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Original articles: Lena P Thia, Sheila A McKenzie, Tom P Blyth, Caro C Minasian, Wanda J Kozlowska, and Siobhan B Carr Randomised controlled trial of nasal Continuous Positive Airways Pressure (CPAP) in bronchiolitis Arch Dis Child 2007; 0: adc.2005.091231v1 [Abstract]

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Electronic letters published:

Crossover design is not appropriate for CPAP RCT

Daniel K Ng, Chin-pang Wong, Chung-hong Chan   (22 June 2007)

The use of nasal continuous positive pressure in bronchiolitis is standard therapy.

Anami Gour, Martin Gray and Linda Murdoch   (6 February 2008)

Power of numbers vs. number of powers

Roy K Philip, Limerick, Ireland   (5 March 2008)

Crossover design is not appropriate for CPAP RCT 22 June 2007
Daniel K Ng, Consultant Paediatrician MD, FRCP, Chin-pang Wong, Chung-hong Chan Send letter to journal: Re: Crossover design is not appropriate for CPAP RCT dkkng{at}ha.org.hk Daniel K Ng, et al.	Dear Editor, We read with great interest on the article “Randomised controlled trial of nasal Continuous Positive Airways Pressure (CPAP) in bronchiolitis” by Thia et al. 1 because the evidence of CPAP use in patients with acute bronchiolitis has not been very well established. 2 Nevertheless, we have adopted CPAP as standard management in bronchiolitis in our department for severe bronchiolitis for a few years and find CPAP very useful. However, we would like to make a few comments about Thia et al's study. A cross-over trial in a dynamic disease like acute bronchiolitis with respiratory failure required considered justification. 3 Early CPAP use in such patients will definitely cause carry-over effect to the group of patients treated with CPAP first and they will likely to have a better outcome. 4 We used the reported data shown on table 2 of the original article and construct a diagram demonstrating the effect (Figure 1). As shown clearly on the graph, the response to CPAP depended on the timing of CPAP with earlier use better than late use. The current research design cannot answer the research question of Thia et al, i.e. to compare CPAP with ST in the management of bronchiolitis but addressed an alternative research question of early CPAP versus late CPAP in the management of bronchiolitis. The current research design could not compare the efficacy of CPAP to ST unless Thia et al provide some evidence to suggest the effect of first treatment was completely washed out before the second treatment. As seen in figure 2 of the original article, however, it was not likely to be the case. Furthermore, Thia et al. should report the CO2 reduction of the whole CPAP group, i.e. early and late use with that of the whole standard treatment group. Reference: Thia LP, McKenZie SA, Blyth TP, et al. Randomized controlled trial of nasal Continuous postive Airways Pressure (CPAP) in bronchiolitis. Arch Dis Child (In press) Shah PS, Ohlsson A, Shah JP. Continuous negative extrathoracic pressure or continuous positive airway pressure for acute hypoxemic respiratory failure in children (The Cochrane Library 2007, Issue 2) Sibbald B, Roberts C. Understanding controlled trials: Crossover trials. BMJ 1998; 316: 1719-1720. Freeman PR. The performance of the two-stage analysis of two-treatment, two-period crossover trial. Stat Med 1989; 8: 1421-1432. Fig. 1.
The use of nasal continuous positive pressure in bronchiolitis is standard therapy. 6 February 2008
Anami Gour, Consultant Paediatric Intensivist St George's Hospital, Martin Gray and Linda Murdoch Send letter to journal: Re: The use of nasal continuous positive pressure in bronchiolitis is standard therapy. anamigour{at}nhs.net Anami Gour, et al.	We read with interest the recent article by Lena Tia et al1. This article describes a randomised controlled trial with crossover that compares standard treatment with nasal Continuous Positive Airways Pressure (nCPAP) against standard treatment alone in patients with a clinical diagnosis of bronchiolitis. Standard treatment is described as minimal handling, oxygen therapy and intravenous fluids. The conclusion of the study is that patients with a clinical diagnosis of bronchiolitis and a PaCO2 of >6KPa should be considered for nCPAP therapy; although it is acknowledged that further investigation is warranted. We agree with the comments of Daniel Ng in his response to this article and have other issues with the article2. Although there may not be a wealth of literature on the use of nCPAP in infants with bronchiolitis; it is and has been standard treatment internationally for many years and there is observational data supporting it’s use3. The notion that nCPAP is a novel therapy in bronchiolitis and not widely accepted standard therapy is simply not the case. In many units nCPAP is used successfully in both the HDU and PICU setting early in the disease process as an adjunct to standard therapy and in many cases prevents the need to transfer to a level II PICU or intubate the patient. The role of nCPAP in improving ventilation by increasing functional residual capacity as well as helping to relieve expiratory flow limitation of small airways in bronchiolitis is already well established4. What is the value of having the end point as a change in PCO2 of 1kPa? It is widely accepted that conducting a RCT in the paediatric population is extremely difficult when using standard end points such as mortality and the authors have to be applauded for selecting a surrogate endpoint. However, we feel that the end point of a change in PCO2 by 1kPa is not powerful enough to demonstrate a treatment benefit; especially as a number of the patients included in the study will have been patients who have baseline elevated PCO2 due to chronic lung disease. These patients may be demonstrating a shift in PCO2 due to the benefits of nCPAP on their chronic lung disease rather than the acute bronchiolitic episode. It is very difficult to construct a placebo to compare a ventilation strategy with. We acknowledge the challenge the authors faced in designing this study, however to compare nCPAP to no ventilatory support given our understanding of the physiological benefits of extrinsically applied CPAP to patients with small airways obstruction is unjustified. We suggest that although there may not be a robust RCT looking at nCPAP in bronchiolitis there is sufficient observational data to suggest that this therapy should be offered to all patients with bronchiolitis and respiratory failure in the same way that patients with asthma are offered ventilation if and when the clinical condition demands it. References 1. Thia LP, McKenzie SA, Blyth TP, Minasian CC, Kozlowska WJ, Carr SB. Randomised controlled trial of nasal continuous positive airways pressure (CPAP) in bronchiolitis. Arch Dis Child 2008;93(1):45-7. 2. Ng D. Crossover design is not appropriate for CPAP RCT. ADC Online 2007. 3. Beasley JM, Jones SE. Continuous positive airway pressure in bronchiolitis. Br Med J (Clin Res Ed) 1981;283(6305):1506-8. 4. Yang KL, Wang C. An intrinsic positive end-expiratory pressure lung model, with and without flow limitation. Crit Care Med 1996;24(7):1261-5.
Power of numbers vs. number of powers 5 March 2008
Roy K Philip, Consultant Paediatrician Limerick Regional Hospital, Limerick, Ireland Send letter to journal: Re: Power of numbers vs. number of powers roykphilip{at}yahoo.co.uk Roy K Philip, et al.	Power of Numbers vs. Number of Powers In their article, Thia et al attempted to address the potential benefit of nasal continuous positive airway pressure (NCPAP) over currently practiced standard treatment (ST) in the management of infants with bronchiolitis1. After the established use of NCPAP in neonates it is promising to see its value being assessed for the use in infants for one of the commonest causes of respiratory compromise. By restricting their outcome measures to demonstrable and achievable partial pressure of arterial carbon dioxide (Pco2) changes the authors have done justice to the aim of the study. However, a number of clinical and methodological concerns need further reflection prior to applying the authors’ conclusions to clinical application. 1. Duration of illness prior to the commencement of treatment between the two groups is not mentioned (even though a comparison was made to the non-included group). 2. To ‘compare NCPAP with ST’ as stated in the aim is not happening by their applied methodology. It is the comparison of staged introduction of NCPAP during varying phases of bronchiolitis. By not having a group with only standard treatment and no NCPAP, authors have lost a great opportunity to truly demonstrate the clinical value of NCPAP. Their cross over design has influenced the disease process perhaps in both groups. 3. The range of Pco2 from 6 to 12 kPa is so wide in the context of respiratory compromise. Potential value of an intervention could be negligible clinically if 1kPa decrease (as chosen by the authors) is happening from 7 to 6 whereas the same rate of fall could be crucial from 11 to 10 or 10 to 9 especially if the clinical picture also corresponds. Authors’ aim to study the moderately severe bronchiolitis patient group is negated by their inclusion criteria and this is further reflected in the standard deviation (SD) of Pco2 between the two study groups. 4. Authors’ justifications not to include the level of hypoxia, hypoxaemia, apnoeas and worsening respiratory distress, seems to move the study further away from the potential clinical usefulness. 5. Supplemental oxygen used in the study groups could be any amount to give an oxygen saturation (SaO2) above 92%. Perhaps those on NCPAP would have required less FiO2 to maintain SaO2 above 92%. Even when agreeing with the authors’ reasons for not taking FiO2 into account, the complete lack of even a mention on PaO2 anywhere in the article puzzles me. 6. Carefully selected secondary outcome measures gives methodological and statistical credibility to the article. A bronchiolitis severity rating or scoring2 could have added clinical validity as well. 7. Block randomization of four at a time and ‘blinding’ only those who recruited the cases, leaves reasonable room for bias. Perhaps there is a reason, but not evident in the article. Permuted – Block randomization is an appropriate tool in this clinical setting however a stratified analysis with blocks as strata would have properly controlled type I error and hence provide the optimal power to detect a possible treatment effect. 8. Power of numbers is demonstrated in a table depicting the expected fall of 1kPa in the NCPAP group. Authors did not consider it unreasonable to add -1.35 and +0.5 to get a difference of -1.85 of Pco2 fall thus getting the p-value. The reality is whatever illness modification was achieved by the initial NCPAP drastically changed when standard treatment was commenced. Ironically there is enough room to argue the safety and efficacy of standard treatment with oxygen and fluid management, as during the 12 hours of standard treatment Pco2 actually decreased by 0.53 (not climbed). 9. Our 3 year review of 21 infants with bronchiolitis managed with NCPAP, as an add-on treatment when clinically indicated, showed that the maximum sustained reduction of Pco2 and improvement of Po2 was in those with chest X-ray changes of collapse / consolidation rather than just uniform hyperinflation. Physiologically also such patients would be more comparable to neonatal respiratory distress syndrome(RDS) and adult respiratory distress syndrome (ARDS). Was chest X-rays performed or analysed in Thia et al study? 10. One mode of action of NCPAP as suggested in the article, based on a previous publication3 analysing a different patient population, by decreasing functional residual capacity seems physiologically not plausible. Perhaps it is increasing the functional residual capacity as in neonatal RDS. This mode of action was reflected in the subgroup of our patient population with volume loss on chest X-ray. As bronchiolitis is a common infantile morbidity with relative sparsity of evidence based treatments, a multi-centre study as suggested by the authors need to be taken seriously by the paediatric community. Hope my intention for combing the article to bring out clinical concerns for an open discussion would be positively received. Authors’ chose the path of ‘power of numbers’ (1kPa) perhaps an approach of ‘number of powers’ (standard treatment only arm) would have had the potential to convert this work to a landmark paediatric respiratory study. References 1. Thia LP, McKenzie SA, Blyth PB, et al. Randomised control trial of nasal continuous positive airway pressure (CPAP) in Bronchiolitis. Arch Dis Child 2008;93:45-47. 2. Willson DF, Horn SD, Smout R, et al. Severity assessment in Children hospitalized with Bronchiolitis using the Pediatric component of the Comprehensive Severity Index. Pediatr Crit Care Med 2000;1(2):127-32. 3. Duncan AN, Oh IE, Hillman DR. PEEP and CPAP. Anaesth Intensive Care 1986;14(3):236-50.