==== Front Arch Dis Child Fetal Neonatal Ed Arch Dis Child Fetal Neonatal Ed fetalneonatal fnn Archives of Disease in Childhood. Fetal and Neonatal Edition 1359-2998 1468-2052 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 36600484 fetalneonatal-2022-324184 10.1136/archdischild-2022-324184 Original Research 1506 1507 Thresholds for surfactant use in preterm neonates: a network meta-analysis http://orcid.org/0000-0001-5220-5372 Branagan Aoife 12 Yu Ivan 12 Gurusamy Kurinchi 23 http://orcid.org/0000-0003-0489-6054 Miletin Jan 1456 1 Paediatric and Newborn Medicine, Coombe Women and Infants University Hospital, Dublin, Ireland 2 Division of Surgery and Interventional Science, UCL, London, UK 3 Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moskva, Russian Federation 4 UCD School of Medicine, University College Dublin, Dublin, Ireland 5 Institute for the Care of Mother and Child, Prague, Czech Republic 6 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic Correspondence to Dr Aoife Branagan, Paediatric and Newborn Medicine, Coombe Women and Infants University Hospital, Dublin, Ireland; branagaa@tcd.ie 7 2023 9 12 2022 108 4 333341 24 3 2022 24 11 2022 © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. 2023 https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. Objective To perform a network meta-analysis of randomised controlled trials of different surfactant treatment strategies for respiratory distress syndrome (RDS) to assess if a certain fraction of inspired oxygen (FiO2) is optimal for selective surfactant therapy. Design Systematic review and network meta-analysis using Bayesian analysis of randomised trials of prophylactic versus selective surfactant for RDS. Setting Cochrane Central Register of Controlled Trials, MEDLINE, Embase and Science Citation Index Expanded. Patients Randomised trials including infants under 32 weeks of gestational age. Interventions Intratracheal surfactant, irrespective of type or dose. Main outcome measures Our primary outcome was neonatal mortality, compared between groups treated with selective surfactant therapy at different thresholds of FiO2. Secondary outcomes included respiratory morbidity and major complications of prematurity. Results Of 4643 identified references, 14 studies involving 5298 participants were included. We found no statistically significant differences between 30%, 40% and 50% FiO2 thresholds. A sensitivity analysis of infants treated in the era of high antenatal steroid use and nasal continuous positive airway pressure as initial mode of respiratory support showed no difference in mortality, RDS or intraventricular haemorrhage alone but suggested an increase in the combined outcome of major morbidities in the 60% threshold. Conclusion Our results do not show a clear benefit of surfactant treatment at any threshold of FiO2. The 60% threshold was suggestive of increased morbidity. There was no advantage seen with prophylactic treatment. Randomised trials of different thresholds for surfactant delivery are urgently needed to guide clinicians and provide robust evidence. PROSPERO registration number CRD42020166620. Intensive Care Units, Neonatal Neonatology Respiratory Medicine special-featureunlocked special-featureeditors-choice access-typefree ==== Body pmcWHAT IS ALREADY KNOW ON THIS TOPIC Intratracheal surfactant, provided to premature infants with neonatal respiratory distress syndrome (RDS), decreases mortality and the respiratory complications of prematurity. Current best practice supports nasal continuous positive airway pressure (NCPAP) and avoidance of mechanical ventilation, with provision of exogenous surfactant with increasing oxygen requirement or need for ventilation. Due to insufficient available evidence, clinical guidelines and therefore practice on when surfactant should be provided to these infants vary. WHAT THIS STUDY ADDS This study adds to a limited evidence base on when is most appropriate to provide selective surfactant to infants with RDS. A threshold of 60% fraction of inspired oxygen has been shown to increase major morbidity, most notably retinopathy of prematurity, and should be avoided. No significant difference was seen between the 30%, 40% and 50% thresholds, which suggests more judicious use of surfactant may be appropriate. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY The results of this study suggest that more judicious use of selective surfactant may be appropriate in premature infants managed on NCPAP. Well designed and adequately powered randomised trials are required to further evaluate the most appropriate threshold of oxygen to provide surfactant to these infants. Introduction Respiratory distress syndrome (RDS) is a common consequence of prematurity.1 Management is through provision of respiratory support alongside exogenous surfactant.2 Early Cochrane reviews supported prophylactic surfactant and intubation.3 A more recent review compared a prophylactic strategy (administration before first breath or after brief stabilisation) to selective use (after evidence of RDS), including subgroup analysis of current best practice (nasal continuous positive airway pressure (NCPAP) and high antenatal steroid use).4 The risk of chronic lung disease (CLD)/death was lower in the selective group in the subgroup supporting more judicious use. Best practice dictates stabilisation of preterm infants with NCPAP and early surfactant if the need for intubation arises. However, the threshold at which this should occur is unclear. Despite a large body of work assessing the best use of surfactant, little work has assessed the threshold of fraction of inspired oxygen (FiO2) that surfactant should be given at, leading to variations in practice and reliance on poor quality evidence.5 6 Differing views exist internationally. The European Consensus Guidelines suggest a 30% threshold.2 Both the American Academy of Paediatrics and the National Institute for Health and Care Excellence (UK) state surfactants should be selectively given to infants on NCPAP but do not include a FiO2 threshold.7 8 More recently, the Canadian Paediatric Society suggested 50%.9 The value of FiO2 in isolation as a measure of RDS severity and surfactant requirement has been disputed, as FiO2 is influenced by multiple factors and pathologies. Our aim was to perform a systematic review and network meta-analysis comparing different thresholds of FiO2 for surfactant treatment in infants under 32 weeks of gestation. Methods A systematic review and network meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards and was registered with the International Prospective Register of Systematic Reviews (PROSPERO) before commencement (CRD42020166620). Network meta-analysis allows indirect comparison of data across studies. In the absence of direct evidence comparing thresholds of FiO2, it allows indirect comparison of intervention arms of trials which compare prophylaxis (control) and selective (intervention) treatment. As selective surfactant was provided at different thresholds of FiO2 in these trials, we can compare thresholds. Criteria for considering studies Studies Randomised controlled trials (RCTs) were considered, irrespective of language, publication status or publication date. Participants The participants included neonates from RCTs born before 32 weeks of postmenstrual age. Interventions Intratracheal surfactant delivery. Outcomes The primary outcome was mortality. Secondary outcomes included Bronchopulmonary dysplasia (BPD) (oxygen requirement or need for respiratory support at 36 weeks of corrected gestational age (CGA))10 CLD (oxygen requirement or need for respiratory support at 28 days).10 Pneumothorax (or other air leak). Surfactant therapy (proportion requiring surfactant and number of doses required) Major morbidity, defined as at least one of severe intraventricular haemorrhage (IVH) (grade 3 or 4),11 periventricular leucomalacia (PVL),12 necrotising enterocolitis (NEC) (stage 2A or above),13 retinopathy of prematurity (ROP) greater than stage 214 or BPD. Neurodevelopmental outcome at 2 years of CGA, defined as one of cerebral palsy, mental retardation (Bayley Scales of Infant Development Mental Developmental Index <70), legal blindness (<20/200 visual acuity) and hearing deficit (aided or <60 dB on audiometric testing). Health-related quality of life (HRQOL).15 Search methods Regarding electronic searches, we searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase and Science Citation Index Expanded between inception and December 2021 without language restrictions. We also searched The US National Institute of Health Ongoing Trials Register (www.clinicaltrials.gov) and WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch/). A combination of controlled vocabulary and free-text terms was used for the population (preterm infants) and intervention (surfactant) (see online supplemental eMethods). 10.1136/fetalneonatal-2022-324184.supp1 Supplementary data Data collection and management Two authors independently screened titles and abstracts and selected articles for inclusion based on full-text examination. Two authors independently extracted data in a prepiloted form, including outcome data, data on potential effect modifiers and individual study data (see online supplemental eMethods). We collected data at maximum follow-up and shorter follow-up where applicable. Trial authors were contacted in the case of missing information. Differences were resolved by discussion. The Cochrane Risk of Bias V.2 tool was used.16 Each domain was classified as ‘low risk’, ‘some concern’ or ‘high risk’, leading to classification of the study. Measurement of treatment effects For dichotomous variables the OR with 95% credible intervals (CrI) were calculated.17 For continuous variables, we calculated the mean difference with 95% CrI. For count outcomes, we calculated the rate ratio with 95% CrI. For time-to-event outcomes, HR with 95% CI was calculated. We estimated the ranking probabilities for all interventions (level of FiO2) of being at each possible rank for each intervention. We obtained the surface under the cumulative ranking curve (cumulative probability), rankogram and relative ranking table with CrI for the ranking probabilities.18 19 The unit of analysis was the participant, according to the intervention group to which the participant was randomly assigned. Data synthesis A network meta-analysis was conducted to compare thresholds of FiO2 simultaneously for each outcome. Our analysis was based on guidance by the National Institute for Clinical Excellence Decision Support Unit.19–21 We obtained a network plot to ensure that the trials were connected by interventions.19 We conducted a Bayesian network meta-analysis using the Markov chain Monte Carlo method (for further details, see online supplemental eMethods). We used fixed-effect and random-effect models, reporting the more conservative. We estimated the probability that each intervention ranks at one of the possible positions. Analysis was carried out using OpenBUGS V.3.2.3 (OpenBUGS Project Management Group, UK). We assessed inconsistency (statistical evidence of the violation of transitivity assumption) by fitting both an inconsistency model and a consistency model. In the presence of inconsistency, we assessed whether the inconsistency was due to clinical or methodological heterogeneity. We performed direct comparisons using the same technical details. Subgroup/sensitivity analysis was planned based on (1) trials at low risk of bias compared with trials at high risk of bias, (2) gestational age and (3) current best practice—use of antenatal steroids and NCPAP. Results A total of 4643 references were identified. Of 138 full-text articles reviewed, 112 were excluded (see online supplemental eResults). Twenty-six references describing 14 trials were included (PRISMA diagram, figure 1). Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. FiO2, fraction of inspired oxygen. The included studies22–35 involved 5588 infants, 5298 after postrandomisation dropouts. Threshold of FiO2 for provision of selective surfactant ranged from 30% (three studies) to 60% (three studies). Five studies provided surfactants at 40% and three studies provided surfactants at 50%. Mean gestational age ranged from 27 weeks to 30 weeks. The range of gestational ages included in trials was variable as shown in table 1. There does not appear to be a systematic difference in the range of gestational ages among the trials using different FiO2 thresholds for selective surfactant provision. Regarding the prophylactic group, in seven studies, surfactant was given straight after birth; in five studies, surfactant was given within 15 min; and in three studies, surfactant was given within 1 hour. The percentage of participants with antenatal steroid exposure ranged from 4% to 99%. Eight studies used Poractant alfa (Curosurf, Chiesi Farmaceutici, Italy). One study allowed Poractant alfa or Beractant (Survanta, AbbVie, USA). Of the five remaining studies, two multicentre trials allowed surfactant as per individual unit protocol, one Calfactant (Infasurf, ONY Biotech, USA) and one a self-prepared bovine surfactant. One study used a self-prepared human surfactant (see table 1 for further details). Twelve publications were identified as follow-up of the cohort in included trials.36–47 Due to the nature of the intervention studied, star-shaped networks were formed for each outcome. No closed loops were present, and each study was connected to the network for each outcome. No studies were found to be at low risk of bias, 12 had some concerns; and 2 had high risk of bias (online supplemental eTable 1). As shown in online supplemental eTable 1, there does not appear to be a systematic difference in the risk of bias among the trials using different FiO2 thresholds. Table 1 Characteristics of included studies Study name Setting Participants analysed Threshold for selective surfactant (%) Primary outcome Gestational age range (weeks) Female gender (%) Antenatal steroids (any) (%) Surfactant type Surfactant dose Ventilation Dropouts Kattwinkel et al 29 8 centres, USA 1248 30 Moderate RDS* 29–33 47 No info Bovine Infasurf 150 mg/dose Both 150 Rojas et al 33 8 centres, Columbia 279 30 Need for MV 27–32 49 86 Bovine Survanta 100 mg/kg CPAP 0 Walti et al 35 12 centres, France 256 30 Survival without BPD at 28 days 25–31 46 15 Porcine Curosurf 200 mg/kg Intubation 32 Bevilacqua et al 22 2 centres: Italy and Bulgaria 93 40 Mortality Grade 3, 4 IVH 26–30 54 29 Porcine Curosurf 200 mg/kg Both 0 Dilmen et al 24 6 centres, Turkey 159 40 Necessity for MV 25–30 55 65 Porcine Curosurf 200 mg/kg CPAP 0 Kendig et al 30 3 centres, USA 479 40 Survival to discharge <30 45 31 Bovine Self-prepared 90 mg/dose Intubation 0 Lefort et al 31 1 centre, Brazil 75 40 Ventilatory parameters <34 45 No info Porcine Curosurf 100 mg/kg Both 0 Sandri et al 34 Multicentre, Europe 208 40 MV in first 5 days 25–29 47 97 Porcine Curosurf 200 mg/kg CPAP 0 Finer et al 27 Multicentre, USA 1316 50 Death/BPD at 36 weeks CGA 24–28 46 96 Individual unit protocol Unit protocol CPAP 0 Kandraju et al 28 1 centre, India 153 50 Need for MV in first week of life 28–34 49 94 Porcine (Curosurf) or bovine (Survanta) 100 mg/kg CPAP 0 Merritt et al 32 3 centres, USA and Finland 148 50 Mortality BPD 24–29 43 4 Human Self-prepared 70 mg/kg Intubation 98† de Winter et al 23 2 centres, Holland 81 60 TcPO2 and FiO2 at 6 hrs 26–30 48 44 Porcine Curosurf 200 mg/kg Intubated 0 Dunn et al 25 27 centres: USA and Canada 656 60 Death/BPD at 36 weeks CGA 26–30 49 99 Individual unit protocol Unit protocol Both 8 Egberts et al 26 4 centres: Sweden and Holland 147 60% TcPO2 and FiO2 at 6 hours 26–30 60 29 Porcine Curosurf 200 mg/kg Intubated 2 *Moderate RDS defined as mean airway pressure ≥8 cmH2O or FiO2 ≥40%. †Including 52 patients in placebo group not included in this analysis. BPD, bronchopulmonary dysplasia; CGA, corrected gestational age; CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; IVH, Intraventricular haemorrhage; MV, mechanical ventilation; RDS, respiratory distress syndrome; TcPO2, transcutaneous oxygen tension. Primary outcome Each of the 14 studies measured mortality, including 5298 patients. A random-effect model was used. OR for each comparison, Deviance Information Criteria (DIC), median between-study SD and variance are summarised in online supplemental eTable 2. None of the estimates reached statistical significance with 30% threshold having the highest OR for this outcome (1.81) with 95% CrI of 1.0 to 3.44 (table 2). Sensitivity analysis of current best practice (NCPAP use with high rates of antenatal steroid) did not show any statistically significant difference (online supplemental eTables 3 and 4). Table 2 Summary of findings table for the primary outcome mortality at maximal follow-up Mortality 30% Threshold 40% Threshold 50% Threshold 60% Threshold Studies: 14 Participants: 5290 Prophylaxis: 123 per 1000 (12.3%) OR 1.81 (1.00 to 3.44) Network estimate 79 more per 1000 (0 fewer to 202 more) OR 1.52 (0.94 to 2.40) Network estimate 53 more per 1000 (7 fewer to 128 more) OR 0.82 (0.50 to 1.41) Network estimate 20 fewer per 1000 (57 fewer to 42 more) OR 1.16 (0.63 to 2.29) Network estimate 17 more per 1000 (41 fewer to 120 more) Quality of evidence: ⊕⊕◯◯ Low *† Based on 1783 participants (3 RCTs) Based on 1014 participants (5 RCTs) Based on 1617 participants (3 RCTs) Based on 876 participants (3 RCTs) *The trials all had some concerns or were at high risk of bias. †There was significant heterogeneity. ‡This is a surrogate outcome or was an indirect comparison. §Less than 300 events in combined groups. ¶There is evidence of publication bias. RCT, randomised controlled trial. Secondary outcomes ORs, DIC and variance for each comparison can be found in online supplemental eTable 5. A summary of results is provided (tables 3–5). Table 3 Summary of findings table for secondary outcomes: respiratory outcomes Threshold 30% Threshold 40% Threshold 50% Threshold 60% Bronchopulmonary dysplasia Studies: 8 Participants: 3003 Prophylaxis: 113 per 1000 (11.3%) OR 1.39 (0.87 to 2.24) Network estimate 38 more per 1000 (13 fewer to 109 more) OR 0.77 (0.37 to 1.58) Network estimate 24 fewer per 1000 (68 fewer to 55 more) OR 0.93 (0.74 to 1.16) Network estimate 7 fewer per 1000 (27 fewer to 16 more) OR 1.02 (0.72 to 1.45) Network estimate 2 more per 1000 (30 fewer to 43 more) Quality of evidence: ⊕◯◯◯ Very low *†‡ Based on 279 participants (1 RCT) Based on 460 participants (3 RCTs) Based on 1469 participants (2 RCTs) Based on 795 participants (2 RCTs) Chronic lung disease Studies: 9 Participants: 2740 Prophylaxis: 284 per 1000 (28.4%) OR 1.48 (0.82 to 2.63) Network estimate 86 more per 1000 (40 fewer to 227 more) OR 1.05 (0.63 to 1.64) Network estimate 10 more per 1000 (84 fewer to 110 more) OR 4.08 (0.77 to 35.45) Network estimate 334 more per 1000 (50 fewer to 650 more) OR 0.59 (0.28 to 1.22) Network estimate 94 fewer per 1000 (185 fewer to 42 more) Quality of evidence ⊕◯◯◯ Very low *†‡ Based on 1504 participants (2 RCTs) Based on 855 participants (4 RCTs) Based on 153 participants (1 RCT) Based on 228 participants (2 RCTs) BPD or CLD Studies: 13 Participants: 5142 Prophylaxis: 171 per 1000 (17.1%) OR 1.45 (0.95 to 2.21) Network estimate 59 more per 1000 (7 fewer to 142 more) OR 0.91 (0.54 to 1.41) Network estimate 13 fewer per 1000 (71 fewer to 54 more) OR 0.96 (0.59 to 2.00) Network estimate 6 fewer per 1000 (63 fewer to 121 more) OR 0.86 (0.47 to 1.34) Network estimate 21 fewer per 1000 (83 fewer to 45 more) Quality of evidence ⊕◯◯◯ Very low *†‡ Based on 1783 participants (3 RCTs) Based on 1014 participants (5 RCTs) Based on 1469 participants (2 RCTs) Based on 876 participants (3 RCTs) Pneumothorax Studies: 14 Participants: 5290 Prophylaxis 33 per 1000 (3.3%) OR 2.41 (0.61 to 10.48) Network estimate 43 more per 1000 (13 fewer to 232 more) OR 1.26 (0.42 to 3.97) Network estimate 8 more per 1000 (19 fewer to 87 more) OR 0.81 (0.19 to 3.47) Network estimate 6 fewer per 1000 (27 fewer to 74 more) OR 2.05 (0.50 to 10.72) Network estimate 33 more per 1000 (16 fewer to 237 more) Quality of evidence ⊕◯◯◯ Very low *†§ Based on 1783 participants (3 RCTs) Based on 1014 participants (5 RCTs) Based on 1617 participants (3 RCTs) Based on 876 participants (3 RCTs) All results are reported as OR with 95% credible intervals. *The trials were all had some concerns or were at high risk of bias. †There was significant heterogeneity. ‡This is a surrogate outcome or was an indirect comparison. §Less than 300 events in combined groups. RCT, randomised controlled trial. Table 4 Summary of findings table for secondary outcomes: number of surfactant doses required Surfactant: doses (n) Threshold 60% Threshold 30% Threshold 50% Threshold 40% Studies: 13 Participants: 5142 Prophylaxis: 1107 per 1000 (110.7 per 100 participants) RaR 0.26 (0.21 to 0.32) Network estimate 815 fewer per 1000 (870 fewer to 750 fewer) RaR 0.51 (0.46 to 0.56) Network estimate 546 fewer per 1000 (602 fewer to 484 fewer) RaR 0.65 (0.58 to 0.73) Network estimate 384 fewer per 1000 (463 fewer to 297 fewer) RaR 0.71 (0.63 to 0.81) Network estimate 316 fewer per 1000 (406 fewer to 215 fewer) Rank: 5 (5–5) Rank: 1 (1–1) Rank: 2 (2–2) Rank: 3 (3–4) Rank: 4 (3–4) Quality of evidence: ⊕⊕◯◯ Low *† Based on 334 participants (3 RCTs) Based on 881 participants (3 RCTs) Based on 742 participants (2 RCTs) Based on 511 participants (5 RCTs) All results are reported as OR with 95% credible intervals. *The trials were all had some concerns or were at high risk of bias. †There was significant heterogeneity. RaR, rate ratio; RCT, randomised controlled trial. Table 5 Summary of findings table for secondary outcome: major morbidities 30% Threshold 40% Threshold 50% Threshold 60% Threshold Total major morbidities (n) Studies: 12 Participants: 5134 Prophylaxis: 316 per 1000 (31.6 per 100 participants) RaR 1.14 (0.94 to 1.40) Network estimate 45 more per 1000 (20 fewer to 126 more) RaR 1.18 (0.89 to 1.56) Network estimate 56 more per 1000 (34 fewer to 176 more) RaR 1.04 (0.92 to 1.18) Network estimate 14 more per 1000 (25 fewer to 58 more) RaR 1.02 (0.81 to 1.28) Network estimate six more per 1000 (62 fewer to 89 more) Quality of evidence ⊕◯◯◯ Very low*†§ Based on 1783 participants (3 RCTs) Based on 939 participants (4 RCTs) Based on 1617 participants (3 RCTs) Based on 795 participants (2 RCTs) Grade 3/4 intraventricular haemorrhage Studies: 12 Participants: 5134 Prophylaxis 44 per 1000 (4.4%) OR 2.01 (0.83 to 5.46) Network estimate 40 more per 1000 (7 fewer to 156 more) OR 1.69 (0.77 to 4.10) Network estimate 28 more per 1000 (10 fewer to 114 more) OR 1.11 (0.44 to 2.47) Network estimate 5 more per 1000 (24 fewer to 58 more) OR 0.68 (0.22 to 2.03) Network estimate 14 fewer per 1000 (34 fewer to 41 more) Quality of Evidence ⊕⊕◯◯ Low *† Based on 1783 participants (3 RCTs) Based on 939 participants (4 RCTs) Based on 1617 participants (3 RCTs) Based on 795 participants (2 RCTs) Periventricular leucomalacia Studies: 8 Participants: 3087 Prophylaxis: 34 per 1000 (3.4%) OR 0.81 (0.51 to 1.28) Network estimate 6 fewer per 1000 (16 fewer to nine more) OR 0.64 (0.07 to 4.25) Network estimate 12 fewer per 1000 (31 fewer to 96 more) OR 0.80 (0.21 to 2.81) Network estimate 7 fewer per 1000 (27 fewer to 56 more) OR 0.58 (0.19 to 1.50) Network estimate 14 fewer per 1000 (27 fewer to 16 more) Quality of evidence: ⊕◯◯◯ Very low *†§ Based on 1783 participants (3 RCTs) Based on 208 participants (1 RCT) Based on 301 participants (2 RCTs) Based on 795 participants (2 RCTs) Necrotising enterocolitis Studies: 10 Participants: 4690 Prophylaxis: 75 per 1000 (7.5%) OR 0.86 (0.55 to 1.35) Network estimate 10 fewer per 1000 (32 fewer to 24 more) OR 1.27 (0.81 to 2.01) Network estimate 18 more per 1000 (13 fewer to 65 more) OR 1.27 (0.91 to 1.77) Network estimate 18 more per 1000 (6 fewer to 51 more) OR 1.15 (0.61 to 2.10) Network estimate 10 more per 1000 (28 fewer to 70 more) Quality of evidence: ⊕⊕◯◯ Low *† Based on 1504 participants (2 RCTs) Based on 921 participants (4 RCTs) Based on 1617 participants (3 RCTs) Based on 648 participants (1 RCT) Retinopathy of prematurity >stage 2 Studies: 6 Participants: 3727 Prophylaxis 52 per 1000 (5.2%) OR 1.01 (0.01 to 96.83) Network estimate 1 more per 1000 (52 fewer to 790 more) OR 0.87 (0.09 to 7.05) Network estimate 6 fewer per 1000 (47 fewer to 228 more) OR 0.99 (0.12 to 6.96) Network estimate 0 fewer per 1000 (45 fewer to 225 more) OR 2.36 (0.13 to 40.29) Network estimate 63 more per 1000 (45 fewer to 638 more) Quality of evidence: ⊕◯◯◯ Very low *†§ Based on 1248 participants (1 RCT) Based on 367 participants (2 RCTs) Based on 1464 participants (2 RCTs) Based on 648 participants (1 RCT) BPD Studies: 8 Participants: 3003 Prophylaxis: 113 per 1000 (11.3%) OR 1.39 (0.87 to 2.24) Network estimate 38 more per 1000 (13 fewer to 109 more) OR 0.77 (0.37 to 1.58) Network estimate 24 fewer per 1000 (68 fewer to 55 more) OR 0.93 (0.74 to 1.16) Network estimate 7 fewer per 1000 (27 fewer to 16 more) OR 1.02 (0.72 to 1.45) Network estimate 2 more per 1000 (30 fewer to 43 more) Quality of evidence: ⊕◯◯◯ Very low*†‡ Based on 279 participants (1 RCT) Based on 460 participants (3 RCT) Based on 1469 participants (2 RCT) Based on 795 participants (2 RCT) All results are reported as OR with 95% credible intervals. *The trials were all had some concerns or were at high risk of bias. †There was significant heterogeneity. ‡This is a surrogate outcome or was an indirect comparison. §Less than 300 events in combined groups. ¶There is evidence of publication bias. BPD, bronchopulmonary dysplasia; RaR, rate ratio; RCT, randomised controlled trial. Respiratory outcomes BPD, CLD and CLD/BPD at maximum follow-up were assessed. There was no difference regarding BPD or CLD alone. When evaluated at maximum follow-up, incidence was higher in the 30% group than prophylaxis when directly compared. The other outcomes showed lower point estimates, although not reaching statistical significance. Use of surfactant Unsurprisingly, the proportion of infants receiving surfactant was significantly higher in the prophylactic group (online supplemental eTable 5e). Regarding the number of surfactant doses, there was a significant difference between thresholds. The 60% threshold had the least use of surfactant, 815 fewer doses per 1000. The 30% threshold ranked second at 546 fewer doses per 1000; the 50% threshold ranked third at 384 fewer doses per 1000; and the 40% threshold ranked last at 316 fewer doses per 1000. Complications of prematurity We showed no significant differences in incidence of IVH, PVL, NEC or BPD. The 60% threshold showed a higher incidence of ROP on direct comparison with prophylaxis (OR 2.35, 95% CrI 1.02 to 5.42). Due to the presentation of components of this outcome separately in included studies, we performed a combined count outcome. Studies were included if they provided data from two or more of the five components of the composite outcome. No significant differences were found. Neurodevelopment at CGA of 2 years One trial27 reported this outcome. Forty-three of 479 in the prophylactic group and 55 of 511 in the selective group developed one or more component. Health-related quality of life No study assessed HRQOL. Quality of evidence The overall quality of the evidence was low or very low for all comparisons due to the high risk of bias, heterogeneity, indirectness, imprecision and publication bias. Heterogeneity Since there was no meaningful way in which to rank these studies, we were unable to perform the comparison-adjusted funnel plot to assess reporting bias. Due to paucity of data, we were unable to perform planned subgroup analyses based on gestation, type of ventilation or antenatal steroid use alone. To explore heterogeneity, a sensitivity analysis was carried out comparing studies using current best practice (over 60% antenatal steroid use and NCPAP for stabilisation). NCPAP and high antenatal steroid use A summary of findings is shown in table 6. Six studies24 25 27 28 33 34 met the criteria, including 2554 infants. There was no statistically significant difference seen in mortality, BPD, pneumothorax or grade 3/4 IVH. There was an increased rate of major morbidity in the 60% threshold group—310 more per 1000 (95% CrI intervals 136 more to 572 more). ORs, DIC and variance for each comparison are provided in online supplemental eTables 3 and 4. Each comparison had a very low quality of evidence. Table 6 Sensitivity analysis of current best practice (stabilisation with NCPAP and high levels of antenatal steroid use) 30% Threshold 40% Threshold 50% Threshold 60% Threshold Mortality Prophylaxis: 103 per 1000 (10.3%) OR 1.03 (0.45 to 2.35) Network estimate 2 more per 1000 (54 fewer to 110 more) OR 1.32 (0.69 to 2.61) Network estimate 29 more per 1000 (29 fewer to 127 more) OR 0.81 (0.61 to 1.07) Network estimate 18 fewer per 1000 (38 fewer to seven more) OR 0.56 (0.23 to 1.29) Network estimate 43 fewer per 1000 (78 fewer to 26 more) Quality of evidence: ⊕◯◯◯ Very low *†‡§ Based on 279 participants (1 RCT) Based on 367 participants (2 RCTs) Based on 1469 participants (2 RCTs) Based on 439 participants (1 RCT) Bronchopulmonary dysplasia Prophylaxis: 175 per 1000 (17.5%) OR 1.40 (0.88 to 2.24) Network estimate 54 more per 1000 (18 fewer to 148 more) OR 0.83 (0.39 to 1.70) Network estimate 26 fewer per 1000 (99 fewer to 91 more) OR 0.93 (0.74 to 1.16) Network estimate 11 fewer per 1000 (39 fewer to 22 more) OR 1.29 (0.84 to 2.02) Network estimate 41 more per 1000 (25 fewer to 125 more) Quality of evidence: ⊕◯◯◯ Very low*†‡ Based on 279 participants (1 RCT) Based on 367 participants (2 RCT) Based on 1469 participants (2 RCT) Based on 439 participants (1 RCT) Pneumothorax Prophylaxis: 27 per 1000 (2.7%) OR 4.99 (0.00 to 6953.50) Network estimate 94 more per 1000 (27 fewer to 968 more) OR 3.09 (0.02 to 2455.29) Network estimate 52 more per 1000 (26 fewer to 959 more) OR 1.52 (0.01 to 324.08) Network estimate 14 more per 1000 (27 fewer to 873 more) OR 1.73 (0.00 to 2151.67) Network estimate 19 more per 1000 (27 fewer to 957 more) Quality of evidence: ⊕◯◯◯ Very low*†‡§ Based on 279 participants (1 RCT) Based on 367 participants (2 RCTs) Based on 1469 participants (2 RCTs) Based on 439 participants (1 RCT) Major morbidity Prophylaxis: 296 per 1000 (29.6 per 100 participants) RaR 1.20 (0.86 to 1.68) Network estimate 60 more per 1000 (41 fewer to 202 more) RaR 1.16 (0.81 to 1.66) Network estimate 47 more per 1000 (56 fewer to 196 more) RaR 1.06 (0.93 to 1.21) Network estimate 19 more per 1000 (20 fewer to 62 more) RaR 2.05 (1.46 to 2.93) Network estimate 310 more per 1000 (136 more to 572 more) Quality of evidence: ⊕◯◯◯ Very low*†‡§ Based on 279 participants (1 RCT) Based on 367 participants (2 RCTs) Based on 1469 participants (2 RCTs) Based on 439 participants (1 RCT) Grade 3/4 intraventricular haemorrhage Prophylaxis: 39 per 1000 (3.9%) OR 1.64 (0.24 to 14.41) Network estimate 23 more per 1000 (29 fewer to 329 more) OR 2.16 (0.87 to 5.98) Network estimate 41 more per 1000 (5 fewer to 156 more) Quality of evidence: ⊕◯◯◯ Very low*†‡§ Based on 279 participants (1 RCT) Based on 367 participants (2 RCTs) Based on 1469 participants (2 RCTs) Based on 439 participants (1 RCT) *The trials were all had some concerns or were at high risk of bias. †There was significant heterogeneity. ‡This is a surrogate outcome or was an indirect comparison. §Less than 300 events in combined groups. ¶There is evidence of publication bias. NCPAP, nasal continuous positive airway pressure; RaR, rate ratio; RCT, randomised conrolled trial. Discussion Our primary outcome, mortality, showed no statistically significant differences between the thresholds of FiO2 examined. Regarding the major morbidities of preterm birth, the 60% threshold showed a higher incidence of ROP on direct comparison with prophylaxis. Regarding surfactant doses received, there was significant differences between thresholds. The 60% threshold had the least doses, 30% threshold second, 50% threshold third and 40% threshold last. This may suggest that earlier selective treatment decreases the need for repeat doses, and that earlier use of surfactant may be appropriate as infants reaching this threshold will need more surfactant if treatment is delayed. However, this would be contradicted by the 60% threshold requiring least doses. Interpretation is complicated by differences in rescue dosing, dosing strategies between studies and total amount of doses allowed. The 30% threshold, despite having less doses of surfactant, had a higher incidence of prolonged respiratory support. This may relate to exposure to harmful effects of ventilation earlier, when the neonatal lung is more vulnerable. A sensitivity analysis of infants treated with the current standard of care showed an increase in major morbidity in the 60% threshold group. While our analysis failed to identify an optimal threshold, it adds to scarce data. In the absence of evidence showing a benefit to treatment at 30%, 40% or 50% FiO2, it warrants consideration of higher thresholds (except 60%)—decreasing invasive procedures, associated mechanical ventilation, surfactant use, sedation and associated side effects. The economic impact is likely to be significant. Despite the common nature of this issue, there are little data to guide clinicians. A secondary analysis of prospectively collected data6 has been used to support lower thresholds. This study reviewed infants between 25 weeks and 32 weeks of gestation initially managed on NCPAP. Multivariate analysis showed NCPAP failure was predicted by the highest FiO2 in the first hours. This study was limited by several factors: its retrospective nature, the small numbers at each gestation and the low number primarily managed with NCPAP (50%). The authors concluded that NCPAP failure was predicted by an FiO2 greater than 30% in the first hours and was associated with adverse outcomes. A review of the literature by Dani5 also evaluated this issue, concluding that the most effective threshold is unknown. The European Consensus Guidelines on the management of RDS,2 based on the above paper by Dargaville et al,6 suggests ‘early’ use of rescue surfactant outside of the delivery room at an FiO2 of 30% or above. However, the guideline also recommends using 30%–40% FiO2 for initial stabilisation despite advising against prophylactic surfactant. Despite the common use of FiO2 as a major criterion for provision of selective surfactant, there are limitations to its use, especially in isolation. A combination of pH, clinical assessment and FiO2 will give a more accurate assessment. FiO2 can be influenced by many factors including NCPAP interface, mode of non-invasive ventilation and level of positive end expiratory pressure and can be a measure of pathologies other than surfactant deficiency. The strength of this review was the range of databases searched without restrictions. Two independent reviewers carried out article identification and data extraction. Analysis was performed using fixed-effect and random-effect models, with the most conservative reported. There were limitations. A scoping search revealed no studies directly comparing thresholds for provision of surfactant, and therefore, we relied on indirect comparisons. A paucity of data decreased confidence in results and precluded planned analyses. There was a lack of long-term neurodevelopmental follow-up and assessment of quality of life. As survival rates of prematurity increase, long-term effects become increasingly important. Parental perspective is vital in this regard. Conclusion This network meta-analysis of 14 studies and 5290 infants suggests no statistically significant difference between a range of 30% to 50% FiO2 for the provision of surfactant to preterm infants regarding mortality, respiratory outcomes or complications of prematurity. A 60% threshold may result in more major morbidities. Despite the low quality of evidence and limitations of indirect comparisons, this review provides the strongest evidence currently available, supporting more judicious use of surfactant in preterm infants. Data availability statement Data are available upon reasonable request. Data is available on reasonable request to the authors. Ethics statements Patient consent for publication Not applicable. Ethics approval Not applicable. Contributors: JM contributed to the conception and design of the study idea and methodology, performed study selection and reviewed the manuscript. AB contributed to the conception and design of the study idea and methodology, performed study selection, data extraction and risk of bias assessment, contributed to the interpretation of the data and drafted the manuscript. KG contributed to the conception and design of the study idea and methodology and the interpretation of the data. IY performed data extraction and risk of bias assessment and contributed to the interpretation of the data. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript. JM is responsible for the overall content as the guarantor. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ==== Refs References 1 Halliday HL . The fascinating story of surfactant. J Paediatr Child Health 2017;53 :327–32. 10.1111/jpc.13500 28271629 2 Sweet DG , Carnielli V , Greisen G , et al . European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update. Neonatology 2019;115 :432–50. 10.1159/000499361 30974433 3 Soll RF , Morley CJ . Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2001;2 :Cd000510. 10.1002/14651858.CD000510 4 Rojas-Reyes MX , Morley CJ , Soll R . Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2012;3 :Cd000510. 10.1002/14651858.CD000510.pub2 5 Dani C . Surfactant treatment threshold during nCPAP for the treatment of preterm infants with respiratory distress syndrome. Am J Perinatol 2016;33 :925–9. 10.1055/s-0036-1582395 27120482 6 Dargaville PA , Aiyappan A , De Paoli AG , et al . Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences. Neonatology 2013;104 :8–14. 10.1159/000346460 23595061 7 Polin RA , Carlo WA , et al , Committee on Fetus and Newborn . Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 2014;133 :156–63. 10.1542/peds.2013-3443 24379227 8 Excellence NIfHaC . Specialist neonatal respiratory care for babies born preterm. NICE guideline [NG124], 2019. 9 Ng EH , Shah V . Guidelines for surfactant replacement therapy in neonates. Paediatr Child Health 2021;26 :35–49. 10.1093/pch/pxaa116 33552321 10 Jobe AJ . The new BPD: an arrest of lung development. Pediatr Res 1999;46 :641–3. 10.1203/00006450-199912000-00007 10590017 11 Papile LA , Burstein J , Burstein R , et al . Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 GM. J Pediatr 1978;92 :529–34. 10.1016/S0022-3476(78)80282-0 305471 12 de Vries LS , Eken P , Dubowitz LM . The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49 :1–6. 10.1016/S0166-4328(05)80189-5 13 Neu J . Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am 1996;43 :409–32. 10.1016/s0031-3955(05)70413-2 8614608 14 International Committee for the Classification of Retinopathy of Prematurity . The International classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005;123 :991–9. 10.1001/archopht.123.7.991 16009843 15 Varni JW , Seid M , Kurtin PS . PedsQL 4.0: reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001;39 :800–12. 10.1097/00005650-200108000-00006 11468499 16 Sterne JAC , Savović J , Page MJ , et al . Rob 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366 :l4898. 10.1136/bmj.l4898 31462531 17 Severini TA . Bayesian interval estimates which are also confidence intervals. J R Stat Soc 1993;55 :533–40. 10.1111/j.2517-6161.1993.tb01921.x 18 Salanti G , Ades AE , Ioannidis JPA . Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 2011;64 :163–71. 10.1016/j.jclinepi.2010.03.016 20688472 19 Chaimani A , Higgins JPT , Mavridis D , et al . Graphical tools for network meta-analysis in STATA. PLoS One 2013;8 :e76654. 10.1371/journal.pone.0076654 24098547 20 Mills EJ , Ioannidis JPA , Thorlund K , et al . How to use an article reporting a multiple treatment comparison meta-analysis. JAMA 2012;308 :1246–53. 10.1001/2012.jama.11228 23011714 21 Dias S , Sutton AJ , Ades AE , et al . Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Making 2013;33 :607–17. 10.1177/0272989X12458724 23104435 22 Bevilacqua G , Chernev T , Parmigiani S , et al . Use of surfactant for prophylaxis versus rescue treatment of respiratory distress syndrome: experience from an Italian-Bulgarian trial. Acta Biomed Ateneo Parmense 1997;68 Suppl 1 :47–54. 23 de Winter JP , Egberts J , de Kleine MJ , et al . [Prevention and treatment of respiratory distress syndrome in premature infants using intratracheally administered surfactants]. Ned Tijdschr Geneeskd 1992;136 :2018–24. 1407193 24 Dilmen U , Özdemir R , Tatar Aksoy H , et al . Early regular versus late selective poractant treatment in preterm infants born between 25 and 30 gestational weeks: a prospective randomized multicenter study. J Matern Fetal Neonatal Med 2014;27 :411–5. 10.3109/14767058.2013.818120 23795582 25 Dunn MS , Kaempf J , de Klerk A , et al . Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011;128 :e1069–76. 10.1542/peds.2010-3848 22025591 26 Egberts J , de Winter JP , Sedin G , et al . Comparison of prophylaxis and rescue treatment with Curosurf in neonates less than 30 weeks' gestation: a randomized trial. Pediatrics 1993;92 :768–74. 10.1542/peds.92.6.768 8233735 27 SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN , Carlo WA , et al . Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362 :1970–9. 10.1056/NEJMoa0911783 20472939 28 Kandraju H , Murki S , Subramanian S , et al . Early routine versus late selective surfactant in preterm neonates with respiratory distress syndrome on nasal continuous positive airway pressure: a randomized controlled trial. Neonatology 2013;103 :148–54. 10.1159/000345198 23235135 29 Kattwinkel J , Bloom BT , Delmore P , et al . Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation. Pediatrics 1993;92 :90–8. 8516091 30 Kendig JW , Notter RH , Cox C , et al . A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation. N Engl J Med 1991;324 :865–71. 10.1056/NEJM199103283241301 2000109 31 Lefort S , Diniz EMA , Vaz FAC . Clinical course of premature infants intubated in the delivery room, submitted or not to porcine-derived lung surfactant therapy within the first hour of life. J Matern Fetal Neonatal Med 2003;14 :187–96. 10.1080/jmf.14.3.187.196 14694974 32 Merritt TA , Hallman M , Berry C , et al . Randomized, placebo-controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity. J Pediatr 1991;118 :581–94. 10.1016/S0022-3476(05)83387-6 2007937 33 Rojas MA , Lozano JM , Rojas MX , et al . Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009;123 :137–42. 10.1542/peds.2007-3501 19117872 34 Sandri F , Plavka R , Ancora G , et al . Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010;125 :e1402–9. 10.1542/peds.2009-2131 20439601 35 Walti H , Paris-Llado J , Bréart G , et al . Porcine surfactant replacement therapy in newborns of 25-31 weeks' gestation: a randomized, multicentre trial of prophylaxis versus rescue with multiple low doses. The French Collaborative multicentre study Group. Acta Paediatr 1995;84 :913–21. 10.1111/j.1651-2227.1995.tb13792.x 7488817 36 Ambalavanan N , Carlo WA , Wrage LA , et al . Paco2 in surfactant, positive pressure, and oxygenation randomised trial (support). Arch Dis Child Fetal Neonatal Ed 2015;100 :F145–9. 10.1136/archdischild-2014-306802 25425651 37 SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA , Finer NN , et al . Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362 :1959–69. 10.1056/NEJMoa0911781 20472937 38 CE M , JW K , CF T . Early neurodevelopmental outcome of premature infants in a randomized trial comparing preventilatory and postventilatory surfactant therapy for respiratory distress syndrome. Ann Neurol 1990;28 :412–3. 39 CE M , JW K , CF T . Early neurodevelopmental outcome of premature-infants in a ransomized trial comparing prophylactic and rescue surfactant therapy. Pediatric Research 1991;29 :A261. 40 Hintz SR , Barnes PD , Bulas D , et al . Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics 2015;135 :e32–42. 10.1542/peds.2014-0898 25554820 41 Navarrete CT , Wrage LA , Carlo WA , et al . Growth outcomes of preterm infants exposed to different oxygen saturation target ranges from birth. J Pediatr 2016;176 :62–8. 10.1016/j.jpeds.2016.05.070 27344218 42 Pelkonen AS , Hakulinen AL , Turpeinen M , et al . Effect of neonatal surfactant therapy on lung function at school age in children born very preterm. Pediatr Pulmonol 1998;25 :182–90. 10.1002/(SICI)1099-0496(199803)25:3<182::AID-PPUL8>3.0.CO;2-O 9556010 43 Sinkin RA , Kramer BM , Merzbach JL , et al . School-Age follow-up of prophylactic versus rescue surfactant trial: pulmonary, neurodevelopmental, and educational outcomes. Pediatrics 1998;101 :E11. 10.1542/peds.101.5.e11 44 Stevens TP , Finer NN , Carlo WA , et al . Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (support). J Pediatr 2014;165 :240–9. 10.1016/j.jpeds.2014.02.054 24725582 45 Vaucher YE , Harker L , Merritt TA , et al . Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant. J Pediatr 1993;122 :126–32. 10.1016/S0022-3476(05)83505-X 8419599 46 Vaucher YE , Peralta-Carcelen M , Finer NN , et al . Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012;367 :2495–504. 10.1056/NEJMoa1208506 23268664 47 Vohr BR , Heyne R , Bann CM , et al . Extreme preterm infant rates of overweight and obesity at school age in the support neuroimaging and neurodevelopmental outcomes cohort. J Pediatr 2018;200 :132–9. 10.1016/j.jpeds.2018.04.073 29793869