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Date: September 15, 2022

Reference:  Ramnarayan P et al. Effect of high-flow nasal cannula therapy vs continuous positive airway pressure therapy on liberation from respiratory support in acutely ill children admitted to pediatric critical care units: a randomized clinical trial. JAMA July 2022

Dr. Spyridon Karageorgos

Guest Skeptic: Dr. Spyridon Karageorgos is a Pediatric Resident at Aghia Sophia Childrens’ Hospital, Athens, Greece and a MSc student in Pediatric Emergency Medicine at Queen Mary University London.

Case: A 10-month-old male infant presents to the emergency department (ED) with a low-grade fever, rhinorrhea and reduced feeding during the last two days. On exam, you notice increased work of breathing, nasal flaring, grunting with subcostal and intercostal retractions. He’s breathing at a rate of 75 per minute with oxygen saturations of 86% on room air. You make a clinical diagnosis of severe bronchiolitis. You start with low-flow O2 therapy but there is no clinical improvement. You discuss with the family the possibility that the child may need to be admitted in the pediatric intensive care unit (PICU) and require escalation of respiratory support with another modality of non-invasive ventilation. Parents look worried and ask you what kind of non-invasive support are you planning to start?

Background: The use of High-Flow Nasal Cannula (HFNC) has increased in both PICU and in the Pediatric ED, especially for infants presenting acutely ill with respiratory distress requiring non-invasive ventilation (NIV). Despite the rise in popularity, there is a lack of high-quality evidence surrounding the use of high flow nasal cannula.

Most studies are observational studies rather than randomized control trials (RCTs) [1-3]. Randomized control trials performed demonstrated that the early initiation of high flow nasal cannula led to lower rates of treatment failure/escalation…to high flow nasal cannula[4]. Even results from meta-analyses are mixed [5-6].

The SGEM covered the use of high flow nasal oxygen for bronchiolitis with Dr. Ben Lawton on SGEM #228.

The bottom line for that episode was:

“High flow oxygen therapy is not required for every child in hospital with bronchiolitis. It will continue to have a role in supporting those with more severe disease, but the potential benefits and harms will need to be considered within the context of where it is being used.”

There are a few proposed mechanisms for HFNC:

  1. Positive pressure
  2. Reduced upper airway resistance
  3. Washout of dead space in the nasopharynx
  4. More comfort from humidified air

However, data regarding the clinical effectiveness of HFNC compared to continuous positive airway pressure (CPAP) is limited.

In 2018, Ramnarayan et al. performed a multicentre pilot randomised controlled trial of HFNC vs CPAP in paediatric critical care that confirmed the feasibility of performing a large multicenter trial on HFNC vs CPAP in PICU [7].

The FIRST-ABC master protocol included two RCTs, one in acutely ill children requiring respiratory support (Step-Up RCT) and one in children requiring respiratory support after extubation from invasive ventilation (Step-Down RCT), with the aim of assessing the clinical and cost-effectiveness of HFNC as the first-line mode of non-invasive respiratory support in critically ill children.

We’re focusing on the Step-Up RCT for today’s episode.

Clinical Question: In acutely ill pediatric patients requiring non-invasive ventilation in the PICU, is High Flow Nasal Cannula (HFNC) noninferior to Continuous Positive Airway Pressure (CPAP) in terms of time to liberation from all forms of respiratory support?

Reference:  Ramnarayan P et al. Effect of high-flow nasal cannula therapy vs continuous positive airway pressure therapy on liberation from respiratory support in acutely ill children admitted to pediatric critical care units: a randomized clinical trial. JAMA July 2022

  • Population: Children between 36 weeks (corrected gestational age) and less than 16 years requiring non-invasive respiratory support for acute illness from 24 PICUs and HDUs in the UK between August 2019 and November 2021
    • Exclusion: Clinical decision to initiate other mode of ventilation (intubation, invasive ventilation), tracheostomy in place, receipt of CPAP or HFNC for >2 hours in the prior to randomization, supplemented O2 at home, presence of air-leak, midfacial/craniofacial anomalies, previously recruited to the FIRST-ABC trial
  • Intervention: HFNC based on body weight

  • Comparison: CPAP of 7 to 8 cm H2
  • Outcome:
    • Primary Outcome: Time from randomization to liberation from respiratory support which was defined as the start of the 48-hour period during which the child was free from any respiratory support, excluding supplemental oxygen.
    • Secondary Outcomes:
      • Mortality at critical care discharge
      • Rate of intubation at 48 hours
      • Duration of critical care and acute hospital stay
      • Patient comfort
      • Sedation during noninvasive respiratory support
      • Parental stress
      • Adverse events up to 48 hours after liberation from respiratory support
  • Trial: unblinded, multicenter, parallel-group, randomized, non-inferiority trial.

Authors’ Conclusions: “Among acutely ill children clinically assessed to require non-invasive respiratory support in a pediatric critical care unit, HFNC compared with CPAP met the criterion for noninferiority for time to liberation from respiratory support”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. Yes.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Unsure.
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure.
  12. Financial conflicts of interest. The lead author reported receiving personal fees from two healthcare companies, but we do not think this impacted the results of the article.

Results: 600 children (41% of those eligible) were randomized. 573 children (HFNC: 295; CPAP: 278) were included in the primary analysis. 533 children (HFNC: 288; CPAP: 245) were included in the per-protocol analysis. Median age for both groups was around 9 months and 40% were female.

Key Result: There were no statistical differences between the HFNC and CPAP groups with regards to time from randomization to liberation from respiratory support.

Primary Outcome: The median time to liberation in the HFNC group was 52.7 hours (95% CI, 45.0-60.1 hours) vs 45.4 hours (95% CI, 40.2-53.7 hours) in the CPAP group

  • Absolute difference, 7.3 hours [95% CI –7.3 to 22.2 hours]
  • Adjusted hazard ratio 1.03 [0.86-1.2]

Secondary Outcomes: 

  • There was no difference between groups regarding mortality at critical care discharge, patient comfort and parental stress scale.
  • Sedation use was lower in the HFNC group compared to the CPAP group (28% vs 39.2%)

  1. Non-invasive Ventilation Devices: This study was attempting to compare HFNC versus CPAP across multiple institutions. However, not all institutions used the same device or interface of delivering HFNC or CPAP. There were 7 different types of devices used across the institutions to deliver HFNC or CPAP. There were 5 or 6 difference CPAP interfaces used. It is hard to guarantee that with this variation, the patients received the same or consistent respiratory support within the same group. The modality of CPAP used may also have impacted patient comfort and decision to switch modalities.
  1. Heterogeneous Disease Processes: While most previous HFNC studies have looked specifically at application to children with bronchiolitis, this study includes a patient population with a variety of disease processes including upper airway problems, asthma, cardiac, neurologic, or sepsis/infection. This both a strength and weakness of this study. Including a heterogeneous group may make the results more generalizable.

However, it leaves much more (appropriate) flexibility on behalf of the clinician as to what modality of NIV to use. For example, a patient for whom we may want to optimize preload, we may prefer a modality that avoids excessive positive pressure, leading to decrease systemic venous return. Disclaimer: I am skeptical of the ability for HFNC to deliver consistent PEEP especially in children, given that it is an open system, variability to size of cannula and nares, and little control over whether a pediatric patient keeps their mouth open or closed.[8]

  1. Selection Bias: As mentioned prior only 41% of eligible patients were randomized in the study. Of the group of that were eligible but not randomized, 35% (325 out of 849) were due to “clinical decision.” The authors cite reasons including preference for HFNC or CPAP, unavailability of PICU (could not initiate CPAP), availability of CPAP masks, cardiac disease, wheeze and unsuitability of CPAP, or unspecified reasons. This may have led to selection bias.
  1. Switching between HFNC and CPAP: The decision to switch from HFNC and CPAP and vice versa was based on clinician’s judgement. Even though there were specific criteria for switching, a high rate of patients initially randomized to CPAP group were switched to HFNC (31%), mainly due to discomfort. 20% of patients randomized to HFNC were switched to CPAP mainly due to clinical deterioration.

This led to two groups being finally more similar than expected (since only 25% of initial CPAP and 50% of initial HFNC groups were receiving allocated treatment 24 hours post starting support). This could lessen any potential differences between HFNC and CPAP.

  1. Clinical Judgement and Weaning Support: Clinician decision and judgement may have impacted how we interpret the results of this study. However, clinical judgement is one of the pillars of evidence-based medicine. EBM is the intersection of the relevant scientific evidence, clinical judgement, and the patient’s or family’s preferences and values.

This was an unblinded study, but investigators did take steps to attempt to reduce bias. One of the things they did was establish standard criteria and algorithms for initiation and weaning of HFNC and CPAP. Per the algorithm, a clinician should consider weaning support if FiO2 ≤0.4 and respiratory distress is not severe. The second part of this is rather subjective and it calls for weaning the flow by 50%.

There may be some clinicians who would be hesitant to wean the flow by dropping it by 50%. It might feel a bit aggressive to go from a flow of 40L immediately down to 20L. Some patients may not tolerate it either, leading to a more treatment failures, escalation, or hesitancy to wean. 

Comment on Authors’ Conclusion Compared to SGEM Conclusion:  HFNC may be non-inferior to CPAP with regards to time to liberation from respiratory support compared to CPAP, with shorter critical care and acute hospital stay and less sedation use. However, limitations of the study should be considered when interpreting the results.

 SGEM Bottom Line: In acutely ill pediatric patients requiring non-invasive respiratory support, HFNC or CPAP may be considered depending on the patient’s presenting condition and pathophysiology.

Case Resolution: You inform the parents that there are different types of non-invasive respiratory support currently available in PICU but your institution commonly uses HFNC and CPAP. Both may be appropriate, but HFNC may be more comfortable in comparison to CPAP. Parents are happy to start with HFNC and the patient is transferred to the PICU for further care.

Clinical Application: In acutely ill pediatric patients requiring non-invasive respiratory support, you may consider either HFNC and CPAP. Use clinical judgement in determining the most appropriate modality of non-invasive ventilation based upon the patient’s presenting condition and pathophysiology. We are looking forward to future multi-national RCTs to potentially identify sub-groups that could be benefited by either mode of therapy.

What Do I Tell the Parents?  Your child has a condition called bronchiolitis and is working very hard to breath. You can see him breathing very fast and using extra muscles to help him breath. I would like to start him on some respiratory support. We have the option of using something call HFNC or CPAP. Both may be helpful, but HFNC might be a bit more comfortable. Let’s start with that and have him stay in the PICU for close monitoring.

Other FOAMed:

  • Don’t Forget the Bubbles: First-ABC Step Up- high flow in acutely unwell children.
  • REBEL EM: The FIRST-ABC Step Up Trial: HFNC vs CPAP for Liberation of Respiratory Support in Children?
  • REBEL EM: High Flow Nasal Cannula (HFNC)-Part 1: How It Works
  • PEM Blog: Is high flow really helpful in bronchiolitis?

 

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Wing R, James C, Maranda LS, Armsby CC. Use of high-flow nasal cannula support in the emergency department reduces the need for intubation in pediatric acute respiratory insufficiency. Pediatr Emerg Care. 2012;28(11):1117-1123.
  2. Lipshaw MJ, Vukovic AA, Dean P, et al. High-flow nasal cannula in bronchiolitis at a pediatric emergency department: trends and outcomes. Hosp Pediatr. 2021;11(2):119-125.
  3. Riese J, Porter T, Fierce J, Riese A, Richardson T, Alverson BK. Clinical outcomes of bronchiolitis after implementation of a general ward high flow nasal cannula guideline. Hosp Pediatr. 2017;7(4):197-203.
  4. Franklin D, Babl FE, Schlapbach LJ, et al. A randomized trial of high-flow oxygen therapy in infants with bronchiolitis. N Engl J Med. 2018;378(12):1121-1131.
  5. Lin J, Zhang Y, Xiong L, Liu S, Gong C, Dai J. High-flow nasal cannula therapy for children with bronchiolitis: a systematic review and meta-analysis. Arch Dis Child. 2019;104(6):564-576.
  6. Zhong Z, Zhao L, Zhao Y, Xia S. Comparison of high flow nasal cannula and non-invasive positive pressure ventilation in children with bronchiolitis: A meta-analysis of randomized controlled trials. Front Pediatr. 2022;10:947667.
  7. Ramnarayan P, Lister P, Dominguez T, et al. FIRST-line support for Assistance in Breathing in Children (First-abc): a multicentre pilot randomised controlled trial of high-flow nasal cannula therapy versus continuous positive airway pressure in paediatric critical care. Crit Care. 2018;22(1):144.
  8. Guglielmo RD, Hotz JC, Ross PA, et al. High-flow nasal cannula reduces effort of breathing but not consistently via positive end-expiratory pressure. Chest. Published online March 16, 2022:S0012-3692(22)00441-X.