MANUSCRIPT CITATION:

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.

REVIEWED BY:

Clyde J. Wright, MD
Assistant Professor
University of Colorado School of Medicine and
Children’s Hospital Colorado

TYPE OF INVESTIGATION:

Therapeutics

QUESTION:

In preterm infants (<32 wks), how does high-flow nasal cannulae (HFNC) compare to nasal CPAP (nCPAP) for prevention of extubation failure?

METHODS:

• 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.
• Outcomes:
  • 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.

MAIN RESULT:

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.

CONCLUSION:

In this non-inferiority trial, high-flow nasal cannulae was found to be non-inferior to nasal CPAP for preventing extubation failure.

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COMMENTARY:

Improving rates of extubation failure in very preterm infants remains an important and elusive goal. Postextubation CPAP prevents extubation failure and is the standard of care for preterm infants [1,2]. Alternative methods of delivering positive distending pressure to preterm infants, including high-flow nasal cannula (HFNC), are widely used and increasingly popular. The stated advantages of HFNC are ease of use, increased comfort and less nasal trauma. Unfortunately, retrospective analysis suggests potential harm from HFNC use in VLBW infants, highlighting the urgent need for prospective, randomised controlled trials to guide clinical practice[3].

Manley and colleagues determined whether HFNC performed similarly to nasal CPAP for preventing extubation failure in very preterm infants (<32 weeks)[4]. The trial revealed that HFNC was noninferior to CPAP in preventing extubation failure. Importantly, noninferiority was defined as 20 percentage points above the extubation failure rate for CPAP. 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 noninferiority. A potential criticism of this otherwise well done trial has been using up to a 20% difference to define ‘noninferior’ [5].

Additionally, the difference in failure rate was exaggerated in infants <26 weeks gestational age. Specifically, 61.3% of infants <26 weeks failed CPAP, while 81.3% of infants failed HFNC. Although the study was not powered to detect differences in this small subgroup of patients (63 infants), the authors urge caution when considering the use of HFNC in these patients. Furthermore, approximately half of the patients failing HFNC were salvaged with CPAP, thus resulting in a lower (17.8%) re-intubation rate in patients randomised to HFNC compared to those randomised to CPAP (25.2%). Lastly, nasal trauma was infrequent and rates did not differ by group.

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’ [6]. Ultimately, does HFNC perform well enough compared to CPAP to justify its use to prevent extubation failure? 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.

	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.

REFERENCES

1. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev 2010:CD000139.
2. 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.
3. Taha DK, Kornhauser M, Greenspan JS, Dysart KC, Aghai ZH. High flow nasal cannula use is associated with increased morbidity and length of hospitalization in extremely low birthweight infants. J Pediatr 2016; 175: 50-5 e1.
4. 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.
5. DeMauro SB, Millar D, Kirpalani H. Noninvasive respiratory support for neonates. Curr Opin Pediatr 2014;26:157-62.
6. Manley BJ, Owen LS, Davis PG. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med 2014;370:385-6.