The BIDS study protocol prespecified that equivalence would be met if the time to resolution of cough was within the CIs of ± 2 days. The median difference in the time to resolution of cough was 1 day with a lower 95% confidence limit of –1 day and an upper 95% confidence limit of 2 days. The outcome of infants with acute viral bronchiolitis within hospital to a modified target oxygen saturation of ≥ 90% is therefore considered similar to management to a standard target oxygen saturation of ≥ 94%, for resolution of cough.
In addition to our primary outcome, we aimed to demonstrate safety and other measures of clinical comparability. We did not prove equivalence for time to parent perspective of return to normal and time to return to adequate feeding; however, the treatment effect was in the direction of favouring the modified care group.
Overall, there were no safety concerns (number of admissions to the HDU, readmissions to hospital, reattendances at health services) and no additional burden on parents from the intervention and earlier discharge home.
The economic analysis shows that the modified therapy dominates the standard therapy when using conventional economic evaluation cost-effectiveness criteria. The economic analysis revealed that total NHS costs are £290 (95% CI –£657 to £78) lower in the modified care arm. Although this total cost difference is not significant, this is likely due to the large variance around the many individual components making up the total cost variable. However, the hospital inpatient stay cost difference comprises the largest individual component of this total NHS cost difference and, accounting for almost 60% of the total cost variable, represents a statistically significant difference in favour of the modified arm. This difference in favour of the modified care arm further increases when patient costs are included within a societal perspective. The economic analysis shows little uncertainty regarding the likelihood of the modified care protocol being cost saving compared with the standard care protocol; however, there is greater uncertainty regarding any improvement or reduction in days to cough resolution. The modified protocol is the dominant option, with a likelihood of being cost-effective of 91.5%, even when society is willing to pay zero for the health improvements. We consider the management of infants with acute viral bronchiolitis to a target oxygen saturation of ≥ 90% to be safe and as clinically effective as an oxygen saturation target of ≥ 94%.
Limitations
Exclusion of infants under 6 weeks of age
Our exclusion criteria were kept to a minimum, as we wished, if successful, for this study to be widely applicable to acute bronchiolitis admissions; however, we did exclude infants under 6 weeks of age. The reasons for this were twofold. First, in our recruitment feasibility assessment in the season prior to the study, parents of children in this age group indicated that they would decline consent to the study because of concerns about the age of their child and their first acute illness. Second, infants in this age group frequently present with apnoea and, although we accommodated this within the protocol, the clinical and parental anxiety associated with infant apnoea may have provided an undue skew to greater length of stay in this age range. We consider that infants under 6 weeks of age will require a higher degree of personalisation of oxygen saturation targets depending on their disease course. Although there are some who may be stable and able to be managed at an oxygen saturation target of ≥ 90%, there will be others who will require a higher target for management and discharge (particularly those with apnoea) and this will be as is clinically appropriate.
Measures of concurrent symptom relief
Supplemental oxygen is provided in hypoxaemia for both tissue oxygenation and perceived symptom relief. In adults, there is no demonstrable effect of supplemental oxygen on relief of respiratory symptoms.4,5 We used proxy measures of symptom relief, assessing heart and respiratory rate as indicators of comfort in acute respiratory disease. At time of discharge, heart rate and respiratory rate were similar in the two groups, suggesting that stopping supplemental oxygen sooner in the modified care group was not associated with an increase in discomfort reflected by an increase in respiratory or heart rate.
Measurement of clinical scores
The study did not use a bronchiolitis clinical score. A range of clinical scores are reported in studies, some specific for bronchiolitis, others adapted from asthma scores. Our reason for not using a bronchiolitis score was threefold. First, bronchiolitis scores are not used clinically in the majority of UK hospitals, in particular in our study site partners, as they have not been demonstrated to be of greater value than routine clinical decision-making. Second, there is no agreed best clinical score. Third, agreement between observers tends to be poor unless the number of trained observers is limited.54 To have study staff available 24 hours per day for scoring would have been expensive for measurement of single outcome. The alternative approach of training clinical staff across all sites to clinical score accurately and precisely for bronchiolitis may have changed behaviour with regard to routine care (which we wished to observe) and still have been associated with unacceptable variance in scoring with corresponding concerns for data surety.
Measures of neurocognitive development
Neurocognitive delay has been associated with hypoxaemia in children, with most anxieties stemming from observation of lower school attainment in children with obstructive sleep apnoea.54 Such children experience recurrent, variable, hypoxaemia with obstructed breathing while asleep. Hypoxaemia in acute respiratory illness tends to be less variable, and often less severe, and with a pattern of resolution over a significantly shorter period of time. Longer periods of hypoxaemia than that experienced by infants with bronchiolitis may have no associated neurocognitive impact. Preterm infants maintained at an oxygen saturation target of 91–94% had no neurocognitive deficit at 2 years compared with those maintained at an oxygen saturation target of 95–98%.55 Neurocognitive scores in children with mild/moderate obstructive sleep apnoea observed for a period of 6 months were no different from scores in children who had undergone immediate tonsillectomy.56 These studies support the perspective that children may be neurocognitively tolerant of short-term borderline hypoxia.
Compliance with study protocol
It could be considered a limitation of the study that we did not collect and download the time-matched ‘true’ oxygen saturation of the modified oximeters; this was predominantly for logistic and cost reasons, and we considered that the additional study resource would not have proportionally added to the study outcome or understanding of the effects of oxygen in borderline hypoxia. The differences noted for use of oxygen and time to stopping supplemental oxygen in each of the groups suggest good compliance to the study protocol in those who received the intervention. We were not aware of any episodes of unblinding associated with the study protocol; hospital oximeters were removed and a study oximeter applied after an interval of 1 minute. The average difference between the hospital and study oximeter display was 2% SpO2 and, as a consequence, to our knowledge, there were no instances of accidental unblinding.
Strengths
This study was sufficiently large to answer this important clinical question, with very good follow-up of infants to 6 months (95%) and data completeness. It can, therefore, provide strong evidence to support recommendations for clinical practice, in a topic area without current evidence and with significant practice variation.
Reducing variance in clinical practice
This is the first study of oxygen saturation targets for acute respiratory infection in children in a developed health-care setting. The recommendation of the AAP that an oxygen saturation of ≥ 90% is acceptable in acute bronchiolitis has not been widely adopted, with varying practice and continued debate.19,57 The AAP recommendation has, however, led to a drift in clinical practice without sufficient evidence, with clinicians now managing bronchiolitis to a range of oxygen saturation targets even within the same hospital. The risks of practice drift are well demonstrated by recent studies in preterm infants, in which a progressive clinical acceptance of lower oxygen saturation targets58 was only subsequently shown to be associated with increased risk of death in exposed infants.7 The results of this study therefore enable the range of oxygen saturation targets currently in use to be coalesced into a clear oxygen saturation target of ≥ 90%.
Unifying oxygen management strategy for acute bronchiolitis
Debate in oxygen management in acute respiratory disease focuses on target oxygen saturations, whether or not oxygen saturation monitoring should be continuous or intermittent and for how long oxygen saturation should be observed to be stable prior to discharge. The debate on oxygen saturation targets is presented in the rationale for the study in Chapter 1, Controversies in approach to hypoxaemia in bronchiolitis, but important within this is the differential approach to starting and stopping oxygen supplementation. In guidelines for respiratory disease, target oxygen saturation for commencing supplemental oxygen is typically lower than that for stopping. In children with respiratory infection, lower oxygen saturation early in the course of the illness often represents clinical instability and the clinical logic for a higher threshold at these times is unclear. A strength of our study was the use of a single target oxygen saturation for starting and stopping supplemental oxygen.
There are concerns that continuous oxygen saturation monitoring leads to clinical overinterpretation of minor physiological and artefactual brief and self-correcting desaturation. Such minor desaturation is considered to delay patient progress to management in air and, consequently, discharge. Unfortunately, there is no agreement on the frequency or duration of intermittent monitoring, and, as a consequence, we considered it safest to provide continuous monitoring over a short period of time.
There is also no agreement on the length of time that infants should be observed to have stable oxygen saturation in room air prior to discharge, with 8–24 hours considered appropriate by over two-thirds of clinicians and 24–48 hours considered appropriate by nearly one-fifth (Clare van Miert, University of Liverpool, 2012, personal communication).
In developing our protocol, while acknowledging these concerns, we hoped to provide a pragmatic, sensible and safe approach that would not miss important desaturation events in acutely infected infants but also would not inappropriately prolong admissions. We therefore elected to have a shorter period of continuous monitoring. The results of this study, by combining these three issues of debate, provide an evidence-based structure for clinical decision-making at discharge.
Context
The study addresses oxygen saturation targets for infants admitted to hospital with acute bronchiolitis. The results will prompt consideration of the generalisability of these results to other inpatient and outpatient health-care settings and also to other acute respiratory diseases in children.
Applicability within UK hospitals and beyond
In general, the care in each of the paediatric units within the BIDS study team was similar and we would consider that the results are generalisable to the care of infants with bronchiolitis in UK paediatric hospitals. We have no reason to believe that the study results would not be applicable to other similar health-care settings across the world. Infants living at higher altitudes have lower oxygen saturation in health and may be managed at lower oxygen saturation limits during disease.1 This study was performed at sea level and, therefore, is widely applicable to most urban areas, in line with recent requests for evidence at sea level.59
Although the study protocol was for infants admitted to hospital, we deliberately chose a more intense (continuous monitoring) but shorter period of observation (4 hours) than most current practice. The debate of continuous or intermittent oxygen saturation monitoring is discussed above; however, our shorter period of observation was intended to capture infants with important prolonged episodes of desaturation during a short period of observation, such that the results could be applicable to acute paediatric observation areas (short stay, acute assessment units, etc.) and negate the need for admission if the criteria for safe discharge were fulfilled. Such acute observation areas typically have fewer time pressures than EDs and therefore provide a better safety net for sick infants.
Use of oxygen saturation target ≥ 90% in emergency departments and primary care
The study did not address appropriate oxygen saturation targets for primary care and EDs. Infants in the first year of life with an acute respiratory infection are a vulnerable patient group. Our study boundary when considering the ethical approach to this research question was the knowledge of a greater risk of death in children with acute respiratory infection managed below an oxygen saturation of 90%,9 a finding recently also seen in infants born preterm.7 Bronchiolitis typically has good outcomes, with few deaths, under current management strategies. Although there is some evidence that infants recovering from bronchiolitis have temporary dips below 90% at home,60 we did not consider it ethical or appropriate to devise a protocol that would lead to a sustained period below the 90% oxygen saturation threshold, and therefore we restricted the trial to those who would be observed in hospital.
In infants with bronchiolitis presenting to an ED with an oxygen saturation of ≤ 92% there is a high probability that oxygen saturation will fall below 90% during the observation period.61 Among ED physicians, the threshold for admitting an infant with an oxygen saturation of 92% is much lower than that for admitting those with an oxygen saturation of 94%.2 These studies, together with the wish to provide a sufficient safety net to young infants, persuaded us that a study of a 90% oxygen saturation target in EDs may not be in the best interests of infants with acute viral bronchiolitis, and a better understanding of the safety and clinical impact of target oxygen saturations during a typically longer period of observation would be most appropriate. The same reasoning would be applicable to primary care.
Applicability of oxygen saturation target ≥ 90% in other acute respiratory disease in childhood
The generalisability of targeting oxygen saturation ≥ 90% in other acute respiratory conditions has not been tested in this study. Our population was infants under 1 year of age with acute respiratory infection, who could be considered potentially more vulnerable than many older children with acute respiratory infection. In children recovering from acute pneumonia (viral or bacterial) or acute virus-induced wheeze, oxygen saturation often follows a pattern of a long tail of recovery (particularly during sleep), during which time the child’s clinical status may have significantly improved, and with no or stable chest signs on auscultation, and with hospitalisation needed only for the provision of supplemental oxygen. Clinicians caring for children who are recovering from such illnesses and who are cardiovascularly stable may consider targeting to a lower threshold of ≥ 90% oxygen saturation for hospital care and discharge. Until appropriately tested, children with acute pneumonia and acute asthma/wheeze at presentation should continue to receive supplemental oxygen according to current guideline recommendations (typically a target of ≥ 92%) because of the risk of acute change in symptoms and tissue hypoxia in these conditions during the acute phase of the illness.
Potential risks not explored within this study
The principal risk not explored by this study methodology was that children who present with clinical bronchiolitis may have an alternative diagnosis. Many conditions masquerading as bronchiolitis would typically be picked up as current (e.g. congenital heart disease). Possible exceptions are rare lung diseases in children, which may present a similar clinical picture similar to bronchiolitis. Children with such conditions (e.g. neuroendocrine hyperplasia of infancy or bronchiolitis obliterans) often struggle to maintain oxygen saturation in air ≥ 90%, and in some cases the presentation will resemble that of recurrent bronchiolitis with oxygen saturation maintained at ≥ 90% but < 94%. Clinicians should be educated that any infant presenting with a second episode of bronchiolitis should be assessed for lack of chest signs and normal oxygen saturation at discharge or follow-up.
Unanticipated findings
The study was not anticipated or designed to identify differences in the outcomes considered for equivalence. Nor did we expect to see the modest but additional benefit to the modified intervention for readmissions to hospital and carer time lost. Post-hoc analyses are discussed further here.
Parents of children in the modified care group reported that their infants had returned to normal 1 day sooner (median 11 days) than parents of children in the standard care group (median 12 days), with the 95% CI of 0 to 3 days falling outside the prespecified limits of –2 to 2 days. When this difference was explored with hazard ratios, the estimate of difference was 1.2 (95% CI 1.0 to 1.4; p-value = 0.0434). Differences between the groups in time to return to normal are more evident in those returning to normal at a time longer than the median value (see ). This difference may represent a relationship between the return to a sense of health and well-being of a child from a parent perspective and the time since hospital discharge. Alternatively, a shorter period in hospital receiving supplemental oxygen may have conferred health benefits that were not captured by cough duration, for example a lower potential risk of nosocomial infection in those discharged home sooner or a reduced viral replication rate as a result of oxygen restriction. Parents appeared to consider their infant ‘back to normal’ even when there was residual cough (as cough took longer to resolve), suggesting that cough is only a component of parents’ perspectives of their child’s health status as normal and does not define it.
Median time to return to adequate feeding (≥ 75% normal) was 2.7 hours shorter in the modified care group (24.1 hours) than in the standard care group (19.5 hours), with the 95% CI of –0.3 to 7.3 hours falling outside the prespecified limits of –4 to 4 hours. When this difference was explored with hazard ratios, the estimate of difference was 1.2 (95% CI 1.0 to 1.4; p-value = 0.0147). Across the whole group of infants, this is a clinically important difference. It may represent altered behaviour by nursing staff to resolve feeding issues sooner in those with apparently better oxygen saturation. However, we also note that fewer infants in the modified care group required nasogastric tube feeding (see Table 12; typically provided for respiratory distress rather than for low oxygen saturation levels). Although speculative, there could be merit in further exploring whether or not supplementation with dry oxygen gas exacerbates nasal obstruction in acute bronchiolitis, compounding feeding difficulties and prolonging hospitalisation, particularly where nasal cannulae increase airflow resistance in obligate nasal breathers.
Medical therapies, including bronchodilators,16 adrenaline,62 corticosteroids30,63 and possibly hypertonic saline, are of limited or no benefit in the treatment of acute bronchiolitis.64 The data from this study pose two further issues. The first is whether or not there is a risk/benefit to supplemental oxygen use in mild/moderate bronchiolitis. Infants in the modified care group appeared to recover sooner. Emerging evidence that RSV replication may be boosted in an enhanced oxygen environment65 suggests that risk–benefit implications of supplemental oxygen should be considered more actively. The second is that the trend for benefits in this study was in favour of the modified care group, who spent less time in hospital with fewer interventions. This concurs with recent evidence that fewer interventions in bronchiolitis result in faster recovery.66 Is less more in the management of acute bronchiolitis in hospital?
Patient and public involvement
In the study set-up stages we engaged with a parent representative to guide protocol development. Unfortunately, that link was lost early in the study and we were unable to engage appropriate patient and public involvement, possibly as acute bronchiolitis is a relatively short-duration illness for many and is often not given a labelled diagnosis in primary care.
In our prestudy feasibility assessment, we were fortunate to be able to meet the parents of children during an admission to hospital with acute bronchiolitis, to gauge their perspective on our proposed trial at a similar time point as that in which we would be engaging with parents of children enrolled to the study. Parents were more positive than we had expected and the discussions gave valuable guidance for study exclusions, parent information sheets and appropriate use of language when conveying potential risks and benefits of the study.
