Manley BJ, Owen LS, Doyle LW, Andersen CC, Cartwright DW, Pritchard MA, Donath SM, Davis PG. High-Flow Nasal Cannulae in Very Preterm Infants after Extubation. N Engl J Med 2013; 369:1425-33. PMID 24106935.
Clyde J. Wright, MD
University of Colorado School of Medicine and
Children’s Hospital Colorado
TYPE OF INVESTIGATION:
In preterm infants (<32 wks), how does high-flow nasal cannulae (HFNC) compare to nasal CPAP (nCPAP) for prevention of extubation failure?
- Design: Randomized controlled trial
- Allocation: Concealed by envelope randomization, stratified for <26 weeks or >26 weeks, and by site. Multiples randomized individually.
- Blinding: Unblinded (patients, clinicians). Impossible to blind patients and clinicians due to the nature of the intervention. Unclear blinding (outcome assessors, data collectors, analysts).
- Follow-up period: Death or first-discharge from hospital (median 81.5 days)
- Setting: Three Australian neonatal intensive care units from May 2010- July 2012
- Patients: 303 patients, average 27.5 wk GA and 1040 g, 53% male, 82% white, 94% received antenatal glucocorticoids, >98% received caffeine prior to extubation, median age of extubation ~40 hrs. Exclusion criteria: >36 weeks corrected age at the time of extubation, participation in a concurrent study prohibiting inclusion, major congenital anomaly that might affect breathing, or if maximal intensive care was not being provided
- Intervention: Upon extubation, CPAP (7 cm of water, n=151) or high-flow nasal cannulae (5-6 lpm depending on prong size, n=152). Maximum nasal CPAP administered was 8 cm of water, and maximum high-flow nasal cannulae was 6-8 lpm depending on cannulae size (which occluded “approximately half of the nares”). Infants randomized to receive high-flow nasal cannulae meeting failure criteria were treated with nasal CPAP prior to re-intubation. High-flow was administered via one device (Optiflow) while CPAP was either underwater bubble CPAP or delivered via the ventilator. If unanticipated extubation, infants were included in the trial if randomization occurred prior to extubation.
- Primary outcome: treatment failure within 7 days after extubation. Treatment failure was defined as an FiO2 of 0.2 above baseline value before extubation (goal oxygen saturation 88-92%); or pH <7.2 and capillary or arterial pCO2 >60 mmHg, >1 apneic episode requiring intermittent PPV within a 24 hr period or six or more apneic episodes requiring stimulation within 6 consecutive hours or an urgent need for reintubation and mechanical ventilation.
- Secondary outcomes: included reintubation within 7 days of extubation, requirement for supplemental oxygen at 36 wk gestation, pneumothorax, total days of any respiratory support, duration of oxygen supplementation, length of hospital admission.
- Analysis and Sample Size: Baseline assumption was that 25% of these infants. Prespecified margin of non-inferiroity for HFNC was 20% above the failure rate for nCPAP. This was not formally ascertained and was “arbitrary”. Using the absolute risk difference and 95% CI for the primary outcome, the Upper limit of the CI had to be below 20% and the lower limit had to be below 0. This required a sample size of 300 infants with a power of 87%.
- Patient follow-up: 100% of patients randomized were included in the primary analysis.
Treatment failure occurred in 52/152 (34.2%) infants randomized to high-flow nasal cannulae, and in 39/151 (25.8%) randomized to CPAP (absolute risk difference 8.4%; 95% confidence interval -1.9 to 18.7). This fell within the pre-specified margins, and was deemed non-inferior. Apnea was the most common cause of extubation in both groups.
In this non-inferiority trial, high-flow nasal cannulae was found to be non-inferior to nasal CPAP for preventing extubation failure.
Improving rates of extubation failure in very preterm infants remains an important and elusive goal. The importance of this issue is highlighted by the following facts: 1) exposure to and duration of mechanical ventilation is a risk factor for developing bronchopulmonary dysplasia and 2) the diagnosis of bronchopulmonary dyplasia increases the risk of poor neurodevelopmental outcome.1 Thus, it stands to reason that efforts to minimize exposure to mechanical ventilation will positively impact the long-term outcomes of very preterm infants. Accordingly, the effort to minimize an infants’ exposure to mechanical ventilation starts before intubation has even occurred (CPAP vs. prophylactic surfactant,2 and continues with efforts to optimize successful extubation. Both caffeine and post-extubation CPAP prevent extubation failure and are the standard-of-care for preterm infants.3, 4
Alternative methods of delivering positive distending pressure to preterm infants, including high-flow nasal cannula (HFNC), are widely used and increasingly popular. The stated and widely accepted advantages of HFNC are ease of use, increased comfort and potential for less nasal trauma. Unfortunately, scant data regarding the risks and benefits of HFNC leaves this practice relatively uninformed.
To inform our practice, Manley and colleagues determined whether HFNC performed similarly to nasal CPAP for preventing extubation failure in very preterm infants (<32 wks).5 This trial was both practical and clinically relevant. At randomization, the initial HFNC flow rate (5-6 lpm depending on prong size) and CPAP pressure (8 cm H2O) were standardized. From this point forward, clinicians set flow and pressure at their discretion. The authors did not attempt to measure delivered distending pressures as this is rarely, if ever, done clinically. Importantly, this was designed as a non-inferiority trial. In this study, non-inferiority was defined as 20 percentage points above the extubation failure rate for CPAP. This is perhaps the major potential criticism of this otherwise well done trial and has been commented on by several authors. 6 The authors themselves acknowledge this in their discussion stating: “the upper limit of the 95% CI was close to the margin of non-inferiority (20 percentage points) and slightly different failure rates in either group could have altered our conclusions.”5
The trial revealed that HFNC was non-inferior to CPAP in preventing extubation failure. Treatment failure occurred in 34.2% of the HFNC group and 25.8% in the CPAP group (risk difference, 8.4 percentage points, 95% confidence interval, -1.9 to 18.7). While this difference did not reach statistical significance, the upper limit of the 95% confidence interval bordered on the margin of non-inferiority. Furthermore, this difference was exaggerated in infants <26 wks gestational age. Specifically, 61.3% of infants <26 wks failed CPAP, while 81.3% of infants failed HFNC (see Table). Although the study was not powered to detect differences in this small subgroup of patients (63 infants), based on these data the authors urge caution when considering the use of HFNC in these patients. Also of note, approximately half of the patients failing HFNC were salvaged with CPAP, thus resulting in a lower (17.8%) re-intubation rate in patients randomized to HFNC compared to those randomized to CPAP (25.2%). The implication of this finding – that ultimately less infants initially randomized to HFNC reached “treatment failure” criteria – is unknown. Lastly, nasal trauma was infrequent and rates did not differ by group. However when analysis of nasal trauma was confined to new cases during assigned therapy, rates were higher in nCPAP than in HFNC (53% vs. 19.1%).
Where do these data leave us? Does HFNC perform similarly to CPAP for preventing extubation failure in very preterm infants (<32 wks GA)? Statistically, yes. However, the authors acknowledge that they “chose a generous non-inferiority margin.”7 Ultimately, does HFNC perform well enough compared to CPAP to justify its use to prevent extubation failure? Do these data support using HFNC along side CPAP as the standard of care? As the authors have pointed out, these data clearly argue against the routine use of HFNC following extubation for infants <26 wks. Furthermore, these data provide no compelling argument that HFNC should be considered as equivalent to nasal CPAP as the current standard of care as it relates to preventing extubation failure. However, these data would suggest that HFNC is safe and well tolerated, and warrants further study in the NICU. Moreover, in a follow-up article the same authors found nurses found HFNC much easier to use.
High-flow nasal cannulae, n/N (%) Nasal CPAP,n/N(%) Risk difference (95% CI), (%) All infants 52/152 (34.2) 39/151 (25.8) 8.4(-1.9, 18.7) Infants <26 weeks’ gestational age (n=63) 26/32 (81.3) 19/31 (61.3) 20.0 (-1.9, 41.8) Infants ≥ 26 weeks’ gestational age (n=240) 26/120 (21.7) 20/120 (16.7) 5.0 (-4.9, 14.9)
*Test for interaction effect of the assigned treatment on gestational age subgroups: P=0.14
Table: Treatment failure within seven days of extubation: overall and by gestational age subgroup.
- Schmidt B, Asztalos EV, Roberts RS, et al. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9.
- Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2012;3:CD000510.
- Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003:CD000143.
- Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev 2010:CD000139.
- Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med 2013;369:1425-33.
- DeMauro SB, Millar D, Kirpalani H. Noninvasive respiratory support for neonates. Curr Opin Pediatr 2014;26:157-62.
- Manley BJ, Owen LS, Davis PG. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med 2014;370:385-6.
- Roberts CT, Manley BJ, Dawson JA, Davis PG. Nursing perceptions of high-flow nasal cannulae treatment for very preterm infants. J Paediatr Child Health 2014;50:806-10.