Randomised controlled studies are needed to evaluate the use of high‐flow nasal cannula therapy in bronchiolitis

Bronchiolitis is the most common infection in infancy that leads to hospitalisation. In a recent two-year study from Finland, 3.7% of all infants under six months of age were admitted to the emergency room for bronchiolitis each year. The majority (70%) were hospitalised, and 6% of those needed intensive care 1. Oxygen and feeding support, if needed, are the cornerstones of bronchiolitis treatment, but the different drugs that have been studied have been ineffective. Administering a warmed, moistened mixture of oxygen and air using a high-flow nasal cannula (HFNC) is a promising new approach for treating infant bronchiolitis. In experimental studies, HFNC treatment has led to beneficial physiological effects on infant bronchiolitis 2-4, and the clinical experiences of using HFNC in neonatology have been good 5. High-flow nasal cannula therapy works by delivering a larger volume of air and oxygen into the nasal passages than standard low-flow oxygen therapy, using a higher flow of humidified and heated gas. Physiological studies have reported that this high flow resulted in more efficient delivery of oxygen to the terminal airways, resulting in reduced work of breathing and improved gas exchange in infant bronchiolitis 2, 3. The end-expiratory lung volume and oxygen saturation were reported to be higher, the respiratory rate was lower and less supplementary oxygen was needed when the 8 L/min flow rate was compared to the 2 L/min flow rate in 13 infants 2. Another study of 14 infants showed that the work of breathing, as estimated by diaphragmatic electrical activity and oesophageal pressure, decreased after starting HFNC treatment with a 2 L/kg/min flow rate 3. Meanwhile, a study of 19 infants reported that nasopharyngeal pressure increased linearly with flow rates up to 6 L/min and that bronchiolitis severity scores improved significantly at this level 6. In this issue of the journal, Milani et al. 7 report the results of their prospective observational study on the use of HFNC therapy in moderate-to-severe infant bronchiolitis treated on the paediatric ward, comparing their results with standard low-flow oxygen administration. The study included 36 infants aged 1.2–5.0 months who needed oxygen support when they were treated on a paediatric ward. The allocation of the patients into the HFNC and standard low-flow treatment groups depended on the availability of the HFNC device. The assessment of the flow rate in the HFNC treatment group was rather complex (L/min = 8 mL/kg*respiratory rate*0.3), but, on the other hand, it was based on the respiratory effort needed. The outcome measures were respiratory rate, the doctors’ clinical assessment of respiratory effort and the ability to feed, which was assessed by nurses who recorded the infants’ milk intake during bottle-feeding or weighed the infants before and after breastfeeding. The improvements in respiratory rate and effort, and the ability to feed, were significantly faster in the infants treated with HFNC than in the controls 7. The median duration of oxygen support was 4 days (interquartile, IQ 3–5 days) in the HFNC group versus 6 days (IQ 5–7 days) in the standard low-flow oxygen group, and the median lengths of hospital stays were 6 days (IQ 5–7 days) versus 9 days (IQ 8–10 days), respectively. Two patients in each group needed to be admitted to the paediatric intensive care unit (PICU). An open, randomised, pilot study of 19 infants treated for bronchiolitis on the paediatric ward that compared HFNC and head-box oxygen supports 8 found that oxygen saturation was higher in the HFNC group at eight and 12 hours, but not at 24 hours onwards. The improvement in respiratory effort was not reported. The total time spent receiving oxygen support and the length of hospital stay did not differ between the groups 8. So far, that study has been the only randomised controlled trial on the effectiveness of HFNC therapy in infant bronchiolitis, but only eight infants were treated with HFNC. As the authors stated, the study did not have significant power to find more differences between the HFNC and control groups. High-flow nasal cannula therapy decreased the need for intensive care in an Australian cohort of 61 infants aged less than 12 months, who were treated for bronchiolitis on a paediatric ward using a 2 L/kg/min flow rate 9. The need for intensive care was 13% in the HFNC group, compared with 31% in the 33 retrospectively collected, matched controls treated with standard low-flow oxygen therapy. In the HFNC group, the responders could be identified from the nonresponders within 60 minutes of treatment, by the decreases in their heart rate and respiratory rate 9. Three retrospective studies evaluated HFNC therapy in infants treated for bronchiolitis in the PICU. In two studies, HFNC therapy decreased the intubation rate compared to historical controls by 14% 10 and 30% 11. However, the reported intubation rates in the HFNC groups were still rather high at 9% 10, 7% 11 and 6.5% 12 in the PICU-treated patient reflecting the severity of the bronchiolitis cases. In one of the studies 10, the median stay in the PICU decreased from six to four days. A retrospective comparative study of 34 infants showed that HFNC therapy was equally effective as treatment with nasal continued positive airway pressure, when assessed by the length of hospital stay or by blood gas analyses, oxygen saturation, respiratory rates and oxygen support during the first five days in the PICU 13. HFNC has been well tolerated and safely used on paediatric wards, and virtually, no adverse events related to HFNC therapy have been reported in infants with bronchiolitis 4, 5, 7, 9. In an Italian observational prospective study, 27 infants under the age of 12 months who suffered from moderate-to-severe bronchiolitis were treated with HFNC on a paediatric ward. The flow rate in L/min was weight plus one until the weight reached 7 kg, and thereafter, it was 8 L/min. Patients treated with HFNC saw their oxygen saturation increase and respiratory rate decrease significantly during the first three hours. No adverse events were reported and no other respiratory support was needed 5. In Australia and New Zealand, 298 infants aged less than 24 months received HFNC therapy in the PICU and no adverse events related to the HFNC therapy were identified 11. In the most recent Australian prospective observational study on 71 children of all ages treated with HFNC in the emergency department, two (3%) did not tolerate HFNC treatment, three others (4%) developed abdominal distension, and after transfer to the PICU, a four-year-old girl with severe asthma developed air leak syndrome 14. Many hospitals have started to use HFNC to treat infant bronchiolitis without definitive evidence on the effectiveness obtained from randomised controlled trials. The small prospective studies published so far, like the study by Milani et al. in this issue 7, are pilot studies that offer preliminary evidence, but do not provide any definitive answers to the fundamental questions: when should bronchiolitis patients be treated with HFNC? and which patients should be treated and for how long? Randomised controlled trials need to be carried out with sufficient power, in infants of different ages, in different viral groups and with different degrees of severity of bronchiolitis. These can be analysed separately or should rather be included in multivariate models. The numbers of patients that need to be included in studies, including the number attending hospitals, depend on the selected outcome measures. The confirmation of hard effects, such as differences in treatment failure, PICU stays or hospital stays, need large patients groups and usually require multicentre studies. In 2015, a multicentre study was started in 17 hospitals in Australia and New Zealand. The aim was to assess the efficacy of early HFNC therapy given on the paediatric ward, compared to standard low-flow nasal oxygen, to treat bronchiolitis in patients under the age of 12 months 15. The primary outcome will be the proportion of infants in each group whose treatment failure leads to PICU admission. The assumption made by the researchers is that the current 10% PICU admission rate will be reduced to less than 5% and that to show this reduction as statistically significant, the sample size will need to be 1164 infants 15. No doubt, such mega studies are needed, but the physiological effects measured by experimental methods, and softer clinical benefits like increased oxygen saturation, decreased respiratory rates or improved clinical scores, can be studied in smaller patient groups. Studies of this size are also needed. The positive clinical experiences reported by studies on the use of HFNC in different respiratory problems in young children do give rise to an important question whether randomisation between HFNC and low-flow oxygen administration is unethical. However, we cannot rely on just clinical experience when selecting treatment modalities for children. In addition, the use of standard low-flow oxygen support is an established and acceptable way to treat children with respiratory problems, including infant bronchiolitis with mild-to-moderate hypoxaemia. This means that the real question we need to ask is whether it is ethical to use HFNC, when its efficacy has not been rated and confirmed by randomised controlled studies and we do not know which patients will really benefit from this treatment? In conclusion, HFNC seems to be an effective way to treat bronchiolitis patients who need oxygen support. Observational studies have reported many beneficial effects of HFNC and have not reported any significant adverse events in infant bronchiolitis. Randomised controlled studies that include bronchiolitis patients with different disease severity at different ages are needed to answer the question about who really benefits from HFNC therapy. Is it those with mild, moderate or severe bronchiolitis or patients with all disease severities? Is HFNC more effective in certain age groups, or can it even be harmful in certain patients, for example in those with bronchial obstruction and air trapping? The jury is still out, but papers like the study by Milani et al. in this issue make an important contribution to the on-going debate. No funding was secured for this study. The authors have no conflict of interests to disclose.