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.

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.

Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.

Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future.

Respiratory distress syndrome (RDS) due to surfactant deficiency is the most common cause of respiratory failure in preterm infants. Tremendous progress has been made since the original description that surfactant deficiency is the major cause of RDS. Surfactant therapy has been extensively studied in preterm infants and has been shown to significantly decrease air leaks and neonatal and infant mortality. Synthetic and animal-derived surfactants from bovine as well as porcine origin have been evaluated in randomized controlled trials. Animal-derived surfactants generally result in faster weaning of respiratory support, shorter duration of invasive ventilation, and decreased mortality when compared to first- or second-generation of synthetic surfactants, but some of the second-generation synthetic surfactants are at least not inferior to the animal-derived surfactants. Using a higher initial dose of porcine derived surfactant may provide better outcomes when compared with using lower doses of bovine surfactants, likely, due to compositional difference and/or the dose. Third-generation synthetic surfactant containing peptide analogs of surfactant protein B and C are currently being studied. Less invasive intra-tracheal surfactant administration techniques in spontaneously breathing neonate receiving noninvasive ventilator support are also being evaluated. In the present era, prophylactic surfactant is not recommended as it may increase the risk of lung injury or death. In the future, surfactants may be used as vector to deliver steroids, or used in combination with molecules, such as, recombinant Club Cell Protein-10 (rhCC-10) to improve pulmonary outcomes. Also, noninvasive surfactant administration techniques, such as aerosolization or atomization of surfactant may play a greater role in the future.

Neonatal resuscitation using a nasal cannula: a single-center experience.

OBJECTIVE: The aim of the study was to describe our experience using a modified nasal cannula to deliver nasal continuous positive airway pressure and/or nasal intermittent positive pressure ventilation during primary neonatal resuscitation of preterm and term newborns. STUDY DESIGN: Data were collected retrospectively for all neonates resuscitated with nasal cannula in the delivery room. The primary outcome was the number of newborns intubated in the delivery room. Secondary outcomes included need for chest compressions, intubations in the first 24 hours, air-leaks, and surfactant administration. RESULTS: A total of 102 infants were resuscitated using nasal cannula. Eight (7.8%) were intubated in the delivery room, five (4.9%) required chest compressions, and five (4.9%) had pneumothorax noted on chest X-ray. No deaths occurred in the delivery room. Twenty-eight patients (27.5%) received early rescue surfactant after admission to the neonatal intensive care unit. CONCLUSION: Neonatal resuscitation can be effectively performed in preterm and term newborns using a modified nasal cannula in the delivery room.

Noninvasive Ventilation.

Systematic Reviews and Randomized clinical trials have shown that the use of noninvasive ventilation (NIV) compared to invasive mechanical ventilation reduces the risk of bronchopulmonary dysplasia and or mortality. Most commonly used NIV modes include nasal continuous positive airway pressure, bi-phasic modes, such as, bi-level positive airway pressure, nasal intermittent positive pressure ventilation, high flow nasal cannula, noninvasive neurally adjusted ventilatory assist, and nasal high frequency ventilation are discussed in this review.

Evaluation of the Puritan Bennett™ 980 Ventilator System Safety and Performance in the Real-World Setting.

Purpose: Mechanical ventilation is a life-supporting intervention but is associated with known risks and complications. To improve the efficacy and safety profile of mechanical ventilation, manufacturers have developed advanced ventilator settings, modes, and alarm strategies to optimize ventilation for patient needs while avoiding complications. However, there is little real-world data published on the deployment of ventilator technology. The main objective of this study was to assess the clinical safety and performance of the Puritan Bennett™ 980 Ventilator System (PB980) using real-world clinical data collected from a diverse, global patient population. Methods: This was a multi-center, post-market registry study that included nine sites: four in the United States of America, one in Europe, and four in China. Patients were enrolled into the registry if they were intended to be treated with a PB980. Data collection began at the start of ventilation and continued until extubation off the ventilator or up to seven days of ventilation, whichever occurred first. Subjects were divided by age into three categories: infants (0-365 days), pediatric (1-17 years), and adult (18 years and older). The primary outcome was device-related complication rate. Results: Two-hundred-and-eleven subjects were enrolled (41 infants, 48 pediatric, and 122 adults). Sixteen deaths, unrelated to device deficiency, occurred during the data collection timeframe (relative frequency: 7.58, 95% CI: 4.40, 12.0). Only one device-related adverse event was reported (relative frequency: 0.47% 95% CI: 0.01%, 2.61%). Conclusion: Ventilation by the PB980 was delivered safely in this multi-center observational study, which included a diverse sample of patients with broad ventilatory needs.

Transcutaneous bilirubin levels in extremely preterm infants less than 30 weeks gestation.

OBJECTIVE: The primary objective of this study was to determine the relationship between transcutaneous bilirubin (TcB) levels and total serum bilirubin (TSB) levels in extremely preterm infants. STUDY DESIGN: We conducted a prospective multicenter study of extremely preterm infants less than 30 weeks gestation in California. Difference between paired TcB and TSB values were compared based on gestational age, birth weight, maternal race/ethnicity, chronological age as well as during and after phototherapy. RESULTS: TSB values ranged from 0 to 12.6 mg/dl and the TcB values ranged from 0 to 14.2 mg/dl. TSB was predicted with a high degree of accuracy at TSB = 2.37 + 0.54 (TcB) with r = 0.786. There was good correlation across gestational age, birth weight, race/ethnic, chronological age subgroups as well as during and after phototherapy. CONCLUSION: Our study supports the use of TcB as a screening tool for monitoring jaundice in extremely preterm infants.

Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

OBJECTIVES: To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). METHODS: Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. RESULTS: Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). CONCLUSIONS: In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.

Nasal high-frequency jet ventilation (NHFJV) as a novel means of respiratory support in extremely low birth weight infants.

OBJECTIVE: Describe our experience of successfully using nasal high-frequency jet ventilation (NHFJV) in extremely low birth weight infants with respiratory failure. STUDY DESIGN: A retrospective review was conducted on 16 infants with birth weights <1000 g who received NHFJV from 2015 to 2019. Successful use was defined as avoiding intubation for at least 72 hours and demonstrating tolerance after being placed on NHFJV. RESULTS: Median gestational age was 24.5 weeks (IQR 24, 25), and weight at the start of NHFJV 1090 g (IQR 905, 1250). NHFJV was used successfully in 13/16 (81%) infants with a median duration of 7 days (IQR 3, 12). Days on invasive (30 vs. 186) and noninvasive (46 vs. 81) ventilation were shorter when compared to those who failed the use of NHFJV. CONCLUSION: This is the first reported case series for the successful use of NHFJV. Our study highlights the feasibility of a potential new mode of noninvasive respiratory support.

Safety of surfactant administration before transport of premature infants.

OBJECTIVE: To assess the safety of surfactant administration prior to transport of premature infants. DESIGN/METHODS: We performed a retrospective review of 24- to 34-weeks premature infants admitted to the Newborn Intensive Care Unit (NICU) between July 1, 1999 and September 30, 2004. Outcome measures were the presence of hyperventilation (PCO2 <40 mm Hg) and/or pneumothorax on admission to the NICU. Factors associated with the presence of hyperventilation and pneumothorax were identified. RESULTS: 955 infants born at 24 to 34 weeks' gestation were admitted to the NICU during the study period. 217 (22.7%) received surfactant prior to transport within 48 hours of birth. The incidence of hyperventilation was 18.9%. Hyperventilated infants had longer transport times, lower birth weights, and lower PCO2 on blood gases obtained prior to transport. Pneumothorax occurred in six subjects (2.9%). Neonates with pneumothorax had lower APGAR scores. CONCLUSIONS: We found the administration of surfactant prior to transport to be safe as evidenced by a low incidence of pneumothorax. Pneumothorax was more likely to occur in infants who needed significant resuscitation at birth. The incidence of hyperventilation appeared to be high and was inversely associated with birth weight.

A Review on Non-invasive Respiratory Support for Management of Respiratory Distress in Extremely Preterm Infants.

Majority of extremely preterm infants require positive pressure ventilatory support at the time of delivery or during the transitional period. Most of these infants present with respiratory distress (RD) and continue to require significant respiratory support in the neonatal intensive care unit (NICU). Bronchopulmonary dysplasia (BPD) remains as one of the major morbidities among survivors of the extremely preterm infants. BPD is associated with long-term adverse pulmonary and neurological outcomes. Invasive mechanical ventilation (IMV) and supplemental oxygen are two major risk factors for the development of BPD. Non-invasive ventilation (NIV) has been shown to decrease the need for IMV and reduce the risk of BPD when compared to IMV. This article reviews respiratory management with current NIV support strategies in extremely preterm infants both in delivery room as well as in the NICU and discusses the evidence to support commonly used NIV modes including nasal continuous positive airway pressure (NCPAP), nasal intermittent positive pressure ventilation (NIPPV), bi-level positive pressure (BI-PAP), high flow nasal cannula (HFNC), and newer NIV strategies currently being studied including, nasal high frequency ventilation (NHFV) and non-invasive neutrally adjusted ventilatory assist (NIV-NAVA). Randomized, clinical trials have shown that early NIPPV is superior to NCPAP to decrease the need for intubation and IMV in preterm infants with RD. It is also important to understand that selection of the device used to deliver NIPPV has a significant impact on its success. Ventilator generated NIPPV results in significantly lower rates of extubation failures when compared to Bi-PAP. Future studies should address synchronized NIPPV including NIV-NAVA and early rescue use of NHFV in the respiratory management of extremely preterm infants.

Early postnatal weight gain as a predictor for the development of retinopathy of prematurity.

OBJECTIVE: The objective of this study is to validate the reliability of early postnatal weight gain as an accurate predictor of type 1 retinopathy of prematurity (ROP) requiring treatment in a large predominantly Hispanic US cohort with the use of an online tool called WINROP (weight, neonatal retinopathy of prematurity (IGF-1), neonatal retinopathy of prematurity). STUDY DESIGN: Retrospective cohort study consisted of preterm infants <32 weeks gestation and birth weight <1500 g. Weekly weights to 36 weeks post-menstrual age or discharge if earlier were entered into the WINROP tool. This tool generated alarm and risk indicator for developing ROP. The infants with type 1 ROP requiring treatment as well as all stages of ROP were compared with the alarms and risks generated by WINROP tool. RESULTS: A total of 492 infants were entered into the WINROP tool. The infants who developed type 1 ROP requiring treatment, the WINROP tool detected 80/89 (90%) at less than 32 weeks gestation. Nine infants developed type 1 ROP were classified as low risk and did not alarm. CONCLUSIONS: Postnatal weight gain alone, in predominantly Hispanic US population, predicted type 1 ROP requiring treatment before 32 weeks of gestation in infants with a sensitivity of 90%. The tool appeared to identify majority of affected infants much earlier than the scheduled screening.

Evaluation of Oxygen Saturation Index Compared With Oxygenation Index in Neonates With Hypoxemic Respiratory Failure.

Importance: Oxygenation index (OI), an invasive measurement, is routinely used as a marker of severity of hypoxemic respiratory failure in neonates. Oxygen saturation index (OSI) is a noninvasive measurement and has been shown to be a reliable surrogate marker of OI in children and adults with respiratory failure. Objectives: To evaluate the correlation of OI with OSI and to derive and validate predictive OI from noninvasive OSI measurements for clinically relevant OI values. Design, Setting, and Participants: For this retrospective cohort study, 220 neonates requiring invasive mechanical ventilation for hypoxic respiratory failure during the first 3 days of admission were recruited from a level III neonatal intensive care unit during a 6-year period, from January 1, 2012, to December 31, 2017. Data were analyzed from January 2017 to December 2017. Main Outcomes and Measures: The primary outcome was correlation of OI with OSI, analyzed using Pearson correlation coefficient. The secondary outcome was derivation and validation of OI from OSI. The data were split into derivative samples, from which a predictive equation for OI was derived using generalized linear model, and a validation sample was used to assess the predictive ability of the derived OI. Bland-Altman plot was used to assess agreement between derived OI and measured OI. Results: A total of 1442 paired OI and OSI measurements from 220 infants (190 preterm and 30 term; median [interquartile range] gestational age, 29 [26-33] weeks; mean [SD] birth weight, 1602 [1092] g) were recorded during the study. The median (interquartile range) number of samples was 5 (3-9) per patient. Overall, OI and OSI showed strong correlation (r = 0.89). The correlation was stronger in preterm infants (<28 weeks, r = 0.93; 28-33 weeks, r = 0.93) and within an oxygen saturation range of 85% to 95% (r = 0.94). The predictive derivative equation showed a strong linear association and good agreement in both derivation and validation data sets, with strong accuracy measures of derived OI for OI cutoffs of 5, 10, 15, 20, and 25. Conclusions and Relevance: A strong correlation of OI with OSI was found. Derived OI from OSI was in good agreement and strongly predictive of clinically relevant OI cutoffs from 5 to 25. Oxygenation index derived from noninvasive sources may be useful to reliably assess severity of respiratory failure and response to therapy on a continuous basis.

Decrease in delivery room intubation rates after use of nasal intermittent positive pressure ventilation in the delivery room for resuscitation of very low birth weight infants.

BACKGROUND: The literature supports minimizing duration of invasive ventilation to decrease lung injury in premature infants. Neonatal Resuscitation Program recommended use of non-invasive ventilation (NIV) in delivery room for infants requiring prolonged respiratory support. OBJECTIVE: To evaluate the impact of implementation of non-invasive ventilation (NIV) using nasal intermittent positive pressure ventilation (NIPPV) for resuscitation in very low birth infants. STUDY DESIGN: Retrospective study was performed after NIPPV was introduced in the delivery room and compared with infants receiving face mask to provide positive pressure ventilation for resuscitation of very low birth weight infants prior to its use. Data collected from 119 infants resuscitated using NIPPV and 102 infants resuscitated with a face mask in a single institution. The primary outcome was the need for endotracheal intubation in the delivery room. Data was analyzed using IBM SPSS Statistics software version 24. RESULTS: A total of 31% of infants were intubated in the delivery room in the NIPPV group compared to 85% in the Face mask group (p=<0.001). Chest compression rates were 11% in the NIPPV group and 31% in the Face mask group (p<0.001). Epinephrine administration was also lower in NIPPV group (2% vs. 8%; P=0.03). Only 38% infants remained intubated at 24hours of age in the NIPPV group compared to 66% in the Face mask group (p<0.001). Median duration of invasive ventilation in the NIPPV group was shorter (2days) compared to the Face mask group (11days) (p=0.01). The incidence of air-leaks was not significant between the two groups. CONCLUSION: NIPPV was safely and effectively used in the delivery room settings to provide respiratory support for VLBW infants with less need for intubation, chest compressions, epinephrine administration and subsequent invasive ventilation.

The role of nutrition in the prevention and management of bronchopulmonary dysplasia.

Nutrition plays a critical role in the prevention and management of bronchopulmonary dysplasia (BPD). Growth failure in infants with BPD is predominantly due to malnutrition. Malnutrition can worsen BPD by compromising lung growth. Feeding difficulties in these infants can further affect nutrition. Dexamethasone, used to facilitate extubation and treat severe BPD, is known to have adverse effects on growth. Nutritional management of very low birth weight (VLBW) infants should be addressed from the first day of life to enhance growth and minimize respiratory morbidity. Fluid restriction, parenteral nutrition with protein and lipids, and early enteral feeding may help decrease the incidence of BPD. High calorie concentrated formula can be used in infants to achieve adequate growth if total daily fluid intake is restricted. Vitamin A supplementation may help to prevent further damage to lungs. The role of such therapies as inositol, vitamin E, and selenium in management of these infants remains speculative. Close post discharge follow up of infants with BPD is necessary to monitor growth and to ensure intake of sufficient protein and calories.