervals (CIs) were as follows, respectively, for physician A and B: interpretation, .61 (.47 to .73) and .48 (.41 to .55); need for bicarbonate,.85 (.73 to.97) and.80 (.72 to.88); and need for intubation .73 (.64 to .82), and .83 (.75 to .91).nnnCONCLUSIONnIn the well-perfused patient, we believe that venous samples are an acceptable alternative to capillary blood samples for determination of blood gas values and for making clinical management decisions.

Cost effectiveness analysis of inhaled anticholinergics for acute childhood and adolescent asthma.

A recent systematic review by the Cochrane Airways Group showed that adding multiple doses of anticholinergics to β2 agonists is safe and effective in improving lung function and avoiding hospital admission for school aged children and adolescents attending casualty departments with severe acute asthma.1 The estimated reduction in the risk of admission was 9.4% (0.4% to 18.4%). This intervention presumably improves bronchodilatation until systemic corticosteroids take effect. Evidence of cost effectiveness, however, is lacking. To clarify whether scarce healthresources should be spent on this intervention we conducted an economic evaluation.nnWe used various assumptions to estimate the financial implications of treatment (see table on the BMJ s website). The costs of drug administration were not included, as anticholinergics are always given with β2 agonists and involvelittle additional manipulation. The cost of nebulisers, other drugs, and the casualty attendance were also excluded. No consideration was given to possible changes in length of stay in casualty. …

Management of acute bronchiolitis.

Inhaled adrenaline shows promise in outpatients, but treatment for inpatients remains unclear

Intramuscular versus oral methylprednisolone in asthma

Recently, Michael Lahn and colleagues published a well designed parallel-group, randomised trial evaluating two routes of administration (oral vs intramuscular) of the same cumulative dose (160 mg) of dexamethasone for asthma. The primary outcome was relapse, determined by phone contact at 10 days; secondary outcomes included relapse at 21 days and side-effects at the intramuscular injection site. The study was powered for detection of a massive (70%) difference in relapse rate at 10 days, from 19% to 5%. The observed relapse rate at 10 days was 14·1% with the intramuscular injection and 13·6% with the oral preparation. While acknowledging that the power of the study was insufficient to prove equivalence, the authors concluded that intramuscular dexamethasone might serve as a substitute for an 8-day oral course of dexamethasone when poor compliance is a consideration. We must consider several important methodological issues before we adopt this strategy for patients with asthma. First, can we assume equivalence? The reader naturally tends to assume that intramuscular and oral administration are equivalent because of the negligible (0·5%) group difference in relapse rate at 10 days. Lahn and colleagues rightfully warned against such interpretation because the sample of 190 patients could not exclude a relapse rate as much as 10% higher (24%) or lower ( 4%) in the intramuscular group compared with the oral group. For the two options to be considered equivalent, we would need to rule out a much smaller group difference in relapse rate (perhaps in the order of a 5% absolute difference). However, such a study would require a much larger sample size (>1000 patients per group). Although relapse is certainly clinically important to patients, physicians, hospital administrators, and policymakers, this outcome happens in less than 15% of patients at 10 days (or 20% at 21 days). Without other data, should we assume that the remaining 80–85% of patients did similarly well in terms of daytime symptoms, night-time awakenings, return to regular activities, quality of life, and use of rescue 2 agonists, irrespective of the treatment they received? Although studies neglecting the traditional array of secondary outcomes are obviously easier to do, they fail to provide sufficient details to show how well patients who did not experience the primary outcome recovered. Was the study designed for a fair comparison? Both groups received the same cumulative dose of dexamethasone; superficially, this would seem to be fair. The pharmacokinetics of oral steroids, however, lead to about 60% absorption while close to 100% is assumed for intramuscular injection. Does this imply that the oral group received about 40% less medication? Given the efficacy of corticosteroids in acute asthma, one could easily argue that the exact dose of corticosteroids is less important than the fact of receiving the agent. Nonetheless, there were three imbalances in potentially important confounders between groups of patients that together might have influenced the results in unclear directions: the intramuscular group had fewer males, fewer patients with previous intubation, and more users of inhaled steroids. The analysis did not account for these group differences, which reduces confidence in these final results. Should this research change clinical practice? Many clinicians would infer from Lahn and colleagues’ study that long-acting intramuscular corticosteroids are as effective as prednisone, an intermediate-acting corticosteroid that is the commonly used oral preparation. It is difficult to conclude that intermediate-acting preparations worked better or worse than long-acting ones, so the question remains unanswered. At least a few additional trials should be represented in this discussion. Perhaps a systematic review derived from a comprehensive search strategy and aggregated in meta-analysis might more clearly answer this question. An efficacy study is done in ideal research conditions that favour adherence to treatment and follow-up. An effectiveness trial attempts to closely resemble real-life where, among other issues, adherence and follow-up might not be complete. In certain cases, an efficacy analysis is done that only considers patients who were adherent to medication and available for assessment of outcome. In Lahn and colleagues’ study, adherence was only reported for the intra-

Leukotriene receptor antagonists as first line or add-on treatment for asthma.

Have lower efficacy but similar effectiveness to inhaled corticosteroids

SYSTEMIC CORTICOSTEROIDS DO NOT EFFECTIVELY TREAT OBSTRUCTIVE SLEEP APNEA(OSA) DUE TO ADENOTONSILLAR HYPERTROPHY (ATH). 768

There is a reason to suspect that pediatric OSA due to ATH could be treated by a short course of systemic steroids. For instance, steroids can reduce tonsillar size in infectious mononucleosis. We therefore performed assessments of symptomatology, ATH, and OSA severity before and after a 5 day course of 1 mg/kg/day of oral prednisone in 9 children (6 girls). Selection criteria included age 1-11 years, a mixed/obstructive apnea/hypopnea index (MOAHI) of≥ 3/hr, ATH, symptoms suggesting OSA, and intent to perform adenotonsillectomy. Before and after steroid treatment, physical and radiographic exams documented ATH, and home polysomnography (Ped Pul 20:241-52, 1995) and a questionnaire based OSA score (J. Ped. 105:10-14, 1984) documented severity of OSA. RESULTS. Only one child showed enough improvement to avoid operation. Clinical symptomatology did not improve after steroid treatment but did after removal of tonsils and/or adenoids: OSA score (x± SD), 1.8 ± 2.2 vs 1.5 ± 2.2 vs -2.7 ± 1.6, p<.01. Polysomnographic indices of OSA severity did not improve after steroid treatment: MOAHI, 13.9 ± 15.2 vs 9.9 ± 7.1, p=0.29. Tonsillar size decreased in only two patients; adenoid size was marginally reduced after steroids: adenoid/nasopharyngeal ratio,.69 ±.10 vs.63±.09, p=.05. CONCLUSIONS. These results suggest that a larger, double-blind placebo controlled trial of systemic corticosteroids is not warranted. However, recent data (Peds 95:355-64, 1995) suggest that a longer course of nasal steroids might reduce adenoidal size, improve symptomatology, and decrease OSA severity. Support: The Hospital for Sick Children Foundation.