Trials and Tribulations in Bronchiolitis

Abstract

See related article, p 17 See related article, p 17 Coronavirus disease times aside, children with viral bronchiolitis fill the hospital wards and pediatric intensive care units (PICUs) each winter.1Zee-Cheng J.E. McCluskey C.K. Klein M.J. Scanlon M.C. Rotta A.T. Shein S.L. et al.Changes in pediatric ICU utilization and clinical trends during the coronavirus pandemic.Chest. 2021; 160: 529-537Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In many parts of the world, this burden is increasingly found in the PICU, in particular among children supported by non-invasive respiratory support like high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP).2Schlapbach L.J. Straney L. Gelbart B. Alexander J. Franklin D. Beca J. et al.Burden of disease and change in practice in critically ill infants with bronchiolitis.Eur Respir J. 2017; 49Crossref PubMed Scopus (68) Google Scholar, 3Linssen R.S. Bem R.A. Kapitein B. Rengerink K.O. Otten M.H. den Hollander B. et al.Burden of respiratory syncytial virus bronchiolitis on the Dutch pediatric intensive care units.Eur J Pediatr. 2021; 180: 3141-3149Crossref PubMed Scopus (5) Google Scholar, 4Slain K.N. Malay S. Shein S.L. Hospital charges associated with critical bronchiolitis from 2009 to 2019.Pediatr Crit Care Med. 2022; 23: 171-180Crossref PubMed Scopus (3) Google Scholar The treatment of critical bronchiolitis varies widely between centers and clinicians, and evidenced-based treatment guidelines primarily focus on patients cared for on general wards, in emergency departments, or at home.5Essouri S. Baudin F. Chevret L. Vincent M. Emeriaud G. Jouvet P. Variability of care in infants with severe bronchiolitis: less-invasive respiratory management leads to similar outcomes.J Pediatr. 2017; 188: 156-162 e1Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 6Shein S.L. Kong M. McKee B. O'Riordan M. Toltzis P. Randolph A.G. Antibiotic prescription in young children with respiratory syncytial virus-associated respiratory failure and associated outcomes.Pediatr Crit Care Med. 2019; 20: 101-109Crossref PubMed Scopus (10) Google Scholar, 7Ralston S.L. Lieberthal A.S. Meissner H.C. Alverson B.K. Baley J.E. Gadomski A.M. et al.Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.Pediatrics. 2014; 134: e1474-e1502Crossref PubMed Scopus (872) Google Scholar, 8NICEBronchiolitis in children: diagnosis and management.www.nice.org.uk/guidance/ng9Date: 2021Date accessed: February 15, 2022Google Scholar This lack of consensus and expert guidance likely stems from inadequate evidence identifying therapies that improve (or do not improve) the outcomes of critical bronchiolitis. There have been few large, randomized trials in critical bronchiolitis and some that predate the era of widespread HFNC and CPAP may be less applicable to contemporary care.9Plint A.C. Johnson D.W. Patel H. Wiebe N. Correll R. Brant R. et al.Epinephrine and dexamethasone in children with bronchiolitis.N Engl J Med. 2009; 360: 2079-2089Crossref PubMed Scopus (203) Google Scholar, 10Milesi C. Essouri S. Pouyau R. Liet J.M. Afanetti M. Portefaix A. et al.High flow nasal cannula (HFNC) versus nasal continuous positive airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (TRAMONTANE study).Intensive Care Med. 2017; 43: 209-216Crossref PubMed Scopus (139) Google Scholar, 11Milesi C. Pierre A.F. Deho A. Pouyau R. Liet J.M. Guillot C. et al.A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2).Intensive Care Med. 2018; 44: 1870-1878Crossref PubMed Scopus (44) Google Scholar, 12van Woensel J.B. Vyas H. Group S.T. Dexamethasone in children mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus: a randomized controlled trial.Crit Care Med. 2011; 39: 1779-1783Crossref PubMed Scopus (29) Google Scholar, 13Wu S. Baker C. Lang M.E. Schrager S.M. Liley F.F. Papa C. et al.Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial.JAMA Pediatr. 2014; 168: 657-663Crossref PubMed Scopus (68) Google Scholar, 14Buckingham S.C. Jafri H.S. Bush A.J. Carubelli C.M. Sheeran P. Hardy R.D. et al.A randomized, double-blind, placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: effects on RSV quantity and clinical outcome.J Infect Dis. 2002; 185: 1222-1228Crossref PubMed Scopus (95) Google Scholar, 15van Woensel J.B. van Aalderen W.M. de Weerd W. Jansen N.J. van Gestel J.P. Markhorst D.G. et al.Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus.Thorax. 2003; 58: 383-387Crossref PubMed Scopus (64) Google Scholar Coupled with increasing costs and risks of post-PICU morbidity, robust studies to guide the care of critical bronchiolitis are urgently needed.16Shein S.L. Slain K.N. Clayton J.A. McKee B. Rotta A.T. Wilson-Costello D. Neurologic and functional morbidity in critically ill children with bronchiolitis.Pediatr Crit Care Med. 2017; 18: 1106-1113Crossref PubMed Scopus (20) Google Scholar,17Shein S.L. Roth E. Pace E. Slain K.N. Wilson-Costello D. Long-term neurodevelopmental and functional outcomes of normally developing children requiring PICU care for bronchiolitis.J Pediatr Intensive Care. 2021; 10: 282-288Crossref PubMed Google Scholar In that light, the new trial published in this volume of The Journal is a welcome addition. Building off a 2009 Canadian trial of 800 emergency department patients with bronchiolitis in which combination therapy with systemic corticosteroids and inhaled epinephrine was associated with decreased hospitalization (although statistical significance was lost after adjustment for multiple comparisons), Gelbart et al randomized 210 PICU patients less than 18 months old with bronchiolitis to systemic corticosteroids and inhaled epinephrine or to routine care.9Plint A.C. Johnson D.W. Patel H. Wiebe N. Correll R. Brant R. et al.Epinephrine and dexamethasone in children with bronchiolitis.N Engl J Med. 2009; 360: 2079-2089Crossref PubMed Scopus (203) Google Scholar,18Gelbart B. McSharry B. Delzoppo C. Erickson S. Lee K. Butt W. et al.Pragmatic randomized trial of corticosteroids and inhaled epinephrine for bronchiolitis in children in intensive care.J Pediatr. 2004; 244: 17-23.e1Abstract Full Text Full Text PDF Scopus (1) Google Scholar All but 1 child was treated with HFNC, CPAP, or invasive mechanical ventilation, termed positive pressure support (PPS) by the authors. As a pragmatic study, there was no explicit study protocol beyond the main intervention, and placebos were regrettably deemed infeasible. The primary outcome, the duration of PPS, was reduced in the treatment arm from a geometric mean of 39.9 hours (95% CI, 33.6-47.4 hours) to 26.4 hours (95% CI, 21.8-31.8 hours), with an adjusted ratio of 0.66 (95% CI, 0.51-0.84). Subgroup analyses show this effect primarily occurred in children infected with respiratory syncytial virus and those without chronic lung disease. Time until “ready for” PICU discharge was also decreased (adjusted ratio of 0.74; 95% CI, 0.61-0.91). There was no increase in adverse events, but also no improvement in actual length of stay in the PICU or hospital. At face value, this is a major advance in the field. If duration of PPS could be decreased by one-third on a large scale, overall PICU use, hospital costs, and length of stay would decrease markedly, especially in centers where low levels of HFNC are used on the general wards. As a multicenter study randomizing a cohort larger than many prior studies in the field with broad inclusion criteria, these results should be widely generalizable.19Davison C. Ventre K.M. Luchetti M. Randolph A.G. Efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis.Pediatr Crit Care Med. 2004; 5: 482-489Crossref PubMed Scopus (88) Google Scholar However, because the devil typically takes up residence in the details, some attention to the specifics of this trial is warranted before applying this treatment strategy to all children with critical bronchiolitis. Although the duration of PPS is “measurable and clinically meaningful” as stated by the authors and a reasonable choice for primary outcome, it was unfortunately determined by the moment-to-moment decisions of clinicians without a study-wide protocol or guidance beyond a suggestion to maintain an oxygen saturation of 92% or more. Clinicians wean PPS more slowly when they are doing so on their own compared with protocolized care. Ventilator weaning protocols and standardized extubation readiness trials can decrease the duration of invasive mechanical ventilation, which was used in 11% of the study subjects with wide variance in duration.20Mehta S.D. Martin K. McGowan N. Dominick C.L. Madu C. Denkin B.K. et al.Ventilator-weaning pathway associated with decreased ventilator days in pediatric acute respiratory distress syndrome.Crit Care Med. 2021; 49: 302-310Crossref PubMed Scopus (3) Google Scholar The lack of an explicit weaning protocol may be even more problematic for the 88% of subjects treated with HFNC during the trial, because clinicians wean HFNC more slowly when not using objective assessments to prompt weaning or discontinuation.21Betters K.A. Hebbar K.B. McCracken C. Heitz D. Sparacino S. Petrillo T. A novel weaning protocol for high-flow nasal cannula in the PICU.Pediatr Crit Care Med. 2017; 18: e274-e280Crossref PubMed Scopus (17) Google Scholar,22Peterson R.J. Hassumani D.O. Hole A.J. Slaven J.E. Tori A.J. Abu-Sultaneh S. Implementation of a high-flow nasal cannula management protocol in the pediatric ICU.Respir Care. 2021; 66: 591-599Crossref PubMed Scopus (4) Google Scholar This point may be particularly true when the clinician knows their patient is not receiving corticosteroids and inhaled epinephrine and feels the need to “just do something.” The urge to do something is prevalent enough that it underpins the Society of Critical Care Medicine’s Choosing Wisely campaign and similar deimplementation efforts. Moreover, HFNC “became routine just as the trial started,” so clinicians by definition did not have considerable experience with it during the study. It is both intuitive and evidence based and, thus, likely that clinicians were inclined to just do something (maintain or escalate HFNC, escalate to CPAP) for children in the standard care arm. When children with bronchiolitis in French PICUs were randomized to HFNC in 2014-2015, 51% of the patients were declared to have failed HFNC by unblinded clinicians and switched to CPAP.10Milesi C. Essouri S. Pouyau R. Liet J.M. Afanetti M. Portefaix A. et al.High flow nasal cannula (HFNC) versus nasal continuous positive airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (TRAMONTANE study).Intensive Care Med. 2017; 43: 209-216Crossref PubMed Scopus (139) Google Scholar Two years later, the same research group used nearly identical inclusion criteria to again randomize to the same level of HFNC.11Milesi C. Pierre A.F. Deho A. Pouyau R. Liet J.M. Guillot C. et al.A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2).Intensive Care Med. 2018; 44: 1870-1878Crossref PubMed Scopus (44) Google Scholar This time, the failure rate was 39% and only 35% received CPAP (or intubation), a 30% relative decrease, leading the principal investigator to conclude that results from the first study may be different if it was repeated now that “clinicians gained experience with HFNC … [and] confidence with this relatively new device.”23Shein S.L. Slain K.N. Rotta A.T. Milesi C. Cambonie G. High-flow nasal cannula flow rate in young infants with severe viral bronchiolitis: the question is still open.Intensive Care Med. 2019; 45: 134-135Crossref PubMed Scopus (3) Google Scholar The lack of protocolized determination of the primary outcome makes the absence of a placebo even more problematic. Unblinded studies are at severe risk of bias on the part of treating clinicians, including for nominally “objective” endpoints like mortality.24Martin G.L. Trioux T. Gaudry S. Tubach F. Hajage D. Dechartres A. Association between lack of blinding and mortality results in critical care randomized controlled trials: a meta-epidemiological study.Crit Care Med. 2021; 49: 1800-1811Crossref PubMed Scopus (3) Google Scholar This raises the concern that less objective endpoints, such as non-protocolized duration of PPS, also suffer from bias. The lack of a placebo control for inhaled epinephrine was justified by the authors by the potential efficacy of inhaled normal saline, the potential harm of inhaled water, and the desire to compare the intervention with “usual care” without nebulized therapy. These concerns have some merit, but they increase the potential for bias. The use of inhaled and systemic placebo is both feasible and preferable and has precedent in the aforementioned Canadian trial of 800 infants.9Plint A.C. Johnson D.W. Patel H. Wiebe N. Correll R. Brant R. et al.Epinephrine and dexamethasone in children with bronchiolitis.N Engl J Med. 2009; 360: 2079-2089Crossref PubMed Scopus (203) Google Scholar Although harmful placebos (inhaled water) are not defensible, the use of an inert (or possibly “efficacious”) placebo definitely is, particularly when there is no current therapy that constitutes an accepted best practice. It is also important to note that the role of placebo control is not to offer the best possible individual therapy to a trial participant; rather, it is a methodologic design to improve the reliability of the trial results. If uncertainty remains regarding these points, then one could consider a 3-arm trial, with separate arms for intervention, placebo, and usual care. Overall, the lack of placebo blinding and the absence of an explicit de-escalation protocol could bias the trial towards favoring the intervention with an over-enthusiastic effect size. Although some of this process has been framed as necessary to maintain the pragmatic nature of this trial, it precludes the reflexive, widespread adoption of this therapy in clinical practice at this time. This caveat does not eliminate our enthusiasm for these results or mean that clinicians should never use combination therapy with inhaled epinephrine and corticosteroids. Rather, bedside providers should consider the pros and cons of this strategy for each individual child, perhaps avoiding an impulse to “just do something” in a stably critically ill child, but considering it in a worsening child in hopes of preventing an escalation in respiratory support. Furthermore, the authors should be congratulated for successfully randomizing a large number of children with critical bronchiolitis, finishing enrollment ahead of schedule, and focusing on an outcome that should be clinically meaningful and feasible to improve. The lessons of this trial, including the potential for benefit and no evidence of harm, should prompt design of a more definitive trial which could change practice and improve outcomes of the most common PICU condition. Until then, we are all still left somewhat flying blind. Pragmatic Randomized Trial of Corticosteroids and Inhaled Epinephrine for Bronchiolitis in Children in Intensive CareThe Journal of PediatricsVol. 244PreviewTo determine whether the combination of systemic corticosteroids and nebulized epinephrine, compared with standard care, reduces the duration of positive pressure support in children with bronchiolitis admitted to intensive care. Full-Text PDF