Response to Aerosolized Calfactant in Infants with Respiratory Distress Syndrome; A Post-hoc Analysis of AERO-02 trial

Response to Aerosolized Calfactant in Infants with Respiratory Distress Syndrome; A Post-hoc Analysis of AERO-02 trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Response to Aerosolized Calfactant in Infants with Respiratory Distress Syndrome; A Post-hoc Analysis of AERO-02 trial Dinushan Kaluarachchi, Henry Zapata, Heather Becker, Michael Lasarev, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2531840/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jul, 2023 Read the published version in Journal of Perinatology → Version 1 posted 9 You are reading this latest preprint version Abstract Background The largest randomized control trial of aerosolized surfactant (AERO-02 trial) demonstrated a reduction in intubation by 50%. Objective To determine the response after aerosolized calfactant treatment. Methods We conducted a post-hoc analysis of moderate to late preterm neonates in the AERO-02 trial. Trends in hourly fraction of oxygen (FiO2), mean airway pressure (MAP) and respiratory severity score (RSS) were compared between the aerosolized surfactant (AS) and usual care (UC) groups. Results Forty-eight percent of subjects in the UC group required intubation compared to 24% in the AS group. FiO2, MAP and RSS were lower in the UC group. FiO2 decrease was seen after the first aerosolized calfactant dose. Conclusion FiO2, MAP and RSS were lower in the UC group. This is likely due to early and higher rate of liquid surfactant administration in the UC group. Decrease in FiO2 was noted in the AS group after the first aerosolization. Health sciences/Diseases/Respiratory tract diseases Health sciences/Health care/Therapeutics Respiratory Distress Syndrome Surfactant Aerosolized Surfactant Calfactant Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Surfactant replacement therapy is an effective treatment for infants with respiratory distress syndrome. 1–3 There are several minimally invasive techniques utilized for surfactant administration; INtubation-SURfactant-Extubation technique 4 , thin catheter surfactant administration 5,6 , surfactant administration through laryngeal or supraglottic airways 7 and aerosolized surfactant 8 . Aerosolized surfactant administration is the least invasive method of administering exogenous surfactant as it doesn’t involve laryngoscopy or other instrumentation. The largest randomized controlled trial of aerosolized surfactant to date (AERO-02) reported that aerosolized calfactant decreased the need for intubation and liquid surfactant instillation by nearly a half. 9 Aerosolized calfactant was delivered through a modified Solarys® nebulizer designed to resemble a pacifier and to allow the surfactant to be delivered directly into the infant’s oropharynx. In this post hoc analysis, we report results on oxygenation response to aerosolized calfactant among moderate to late preterm infants with RDS in the AERO-02 trial. We also sought to identify predictors of improved oxygenation after aerosolized calfactant treatment. Methods This is a post-hoc analysis of the AERO-02 randomized controlled clinical trial that compared aerosolized calfactant (Infasurf®; ONY Biotech, Amherst, NY) to usual care in newborns with early mild to moderate respiratory distress syndrome in 22 level III or IV NICUs in the United States. Newborns who were non-intubated, had not previously received surfactant, were > 1 hour but < 12 hours of age, and had suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by nasal continuous positive airway pressure, high-flow nasal cannula, or noninvasive ventilation were eligible for inclusion in the AERO-02 trial. Exclusion criteria were a congenital anomaly limiting care or requiring surgery; hypotension with metabolic acidosis (a base deficit > 10 mEq/L); hypoxemia (O2 saturation = 60 mm Hg) unresponsiveness to intervention; grade 3 or 4 intraventricular brain hemorrhage; or acute hypoxic encephalopathy, defined as disturbed neurologic function, including abnormal tone and/or reflexes for gestational age, after a suspected perinatal hypoxic- ischemic event, as evidenced by a 5-minute Apgar score < 5 and/or umbilical cord acidosis (pH = 16 mmol/L). The aerosol group received 6 mL/kg body weight (210 mg phospholipids/kg body weight) calfactant suspension through a modified Solarys® nebulizer. Infants in the aerosol group could receive up to 3 doses during the first 72 hours of age. Further care was determined based on the usual care standards and guidelines of that particular NICU. The control group was also managed according to standard local NICU protocols and infants were intubated and given liquid surfactant for persistent or worsening respiratory distress per provider discretion. For this post hoc analysis, we included moderate to late preterm infants who are born at 28 0/6–36 6/7 weeks of gestation at birth. This gestational age range was selected as these subjects have the highest likelihood for having RDS (confirmatory chest X ray was not required by the study protocol) and likely to benefit from aerosolized calfactant treatment. Groups were analyzed according to the treatment received (aerosolized calfactant vs usual care). Demographic, procedural, outcome and safety data were collected prospectively for the AERO-02 clinical trial. Prospective data collection included recording of FiO2 before and up to 4 hours after each aerosolized calfactant treatment. Hourly respiratory support data (mode of respiratory support, respiratory support settings including mean airway pressure (MAP) and fraction of oxygen (FiO2) were collected from birth to 96 hours of life by a retrospective chart review following the conclusion of the clinical trial. When MAP was not given, MAP was calculated or estimated as presented in Table 1. 10 Respiratory severity score (RSS) was calculated as, RSS = MAP x FiO2. The University of Wisconsin-Madison’s Institutional Review Board granted exemption status for this study. Statistical Analysis Data were calculated using frequencies and percentages for categorical factors or with the median and interquartile range (IQR) for continuous characteristics. Chi-square or Wilcoxon rank-sum tests were used to make comparisons between groups (usual care vs aerosolized calfactant). Time to first instillation of surfactant was analyzed using Kaplan-Meier methods with time censored at 72 hours if the event did not occur by that time. Pseudo values for time to instillation were created at six fixed points in time and used in a generalized estimating equation (GEE) to estimate the difference in risk between groups. 11,12 Poisson regression was used to estimate the rate of instillation events within the first 72 hours for each group and compare rates between groups. Linear mixed-effect models were used estimate changes in MAP, FiO2, and RSS over time within the first 72 hours of randomization and to compare these profiles over time between groups. Time was treated as a fixed effect and entered these models by way of restricted cubic splines with four knots (placed at 12, 24, 48, and 60 hours) to account for potential non- linear behavior; individual subject was treated as a random effect. Similar mixed-effect models were fit to changes in FiO2 during the first four hours of the study but with time (seven discrete points) treated as a factor instead of a continuous term. The model was used to estimate average FiO2 just prior to and four hours after the first aerosolization as well as the difference in FiO2 between these moments. Change in FiO2 before and 4 hours after each aerosolized calfactant administration was compared. Change in FiO2 after first aerosolized calfactant treatment was analyzed by gestational age (GA), birthweight (BW), age at randomization, and RSS subgroups. Statistical significance was defined as p < 0.05 with no adjustment for multiple testing. All analyses were done using R (v. 4.2.1). 13 Results A total of 457 subjects were included in AERO-02 clinical trial. Seventy-five subjects were excluded due to either ineligibility or gestational age being outside of 28 0/7–36 6/7 weeks. Sixteen subjects were excluded due to undocumented time of randomization. Thirteen more subjects were excluded due to incomplete or inconsistent data related to time of randomization and time of intubation/instillation (Fig. 1). These exclusions brought the effective sample size to 353 subjects with 164 subjects who received usual care (UC group) and 189 subjects who received aerosolized calfactant (AC group). Demographic and clinical characteristics at baseline were comparable between the two groups (Table 2 ). Study outcomes for two groups are presented in Table 3 . Intubation for liquid surfactant instillation occurred in 95 infants (47.6%) for the usual care group and 45 infants (23.8%) for the aerosol group (RR = 0.50; 95% CI: 0.37–0.67, p < 0.001). Subjects in the UC group were intubated at median age of 5 hours compared to median age of 22 hours in the AC group. The Kaplan-Meier curve (Fig. 2 ) shows the cumulative incidence of liquid surfactant instillation with UC group needing significantly higher liquid surfactant instillations compared to AC group over time (p < 0.001; log-rank test). Higher number of infants in the AC group were on respiratory support at 3 days of life but other short term respiratory outcomes (respiratory support at 7 days, pneumothorax and bronchopulmonary dysplasia), mortality and length of stay were not different between the two groups (Table 3 ). Table 1 Criteria for mean airway pressure (MAP) calculation or estimation based on mode of respiratory support Mode of Respiratory Support Mean Airway Pressure Calculation or Estimation Mechanical Ventilation MAP = PEEP + {[PIP-PEEP] x [I time x rate/ 60]} Non-invasive positive pressure ventilation MAP = PEEP + {[PIP-PEEP] x [I time x rate/ 60]} Continuous positive pressure airway pressure MAP = CPAP level High flow nasal canula > = 2L MAP = Flow in liters per min (LPM) Low flow nasal canula < 2L MAP = 1 Room air MAP = 0 Table 2 Characteristics of the study cohort. Median (IQ) or number (%) Characteristic Usual Care Group (n = 164) Aerosolized Surfactant Group (n = 189) P Value Gestational age (weeks) 33.0 (31.0, 34.6) 32.6 (31.3, 34.1) 0.68 Birth weight (Kg) 1.90 (1.53, 2.38) 1.91 (1.48, 2.40) 0.93 Male sex 96 (58.5) 107 (56.6) 0.72 Singleton birth 118 (72.0) 127 (67.2) 0.33 Vaginal delivery 50 (30.5) 46 (24.3) 0.19 Antenatal steroids None 12 hours Unknown 31 (18.9) 37 (22.6) 86 (52.4) 10 (6.1) 35 (18.5) 34 (18.0) 106 (56.1) 14 (7.4) 0.72 APGAR score at 5 minutes 8 (8, 9) 8 (8, 9) 0.99 Age at randomization 3 [ 2 , 6 ] 4 [ 2 , 6 ] 0.06 Respiratory support at randomization NIPPV CPAP HFNC Room air 25 (15.2) 131 (79.9) 7 (4.3) 1 (0.6) 39 (20.6) 145 (76.7) 5 (2.6) 0 (0.0) 0.34 FiO2 at randomization 0.26 (0.21–0.30) 0.26 (0.21–0.30) 0.45 RSS at randomization 1.68 (1.26, 2.10) 1.50 (1.26, 2.10) 0.26 Table 3 Outcomes of the study cohort. Median (IQ) or number (%) Characteristic Usual Care Group (n = 164) Aerosolized Surfactant Group (n = 189) P Value Intubation and liquid surfactant instillation 78 (47.6) 45 (23.8) < 0.001 Age at first liquid surfactant instillation (hrs) 5 (3, 14) 22 (12, 34) < 0.001 Pneumothorax 4 (2.4) 8 (4.2) 0.35 Respiratory support at 3 days No support Nasal canula CPAP Mechanical ventilation 61 (37.2) 19 (11.6) 73 (44.6) 11 (6.7) 63 (33.3) 8 (4.2) 100 (52.9) 18 (9.5) 0.03 Respiratory support at 7 days No support Nasal canula CPAP Mechanical ventilation 102 (62.6) 17 (10.4) 38 (23.3) 6 (3.7) 100 (52.9) 17 (9.0) 65 (34.4) 7 (3.7) 0.15 Bronchopulmonary dysplasia 3 (3.7) 6 (3.2) 0.80 Length of stay (days) 25 (13.29) 28 (15, 29) 0.23 Death 1 (0.6) 0(0.0) 1.00 Trends in hourly FiO2, MAP, and RSS are given for both groups for the first 72 hours. Mixed-effect models indicate these profiles of the average response over time differ between groups for FiO2 (p < 0.001), MAP (p < 0.001), and RSS (p < 0.001) where UC care group had lower FiO2, MAP, and RSS compared to AC group (Fig. 3 ). Trends in FiO2 over time during the first 4 hours after the first, second, and third aerosolization treatments are shown for infants in the AC group (Fig. 4 ). FiO2 decrease was seen after the first aerosolized calfactant treatment (p < 0.001), but it did not differ after second (p = 0.08) or third doses (p = 0.14) (Table 4 ). Table 4 Change in FiO2 before and 4 hours after aerosolized calfactant treatment. Mean and 95% CI Number of treatments FiO2 before treatment FiO2 4 hours after treatment Change in FiO2 P Value First 0.28 (0.27, 0.30) 0.26 (0.25, 0.28) -0.02 (-0.03, -0.01) < 0.001 Second 0.31 (0.28, 0.34) 0.29 (0.26, 0.32) -0.02 (-0.04, 0.0) 0.08 Third 0.32 (0.29, 0.35) 0.34 (0.31, 0.37) 0.02 (-0.01, 0.05) 0.14 FiO2 decrease was seen in subgroups of 32 0/6–36 6/7 weeks (p = 0.003), BW > 1500g (p = 0.02), treatment prior to 4 HOL (p 1.5 (p < 0.001) after the first aerosolized calfactant administration (Table 5 ). However, there was no evidence to suggest that changes in FiO2 differed by subgroups of gestational age (p = 0.99), birth weight (p = 0.52), age at randomization (p = 0.56) or RSS at the time of randomization (p = 0.20). Table 5 Change in FiO2 before and 4 hours after the first aerosolized calfactant treatment for sub groups. Mean and 95% CI Subgroup FiO2 before treatment FiO2 4 hours after treatment Change in FiO2 P Value Gestational age 28 0/7–31 6/7 32 0/7–36 6/7 0.29 (0.26, 0.31) 0.28 (0.26, 0.30) 0.27 (0.24, 0.30) 0.26 (0.24, 0.28) -0.01(-0.03, 0.0) -0.02(-0.03, -0.01) 0.11 0.003 Birth Weight 2500 0.27 (0.24, 0.30) 0.28 (0.26, 0.30) 0.30 (0.27, 0.33) 0.26 (0.23, 0.29) 0.26 (0.24, 0.29) 0.28 (0.24, 0.31) -0.01(-0.03, 0.01) -0.02(-0.03, -0.0) -0.03(-0.05, -0.0) 0.21 0.02 0.02 Age at randomization 0–4 5–8 9–12 0.30 (0.28, 0.32) 0.26 (0.23, 0.29) 0.25 (0.21, 0.29) 0.27 (0.25, 0.29) 0.26 (0.23, 0.29) 0.24 (0.20, 0.28) -0.03(-0.04, -0.01) -0.01(-0.03, 0.02) -0.01(-0.04, 0.02) < 0.001 0.64 0.40 RSS at randomization 2.0 0.25 (0.23, 0.27) 0.29 (0.27, 0.31) 0.31 (0.28, 0.33) 0.24 (0.22, 0.26) 0.26 (0.24, 0.28) 0.28 (0.26, 0.30) -0.01(-0.02, 0.01) -0.03(-0.05, -0.01) -0.03(-0.04, -0.01) 0.46 < 0.001 0.003 Discussion First clinical trials on aerosolized surfactant were done in 1960s. These studies used nebulized beta-gamma-dipalmitoyl-L-alpha-lecithin with no apparent beneficial effects. 14,15 Since then there have been several aerosolized surfactant clinical trials that have reported variable results. 9, 16–22 The AERO-02 trial which is the largest aerosolized surfactant clinical trial to date demonstrated that aerosolized calfactant is safe and efficacious. 9 This post hoc analysis of the AERO-02 trial specifically investigating moderate to late preterm infants revealed that treatment with aerosolized calfactant decreased the need for intubation and liquid surfactant by 51% compared to subjects receiving usual care. These findings are consistent with the original AERO-02 results. 9 We found that that FiO2, MAP and RSS were lower in the UC group. This is most likely due to early and higher rate of liquid surfactant administration in the UC group leading to rapidly improved oxygenation with therapy. Despite higher FiO2, MAP, and RSS, the AS group had similar short term secondary outcomes except for having a higher number of subjects on respiratory support on day 3 of life. However, it should be noted that respiratory support at 3 days was not different between the two groups if all subjects within the specified gestational age range were accounted for (Supplemental Table 1). Furthermore, there was no difference in short term secondary outcomes between the groups for the whole AERO-02 study cohort. 9 A modest decrease in FiO2 was noted in the AS group after the first aerosolization but importantly no elevation in FiO2 which required liquid surfactant treatment. We saw no decrease in FiO2 following second or third doses of aerosolized calfactant indicating that there might be no additional benefits from repeat doses. Similar to AERO-02, Minocchieri and collegues reported promising results that aerosolized surfactant is efficacious in preventing the need for intubation and liquid surfactant. 21 Another randomized clinical trial investigating efficacy of four dosing schedules reported that infants who received AS were less likely to receive intubation within 72 h compared to historical controls. 20 However, Curoneb trial, a randomized controlled trial to investigate the efficacy of nebulized poractant alfa was halted early due to a change in the benefit-risk balance of the intervention driven by a negligible efficacy. 22 A recent met-analysis concluded that surfactant nebulization reduced the intubation rate in preterm infants with a higher efficacy for specific subgroups. 23 It should be noted that this result was mainly driven by the results from the AERO-02 trial as more than 1/3 of subjects out of 9 included studies in this meta-nalysis were from AERO-02. This study redemonstrated the efficacy of aerosolized calfactant in preventing the need for intubation and liquid surfactant. It also gives insight as to how aerosolized calfactant improved respiratory function in subjects with RDS. It is likely that surfactant distribution and dispersion in distal airspaces prevents alveolar collapse and improves gas exchange leading to better oxygenation. Calfactant’s relatively low viscosity compared with other commercial surfactants may be beneficial for aerosolization. 24 AERO-02 also used a delivery system that does not require a respiratory circuit interface which is also an added advantage. 9 Flow driven delivery system used in the AERO-02 doesn’t require an external power source which is advantageous in low resource settings. Response to aerosolized surfactant was clearly less compared to intratracheal liquid surfactant administration as demonstrated by lower FiO2, MAP and RSS in the usual care group where significantly higher number of infants received early intratracheal liquid surfactant. Amount of surfactant delivered by aerosolization depends on multiple factors including particle size, respiratory effort, airway flow velocity and pressure etc. 8 A considerable portion of a delivered surfactant dose is lost before surfactant descends below alveolar ducts. However, infants in our analysis who were treated with aerosolized surfactant had a modest improvement in oxygenation and avoided the need for intubation. Avoiding intubation has significant clinical benefits since it is associated with a number of adverse effects such as hypoxia, bradycardia, alterations in blood pressure and airway injury. 25 Efficacy of aerosolized surfactant has been mainly demonstrated in more mature preterm infants. 9,20−22 This might be due to less severe surfactant deficiency among more mature preterm infants. Amount of surfactant delivered by aerosolization in these infants might be enough to prevent progressive atelectasis and worsening of the disease process. Since more moderate to late preterm infants are born compared to more immature infants, these infants account for nearly a half of the infants needing surfactant. 26 Hence, aerosolized surfactant will likely benefit a large portion of patients cared for in the neonatal clinical practice. On the other hand, more immature preterm infants likely require a higher dose of exogenous surfactant delivered into distal air spaces. Further studies using a higher dose of aerosolized surfactant and/ or prophylactic/ early rescue treatment is warranted to investigate the efficacy of aerosolized surfactant in this population. It is important to identify infants who are most likely to benefit from aerosolized surfactant treatment. A significant decrease in FiO2 after aerosolized treatment was seen in subgroups of 32 0/6–36 6/7, birth weight > 1500g, treatment prior to 4 hours of life and RSS > 1.5. Similarly sized decreases in FiO2 were seen in all other subgroups as well but these trends didn’t reach statistical significance. There was no evidence to suggest that change in FiO2 differed by subgroups. We think the observed statistical difference in above subgroups was seen because of the larger number of subjects in those specific subgroups. Further studies are needed to determine optimal criteria to identify patients who are most likely to benefit from aerosolized surfactant. This study presents detailed information on response to aerosolized calfactant treatment in the largest aerosolized surfactant clinical trial to date. However, there are several limitations to this study. We evaluated a selective sample of infants born at 28 0/6–36 6/7 weeks in this post-hoc analysis. These moderate to late preterm infants accounted for 83% of the original trial cohort. We selected this specific subgroup as these infants are likely to benefit from aerosolized calfactant treatment. We had to exclude 29 more subjects due to missing or inconsistent data, all from the UC group. These exclusions effectively decreased the original study cohort by 23%. Hourly respiratory support data during the first 96 hours were collected retrospectively but all other data including FiO2 during the 4 hours after aerosolization treatment were collected prospectively. While randomized, the AERO-02 trial was not a blinded trial. The decision to intubate and administer liquid surfactant was not defined by the study and left up to the clinical provider. Safe and efficacious aerosolized surfactant to treat RDS will allow replacement of exogenous surfactant without any potentially harmful airway instrumentation or manipulation. It avoids positive pressure breaths and the need for sedative medications. The infant can be maintained on a non-invasive mode of respiratory support during the surfactant administration while maintaining the functional residual capacity. The noninvasive nature of aerosolized surfactant will allow early administration of exogenous surfactant which should enhance the success of noninvasive respiratory support strategy to treat RDS. Aerosolized surfactant has important global health implications as the administration is simple and not procedurally challenging. Even in high income countries, this will allow treatment of neonates with RDS in local intensive care units without needing to transfer to a higher level of care facility. Conclusion Aerosolized calfactant treatment of moderate to late preterm infants with RDS resulted in decreased need for intubation by nearly one half compared to infants receiving usual care. A modest decrease in FiO2 was noted in the AS group after the first aerosolization. Early and higher rate liquid surfactant administration in the UC group resulted in lower FiO2, MAP and RSS in the UC group. Despite relatively higher FiO2, MAP, and RSS, the AS group had similar short term respiratory outcomes while avoiding intubation and liquid surfactant. Declarations Funding source: none Conflicts of Interest statement: PF and SG have worked for and received payments from ONY Biotech in the past. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgement: All AERO-02 study investigators, Melissa Brown, Corey Commaroto, ONY Biotech Inc. References Polin RA, Carlo WA, Committee on Fetus and Newborn; American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics. 2014; 133:156–63. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update. Neonatology. 2019; 115:432–50. Ng EH, Shah V, Fetus and Newborn Committee; Canadian Paediatric Society. Guidelines for surfactant replacement therapy in neonates. Paediatr Child Health. 2021; 26:35–49. IsayamaT, Chai-Adisaksopha C, McDonald SD. Noninvasive ventilation with vs without early surfactant to prevent chronic lung disease in preterm infants: a systematic review and meta-analysis. JAMA Pediatr. 2015;169:731–739. Herting E, Härtel C, Göpel W.Less invasive surfactant administration: best practices and unanswered questions. Curr Opin Pediatr2020; 32:228–234. Kakkilaya V, Gautham SK. Should less invasive surfactant administration (LISA) become routine practice in US neonatal units? Pediatr Res 2022 Aug 19;1–11. Zapata HA, Fort P, Roberts KD, Kaluarachchi DC, Guthrie SO. Surfactant Administration Through Laryngeal or Supraglottic Airways (SALSA): A Viable Method for Low-Income and Middle-Income Countries. Front Pediatr. 2022; 10:853831. Brasher M, Raffay TM, Cunningham MD, Abu Jawdeh EG. Aerosolized Surfactant for Preterm Infants with Respiratory Distress Syndrome. Children. 2021;8 :493. Cummings JJ, Gerday E, Minton S, Katheria A, Albert G, Flores-Torres J, et al. Aerosolized Calfactant for Newborns with Respiratory Distress: A Randomized Trial. Pediatrics. 2020;146(5). Kielt MJ, Logan JW, Backes CH, Conroy S, Reber KM, Shepherd EG, et al. Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia. 2022;242:129–136.e2. Klein JP, Logan B, Harhoff M, and Anderson PK. Analyzing survival curves at a fixed point in time. Statistics in Medicine. 2007; 26:4505–4519. Anderson PK and Perme MP. Pseudo-observations in survival analysis. Statistical Methods in Medical Reearch. 2010; 19:71–99. R Core Team. (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Robillard F, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Micro- aerosol administration of synthetic beta-gamma-dipalmitoyl-L-alpha- lecithin in the respiratory distress syndrome. A preliminary report. Can. Med. Assoc. J. 1964; 90: 55–7. Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH. Neo- natal pulmonary ischemia: Clinical and physiologic studies. Pediatrics 1967; 40: 709–82. Jorch G, Weller E, Murlat A, Hentschel R. Feasibility study on nebulization of bovine surfactant (SF-RI 1) by pharyngeal continuous positive airway pressure (CPAP). Biol. Neonate 1994, 66. Berggren E, Liljedahl M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al. Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Acta Pediatr. 2000, 89, 460–464. Finer NN, Allen Merritt T, Bernstein G, Job L, Mazela J, Segal R. An Open Label, Pilot Study of Aerosurf Combined with nCPAP to Prevent RDS in Preterm Neonates. J. Aerosol. Med. Pulm. Drug Deliv. 2010, 23, 303–309. Sood BG, Cortez J, Kolli M, Sharma A, Delaney-Black V, Chen X. Aerosolized surfactant in neonatal respiratory distress syndrome: phase I study. Early Hum Dev. 2019; 134:19–25. Sood B, Thomas R, Delaney-Black V, Xin Y, Sharma A, Chen X. Aerosolized beractant in neonatal respiratory distress syndrome: a randomized fixed-dose parallel-arm phase II trial. Pulm Pharm & Ther. 2021; 66:101986. Minocchieri S, Berry CA, Pillow JJ, CureNeb Study Team. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019; 104: F313-F319. Dani C, Talosi G, Piccinno A, et al. A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome. J Pediatr. 2022;246:40–47 e45. Gaertner VD, Thomann J, Bassler D, Ruegger CM. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics. 2021;148(5). Kim K, Choi SQ, Zell ZA, Squires TM, Zasadzinski JA. Effect of cholesterol nanodomains on monolayer morphology and dynamics. Proc Natl Acad Sci USA 2013; ;110:E3054-60. Hatch LD, Grubb PH, Lea AS, Walsh WF, Markham MH, Maynordet PO, et al. Endotracheal intubation in neonates: A prospective study of adverse safety events in 162 infants. J Pediatr 2016; 168:62–66. Trembath A, Hornik CP, Clark R, Smith PB, Daniels J, Laughon M, et al. Comparative effectiveness of surfactant preparations in premature infants. The Journal of pediatrics 2013;163:955–60. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementaryTable1.docx Supplementary Table 1 Cite Share Download PDF Status: Published Journal Publication published 10 Jul, 2023 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 24 Feb, 2023 Review # 1 received at journal 19 Feb, 2023 Review # 2 received at journal 04 Feb, 2023 Reviewer # 2 agreed at journal 03 Feb, 2023 Reviewer # 1 agreed at journal 03 Feb, 2023 Reviewers invited by journal 03 Feb, 2023 Submission checks completed at journal 31 Jan, 2023 First submitted to journal 30 Jan, 2023 Editor assigned by journal 30 Jan, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2531840","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":173211626,"identity":"bb582511-724f-413a-b383-3854194c54ab","order_by":0,"name":"Dinushan Kaluarachchi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8334-6282","institution":"University of Wisconsin - Madison","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Dinushan","middleName":"","lastName":"Kaluarachchi","suffix":""},{"id":173211627,"identity":"5a048eb0-0029-4248-8e06-63617a8c91ce","order_by":1,"name":"Henry Zapata","email":"","orcid":"","institution":"University of Wisconsin - Madison","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Henry","middleName":"","lastName":"Zapata","suffix":""},{"id":173211628,"identity":"17354fbd-10bf-4391-8c49-592d47cd0d9d","order_by":2,"name":"Heather Becker","email":"","orcid":"","institution":"University of Wisconsin-Madison","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Heather","middleName":"","lastName":"Becker","suffix":""},{"id":173211629,"identity":"2f2a7c17-c514-4cbb-9e8a-b4dc42e86f0b","order_by":3,"name":"Michael Lasarev","email":"","orcid":"https://orcid.org/0000-0002-1896-2705","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Lasarev","suffix":""},{"id":173211630,"identity":"9c7f76aa-856a-4bb2-8686-0136a2dcdb81","order_by":4,"name":"Prem Fort","email":"","orcid":"","institution":"John's Hopkins All Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Prem","middleName":"","lastName":"Fort","suffix":""},{"id":173211631,"identity":"e5b82bbb-3ebf-424a-9aa4-9d163dd2efbd","order_by":5,"name":"Scott Guthrie","email":"","orcid":"https://orcid.org/0000-0001-9703-5266","institution":"Tennessee Initiative for Perinatal Quality Care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Scott","middleName":"","lastName":"Guthrie","suffix":""}],"badges":[],"createdAt":"2023-01-31 02:55:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2531840/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2531840/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41372-023-01717-1","type":"published","date":"2023-07-10T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":32609189,"identity":"46ca3fdf-c1eb-4c74-84f3-cc571f291857","added_by":"auto","created_at":"2023-02-07 19:37:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":13691,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Cohort\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/81a0d82ebdc308dbe86ba606.png"},{"id":32609190,"identity":"e84ed6ae-ce16-459a-a66b-8fce353594aa","added_by":"auto","created_at":"2023-02-07 19:37:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":56127,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve demonstrating time to first liquid surfactant instillation for aerosolized surfactant and usual care groups\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/006758ceb5728a5cc809bd0f.png"},{"id":32609193,"identity":"970c2440-dad5-405d-9093-4b66b4828136","added_by":"auto","created_at":"2023-02-07 19:37:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":329372,"visible":true,"origin":"","legend":"\u003cp\u003eTrends of fraction of oxygen (a), mean airway pressure (b), respiratory severity score (c) for aerosolized calfactant and usual care groups for 72 hours from time of randomization.\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/099287d415ef18c877ac8df0.png"},{"id":32609456,"identity":"bfcd2e97-e485-426c-a91c-efe19812b2da","added_by":"auto","created_at":"2023-02-07 19:45:59","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":217024,"visible":true,"origin":"","legend":"\u003cp\u003eTrends of fraction of oxygen after first (a), second (b) and third (c) aerosolized calfactant treatment.\u003c/p\u003e","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/8da5f14c7da3bbc614d08bcf.png"},{"id":39837178,"identity":"483c8275-b2a7-4deb-9045-1e8c9193f458","added_by":"auto","created_at":"2023-07-11 07:09:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":820440,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/10bff334-edbf-4917-ad30-5398b829c007.pdf"},{"id":32609455,"identity":"c0464c29-7d6f-4da7-a6f9-1e056ceb08e7","added_by":"auto","created_at":"2023-02-07 19:45:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15192,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1\u003c/p\u003e","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2531840/v1/b42fbe76a2cf25c0a6c48852.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Response to Aerosolized Calfactant in Infants with Respiratory Distress Syndrome; A Post-hoc Analysis of AERO-02 trial","fulltext":[{"header":"Background","content":"\u003cp\u003eSurfactant replacement therapy is an effective treatment for infants with respiratory distress syndrome.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e There are several minimally invasive techniques utilized for surfactant administration; INtubation-SURfactant-Extubation technique \u003csup\u003e4\u003c/sup\u003e, thin catheter surfactant administration \u003csup\u003e5,6\u003c/sup\u003e, surfactant administration through laryngeal or supraglottic airways \u003csup\u003e7\u003c/sup\u003e and aerosolized surfactant\u003csup\u003e8\u003c/sup\u003e. Aerosolized surfactant administration is the least invasive method of administering exogenous surfactant as it doesn\u0026rsquo;t involve laryngoscopy or other instrumentation.\u003c/p\u003e \u003cp\u003eThe largest randomized controlled trial of aerosolized surfactant to date (AERO-02) reported that aerosolized calfactant decreased the need for intubation and liquid surfactant instillation by nearly a half. \u003csup\u003e9\u003c/sup\u003e Aerosolized calfactant was delivered through a modified Solarys\u0026reg; nebulizer designed to resemble a pacifier and to allow the surfactant to be delivered directly into the infant\u0026rsquo;s oropharynx.\u003c/p\u003e \u003cp\u003eIn this post hoc analysis, we report results on oxygenation response to aerosolized calfactant among moderate to late preterm infants with RDS in the AERO-02 trial. We also sought to identify predictors of improved oxygenation after aerosolized calfactant treatment.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eThis is a post-hoc analysis of the AERO-02 randomized controlled clinical trial that compared aerosolized calfactant (Infasurf\u0026reg;; ONY Biotech, Amherst, NY) to usual care in newborns with early mild to moderate respiratory distress syndrome in 22 level III or IV NICUs in the United States.\u003c/p\u003e \u003cp\u003eNewborns who were non-intubated, had not previously received surfactant, were \u0026gt;\u0026thinsp;1 hour but \u0026lt;\u0026thinsp;12 hours of age, and had suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by nasal continuous positive airway pressure, high-flow nasal cannula, or noninvasive ventilation were eligible for inclusion in the AERO-02 trial. Exclusion criteria were a congenital anomaly limiting care or requiring surgery; hypotension with metabolic acidosis (a base deficit\u0026thinsp;\u0026gt;\u0026thinsp;10 mEq/L); hypoxemia (O2 saturation\u0026thinsp;\u0026lt;\u0026thinsp;88%) or hypercapnia (arterial partial pressure of carbon dioxide [PaCO2]\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;60 mm Hg) unresponsiveness to intervention; grade 3 or 4 intraventricular brain hemorrhage; or acute hypoxic encephalopathy, defined as disturbed neurologic function, including abnormal tone and/or reflexes for gestational age, after a suspected perinatal hypoxic- ischemic event, as evidenced by a 5-minute Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;5 and/or umbilical cord acidosis (pH\u0026thinsp;\u0026lt;\u0026thinsp;7.0 and/or based deficit\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;16 mmol/L).\u003c/p\u003e \u003cp\u003eThe aerosol group received 6 mL/kg body weight (210 mg phospholipids/kg body weight) calfactant suspension through a modified Solarys\u0026reg; nebulizer. Infants in the aerosol group could receive up to 3 doses during the first 72 hours of age. Further care was determined based on the usual care standards and guidelines of that particular NICU. The control group was also managed according to standard local NICU protocols and infants were intubated and given liquid surfactant for persistent or worsening respiratory distress per provider discretion.\u003c/p\u003e \u003cp\u003eFor this post hoc analysis, we included moderate to late preterm infants who are born at 28 0/6\u0026ndash;36 6/7 weeks of gestation at birth. This gestational age range was selected as these subjects have the highest likelihood for having RDS (confirmatory chest X ray was not required by the study protocol) and likely to benefit from aerosolized calfactant treatment. Groups were analyzed according to the treatment received (aerosolized calfactant vs usual care).\u003c/p\u003e \u003cp\u003eDemographic, procedural, outcome and safety data were collected prospectively for the AERO-02 clinical trial. Prospective data collection included recording of FiO2 before and up to 4 hours after each aerosolized calfactant treatment. Hourly respiratory support data (mode of respiratory support, respiratory support settings including mean airway pressure (MAP) and fraction of oxygen (FiO2) were collected from birth to 96 hours of life by a retrospective chart review following the conclusion of the clinical trial. When MAP was not given, MAP was calculated or estimated as presented in Table\u0026nbsp;1.\u003csup\u003e10\u003c/sup\u003e Respiratory severity score (RSS) was calculated as, RSS\u0026thinsp;=\u0026thinsp;MAP x FiO2.\u003c/p\u003e \u003cp\u003eThe University of Wisconsin-Madison\u0026rsquo;s Institutional Review Board granted exemption status for this study.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were calculated using frequencies and percentages for categorical factors or with the median and interquartile range (IQR) for continuous characteristics. Chi-square or Wilcoxon rank-sum tests were used to make comparisons between groups (usual care vs aerosolized calfactant). Time to first instillation of surfactant was analyzed using Kaplan-Meier methods with time censored at 72 hours if the event did not occur by that time. Pseudo values for time to instillation were created at six fixed points in time and used in a generalized estimating equation (GEE) to estimate the difference in risk between groups.\u003csup\u003e11,12\u003c/sup\u003e Poisson regression was used to estimate the rate of instillation events within the first 72 hours for each group and compare rates between groups.\u003c/p\u003e \u003cp\u003eLinear mixed-effect models were used estimate changes in MAP, FiO2, and RSS over time within the first 72 hours of randomization and to compare these profiles over time between groups. Time was treated as a fixed effect and entered these models by way of restricted cubic splines with four knots (placed at 12, 24, 48, and 60 hours) to account for potential non- linear behavior; individual subject was treated as a random effect.\u003c/p\u003e \u003cp\u003eSimilar mixed-effect models were fit to changes in FiO2 during the first four hours of the study but with time (seven discrete points) treated as a factor instead of a continuous term. The model was used to estimate average FiO2 just prior to and four hours after the first aerosolization as well as the difference in FiO2 between these moments.\u003c/p\u003e \u003cp\u003eChange in FiO2 before and 4 hours after each aerosolized calfactant administration was compared. Change in FiO2 after first aerosolized calfactant treatment was analyzed by gestational age (GA), birthweight (BW), age at randomization, and RSS subgroups.\u003c/p\u003e \u003cp\u003eStatistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 with no adjustment for multiple testing. All analyses were done using R (v. 4.2.1). \u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 457 subjects were included in AERO-02 clinical trial. Seventy-five subjects were excluded due to either ineligibility or gestational age being outside of 28 0/7\u0026ndash;36 6/7 weeks. Sixteen subjects were excluded due to undocumented time of randomization. Thirteen more subjects were excluded due to incomplete or inconsistent data related to time of randomization and time of intubation/instillation (Fig.\u0026nbsp;1). These exclusions brought the effective sample size to 353 subjects with 164 subjects who received usual care (UC group) and 189 subjects who received aerosolized calfactant (AC group).\u003c/p\u003e \u003cp\u003eDemographic and clinical characteristics at baseline were comparable between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Study outcomes for two groups are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Intubation for liquid surfactant instillation occurred in 95 infants (47.6%) for the usual care group and 45 infants (23.8%) for the aerosol group (RR\u0026thinsp;=\u0026thinsp;0.50; 95% CI: 0.37\u0026ndash;0.67, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Subjects in the UC group were intubated at median age of 5 hours compared to median age of 22 hours in the AC group. The Kaplan-Meier curve (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e) shows the cumulative incidence of liquid surfactant instillation with UC group needing significantly higher liquid surfactant instillations compared to AC group over time (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; log-rank test). Higher number of infants in the AC group were on respiratory support at 3 days of life but other short term respiratory outcomes (respiratory support at 7 days, pneumothorax and bronchopulmonary dysplasia), mortality and length of stay were not different between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCriteria for mean airway pressure (MAP) calculation or estimation based on mode of respiratory support\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMode of Respiratory Support\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean Airway Pressure Calculation or Estimation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical Ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;PEEP + {[PIP-PEEP] x [I time x rate/ 60]}\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-invasive positive pressure ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;PEEP + {[PIP-PEEP] x [I time x rate/ 60]}\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContinuous positive pressure airway pressure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;CPAP level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh flow nasal canula\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;2L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;Flow in liters per min (LPM)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow flow nasal canula\u0026thinsp;\u0026lt;\u0026thinsp;2L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRoom air\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u0026thinsp;=\u0026thinsp;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study cohort. Median (IQ) or number (%)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUsual Care Group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;164)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAerosolized Surfactant Group (n\u0026thinsp;=\u0026thinsp;189)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.0 (31.0, 34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.6 (31.3, 34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.90 (1.53, 2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.91 (1.48, 2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96 (58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107 (56.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingleton birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118 (72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127 (67.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaginal delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal steroids\u003c/p\u003e \u003cp\u003eNone\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;12 hours\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;12 hours\u003c/p\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (18.9)\u003c/p\u003e \u003cp\u003e37 (22.6)\u003c/p\u003e \u003cp\u003e86 (52.4)\u003c/p\u003e \u003cp\u003e10 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (18.5)\u003c/p\u003e \u003cp\u003e34 (18.0)\u003c/p\u003e \u003cp\u003e106 (56.1)\u003c/p\u003e \u003cp\u003e14 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPGAR score at 5 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8, 9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (8, 9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory support at randomization\u003c/p\u003e \u003cp\u003eNIPPV\u003c/p\u003e \u003cp\u003eCPAP\u003c/p\u003e \u003cp\u003eHFNC\u003c/p\u003e \u003cp\u003eRoom air\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (15.2)\u003c/p\u003e \u003cp\u003e131 (79.9)\u003c/p\u003e \u003cp\u003e7 (4.3)\u003c/p\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (20.6)\u003c/p\u003e \u003cp\u003e145 (76.7)\u003c/p\u003e \u003cp\u003e5 (2.6)\u003c/p\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFiO2 at randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.26 (0.21\u0026ndash;0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.26 (0.21\u0026ndash;0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRSS at randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.68 (1.26, 2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.50 (1.26, 2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes of the study cohort. Median (IQ) or number (%)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUsual Care Group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;164)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAerosolized Surfactant Group (n\u0026thinsp;=\u0026thinsp;189)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntubation and liquid surfactant instillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (47.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at first liquid surfactant instillation (hrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3, 14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (12, 34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory support at 3 days\u003c/p\u003e \u003cp\u003eNo support\u003c/p\u003e \u003cp\u003eNasal canula\u003c/p\u003e \u003cp\u003eCPAP\u003c/p\u003e \u003cp\u003eMechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (37.2)\u003c/p\u003e \u003cp\u003e19 (11.6)\u003c/p\u003e \u003cp\u003e73 (44.6)\u003c/p\u003e \u003cp\u003e11 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (33.3)\u003c/p\u003e \u003cp\u003e8 (4.2)\u003c/p\u003e \u003cp\u003e100 (52.9)\u003c/p\u003e \u003cp\u003e18 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory support at 7 days\u003c/p\u003e \u003cp\u003eNo support\u003c/p\u003e \u003cp\u003eNasal canula\u003c/p\u003e \u003cp\u003eCPAP\u003c/p\u003e \u003cp\u003eMechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102 (62.6)\u003c/p\u003e \u003cp\u003e17 (10.4)\u003c/p\u003e \u003cp\u003e38 (23.3)\u003c/p\u003e \u003cp\u003e6 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 (52.9)\u003c/p\u003e \u003cp\u003e17 (9.0)\u003c/p\u003e \u003cp\u003e65 (34.4)\u003c/p\u003e \u003cp\u003e7 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchopulmonary dysplasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (13.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (15, 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTrends in hourly FiO2, MAP, and RSS are given for both groups for the first 72 hours. Mixed-effect models indicate these profiles of the average response over time differ between groups for FiO2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), MAP (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and RSS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) where UC care group had lower FiO2, MAP, and RSS compared to AC group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTrends in FiO2 over time during the first 4 hours after the first, second, and third aerosolization treatments are shown for infants in the AC group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). FiO2 decrease was seen after the first aerosolized calfactant treatment (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but it did not differ after second (p\u0026thinsp;=\u0026thinsp;0.08) or third doses (p\u0026thinsp;=\u0026thinsp;0.14) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in FiO2 before and 4 hours after aerosolized calfactant treatment. Mean and 95% CI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of treatments\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFiO2 before treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFiO2 4 hours after treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChange in FiO2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003cp\u003e(0.27, 0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003cp\u003e(0.25, 0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.02\u003c/p\u003e \u003cp\u003e(-0.03, -0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003cp\u003e(0.28, 0.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003cp\u003e(0.26, 0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.02\u003c/p\u003e \u003cp\u003e(-0.04, 0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThird\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003cp\u003e(0.29, 0.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003cp\u003e(0.31, 0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003cp\u003e(-0.01, 0.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFiO2 decrease was seen in subgroups of 32 0/6\u0026ndash;36 6/7 weeks (p\u0026thinsp;=\u0026thinsp;0.003), BW\u0026thinsp;\u0026gt;\u0026thinsp;1500g (p\u0026thinsp;=\u0026thinsp;0.02), treatment prior to 4 HOL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and RSS\u0026thinsp;\u0026gt;\u0026thinsp;1.5 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after the first aerosolized calfactant administration (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). However, there was no evidence to suggest that changes in FiO2 differed by subgroups of gestational age (p\u0026thinsp;=\u0026thinsp;0.99), birth weight (p\u0026thinsp;=\u0026thinsp;0.52), age at randomization (p\u0026thinsp;=\u0026thinsp;0.56) or RSS at the time of randomization (p\u0026thinsp;=\u0026thinsp;0.20).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in FiO2 before and 4 hours after the first aerosolized calfactant treatment for sub groups. Mean and 95% CI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubgroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFiO2 before treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFiO2 4 hours after treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChange in FiO2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003cp\u003e28 0/7\u0026ndash;31 6/7\u003c/p\u003e \u003cp\u003e32 0/7\u0026ndash;36 6/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.29 (0.26, 0.31)\u003c/p\u003e \u003cp\u003e0.28 (0.26, 0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27 (0.24, 0.30)\u003c/p\u003e \u003cp\u003e0.26 (0.24, 0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.01(-0.03, 0.0)\u003c/p\u003e \u003cp\u003e-0.02(-0.03, -0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Weight\u003c/p\u003e \u003cp\u003e\u0026lt;=1500\u003c/p\u003e \u003cp\u003e1501\u0026ndash;2500\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.27 (0.24, 0.30)\u003c/p\u003e \u003cp\u003e0.28 (0.26, 0.30)\u003c/p\u003e \u003cp\u003e0.30 (0.27, 0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.26 (0.23, 0.29)\u003c/p\u003e \u003cp\u003e0.26 (0.24, 0.29)\u003c/p\u003e \u003cp\u003e0.28 (0.24, 0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.01(-0.03, 0.01)\u003c/p\u003e \u003cp\u003e-0.02(-0.03, -0.0)\u003c/p\u003e \u003cp\u003e-0.03(-0.05, -0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003cp\u003e0.02\u003c/p\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at randomization\u003c/p\u003e \u003cp\u003e0\u0026ndash;4\u003c/p\u003e \u003cp\u003e5\u0026ndash;8\u003c/p\u003e \u003cp\u003e9\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.30 (0.28, 0.32)\u003c/p\u003e \u003cp\u003e0.26 (0.23, 0.29)\u003c/p\u003e \u003cp\u003e0.25 (0.21, 0.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27 (0.25, 0.29)\u003c/p\u003e \u003cp\u003e0.26 (0.23, 0.29)\u003c/p\u003e \u003cp\u003e0.24 (0.20, 0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.03(-0.04, -0.01)\u003c/p\u003e \u003cp\u003e-0.01(-0.03, 0.02)\u003c/p\u003e \u003cp\u003e-0.01(-0.04, 0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.64\u003c/p\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRSS at randomization\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.5\u003c/p\u003e \u003cp\u003e1.51-2.0\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25 (0.23, 0.27)\u003c/p\u003e \u003cp\u003e0.29 (0.27, 0.31)\u003c/p\u003e \u003cp\u003e0.31 (0.28, 0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.24 (0.22, 0.26)\u003c/p\u003e \u003cp\u003e0.26 (0.24, 0.28)\u003c/p\u003e \u003cp\u003e0.28 (0.26, 0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.01(-0.02, 0.01)\u003c/p\u003e \u003cp\u003e-0.03(-0.05, -0.01)\u003c/p\u003e \u003cp\u003e-0.03(-0.04, -0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFirst clinical trials on aerosolized surfactant were done in 1960s. These studies used nebulized beta-gamma-dipalmitoyl-L-alpha-lecithin with no apparent beneficial effects.\u003csup\u003e14,15\u003c/sup\u003e Since then there have been several aerosolized surfactant clinical trials that have reported variable results.\u003csup\u003e9, 16\u0026ndash;22\u003c/sup\u003e The AERO-02 trial which is the largest aerosolized surfactant clinical trial to date demonstrated that aerosolized calfactant is safe and efficacious. \u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis post hoc analysis of the AERO-02 trial specifically investigating moderate to late preterm infants revealed that treatment with aerosolized calfactant decreased the need for intubation and liquid surfactant by 51% compared to subjects receiving usual care. These findings are consistent with the original AERO-02 results.\u003csup\u003e9\u003c/sup\u003e We found that that FiO2, MAP and RSS were lower in the UC group. This is most likely due to early and higher rate of liquid surfactant administration in the UC group leading to rapidly improved oxygenation with therapy.\u003c/p\u003e \u003cp\u003eDespite higher FiO2, MAP, and RSS, the AS group had similar short term secondary outcomes except for having a higher number of subjects on respiratory support on day 3 of life. However, it should be noted that respiratory support at 3 days was not different between the two groups if all subjects within the specified gestational age range were accounted for (Supplemental Table\u0026nbsp;1). Furthermore, there was no difference in short term secondary outcomes between the groups for the whole AERO-02 study cohort.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA modest decrease in FiO2 was noted in the AS group after the first aerosolization but importantly no elevation in FiO2 which required liquid surfactant treatment. We saw no decrease in FiO2 following second or third doses of aerosolized calfactant indicating that there might be no additional benefits from repeat doses.\u003c/p\u003e \u003cp\u003eSimilar to AERO-02, Minocchieri and collegues reported promising results that aerosolized surfactant is efficacious in preventing the need for intubation and liquid surfactant.\u003csup\u003e21\u003c/sup\u003e Another randomized clinical trial investigating efficacy of four dosing schedules reported that infants who received AS were less likely to receive intubation within 72 h compared to historical controls. \u003csup\u003e20\u003c/sup\u003e However, Curoneb trial, a randomized controlled trial to investigate the efficacy of nebulized poractant alfa was halted early due to a change in the benefit-risk balance of the intervention driven by a negligible efficacy. \u003csup\u003e22\u003c/sup\u003e A recent met-analysis concluded that surfactant nebulization reduced the intubation rate in preterm infants with a higher efficacy for\u003c/p\u003e \u003cp\u003especific subgroups.\u003csup\u003e23\u003c/sup\u003e It should be noted that this result was mainly driven by the results from the AERO-02 trial as more than 1/3 of subjects out of 9 included studies in this meta-nalysis were from AERO-02.\u003c/p\u003e \u003cp\u003eThis study redemonstrated the efficacy of aerosolized calfactant in preventing the need for intubation and liquid surfactant. It also gives insight as to how aerosolized calfactant improved respiratory function in subjects with RDS. It is likely that surfactant distribution and dispersion in distal airspaces prevents alveolar collapse and improves gas exchange leading to better oxygenation.\u003c/p\u003e \u003cp\u003eCalfactant\u0026rsquo;s relatively low viscosity compared with other commercial surfactants may be beneficial for aerosolization. \u003csup\u003e24\u003c/sup\u003e AERO-02 also used a delivery system that does not require a respiratory circuit interface which is also an added advantage. \u003csup\u003e9\u003c/sup\u003e Flow driven delivery system used in the AERO-02 doesn\u0026rsquo;t require an external power source which is advantageous in low resource settings.\u003c/p\u003e \u003cp\u003eResponse to aerosolized surfactant was clearly less compared to intratracheal liquid surfactant administration as demonstrated by lower FiO2, MAP and RSS in the usual care group where significantly higher number of infants received early intratracheal liquid surfactant. Amount of surfactant delivered by aerosolization depends on multiple factors including particle size, respiratory effort, airway flow velocity and pressure etc. \u003csup\u003e8\u003c/sup\u003e A considerable portion of a delivered surfactant dose is lost before surfactant descends below alveolar ducts. However, infants in our analysis who were treated with aerosolized surfactant had a modest improvement in oxygenation and avoided the need for intubation. Avoiding intubation has significant clinical benefits since it is associated with a number of adverse effects such as hypoxia, bradycardia, alterations in blood pressure and airway injury.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEfficacy of aerosolized surfactant has been mainly demonstrated in more mature preterm infants.\u003csup\u003e9,20\u0026minus;22\u003c/sup\u003e This might be due to less severe surfactant deficiency among more mature preterm infants. Amount of surfactant delivered by aerosolization in these infants might be enough to prevent progressive atelectasis and worsening of the disease process. Since more moderate to late preterm infants are born compared to more immature infants, these infants account for nearly a half of the infants needing surfactant.\u003csup\u003e26\u003c/sup\u003e Hence, aerosolized surfactant will likely benefit a large portion of patients cared for in the neonatal clinical practice. On the other hand, more immature preterm infants likely require a higher dose of exogenous surfactant delivered into distal air spaces. Further studies using a higher dose of aerosolized surfactant and/ or prophylactic/ early rescue treatment is warranted to investigate the efficacy of aerosolized surfactant in this population.\u003c/p\u003e \u003cp\u003eIt is important to identify infants who are most likely to benefit from aerosolized surfactant treatment. A significant decrease in FiO2 after aerosolized treatment was seen in subgroups of 32 0/6\u0026ndash;36 6/7, birth weight\u0026thinsp;\u0026gt;\u0026thinsp;1500g, treatment prior to 4 hours of life and RSS\u0026thinsp;\u0026gt;\u0026thinsp;1.5. Similarly sized decreases in FiO2 were seen in all other subgroups as well but these trends didn\u0026rsquo;t reach statistical significance. There was no evidence to suggest that change in FiO2 differed by subgroups. We think the observed statistical difference in above subgroups was seen because of the larger number of subjects in those specific subgroups. Further studies are needed to determine optimal criteria to identify patients who are most likely to benefit from aerosolized surfactant.\u003c/p\u003e \u003cp\u003eThis study presents detailed information on response to aerosolized calfactant treatment in the largest aerosolized surfactant clinical trial to date. However, there are several limitations to this study. We evaluated a selective sample of infants born at 28 0/6\u0026ndash;36 6/7 weeks in this post-hoc analysis. These moderate to late preterm infants accounted for 83% of the original trial cohort. We selected this specific subgroup as these infants are likely to benefit from aerosolized calfactant treatment. We had to exclude 29 more subjects due to missing or inconsistent data, all from the UC group. These exclusions effectively decreased the original study cohort by 23%. Hourly respiratory support data during the first 96 hours were collected retrospectively but all other data including FiO2 during the 4 hours after aerosolization treatment were collected prospectively. While randomized, the AERO-02 trial was not a blinded trial. The decision to intubate and administer liquid surfactant was not defined by the study and left up to the clinical provider.\u003c/p\u003e \u003cp\u003eSafe and efficacious aerosolized surfactant to treat RDS will allow replacement of exogenous surfactant without any potentially harmful airway instrumentation or manipulation. It avoids positive pressure breaths and the need for sedative medications. The infant can be maintained on a non-invasive mode of respiratory support during the surfactant administration while maintaining the functional residual capacity. The noninvasive nature of aerosolized surfactant will allow early administration of exogenous surfactant which should enhance the success of noninvasive respiratory support strategy to treat RDS. Aerosolized surfactant has important global health implications as the administration is simple and not procedurally challenging. Even in high income countries, this will allow treatment of neonates with RDS in local intensive care units without needing to transfer to a higher level of care facility.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAerosolized calfactant treatment of moderate to late preterm infants with RDS resulted in decreased need for intubation by nearly one half compared to infants receiving usual care. A modest decrease in FiO2 was noted in the AS group after the first aerosolization. Early and higher rate liquid surfactant administration in the UC group resulted in lower FiO2, MAP and RSS in the UC group. Despite relatively higher FiO2, MAP, and RSS, the AS group had similar short term respiratory outcomes while avoiding intubation and liquid surfactant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding source: none\u003c/p\u003e\n\u003cp\u003eConflicts of Interest statement: PF and SG have worked for and received payments from ONY Biotech in the past. \u0026nbsp; The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eAcknowledgement: All AERO-02 study investigators, Melissa Brown, Corey Commaroto, ONY Biotech Inc.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePolin RA, Carlo WA, Committee on Fetus and Newborn; American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics. 2014; 133:156\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome \u0026ndash; 2019 Update. Neonatology. 2019; 115:432\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg EH, Shah V, Fetus and Newborn Committee; Canadian Paediatric Society. Guidelines for surfactant replacement therapy in neonates. Paediatr Child Health. 2021; 26:35\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsayamaT, Chai-Adisaksopha C, McDonald SD. Noninvasive ventilation with vs without early surfactant to prevent chronic lung disease in preterm infants: a systematic review and meta-analysis. JAMA Pediatr. 2015;169:731\u0026ndash;739.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerting E, H\u0026auml;rtel C, G\u0026ouml;pel W.Less invasive surfactant administration: best practices and unanswered questions. Curr Opin Pediatr2020; 32:228\u0026ndash;234.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKakkilaya V, Gautham SK. Should less invasive surfactant administration (LISA) become routine practice in US neonatal units? Pediatr Res 2022 Aug 19;1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZapata HA, Fort P, Roberts KD, Kaluarachchi DC, Guthrie SO. Surfactant Administration Through Laryngeal or Supraglottic Airways (SALSA): A Viable Method for Low-Income and Middle-Income Countries. Front Pediatr. 2022; 10:853831.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrasher M, Raffay TM, Cunningham MD, Abu Jawdeh EG. Aerosolized Surfactant for Preterm Infants with Respiratory Distress Syndrome. Children. 2021;8 :493.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCummings JJ, Gerday E, Minton S, Katheria A, Albert G, Flores-Torres J, et al. Aerosolized Calfactant for Newborns with Respiratory Distress: A Randomized Trial. Pediatrics. 2020;146(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKielt MJ, Logan JW, Backes CH, Conroy S, Reber KM, Shepherd EG, et al. Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia. 2022;242:129\u0026ndash;136.e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlein JP, Logan B, Harhoff M, and Anderson PK. Analyzing survival curves at a fixed point in time. Statistics in Medicine. 2007; 26:4505\u0026ndash;4519.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnderson PK and Perme MP. Pseudo-observations in survival analysis. Statistical Methods in Medical Reearch. 2010; 19:71\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR Core Team. (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobillard F, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Micro- aerosol administration of synthetic beta-gamma-dipalmitoyl-L-alpha- lecithin in the respiratory distress syndrome. A preliminary report. Can. Med. Assoc. J. 1964; 90: 55\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH. Neo- natal pulmonary ischemia: Clinical and physiologic studies. Pediatrics 1967; 40: 709\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJorch G, Weller E, Murlat A, Hentschel R. Feasibility study on nebulization of bovine surfactant (SF-RI 1) by pharyngeal continuous positive airway pressure (CPAP). Biol. Neonate 1994, 66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerggren E, Liljedahl M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al. Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome. Acta Pediatr. 2000, 89, 460\u0026ndash;464.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiner NN, Allen Merritt T, Bernstein G, Job L, Mazela J, Segal R. An Open Label, Pilot Study of Aerosurf Combined with nCPAP to Prevent RDS in Preterm Neonates. J. Aerosol. Med. Pulm. Drug Deliv. 2010, 23, 303\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSood BG, Cortez J, Kolli M, Sharma A, Delaney-Black V, Chen X. Aerosolized surfactant in neonatal respiratory distress syndrome: phase I study. Early Hum Dev. 2019; 134:19\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSood B, Thomas R, Delaney-Black V, Xin Y, Sharma A, Chen X. Aerosolized beractant in neonatal respiratory distress syndrome: a randomized fixed-dose parallel-arm phase II trial. Pulm Pharm \u0026amp; Ther. 2021; 66:101986.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinocchieri S, Berry CA, Pillow JJ, CureNeb Study Team. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019; 104: F313-F319.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDani C, Talosi G, Piccinno A, et al. A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome. J Pediatr. 2022;246:40\u0026ndash;47 e45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaertner VD, Thomann J, Bassler D, Ruegger CM. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics. 2021;148(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim K, Choi SQ, Zell ZA, Squires TM, Zasadzinski JA. Effect of cholesterol nanodomains on monolayer morphology and dynamics. Proc Natl Acad Sci USA 2013; ;110:E3054-60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHatch LD, Grubb PH, Lea AS, Walsh WF, Markham MH, Maynordet PO, et al. Endotracheal intubation in neonates: A prospective study of adverse safety events in 162 infants. J Pediatr 2016; 168:62\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrembath A, Hornik CP, Clark R, Smith PB, Daniels J, Laughon M, et al. Comparative effectiveness of surfactant preparations in premature infants. The Journal of pediatrics 2013;163:955\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Respiratory Distress Syndrome, Surfactant, Aerosolized Surfactant, Calfactant","lastPublishedDoi":"10.21203/rs.3.rs-2531840/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2531840/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe largest randomized control trial of aerosolized surfactant (AERO-02 trial) demonstrated a reduction in intubation by 50%.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo determine the response after aerosolized calfactant treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a post-hoc analysis of moderate to late preterm neonates in the AERO-02 trial. Trends in hourly fraction of oxygen (FiO2), mean airway pressure (MAP) and respiratory severity score (RSS) were compared between the aerosolized surfactant (AS) and usual care (UC) groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eForty-eight percent of subjects in the UC group required intubation compared to 24% in the AS group. FiO2, MAP and RSS were lower in the UC group. FiO2 decrease was seen after the first aerosolized calfactant dose.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFiO2, MAP and RSS were lower in the UC group. This is likely due to early and higher rate of liquid surfactant administration in the UC group. Decrease in FiO2 was noted in the AS group after the first aerosolization.\u003c/p\u003e","manuscriptTitle":"Response to Aerosolized Calfactant in Infants with Respiratory Distress Syndrome; A Post-hoc Analysis of AERO-02 trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-07 19:37:54","doi":"10.21203/rs.3.rs-2531840/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-02-24T11:39:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-02-20T03:58:56+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-02-04T09:56:16+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-02-03T19:20:31+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-02-03T19:19:59+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-02-03T18:46:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-01-31T11:05:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2023-01-31T02:52:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-01-31T02:52:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"66e34a1a-4104-496c-b66f-1b0a2844d07f","owner":[],"postedDate":"February 7th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":18945302,"name":"Health sciences/Diseases/Respiratory tract diseases"},{"id":18945303,"name":"Health sciences/Health care/Therapeutics"}],"tags":[],"updatedAt":"2023-07-11T07:09:36+00:00","versionOfRecord":{"articleIdentity":"rs-2531840","link":"https://doi.org/10.1038/s41372-023-01717-1","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2023-07-10 04:00:00","publishedOnDateReadable":"July 10th, 2023"},"versionCreatedAt":"2023-02-07 19:37:54","video":"","vorDoi":"10.1038/s41372-023-01717-1","vorDoiUrl":"https://doi.org/10.1038/s41372-023-01717-1","workflowStages":[]},"version":"v1","identity":"rs-2531840","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2531840","identity":"rs-2531840","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}