PARIS: One Swallow Does Not A Spring Make!

M. Nadeem, P. Greally

Tallaght University Hospital & Department of Paediatrics, Trinity College Dublin


Viral bronchiolitis is the most common cause of respiratory illness and hospitalization in infants accounting for 18% of all paediatric admissions1. Respiratory syncytial virus (RSV) accounts for almost 80% of cases. Although there have been significant increases in admission rates with bronchiolitis over several decades in the UK, rates of PICU admission have remained remarkably constant (1.3 to 1.6 per 1000 infants aged <1 year)2. Access to respiratory support has led to low mortality rates in developed countries however in resource-poor countries RSV is second only to malaria as the leading cause of all infant mortality3.

Bronchiolitis represents a considerable economic burden for all stakeholders. Direct costs include GP visits, ED attendances and bed-days utilised particularly during winter epidemics. Indirect costs consist of cancellation of hospitals’ elective activity and loss of income for parents from missed days at work. Severity of illness is variable ranging from mild coryzal symptoms to severe respiratory distress. Between 2-3% of primary infections require hospitalisation. Increased morbidity is observed in those born prematurely, neonates & young infants, and those from lower socio-economic groups. During the course of the illness, respiratory distress typically progresses, peaking between days three to five and then gradually resolving .  Management is supportive and consists largely of hydration and supplemental oxygen when necessary.  

Oxygen typically administered by nasal cannula is currently the standard care for bronchiolitis. However, any intervention that reduces the severity or duration of illness, the number of days spent in ICU or hospital would be of great benefit for infants, their parents and the healthcare systems that cater for them.

Over the years many interventions have entered routine clinical practice which when subsequently scrutinized by larger randomised control trials or systematic reviews have been shown not to be effective. Examples of pharmacological therapies include nebulised or inhaled salbutamol, nebulised adrenaline, inhaled corticosteroids, dexamethasone or antibiotics. It is noteworthy that none of the aforementioned were included in guidelines recommended by American Academy of Pediatrics (AAP) in 20143 or National Institutes for Clinical Excellence (NICE) in 20154.  Even the commonly prescribed 3% hypertonic saline solution was not recommended by the NICE guideline, and the AAP guideline stated that cclinicians may prescribe hypertonic saline to infants and children who are hospitalized for bronchiolitis, thus, excluding it’s use for ED and primary care.

More recently the prescription of humidified oxygen by high-flow nasal cannula (HFNC) therapy has crept by stealth into practice and is considered by some as superior to standard oxygen and a possible alternative to continuous positive airway pressure (CPAP) for deteriorating infants. Its mechanism of action is unclear and is likely to be mediated by more than just better delivery of supplemental oxygen as it is likely to alter lung mechanics as flow rates of ≥6 L/min appear to provide positive pressure throughout the respiratory cycle, with positive end expiratory pressures in the range of 2 to 5 cm H2O. HFNC is generally well tolerated and complications are rare but include gastric distension from swallowed air, epistaxis, pneumothorax and pneumomedistinum. HFNC is technically easier to administer than nasal CPAP and doesn’t require PICU or HDU facilities.

Despite it’s almost universal adoption by general paediatricians in Ireland as a step-up treatment modality for bronchiolitis there has been considerable uncertainty as to a) whether it is superior to standard care and b) what role it has for the infant who has progressed to more severe disease. These questions, to some extent, have been answered by a recent non-blinded randomised controlled clinical trial (RCCT) from Australia and New Zealand by the Paediatric Acute Respiratory Investigation Study (PARIS), where HFNC had become standard care. Franklin et al5, reported that of 1,472 infants included in the analysis, 12% in the high-flow group received escalated care compared to 23% in the standard therapy group. However, there was no significant difference between the two groups either in terms of the duration of hospital stay or the duration of oxygen therapy. Both groups had similar rates of pneumothorax and apnoea.

Once escalated, there were no differences between the groups in terms of rates of endotracheal intubation or days spent in PICU. In a pragmatic protocol, treatment failure led to escalation of care and was defined when infants met at least 3 of 4 criteria5. However, clinicians were allowed to escalate therapy if they were concerned for other clinical reasons that were not captured by the criteria.

Consequently, the treatment failure rate was significantly higher in those who received standard therapy, compared to infants randomised to HFNC, albeit there was no significant difference between the two groups in terms of the percentage of individuals who met ≥ three of four these criteria. This probably says more about the deficiencies of the criteria and that there were other elements in clinical judgement were not captured in this trial when escalation of care occurred.

In Ireland HFNC is typically used in infants failing standard therapy, a practice that would appear to be supported by the outcomes in the subgroup (N=167) who needed escalation of therapy despite standard care, where almost two-thirds improved with HFNC. The key message that emanates from this paper is that HFNC appears to be superior to standard care. An important unanswered question is whether HFNC is equivalent to CPAP in patients who have progressed to more severe disease and this requires large multicentre RCCTs.

Whether findings from PARIS apply to our population require further corroboration in large multi-centre RCCTs in Europe. Ultimately, if it were proposed that HFNC replace supplemental oxygen as the new standard care for bronchiolitis, a detailed cost-benefit analysis would be required as part of any pharmaco-economic assessment. While fewer PICU admissions are always highly desirable outcomes, HFNC did not lead to lower intubation rates, shorter length of stays either in ICU or hospital, or duration of oxygen therapy5. HFNC generally requires higher nursing input and nasogastric intubation, additionally there are capital costs of procuring multiple pieces HFNC equipment and their on-going maintenance to be considered. When a health technology assessment was applied to Palivizumab for RSV bronchiolitis, estimates derived from effectiveness models in preterm high-risk infants used a threshold of 30,000€/QALY6. It is unclear whether HFNC would fall within the socially acceptable range of financing by public health care systems in developed countries.

Correspondence:
Prof. Peter Greally

Tallaght University Hospital,
Department of Paediatrics

Email: peter.greally@TUH.ie

References

1. Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics 2013;132:28–36
2. Green CA, Yeates D, Goldacre A, Sande C, Parslow RC, McShane P, Pollard AJ, Goldacre MJ. Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma. Arch Dis Child. 2016;101(2):140-63)
3. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, Johnson DW, Light MJ, Maraqa NF, Mendonca EA, Phelan KJ, Zorc JJ, Stanko-Lopp D, Brown MA, Nathanson I, Rosenblum E, Sayles S 3rd, Hernandez-Cancio S; American Academy of Pediatrics.Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134(5):e1474-e1502 Pediatrics. 2014 Nov;134(5):e1474-502. doi: 10.1542/peds.2014-2742.
4. Bronchiolitis in children: diagnosis and management. Current National Institute for Health and Care Excellence guidelines, NICE guideline [NG9], 2015
5. Franklin D, Babl FE, Schlapbach LJ, Oakley E, Craig S, Neutze J, Furyk J, Fraser JF, Jones M, Whitty JA, Dalziel SR, Schibler A. Randomized Trial of High-Flow Oxygen Therapy in Infants with Bronchiolitis. N Engl J Med. 2018, 22;378(12):1121-1131.
6. Lázaro P, Figueras J, Doménech E, Echániz I, Closa R, Wood M, Fitch K: La eficiencia (coste-efectividad) de palivizumab como profilaxis para la infección por virus respiratorio sincitial en prematuros de 32-35 semanas en España. Anales de Pediatría. 2006, 65 (4): 316-324.


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