Update on management of bronchiolitis  Suzanne Schuha,b,c  a  b   Research Institute, The Hospital for Sick Children,   Pu...
Management of bronchiolitis Schuh 111use of oximetry is at least in part related to this increase in                      ...
112 Infectious diseases and immunization  seems prudent to investigate a corticosteroid dose con-        atory effort shou...
Management of bronchiolitis Schuh 113                                                            to benefit from given inte...
114 Infectious diseases and immunization  25 Bajaj L, Turner CG, Bothner J. A randomized trial of home oxygen therapy from...
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  1. 1. Update on management of bronchiolitis Suzanne Schuha,b,c a b Research Institute, The Hospital for Sick Children, Purpose of review Division of Paediatric Emergency Medicine and c Department of Paediatrics, University of Toronto, Bronchiolitis impacts millions of infants worldwide. Although several therapeutic options Toronto, Ontario, Canada stem from highly plausible theoretical rationales for success and some may even offer Correspondence to Suzanne Schuh, The Hospital for modest short-term symptom relief, none has been conclusively shown to alter the Sick Children, 555 University Ave., Toronto, ON M5G course of the disease or its major outcomes. However, several recent papers shed light 1X8, Canada Tel: +1 416 813 6239; fax: +1 416 813 5043; on which treatments show promising preliminary evidence and offer insight into future e-mail: suzanne.schuh@sickkids.ca research endeavors on this topic. This review will summarize bronchiolitis therapy in Current Opinion in Pediatrics 2011, 23:110–114 view of this recent evidence. Recent findings The agents in which theory promises but treatment does not deliver include systemic corticosteroids alone, inhaled bronchodilators alone and antileukotrienes. The most promising combination to date appears to be that of oral dexamethasone and inhaled epinephrine but numerous related issues need to be clarified further. Caretakers need to be counselled about the usual protracted clinical course of bronchiolitis. Summary Because bronchiolitis is a highly heterogeneous entity, future research challenges should include detailed characterization of infants most likely to benefit from given interventions. In the meantime, stick with the good old time-honored supportive route! Keywords bronchiolitis, dexamethasone, epinephrine, heliox, respiratory distress Curr Opin Pediatr 23:110–114 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8703 the results of therapeutic trials of bronchiolitis becomes Introduction challenging [14,15]. Bronchiolitis is the leading cause of infant hospitaliz- ations during the first year of life [1]. It is usually defined In 2006, the American Academy of Pediatrics (AAP) as the first viral episode of respiratory distress, accom- released a comprehensive evidence-based guideline on panied by coryza, cough, crepitations and wheezing [2]. the management of bronchiolitis [16]. Since then, two The respiratory syncytial virus (RSV) accounts for the large multicenter bronchiolitis trials have shed light on majority of cases [3], although other important viruses the management with oral dexamethasone with and have also been implicated [4–6]. Several excellent without nebulized epinephrine [17,18] and raised sev- reviews of the etiology and treatment approaches to eral unanswered questions. Furthermore, several recent bronchiolitis have recently been published [7–11], all systematic reviews of various other inhaled therapies of which highlight importance of oxygenation, hydration guide us when these interventions may be effective and airway support if necessary [12,13]. [19–21]. Two recent bronchiolitis papers have clarified predictors of the return for care after discharge from the However, no single pharmacological agent has been emergency department (ED) [22] and highlighted the conclusively found to change the course of the disease. usual protracted course of this disease [9]. This review An important challenge is that bronchiolitis has wide will therefore focus on the update of pharmacotherapy in etiologic heterogeneity, encompassing the only episode bronchiolitis in light of this recent information. of viral-induced wheezing and the first attack of episodic wheezing without atopy/interval symptoms as well as the initial exacerbation of a multitrigger wheeze often associ- Supplemental oxygen ated with asthma [7]. The bad news is that these wheez- Since the invention of routine transcutaneous oxygen ing phenotypes respond differently to treatment [7]. saturation monitoring two decades ago, the hospitaliz- Because it is impossible to reliably identify these sub- ation rate for bronchiolitis has increased 2.5-fold, without groups during their initial presentation, interpretation of increase in mortality [23]. Several authors postulate the 1040-8703 ß 2011 Wolters Kluwer Health | Lippincott Williams Wilkins DOI:10.1097/MOP.0b013e3283425442Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. Management of bronchiolitis Schuh 111use of oximetry is at least in part related to this increase in Key pointsadmissions [24]. The significance of mild hypoxemia withsaturations below 95% as it relates to bronchiolitis out- Systemic corticosteroids alone, inhaled bronchodi-comes has not been specifically studied and the lators alone and anti-leukotrienes do not change thethresholds for administering supplemental oxygen vary clinical course and outcomes in bronchiolitis.widely [25–29]. Indeed, a small difference in oximetry of The most promising therapeutic combination tominimal physiologic significance between 94 and 92% has date may be that of oral dexamethasone and inhaled epinephrine but many issues need to be clarifiedbeen shown on its own to raise postulated hospitalization further.rate from 58 to 85% [24]. Another study showed that Caretakers need to be counselled about the usualapproximately 26% of infants with bronchiolitis experi- protracted clinical course of bronchiolitis.ence prolonged hospital stays based on periodic desatura- Future research should focus on characterization oftions, despite satisfactory clinical status [30,31]. As a infants most likely to benefit from given interven-result of the arbitrary nature of various thresholds for tions.using supplemental oxygen which are likely not cost-effective [31–33], the AAP recommends the use of thisintervention in previously healthy infants with satur- sone and the combination of both with the use of twoations below 90% [16]. Further studies of the impact placebos in 800 previously healthy outpatients withof desaturations and mild hypoxemia on bronchiolitis bronchiolitis in the ED [17]. Although infants in theoutcomes are needed. epinephrine group had achieved significantly lower clinical scores during the initial hour of the study com- pared with those receiving placebo, there was no impactBronchodilators of epinephrine on hospitalization and this interventionBoth nebulized epinephrine and albuterol are commonly was accompanied by more side-effects.given for bronchiolitis, with highly variable frequency[34]. The attractive features of inhaled epinephrine inbronchiolitis include its vasoconstrictive and beta agonist Corticosteroidsproperties [35,36]. Because patients with bronchiolitis are A recent systematic review of 13 trials of 1198 childrena highly heterogeneous group, some of whom may have with bronchiolitis given systemic corticosteroids showedtheir first asthma episode, the AAP guideline recom- no difference in hospitalization, length of hospital stay,mends that a monitored trial of a bronchodilator may clinical scores and readmission rates compared withbe given [16]. However, this guideline strongly advises placebo [42]. The AAP guideline also recommendsagainst routine use of bronchodilators in this disease and against the use of corticosteroids in bronchiolitis [16].recent evidence outlined below certainly points tothis conclusion. Since then, two large multicenter placebo-controlled trials have been carried out [17,18]. The first was aOf the four studies published since 2003 focusing on short- US trial which found that a single high dose of oralterm outcomes after nebulized epinephrine versus albu- dexamethasone conveys no benefit compared withterol/placebo in bronchiolitis [37–40], the largest was a placebo with respect to hospitalizations from the ED,multicenter randomized controlled trial from 2008 which length of stay, return for care or clinical score [18]. Shortlyfound no difference between three consecutive doses of thereafter, the aforementioned Canada-wide study bynebulized albuterol and a single dose of epinephrine [40]. Plint et al. [17] used a factorial design to compare theLikewise, hospitalized infants given nebulized epineph- effect of daily dexamethasone alone, two doses of inhaledrine appear to derive no added benefit compared with epinephrine in the ED alone and the combination of thethose treated with albuterol or placebo [33,41]. A systema- two with using two placebos. Although neither agenttic review [20] showed four of five inpatient studies alone produced any benefit, the authors found that thedemonstrated no benefit of epinephrine over placebo with dexamethasone–epinephrine combination resulted in arespect to the clinical score [20]. Although the authors nine-percentage point reduction in hospitalization withinfound some evidence of short-term clinical benefit of 7 days [17]. The authors postulated this potentialepinephrine over albuterol in the four included outpatient beneficial effect may stem from a synergy between thestudies, epinephrine inferred no advantage with respect to two therapeutic agents. Although this difference mayhospitalization. They recommend a large randomized translate into substantial reduction in hospitalizationscontrolled trial comparing epinephrine with placebo and in the population as a whole, this effect size is relativelysalbutamol in the outpatient setting. modest. Because the effects of the high dose of dexa- methasone used on the brain and lungs of babies areA recent Canada-wide trial compared the impact of two uncertain [43], this treatment cannot be currently recom-doses of nebulized epinephrine, daily oral dexametha- mended without further evidence. For these reasons, itCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. 112 Infectious diseases and immunization seems prudent to investigate a corticosteroid dose con- atory effort should be needed for effective breathing [54]. siderably smaller compared with that used in the study by This may be particularly useful in the ICU setting in Plint. The optimal treatment duration is also unknown, combination with the continuous positive airway pressure and, although a previous small study showed infants management. However, the evidence to date cannot given regular albuterol with a single dose of oral dexa- recommend this intervention for practice. The four stu- methasone achieved outcomes comparable to those given dies performed in this setting are all small, one has no a longer course of corticosteroids, this needs to be verified control group and two lack blinding [55–58]. Although a in a large trial [44]. recent Cochrane Systematic Review on the subject suggests that the addition of heliox may significantly reduce A recent small but worthwhile study clarifies the reasons respiratory distress, heliox appears to show no impact for the lack of benefit of isolated steroid therapy in on the rate of intubation or ventilation or the length of bronchiolitis [45]. The authors showed that dexametha- ICU stay [21]. sone fails to produce anti-inflammatory effect in acute RSV bronchiolitis because it lacks sufficient impact on the production of inflammatory cytokines which play a Antibiotics major role in this disease. Bacteremia rate in febrile infants with bronchiolitis is very low, at 0.2% [59] – much superceded by urinary tract infections and otitis media [60,61]. However, antibiotics Hypertonic saline should only be used when specific evidence of coexistent Both the hypertonic saline and deoxyribonuclease agents bacterial infection is present [16]. work by decreasing viscosity of airway mucus [46– 48,49]. A recently published Cochrane Systematic Review Interestingly, the macrolides appear to have anti-inflam- of four trials [46,50–52] involving 254 infants with acute matory and immunomodulating properties in addition to bronchiolitis found that 3% saline results in a significantly their antibacterial activity. However, the clinical evi- shorter length of hospital stay as well as a lower clinical dence of benefit of this class of drugs in bronchiolitis score [19]. However, none of these studies involved is scarce, with disparate results [62,63]. Infants with infants presenting to the ED. A recent small ED study severe bronchiolitis requiring assisted ventilation have of this population using inhaled hypertonic saline and been found to have surprisingly high bacterial co-infec- epinephrine versus normal saline and epinephrine found tion rate in the tracheal secretions, although to what no difference between these interventions with respect degree this finding contributes to the clinical manifes- to the improvement in the clinical score, oxygen satur- tation is currently not clear [64]. Although this may be a ation, hospitalization and return for care [53]. Likewise, fruitful area of future research in this highly select two inpatient studies of the deoxyribonuclease have population, its results are unlikely to impact the vast demonstrated no benefit [47,48]. Clearly, not enough majority of infants with bronchiolitis. compelling evidence currently exists to recommend the use of mucolytic agents in bronchiolitis and further research is necessary. Ribavirin Although ribavirin produces good in-vitro activity against A recent published review article clarifies the postulated the viruses causing bronchiolitis, more recent studies basic science mechanisms of action involving hypertonic have failed to show its benefit in either the outcomes saline in bronchiolitis [49]. Hypothetically, hypertonic of infants admitted to the ICU or the rate of viral saline may help reverse some of the pathophysiological clearance [65,66]. Because this agent may be teratogenic abnormalities in bronchiolitis by increasing airway sur- and is cumbersome to use, the AAP has recently recom- face thickness, decreasing epithelial edema, improving mended against its routine use [16]. It may be considered elasticity and viscosity of mucus as well as accelerating for immunosuppressed infants and those with hemo- mucus transport rates [49]. Hopefully, the authors’ dynamically significant cardiac disease. highly credible rationale for benefit of this agent on the inflamed airway will translate into clinical effect on major outcomes such as hospitalization in a large rando- Montelukast mized trial. The use of montelukast is another example of where theory promises but treatment does not deliver. Although infants with bronchiolitis have high levels of pro-inflam- Heliox matory leukotrienes in their airway, a recent randomized The mixture of helium and oxygen in an 80 : 20 ratio is controlled trial of oral montelukast in infants under much lighter and less dense than air. Because of associ- 2 years of age with acute bronchiolitis over 6 months ated greater laminar and lower turbulent flow, less respir- failed to reduce subsequent respiratory symptoms [67].Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. Management of bronchiolitis Schuh 113 to benefit from given interventions. In the meantime,Continuous positive airway pressure stick with the good old time-honored supportive route!Infants with progressive hypoxemia and increasingrespiratory distress may require continuous positive air-way pressure support in the ICU setting which constitu-tes an effective mode of airway support for early venti- References and recommended reading Papers of particular interest, published within the annual period of review, havelatory decompensation [68,69] and obviates the been highlighted as: of special interestcomplications associated with intubation and sedation of outstanding interestrequired for children in frank respiratory failure. Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 138–139). 1 Leader S, Kohlhase K. 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[22] conducted a study examin- Crit Care Med 2002; 165:1285–1289.ing predictors of unscheduled medical visits in infants 5 Xepapadaki P, Psarras S, Bossios A, et al. Human Metapneumovirus as awith bronchiolitis discharged home from the ED. They causative agent of acute bronchiolitis in infants. J Clin Virol 2004; 30:267– 270.found that the significant independent predictors of this 6 Jacques J, Moret H, Renois F, et al. Human Bocavirus quantitative DNAoutcome were age less than 2 months, history of pre- detection in French children hospitalized for acute bronchiolitis. J Clin Virolmaturity less than 35 weeks of gestation and history of 2008; 43:142–147.hospitalization [22]. Several years ago, Mansbach et al. 7 Frey U, von Mutius E. The challenge of managing wheezing in infants. N Engl J Med 2009; 360:2130–2133.[71] also found that the factors associated with a safe 8 Vicencio AG. Susceptibility to bronchiolitis in infants. 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N Engl J Med 2009; 360:329–body prophylaxis is recommended for infants 2 years of 338.age and younger with hemodynamically significant con- 15 Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dosegenital heart disease requiring pharmacotherapy, those fluticasone for virus-induced wheezing in young children. N Engl J Med 2009; 360:339–353.suffering from pulmonary hypotension, infants with 16 Diagnosis and management of bronchiolitis. Pediatrics 2006; 118:1774–chronic lung disease or prematurity who required medical 1793.therapy within 6 months of the start of the bronchiolitis 17 Plint AC, Johnson DW, Patel H, et al. Epinephrine and dexamethasone inseason and infants born at or before 32 weeks’ gestation, children with bronchiolitis. N Engl J Med 2009; 360:2079–2089. To date the most definitive trial comparing the two treatments with the greatestparticularly if they are less than 12 months old during potential – dexamethasone and nebulized epinephrine – with two placebos.their first bronchiolitis season [16]. 18 Corneli HM, Zorc JJ, Mahajan P, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med 2007; 357:331–339. 19 Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hyper- tonic saline solution for acute bronchiolitis in infants. Cochrane Database SystConclusion Rev 2008:CD006458.The agents unlikely to impact bronchiolitis outcomes 20 Hartling L, Wiebe N, Russell K, et al. Epinephrine for bronchiolitis. Cochraneinclude systemic corticosteroids alone, inhaled broncho- Database Syst Rev 2004:CD003123.dilators alone and antileukotrienes. The most promising 21 Liet JM, Ducruet T, Gupta V, Cambonie G. Heliox inhalation therapy for bronchiolitis in infants. 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Bronchiolitis management preferences and the influence of pulse oximetry and respiratory rate on theinclude detailed characterization of subjects most likely decision to admit. Pediatrics 2003; 111:e45–e51.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
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Recombinant human evaluated in the emergency department. Pediatrics 2010; 126:285–290. deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis. This article offers invaluable information for counselling caretakers of infants with Chest 2007; 131:788–795. bronchiolitis in the ED. 48 Nasr SZ, Strouse PJ, Soskolne E, et al. Efficacy of recombinant human 71 Mansbach JM, Clark S, Christopher NC, et al. Prospective multicenter study deoxyribonuclease I in the hospital management of respiratory syncytial virus of bronchiolitis: predicting safe discharges from the emergency department. bronchiolitis. Chest 2001; 120:203–208. Pediatrics 2008; 121:680–688.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.