Early, Low-Dose Pulmonary Surfactant Administration in Infants with Post-Cardiotomy Acute Respiratory Distress Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Early, Low-Dose Pulmonary Surfactant Administration in Infants with Post-Cardiotomy Acute Respiratory Distress Syndrome: A Randomized, Double-Blind, Placebo-Controlled 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 Research Article Early, Low-Dose Pulmonary Surfactant Administration in Infants with Post-Cardiotomy Acute Respiratory Distress Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial Rongyuan Zhang, Xu Wang, Shoujun Li, Keming Yang, Benqing Zhang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8832676/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: ​ Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) in infants is associated with high morbidity and mortality, driven in part by surfactant dysfunction. While exogenous surfactant is a mainstay for neonatal respiratory distress syndrome, its efficacy in pediatric ARDS remains unproven. This study tested the hypothesis that early, low-dose surfactant therapy improves outcomes in infants with post-cardiotomy ARDS. Methods: ​ In this single-center, double-blind, randomized, placebo-controlled trial, we enrolled infants (≤3 months; weight ≤6 kg) who developed moderate-to-severe ARDS (PaO₂/FiO₂ ≤300 mmHg by PALICC-2 criteria) within 6 hours after CPB. Participants were randomly assigned (1:1) to receive a single endotracheal dose of surfactant (15 mg/kg) or an equivalent volume of saline placebo within 24 hours postoperatively. The primary outcome was the duration of invasive mechanical ventilation. Secondary outcomes included lengths of pediatric intensive care unit (PICU) and hospital stay, oxygenation indices, and safety. Results: ​ Between August 2023 and August 2025, 128 infants were included in the intention-to-treat analysis (65 surfactant, 63 placebo). Groups were well-balanced at baseline. Surfactant administration significantly reduced ventilator duration (69.0 ± 49.6 h vs. 106.2 ± 89.7 h; mean difference –37.1 h, 95% CI –61.2 to –13.0; P < 0.01) and shortened PICU stay (14.3 ± 7.8 d vs. 17.9 ± 8.2 d; P < 0.05) and hospital stay (22.0 ± 11.0 d vs. 26.0 ± 9.1 d; P < 0.05). The surfactant group demonstrated a 26.3% reduction in total hospitalization costs (160.45 ± 44.00 vs. 217.71 ± 155.56 ×10³ CNY; P = 0.005) and exhibited superior lactate clearance (1.19 ± 0.55 vs. 1.58 ± 1.01 mmol/L; P < 0.01) and PaO₂/FiO₂ ratios (292.0 ± 126.3 vs. 229.5 ± 85.6; P < 0.01) at 48 hours. No surfactant-related adverse events occurred. Subgroup analyses suggested enhanced benefit in neonates (≤28 d) and low-birth-weight infants (<3.3 kg). Conclusions: ​ Early, low-dose surfactant administered within 24 h after surgery is safe, cost-effective, and associated with improved gas exchange, reduced ventilator dependency, and shorter ICU and hospital stays in infants with post-cardiotomy ARDS. These findings support further evaluation in multicenter trials. Acute Respiratory Distress Syndrome Pulmonary Surfactant Congenital Heart Disease Cardiopulmonary Bypass Infant Critical Care Figures Figure 1 Figure 2 Background Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality following corrective surgery for congenital heart disease (CHD) with cardiopulmonary bypass (CPB) in infants [ 1 , 2 ]. The reported incidence of post-cardiotomy ARDS in this population approaches 22%, frequently resulting in prolonged mechanical ventilation, extended pediatric intensive care unit (PICU) stays, and substantial healthcare resource utilization [ 3 , 4 ]. The pathophysiology of CPB-induced lung injury is multifactorial, involving a systemic inflammatory response triggered by contact activation, ischemia–reperfusion injury, and hemodilution [ 5 , 6 ]. A central consequence is the disruption of pulmonary surfactant homeostasis, leading to both quantitative deficiency and qualitative dysfunction [ 7 , 8 ]. Surfactant, a lipoprotein complex essential for reducing alveolar surface tension and maintaining pulmonary compliance, is inactivated by inflammatory mediators and plasma proteins that extravasate into the alveoli, promoting atelectasis, ventilation–perfusion mismatch, and refractory hypoxemia [ 9 ]. While exogenous surfactant replacement therapy is life-saving in neonatal respiratory distress syndrome (NRDS) [ 10 ], its role in pediatric ARDS has yielded inconsistent results. Prior trials, such as the CALIPSO study, evaluated surfactant as a rescue therapy for established ARDS of varied etiologies with mixed outcomes [ 11 , 12 ]. Post-cardiotomy ARDS in infants represents a unique clinical context where surfactant dysfunction is a primary, early event in the pathogenesis, suggesting a potential therapeutic window for early intervention [ 13 , 14 ]. However, the optimal timing, dosing, patient selection criteria, and cost-effectiveness of such an approach remain poorly defined. Given the high disease burden, strong pathophysiological rationale, and the critical need for economic evaluations in pediatric critical care, we conducted a randomized, placebo-controlled trial to test the hypothesis that early administration of a single, low dose of exogenous surfactant reduces the duration of invasive mechanical ventilation and is cost-effective in infants who develop moderate ARDS following CPB surgery for CHD. Methods Study design and oversight This was a single-center, double-blind, randomized, placebo-controlled, parallel-group trial conducted in the PICU of Fuwai Hospital, Beijing, China. It was initiated in August 2023 and completed in August 2025 after receiving approval from the Ethics Committee of Fuwai Hospital, CAMS&PUMC (2023–2033). All parents or guardians provided written informed consent for their infant before joining the study, reflecting the commitment to ethical research practices. The trail was registered in the Chinese Clinical Trial Registry (ChiCTR2500104855 || http://www.chictr.org.cn/ ), it was a retrospective registration and the registration date was 2025-06-24. An independent Data and Safety Monitoring Board (DSMB) provided oversight for patient safety and conducted a pre-specified interim analysis. The database from this study was approved to be shared by Fuwai Hospital. Participants Eligible participants were infants aged ≤ 3 months, weighing ≤ 6 kg, scheduled for CHD surgery requiring CPB with an anticipated duration of ≥ 90 minutes, and classified as Risk Adjustment for Congenital Heart Surgery (RACHS-1) category 2–5. Enrollment required the development of moderate-to-severe ARDS within 6 hours postoperatively, as defined by the Pediatric Acute Lung Injury Consensus Conference-2 (PALICC-2) criteria: an oxygenation index (OI) ≥ 4 and a PaO₂/FiO₂ ratio ≤ 300 mmHg, accompanied by bilateral infiltrates on chest imaging not fully explained by cardiac failure or fluid overload [ 15 ]. Key exclusion criteria included: residual hemodynamically significant cardiac lesions, palliative surgery, and postoperative left ventricular ejection fraction ≤ 35%, intraoperative decision for extracorporeal membrane oxygenation (ECMO) support, known congenital airway malformations, or major congenital anomalies /significant extracardiac comorbidities. Randomization and blinding Eligible infants were randomly assigned in a 1:1 ratio to receive either surfactant or placebo. A computer-generated randomization sequence with variable block sizes was prepared by an independent statistician. Allocation concealment was maintained using sequentially numbered, opaque, sealed envelopes. An unblinded pharmacy team prepared identical syringes containing either surfactant or 0.9% saline placebo. All treating clinicians, nursing staff, outcome assessors, and data analysts remained blinded to group assignment throughout the study. Intervention The intervention consisted of a single endotracheal instillation of 15 mg/kg of calf lung-derived pulmonary surfactant (Calsurf; Shuanghe Pharmaceutical, Beijing, China) or an equivalent volume of saline placebo, administered within 24 hours of PICU admission following ARDS confirmation. Installation was performed via a catheter inserted into the endotracheal tube, with the total dose divided into three aliquots. Following each aliquot, the infant was repositioned sequentially (left lateral decubitus, supine with head elevated 30°, right lateral decubitus). Manual bag ventilation with 100% FiO₂ was provided for 1 minute after each aliquot and for 5 minutes following the complete dose. Continuous sedation and neuromuscular blockade were maintained for at least 4 hours post-administration to minimize coughing and promote uniform pulmonary distribution. Standardized perioperative and postoperative care All surgical procedures were performed by senior congenital cardiac surgeons using standardized techniques. Postoperative management in the PICU adhered to strict institutional protocols for lung-protective ventilation (tidal volume 6–8 mL/kg predicted body weight, with titrated positive end-expiratory pressure), hemodynamic support, sedation-analgesia, and infection prophylaxis, consistent with current international guidelines [ 16 , 17 ]. The decision to extubate was made by the treating clinical team based on standardized weaning criteria, independent of the research team. Outcomes The primary outcome was the total duration of invasive mechanical ventilation, defined as the time from postoperative PICU admission to successful extubation (without reintubation within 48 hours). Secondary outcomes included: Length of PICU stay. Total postoperative hospital length of stay. Oxygenation parameters (PaO₂/FiO₂ ratio, arterial lactate, oxygenation index) measured at 24, 48, and 72 hours post-intervention. A composite safety endpoint comprising in-hospital mortality, need for cardiopulmonary resuscitation within 24 hours of intervention, requirement for ECMO or high-frequency oscillatory ventilation, and incidence of nosocomial infections. Economic outcomes:​ Total direct medical costs from randomization to hospital discharge. Economic evaluation A prospective cost-effectiveness analysis was performed from the healthcare system perspective. Direct medical costs included surfactant acquisition, mechanical ventilation (per day), PICU stay (per day), hospital ward stay (per day), medications (vasoactive drugs, sedatives, antibiotics), and costs associated with laboratory tests and imaging studies. Unit costs were obtained from the hospital finance department based on 2024 national reimbursement rates. Statistical analysis Sample size calculation was based on historical institutional data (mean ± SD postoperative ventilator duration = 120 ± 24 hours). To detect a 10% reduction (12 hours) with 80% power and a two-sided α level of 0.05, 63 patients per group were required. Allowing for a 5% dropout rate, a total sample size of 132 infants was targeted. Statistical analyses were performed using IBM SPSS Statistics (version 25.0) and R (version 4.2.2). Continuous variables are presented as mean ± standard deviation (SD) or median (interquartile range, IQR) based on normality assessment using the Shapiro-Wilk test. Between-group comparisons for continuous variables utilized Student's t-test or the Mann-Whitney U test, as appropriate. Categorical variables were compared using the chi-square test or Fisher's exact test. The primary analysis followed the intention-to-treat principle. Pre-specified subgroup analyses were conducted for neonates (≤ 28 days) and low-birth-weight infants (< 3.3 kg). Cost data were log-transformed for analysis due to right-skewness. Bootstrapping with 1000 replications was used to estimate 95% confidence intervals for cost differences and ICERs. A two-sided P-value < 0.05 was considered statistically significant. Results Study population A total of 8167 children were screened for eligibility, of whom 132 were randomized. After exclusions, 128 infants were included in the intention-to-treat analysis (65 in the surfactant group, 63 in the placebo group; see Fig. 1 for the study flowchart). Baseline demographic and clinical characteristics, including age, weight, sex, RACHS-1 category, CPB and aortic cross-clamp times, and preoperative organ function, were well-balanced between the two groups (Table 1). Preoperative respiratory support requirements and baseline oxygenation indices were also comparable. Primary and secondary outcomes Surfactant administration significantly reduced the duration of mechanical ventilation by approximately 37 hours compared to placebo (69.0 ± 49.6 hours vs. 106.2 ± 89.7 hours; mean difference –37.1 hours, 95% CI –61.2 to –13.0; P < 0.01). Consequently, the surfactant group had significantly shorter PICU stays (14.3 ± 7.8 days vs. 17.9 ± 8.2 days; P < 0.05) and hospital stays (22.0 ± 11.0 days vs. 26.0 ± 9.1 days; P < 0.05; Table 2). Kaplan-Meier analysis for time to successful extubation demonstrated significant separation between the groups, favoring the surfactant group (log-rank P < 0.01; Fig. 2). Physiological outcomes Baseline arterial lactate levels and oxygenation parameters were similar between groups. Following the intervention, the surfactant group demonstrated significantly better lactate clearance at 24 hours (P < 0.05), with differences becoming more pronounced at 48 and 72 hours (P < 0.01). The PaO₂/FiO₂ ratio and oxygenation index also showed significant improvement in the surfactant group at 48 hours (PaO₂/FiO₂: 292.0 ± 126.3 vs. 229.5 ± 85.6, P < 0.01; OI: 5.43 ± 2.7 vs. 6.63 ± 2.26, P < 0.01), and these benefits were sustained at the 72-hour mark (Table 3). Cost-effectiveness analysis The economic evaluation revealed that early, low-dose surfactant administration was not only clinically superior but also economically advantageous. The total hospitalization cost was significantly lower in the surfactant group compared to the control group (160.45 ± 44.00 vs. 217.71 ± 155.56 ×10³ CNY; mean difference -57.26 ×10³ CNY, 95% CI -96.12 to -18.40; P = 0.0051), representing a 26.3% reduction in total medical costs (Table 2). The intervention demonstrated a dominant cost-effectiveness profile. The significantly smaller standard deviation in the treatment group's costs (44.00 vs. 155.56 ×10³ CNY) indicates more predictable and stable resource utilization compared to conventional management. Safety The intervention was well tolerated. No instances of acute hemodynamic compromise, significant hypoxemia, or airway obstruction attributable to surfactant administration occurred. All infants survived to hospital discharge. No patient in either group required ECMO or high-frequency oscillatory ventilation. The rates of nosocomial infections and other adverse events were similar between the groups. One patient in the control group required continuous renal replacement therapy, whereas no patient in the surfactant group did (Table 2). Subgroup analyses Pre-specified subgroup analyses confirmed the reduction in ventilator days and shorter length of stay in neonates (≤28 days) receiving surfactant. In the low-birth-weight subgroup (<3.3 kg), surfactant administration was associated with higher PaO₂/FiO₂ ratios at 48 hours and shorter PICU and hospital stays compared to placebo (Tables 3, 4). Discussion This randomized, double-blind, placebo-controlled trial provides robust evidence that early, low-dose exogenous surfactant therapy improves clinically meaningful outcomes and is cost-effective in infants with post-cardiotomy ARDS. The 35% reduction in the duration of mechanical ventilation is both statistically significant and clinically substantial, translating into shorter ICU and hospital stays, alongside significant cost savings, without an increase in adverse events. Our findings advance the field by addressing critical limitations of prior studies. Unlike earlier trials that investigated surfactant as a rescue therapy in heterogeneous pediatric ARDS populations [ 11 , 12 ], we focused on a homogeneous, high-risk cohort in which surfactant dysfunction is a primary pathophysiological event [ 8 , 9 , 18 ]. The early intervention window (within 24 hours postoperatively) strategically targets the incipient phase of lung injury, potentially mitigating the vicious cycle of ventilator-induced lung injury and progressive inflammation [ 13 , 14 , 19 ]. The low dose (15 mg/kg) was a pragmatic choice, aiming to supplement the endogenous pool rather than replace it entirely, which may minimize the risks of airway occlusion and reduce overall treatment cost [ 20 ]. Economic implications and value-based care The economic evaluation provides crucial evidence for healthcare decision-makers. The significant reduction in total hospital costs (approximately 26.3% per patient) establishes early surfactant therapy as a dominant strategy—improving outcomes while reducing expenditures. This finding challenges the perception that novel biologic therapies in critical care are invariably cost-increasing [ 21 ]. The cost savings were primarily driven by reduced ventilator and ICU days, which are major cost drivers in postoperative cardiac care. The more predictable and lower variance in costs within the treatment group further enhances its value proposition for healthcare systems, allowing for better budgeting and resource planning [ 22 ]. Mechanistic insights and phenotypic response The pronounced treatment effect observed in neonates (≤ 28 days) and low-birth-weight infants (< 3.3 kg) offers compelling mechanistic and clinical insights. The < 3.3 kg threshold is physiologically relevant, approximating the mean birth weight of term newborns in contemporary Chinese cohorts and identifying a subgroup with heightened biological vulnerability [ 23 ]. The enhanced benefit in these patients likely stems from convergent developmental and physiological factors. The lungs of neonates and low-birth-weight infants are structurally and functionally immature, with a simpler alveolar architecture that may promote more homogeneous distribution of the instilled surfactant [ 24 ]. More critically, their endogenous surfactant system is both quantitatively limited and qualitatively immature, with a smaller, more labile pool that is exquisitely sensitive to CPB-induced inactivation by inflammatory mediators and plasma proteins [ 8 , 18 , 25 ]. Consequently, exogenous supplementation provides a proportionally greater rescue effect. Furthermore, these infants exhibit higher metabolic rates and body surface area-to-weight ratios, increasing oxygen consumption and the work of breathing. Surfactant dysfunction thus imposes a disproportionate cardiopulmonary strain, making the rapid restoration of alveolar stability and efficient gas exchange especially critical—an effect reflected in the marked improvements in PaO₂/FiO₂ and lactate clearance we observed. This finding underscores a precision medicine principle: the greatest absolute benefit from an intervention may be derived by targeting the most vulnerable, identifiable subgroups [ 26 ]. Strengths and limitations The key strengths of our study include its randomized, double-blind, placebo-controlled design, rigorous methodology, inclusion of a comprehensive economic evaluation, and focus on a well-defined, high-risk population. However, several limitations should be acknowledged. First, the single-center design may affect the generalizability of our findings, although the high patient volume and standardized protocols at our center strengthen internal validity. Second, while subgroup analyses were pre-specified, they should be considered exploratory and hypothesis-generating due to the sample size. Third, the cost analysis reflects the context of the Chinese healthcare system; applicability to other healthcare systems with different cost structures requires further validation. Finally, the optimal dosing strategy, including the potential need for re-dosing, and the precise mechanisms underlying the differential response based on age and weight warrant further investigation through pharmacokinetic studies and advanced imaging techniques. Conclusions In infants who develop moderate-to-severe ARDS following CPB surgery for CHD, early administration of low-dose surfactant within 24 hours is safe, cost-effective, and associated with significantly improved oxygenation, reduced ventilator dependency, and shorter ICU and hospital stays. The benefits appear most pronounced in neonates and low-birth-weight infants (< 3.3 kg), suggesting these subgroups may derive the greatest clinical and economic advantage. These results provide a strong rationale for conducting a larger, multicenter randomized trial to confirm efficacy, refine patient selection criteria, and inform evidence-based clinical guidelines for managing post-cardiotomy respiratory failure in this vulnerable population. Declarations Acknowledgements Not applicable Author contributions Z-RY and WX drafted the article and made contributions to the acquisition of data. LX and L-ZY participated in the analysis and interpretation of data and made substantial contributions to the acquisition of data. Z-RY, WX and L-SJ participated in the design and refinement of the study protocol. L-SJ, Y-KM and Z-BQ performed all surgical procedures and participated in revising it critically for important intellectual content. All of the authors had given final approval for the version to be published. All authors read and approved the final manuscript. Funding Funding was provided by the National High Level Hospital Clinical Research Funding (Grant ID 2023-GSP-GG-39; 2025-GSP-GG-19). Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The Institutional Review Board of Fuwai Hospital, CAMS&PUMC approved the study and protocol (approval number: 2023-2033). The trial was conducted in accordance with the ethical principles of the “Declaration of Helsinki,” the International Conference on Harmonisation–Good Clinical Practice (ICH-GCP) guideline, the “Quality Management Standards for Drug Clinical Trials” of the Chinese Food and Drug Administration (CFDA), the “Medical Devices Clinical Trial Quality Management Standards” of the CFDA, the “Ethical Review Measures for Biomedical Research Involving Humans” of the National Health Commission of China, and other relevant national laws and regulations. Informed consent by the study participant or a legally authorized representative was given prior to inclusion in the study. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Mastropietro CW, Rojas M, Bansal N, Gadepalli SK. Acute respiratory distress syndrome after pediatric cardiac surgery: incidence, risk factors, and outcomes. J Thorac Cardiovasc Surg. 2021;161(4):1441–9. https://doi.org/10.1016/j.jtcvs.2020.10.102 . Ramanathan R, Sinha P, Koval C, Hsin T, Loomba RS. Epidemiology and outcomes of acute respiratory distress syndrome in children after cardiac surgery. Ann Am Thorac Soc. 2020;17(1):105–12. https://doi.org/10.1513/AnnalsATS.201904-320OC . Brown KL, Ridout DA, Goldman AP, Hoskote A, Penny DJ. The impact of pulmonary complications on outcomes after pediatric cardiac surgery. Ann Thorac Surg. 2019;107(4):1227–33. https://doi.org/10.1016/j.athoracsur.2018.10.020 . Gupta P, McDonald R, Gossett JM, Butt W, Rettiganti M. Risk factors for prolonged mechanical ventilation after surgery for congenital heart disease. Pediatr Crit Care Med. 2018;19(3):e153–61. https://doi.org/10.1097/PCC.0000000000001440 . Davidson JA, Hurlbut B, Mastropietro CW. Cardiopulmonary bypass-induced inflammation and pulmonary surfactant: mechanisms and therapeutic implications. Thorac Cardiovasc Surg. 2020;68(5):401–11. https://doi.org/10.1055/s-0039-1701000 . Rizzo AN, Schmidt EP. Pathobiology of acute respiratory distress syndrome in children. Lancet Respir Med. 2019;7(2):185–96. https://doi.org/10.1016/S2213-2600(18)30360-0 . Bautista-Hernandez V, Delgado-Montero A, Rivas-Lasarte M. Surfactant dysfunction in pediatric acute respiratory distress syndrome. Front Pediatr. 2022;10:829843. https://doi.org/10.3389/fped.2022.829843 . Dushianthan A, Cusack R, Goss V, Postle AD, Grocott MP. Clinical review: exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome–where do we go from here? Crit Care. 2012;16(6):238. https://doi.org/10.1186/cc10420 . Agrawal A, Zhuo H, Brady S, Levitt J, Steingrub J, Siegel MD, et al. Altered pulmonary surfactant in sepsis: mechanisms and functional consequences. Front Immunol. 2021;12:690561. https://doi.org/10.3389/fimmu.2021.690561 . 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: 2022 update. Neonatology. 2022;120(1):3–23. https://doi.org/10.1159/000524678 . Thomas NJ, Guardia CG, Moya FR, Cheifetz IM, Markovitz B, Cruces P, et al. A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure. Pediatr Crit Care Med. 2012;13(6):646–53. https://doi.org/10.1097/PCC.0b013e31824176f6 . Willson DF, Thomas NJ, Tamburro RF, Truemper E, Bhalala U, Traube C, et al. Pediatric CALIPSO: a randomized, double-blind, placebo-controlled trial of calfactant for acute hypoxemic respiratory failure in children. Am J Respir Crit Care Med. 2018;198(5):622–31. https://doi.org/10.1164/rccm.201802-0350OC . Fajardo CA, Whyte H, Bando D, O'Connell C, Lee KS, Laussen PC. Early surfactant administration in infants with congenital heart disease and acute lung injury: a pilot randomized trial. Pediatr Pulmonol. 2020;55(7):1765–73. https://doi.org/10.1002/ppul.24798 . Teke T, Cömert S, Sahin A, Kılınç M, Koca U. Exogenous surfactant therapy in pediatric acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2020;48(11):e1113–21. https://doi.org/10.1097/CCM.0000000000004614 . Emeriaud G, López-Fernández YM, Iyer NP, Bembea MM, Agulnik A, Barbaro RP, et al. Executive summary of the second international guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PALICC-2). Pediatr Crit Care Med. 2023;24(2):143–68. https://doi.org/10.1097/PCC.0000000000003144 . Kneyber MCJ, de Luca D, Calderini E, Jarreau PH, Javouhey E, Lopez-Herce J et al. Recommendations for mechanical ventilation of critically ill children from the Paediatric Mechanical Ventilation Consensus Conference (PEMVECC). Intensive Care Med. 2017;43(12):1764–80. https://doi.org/10.1007/s00134-017-4920-z Curley MAQ, Wypij D, Watson RS, Grant MJC, Asaro LA, Cheifetz IM, et al. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379–89. https://doi.org/10.1001/jama.2014.18399 . Pérez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: current models and open questions. Physiology. 2010;25(3):132–41. https://doi.org/10.1152/physiol.00006.2010 . Khemani RG, Smith L, Lopez-Fernandez YM, Kwok J, Morzov R, Klein MJ, et al. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study. Lancet Respir Med. 2019;7(2):115–28. https://doi.org/10.1016/S2213-2600(18)30344-2 . Filoche M, Tai CF, Grotberg JB. Can one predict the fate of an inhaled therapy? The case of instilled surfactant. Eur Phys J E Soft Matter. 2017;40(3):33. https://doi.org/10.1140/epje/i2017-11523-7 . Deftereos S, Giannopoulos G, Angelidis C, Alexopoulos N, Filippatos G, Papoutsidakis N, et al. Anti-inflammatory treatment with colchicine in acute myocardial infarction: a pilot study. Circulation. 2015;132(15):1395–403. https://doi.org/10.1161/CIRCULATIONAHA.115.017611 . Tan SS, Bakker J, Hoogendoorn ME, Kapila A, Martin J, Pezzi A, et al. Direct cost analysis of intensive care unit stay in four European countries: applying a standardized costing methodology. Value Health. 2012;15(1):81–6. https://doi.org/10.1016/j.jval.2011.09.008 . Li H, Zong XN, Zhang J, Zhu Z, Wang YH, Wang XQ, et al. Secular trend of birth weight in China from 1990 to 2019: a joinpoint analysis and generalized additive model. Front Endocrinol. 2022;13:888637. https://doi.org/10.3389/fendo.2022.888637 . van Zellem L, Buysse C, Madderom M, Tibboel D, Utens E. Long-term neurodevelopmental outcomes in children with congenital heart disease: a systematic review and meta-analysis. J Am Heart Assoc. 2015;4(9):e001963. https://doi.org/10.1161/JAHA.115.001963 . Davidson JA, Fernández-Velasco MA. Pulmonary surfactant alterations in congenital heart disease-associated pediatric acute respiratory distress syndrome: pathophysiology and therapeutic perspectives. Pediatr Crit Care Med. 2024;25(3):e146–57. https://doi.org/10.1097/PCC.0000000000003429 . Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, et al. Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med. 2017;195(3):331–8. https://doi.org/10.1164/rccm.201606-1305OC . Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files data.xlsx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted 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-8832676","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":602018426,"identity":"7bbf3b61-c5fc-4353-864a-659da237ce57","order_by":0,"name":"Rongyuan Zhang","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rongyuan","middleName":"","lastName":"Zhang","suffix":""},{"id":602018427,"identity":"cee26ba9-53a1-4fda-9785-7366e32974b1","order_by":1,"name":"Xu Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqklEQVRIiWNgGAWjYBAC9gYGhgMMDDY8/PwNRGrhOQDWkiYjOeMACVqA4LCNQUMCsVokcg8e+Nl2nseA4QDjh485RGnJSzjY23abx5y5gVly5jYitNhL5xgcZgRqsWw4wMbMS4wWHoiWczwGBxJI03KAFC3y7xIO9pxL5pGccbCZOL/w8Jw9/OFHmZ09P3/zwQ8fidEC1ARjMDYQpR5ZyygYBaNgFIwCHAAAjlk13dowlg0AAAAASUVORK5CYII=","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Xu","middleName":"","lastName":"Wang","suffix":""},{"id":602018428,"identity":"27131708-90a9-4911-9b5b-168f337971d7","order_by":2,"name":"Shoujun Li","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shoujun","middleName":"","lastName":"Li","suffix":""},{"id":602018429,"identity":"8c73c65b-f8c3-4ec3-b942-815bcbbe0e9c","order_by":3,"name":"Keming Yang","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Keming","middleName":"","lastName":"Yang","suffix":""},{"id":602018430,"identity":"65e8cc77-93d8-41e6-9dc1-4727a14a9292","order_by":4,"name":"Benqing Zhang","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Benqing","middleName":"","lastName":"Zhang","suffix":""},{"id":602018431,"identity":"c821309e-dbab-468f-a17c-48420bf2d243","order_by":5,"name":"Xia Li","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Li","suffix":""},{"id":602018432,"identity":"279f0793-fa98-47fd-aac5-edad02abd3f0","order_by":6,"name":"Zhongyuan Lu","email":"","orcid":"","institution":"National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zhongyuan","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2026-02-09 16:27:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8832676/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8832676/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104322785,"identity":"860ca162-da6c-49f6-8e48-952d93c093fe","added_by":"auto","created_at":"2026-03-10 13:27:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102267,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8832676/v1/192db76ff285b38910d36628.png"},{"id":104322789,"identity":"1000c85b-99f0-4196-b581-d1a1f6139acc","added_by":"auto","created_at":"2026-03-10 13:27:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70281,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8832676/v1/9d1d0466b38cba9bbc444338.png"},{"id":105564971,"identity":"9f5d57e2-38d3-49e9-a895-8960026d03cb","added_by":"auto","created_at":"2026-03-27 12:51:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":808903,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8832676/v1/eb23164c-2a67-491d-9148-264c8d76de61.pdf"},{"id":104322786,"identity":"4f796f71-8583-497d-a823-58220260a3d9","added_by":"auto","created_at":"2026-03-10 13:27:22","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":89928,"visible":true,"origin":"","legend":"","description":"","filename":"data.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8832676/v1/e304b5a4b0cc9128277e94e1.xlsx"},{"id":104322793,"identity":"e69381e6-d08a-4925-bc3c-6a0712576082","added_by":"auto","created_at":"2026-03-10 13:27:26","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":50693,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8832676/v1/2de071697bdec229df251264.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early, Low-Dose Pulmonary Surfactant Administration in Infants with Post-Cardiotomy Acute Respiratory Distress Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eAcute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality following corrective surgery for congenital heart disease (CHD) with cardiopulmonary bypass (CPB) in infants [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The reported incidence of post-cardiotomy ARDS in this population approaches 22%, frequently resulting in prolonged mechanical ventilation, extended pediatric intensive care unit (PICU) stays, and substantial healthcare resource utilization [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe pathophysiology of CPB-induced lung injury is multifactorial, involving a systemic inflammatory response triggered by contact activation, ischemia\u0026ndash;reperfusion injury, and hemodilution [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A central consequence is the disruption of pulmonary surfactant homeostasis, leading to both quantitative deficiency and qualitative dysfunction [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Surfactant, a lipoprotein complex essential for reducing alveolar surface tension and maintaining pulmonary compliance, is inactivated by inflammatory mediators and plasma proteins that extravasate into the alveoli, promoting atelectasis, ventilation\u0026ndash;perfusion mismatch, and refractory hypoxemia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile exogenous surfactant replacement therapy is life-saving in neonatal respiratory distress syndrome (NRDS) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], its role in pediatric ARDS has yielded inconsistent results. Prior trials, such as the CALIPSO study, evaluated surfactant as a rescue therapy for established ARDS of varied etiologies with mixed outcomes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Post-cardiotomy ARDS in infants represents a unique clinical context where surfactant dysfunction is a primary, early event in the pathogenesis, suggesting a potential therapeutic window for early intervention [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the optimal timing, dosing, patient selection criteria, and cost-effectiveness of such an approach remain poorly defined.\u003c/p\u003e \u003cp\u003e Given the high disease burden, strong pathophysiological rationale, and the critical need for economic evaluations in pediatric critical care, we conducted a randomized, placebo-controlled trial to test the hypothesis that early administration of a single, low dose of exogenous surfactant reduces the duration of invasive mechanical ventilation and is cost-effective in infants who develop moderate ARDS following CPB surgery for CHD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and oversight\u003c/h2\u003e \u003cp\u003eThis was a single-center, double-blind, randomized, placebo-controlled, parallel-group trial conducted in the PICU of Fuwai Hospital, Beijing, China. It was initiated in August 2023 and completed in August 2025 after receiving approval from the Ethics Committee of Fuwai Hospital, CAMS\u0026amp;PUMC (2023\u0026ndash;2033). All parents or guardians provided written informed consent for their infant before joining the study, reflecting the commitment to ethical research practices. The trail was registered in the Chinese Clinical Trial Registry (ChiCTR2500104855 ||\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chictr.org.cn/\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), it was a retrospective registration and the registration date was 2025-06-24. An independent Data and Safety Monitoring Board (DSMB) provided oversight for patient safety and conducted a pre-specified interim analysis. The database from this study was approved to be shared by Fuwai Hospital.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eEligible participants were infants aged\u0026thinsp;\u0026le;\u0026thinsp;3 months, weighing\u0026thinsp;\u0026le;\u0026thinsp;6 kg, scheduled for CHD surgery requiring CPB with an anticipated duration of \u0026ge;\u0026thinsp;90 minutes, and classified as Risk Adjustment for Congenital Heart Surgery (RACHS-1) category 2\u0026ndash;5. Enrollment required the development of moderate-to-severe ARDS within 6 hours postoperatively, as defined by the Pediatric Acute Lung Injury Consensus Conference-2 (PALICC-2) criteria: an oxygenation index (OI)\u0026thinsp;\u0026ge;\u0026thinsp;4 and a PaO₂/FiO₂ ratio\u0026thinsp;\u0026le;\u0026thinsp;300 mmHg, accompanied by bilateral infiltrates on chest imaging not fully explained by cardiac failure or fluid overload [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eKey exclusion criteria included: residual hemodynamically significant cardiac lesions, palliative surgery, and postoperative left ventricular ejection fraction\u0026thinsp;\u0026le;\u0026thinsp;35%, intraoperative decision for extracorporeal membrane oxygenation (ECMO) support, known congenital airway malformations, or major congenital anomalies /significant extracardiac comorbidities.\u003c/p\u003e\n\u003ch3\u003eRandomization and blinding\u003c/h3\u003e\n\u003cp\u003eEligible infants were randomly assigned in a 1:1 ratio to receive either surfactant or placebo. A computer-generated randomization sequence with variable block sizes was prepared by an independent statistician. Allocation concealment was maintained using sequentially numbered, opaque, sealed envelopes. An unblinded pharmacy team prepared identical syringes containing either surfactant or 0.9% saline placebo. All treating clinicians, nursing staff, outcome assessors, and data analysts remained blinded to group assignment throughout the study.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eThe intervention consisted of a single endotracheal instillation of 15 mg/kg of calf lung-derived pulmonary surfactant (Calsurf; Shuanghe Pharmaceutical, Beijing, China) or an equivalent volume of saline placebo, administered within 24 hours of PICU admission following ARDS confirmation. Installation was performed via a catheter inserted into the endotracheal tube, with the total dose divided into three aliquots. Following each aliquot, the infant was repositioned sequentially (left lateral decubitus, supine with head elevated 30\u0026deg;, right lateral decubitus). Manual bag ventilation with 100% FiO₂ was provided for 1 minute after each aliquot and for 5 minutes following the complete dose. Continuous sedation and neuromuscular blockade were maintained for at least 4 hours post-administration to minimize coughing and promote uniform pulmonary distribution.\u003c/p\u003e\n\u003ch3\u003eStandardized perioperative and postoperative care\u003c/h3\u003e\n\u003cp\u003eAll surgical procedures were performed by senior congenital cardiac surgeons using standardized techniques. Postoperative management in the PICU adhered to strict institutional protocols for lung-protective ventilation (tidal volume 6\u0026ndash;8 mL/kg predicted body weight, with titrated positive end-expiratory pressure), hemodynamic support, sedation-analgesia, and infection prophylaxis, consistent with current international guidelines [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The decision to extubate was made by the treating clinical team based on standardized weaning criteria, independent of the research team.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was the total duration of invasive mechanical ventilation, defined as the time from postoperative PICU admission to successful extubation (without reintubation within 48 hours).\u003c/p\u003e \u003cp\u003eSecondary outcomes included:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLength of PICU stay.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTotal postoperative hospital length of stay.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOxygenation parameters (PaO₂/FiO₂ ratio, arterial lactate, oxygenation index) measured at 24, 48, and 72 hours post-intervention.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA composite safety endpoint comprising in-hospital mortality, need for cardiopulmonary resuscitation within 24 hours of intervention, requirement for ECMO or high-frequency oscillatory ventilation, and incidence of nosocomial infections.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEconomic outcomes:​ Total direct medical costs from randomization to hospital discharge.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEconomic evaluation\u003c/h3\u003e\n\u003cp\u003eA prospective cost-effectiveness analysis was performed from the healthcare system perspective. Direct medical costs included surfactant acquisition, mechanical ventilation (per day), PICU stay (per day), hospital ward stay (per day), medications (vasoactive drugs, sedatives, antibiotics), and costs associated with laboratory tests and imaging studies. Unit costs were obtained from the hospital finance department based on 2024 national reimbursement rates.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSample size calculation was based on historical institutional data (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD postoperative ventilator duration\u0026thinsp;=\u0026thinsp;120\u0026thinsp;\u0026plusmn;\u0026thinsp;24 hours). To detect a 10% reduction (12 hours) with 80% power and a two-sided α level of 0.05, 63 patients per group were required. Allowing for a 5% dropout rate, a total sample size of 132 infants was targeted.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics (version 25.0) and R (version 4.2.2). Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range, IQR) based on normality assessment using the Shapiro-Wilk test. Between-group comparisons for continuous variables utilized Student's t-test or the Mann-Whitney U test, as appropriate. Categorical variables were compared using the chi-square test or Fisher's exact test. The primary analysis followed the intention-to-treat principle. Pre-specified subgroup analyses were conducted for neonates (\u0026le;\u0026thinsp;28 days) and low-birth-weight infants (\u0026lt;\u0026thinsp;3.3 kg). Cost data were log-transformed for analysis due to right-skewness. Bootstrapping with 1000 replications was used to estimate 95% confidence intervals for cost differences and ICERs. A two-sided P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 8167 children were screened for eligibility, of whom 132 were randomized. After exclusions, 128 infants were included in the intention-to-treat analysis (65 in the surfactant group, 63 in the placebo group; see Fig. 1 for the study flowchart). Baseline demographic and clinical characteristics, including age, weight, sex, RACHS-1 category, CPB and aortic cross-clamp times, and preoperative organ function, were well-balanced between the two groups (Table 1). Preoperative respiratory support requirements and baseline oxygenation indices were also comparable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary and secondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurfactant administration significantly reduced the duration of mechanical ventilation by approximately 37 hours compared to placebo (69.0 ± 49.6 hours vs. 106.2 ± 89.7 hours; mean difference –37.1 hours, 95% CI –61.2 to –13.0; P \u0026lt; 0.01). Consequently, the surfactant group had significantly shorter PICU stays (14.3 ± 7.8 days vs. 17.9 ± 8.2 days; P \u0026lt; 0.05) and hospital stays (22.0 ± 11.0 days vs. 26.0 ± 9.1 days; P \u0026lt; 0.05; Table 2). Kaplan-Meier analysis for time to successful extubation demonstrated significant separation between the groups, favoring the surfactant group (log-rank P \u0026lt; 0.01; Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysiological outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline arterial lactate levels and oxygenation parameters were similar between groups. Following the intervention, the surfactant group demonstrated significantly better lactate clearance at 24 hours (P \u0026lt; 0.05), with differences becoming more pronounced at 48 and 72 hours (P \u0026lt; 0.01). The PaO₂/FiO₂ ratio and oxygenation index also showed significant improvement in the surfactant group at 48 hours (PaO₂/FiO₂: 292.0 ± 126.3 vs. 229.5 ± 85.6, P \u0026lt; 0.01; OI: 5.43 ± 2.7 vs. 6.63 ± 2.26, P \u0026lt; 0.01), and these benefits were sustained at the 72-hour mark (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCost-effectiveness analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe economic evaluation revealed that early, low-dose surfactant administration was not only clinically superior but also economically advantageous. The total hospitalization cost was significantly lower in the surfactant group compared to the control group (160.45 ± 44.00 vs. 217.71 ± 155.56 ×10³ CNY; mean difference -57.26 ×10³ CNY, 95% CI -96.12 to -18.40; P = 0.0051), representing a 26.3% reduction in total medical costs (Table 2). The intervention demonstrated a dominant cost-effectiveness profile. The significantly smaller standard deviation in the treatment group's costs (44.00 vs. 155.56 ×10³ CNY) indicates more predictable and stable resource utilization compared to conventional management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intervention was well tolerated. No instances of acute hemodynamic compromise, significant hypoxemia, or airway obstruction attributable to surfactant administration occurred. All infants survived to hospital discharge. No patient in either group required ECMO or high-frequency oscillatory ventilation. The rates of nosocomial infections and other adverse events were similar between the groups. One patient in the control group required continuous renal replacement therapy, whereas no patient in the surfactant group did (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePre-specified subgroup analyses confirmed the reduction in ventilator days and shorter length of stay in neonates (≤28 days) receiving surfactant. In the low-birth-weight subgroup (\u0026lt;3.3 kg), surfactant administration was associated with higher PaO₂/FiO₂ ratios at 48 hours and shorter PICU and hospital stays compared to placebo (Tables 3, 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis randomized, double-blind, placebo-controlled trial provides robust evidence that early, low-dose exogenous surfactant therapy improves clinically meaningful outcomes and is cost-effective in infants with post-cardiotomy ARDS. The 35% reduction in the duration of mechanical ventilation is both statistically significant and clinically substantial, translating into shorter ICU and hospital stays, alongside significant cost savings, without an increase in adverse events.\u003c/p\u003e \u003cp\u003eOur findings advance the field by addressing critical limitations of prior studies. Unlike earlier trials that investigated surfactant as a rescue therapy in heterogeneous pediatric ARDS populations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], we focused on a homogeneous, high-risk cohort in which surfactant dysfunction is a primary pathophysiological event [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The early intervention window (within 24 hours postoperatively) strategically targets the incipient phase of lung injury, potentially mitigating the vicious cycle of ventilator-induced lung injury and progressive inflammation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The low dose (15 mg/kg) was a pragmatic choice, aiming to supplement the endogenous pool rather than replace it entirely, which may minimize the risks of airway occlusion and reduce overall treatment cost [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eEconomic implications and value-based care\u003c/h2\u003e \u003cp\u003eThe economic evaluation provides crucial evidence for healthcare decision-makers. The significant reduction in total hospital costs (approximately 26.3% per patient) establishes early surfactant therapy as a dominant strategy\u0026mdash;improving outcomes while reducing expenditures. This finding challenges the perception that novel biologic therapies in critical care are invariably cost-increasing [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The cost savings were primarily driven by reduced ventilator and ICU days, which are major cost drivers in postoperative cardiac care. The more predictable and lower variance in costs within the treatment group further enhances its value proposition for healthcare systems, allowing for better budgeting and resource planning [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eMechanistic insights and phenotypic response\u003c/h2\u003e \u003cp\u003eThe pronounced treatment effect observed in neonates (\u0026le;\u0026thinsp;28 days) and low-birth-weight infants (\u0026lt;\u0026thinsp;3.3 kg) offers compelling mechanistic and clinical insights. The \u0026lt;\u0026thinsp;3.3 kg threshold is physiologically relevant, approximating the mean birth weight of term newborns in contemporary Chinese cohorts and identifying a subgroup with heightened biological vulnerability [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The enhanced benefit in these patients likely stems from convergent developmental and physiological factors. The lungs of neonates and low-birth-weight infants are structurally and functionally immature, with a simpler alveolar architecture that may promote more homogeneous distribution of the instilled surfactant [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. More critically, their endogenous surfactant system is both quantitatively limited and qualitatively immature, with a smaller, more labile pool that is exquisitely sensitive to CPB-induced inactivation by inflammatory mediators and plasma proteins [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Consequently, exogenous supplementation provides a proportionally greater rescue effect. Furthermore, these infants exhibit higher metabolic rates and body surface area-to-weight ratios, increasing oxygen consumption and the work of breathing. Surfactant dysfunction thus imposes a disproportionate cardiopulmonary strain, making the rapid restoration of alveolar stability and efficient gas exchange especially critical\u0026mdash;an effect reflected in the marked improvements in PaO₂/FiO₂ and lactate clearance we observed. This finding underscores a precision medicine principle: the greatest absolute benefit from an intervention may be derived by targeting the most vulnerable, identifiable subgroups [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe key strengths of our study include its randomized, double-blind, placebo-controlled design, rigorous methodology, inclusion of a comprehensive economic evaluation, and focus on a well-defined, high-risk population. However, several limitations should be acknowledged. First, the single-center design may affect the generalizability of our findings, although the high patient volume and standardized protocols at our center strengthen internal validity. Second, while subgroup analyses were pre-specified, they should be considered exploratory and hypothesis-generating due to the sample size. Third, the cost analysis reflects the context of the Chinese healthcare system; applicability to other healthcare systems with different cost structures requires further validation. Finally, the optimal dosing strategy, including the potential need for re-dosing, and the precise mechanisms underlying the differential response based on age and weight warrant further investigation through pharmacokinetic studies and advanced imaging techniques.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn infants who develop moderate-to-severe ARDS following CPB surgery for CHD, early administration of low-dose surfactant within 24 hours is safe, cost-effective, and associated with significantly improved oxygenation, reduced ventilator dependency, and shorter ICU and hospital stays. The benefits appear most pronounced in neonates and low-birth-weight infants (\u0026lt;\u0026thinsp;3.3 kg), suggesting these subgroups may derive the greatest clinical and economic advantage. These results provide a strong rationale for conducting a larger, multicenter randomized trial to confirm efficacy, refine patient selection criteria, and inform evidence-based clinical guidelines for managing post-cardiotomy respiratory failure in this vulnerable population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZ-RY and WX drafted the article and made contributions to the acquisition of data. LX and L-ZY participated in the analysis and interpretation of data and made substantial contributions to the acquisition of data. Z-RY, WX and L-SJ participated in the design and refinement of the study protocol. L-SJ, Y-KM and Z-BQ performed all surgical procedures and participated in revising it critically for important intellectual content. All of the authors had given final approval for the version to be published. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding was provided by the National High Level Hospital Clinical Research Funding (Grant ID 2023-GSP-GG-39; 2025-GSP-GG-19).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board of Fuwai Hospital, CAMS\u0026amp;PUMC approved the study and protocol (approval number: 2023-2033). The trial was conducted in accordance with the ethical principles of the “Declaration of Helsinki,” the International Conference on Harmonisation–Good Clinical Practice (ICH-GCP) guideline, the “Quality Management Standards for Drug Clinical Trials” of the Chinese Food and Drug Administration (CFDA), the “Medical Devices Clinical Trial Quality Management Standards” of the CFDA, the “Ethical Review Measures for Biomedical Research Involving Humans” of the National Health Commission of China, and other relevant national laws and regulations. Informed consent by the study participant or a legally authorized representative was given prior to inclusion in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMastropietro CW, Rojas M, Bansal N, Gadepalli SK. Acute respiratory distress syndrome after pediatric cardiac surgery: incidence, risk factors, and outcomes. J Thorac Cardiovasc Surg. 2021;161(4):1441\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jtcvs.2020.10.102\u003c/span\u003e\u003cspan address=\"10.1016/j.jtcvs.2020.10.102\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamanathan R, Sinha P, Koval C, Hsin T, Loomba RS. Epidemiology and outcomes of acute respiratory distress syndrome in children after cardiac surgery. Ann Am Thorac Soc. 2020;17(1):105\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1513/AnnalsATS.201904-320OC\u003c/span\u003e\u003cspan address=\"10.1513/AnnalsATS.201904-320OC\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown KL, Ridout DA, Goldman AP, Hoskote A, Penny DJ. The impact of pulmonary complications on outcomes after pediatric cardiac surgery. Ann Thorac Surg. 2019;107(4):1227\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.athoracsur.2018.10.020\u003c/span\u003e\u003cspan address=\"10.1016/j.athoracsur.2018.10.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta P, McDonald R, Gossett JM, Butt W, Rettiganti M. Risk factors for prolonged mechanical ventilation after surgery for congenital heart disease. Pediatr Crit Care Med. 2018;19(3):e153\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/PCC.0000000000001440\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0000000000001440\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavidson JA, Hurlbut B, Mastropietro CW. Cardiopulmonary bypass-induced inflammation and pulmonary surfactant: mechanisms and therapeutic implications. Thorac Cardiovasc Surg. 2020;68(5):401\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1055/s-0039-1701000\u003c/span\u003e\u003cspan address=\"10.1055/s-0039-1701000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRizzo AN, Schmidt EP. Pathobiology of acute respiratory distress syndrome in children. Lancet Respir Med. 2019;7(2):185\u0026ndash;96. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2213-2600(18)30360-0\u003c/span\u003e\u003cspan address=\"10.1016/S2213-2600(18)30360-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBautista-Hernandez V, Delgado-Montero A, Rivas-Lasarte M. Surfactant dysfunction in pediatric acute respiratory distress syndrome. Front Pediatr. 2022;10:829843. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fped.2022.829843\u003c/span\u003e\u003cspan address=\"10.3389/fped.2022.829843\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDushianthan A, Cusack R, Goss V, Postle AD, Grocott MP. Clinical review: exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome\u0026ndash;where do we go from here? Crit Care. 2012;16(6):238. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/cc10420\u003c/span\u003e\u003cspan address=\"10.1186/cc10420\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgrawal A, Zhuo H, Brady S, Levitt J, Steingrub J, Siegel MD, et al. Altered pulmonary surfactant in sepsis: mechanisms and functional consequences. Front Immunol. 2021;12:690561. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2021.690561\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2021.690561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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: 2022 update. Neonatology. 2022;120(1):3\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000524678\u003c/span\u003e\u003cspan address=\"10.1159/000524678\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas NJ, Guardia CG, Moya FR, Cheifetz IM, Markovitz B, Cruces P, et al. A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure. Pediatr Crit Care Med. 2012;13(6):646\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/PCC.0b013e31824176f6\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0b013e31824176f6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWillson DF, Thomas NJ, Tamburro RF, Truemper E, Bhalala U, Traube C, et al. Pediatric CALIPSO: a randomized, double-blind, placebo-controlled trial of calfactant for acute hypoxemic respiratory failure in children. Am J Respir Crit Care Med. 2018;198(5):622\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1164/rccm.201802-0350OC\u003c/span\u003e\u003cspan address=\"10.1164/rccm.201802-0350OC\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFajardo CA, Whyte H, Bando D, O'Connell C, Lee KS, Laussen PC. Early surfactant administration in infants with congenital heart disease and acute lung injury: a pilot randomized trial. Pediatr Pulmonol. 2020;55(7):1765\u0026ndash;73. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ppul.24798\u003c/span\u003e\u003cspan address=\"10.1002/ppul.24798\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeke T, C\u0026ouml;mert S, Sahin A, Kılın\u0026ccedil; M, Koca U. Exogenous surfactant therapy in pediatric acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2020;48(11):e1113\u0026ndash;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/CCM.0000000000004614\u003c/span\u003e\u003cspan address=\"10.1097/CCM.0000000000004614\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEmeriaud G, L\u0026oacute;pez-Fern\u0026aacute;ndez YM, Iyer NP, Bembea MM, Agulnik A, Barbaro RP, et al. Executive summary of the second international guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PALICC-2). Pediatr Crit Care Med. 2023;24(2):143\u0026ndash;68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/PCC.0000000000003144\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0000000000003144\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKneyber MCJ, de Luca D, Calderini E, Jarreau PH, Javouhey E, Lopez-Herce J et al. Recommendations for mechanical ventilation of critically ill children from the Paediatric Mechanical Ventilation Consensus Conference (PEMVECC). Intensive Care Med. 2017;43(12):1764\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00134-017-4920-z\u003c/span\u003e\u003cspan address=\"10.1007/s00134-017-4920-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurley MAQ, Wypij D, Watson RS, Grant MJC, Asaro LA, Cheifetz IM, et al. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379\u0026ndash;89. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jama.2014.18399\u003c/span\u003e\u003cspan address=\"10.1001/jama.2014.18399\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP\u0026eacute;rez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: current models and open questions. Physiology. 2010;25(3):132\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1152/physiol.00006.2010\u003c/span\u003e\u003cspan address=\"10.1152/physiol.00006.2010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhemani RG, Smith L, Lopez-Fernandez YM, Kwok J, Morzov R, Klein MJ, et al. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study. Lancet Respir Med. 2019;7(2):115\u0026ndash;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2213-2600(18)30344-2\u003c/span\u003e\u003cspan address=\"10.1016/S2213-2600(18)30344-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiloche M, Tai CF, Grotberg JB. Can one predict the fate of an inhaled therapy? The case of instilled surfactant. Eur Phys J E Soft Matter. 2017;40(3):33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1140/epje/i2017-11523-7\u003c/span\u003e\u003cspan address=\"10.1140/epje/i2017-11523-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeftereos S, Giannopoulos G, Angelidis C, Alexopoulos N, Filippatos G, Papoutsidakis N, et al. Anti-inflammatory treatment with colchicine in acute myocardial infarction: a pilot study. Circulation. 2015;132(15):1395\u0026ndash;403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/CIRCULATIONAHA.115.017611\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.115.017611\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan SS, Bakker J, Hoogendoorn ME, Kapila A, Martin J, Pezzi A, et al. Direct cost analysis of intensive care unit stay in four European countries: applying a standardized costing methodology. Value Health. 2012;15(1):81\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jval.2011.09.008\u003c/span\u003e\u003cspan address=\"10.1016/j.jval.2011.09.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi H, Zong XN, Zhang J, Zhu Z, Wang YH, Wang XQ, et al. Secular trend of birth weight in China from 1990 to 2019: a joinpoint analysis and generalized additive model. Front Endocrinol. 2022;13:888637. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fendo.2022.888637\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2022.888637\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Zellem L, Buysse C, Madderom M, Tibboel D, Utens E. Long-term neurodevelopmental outcomes in children with congenital heart disease: a systematic review and meta-analysis. J Am Heart Assoc. 2015;4(9):e001963. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/JAHA.115.001963\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.115.001963\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavidson JA, Fern\u0026aacute;ndez-Velasco MA. Pulmonary surfactant alterations in congenital heart disease-associated pediatric acute respiratory distress syndrome: pathophysiology and therapeutic perspectives. Pediatr Crit Care Med. 2024;25(3):e146\u0026ndash;57. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/PCC.0000000000003429\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0000000000003429\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFamous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, et al. Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med. 2017;195(3):331\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1164/rccm.201606-1305OC\u003c/span\u003e\u003cspan address=\"10.1164/rccm.201606-1305OC\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute Respiratory Distress Syndrome, Pulmonary Surfactant, Congenital Heart Disease, Cardiopulmonary Bypass, Infant, Critical Care","lastPublishedDoi":"10.21203/rs.3.rs-8832676/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8832676/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e​ Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) in infants is associated with high morbidity and mortality, driven in part by surfactant dysfunction. While exogenous surfactant is a mainstay for neonatal respiratory distress syndrome, its efficacy in pediatric ARDS remains unproven. This study tested the hypothesis that early, low-dose surfactant therapy improves outcomes in infants with post-cardiotomy ARDS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e​ In this single-center, double-blind, randomized, placebo-controlled trial, we enrolled infants (≤3 months; weight ≤6 kg) who developed moderate-to-severe ARDS (PaO₂/FiO₂ ≤300 mmHg by PALICC-2 criteria) within 6 hours after CPB. Participants were randomly assigned (1:1) to receive a single endotracheal dose of surfactant (15 mg/kg) or an equivalent volume of saline placebo within 24 hours postoperatively. The primary outcome was the duration of invasive mechanical ventilation. Secondary outcomes included lengths of pediatric intensive care unit (PICU) and hospital stay, oxygenation indices, and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e​ Between August 2023 and August 2025, 128 infants were included in the intention-to-treat analysis (65 surfactant, 63 placebo). Groups were well-balanced at baseline. Surfactant administration significantly reduced ventilator duration (69.0 ± 49.6 h vs. 106.2 ± 89.7 h; mean difference –37.1 h, 95% CI –61.2 to –13.0; P \u0026lt; 0.01) and shortened PICU stay (14.3 ± 7.8 d vs. 17.9 ± 8.2 d; P \u0026lt; 0.05) and hospital stay (22.0 ± 11.0 d vs. 26.0 ± 9.1 d; P \u0026lt; 0.05). The surfactant group demonstrated a 26.3% reduction in total hospitalization costs (160.45 ± 44.00 vs. 217.71 ± 155.56 ×10³ CNY; P = 0.005) and exhibited superior lactate clearance (1.19 ± 0.55 vs. 1.58 ± 1.01 mmol/L; P \u0026lt; 0.01) and PaO₂/FiO₂ ratios (292.0 ± 126.3 vs. 229.5 ± 85.6; P \u0026lt; 0.01) at 48 hours. No surfactant-related adverse events occurred. Subgroup analyses suggested enhanced benefit in neonates (≤28 d) and low-birth-weight infants (\u0026lt;3.3 kg).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e​ Early, low-dose surfactant administered within 24 h after surgery is safe, cost-effective, and associated with improved gas exchange, reduced ventilator dependency, and shorter ICU and hospital stays in infants with post-cardiotomy ARDS. These findings support further evaluation in multicenter trials.\u003c/p\u003e","manuscriptTitle":"Early, Low-Dose Pulmonary Surfactant Administration in Infants with Post-Cardiotomy Acute Respiratory Distress Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 13:25:15","doi":"10.21203/rs.3.rs-8832676/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e9f60610-ab5d-4de4-bbb8-fa029d499048","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-24T17:10:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 13:25:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8832676","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8832676","identity":"rs-8832676","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}