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EBNEO commentary on HIPSTER trial on HFNC and nCPAP

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We would like to share one of our most recent EBNEO commentaries, on the recently published HIPSTER trial on whether HFNC is noninferior to nCPAP.

Please find full commentary on ebneo.org



The study question builds on the group’s earlier work, which demonstrated HFNC was noninferior to nCPAP as post-extubation support (1). Noninferiority trials are designed to show whether a new treatment is “not unacceptably less efficacious” than the standard of care (2). A new treatment that is nearly as effective may be acceptable to providers and patients if it is less invasive, less costly, or more convenient. (3) Of note, the authors defined 20% margin for noninferiority in their earlier study (1), a 10% difference in the rate of treatment failure between HFNC and nCPAP here may be too conservative.

In contrast to studies of HFNC as post-extubation support, (1, 4) Roberts et al found HFNC as primary support to be not only inferior to nCPAP, but the difference was obvious prior to full recruitment, and was significant in both the intention-to-treat and per-protocol analyses. The authors posit the higher rate of treatment failure in the HFNC group “may reflect its reduced effectiveness in infants with surfactant-deficient lungs.” Were this the case, the HFNC group should have had higher need for subsequent surfactant therapy than the CPAP group, but the rates of surfactant administration were equivalent. Treatment failure (in either group) may have occurred after the window during which surfactant is considered to be most efficacious (

Defining “treatment failure” by two objective and three somewhat subjective criteria complicates the interpretation of the results. Apnea in particular is subjective in terms of nursing documentation, and the inability to blind caregivers to mode of respiratory support may have impacted the perceived frequency and severity of apneic episodes. In practice, failure of noninvasive respiratory support typically means need for intubation and mechanical ventilation, but intubation rates during the treatment period were not significantly different between the HFNC and nCPAP groups. Approximately 30 infants on HFNC had treatment failure but stabilized on nCPAP; 40 infants failed HFNC and ultimately required intubation and surfactant. While this confirms something about nCPAP therapy was superior to HFNC, it seems unlikely to indicate such a substantial treatment effect that continued enrollment in the study would have been unsafe or unethical. Overall rates of intubation and pneumothorax were the same, length of stay was unchanged, and the rate of nasal breakdown Ihigher in the nCPAP group. It would be helpful to know if there was a clinically important increase in the frequency of pneumothorax and nasal breakdown specifically in the crossover group from HFNC to nCPAP. Because an increased cumulative oxygen exposure in the HFNC group is plausible, reporting the average FiO2 requirement for both groups also would be helpful.

Based on these findings, the standard use of HFNC as primary respiratory support in preterm infants who would otherwise receive CPAP cannot be recommended. However, the important complications of pneumothorax and intubation were ultimately not different between groups, nor did length of stay or cost of care differ significantly. This suggests HFNC may be an option for some infants without fear of significant adverse events.



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