Non-invasive high-frequency ventilation in newborn infants with respiratory distress.

BACKGROUND: Respiratory distress occurs in up to 7% of newborns, with respiratory support (RS) provided invasively via an endotracheal (ET) tube or non-invasively via a nasal interface. Invasive ventilation increases the risk of lung injury and chronic lung disease (CLD). Using non-invasive strategies, with or without minimally invasive surfactant, may reduce the need for mechanical ventilation and the risk of lung damage in newborn infants with respiratory distress. OBJECTIVES: To evaluate the benefits and harms of nasal high-frequency ventilation (nHFV) compared to invasive ventilation via an ET tube or other non-invasive ventilation methods on morbidity and mortality in preterm and term infants with or at risk of respiratory distress. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and three trial registries in April 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of nHFV in newborn infants with respiratory distress compared to invasive or non-invasive ventilation. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials for inclusion, extracted data, assessed the risk of bias, and undertook GRADE assessment. MAIN RESULTS: We identified 33 studies, mostly in low- to middle-income settings, that investigated this therapy in 5068 preterm and 46 term infants. nHFV compared to invasive respiratory therapy for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 0.67, 95% CI 0.20 to 2.18; 1 study, 80 infants) or the incidence of CLD (RR 0.38, 95% CI 0.09 to 1.59; 2 studies, 180 infants), both very low-certainty. ET intubation, death or CLD, severe intraventricular haemorrhage (IVH) and neurodevelopmental disability (ND) were not reported. nHFV vs nasal continuous positive airway pressure (nCPAP) used for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 1.00, 95% CI 0.41 to 2.41; 4 studies, 531 infants; very low-certainty). nHFV may reduce ET intubation (RR 0.52, 95% CI 0.33 to 0.82; 5 studies, 571 infants), but there may be little or no difference in CLD (RR 1.35, 95% CI 0.80 to 2.27; 4 studies, 481 infants); death or CLD (RR 2.50, 95% CI 0.52 to 12.01; 1 study, 68 participants); or severe IVH (RR 1.17, 95% CI 0.36 to 3.78; 4 studies, 531 infants), all low-certainty evidence. ND was not reported. nHFV vs nasal intermittent positive-pressure ventilation (nIPPV) used for initial RS nHFV may result in little to no difference in mortality before hospital discharge (RR 1.86, 95% CI 0.90 to 3.83; 2 studies, 84 infants; low-certainty). nHFV may have little or no effect in reducing ET intubation (RR 1.33, 95% CI 0.76 to 2.34; 5 studies, 228 infants; low-certainty). There may be a reduction in CLD (RR 0.63, 95% CI 0.42 to 0.95; 5 studies, 307 infants; low-certainty). A single study (36 infants) reported no events for severe IVH. Death or CLD and ND were not reported. nHFV vs high-flow nasal cannula (HFNC) used for initial RS We are very uncertain whether nHFV reduces ET intubation (RR 2.94, 95% CI 0.65 to 13.27; 1 study, 37 infants) or reduces CLD (RR 1.18, 95% CI 0.46 to 2.98; 1 study, 37 participants), both very low-certainty. There were no mortality events before hospital discharge or severe IVH. Other deaths, CLD and ND, were not reported. nHFV vs nCPAP used for RS following planned extubation nHFV probably results in little or no difference in mortality before hospital discharge (RR 0.92, 95% CI 0.52 to 1.64; 6 studies, 1472 infants; moderate-certainty). nHFV may result in a reduction in ET reintubation (RR 0.42, 95% CI 0.35 to 0.51; 11 studies, 1897 infants) and CLD (RR 0.78, 95% CI 0.67 to 0.91; 10 studies, 1829 infants), both low-certainty. nHFV probably has little or no effect on death or CLD (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 966 infants) and severe IVH (RR 0.80, 95% CI 0.57 to 1.13; 3 studies, 1117 infants), both moderate-certainty. We are very uncertain whether nHFV reduces ND (RR 0.92, 95% CI 0.37 to 2.29; 1 study, 74 infants; very low-certainty). nHFV versus nIPPV used for RS following planned extubation nHFV may have little or no effect on mortality before hospital discharge (RR 1.83, 95% CI 0.70 to 4.79; 2 studies, 984 infants; low-certainty). There is probably a reduction in ET reintubation (RR 0.69, 95% CI 0.54 to 0.89; 6 studies, 1364 infants), but little or no effect on CLD (RR 0.88, 95% CI 0.75 to 1.04; 4 studies, 1236 infants); death or CLD (RR 0.92, 95% CI 0.79 to 1.08; 3 studies, 1070 infants); or severe IVH (RR 0.78, 95% CI 0.55 to 1.10; 4 studies, 1162 infants), all moderate-certainty. One study reported there might be no difference in ND (RR 0.88, 95% CI 0.35 to 2.16; 1 study, 72 infants; low-certainty). nHFV versus nIPPV following initial non-invasive RS failure nHFV may have little or no effect on mortality before hospital discharge (RR 1.44, 95% CI 0.10 to 21.33); or ET intubation (RR 1.23, 95% CI 0.51 to 2.98); or CLD (RR 1.01, 95% CI 0.70 to 1.47); or severe IVH (RR 0.47, 95% CI 0.02 to 10.87); 1 study, 39 participants, all low- or very low-certainty. Other deaths or CLD and ND were not reported. AUTHORS' CONCLUSIONS: For initial RS, we are very uncertain if using nHFV compared to invasive respiratory therapy affects clinical outcomes. However, nHFV may reduce intubation when compared to nCPAP. For planned extubation, nHFV may reduce the risk of reintubation compared to nCPAP and nIPPV. nHFV may reduce the risk of CLD when compared to nCPAP. Following initial non-invasive respiratory support failure, nHFV when compared to nIPPV may result in little to no difference in intubation. Large trials, particularly in high-income settings, are needed to determine the role of nHFV in initial RS and following the failure of other non-invasive respiratory support. Also, the optimal settings of nHVF require further investigation.

Increased circulating cytokeratin 19 fragment levels in preterm neonates receiving mechanical ventilation are associated with poor outcome.

Invasive mechanical ventilation and oxygen toxicity are postnatal contributors to chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Cyfra 21-1 is a soluble fragment of cytokeratin 19, which belongs to the cytoskeleton stabilizing epithelial intermediate filaments. As a biomarker of structural integrity, Cyfra 21-1 might be associated with airway injury and lung hypoplasia in neonates. Serum Cyfra 21-1 concentrations for 80 preterm and 80 healthy term newborns were measured within 48 h after birth. Preterm infants with the combined endpoint BPD/mortality had significantly higher Cyfra 21-1 levels compared with those without fulfilling BPD/mortality criteria (P = 0.01). Also, severe RDS (>grade III) was associated with higher Cyfra levels (P = 0.01). Total duration of oxygen therapy was more than five times longer in neonates with high Cyfra 21-1 levels (P = 0.01). Infants with higher Cyfra 21-1 values were more likely to receive mechanical ventilation (50% vs. 17.5%). However, the duration of mechanical ventilation was similar between groups. The median Cyfra value was 1.93 ng/mL (IQR: 1.68-2.53 ng/mL) in healthy term neonates and 8.5 ng/mL (IQR: 3.6-16.0 ng/mL) in preterm infants. Using ROC analysis, we calculated a Cyfra cutoff > 8.5 ng/mL to predict BPD/death with an AUC of 0.795 (P = 0.004), a sensitivity of 88.9%, and a specificity of 55%. Mortality was predicted with a cutoff > 17.4 ng/mL (AUC: 0.94; P = 0.001), a sensitivity of 100%, and a specificity of 84%. These findings suggest that Cyfra 21-1 concentration might be useful to predict poor outcome in premature infants.

Growth Rates of Infants Randomized to Continuous Positive Airway Pressure or Intubation After Extremely Preterm Birth.

OBJECTIVE: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (240/7-276/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002). CONCLUSIONS: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation.

Causes of preterm and low birth weight neonatal mortality in a rural community in Kenya: evidence from verbal and social autopsy.

BACKGROUND: Under-five mortality in Kenya has declined over the past two decades. However, the reduction in the neonatal mortality rate has remained stagnant. In a country with weak civil registration and vital statistics systems, there is an evident gap in documentation of mortality and its causes among low birth weight (LBW) and preterm neonates. We aimed to establish causes of neonatal LBW and preterm mortality in Migori County, among participants of the PTBI-K (Preterm Birth Initiative-Kenya) study. METHODS: Verbal and social autopsy (VASA) interviews were conducted with caregivers of deceased LBW and preterm neonates delivered within selected 17 health facilities in Migori County, Kenya. The probable cause of death was assigned using the WHO International Classification of Diseases (ICD-10). RESULTS: Between January 2017 to December 2018, 3175 babies were born preterm or LBW, and 164 (5.1%) died in the first 28 days of life. VASA was conducted among 88 (53.7%) of the neonatal deaths. Almost half (38, 43.2%) of the deaths occurred within the first 24 h of life. Birth asphyxia (45.5%), neonatal sepsis (26.1%), respiratory distress syndrome (12.5%) and hypothermia (11.0%) were the leading causes of death. In the early neonatal period, majority (54.3%) of the neonates succumbed to asphyxia while in the late neonatal period majority (66.7%) succumbed to sepsis. Delay in seeking medical care was reported for 4 (5.8%) of the neonatal deaths. CONCLUSION: Deaths among LBW and preterm neonates occur early in life due to preventable causes. This calls for enhanced implementation of existing facility-based intrapartum and immediate postpartum care interventions, targeting asphyxia, sepsis, respiratory distress syndrome and hypothermia.

High Flow Nasal Cannula versus Nasal Continuous Positive Airway Pressure for Primary Respiratory Support in Preterm Infants: A Prospective Randomized Study.

OBJECTIVE: This study compares high flow nasal cannula (HFNC) with nasal continuous positive airway pressure (nCPAP) within the first hour of life as the primary respiratory support in neonates of ≤32 weeks of gestational age. STUDY DESIGN: This prospective, randomized study was conducted in infants with a gestational age of ≤32 weeks who had spontaneous respiration. HFNC or nCPAP was used as a first line respiratory support after admission to intensive care unit. Primary outcome was primary treatment failure. Secondary outcomes were duration of noninvasive respiratory support and oxygen treatment, maximum FiO2 level, length of hospital stay, intubation rate, rates of respiratory distress syndrome, pneumothorax, and bronchopulmonary dysplasia. Subgroup analysis was performed for infants ≤28 weeks of gestational age. RESULTS: We enrolled 107 infants, 53 in HFNC and 54 to nCPAP group. There was no difference in primary outcome between the two groups. There was no difference between the groups in aspect of secondary outcomes. CONCLUSION: HFNC and nCPAP have no significant differences as a primary mode of respiratory support in preterm infants, in the time to wean off the devices and oxygen support, respiratory distress syndrome and bronchopulmonary dysplasia incidence, hospitalization duration, and rates of complications of prematurity.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Early versus delayed continuous positive airway pressure (CPAP) for respiratory distress in preterm infants.

BACKGROUND: The application of continuous positive airway pressure (CPAP) has been shown to have some benefits in the treatment of preterm infants with respiratory distress. CPAP has the potential to reduce lung damage, particularly if applied early before atelectasis has occurred. Early application may better conserve an infant's own surfactant stores and consequently may be more effective than later application. OBJECTIVES: • To determine if early compared with delayed initiation of CPAP results in lower mortality and reduced need for intermittent positive-pressure ventilation in preterm infants in respiratory distress ○ Subgroup analyses were planned a priori on the basis of weight (with subdivisions at 1000 grams and 1500 grams), gestation (with subdivisions at 28 and 32 weeks), and according to whether surfactant was used ▫ Sensitivity analyses based on trial quality were also planned ○ For this update, we have excluded trials using continuous negative pressure SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 6), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literatue (CINAHL), on 30 June 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included trials that used random or quasi-random allocation to either early or delayed CPAP for spontaneously breathing preterm infants in respiratory distress. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and Cochrane Neonatal, including independent assessment of trial quality and extraction of data by two review authors. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We found four studies that recruited a total of 119 infants. Two were quasi-randomised, and the other two did not provide details on the method of randomisation or allocation used. None of these studies used blinding of the intervention or the outcome assessor. Evidence showed uncertainty about whether early CPAP has an effect on subsequent use of intermittent positive-pressure ventilation (IPPV) (typical risk ratio (RR) 0.77, 95% confidence interval (CI) 0.43 to 1.38; typical risk difference (RD) -0.08, 95% CI -0.23 to 0.08; I² = 0%, 4 studies, 119 infants; very low-certainty evidence) or mortality (typical RR 0.93, 95% CI 0.43 to 2.03; typical RD -0.02, 95% CI -0.15 to 0.12; I² = 33%, 4 studies, 119 infants; very low-certainty evidence). The outcome 'failed treatment' was not reported in any of these studies. There was an uncertain effect on air leak (pneumothorax) (typical RR 1.09, 95% CI 0.39 to 3.04, I² = 0%, 3 studies, 98 infants; very low-certainty evidence). No trials reported intraventricular haemorrhage or necrotising enterocolitis. No cases of retinopathy of prematurity were reported in one study (21 infants). One case of bronchopulmonary dysplasia was reported in each group in one study involving 29 infants. Long-term outcomes were not reported. AUTHORS' CONCLUSIONS: All four small trials included in this review were performed in the 1970s or the early 1980s, and we are very uncertain whether early application of CPAP confers clinical benefit in the treatment of respiratory distress, or whether it is associated with any adverse effects. Further trials should be directed towards establishing the appropriate level of CPAP and the timing and method of administration of surfactant when used along with CPAP.

Continuous positive airway pressure (CPAP) for respiratory distress in preterm infants.

BACKGROUND: Respiratory distress, particularly respiratory distress syndrome (RDS), is the single most important cause of morbidity and mortality in preterm infants. In infants with progressive respiratory insufficiency, intermittent positive pressure ventilation (IPPV) with surfactant has been the usual treatment, but it is invasive, potentially resulting in airway and lung injury. Continuous positive airway pressure (CPAP) has been used for the prevention and treatment of respiratory distress, as well as for the prevention of apnoea, and in weaning from IPPV. Its use in the treatment of RDS might reduce the need for IPPV and its sequelae. OBJECTIVES: To determine the effect of continuous distending pressure in the form of CPAP on the need for IPPV and associated morbidity in spontaneously breathing preterm infants with respiratory distress. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search CENTRAL (2020, Issue 6); Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions; and CINAHL on 30 June 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: All randomised or quasi-randomised trials of preterm infants with respiratory distress were eligible. Interventions were CPAP by mask, nasal prong, nasopharyngeal tube or endotracheal tube, compared with spontaneous breathing with supplemental oxygen as necessary. DATA COLLECTION AND ANALYSIS: We used standard methods of Cochrane and its Neonatal Review Group, including independent assessment of risk of bias and extraction of data by two review authors. We used the GRADE approach to assess the certainty of evidence. Subgroup analyses were planned on the basis of birth weight (greater than or less than 1000 g or 1500 g), gestational age (groups divided at about 28 weeks and 32 weeks), timing of application (early versus late in the course of respiratory distress), pressure applied (high versus low) and trial setting (tertiary compared with non-tertiary hospitals; high income compared with low income) MAIN RESULTS: We included five studies involving 322 infants; two studies used face mask CPAP, two studies used nasal CPAP and one study used endotracheal CPAP and continuing negative pressure for a small number of less ill babies. For this update, we included one new trial. CPAP was associated with lower risk of treatment failure (death or use of assisted ventilation) (typical risk ratio (RR) 0.64, 95% confidence interval (CI) 0.50 to 0.82; typical risk difference (RD) -0.19, 95% CI -0.28 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 4 to 11; I2 = 50%; 5 studies, 322 infants; very low-certainty evidence), lower use of ventilatory assistance (typical RR 0.72, 95% CI 0.54 to 0.96; typical RD -0.13, 95% CI -0.25 to -0.02; NNTB 8, 95% CI 4 to 50; I2 = 55%; very low-certainty evidence) and lower overall mortality (typical RR 0.53, 95% CI 0.34 to 0.83; typical RD -0.11, 95% CI -0.18 to -0.04; NNTB 9, 95% CI 2 to 13; I2 = 0%; 5 studies, 322 infants; moderate-certainty evidence). CPAP was associated with increased risk of pneumothorax (typical RR 2.48, 95% CI 1.16 to 5.30; typical RD 0.09, 95% CI 0.02 to 0.16; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 7 to 50; I2 = 0%; 4 studies, 274 infants; low-certainty evidence). There was no evidence of a difference in bronchopulmonary dysplasia, defined as oxygen dependency at 28 days (RR 1.04, 95% CI 0.35 to 3.13; I2 = 0%; 2 studies, 209 infants; very low-certainty evidence). The trials did not report use of surfactant, intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis and neurodevelopment outcomes in childhood. AUTHORS' CONCLUSIONS: In preterm infants with respiratory distress, the application of CPAP is associated with reduced respiratory failure, use of mechanical ventilation and mortality and an increased rate of pneumothorax compared to spontaneous breathing with supplemental oxygen as necessary. Three out of five of these trials were conducted in the 1970s. Therefore, the applicability of these results to current practice is unclear. Further studies in resource-poor settings should be considered and research to determine the most appropriate pressure level needs to be considered.

Complications and mortality of venovenous extracorporeal membrane oxygenation in the treatment of neonatal respiratory failure: a systematic review and meta-analysis.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been increasingly used for severe neonatal respiratory failure refractory to conventional treatments. To systematically evaluate the complications and mortality of venovenous ECMO (VV ECMO) in the treatment of neonatal respiratory failure, we performed a systematic review and meta-analysis of all the related studies. METHODS: PubMed, Embase, and Cochrane Library were searched. The retrieval period was from the establishment of the database to February 2019. Two investigators independently screened articles according to the inclusion and exclusion criteria. The quality of article was assessed by the Newcastle-Ottawa scale (NOS). The meta-analysis was performed by Stata 15.0 software. RESULTS: Four observational studies were included, with a total of 347 newborns. VV ECMO was used for neonates with refractory respiratory failure unresponsive to maximal medical therapy. Median ages of the newborns at cannulation were 43.2 h, 23 h, 19 h, and 71 h in the included four studies, respectively. The overall mortality at hospital charge was 12% (5-18%) with a heterogeneity of I2 = 73.8% (p = 0.01). Two studies reported mortality during ECMO and after decannulation, with 10% (0.8-19.2%) and 6.1% (2.6-9.6%), respectively. The most common complications associated with VV ECMO were: pneumothorax (20.6%), hypertension (20.4%), cannula dysfunction (20.2%), seizure (14.9%), renal failure requiring hemofiltration (14.7%), infectious complications (10.3%), thrombi (7.4%), intracranial hemorrhage or infarction (6.6%), hemolysis (5.3%), cannula site bleeding (4.4%), gastrointestinal bleeding (3.7%), oxygenator failure (2.8%), other bleeding events (2.8%), brain death (1.9%), and myocardial stun (0.9%). CONCLUSION: The overall mortality at discharge of VV ECMO in the treatment of neonatal respiratory failure was 12%. Although complications are frequent, the survival rate during hospitalization is still high. Further larger samples, and higher quality of randomized controlled trials (RCTs) are needed to clarify the efficacy and safety of this technique in the treatment of neonatal respiratory failure.

Pulmonary Surfactant Replacement Therapy for Respiratory Distress Syndrome in Neonates: a Nationwide Epidemiological Study in Korea.

BACKGROUND: Pulmonary surfactant (PS) replacement therapy, as a safe and effective treatment for respiratory distress syndrome (RDS) may have further increased with the extended insurance coverage since 2011 in Korea. Thus, this study aimed to investigate the epidemiologic data of PS replacement therapy for RDS in Korea and to analyze the complications associated with RDS. METHODS: We included 19,442 infants who were treated with PS and diagnosed with RDS (International Classification of Diseases-10 codes: P22.0) between 2014 and 2018 from the Health Insurance Review and Assessment database. Birth certificate data from Statistics Korea were used to estimate the incidence of RDS. RESULTS: The average incidence of RDS within the study period was 0.99% among live births. Repeated doses of PS were administered to 1,688 infants (8.7%), ranging from 2 doses in 929 infants (4.8%) to 9 doses in 1 infant (0.01%). The incidence of RDS in term infants markedly increased over 5 years from 0.2% to 0.34%. The incidence was similarly increased among the preterm infants. The RDS mortality rate was 6.3% and showed a decreasing trend according to year. The mortality rate was significantly higher in the lower gestational age group. A decreasing trend was observed in the incidence of the complications, such as patent ductus arteriosus, intraventricular hemorrhage, and bronchopulmonary dysplasia, except for pneumothorax in term infants. The complications were also higher in the lower gestational age group and the lower birth weight group. However, pneumothorax was the most frequent complication in the term infant group and in infants with birth weight ≥ 2,500 g. CONCLUSION: Advancements in neonatal care and extended insurance coverage have increased the use of PS replacement therapy for RDS. This, in turn, decreased neonatal mortality and the incidence of the associated complications. The appropriate therapeutic strategy for RDS should be decided according to the gestational age and lung pathology.

Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants.

BACKGROUND: Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved. METHODS: In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated. RESULTS: Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events. CONCLUSIONS: When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).

Successful extracorporeal membrane oxygenation transport of a 4-month-old brain-dead infant for organ donation: A case report.

A 4-month-old infant was declared brain-dead 2 days after being initiated on venoarterial ECMO for a refractory septic shock. All brain death diagnostic criteria were fulfilled according to French law, and parental consent was given for organ donation. The hospital where ECMO was initiated had no authorization for organ procurement, and the donor was then transferred to the local referral center for child organ recovery with our mobile ECMO team to maintain organ perfusion. The kidneys were recovered and successfully transplanted to a child who is now well and alive. Although the transport elements of this case report are of limited relevance to an international audience as no other country, to our knowledge, has this particular organization, it does show excellent collaboration between teams to realize the goal of organ donation for this family. This is the first case describing a successful inter-hospital transport for organ procurement of a brain-dead infant on ECMO. Brain-dead pediatric patients undergoing ECMO can be considered as potential organ donors to expand the donor pool.

Oral vitamin A supplementation in very low birth weight neonates: a randomized controlled trial.

This randomized double-blind placebo-controlled trial evaluated the effects of early postnatal oral vitamin A supplementation (VAS) in 196 inborn very-low birth weight (VLBW) infants requiring respiratory support at 24 h of age. Eligible infants were randomized to receive aqueous syrup of vitamin A (10,000 IU of retinol/dose; n = 98) or placebo (n = 98) on alternate days for 28 days. Primary outcome variable was composite incidence of all-cause mortality and/or oxygen requirement for 28 days. Secondary outcome variables were safety/tolerability of VAS, serum retinol concentration at recruitment and day 28, duration of oxygen requirement and respiratory support and incidences of complications. On intention-to-treat analysis, composite incidence of all-cause mortality and oxygen requirement for 28 days was significantly lower in vitamin A group (relative risk (95% confidence interval), 0.440 (0.229-0.844); p < 0.05, number needed to benefit, 7). Requirement and duration of oxygen supplementation and non-invasive respiratory support, incidences of late-onset sepsis, patent ductus arteriosus, and duration of hospital stay were also significantly lower in vitamin A group. Serum retinol concentration improved significantly after VAS. No major adverse effect was observed.Conclusions: Early postnatal oral VAS was associated with better composite outcome of all-cause mortality and oxygen requirement without any major adverse effects.Clinical Trial Registration: Clinical Trials Registry of India (CTRI/2017/03/008131). What is Known: • Postnatal intramuscular vitamin A supplementation improves the survival, respiratory outcome and other morbidities in very low birth weight neonates without major adverse effects. • Limited studies on oral vitamin A supplementation did not document substantial benefits. What is New: • Early postnatal alternate-day oral vitamin A supplementation at the dose of 10,000 IU/dose for 28 days improves the composite outcome of death and oxygen requirement in very low birth weight neonates with respiratory distress • No major adverse effects were documented.

Positive end-expiratory pressure for preterm infants requiring conventional mechanical ventilation for respiratory distress syndrome or bronchopulmonary dysplasia.

BACKGROUND: Conventional mechanical ventilation (CMV) is a common therapy for neonatal respiratory failure. While CMV facilitates gas exchange, it may simultaneously injure the lungs. Positive end-expiratory pressure (PEEP) has received less attention than other ventilation parameters when considering this benefit-risk balance. While an appropriate PEEP level may result in clinical benefits, both inappropriately low or high levels may cause harm. An appropriate PEEP level may also be best achieved by an individualized approach. OBJECTIVES: 1. To compare the effects of PEEP levels in preterm infants requiring CMV for respiratory distress syndrome (RDS). We compare both: zero end-expiratory pressure (ZEEP) (0 cm H2O) versus any PEEP and low (< 5 cm H2O) vs high (≥ 5 cm H2O) PEEP.2. To compare the effects of PEEP levels in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD). We compare both: ZEEP (0 cm H2O) vs any PEEP and low (< 5 cm H2O) versus high (≥ 5 cm H2O) PEEP.3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials, MEDLINE via PubMed, Embase, and CINAHL to 14 February 2018. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: We included all randomized or quasi-randomized controlled trials studying preterm infants born at less than 37 weeks' gestational age, requiring CMV and undergoing randomization to either different PEEP levels (RDS or BPD); or, two or more alternative methods for individualizing PEEP levels (RDS only). We included cross-over trials but limited outcomes to those from the first cross-over period. DATA COLLECTION AND ANALYSIS: We performed data collection and analysis according to the recommendations of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for prespecified key clinically relevant outcomes. MAIN RESULTS: Four trials met the inclusion criteria. Two cross-over trials with 28 participants compared different PEEP levels in infants with RDS. Meta-analysis was limited to short-term measures of pulmonary gas exchange and showed no differences between low and high PEEP.We identified no trials comparing PEEP levels in infants with BPD.Two trials enrolling 44 participants compared different methods for individualizing PEEP in infants with RDS. Both trials compared an oxygenation-guided lung-recruitment maneuver (LRM) with gradual PEEP level titrations for individualizing PEEP to routine care (control). Meta-analysis showed no difference between LRM and control on mortality by hospital discharge (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.17 to 5.77); there was no statistically significant difference on BPD, with an effect estimate favoring LRM (RR 0.25, 95% CI 0.03 to 2.07); and a statistically significant difference favoring LRM for the outcome of duration of ventilatory support (mean difference -1.06 days, 95% CI -1.85 to -0.26; moderate heterogeneity, I2 = 67%). Short-term oxygenation measures also favored LRM. We graded the quality of the evidence as low for all key outcomes due to risk of bias and imprecision of the effect estimates. AUTHORS' CONCLUSIONS: There continues to be insufficient evidence to guide PEEP level selection for preterm infants on CMV for RDS or BPD. Low-quality data suggests that selecting PEEP levels through the application of an oxygenation-guided LRM may result in clinical benefit. Well-conducted randomized trials, particularly to further evaluate the potential benefits of oxygenation-guided LRMs, are needed.

Inositol in preterm infants at risk for or having respiratory distress syndrome.

BACKGROUND: Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life. A drop in inositol levels in infants with respiratory distress syndrome (RDS) can be a sign that their illness will be severe. OBJECTIVES: To assess the effectiveness and safety of supplementary inositol in preterm infants with or without respiratory distress syndrome (RDS) in reducing adverse neonatal outcomes including: death (neonatal and infant deaths), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC) and sepsis. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 11), MEDLINE via PubMed (1966 to 5 November 2018), Embase (1980 to 5 November 2018), and CINAHL (1982 to 5 November 2018). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included all randomised controlled trials of inositol supplementation of preterm infants compared with a control group that received a placebo or no intervention. Outcomes included neonatal death, infant death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and sepsis. DATA COLLECTION AND ANALYSIS: The three review authors independently abstracted data on neonatal outcomes and resolved any disagreements through discussion and consensus. Outcomes were reported as typical risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Six published randomised controlled trials were identified, with a total of 1177 infants. Study quality varied for the comparison 'Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment) versus control' and interim analyses had occurred in several trials for the outcomes of interest. In this comparison, neonatal death was found to be significantly reduced (typical RR 0.53, 95% CI 0.31 to 0.91; typical RD -0.09, 95% CI -0.16 to -0.01; NNTB 11, 95% CI 6 to 100; 3 trials, 355 neonates). Infant deaths were not reduced (typical RR 0.89, 95% CI 0.71 to 1.13; typical RD -0.02, 95% CI -0.07 to 0.02; 5 trials, 1115 infants) (low-quality evidence). ROP stage 2 or higher or stage 3 or higher was not significantly reduced (typical RR 0.89, 95% CI 0.75 to 1.06; typical RD -0.04, 95% CI -0.10 to 0.02; 3 trials, 810 infants) (moderate-quality evidence). There were no significant findings for ROP (any stage), NEC (suspected or proven), sepsis, IVH grade greater than II (moderate-quality evidence). For the comparison 'Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at less than 30 weeks' postmenstrual age (PMA) compared to placebo for preterm infants at risk for or having respiratory distress syndrome' the results from two studies of high quality were included (N = 760 neonates). Recruitment to the larger study (N = 638) was terminated because of a higher rate of deaths in the inositol group. We did not downgrade the quality of the study. The meta-analyses of the outcomes of 'Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome', 'Type 1 ROP including adjudicated ROP outcome', 'All-cause mortality (outcome collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)' and 'Severe IVH (grade 3 or 4)' did not show significant findings (moderate-quality evidence). There were no significant findings for the outcomes 'BPD or death by it prior to 37 weeks' postmenstrual age (outcomes collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)', 'Late onset sepsis (> 72 hours of age)', and 'Suspected or proven NEC' (high-quality evidence). AUTHORS' CONCLUSIONS: Based on the evidence from randomised controlled trials to date, inositol supplementation does not result in important reductions in the rates of infant deaths, ROP stage 3 or higher, type 1 ROP, IVH grades 3 or 4, BPD, NEC, or sepsis. These conclusions are based mainly on two recent randomised controlled trials in neonates less than 30 weeks' postmenstrual age (N = 760), the most vulnerable population. Currently inositol supplementation should not be routinely instituted as part of the nutritional management of preterm infants with or without RDS. It is important that infants who have been enrolled in the trials included in this review are followed to assess any effects of inositol supplementation on long-term outcomes in childhood. We do not recommend any additional trials in neonates.

Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

BACKGROUND: Antenatal corticosteroids have been proven to prevent adverse outcomes including respiratory morbidities in preterm neonates before 34 weeks of gestation. Recently, it has been suggested that antenatal corticosteroids may also be effective in singleton late preterm pregnancies, and guidelines recommend the use of corticosteroids in singleton pregnant women who are at risk for late preterm birth. On the contrary, there is a paucity of information regarding the effectiveness of corticosteroids in twin neonates with late preterm birth. This study aims to determine the effectiveness of antenatal corticosteroids in late preterm twin neonates. METHODS: In this multicentre randomized controlled trial, women who are at risk for late preterm birth will be enrolled at 34 0/7 to 36 5/7 weeks of gestation. The participants will be randomly assigned to receive antenatal corticosteroids (betamethasone 12 mg, 3 mL intramuscularly [IM]) or placebo (normal saline 3 mL IM). The perinatal outcomes will be compared between the two groups of cases. The primary outcome is severe respiratory complications (the use of continuous positive airway pressure or high-flow nasal cannula for at least 12 h, supplemental oxygen administration with a fraction of oxygen 0.3 or more for at least 24 h, mechanical ventilation, or extracorporeal membranes oxygenation) or perinatal death within the first 72 h of delivery. The secondary outcomes are neonatal mortality and/or other neonatal morbidities. DISCUSSION: This study will be the first randomized controlled trial that evaluates the effectiveness of antenatal corticosteroids in late preterm twin neonates. TRIAL REGISTRATION: NCT03547791 (ClinicalTrials.gov), first submitted date: March 29, 2018, first posted date: June 6, 2018 (retrospectively registered).

Reducing preterm mortality in eastern Uganda: the impact of introducing low-cost bubble CPAP on neonates <1500 g.

BACKGROUND: Complications of prematurity are the leading cause of deaths in children under the age of five. The predominant reason for these preterm deaths is respiratory distress syndrome (RDS). In low-income countries (LICs) there are limited treatment options for RDS. Due to their simplicity and affordability, low-cost bubble continuous positive airway pressure (bCPAP) devices have been introduced in neonatal units in LICs to treat RDS. This study is the first observational study from a LIC to compare outcomes of very-low-birth-weight (VLBW) neonates in pre- and post-CPAP periods. METHODS: This was a retrospective study of VLBW neonates (weight < 1500 g) in Mbale Regional Referral Hospital Neonatal Unit (MRRH-NNU), a government hospital in eastern Uganda. It aimed to measure the outcome of VLBW neonates in two distinct study periods: A 14-month period beginning at the opening of MRRH-NNU and covering the period until bCPAP was introduced (pre-bCPAP) and an 18-month period following the introduction of bCPAP (post-bCPAP). After the introduction of bCPAP, it was applied to preterm neonates with RDS when clinically indicated and if a device was available. Clinical features and outcomes of all neonates < 1500 g were compared before and after the introduction of bCPAP. RESULTS: The admission records of 377 VLBW neonates < 1500 g were obtained. One hundred fifty-eight were admitted in the pre-bCPAP period and 219 in the post-bCPAP period. The mortality rate in the pre- bCPAP period was 39.2% (62/158) compared with 26.5% (58/219, P = 0.012) in the post-bCPAP period. Overall, there was a 44% reduction in mortality (OR 0.56, 95%CI 0.36-0.86, P = 0.01). There were no differences in birthweight, sex, presence of signs of respiratory distress or apnoea between the two groups. CONCLUSION: Specialized and resource-appropriate neonatal care, that appropriately addresses the challenges of healthcare provision in LICs, has the potential to reduce neonatal deaths. The use of a low-cost bCPAP to treat RDS in VLBW neonates resulted in a significant improvement in their survival in a neonatal unit in eastern Uganda. Since RDS is one of the leading causes of neonatal mortality, it is possible that this relatively simple and affordable intervention could have a huge impact on global neonatal mortality.

Prospective observational study of early respiratory management in preterm neonates less than 35 weeks of gestation.

BACKGROUND: Current guidelines for management of respiratory distress syndrome (RDS) recommend continuous positive airway pressure (CPAP) as the primary mode of respiratory support even in the most premature neonates, reserving endotracheal intubation (ETI) for rescue surfactant or respiratory failure. The incidence and timing of ETI in practice is poorly documented. METHODS: In 27 Level III NICUs in the US (n = 19), Canada (n = 3) and Poland (n = 5), demographics and baseline characteristics, respiratory support modalities including timing of ETI, administration of surfactant and caffeine/other methylxanthines, and neonatal morbidities were prospectively recorded in consecutive preterm neonates following written parental consent. Infants were divided into three groups according to gestational age (GA) at birth, namely 26-28, 29-32 and 33-34 weeks. Statistical comparisons between groups were done using Chi-Square tests. RESULTS: Of 2093 neonates (US = 1507, 254 Canada, 332 Poland), 378 (18%) were 26-28 weeks gestational age (GA), 835 (40%) were 29-32 weeks, and 880 (42%) were 33-34 weeks. Antenatal steroid use was 81% overall, and approximately 89% in neonates ≤32 weeks. RDS incidence and use of ventilatory or supplemental oxygen support were similar across all sites. CPAP was initiated in 43% of all infants, being highest in the 29-32-week group, with a lower proportion in other GA categories (p < 0.001). The overall rate of ETI was 74% for neonates 26-28 weeks (42% within 15 min of birth, 49% within 60 min, and 57% within 3 h), 33% for 29-32 weeks (13 16 and 21%, respectively), and 16% for 33-34 weeks (5, 6 and 8%, respectively). Overall intubation rates and timing were similar between countries in all GAs. Rates within each country varied widely, however. Across US sites, overall ETI rates in 26-28-week neonates were 30-60%, and ETI within 15 min varied from 0 to 83%. Similar within 15-min variability was seen at Polish sites (22-67%) in this GA, and within all countries for 29-32 and 33-34-week neonates. CONCLUSION: Despite published guidelines for management of RDS, rate and timing of ETI varies widely, apparently unrelated to severity of illness. The impact of this variability on outcome is unknown but provides opportunities for further approaches which can avoid the need for ETI.

Small for gestational age and extremely low birth weight infant outcomes.

Background Small for gestational age (SGA) infants are less likely to develop respiratory distress syndrome (RDS), but more likely to develop bronchopulmonary dysplasia (BPD) and have a higher mortality. Our aim was to focus on outcomes of those with a birth weight less than or equal to 750 g. Methods The mortality, BPD severity, necrotising enterocolitis (NEC), home oxygen requirement and length of hospital stay were determined according to SGA status of all eligible infants in a 5-year period admitted within the first 24 h after birth. Results The outcomes of 84 infants were assessed, and 35 (42%) were SGA. The SGA infants were more mature (P<0.001), had a lower birth weight centile (P<0.001) and a greater proportion exposed to antenatal corticosteroids (P=0.022). Adjusted for gestational age (GA), there was no significant difference in mortality between the two groups (P=0.242), but a greater proportion of the SGA infants developed severe BPD (P=0.025). The SGA infants had a lower weight z-score at discharge (-3.64 vs. -1.66) (P=0.001), but a decrease in z-score from birth to discharge was observed in both groups (median -1.53 vs. -1.07, P=0.256). Conclusion Despite being more mature, the SGA infants had a similar mortality rate and a greater proportion developed severe BPD.

Birth Size and Gestational Age Specific Outcomes of Inhaled Nitric Oxide Therapy in Preterm Neonates with Clinically Diagnosed Pulmonary Hypertension.

OBJECTIVE: Among neonates of 22 to 29 weeks' gestational age (GA) who required mechanical ventilation for the treatment of respiratory distress syndrome (RDS) and clinically diagnosed pulmonary hypertension (PH), we tested our hypothesis that the association between early treatment with inhaled nitric oxide (iNO) and survival would vary according to birth size and GA. STUDY DESIGN: Because iNO was not randomly prescribed to patients in this cohort, we used propensity score matching to pair a neonate who received iNO at a chronological age of ≤7 days with an unexposed neonate with similar baseline characteristics. The primary outcome was inhospital mortality, which we evaluated based on size for GA and GA strata using the Cox proportional hazards regression model. RESULTS: Among 1,531 neonates who met study criteria, we created a propensity score matched cohort of 615 pairs of neonates (iNO-exposed and unexposed). The risk of inhospital mortality for iNO-exposed neonates was observed only in the minority (<10%) who were large for GA, though this finding did not persist when matching for illness severity. CONCLUSION: Early treatment with iNO is not associated with survival in most extremely premature neonates with RDS and clinically diagnosed PH when stratified for birth size or GA.