Heated, Humidified High-Flow Nasal Cannula Versus Nasal CPAP for Respiratory Support in Neonates

Discussion

In this multicenter randomized trial involving neonates ≥28 weeks’ gestational age undergoing planned noninvasive respiratory support, we found no significant difference between HHHFNC and nCPAP with regard to the primary outcome of intubation within the initial 72 hours of support. In addition, we found no differences between infants randomly assigned to nCPAP compared with HHHFNC for several respiratory outcomes, including duration of oxygen supplementation, diagnosis of BPD, or discharge from the hospital on oxygen. Despite concerns over unregulated/unmonitored pressure delivery during HHHFNC support, we found no differences in the occurrence rate for any form of air leak. The outcome results from this relatively large randomized trial indicate that the use of HHHFNC, as described in this report, appears to be as effective and as safe as nCPAP in this population of infants.

The actual approach to “high-flow” nasal cannula must be carefully considered in evaluating all studies. Some investigators have described “high-flow” in the presence of flow limited to 1 to 2 lpm and in the absence of a well-heated, humidified gas source for flow. Flow limitation has been based on earlier studies from Locke et al⁵ and Sreenan et al⁶ suggesting the potential for high, unregulated positive airway pressure. Over the past decade, systems have been designed to allow much higher flow rates (2–8 lpm for neonates and up to 50 lpm in adults) accompanied by optimal heating (37°C) and humidification (100%) of the delivered gas. We, and others, have defined this system of NC therapy as heated, humidified high-flow nasal cannula or HHHFNC.¹⁹ Recent studies have reported much lower airway pressures using HHHFNC, both indirectly via pharyngeal or esophageal pressure measurement and, in an animal model of neonatal respiratory distress, directly via intratracheal pressure monitor.^20–23 The importance of the NC interface in the potential delivery of airway pressure should not be minimized. In recent neonatal studies, external NC diameters were typically limited to <3 mm. This size appears to be a critical dimension for neonatal HHHFNC, because Locke et al⁵ demonstrated that high airway pressures were measurable with a cannula diameter of 3 mm but not when the cannula was 2 mm in diameter. All infants in our study were managed with NC having an external diameter of <3 mm, with 95% measuring <2.0 mm.

Several retrospective and observational studies have been published suggesting that HHHFNC may be effective and safe in managing preterm infants with respiratory dysfunction.^8,12–14 It is important to differentiate findings from these reports from those of other investigations in which high-flow nasal cannula has been applied with the use of inadequately heated/humidified gas at significantly lower flow rates. Abdel-Hady et al²⁴ reported that weaning from nCPAP to high-flow NC limited to 2 lpm was associated with longer duration of oxygen and respiratory support compared with infants maintained on nCPAP until weaned directly to room air. In their study, not only was NC flow rate limited but the gas conditioning may have been inadequate. Campbell et al²⁵ reported in 40 infants that “HF-CPAP” [high-flow CPAP], administered via standard NC, was less effective at preventing reintubation than nCPAP. There were limitations in NC flow rate (range: 1.4–1.7 lpm) and gas conditioning similar to those in the Abdel-Hady et al study, and “HF-CPAP” pressures were assumed rather than measured. The importance of adequate gas conditioning to upper and lower airway function is well described and includes reduced metabolic work, maintained ciliary function, prevention of airway desiccation and squamous epithelial cell injury, reduced inspiratory work of breathing, and improved lung mechanics.^7,19,26–28

With the inclusion of HHHFNC as a mode of “positive pressure” support, we found a slight but significant increase in days of any positive pressure support among infants randomly assigned to HHHFNC. This increase was associated with an extended use of HHHFNC in that study group. The reasons for this are unclear. We were not able to identify differences between groups in bedside nurse or respiratory therapist assessment of patient comfort, device humidification, or ease of use. This result is in contrast to recent pediatric and adult studies reporting improved patient comfort with HHHFNC compared with nCPAP.^29,30 Although we did not find a measureable difference in nursing/respiratory therapist assessment, a potential “preference” by care providers may still have existed and contributed to the median 2-day increased time infants in the HHHFNC study group were managed on the study mode. Despite the difference in duration of positive pressure support we did not observe sustained long-term effects between infants managed on nCPAP compared with HHFNC based on similar duration of oxygen support, BPD rates among preterm infants, length of hospitalization, and home oxygen use.

Similar to the study by Miller and Dowd¹³ we did not identify any difference in preventing early intubation between the different HHHFNC devices used. However, numbers were small and the power to detect any difference was limited.

There are several limitations to our study. First, the study groups could not be blinded. Given that more infants in the nCPAP group were switched to HHHFNC after the initial 72-hour study window, it is possible that HHHFNC may have been preferred by the bedside providers. In addition, in some centers it became more difficult over time to get permission to approach parents about study participation due to clinical provider preference for 1 mode of support over the other (more often HHHFNC than nCPAP); given limited study resources we were unable to track this additional source of potential study bias. Thus, some degree of bias cannot be completely ruled out. We did not measure pressure at any point in the airway. Other studies have measured these pressures in similar or smaller infant populations by using flow rates comparable to those we used.^21–23 Given the large number of infants enrolled and the multiple centers participating, we determined that measurement efforts would be problematic. We did restrict enrollment to infants ≥28 weeks’ gestational age. This restriction was due to the presence of competing studies initiated at several centers before the HHHFNC/nCPAP trial that involved infants <28 weeks and/or <1000 g, and in which the use of HHHFNC was specifically proscribed. Other large randomized trials will be needed to investigate the efficacy and safety of HHHFNC use in this population. Because the majority of infants had a primary diagnosis of respiratory distress syndrome, we cannot necessarily infer that the apparent effectiveness and safety of HHHFNC compared with nCPAP will be found for all types of neonatal respiratory diseases. Finally, we did not limit participation to only those infants being extubated from mechanical ventilator support. Approximately one-third of the study population was randomly assigned before any mechanical ventilation, and the majority were already on early CPAP support. Given the significant trend over the past decade to use noninvasive modes of respiratory support to prevent intubation and mechanical ventilation, we decided that it would be important to include any infants deemed candidates for nCPAP as appropriate study participants. We found similar early failure rates regardless of prestudy respiratory support mode, suggesting this was a reasonable assumption.

By the study design, we planned to achieve 80% power to detect a 50% risk reduction in early intubation between nCPAP and HHHFNC by assuming a pooled outcome rate of 15% and 420 subjects. The actual pooled primary outcome rate observed was 9.5% in the study based on a total of 432 study patients. On the basis of the actual n and observed outcome rates, we obtained 80% power to detect a 60% relative risk reduction. Assuming the observed rates for early intubation remain the same (8.2% vs 10.8%), a total of 3000 infants would need to be randomly assigned to the 2 study groups to demonstrate statistical significance with a power of 80% and a P value <0.05.