High vs Low CPAP Strategy with Aerosolized Calfactant in Preterm Infants with Respiratory Distress Syndrome

Background. CPAP levels used for respiratory distress syndrome are variable. Optimal CPAP strategy to prevent CPAP failure is unknown. Objective. To evaluate the risk of CPAP failure in infants treated with high vs low CPAP strategy while receiving aerosolized calfactant in the AERO-02 clinical trial and AERO-03 expanded access program. Methods. Comparisons were made between low and high CPAP groups (Low, 4-7 cm H 2 0; High, 8-10 cm H 2 0). Results. Low and high CPAP groups had 215 and 106 infants respectively. CPAP failure and pneumothorax were not different between the groups. Odds of CPAP failure was not different after adjustment for baseline characteristics (OR = 0.61; 95% CI: 0.29, 1.24). Conclusion. We found no difference in CPAP failure among infants who received aerosolized calfactant that were treated with high vs low CPAP strategy. E�cacy of high CPAP strategy with less invasive surfactant treatment needs to be evaluated in future studies.


Background
2][3][4][5] Continuous positive airway pressure (CPAP) is the most commonly used mode of NIV.CPAP recruits lungs, maintains functional residual capacity, improves gas exchange, and decreases the work of breathing.CPAP also helps to stent open airways and prevent apnea.
CPAP failure is associated with adverse outcomes such as death, bronchopulmonary dysplasia, pneumothorax, intraventricular hemorrhage, and prolonged hospitalization. 6,7Prevention of CPAP failure is of high importance to avoid these undesirable outcomes. 8Aerosolized calfactant has been shown to decrease CPAP failure in patients with RDS.The AERO-02 clinical trial (NCT03058666) revealed that aerosolized calfactant decreased the need for intubation and liquid surfactant instillation by nearly 50%. 9,10ring the AERO-02 clinical trial and the AERO-03 expanded access program by our study group, we noted that CPAP level use was highly variable ranging from 4-10 cm H 2 0. 11 The optimal CPAP pressure needed to avoid CPAP failure is unknown and is currently under investigation. 12In this study we evaluate the e cacy of a high CPAP strategy (8-10 cm H 2 0) compared to a low CPAP strategy (4-7 cm H 2 0) while receiving aerosolized calfactant in preventing CPAP failure.We hypothesize that high CPAP strategy with aerosolized calfactant decreases CPAP failure within the rst 72 hours of life.

Methods
We performed a secondary analysis of preterm infants with RDS who received aerosolized calfactant under the AERO-02 clinical trial and the AERO-03 expanded access program.AERO-02 was conducted from 2017 to 2018 in 22 level III-IV Neonatal Intensive Care Units (NICUs) as a pragmatic randomized clinical trial (NCT03058666) comparing aerosolized calfactant (Infasurf®; ONY Biotech, Amherst, NY) to the usual care for that NICU in newborns with early mild to moderate RDS. 9 AERO-03 prospectively collected data from 2018-2023 of aerosolized calfactant use in 13 level III-IV NICUs after written informed consent was obtained from each infant's parent(s) or guardian. 11bjects from AERO-02 were included if neonates were between 1 and 12 hours of life with suspected mild to moderate RDS on NIV, who had not previously received surfactant.Details on the inclusion and exclusion criteria have been previously published. 9AERO-03 fell under the expanded access program that allowed further use of the study device for delivery of aerosolized calfactant.The protocol for aerosolized calfactant administration and the determination of failure was similar to AERO-02, but unlike AERO-02, there was no randomization.Clinical care apart from the aerosolized calfactant administration was based on the usual care standards and guidelines of that particular NICU.The decision to intubate and administer liquid surfactant was also at provider discretion.
Participants in both AERO-02 and AERO-03 received 6 mL/kg body weight (210 mg phospholipids/kg body weight) calfactant suspension through a modi ed Solarys® nebulizer (Trudell Medical, London, ON).The patient end of the Solarys® nebulizer was modi ed to resemble a paci er with the tip shaped as an inverted dome to direct the aerosolized calfactant into the oropharynx.The device is secured to the infant with a bonnet.The rate of delivery was 0.20 ± 0.02 mL/min.Aerosol delivery was independent of the respiratory device attached to the patient.The aerosolized calfactant treatment could be administered up to 3 times in the rst 72 hours of life.
Prospectively collected data were obtained from the AERO-02 and AERO-03 databases.Analysis was restricted to subjects with gestational age between 29 0/7 -36 6/7 weeks and on CPAP at the time of initiation of aerosolized calfactant treatment.Infants were divided into two groups based on level of CPAP (Low, 4-7 cm H 2 0; High, 8-10 cm H 2 0).One center that was part of both AERO-02 and AERO-03 was at a high-altitude environment located in Provo, UT at 4,549 feet (1,387 m) above sea level.
Correction for FiO2 was done by multiplying FiO2 by 0.85 to account for lower atmospheric pressure at this center's altitude.Data were described using frequencies and percentages for categorical factors or with the median and interquartile range (IQR) for continuous characteristics.Chi-square and Wilcoxon rank-sum tests were used to make comparisons between groups.Logistic regression was used to determine the association between demographic characteristics and odds of CPAP failure, which was de ned as intubation for liquid surfactant administration or need for mechanical ventilation.Statistical signi cance was de ned as p < 0.05 with no adjustment for multiple testing.All analyses were done using R (v. 4.2.1). 13he study protocols (AERO-02 & AERO-03) were approved by a national IRB, Western IRB (Olympia, WA).
The University of Wisconsin-Madison's Institutional Review Board granted exemption status for this study.

Results
A total of 321 infants born between 29 0/7 and 36 6/7 weeks were included in the study.There were 126 infants from AERO-02 and 195 from AERO-03 (Fig. 1).The study cohort was divided into a low CPAP group (215 infants) and a high CPAP group (106 infants).Median CPAP level in the low CPAP group was 6 cm H 2 0 and median CPAP level in the high CPAP group was 10 cm H 2 0. Baseline characteristics of the two groups are presented in Table 1.Gestational age was higher in the high CPAP group (32.9 weeks in low CPAP group vs 34 weeks in high CPAP group).The high CPAP group was older and had lower FiO2 levels at time of rst aerosolization; those in the high CPAP group also received fewer aerosol treatments overall (Table 1).2).There was no difference in incidence of CPAP failure in each of the gestational age subgroups (Fig. 2).Pneumothorax and death were also not different between the two groups (Table 2).Odds of CPAP failure was not different (OR = 0.61; 95% CI: 0.29, 1.24) between the two groups after adjustment for baseline characteristics (Table 3).Younger gestational age and higher respiratory severity score at the start of treatment showed strong associations with the odds of CPAP failure.

Discussion
This secondary analysis of AERO-02 and AERO-03 showed that both high CPAP and low CPAP strategies with aerosolized calfactant administration resulted in similar rates of CPAP failure within the rst 72 hours of life.Incidence of pneumothorax in infants managed with high CPAP strategy was no different to infants managed with low CPAP strategy.
Animal studies have demonstrated that high CPAP resulted in improved pulmonary outcomes such as early respiratory transition, improved compliance and oxygenation. 14,15In clinical practice CPAP of 4-8 cm H 2 0 is typically reported during the early phase of RDS.There are no clinical trial data on the use of high CPAP levels.Some inferences, however, can be made from clinical trials on CPAP following extubation.Kidman et al, recently reported that extubation of extremely preterm infants to higher CPAP (10 cm H 2 0) signi cantly reduced extubation failure compared with extubation to standard CPAP (7 cm H 2 0), without increasing rates of adverse effects. 16However, it should be noted that this trial recruitment was stopped at 74% of the planned sample size.Buzzella and colleagues also reported reduction of extubation failure with higher CPAP at 7-9 cm H 2 0 compared to 4-6 cm H 2 0. 17 Risk of pneumothorax is a concern with the use of high CPAP levels.In the current study we didn't nd a difference in the likelihood of pneumothorax between the two groups, but it should be noted that infants in both groups received aerosolized calfactant.Clinical trials on high CPAP for post extubation respiratory support also reported no increased risk of pneumothorax with high CPAP, but those infants were also treated with surfactant. 16,17Risk of pneumothorax in infants not treated with surfactant might be higher, especially if a higher FiO2 threshold is used for surfactant treatment. 18lmost all infants (102 out of 106) in the high CPAP group came from a single center where starting CPAP of 10 cm H 2 0 is the standard of care for preterm infants with RDS.These infants were monitored closely with a neonatologist performing targeted echocardiography to ensure adequate cardiac output.In addition, this center is also in a high-altitude environment.Because of the lower atmospheric pressure at this altitude, the inspired oxygen pressure also decreases so that room air FiO 2 is approximately 0.175 at this location.Any additional oxygen these neonates received would also be lower than the cohort treated closer to sea level.
The number of patients on respiratory support was higher at days 3, 7 and 28 in the high CPAP group.This nding should be interpreted with caution given data was only available for 22 subjects in the high CPAP group.Additionally, the need for respiratory support in this high CPAP group might be due to slower weaning of respiratory support given the patients were started at higher CPAP level rather than actual lung disease and were in a high-altitude environment.
Prevention of CPAP failure is an important area in neonatology that requires further investigation.Early identi cation of at-risk infants and measures to prevent CPAP failure needs to be studied in larger cohorts and in randomized clinical trials.High CPAP strategy with less invasive surfactant administration (aerosolized, thin catheter based or supraglottic surfactant) is a physiologically plausible method to prevent CPAP failure.High CPAP would recruit alveoli, prevent atelectasis and maintain functional residual capacity.This strategy is supported by evidence from trials investigating high CPAP extubation.However, potential bene ts need to be balanced with potential risks of air leaks and the effect on hemodynamics as high CPAP can result in decreased cardiac output due to decreased venous return into the right atrium.In addition, overdistension of alveoli due to high CPAP could result in compression of pulmonary capillaries leading to increased pulmonary vascular resistance.
Given the theoretical physiological bene ts and relative safety of combining a high CPAP strategy with less invasive surfactant treatment as shown in this study, we suggest that this strategy needs to be investigated further in prospective multi center cohort studies or pilot clinical trials.Such studies should include routine targeted neonatal echocardiography for careful monitoring of the hemodynamic status.Clear guidance on weaning of respiratory support is also needed to avoid prolonged need for respiratory support.
This study investigated a novel concept of high CPAP strategy with aerosolized calfactant treatment.Use of prospectively collected data is another strength of the study.However, there are notable limitations.First, this is a secondary analysis of previously collected data, so should be considered hypothesis generating.Second, 96% of the infants in the high CPAP group came from a single center at a highaltitude environment making generalization of this data to other centers di cult.Third, respiratory outcome data after the early phase of RDS was only available for a subset of infants.

Table 1
Incidence of CPAP failure was not different between the two groups (24.2% in low CPAP group vs 24.5% in high CPAP group) (Table * Room air FiO 2 is approximately 0.175 at the high altitude center

Table 3
Multivariable logistic regression for odds of CPAP failure

Table 4
Respiratory support at day 3, 7 and 28 for infants in the AERO-02 trial