Abstract: We included seven trials involving 447 infants younger than two years with respiratory distress secondary to viral bronchiolitis. All children were recruited from a paediatric intensive care unit (PICU; 378 infants), except in one trial (emergency department; 69 infants). All children were younger than two (under nine months in two trials and under three months in one trial). Positive tests for respiratory syncytial virus (RSV) were required for inclusion in five trials. The two other trials were carried out in the bronchiolitis seasons. Seven different protocols were used for inhalation therapy with heliox. When heliox was used in the PICU, we observed no significant reduction in the rate of intubation: risk ratio (RR) 2.73 (95% confidence interval (CI) 0.96 to 7.75, four trials, 408 infants, low quality evidence). When heliox inhalation was used in the emergency department, we observed no increase in the rate of discharge: RR 0.51 (95% CI 0.17 to 1.55, one trial, 69 infants, moderate quality evidence). There was no decrease in the length of treatment for respiratory distress: mean difference (MD) -0.19 days (95% CI -0.56 to 0.19, two trials, 320 infants, moderate quality evidence). However, in the subgroup of infants who were started on nasal continuous positive airway pressure (nCPAP) right from the start, because of severe respiratory distress, heliox therapy reduced the length of treatment: MD -0.76 days (95% CI -1.45 to -0.08, one trial, 21 infants, low quality evidence). No adverse events related to heliox inhalation were reported. We found that infants treated with heliox inhalation had a significantly lower mean clinical respiratory score in the first hour after starting treatment when compared to those treated with air or oxygen inhalation: MD -1.04 (95% CI -1.60 to -0.48, four trials, 138 infants, moderate quality evidence). This outcome had statistical heterogeneity, which remained even after removing the study using a standard high-concentration reservoir mask. Several factors may explain this heterogeneity, including first the limited number of patients in each trial, and the wide differences in the baseline severity of disease between studies, with the modified Wood Clinical Asthma Score (m-WCAS) in infants treated with heliox ranging from less than two to more than seven. Current evidence suggests that the addition of heliox therapy may significantly reduce a clinical score evaluating respiratory distress in the first hour after starting treatment in infants with acute RSV bronchiolitis. We noticed this beneficial effect regardless of which heliox inhalation protocol was used. Nevertheless, there was no reduction in the rate of intubation, in the rate of emergency department discharge, or in the length of treatment for respiratory distress. Heliox could reduce the length of treatment in infants requiring CPAP for severe respiratory distress. Further studies with homogeneous logistics in their heliox application are needed. Inclusion criteria must include a clinical severity score that reflects severe respiratory distress to avoid inclusion of children with mild bronchiolitis who may not benefit from heliox inhalation. Such studies would provide the necessary information as to the appropriate place for heliox in the therapeutic schedule for severe bronchiolitis.

Plain-language summary: We retrieved seven trials involving 447 infants requiring hospitalisation for marked breathing difficulties. Six trials recruited infants from paediatric intensive care units and one trial from the emergency department. Four trials were supported in part by unrestricted grants from a manufacturer with a commercial interest in the results. The evidence is current to March 2015. Pooled results failed to demonstrate a reduction in the rate of emergency department discharge, in the rate of intubation to achieve respiratory support, or in the length of respiratory support. However, four trials involving 138 infants used a clinical respiratory score system, with increased severity receiving a higher score. The pooled results show that infants treated with heliox inhalation had a reduction in this respiratory score in the first hour. In a small subgroup of infants who were started on a nasal device providing a continuous positive airway pressure right from the start, because of the severity of their disease, heliox inhalation could reduce length of treatment. Each trial included in this review used a different method for delivering heliox. They also used different thresholds of clinical respiratory score for inclusion, and were often underpowered for the major endpoints. Further studies using a valid method of heliox application in addition to standard medical care are needed. Inclusion criteria must include a clinical severity score that reflects severe respiratory distress to avoid the inclusion of children who are not very sick, who may not benefit from heliox inhalation. Such studies would provide necessary information about the appropriate place of heliox in the management of seasonal pulmonary infection in infants.