Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a useful method for providing respiratory support after extubation. Nasal intermittent positive pressure ventilation (NIPPV) can augment NCPAP by delivering ventilator breaths via nasal prongs. OBJECTIVES: Primary objective To determine the effects of management with NIPPV versus NCPAP on the need for additional ventilatory support in preterm infants whose endotracheal tube was removed after a period of intermittent positive pressure ventilation. Secondary objectives To compare rates of abdominal distension, gastrointestinal perforation, necrotising enterocolitis, chronic lung disease, pulmonary air leak, mortality, duration of hospitalisation, rates of apnoea and neurodevelopmental status at 18 to 24 months for NIPPV and NCPAP. To compare the effect of NIPPV versus NCPAP delivered via ventilators versus bilevel devices, and assess the effects of the synchronisation of ventilation, and the strength of interventions in different economic settings. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was January 2023. SELECTION CRITERIA: We included randomised and quasi-randomised trials of ventilated preterm infants (less than 37 weeks' gestational age (GA)) ready for extubation to non-invasive respiratory support. Interventions were NIPPV and NCPAP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. respiratory failure. Our secondary outcomes were 2. endotracheal reintubation, 3. abdominal distension, 4. gastrointestinal perforation, 5. necrotising enterocolitis (NEC), 6. chronic lung disease, 7. pulmonary air leak, 8. mortality, 9. hospitalisation, 10. apnoea and bradycardia, and 11. neurodevelopmental status. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 19 trials (2738 infants). Compared to NCPAP, NIPPV likely reduces the risk of respiratory failure postextubation (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.67 to 0.84; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 8 to 17; 19 trials, 2738 infants; moderate-certainty evidence) and endotracheal reintubation (RR 0.78, 95% CI 0.70 to 0.87; NNTB 12, 95% CI 9 to 25; 17 trials, 2608 infants, moderate-certainty evidence), and may reduce pulmonary air leaks (RR 0.57, 95% CI 0.37 to 0.87; NNTB 50, 95% CI 33 to infinite; 13 trials, 2404 infants; low-certainty evidence). NIPPV likely results in little to no difference in gastrointestinal perforation (RR 0.89, 95% CI 0.58 to 1.38; 8 trials, 1478 infants, low-certainty evidence), NEC (RR 0.86, 95% CI 0.65 to 1.15; 10 trials, 2069 infants; moderate-certainty evidence), chronic lung disease defined as oxygen requirement at 36 weeks (RR 0.93, 95% CI 0.84 to 1.05; 9 trials, 2001 infants; moderate-certainty evidence) and mortality prior to discharge (RR 0.81, 95% CI 0.61 to 1.07; 11 trials, 2258 infants; low-certainty evidence). When considering subgroup analysis, ventilator-generated NIPPV likely reduces respiratory failure postextubation (RR 0.49, 95% CI 0.40 to 0.62; 1057 infants; I2 = 47%; moderate-certainty evidence), while bilevel devices (RR 0.95, 95% CI 0.77 to 1.17; 716 infants) or a mix of both ventilator-generated and bilevel devices likely results in little to no difference (RR 0.87, 95% CI 0.73 to 1.02; 965 infants). AUTHORS' CONCLUSIONS: NIPPV likely reduces the incidence of extubation failure and the need for reintubation within 48 hours to one-week postextubation more effectively than NCPAP in very preterm infants (GA 28 weeks and above). There is a paucity of data for infants less than 28 weeks' gestation. Pulmonary air leaks were also potentially reduced in the NIPPV group. However, it has no effect on other clinically relevant outcomes such as gastrointestinal perforation, NEC, chronic lung disease or mortality. Ventilator-generated NIPPV appears superior to bilevel devices in reducing the incidence of respiratory failure postextubation failure and need for reintubation. Synchronisation used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. Future trials should enrol a sufficient number of infants, particularly those less than 28 weeks' GA, to detect differences in death or chronic lung disease and should compare different categories of devices, establish the impact of synchronisation of NIPPV on safety and efficacy of the technique as well as the best combination of settings for NIPPV (rate, peak pressure and positive end-expiratory). Trials should strive to match the mean airway pressure between the intervention groups to allow a better comparison. Neurally adjusted ventilatory assist needs further assessment with properly powered randomised trials.

Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.

BACKGROUND: Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. METHODS: To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. RESULTS: From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. CONCLUSION: Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.

Nasal high flow therapy for primary respiratory support in preterm infants.

BACKGROUND: Nasal high flow (nHF) therapy provides heated, humidified air and oxygen via two small nasal prongs, at gas flows of more than 1 litre/minute (L/min), typically 2 L/min to 8 L/min. nHF is commonly used for non-invasive respiratory support in preterm neonates. It may be used in this population for primary respiratory support (avoiding, or prior to the use of mechanical ventilation via an endotracheal tube) for prophylaxis or treatment of respiratory distress syndrome (RDS). This is an update of a review first published in 2011 and updated in 2016. OBJECTIVES: To evaluate the benefits and harms of nHF for primary respiratory support in preterm infants compared to other forms of non-invasive respiratory support. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date March 2022. SELECTION CRITERIA: We included randomised or quasi-randomised trials comparing nHF with other forms of non-invasive respiratory support for preterm infants born less than 37 weeks' gestation with respiratory distress soon after birth. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Neonatal methods. Our primary outcomes were 1. death (before hospital discharge) or bronchopulmonary dysplasia (BPD), 2. death (before hospital discharge), 3. BPD, 4. treatment failure within 72 hours of trial entry and 5. mechanical ventilation via an endotracheal tube within 72 hours of trial entry. Our secondary outcomes were 6. respiratory support, 7. complications and 8. neurosensory outcomes. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 13 studies (2540 infants) in this updated review. There are nine studies awaiting classification and 13 ongoing studies. The included studies differed in the comparator treatment (continuous positive airway pressure (CPAP) or nasal intermittent positive pressure ventilation (NIPPV)), the devices for delivering nHF and the gas flows used. Some studies allowed the use of 'rescue' CPAP in the event of nHF treatment failure, prior to any mechanical ventilation, and some allowed surfactant administration via the INSURE (INtubation, SURfactant, Extubation) technique without this being deemed treatment failure. The studies included very few extremely preterm infants less than 28 weeks' gestation. Several studies had unclear or high risk of bias in one or more domains. Nasal high flow compared with continuous positive airway pressure for primary respiratory support in preterm infants Eleven studies compared nHF with CPAP for primary respiratory support in preterm infants. When compared with CPAP, nHF may result in little to no difference in the combined outcome of death or BPD (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.74 to 1.60; risk difference (RD) 0, 95% CI -0.02 to 0.02; 7 studies, 1830 infants; low-certainty evidence). Compared with CPAP, nHF may result in little to no difference in the risk of death (RR 0.78, 95% CI 0.44 to 1.39; 9 studies, 2009 infants; low-certainty evidence), or BPD (RR 1.14, 95% CI 0.74 to 1.76; 8 studies, 1917 infants; low-certainty evidence). nHF likely results in an increase in treatment failure within 72 hours of trial entry (RR 1.70, 95% CI 1.41 to 2.06; RD 0.09, 95% CI 0.06 to 0.12; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 8 to 17; 9 studies, 2042 infants; moderate-certainty evidence). However, nHF likely does not increase the rate of mechanical ventilation (RR 1.04, 95% CI 0.82 to 1.31; 9 studies, 2042 infants; moderate-certainty evidence). nHF likely results in a reduction in pneumothorax (RR 0.66, 95% CI 0.40 to 1.08; 10 studies, 2094 infants; moderate-certainty evidence) and nasal trauma (RR 0.49, 95% CI 0.36 to 0.68; RD -0.06, 95% CI -0.09 to -0.04; 7 studies, 1595 infants; moderate-certainty evidence). Nasal high flow compared with nasal intermittent positive pressure ventilation for primary respiratory support in preterm infants Four studies compared nHF with NIPPV for primary respiratory support in preterm infants. When compared with NIPPV, nHF may result in little to no difference in the combined outcome of death or BPD, but the evidence is very uncertain (RR 0.64, 95% CI 0.30 to 1.37; RD -0.05, 95% CI -0.14 to 0.04; 2 studies, 182 infants; very low-certainty evidence). nHF may result in little to no difference in the risk of death (RR 0.78, 95% CI 0.36 to 1.69; RD -0.02, 95% CI -0.10 to 0.05; 3 studies, 254 infants; low-certainty evidence). nHF likely results in little to no difference in the incidence of treatment failure within 72 hours of trial entry compared with NIPPV (RR 1.27, 95% CI 0.90 to 1.79; 4 studies, 343 infants; moderate-certainty evidence), or mechanical ventilation within 72 hours of trial entry (RR 0.91, 95% CI 0.62 to 1.33; 4 studies, 343 infants; moderate-certainty evidence). nHF likely results in a reduction in nasal trauma, compared with NIPPV (RR 0.21, 95% CI 0.09 to 0.47; RD -0.17, 95% CI -0.24 to -0.10; 3 studies, 272 infants; moderate-certainty evidence). nHF likely results in little to no difference in the rate of pneumothorax (RR 0.78, 95% CI 0.40 to 1.53; 4 studies, 344 infants; moderate-certainty evidence). Nasal high flow compared with ambient oxygen We found no studies examining this comparison. Nasal high flow compared with low flow nasal cannulae We found no studies examining this comparison. AUTHORS' CONCLUSIONS: The use of nHF for primary respiratory support in preterm infants of 28 weeks' gestation or greater may result in little to no difference in death or BPD, compared with CPAP or NIPPV. nHF likely results in an increase in treatment failure within 72 hours of trial entry compared with CPAP; however, it likely does not increase the rate of mechanical ventilation. Compared with CPAP, nHF use likely results in less nasal trauma and likely a reduction in pneumothorax. As few extremely preterm infants less than 28 weeks' gestation were enrolled in the included trials, evidence is lacking for the use of nHF for primary respiratory support in this population.

Bubble devices versus other pressure sources for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Several types of pressure sources, including underwater bubble devices, mechanical ventilators, and the Infant Flow Driver, are used for providing continuous positive airway pressure (CPAP) to preterm infants with respiratory distress. It is unclear whether the use of bubble CPAP versus other pressure sources is associated with lower rates of CPAP treatment failure, or mortality and other morbidity.  OBJECTIVES: To assess the benefits and harms of bubble CPAP versus other pressure sources (mechanical ventilators or Infant Flow Driver) for reducing treatment failure and associated morbidity and mortality in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 1); MEDLINE (1946 to 6 January 2023), Embase (1974 to 6 January 2023), Maternity & Infant Care Database (1971 to 6 January 2023), and the Cumulative Index to Nursing and Allied Health Literature (1982 to 6 January 2023). We searched clinical trials databases and the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials comparing bubble CPAP with other pressure sources (mechanical ventilators or Infant Flow Driver) for the delivery of nasal CPAP to preterm infants. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of the evidence for effects on treatment failure, all-cause mortality, neurodevelopmental impairment, pneumothorax, moderate-severe nasal trauma, and bronchopulmonary dysplasia. MAIN RESULTS: We included 15 trials involving a total of 1437 infants. All trials were small (median number of participants 88). The methods used to generate the randomisation sequence and ensure allocation concealment were unclear in about half of the trial reports. Lack of measures to blind caregivers or investigators was a potential source of bias in all of the included trials. The trials took place during the past 25 years in care facilities internationally, predominantly in India (five trials) and Iran (four trials). The studied pressure sources were commercially available bubble CPAP devices versus a variety of mechanical ventilator (11 trials) or Infant Flow Driver (4 trials) devices.  Meta-analyses suggest that the use of bubble CPAP compared with mechanical ventilator or Infant Flow Driver CPAP may reduce the rate of treatment failure (RR 0.76, 95% confidence interval (CI) 0.60 to 0.95; (I² = 31%); RD -0.05, 95% CI -0.10 to -0.01; number needed to treat for an additional beneficial outcome 20, 95% CI 10 to 100; 13 trials, 1230 infants; low certainty evidence). The type of pressure source may not affect mortality prior to hospital discharge (RR 0.93, 95% CI 0.64 to 1.36 (I² = 0%); RD -0.01, 95% CI -0.04 to 0.02; 10 trials, 1189 infants; low certainty evidence). No data were available on neurodevelopmental impairment. Meta-analysis suggests that the pressure source may not affect the risk of pneumothorax (RR 0.73, 95% CI 0.40 to 1.34 (I² = 0%); RD -0.01, 95% CI -0.03 to 0.01; 14 trials, 1340 infants; low certainty evidence). Bubble CPAP likely increases the risk of moderate-severe nasal injury (RR 2.29, 95% CI 1.37 to 3.82 (I² = 17%); RD 0.07, 95% CI 0.03 to 0.11; number needed to treat for an additional harmful outcome 14, 95% CI 9 to 33; 8 trials, 753 infants; moderate certainty evidence). The pressure source may not affect the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.53 to 1.10 (I² = 0%); RD -0.04, 95% CI -0.09 to 0.01; 7 trials, 603 infants; low certainty evidence).  AUTHORS' CONCLUSIONS: Given the low level of certainty about the effects of bubble CPAP versus other pressure sources on the risk of treatment failure and most associated morbidity and mortality for preterm infants, further large, high-quality trials are needed to provide evidence of sufficient validity and applicability to inform context- and setting-relevant policy and practice.

Impact of probiotic administration on the incidence of necrotising enterocolitis: A single-centre cohort study.

AIM: To examine the effect of probiotic administration on the incidence of necrotising enterocolitis (NEC) in preterm infants. METHODS: We conducted a retrospective study examining the incidence of NEC in a cohort of infants that received probiotics compared to those that had not, over an 18-year period in a single centre. Infants were included if they were born <32 weeks' gestation with birthweight <1500 g and survived beyond 72 h. Infants in the probiotic group received either ABC Dophilus or Infloran. The primary outcome was the rate of NEC. The main secondary outcomes were late-onset sepsis and mortality. Differences in these outcomes between cohorts were examined in univariate and multivariate analyses, taking account of confounding variables, reporting adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: 805 infants were included in the study. Infants receiving probiotics had a lower risk of developing NEC compared with those that did not (32/419 (7.6%) vs. 14/386 (3.6%); aOR 0.37 (95% CI 0.18-0.74)). There was also a reduction in the late-onset sepsis rate (22.4% vs. 14.2%, aOR 0.52, 95% CI 0.35-0.77) and mortality rate (9.5% vs. 4.6%, aOR 0.35, 95% CI 0.17-0.73). CONCLUSION: The administration of a multi-organism probiotic formulation, including Bifidobacteria, to very preterm infants in our unit was associated with a reduced incidence of NEC, late-onset sepsis and mortality.

Masks versus prongs as interfaces for nasal continuous positive airway pressure in preterm infants.

BACKGROUND: Nasal masks and nasal prongs are used as interfaces for providing continuous positive airway pressure (CPAP) for preterm infants with or at risk of respiratory distress, either as primary support after birth or as ongoing support after endotracheal extubation from mechanical ventilation. It is unclear which type of interface is associated with lower rates of CPAP treatment failure, nasal trauma, or mortality and other morbidity. OBJECTIVES: To assess the benefits and harms of nasal masks versus nasal prongs for reducing CPAP treatment failure, nasal trauma, or mortality and other morbidity in newborn preterm infants with or at risk of respiratory distress. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was October 2021. SELECTION CRITERIA: We included randomised controlled trials comparing masks versus prongs as interfaces for delivery of nasal CPAP in newborn preterm infants (less than 37 weeks' gestation) with or at risk of respiratory distress. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. treatment failure, 2. all-cause mortality, and 3. neurodevelopmental impairment. Our secondary outcomes were 4. pneumothorax, 5. moderate-severe nasal trauma, 6. bronchopulmonary dysplasia, 7. duration of CPAP use, 8. duration of oxygen supplementation, 9. duration of hospitalisation, 10. patent ductus arteriosus receiving medical or surgical treatment, 11. necrotising enterocolitis, 12. severe intraventricular haemorrhage, and 13. severe retinopathy of prematurity. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 12 trials with 1604 infants. All trials were small (median number of participants 118). The trials occurred after 2001 in care facilities internationally, predominantly in India (eight trials). Most participants were preterm infants of 26 to 34 weeks' gestation who received nasal CPAP as the primary form of respiratory support after birth. The studied interfaces included commonly used commercially available masks and prongs. Lack of measures to blind caregivers or investigators was a potential source of performance and detection bias in all the trials. Meta-analyses suggested that use of masks compared with prongs may reduce CPAP treatment failure (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 8 trials, 919 infants; low certainty). The type of interface may not affect mortality prior to hospital discharge (RR 0.83, 95% CI 0.56 to 1.22; 7 trials, 814 infants; low certainty). There are no data on neurodevelopmental impairment. Meta-analyses suggest that the choice of interface may result in little or no difference in the risk of pneumothorax (RR 0.93, 95% CI 0.45 to 1.93; 5 trials, 625 infants; low certainty). Use of masks rather than prongs may reduce the risk of moderate-severe nasal injury (RR 0.55, 95% CI 0.44 to 0.71; 10 trials, 1058 infants; low certainty). The evidence is very uncertain about the effect on bronchopulmonary dysplasia (RR 0.69, 95% CI 0.46 to 1.03; 7 trials, 843 infants; very low certainty). AUTHORS' CONCLUSIONS: The available trial data provide low-certainty evidence that use of masks compared with prongs as the nasal CPAP interface may reduce treatment failure and nasal injury, and may have little or no effect on mortality or the risk of pneumothorax in newborn preterm infants with or at risk of respiratory distress. The effect on bronchopulmonary dysplasia is very uncertain. Large, high-quality trials would be needed to provide evidence of sufficient validity and applicability to inform policy and practice.

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.

Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome.

BACKGROUND: Non-invasive respiratory support is increasingly used for the management of respiratory dysfunction in preterm infants. This approach runs the risk of under-treating those with respiratory distress syndrome (RDS), for whom surfactant administration is of paramount importance. Several techniques of minimally invasive surfactant therapy have been described. This review focuses on surfactant administration to spontaneously breathing infants via a thin catheter briefly inserted into the trachea. OBJECTIVES: Primary objectives In non-intubated preterm infants with established RDS or at risk of developing RDS to compare surfactant administration via thin catheter with: 1. intubation and surfactant administration through an endotracheal tube (ETT); or 2. continuation of non-invasive respiratory support without surfactant administration or intubation. Secondary objective 1. To compare different methods of surfactant administration via thin catheter Planned subgroup analyses included gestational age, timing of intervention, and use of sedating pre-medication during the intervention. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL), 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 Literature (CINAHL), on 30 September 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: We included randomised trials comparing surfactant administration via thin catheter (S-TC) with (1) surfactant administration through an ETT (S-ETT), or (2) continuation of non-invasive respiratory support without surfactant administration or intubation. We also included trials comparing different methods/strategies of surfactant administration via thin catheter. We included preterm infants (at < 37 weeks' gestation) with or at risk of RDS. DATA COLLECTION AND ANALYSIS: Review authors independently assessed study quality and risk of bias and extracted data. Authors of all studies were contacted regarding study design and/or missing or unpublished data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 studies (18 publications; 2164 neonates) in this review. These studies compared surfactant administration via thin catheter with surfactant administration through an ETT with early extubation (Intubate, Surfactant, Extubate technique - InSurE) (12 studies) or with delayed extubation (2 studies), or with continuation of continuous positive airway pressure (CPAP) and rescue surfactant administration at pre-specified criteria (1 study), or compared different strategies of surfactant administration via thin catheter (1 study). Two trials reported neurosensory outcomes of of surviving participants at two years of age. Eight studies were of moderate certainty with low risk of bias, and eight studies were of lower certainty with unclear risk of bias. S-TC versus S-ETT in preterm infants with or at risk of RDS Meta-analyses of 14 studies in which S-TC was compared with S-ETT as a control demonstrated a significant decrease in risk of the composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.48 to 0.73; risk difference (RD) -0.11, 95% CI -0.15 to -0.07; number needed to treat for an additional beneficial outcome (NNTB) 9, 95% CI 7 to 16; 10 studies; 1324 infants; moderate-certainty evidence); the need for intubation within 72 hours (RR 0.63, 95% CI 0.54 to 0.74; RD -0.14, 95% CI -0.18 to -0.09; NNTB 8, 95% CI; 6 to 12; 12 studies, 1422 infants; moderate-certainty evidence); severe intraventricular haemorrhage (RR 0.63, 95% CI 0.42 to 0.96; RD -0.04, 95% CI -0.08 to -0.00; NNTB 22, 95% CI 12 to 193; 5 studies, 857 infants; low-certainty evidence); death during first hospitalisation (RR 0.63, 95% CI 0.47 to 0.84; RD -0.02, 95% CI -0.10 to 0.06; NNTB 20, 95% CI 12 to 58; 11 studies, 1424 infants; low-certainty evidence); and BPD among survivors (RR 0.57, 95% CI 0.45 to 0.74; RD -0.08, 95% CI -0.11 to -0.04; NNTB 13, 95% CI 9 to 24; 11 studies, 1567 infants; moderate-certainty evidence). There was no significant difference in risk of air leak requiring drainage (RR 0.58, 95% CI 0.33 to 1.02; RD -0.03, 95% CI -0.05 to 0.00; 6 studies, 1036 infants; low-certainty evidence). None of the studies reported on the outcome of death or survival with neurosensory disability. Only one trial compared surfactant delivery via thin catheter with continuation of CPAP, and one trial compared different strategies of surfactant delivery via thin catheter, precluding meta-analysis. AUTHORS' CONCLUSIONS: Administration of surfactant via thin catheter compared with administration via an ETT is associated with reduced risk of death or BPD, less intubation in the first 72 hours, and reduced incidence of major complications and in-hospital mortality. This procedure had a similar rate of adverse effects as surfactant administration through an ETT. Data suggest that treatment with surfactant via thin catheter may be preferable to surfactant therapy by ETT. Further well-designed studies of adequate size and power, as well as ongoing studies, will help confirm and refine these findings, clarify whether surfactant therapy via thin tracheal catheter provides benefits over continuation of non-invasive respiratory support without surfactant, address uncertainties within important subgroups, and clarify the role of sedation.

Assessment of resistance of nasal continuous positive airway pressure interfaces.

OBJECTIVE: To compare the resistance of interfaces used for the delivery of nasal continuous positive airway pressure (CPAP) in neonates, as measured by the generated system pressure at fixed gas flows, in an in vitro setting. DESIGN: Gas flows of 6, 8 and 10 L/min were passed through three sizes of each of a selection of available neonatal nasal CPAP interfaces (Hudson prong, RAM Cannula, Fisher & Paykel prong, Infant Flow prong, Fisher & Paykel mask, Infant Flow mask). The expiratory limb was occluded and pressure differential measured using a calibrated pressure transducer. RESULTS: Variation in resistance, assessed by mean pressure differential, was seen between CPAP interfaces. Binasal prong interfaces typically had greater resistance at the smallest assessed sizes, and with higher gas flows. However, Infant Flow prongs produced low pressures (<1.5 cmH2O) at all sizes and gas flows. RAM Cannula had a high resistance, producing a pressure >4.5 cmH2O at all sizes and gas flows. Both nasal mask interfaces had low resistance at all assessed sizes and gas flows, with recorded pressure <1 cmH2O in all cases. CONCLUSIONS: There is considerable variation in measured resistance of available CPAP interfaces at gas flows commonly applied in clinical neonatal care. Use of interfaces with high resistance may result in a greater drop in delivered airway pressure in comparison to set circuit pressure, which may have implications for clinical efficacy. Device manufacturers and clinicians should consider CPAP interface resistance prior to introduction into routine clinical care.

Impact of Minimally Invasive Surfactant Therapy in Preterm Infants at 29-32 Weeks Gestation.

BACKGROUND: Most preterm infants born at 29-32 weeks gestation now avoid intubation in early life, and thus lack the usual conduit through which exogenous surfactant is given if needed. OBJECTIVE: The aim of this work was to examine whether a technique of minimally invasive surfactant therapy used selectively at 29-32 weeks gestation would improve outcomes. METHODS: We studied the impact of selective administration of surfactant (poractant alfa 100-200 mg/kg) by thin catheter in infants with respiratory distress syndrome on continuous positive airway pressure (CPAP). The threshold for consideration of treatment was CPAP ≥7 cm H2O and FiO2 ≥0.35 prior to 24 h of life. In-hospital outcomes were compared before and after introducing minimally invasive surfactant therapy (epochs 1 and 2, respectively). RESULTS: During epoch 2, of 266 infants commencing CPAP, 51 (19%) reached the treatment threshold. Thirty-seven infants received surfactant via thin catheter, and CPAP failure was avoided in 34 of these (92%). For the overall cohort of infants at 29-32 weeks gestation, after the introduction of minimally invasive surfactant therapy, there were reductions in CPAP failure (epoch 1: 14%, epoch 2: 7.2%) and average days of intubation, with equivalent surfactant use and days of respiratory support (intubation + CPAP). Pneumothorax was substantially reduced (from 8.0 to 2.4%). These findings were mirrored within the subgroups reaching the severity threshold in each epoch. The incidence of bronchopulmonary dysplasia was low in both epochs. CONCLUSIONS: Selective use of minimally invasive surfactant therapy at 29-32 weeks gestation permits a primary CPAP strategy to be pursued with a high rate of success, and a low risk of pneumothorax.

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

BACKGROUND: Previous randomised trials and meta-analyses have shown that nasal continuous positive airway pressure (NCPAP) is a useful method for providing respiratory support after extubation. However, this treatment sometimes 'fails' in infants, and they may require endotracheal re-intubation with its attendant risks and expense. Nasal intermittent positive pressure ventilation (NIPPV) can augment NCPAP by delivering ventilator breaths via nasal prongs. Older children and adults with chronic respiratory failure benefit from NIPPV, and the technique has been applied to neonates. However, serious side effects including gastric perforation have been reported with older methods of providing NIPPV. OBJECTIVES: Primary objective To compare effects of management with NIPPV versus NCPAP on the need for additional ventilatory support in preterm infants whose endotracheal tube was removed after a period of intermittent positive pressure ventilation. Secondary objectives To compare rates of gastric distension, gastrointestinal perforation, necrotising enterocolitis and chronic lung disease; duration of hospitalisation; and rates of apnoea, air leak and mortality for NIPPV and NCPAP. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 9), MEDLINE via PubMed (1966 to 28 September 2015), Embase (1980 to 28 September 2015) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 28 September 2015). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing use of NIPPV versus NCPAP in extubated preterm infants. NIPPV included non-invasive support delivered by a mechanical ventilator or a bilevel device in a synchronised or non-synchronised way. Participants included ventilated preterm infants who were ready to be extubated to non-invasive respiratory support. Interventions compared were NIPPV, delivered by short nasal prongs or nasopharyngeal tube, and NCPAP, delivered by the same methods.Types of outcomes measures included failure of therapy (respiratory failure, rates of endotracheal re-intubation); gastrointestinal complications (i.e. abdominal distension requiring cessation of feeds, gastrointestinal perforation or necrotising enterocolitis); pulmonary air leak; chronic lung disease (oxygen requirement at 36 weeks' postmenstrual age) and mortality. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data regarding clinical outcomes including extubation failure; endotracheal re-intubation; rates of apnoea, gastrointestinal perforation, feeding intolerance, necrotising enterocolitis, chronic lung disease and air leak; and duration of hospital stay. We analysed trials using risk ratio (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: Through the search, we identified 10 trials enrolling a total of 1431 infants and comparing extubation of infants to NIPPV or NCPAP. Three trials had methodological limitations and possible selection bias.Five trials used the synchronised form of NIPPV, four used the non-synchronised form and one used both methods. Eight studies used NIPPV delivered by a ventilator, one used a bilevel device and one used both methods. When all studies were included, meta-analysis demonstrated a statistically and clinically significant reduction in the risk of meeting extubation failure criteria (typical RR 0.70, 95% CI 0.60 to 0.80; typical RD -0.13, 95% CI -0.17 to -0.08; NNTB 8, 95% CI 6 to 13; 10 trials, 1431 infants) and needing re-intubation (typical RR 0.76, 95% CI 0.65 to 0.88; typical RD -0.10, 95% CI -0.15 to -0.05; NNTB 10, 95% CI 7 to 20; 10 trials, 1431 infants). We graded evidence for these outcomes as moderate, as all trial interventions were unblinded. Although methods of synchronisation varied (Graseby capsule or pneumotachograph/flow-trigger), the five trials that synchronised NIPPV showed a statistically significant benefit for infants extubated to NIPPV in terms of prevention of extubation failure up to one week after extubation.Unsynchronised NIPPV also reduced extubation failure. NIPPV provided via a ventilator is more beneficial than that provided by bilevel devices in reducing extubation failure during the first week. When comparing interventions, investigators found no significant reduction in rates of chronic lung disease (typical RR 0.94, 95% CI 0.80 to 1.10; typical RD -0.02, 95% CI -0.08 to 0.03) or death, and no difference in the incidence of necrotising enterocolitis. Air leaks were reduced in infants randomised to NIPPV (typical RR 0.48, 95% CI 0.28 to 0.82; typical RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100). We graded evidence quality as moderate (unblinded studies) or low (imprecision) for secondary outcomes. AUTHORS' CONCLUSIONS: Implications for practice NIPPV reduces the incidence of extubation failure and the need for re-intubation within 48 hours to one week more effectively than NCPAP; however, it has no effect on chronic lung disease nor on mortality. Synchronisation may be important in delivering effective NIPPV. The device used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. NIPPV does not appear to be associated with increased gastrointestinal side effects. Implications for research Large trials should establish the impact of synchronisation of NIPPV on safety and efficacy of the technique and should compare the efficacy of bilevel devices versus a ventilator for providing NIPPV.

Incidence and Outcome of CPAP Failure in Preterm Infants.

BACKGROUND AND OBJECTIVES: Data from clinical trials support the use of continuous positive airway pressure (CPAP) for initial respiratory management in preterm infants, but there is concern regarding the potential failure of CPAP support. We aimed to examine the incidence and explore the outcomes of CPAP failure in Australian and New Zealand Neonatal Network data from 2007 to 2013. METHODS: Data from inborn preterm infants managed on CPAP from the outset were analyzed in 2 gestational age ranges (25-28 and 29-32 completed weeks). Outcomes after CPAP failure (need for intubation <72 hours) were compared with those succeeding on CPAP using adjusted odds ratios (AORs). RESULTS: Within the cohort of 19 103 infants, 11 684 were initially managed on CPAP. Failure of CPAP occurred in 863 (43%) of 1989 infants commencing on CPAP at 25-28 weeks' gestation and 2061 (21%) of 9695 at 29-32 weeks. CPAP failure was associated with a substantially higher rate of pneumothorax, and a heightened risk of death, bronchopulmonary dysplasia (BPD) and other morbidities compared with those managed successfully on CPAP. The incidence of death or BPD was also increased: (25-28 weeks: 39% vs 20%, AOR 2.30, 99% confidence interval 1.71-3.10; 29-32 weeks: 12% vs 3.1%, AOR 3.62 [2.76-4.74]). The CPAP failure group had longer durations of respiratory support and hospitalization. CONCLUSIONS: CPAP failure in preterm infants is associated with increased risk of mortality and major morbidities, including BPD. Strategies to promote successful CPAP application should be pursued vigorously.

High flow nasal cannula for respiratory support in preterm infants.

BACKGROUND: High flow nasal cannulae (HFNC) are small, thin, tapered binasal tubes that deliver oxygen or blended oxygen/air at gas flows of more than 1 L/min. HFNC are increasingly being used as a form of non-invasive respiratory support for preterm infants. OBJECTIVES: To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE via PubMed (1966 to 1 January 2016), EMBASE (1980 to 1 January 2016), and CINAHL (1982 to 1 January 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. DATA COLLECTION AND ANALYSIS: The authors extracted and analysed data, and calculated risk ratio, risk difference and number needed to treat for an additional beneficial outcome. MAIN RESULTS: We identified 15 studies for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), non-humidified HFNC, models for delivering HFNC), the gas flows used and the indications for respiratory support (primary support from soon after birth, post-extubation support, weaning from CPAP support). When used as primary respiratory support after birth compared to CPAP (4 studies, 439 infants), there were no differences in the primary outcomes of death (typical risk ratio (RR) 0.36, 95% CI 0.01 to 8.73; 4 studies, 439 infants) or chronic lung disease (CLD) (typical RR 2.07, 95% CI 0.64 to 6.64; 4 studies, 439 infants). HFNC use resulted in longer duration of respiratory support, but there were no differences in other secondary outcomes. One study (75 infants) showed no differences between HFNC and NIPPV as primary support. Following extubation (total 6 studies, 934 infants), there were no differences between HFNC and CPAP in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD (typical RR 0.96, 95% CI 0.78 to 1.18; 5 studies, 893 infants). There was no difference in the rate of treatment failure (typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation (typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants). Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) -0.14, 95% CI -0.20 to -0.08; 4 studies, 645 infants). There was a small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD -0.02, 95% CI -0.03 to -0.00; 5 studies 896 infants) in infants treated with HFNC. Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants. One trial (28 infants) found similar rates of reintubation for humidified and non-humidified HFNC, and two other trials (100 infants) found no difference between different models of equipment used to deliver humidified HFNC. For infants weaning from non-invasive respiratory support (CPAP), two studies (149 infants) found that preterm infants randomised to HFNC had a reduced duration of hospitalisation compared with infants who remained on CPAP. AUTHORS' CONCLUSIONS: HFNC has similar rates of efficacy to other forms of non-invasive respiratory support in preterm infants for preventing treatment failure, death and CLD. Most evidence is available for the use of HFNC as post-extubation support. Following extubation, HFNC is associated with less nasal trauma, and may be associated with reduced pneumothorax compared with nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with other forms of primary non-invasive support after birth and for weaning from non-invasive support. Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices.

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

BACKGROUND: Previous randomised trials and meta-analyses have shown nasal continuous positive airway pressure (NCPAP) to be a useful method of respiratory support after extubation. However, infants managed in this way sometimes 'fail' and require endotracheal reintubation with its attendant risks and expense. Nasal intermittent positive pressure ventilation (NIPPV) is a method of augmenting NCPAP by delivering ventilator breaths via nasal prongs. Older children and adults with chronic respiratory failure benefit from NIPPV and the technique has been applied to neonates. However, serious side effects including gastric perforation have been reported with older techniques to provide NIPPV. OBJECTIVES: To determine the effect of management with NIPPV compared with NCPAP on the need for additional ventilatory support in preterm infants having their endotracheal tube removed following a period of intermittent positive pressure ventilation.To compare the rates of gastric distension, gastrointestinal perforation, necrotising enterocolitis, chronic lung disease, duration of hospitalisation, rates of apnoea, air leaks and mortality between NIPPV and NCPAP. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 7, 2013), MEDLINE (1966 to 4 September 2013), EMBASE (1980 to 4 September 2013), CINAHL (1982 week 3 to August 2013) and PubMed (4 September 2013). We searched previous reviews including cross-references, and conference and symposia proceedings. We contacted experts in the field. We also searched Clinicaltrials.gov for any ongoing trials. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing the use of NIPPV with NCPAP in preterm infants being extubated. NIPPV included non-invasive support delivered by a mechanical ventilator or a bilevel device in a synchronised or non-synchronised way. Participants included ventilated preterm infants who were ready to be extubated to non-invasive respiratory support. Interventions compared were NIPPV, either by short nasal prongs or nasopharyngeal tube, and NCPAP, delivered by the same methods.Types of outcomes measures included: failure of therapy (respiratory failure, rates of endotracheal reintubations); gastrointestinal complications (i.e. abdominal distension requiring cessation of feeds, gastrointestinal perforation or necrotising enterocolitis); pulmonary air leaks; chronic lung disease (oxygen requirement at 36 weeks' postmenstrual age) and mortality. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data regarding clinical outcomes including extubation failure, endotracheal reintubation, rates of apnoea, gastrointestinal perforation, feeding intolerance, necrotising enterocolitis, chronic lung disease, air leaks and duration of hospital stay. We analysed the trials using risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) or additional harmful outcome (NNTH) for dichotomous outcomes and mean difference (MD) for continuous outcomes. MAIN RESULTS: The search identified eight trials enrolling 1316 infants in total and comparing extubation of infants to NIPPV or NCPAP. Five trials used the synchronised form of NIPPV, two trials used the non-synchronised form and one trial used both methods. Six studies used NIPPV delivered by a ventilator, one study used a bilevel device and one study used both methods. When all studies were included, the meta-analysis demonstrated a statistically and clinically significant reduction in the risk of meeting extubation failure criteria (typical RR 0.71, 95% CI 0.61 to 0.82; typical RD -0.12, 95% CI -0.17 to -0.07; NNTB 8, 95% CI 6 to 14; 8 trials, 1301 infants) and needing reintubation (typical RR 0.76, 95% CI 0.65 to 0.88; typical RD -0.10, 95% CI -0.15 to -0.05; NNTB 10, 95% CI 7 to 20; 8 trials, 1301 infants). While the method of synchronisation varied (Graseby capsule or pneumotachograph/flow-trigger), the five trials that synchronised NIPPV showed a statistically significant benefit for infants extubated to NIPPV in terms of prevention of extubation failure up to one week after extubation. NIPPV provided via a ventilator appeared more beneficial than bilevel devices in reducing extubation failure in the first week. There was no significant reduction in the rates of chronic lung disease (typical RR 0.97, 95% CI 0.83 to 1.14; typical RD -0.01, 95% CI -0.07 to 0.05), death or difference in the incidence of necrotising enterocolitis between interventions. There was a reduction in air leaks in infants randomised to NIPPV (typical RR 0.50, 95% CI 0.28 to 0.89; typical RD -0.03; 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100). IMPLICATIONS FOR PRACTICE: NIPPV reduces the incidence of symptoms of extubation failure and need for reintubation within 48 hours to one week more effectively than NCPAP; however, it has no effect on chronic lung disease or mortality. Synchronisation may be important in delivering effective NIPPV. The device used to deliver NIPPV may also be important; however, there are insufficient data to support strong conclusions. NIPPV does not appear to be associated with increased gastrointestinal side effects. IMPLICATIONS FOR RESEARCH: the impact of synchronisation of NIPPV on the technique's safety and efficacy should be established in large trials. The efficacy of bilevel devices should be compared with NIPPV provided by a ventilator in trials. The best combination of settings for NIPPV needs to be established in future trials.

The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25-28 weeks gestation.

BACKGROUND: It is now recognized that preterm infants ≤28 weeks gestation can be effectively supported from the outset with nasal continuous positive airway pressure. However, this form of respiratory therapy may fail to adequately support those infants with significant surfactant deficiency, with the result that intubation and delayed surfactant therapy are then required. Infants following this path are known to have a higher risk of adverse outcomes, including death, bronchopulmonary dysplasia and other morbidities. In an effort to circumvent this problem, techniques of minimally-invasive surfactant therapy have been developed, in which exogenous surfactant is administered to a spontaneously breathing infant who can then remain on continuous positive airway pressure. A method of surfactant delivery using a semi-rigid surfactant instillation catheter briefly passed into the trachea (the "Hobart method") has been shown to be feasible and potentially effective, and now requires evaluation in a randomised controlled trial. METHODS/DESIGN: This is a multicentre, randomised, masked, controlled trial in preterm infants 25-28 weeks gestation. Infants are eligible if managed on continuous positive airway pressure without prior intubation, and requiring FiO2 ≥ 0.30 at an age ≤6 hours. Randomisation will be to receive exogenous surfactant (200 mg/kg poractant alfa) via the Hobart method, or sham treatment. Infants in both groups will thereafter remain on continuous positive airway pressure unless intubation criteria are reached (FiO2 ≥ 0.45, unremitting apnoea or persistent acidosis). Primary outcome is the composite of death or physiological bronchopulmonary dysplasia, with secondary outcomes including incidence of death; major neonatal morbidities; durations of all modes of respiratory support and hospitalisation; safety of the Hobart method; and outcome at 2 years. A total of 606 infants will be enrolled. The trial will be conducted in >30 centres worldwide, and is expected to be completed by end-2017. DISCUSSION: Minimally-invasive surfactant therapy has the potential to ease the burden of respiratory morbidity in preterm infants. The trial will provide definitive evidence on the effectiveness of this approach in the care of preterm infants born at 25-28 weeks gestation. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Registry: ACTRN12611000916943; ClinicalTrials.gov: NCT02140580.

High-frequency oscillatory ventilation with low oscillatory frequency in pulmonary interstitial emphysema.

BACKGROUND: Pulmonary interstitial emphysema (PIE) is a common respiratory illness in preterm infants associated with significant morbidity and mortality for which the ventilatory management is imperfect. OBJECTIVES: To evaluate the impact of high-frequency oscillatory ventilation (HFOV) with a low oscillatory frequency and thus prolonged expiratory time in preterm infants with severe PIE. METHODS: In a retrospective cohort study, preterm infants ≤30 weeks' gestation with radiological findings of severe PIE, and either high FiO2 or persistent respiratory acidosis were studied if managed on HFOV with a low frequency (5-6 Hz, inspiratory time 30%) for >24 h. Trends in physiological and ventilatory parameters were examined over the first 72 h, radiological changes noted, and in-hospital outcomes ascertained. RESULTS: 19 cases were identified and analysed in two groups: 14 with bilateral and 5 with predominantly unilateral disease. After transition to low-frequency HFOV, physiological responses were seen in both groups, in particular a rapid and sustained improvement in oxygenation in the bilateral group (mean (SD) alveolar-arterial oxygen difference at baseline: 404 ± 206 mm Hg; 4 h post-transition: 262 ± 181 mm Hg; 72 h: 155 ± 74 mm Hg; p = 0.0003). This occurred following a reduction in mean airway pressure (mean (SD) baseline: 14 ± 3.9 cm H2O; 72 h: 12 ± 2.9 cm H2O; p = 0.011). In the unilateral group, radiological resolution of PIE was observed on re-inflation following collapse of the affected lung. Overall, 15 infants survived, including 10 of the bilateral cases (71%), and all of the unilateral cases. CONCLUSION: HFOV with a low oscillatory frequency may afford benefit in preterm babies with severe PIE.

Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.

BACKGROUND: Preterm infants ≤32 weeks' gestation are increasingly being managed on continuous positive airway pressure (CPAP), without prior intubation and surfactant therapy. Some infants treated in this way ultimately fail on CPAP and require intubation and ventilation. OBJECTIVES: To define the incidence, predictors and consequences of CPAP failure in preterm infants managed with CPAP from the outset. METHODS: Preterm infants 25-32 weeks' gestation were included in the study if inborn and managed with CPAP as the initial respiratory support, with division into two gestation ranges and grouping according to whether they were successfully managed on CPAP (CPAP-S) or failed on CPAP and required intubation <72 h (CPAP-F). Predictors of CPAP failure were sought, and outcomes compared between the groups. RESULTS: 297 infants received CPAP, of which 65 (22%) failed, with CPAP failure being more likely at lower gestational age. Most infants failing CPAP had moderate or severe respiratory distress syndrome radiologically. In multivariate analysis, CPAP failure was found to be predicted by the highest FiO2 in the first hours of life. CPAP-F infants had a prolonged need for respiratory support and oxygen therapy, and a higher risk of death or bronchopulmonary dysplasia at 25-28 weeks' gestation (CPAP-F 53% vs. CPAP-S 14%, relative risk 3.8, 95% CI 1.6, 9.3) and a substantially higher risk of pneumothorax at 29-32 weeks. CONCLUSION: CPAP failure in preterm infants usually occurs because of unremitting respiratory distress syndrome, is predicted by an FiO2 ≥0.3 in the first hours of life, and is associated with adverse outcomes.

Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure.

OBJECTIVE: To evaluate the applicability and potential effectiveness of a technique of minimally-invasive surfactant therapy (MIST) in preterm infants on continuous positive airway pressure (CPAP). METHODS: An open feasibility study of MIST was conducted at two sites. Infants were eligible for MIST if needing CPAP pressure ≥7 cm H(2)O and FiO(2) ≥0.3 (25-28 weeks gestation, n=38) or ≥0.35 (29-32 weeks, n=23). Without premedication, a narrow-bore catheter was inserted through the vocal cords under direct vision. Surfactant (100 or 200 mg/kg Curosurf) was then instilled, followed by reinstitution of CPAP. Outcomes were compared between surfactant-treated infants and historical controls achieving the same CPAP and FiO(2) thresholds. RESULTS: Surfactant was successfully administered via MIST in all cases, with a rapid and sustained reduction in FiO(2) thereafter. For infants at 25-28 weeks gestation, need for intubation <72 h was diminished after MIST compared with controls (32% vs 68%; OR 0.21, 95% CI 0.083 to 0.55), with a similar trend at 29-32 weeks (22% vs 45%; OR 0.34, 95% CI 0.11 to 1.1). Duration of ventilation and incidence of bronchopulmonary dysplasia were similar, but infants receiving MIST had a shorter duration of oxygen therapy. CONCLUSION: Surfactant delivery via a narrow-bore tracheal catheter is feasible and potentially effective, and deserves further investigation in clinical trials.

High flow nasal cannula for respiratory support in preterm infants.

BACKGROUND: High flow nasal cannulae (HFNC) are small, thin, tapered cannulae used to deliver oxygen or blended oxygen and air at flow rates of > 1 L/min. HFNC can be used to provide high concentrations of oxygen and may deliver positive end-expiratory pressure. OBJECTIVES: To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. SEARCH STRATEGY: The strategy included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010), MEDLINE, CINAHL, EMBASE and abstracts from conference proceedings. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed by the authors. Relative risk, risk difference and number needed to treat were calculated. MAIN RESULTS: Four studies were identified for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), humidified HFNC, non-humidified HFNC), the flow rates provided and the indications for respiratory support. Meta-analysis and subgroup analysis were not possible. When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. AUTHORS' CONCLUSIONS: There is insufficient evidence to establish the safety or effectiveness of HFNC as a form of respiratory support in preterm infants. When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with nasal CPAP and with other means of respiratory support; or of support following extubation. These trials should measure clinically important outcomes.