Neonatal respiratory distress syndrome (RDS) is a disorder that mainly affects premature infants at <34 weeks of gestation. It occurs due to surfactant deficiency in the context of immature lungs, which prevents proper tissue oxygenation. RDS is a common cause of morbidity and mortality in preterm infants, with more severe diseases in smaller and more premature neonates.

The objective of respiratory management of preterm infants with or at risk of RDS is to maximize survival while minimizing potential adverse effects, such as bronchopulmonary dysplasia (BPD). The 2019 European Consensus Guidelines on the management of RDS recommend the early use of continuous positive airway pressure (CPAP) of at least 6 cm H₂O in all babies at risk of RDS who do not need intubation for delivery room stabilization (1). Early initiation of CPAP potentially reduces the need for mechanical ventilation and surfactant replacement (2, 3) while improving clinical outcomes (2, 4, 5).

Although RDS management has evolved dramatically over the last decade, almost half of the infants who are started on CPAP fail this therapy and are ultimately intubated (6, 7). It should be noted that CPAP failure is associated with an increased risk of death and morbidities, including BPD and pneumothorax (8–10).

Studies have shown that birth weight and male gender are risk factors for CPAP failure (9, 11–13). Furthermore, observational data demonstrate that a fraction of inspired oxygen (FiO₂) exceeding 0.30 in the first hours after birth in preterm neonates on CPAP is a reasonably good test to predict subsequent CPAP failure (9, 14). However, non-adherence to the recommended FiO₂ threshold is common in clinical practice (15, 16), which can have negative consequences such as the prolonged need for mechanical ventilation and increased incidence of adverse outcomes.

To mitigate CPAP failure, and in parallel with technological advances in the field of neonatal ventilators, different modes of non-invasive ventilation (NIV) have been introduced, with nasal intermittent positive-pressure ventilation (NIPPV) being the most frequently used alternative. This intervention has been found to have variable success rates in different studies (6, 17, 18). Heated and humidified oxygen delivered by a high-flow nasal cannula (HFNC) has also been studied as the first respiratory support. Still, it was found to be inferior to CPAP in terms of failure rate, and infants randomized to HFNC often need rescue therapy with CPAP to avoid intubation (19).

Although several studies have analyzed the factors associated with CPAP failure in premature infants, there is a lack of sufficient and updated data on the failure of the NIV methods currently used in clinical practice, including HFNC and NIPPV. We designed this observational and prospective study (VENTIS) to evaluate the incidence, predictive factors, and clinical outcomes of NIV failure in preterm infants at risk for RDS admitted to Spanish level-III neonatal intensive care units (NICUs).

Our observational study included 173 very preterm infants (GA < 32 weeks) who underwent NIV within the first 30 min after birth. The global incidence of NIV failure was 15.6%, and these patients required invasive MV for 72 h. This study allowed us to obtain new data on the global success of NIV in current clinical practice, including the most widely used NIV methods today. In our cohort, 56% of patients underwent CPAP, and 44% had NIPPV in the first 24 h of life. NIPPV was used more often to treat more immature babies and as rescue therapy for those about to fail. Therefore, individual analysis of NIPPV failure could not be performed. European guidelines recommend initiating CPAP of at least 6 cm H₂O, but the mean pressure with CPAP was significantly lower than with NIPPV on the first hour (5.4 vs. 7.1 cm H₂O) and this difference persisted throughout. It appears that use of NIPPV enabled clinicians to apply adequate distending pressure.

Previous studies focused only on the CPAP technique and found a higher percentage of failure (failure rates: 20.6%, Rocha et al. (13); 27.8%, Gulczynska et al. (14); 34%, De Jaegere et al. (12); 22%, Dargaville et al. (20). According to our data, if we consider only patients who underwent CPAP in the first 24 h of life, the failure rate was 14.6%. However, we must remember that the aforementioned studies included infants with different GA ranges, the use of LISA or INSURE was not standardized, and the most severe cases of RDS were treated with NIPPV. Dargaville et al. studied a cohort of 25–32 weeks GA patients in a large retrospective study and found a CPAP failure rate of 22%. Given that nearly a decade has passed since the Dargaville study, the higher percentage of success obtained in our cohort can be interpreted as an advance in the use of NIV and surfactant administration techniques or, in general, an improvement in early respiratory management in these patients (20). The Dargaville definition of CPAP failure is the need for mechanical ventilation within 72 h after birth. We used the same definition, but most of our patients received surfactant by a non-invasive technique and were kept on NIV. Therefore, despite using the same definitions, the groups were not comparable.

Given that new NIV methods are being used in addition to CPAP, and its early use has been shown to reduce the use of MV while improving clinical outcomes, it is of utmost importance to know which factors are predictive of NIV failure. Early identification of those premature infants who most likely fail NIV can allow specific therapeutic interventions to be aimed at them. The final multivariate model identified GA as an independent predictor of NIV failure. The risk of unfavorable outcomes increased by 37% with each week of gestational age. Gestational age has been associated with CPAP failure. Gulczyńska et al. found that each gestational week reduced the odds of CPAP failure by 19% in infants with <30 GA (19). Dargaville et al. found a significant association in the most premature infants, 25–28 weeks of GA, in whom each additional week reduced the risk of failure by 39% (9). However, in both cases and unlike our study, GA did not prove to be an independent predictor in multivariate logistic regression.

Interestingly, FiO₂ between the second and sixth hours of life was predictive of failure in our univariate model but was not significant in the multivariable model. Several authors have pointed out FiO₂ as a powerful predictor of CPAP failure (21). Specifically, Dargaville et al. found that a FiO₂ > 0.3 in the first hours of life was predictive of CPAP failure, and this threshold is used in current European RDS guidelines for early rescue administration of surfactants (1, 9). Due to the observational nature of the present study, the surfactant was administered following clinical practice, with a median FiO₂ slightly higher than that recommended in the European guidelines (1). Therefore, the statistically significant association between surfactant use and NIV failure should be interpreted with caution. This association probably exists because the VENTIS is an observational study and was not designed to evaluate the use of surfactants. All patients with mild RDS who did not receive surfactant were in the NIV success group, and all patients who failed NIV received surfactant at the time of intubation. Furthermore, the correct timing of surfactant use may have contributed to a higher percentage of success of non-invasive techniques. Therefore, proper adherence to the recommendations of the current European RDS guidelines can be confirmed. Early administration of surfactants, especially with the LISA technique using a thin catheter while continuing CPAP, reduces the need for subsequent MV (22–26).

Infants for whom NIV failed were at a considerably higher risk of adverse outcomes and morbidity than those successfully managed with NIV (9, 14, 20). Non-invasive ventilation failure was associated with a higher percentage of BPD and the composite outcome of moderate-to-severe BPD plus death. However, the number of deaths did not differ significantly between the success and failure groups. Furthermore, non-invasive respiratory support failure was associated with higher rates of other unfavorable outcomes, including pneumothorax, IVH, PVL, and pulmonary hemorrhage. All these complications have previously been related to RDS and prematurity, especially in seriously ill infants who need MV because non-invasive support fails. As in the Dargaville study, the duration of hospital stay and oxygen therapy was significantly higher in infants who failed NIV. We also observed that the need for home oxygen at discharge and duration of NIV were significantly higher in the failure group than in the success group. Our data show that the predictive variables for NIV failure evolve towards GA rather than FiO₂ in the initial hours if the current threshold recommendations for surfactant administration are followed. There is a need to improve respiratory management in premature infants to avoid unfavorable outcomes.

Our study had some limitations. This was an observational study, and the results obtained showed the variability of real-life clinical practice. Although we recorded the PEEP and MAP (median and IQR) for CPAP and NIPPV at intervals (first hour of life, first 24 h of life, 24–72 h of life), we did not record the level of support immediately before failure.

The incidence of NIV failure in our cohort of very preterm infants managed according to current RDS respiratory management standards was 15.6%. The lower failure rate observed compared with previous studies is most likely due to LISA and the newer NIV modes currently used in our units. The use of NIPPV likely facilitated the use of higher distending pressure. Gestational age remains the best predictor of NIV failure as primary respiratory support in premature infants. FiO₂ during the first hours of life was not an independent risk factor for NIV failure in our cohort, confirming that FiO₂> 0.3 is a good indicator for surfactant administration as recommended in the European guidelines for the management of RDS.