Clinical decision thresholds for surfactant administration in preterm infants: a systematic review and network meta-analysis.

Background: The ideal threshold at which surfactant administration in preterm neonates with respiratory distress syndrome (RDS) is most beneficial is contentious. The aim of this systematic review was to determine the optimal clinical criteria to guide surfactant administration in preterm neonates with RDS. Methods: The systematic review was registered in PROSPERO (CRD42022309433). Medline, Embase, CENTRAL and CINAHL were searched from inception till 16th May 2023. Only randomized controlled trials (RCTs) were included. A Bayesian random effects network meta-analysis (NMA) evaluating 33 interventions was performed. The primary outcome was requirement of invasive mechanical ventilation (IMV) within 7 days of life. Findings: 58 RCTs were included. In preterm neonates ≤30 weeks after adjusting for the confounding factor of modality of surfactant administration, an arterial alveolar oxygen tension ratio (aAO2) <0.36 (FiO2: 37-55%) was ranked the best threshold for decreasing the risk of IMV, very low certainty. Further, surfactant administration at an FiO2 40-45% possibly decreased mortality compared to rescue treatment when respiratory failure was diagnosed, certainty very low. The reasonable inference that could be drawn from these findings is that surfactant administration may be considered in preterm neonates of ≤30 weeks' with RDS requiring an FiO2 ≥ 40%. There was insufficient evidence for the comparison of FiO2 thresholds: 30% vs. 40%. The evidence was sparse for surfactant administration guided by lung ultrasound. For the sub-group >30 weeks, nebulized surfactant administration at an FiO2 < 30% possibly increased the risk of IMV compared to Intubate-Surfactant-Extubate at FiO2 < 30% and 40%, and less invasive surfactant administration at FiO2 40%, certainty very low. Interpretation: Surfactant administration may be considered in preterm neonates of ≤30 weeks' with RDS if the FiO2 requirement is ≥40%. Future trials are required comparing lower FiO2 thresholds of 30% vs. 40% and that guided by lung ultrasound. Funding: None.

Multisystem inflammatory disease in neonates (MIS-N) due to maternal COVID-19.

Multisystem inflammatory disease in neonates (MIS-N) is a disease of immune dysregulation presenting in the newborn period. Thouvgh its etiopathogenesis is proposed to be similar to multisystem inflammatory disease in Children (MIS-C), the exact pathophysiology is largely unknown as of present. The definition of MIS-N is contentious. The evidence for its incidence, the clinical features, profile of raised inflammatory markers, treatment strategies and outcomes stem from case reports, case series and cohort studies with small sample sizes. Though the incidence of MIS-N in severe acute respiratory syndrome caused by the coronavirus CoVID-2 (SARS-CoV-2) infected asymptomatic neonates is low, its incidence in symptomatic neonates is relatively higher. Further, amongst the neonates who are treated as MIS-N, the mortality rate is high. The review also evaluates the various other unresolved aspects of MIS-N from limited published literature and identifies knowledge gaps which could be areas of future research.

Placental Transfusion Strategies in Preterm Infants in Low- and Middle-Income Countries: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Placental transfusion strategies in preterm newborns have not been evaluated in low- and middle-income countries (LMICs). The objective of this systematic review was to compare placental transfusion strategies in preterm newborns in LMICs, including delayed cord clamping (DCC) for various time intervals, DCC until cord pulsations stop, umbilical cord milking, and immediate cord clamping (ICC). METHODS: Medline, Embase, CINAHL, and CENTRAL were searched from inception. Observational studies and randomized controlled trials (RCTs) were included. Two authors independently extracted data for Bayesian random-effects network meta-analysis (NMA) if more than 3 interventions reported an outcome or a pairwise meta-analysis was utilized. RESULTS: Among newborns <34 weeks of gestation, NMA of 9 RCTs could not rule out benefit or harm for survival from DCC 30-60 s compared to ICC: relative risk (RR) (95% credible interval) 0.96 (0.78-1.12), moderate certainty, or any included strategy compared to each other (low to very low certainty). Among late preterm newborns, DCC 120 s might be associated with improved survival: RR (95% confidence interval) 1.11 (1.01-1.22), very low certainty. We could not detect differences in the risk of intraventricular hemorrhage grade > II and bronchopulmonary dysplasia for any included intervention (low to very low certainty). DCC 60 s and 120 s might improve the hematocrit level among all preterm newborns (very low certainty), and DCC 45 s may decrease the risk of receipt of inotropes among newborns <34 weeks of gestation (low certainty). CONCLUSIONS: In LMICs, DCC for 60 s and 120 s might improve hematocrit level in preterm newborns, and DCC for 45 s may decrease the risk of receipt of inotropes in newborns <34 weeks, with no conclusive effect on survival.

Nasal Cannula with Long and Narrow Tubing for Non-Invasive Respiratory Support in Preterm Neonates: A Systematic Review and Meta-Analysis.

BACKGROUND: Cannulas with long and narrow tubing (CLNT) are increasingly being used as an interface for noninvasive respiratory support (NRS) in preterm neonates; however, their efficacy compared to commonly used nasal interfaces such as short binasal prongs (SBP) and nasal masks (NM) has not been widely studied. MATERIAL AND METHODS: Medline, Embase, CENTRAL, Health Technology Assessment Database, and Web of Science were searched for randomized clinical trials (RCTs) and observational studies investigating the efficacy of CLNT compared to SBP or NM in preterm neonates requiring NRS for primary respiratory and post-extubation support. A random-effects meta-analysis was used for data synthesis. RESULTS: Three RCTs and three observational studies were included. Clinical benefit or harm could not be ruled out for the outcome of need for invasive mechanical ventilation (IMV) for CLNT versus SBP or NM [relative risk (RR) 1.37, 95% confidence interval (CI) 0.61-3.04, certainty of evidence (CoE) low]. The results were also inconclusive for the outcome of treatment failure [RR 1.20, 95% CI 0.48-3.01, CoE very low]. Oropharyngeal pressure transmission was possibly lower with CLNT compared to other interfaces [MD -1.84 cm H20, 95% CI -3.12 to -0.56, CoE very low]. Clinical benefit or harm could not be excluded with CLNT compared to SBP or NM for the outcomes of duration of IMV, nasal trauma, receipt of surfactant, air leak, and NRS duration. CONCLUSION: Very low to low CoE and statistically nonsignificant results for the clinical outcomes precluded us from making any reasonable conclusions; however, the use of CLNT as an NRS interface, compared to SBP or NM, possibly transmits lower oropharyngeal pressures. We suggest adequately powered multicentric RCTs to evaluate the efficacy of CLNT when compared to other interfaces.

Delivery room CPAP in improving outcomes of preterm neonates in low-and middle-income countries: A systematic review and network meta-analysis.

AIM: To study the impact of delivery room continuous positive airway pressure (DRCPAP) on outcomes of preterm neonates in low- and middle- income countries (LMICs) by comparing with interventions: oxygen supplementation, late DRCPAP, DRCPAP with sustained inflation, DRCPAP with surfactant and invasive mechanical ventilation (IMV). METHODS: Medline, Embase, CENTRAL, WOS and CINAHL searched. Observational studies and randomized controlled trials (RCTs) were included. Pair-wise meta-analysis and Bayesian network meta-analysis (NMA) were utilized. Primary outcome was receipt of IMV. RESULTS: Data from 11 of the 18 included studies (4 observational studies, 7 RCTs) enrolling 4210 preterm infants was synthesized. Moderate certainty of evidence (CoE) from NMA of RCTs comparing DRCPAP with surfactant administration versus DRCPAP alone suggested no decrease in subsequent receipt of IMV [Risk ratio (RR); 95% Credible Interval (CrI): 0.73; (0.34, 1.40)]. Very low CoE from observational studies comparing use of DRCPAP versus oxygen supplementation indicated a trend towards decreased IMV [RR; 95% Confidence Interval (CI): 0.75; (0.56-1.00)]. Although moderate CoE from NMA evaluating DRCPAP versus oxygen supplementation showed a trend towards decreased receipt of surfactant, it did not reach statistical significance [RR; 95% CrI: 0.69; (0.44, 1.06)]. Moderate CoE from NMA indicated that none of the interventions, when compared with use of supplemental oxygen alone or with each other decreased mortality or bronchopulmonary dysplasia. LIMITATIONS: CoE was very low for primary outcome. CONCLUSIONS: Present evidence is not sufficient for use of DRCPAP, but also did not show harm. Since it seems unlikely that there are marked variations in patient physiology to explain the difference in efficacy between high income countries and LMICs, we suggest future research evaluating other barriers in improving the effectiveness of DRCPAP in LMICs.

ELBW and ELGAN outcomes in developing nations-Systematic review and meta-analysis.

CONTEXT: Morbidity and mortality amongst extremely low birth weight (ELBW) and extremely low gestational age neonates (ELGANs) in developing nations has not been well studied. OBJECTIVES: Evaluate survival until discharge, short- and long-term morbidities of ELBW and ELGANs in LMICs. DATA SOURCES: CENTRAL, EMBASE, MEDLINE and Web of Science. STUDY SELECTION: Prospective and retrospective observational studies were included. DATA EXTRACTION AND SYNTHESIS: Four authors extracted data independently. Random-effects meta-analysis of proportions was used to synthesize data, modified QUIPS scale to evaluate quality of studies and GRADE approach to ascertain the certainty of evidence (CoE). RESULTS: 192 studies enrolling 22,278 ELBW and 18,338 ELGANs were included. Survival was 34% (95% CI: 31% - 37%) (CoE-low) for ELBW and 39% (34% - 44%) (CoE-moderate) for ELGANs. For ELBW neonates, the survival for low-income (LI), lower middle-income (LMI) and upper middle income (UMI) countries was 18% (11% - 28%), 28% (21% - 35%) and 39% (36% - 42%), respectively. For ELGANs, it was 13% (8% - 20%) for LI, 28% (21% - 36%) for LMI and 48% (42% - 53%) for UMI countries. There was no difference in survival between two epochs: 2000-2009 and 2010-2020. Except for necrotising enterocolitis [ELBW and ELGANs-8% (7% - 10%)] and periventricular leukomalacia [ELBW-7% (4% - 11%); ELGANs-6% (5%-7%)], rates of all other morbidities were higher compared to developed nations. Rates of neurodevelopmental impairment was 17% (7% - 34%) in ELBW neonates and 29% (23% - 37%) in ELGANs. LIMITATIONS: CoE was very low to low for all secondary outcomes. CONCLUSIONS: Mortality and morbidity amongst ELBW and ELGANs is still a significant burden in LMICs. CoE was very low to low for all the secondary outcomes, emphasizing the need for high quality prospective cohort studies. TRIAL REGISTRATION: PROSPERO (CRD42020222873).

Preclinical Experiments for Hypospadias Surgery: Systematic Review and Quality Assessment.

Background: There is a steadily growing number of different reconstructive surgical procedures for hypospadias that were tested on animal models prior to their human application. However, the clinical translatability and reproducibility of the results encountered in preclinical urethral reconstruction experiments is considered poor, with significant factors contributing to the poor design and reporting of animal experiments. Our objective was to evaluate the quality of the design and reporting in published articles of urethral reconstructive preclinical studies. Methods: Both PubMed and EMBASE databases were searched for animal urethral repair experiments between January 2014 and September 2019. Internal quality (bias) was evaluated through several signaling questions arising from the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE), while the quality of reporting was assessed by the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines by scoring of a 20-item checklist. Results: A total of 638 articles were initially screened after the literature search. Employing the inclusion and exclusion criteria, 30 studies were chosen for full-text screening and 21 studies were considered eligible for the quality assessment. The mean score of the checklist was 66%. The elements that accomplished the highest grades included the number of animals utilized, the number in each investigational and control group, and the delineation of investigational conclusions. The items that were least commonly stated comprised information about the experimental method, housing and husbandry, rationalization of the number of animals, and reporting of adverse events. No paper stated the sample size estimation. Conclusion: We found that several critical experiment design principles were poorly reported, which hinders a rigorous appraisal of the scientific quality and reproducibility of the experiments. A comprehensive implementation of the ARRIVE guidelines in animal studies exploring urethral repair is necessary to facilitate the effective translation of preclinical research findings into clinical therapies.

Quality of Reporting in Preclinical Urethral Tissue Engineering Studies: A Systematic Review to Assess Adherence to the ARRIVE Guidelines.

Preclinical research within the area of urethral tissue engineering has not yet been successfully translated into an efficient therapeutic option for patients. This gap could be attributed, in part, to inadequate design and reporting of the studies employing laboratory animals. In this study, a systematic review was conducted to investigate the quality of reporting in preclinical studies utilizing tissue engineering approaches for urethral repair. The scope was on studies performed in rabbits, published between January 2014 and March 2020. Quality assessment of the data was conducted according to the Animal Research: Reporting of in Vivo Experiments (ARRIVE) guidelines by the scoring of a 38-item checklist in different categories. A total of 28 articles that fulfilled the eligibility criteria were included in the study. The range of ARRIVE score was from 0 to 100, taking into consideration having reported the item in question or not. The mean checklist score was 53%. The items that attained the highest scores included the number of animals utilized, the size of control and experimental groups, and the definition of experimental outcomes. The least frequently reported items included the data regarding the experimental procedure, housing and husbandry, determination and justification of the number of animals, and reporting of adverse events. Surprisingly, full disclosure about ethical guidelines and animal protocol approval was missing in 54% of the studies. No paper stated the sample size estimation. Overall, our study found that a large number of studies display inadequate reporting of fundamental information and that the quality of reporting improved marginally over the study period. We encourage a comprehensive implementation of the ARRIVE guidelines in animal studies exploring tissue engineering for urethral repair, not only to facilitate effective translation of preclinical research findings into clinical therapies, but also to ensure compliance with ethical principles and to minimize unnecessary animal studies.

Digital tracheal intubation and finger palpation to confirm endotracheal tube tip position in neonates: A systematic review and meta-analysis.

BACKGROUND: To evaluate digital tracheal intubation (DTI) when compared to laryngoscope-assisted TI; finger palpation of endotracheal tube (ETT) tip position when compared to any standard method. DESIGN: A systematic review of Medline, Embase, CENTRAL, and CINAHL with synthesis of data using meta-analysis was performed. MAIN OUTCOME MEASURE: The proportion of successful TI and correct ETT tip positioning were the main outcome measures. RESULTS: Five studies (one observational study and four RCTs) enrolling 310 neonates were included. 94% (81%-98%) of the DTI were successful on the first attempt (certainty of evidence [CoE]: low). The proportion of successful intubation on the first attempt was higher with DTI when compared to laryngoscope-assisted TI (RR 95% CI: 1.81 [1.18; 2.76]) (CoE: very low). Time to successful TI with DTI was 7.4 (95% CI: 6.3, 8.5) s (CoE: low). Time to successful TI was significantly shorter with DTI when compared to laryngoscope assisted TI (MD [95% CI]: -4.9 [-7.3, -2.4] s) (CoE: very low). There was a trend towards a higher proportion of correct ETT tip positions with finger palpation when compared to weight-based formulae alone (RR 95% CI: 1.12 [0.96; 1.31]) (CoE: very low). CONCLUSIONS: DTI and finger palpation to ascertain ETT tip position in neonates are promising strategies. Future studies with emphasis on their learning trajectory and generalizability are needed.

Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials.

OBJECTIVE: Melatonin has shown neuroprotective properties in pre-clinical studies of perinatal asphyxia through antioxidant, anti-apoptotic and anti-inflammatory actions. Studies have also demonstrated its safety and efficacy in neonatal encephalopathy (NE). However, its role in the current era of therapeutic hypothermia (HT) is unclear. The review aims to describe the currently available clinical evidence for Melatonin as a potential therapy for NE. METHODS: Data Sources: We searched Medline, EMBASE, CINAHL, LILACS, and Cochrane central databases, published journals, and conference proceedings from inception to May 31, 2020. STUDY SELECTION: Randomized controlled trials (RCTs) of Melatonin for NE in term or late preterm infants reporting neurodevelopmental outcomes, death, or both. The evidence quality was evaluated using the GRADE system, while the recommendations were taken according to the quality. RESULTS: We included five RCTs involving 215 neonates. Long-term development outcome data is lacking in all except in one small study, reporting significantly higher composite cognition scores at 18 months. One study reported intermediate 6-month favorable development on follow-up. Meta-analysis of mortality in combined HT + Melatonin group vs HT alone (Studies = 2, participants = 54) demonstrated no significant reduction with relative risk (RR) 0.42; 95%CI, 0.99-1.12). The overall GRADE evidence quality was very low for a very small sample size. We did not meta-analyze the data for Melatonin alone therapy without HT, as the included studies were of very low quality. CONCLUSIONS: Despite strong experimental data supporting the role of Melatonin as a neuroprotective agent in NE (both alone and as an adjunct with therapeutic hypothermia), the clinical data supporting the neuroprotective effects in neonates is limited. Larger well designed, adequately powered multicentre clinical trials are urgently needed to define the neuroprotective role of Melatonin in optimizing outcomes of NE.