COMMENT Continuous positive airway pressure and high flow nasal cannula: the search for effectiveness continues Hany Aly 1 and Mohamed A. Mohamed 2 Pediatric Research (2020) 87:11–12; https://doi.org/10.1038/s41390-019-0626-y In this issue, Kanbar et al. 1 prospectively studied the cardiorespiratory behavior of preterm infants while receiving continuous positive airway pressure (CPAP) and high flow nasal cannula (HFNC). At the time of extubation, mechanically ventilated premature infants with birth weight <1250 g were randomly assigned to receive either one of the two modes. Crossover occurred after 45 min with infants who had received CPAP to be supported with HFNC and vice versa. The study did not find differences in cardiorespiratory parameters when alternating between the two non-invasive modalities. However, when receiving support via HFNC, infants experienced longer respiratory pauses (9.2 vs. 7.3 s) and some of them developed bradycardia that required tactile stimulation. During this short period of monitoring, infants required significantly higher oxygen concentration while supported with HFNC when compared to the time of CPAP support. 1 Respiratory support of premature infants has recently shown a significant shift towards non-invasive modalities. They have been used to facilitate the discontinuation of invasive mechanical ventilation as well as primary mode of support immediately after birth. 2 HFNC is thought to work via washout of the dead space in the nasopharynx. 2 In addition, gas flow via nasal cannula may provide a distending pressure. However, provided pressure may be inconsistent depending on multiple factors, including cannula caliber, infant weight, and gas flow rate. A recent study measured mean hypopharyngeal pressures of 2–6 cmH 2 O when using gas flows of 0.5–3 L/min via nasal cannula. However, peak pressures frequently measured >15 cmH 2 O when the flow rate was 2–3 L/ min. 3 Therefore, pressures delivered by nasal cannula with similar flow rates may be negligible or dangerously high. Furthermore, the current administration devices do not permit controlling or monitoring of the delivered pressure. The use of nasal cannula gained popularity in neonatal units mostly due to its convenient simplicity and therefore being preferred by nursing staff and parents. 2 CPAP delivers more consistent pressures than HFNC and cannot exceed what is intended to be delivered. When provided to spontaneously breathing premature infants, CPAP pressure allows several physiologic benefits that include stimulating the respira- tory drive splinting the airway and the diaphragm. Provided end- expiratory pressure maintains air sacs inflated, improves lung capacity, and decreases intrapulmonary ventilation–perfusion mismatch. 4 These mechanisms may explain shortened respiratory pauses and decreased oxygen requirement during CPAP use that is reported in this issue. 1 Multiple clinical trials were conducted to assess the efficacy of CPAP as a primary mode for respiratory support in premature infants. The three largest trials included infants with gestational ages of 24–27 weeks (Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) trial, n = 1316), 25–28 weeks (CPAP or INtubation (COIN) trial, n = 610), and 26–29 weeks (Dunn et al. trial, n = 648). 5–7 Bronchopulmonary dysplasia (BPD) was identified when infants required oxygen support at 36 weeks of postconceptual age. When compared to mechanical ventilation, early use of CPAP was not associated with BPD reduction in the SUPPORT (40% vs. 44%), the COIN (29% vs. 35%), or Dunn et al. (26% vs. 25%) trials. However, a meta-analysis including all CPAP trials reported a borderline reduction of BPD (relative risk (RR) = 0.91; confidence interval (CI): 0.81–1.01) and a significant reduction in the composite outcome of death or BPD (RR = 0.91; CI: 0.84–0.99). 8 The use of HFNC as the primary mode of respiratory support was recently studied in randomized controlled trials in premature infants. A large multicenter trial recruited 583 premature infants with gestational age ≥28 weeks aiming to compare HFNC to CPAP for early respiratory support without surfactant replacement therapy. Further recruitment for the study was stopped at the recommendation of the safety committee because of the significant inferiority of outcomes in infants who received HFNC. The rate of treatment failure was almost doubled with HFNC compared to CPAP (25.5% vs. 13.3%, p < 0.001). 9 A more recent trial was conducted on premature infants with older gestational age ≥31 weeks. The study recruited 754 infants and showed significant inferiority in outcomes when using HFNC. The treatment failure rate with HFNC was again double the CPAP failure rate (20.5% vs. 10.2%, p < 0.001). 10 As HFNC is significantly inferior in premature infants ≥28 weeks, it will be unlikely to conduct another trial with HFNC in the most vulnerable infants with gestational age <28 weeks. Since nasal cannula is convenient to use by caregivers and comfortable for infants when attached to their nose, a newer version (RAM cannula, Neotech, Valencia, CA) that has a back hub to attach to the ventilator has been designed with the hope to deliver CPAP to the infant. However, this type of interface does not allow laminar gas flow since both inspiratory and expiratory gas meet in the common hub; turbulent gas flow typically creates high resistance. Studies on the use of RAM cannula showed high airway resistance and significant decrease in the delivered pressure. 11 In addition, this type of NC has narrow lumens that are not suited to deliver well-heated and humidified gas, thereby exposing the Received: 22 July 2019 Revised: 18 September 2019 Accepted: 7 October 2019 Published online: 22 October 2019 1 Department of Neonatology, Cleveland Clinic Children’s, Cleveland, OH, USA and 2 Division of Newborn Services, The George Washington University Hospital, Washington, DC, USA Correspondence: Hany Aly (alyh@ccf.org) www.nature.com/pr © International Pediatric Research Foundation, Inc. 2019 1234567890();,: