Transcatheter patent ductus arteriosus closure in premature infants requiring high-frequency ventilation.

Transcatheter closure has become a common treatment method for patent ductus arteriosus in premature infants at many centres; however, many remain uncertain about the ability to perform the procedure in the catheterisation laboratory for infants requiring high-frequency ventilation. This study presents our centre's experience following the implementation of neonatal ventilatory guidelines, which resulted in 100% procedural success without any procedural or respiratory adverse events.

The Diaphragmatic Initiated Ventilatory Assist (DIVA) trial: study protocol for a randomized controlled trial comparing rates of extubation failure in extremely premature infants undergoing extubation to non-invasive neurally adjusted ventilatory assist versus non-synchronized nasal intermittent positive pressure ventilation.

BACKGROUND: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7-276/7 weeks' gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. METHODS: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24-276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks' postmenstrual age, discharge, death, or transfer. DISCUSSION: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , trial identifier NCT05446272 , registered July 6, 2022.

Neonatal high frequency ventilation: Current trends and future directions.

High frequency ventilation (HFV) in neonates has been in use for over forty years. Some early HFV ventilators are no longer available, but high frequency oscillatory ventilation (HFOV) and jet ventilators (HFJV) continue to be commonly employed. Advanced HFOV models available outside of the United States are much quieter and easier to use, and are available as options on many conventional ventilators, providing important improvements such as tidal volume measurement and targeting. HFJV excels in treating air leak and non-homogenous lung disease and is often used for other diseases as well. High frequency non-invasive ventilation (hfNIV) is a novel application of HFV that remains under investigation. Similar to bubble CPAP, hfNIV has been applied with a variety of high-frequency ventilators. Efficacy and safety of hfNIV with any device have not yet been established. This article describes the current approaches to these HFV therapies and stresses the importance of understanding how each device works and what disease processes may respond best to the technology employed.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

The effect of bethanechol on tracheobronchomalacia in preterm infants with bronchopulmonary dysplasia: a retrospective cohort study.

OBJECTIVE: Bethanechol has demonstrated improvement in trachealis tone in animal models, but no trials have studied efficacy in infants. This study aimed to examine if bethanechol improves a standardized pulmonary severity score (PSS) in infants with severe bronchopulmonary dysplasia with a diagnosis of tracheobronchomalacia (TBM). STUDY DESIGN: This retrospective cohort study evaluated cases treated with bethanechol matched with controls who did not receive bethanechol. TBM was diagnosed by dynamic computography. Daily PSS was recorded for each infant from 40 to 55 weeks post-menstrual age. RESULTS: Cases' mean PSS change was 21% lower than the controls' mean PSS change pre- and post-bethanechol (95% CI -40%, -2%) by paired t-test (p = 0.03). Matched differences (controls' PSS - cases' PSS) demonstrated greater mean PSS difference post-bethanechol compared to pre-bethanechol 0.17, (95% CI 0.05, 0.29) by paired t-test (p = 0.009). CONCLUSION: Infants with TBM treated with bethanechol compared to those not treated had a lower PSS reflecting improved respiratory status.

Tidal volume delivery during nasal intermittent positive pressure ventilation: infant cannula vs. nasal continuous positive airway pressure prongs.

OBJECTIVE: To measure tidal volume delivery during nasal intermittent positive pressure ventilation with two nasal interfaces: infant cannula and nasal prongs. STUDY DESIGN: A single-center crossover study of neonates with mild respiratory distress. Fifteen preterm neonates were randomized to initial interface of infant cannula or nasal prongs and monitored on a sequence of pressure settings first on the initial interface, then repeated on the alternate interface. We compared relative tidal volumes between the two interfaces with two-way repeated measures ANOVA during three breath types: synchronized (I), patient effort without ventilator breaths (II), and ventilator breaths without patient effort (III). Clinical trial #NCT04326270. RESULTS: Type III breaths delivered no significant tidal volume. No significant difference was measured in relative tidal volume delivery between the interfaces when breath types were matched. CONCLUSIONS: Nasal intermittent positive pressure ventilation delivers neither clinically nor statistically significant tidal volume with either infant cannula or nasal prongs.

Renal oximetry for early acute kidney injury detection in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia are at high risk of acute kidney injury (AKI). METHODS: We performed a two-site prospective observational study from 2018 to 2019 to evaluate the utility of renal near-infrared spectroscopy (NIRS) in detecting AKI in 38 neonates with HIE receiving therapeutic hypothermia. AKI was defined by a delayed rate of serum creatinine decline (< 33% on day 3 of life, < 40% on day 5, and < 46% on day 7). Renal saturation (Rsat) and systemic oxygen saturation (SpO2) were continuously measured for the first 96 h of life (HOL). Renal fractional tissue oxygen extraction (RFTOE) was calculated as (SpO2 - Rsat)/(SpO2). Using renal NIRS, urine biomarkers, and perinatal factors, logistic regression was performed to develop a model that predicted AKI. RESULTS: AKI occurred in 20 of 38 neonates (53%). During the first 96 HOL, Rsat was higher, and RFTOE was lower in the AKI group vs. the no AKI group (P < 0.001). Rsat > 70% had a fair predictive performance for AKI at 48-84 HOL (AUC 0.71-0.79). RFTOE ≤ 25 had a good predictive performance for AKI at 42-66 HOL (AUC 0.8-0.83). The final statistical model with the best fit to predict AKI (AUC = 0.88) included RFTOE at 48 HOL (P = 0.012) and pH of the infants' first postnatal blood gas (P = 0.025). CONCLUSIONS: Lower RFTOE on renal NIRS and pH on infant first blood gas may be early predictors for AKI in neonates with HIE receiving therapeutic hypothermia. A higher resolution version of the Graphical abstract is available as Supplementary information.

Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

Epidemiology of Neonatal Acute Respiratory Distress Syndrome: Prospective, Multicenter, International Cohort Study.

OBJECTIVES: Age-specific definitions for acute respiratory distress syndrome (ARDS) are available, including a specific definition for neonates (the "Montreux definition"). The epidemiology of neonatal ARDS is unknown. The objective of this study was to describe the epidemiology, clinical course, treatment, and outcomes of neonatal ARDS. DESIGN: Prospective, international, observational, cohort study. SETTING: Fifteen academic neonatal ICUs. PATIENTS: Consecutive sample of neonates of any gestational age admitted to participating sites who met the neonatal ARDS Montreux definition criteria. MEASUREMENTS AND MAIN RESULTS: Neonatal ARDS was classified as direct or indirect, infectious or noninfectious, and perinatal (≤ 72 hr after birth) or late in onset. Primary outcomes were: 1) survival at 30 days from diagnosis, 2) inhospital survival, and 3) extracorporeal membrane oxygenation (ECMO)-free survival at 30 days from diagnosis. Secondary outcomes included respiratory complications and common neonatal extrapulmonary morbidities. A total of 239 neonates met criteria for the diagnosis of neonatal ARDS. The median prevalence was 1.5% of neonatal ICU admissions with male/female ratio of 1.5. Respiratory treatments were similar across gestational ages. Direct neonatal ARDS (51.5% of neonates) was more common in term neonates and the perinatal period. Indirect neonatal ARDS was often triggered by an infection and was more common in preterm neonates. Thirty-day, inhospital, and 30-day ECMO-free survival were 83.3%, 76.2%, and 79.5%, respectively. Direct neonatal ARDS was associated with better survival outcomes than indirect neonatal ARDS. Direct and noninfectious neonatal ARDS were associated with the poorest respiratory outcomes at 36 and 40 weeks' postmenstrual age. Gestational age was not associated with any primary outcome on multivariate analyses. CONCLUSIONS: Prevalence and survival of neonatal ARDS are similar to those of pediatric ARDS. The neonatal ARDS subtypes used in the current definition may be associated with distinct clinical outcomes and a different distribution for term and preterm neonates.

Ventilatory Strategies in Infants with Established Severe Bronchopulmonary Dysplasia: A Multicenter Point Prevalence Study.

We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes.

Use of inhaled nitric oxide in preterm vs term/near-term neonates with pulmonary hypertension: results of the PaTTerN registry study.

OBJECTIVE: To evaluate inhaled nitric oxide (iNO) in preterm (PT) vs term/near-term (TNT) neonates with hypoxic respiratory failure (HRF) and pulmonary hypertension (PH) in an observational registry (PaTTerN). STUDY DESIGN: Non-inferiority study comparing PT neonates of GA ≥ 27 to <34 weeks vs TNT neonates of GA ≥ 34 to ≤40 weeks with HRF associated with PH, who received iNO for 24-96 h during the first 0-7 days after birth. Primary endpoint: Achieving ≥25% decrease in oxygenation index/surrogate oxygenation index during iNO treatment. RESULTS: Of 140 neonates (PT, n = 55; TNT, n = 85), the primary endpoint was achieved in 50 (90.9%) PT vs 75 (88.2%) TNT neonates (difference [95% CI]: 0.027 [-0.033, 0.087]); PT neonates achieved non-inferiority interval, and the study was stopped early based on prespecified criteria. CONCLUSIONS: Use of iNO for improving oxygenation in PT neonates with HRF associated with PH is at least as effective as in TNT neonates. CLINICAL TRIAL REGISTRATION: #NCT03132428, registered April 27, 2017.

Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia.

OBJECTIVE: To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: We performed a multicenter prospective observational study of 64 neonates. Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria. RESULTS: AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0-5] days vs 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; P = .012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction. KIM-1 had the best predictive performance across time points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life. CONCLUSIONS: Urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving therapeutic hypothermia who developed AKI. However, wide variability and unclear cutoff levels make their clinical utility unclear.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.

BACKGROUND: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. METHODS: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. RESULTS: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499.

Implementing a Weaning Protocol for Noninvasive Respiratory Support in Neonates Decreases Overuse and Length of Stay.

BACKGROUND: As part of efforts to decrease length of hospital stay, a protocol for weaning noninvasive respiratory support was implemented using quality improvement methodology. The objective of this study was to determine whether protocol implementation decreased the time to wean to no respiratory support by 24 h (30% reduction) over 3 months in preterm infants 30-34 weeks gestational age. METHODS: A quality improvement project was conducted with the following outcome measures: primary outcome measured was hours to wean; secondary outcomes included duration of respiratory support, length of stay, and postmenstrual age at feeding milestones; and balance measures were duration of oxygen exposure and growth velocity. RESULTS: Data from 89 subjects were included. Following implementation, decreases were seen in time to wean (40% reduction, P < .001), length of stay (25% reduction, P = .02), and growth velocity (21% reduction, P = .02). CONCLUSIONS: Implementing a weaning protocol decreases duration of support and length of stay in infants 30-34 weeks gestational age. Weaning respiratory support more quickly may decrease growth velocity.

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. Objectives: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. Design, Setting, and Participants: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. Interventions: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. Main Outcomes and Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. Results: A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001). Conclusions and Relevance: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

Safety of Metronidazole in Late Pre-term and Term Infants with Complicated Intra-abdominal Infections.

BACKGROUND: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown. METHODS: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections open-label multicenter trial infants ≥34 weeks gestation at birth and <121 days postnatal age with cIAIs were administered metronidazole as part of multimodal therapy. Metronidazole safety was evaluated by reporting of adverse events (AEs) and safety events of special interest. Cure from disease was determined by blood cultures and a clinical cure score >4. A blinded adjudication committee reviewed all safety events of special interest. RESULTS: Fifty-five infants were included, median gestational age was 36 weeks (range: 34-41) and postnatal age was 7 days (0-63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin and vancomycin. Only one AE, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was 1 (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4. CONCLUSIONS: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

Work of Breathing in Premature Neonates: Noninvasive Neurally-Adjusted Ventilatory Assist versus Noninvasive Ventilation.

BACKGROUND: We tested whether work of breathing in premature newborns estimated by phase angle (θ) by using respiratory inductance plethysmography is decreased during neurally-adjusted ventilatory assist (NAVA) noninvasive ventilation (NIV) versus NIV alone. METHODS: NAVA NIV and NIV were applied in random order while using respiratory inductance plethysmography to measure the phase angle. RESULTS: Patient-ventilator asynchrony was decreased during NAVA NIV; however, the phase angle was not different between the modes. A large number of repeated assists with switches to backup were found when using NAVA NIV. Results of the analysis indicated these were due to the apnea alarm limit set during NAVA NIV. CONCLUSIONS: The improvement in patient-ventilator synchrony supports the hypothesis that work of breathing may be decreased with NAVA NIV; however, we were unable to demonstrate this with our study design. Short apnea time settings with NAVA NIV led to a large number of switches to backup and repeated assists during the same neural effort. (ClinicalTrials.gov registration NCT02788110.).

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Tidal volume transmission during non-synchronized nasal intermittent positive pressure ventilation via RAM® cannula.

BACKGROUND: Nasal intermittent positive pressure ventilation (NIPPV) is a widely used mode of support in neonates, during which ventilator inflations may or may not coincide with spontaneous breathing. OBJECTIVE: We tested the hypothesis that inflations delivered with NIPPV via RAM® cannula and not accompanied by patient effort produce minimal tidal volume as measured by respiratory inductance plethysmography. DESIGN/METHODS: Fourteen subjects were monitored while receiving NIPPV. We compared tidal volumes during ventilator-supported breaths, unsupported breaths, and ventilator inflations not accompanied by patient effort (defined using electrical activity of the diaphragm). RESULTS: Mean tidal volumes in arbitrary units were 0.30 ± 0.22 in NIPPV inflations associated with patient effort and 0.27 ± 0.15 in spontaneous breaths without ventilator assistance (p = 0.82). Tidal volumes during ventilator-only inflations were 0.06 ± 0.04 (p < 0.005 vs. both ventilator-assisted and unassisted efforts). CONCLUSIONS: NIPPV via RAM cannula produces minimal, clinically insignificant tidal volumes during non-spontaneous inflations.

Comparison of Work of Breathing Between Noninvasive Ventilation and Neurally Adjusted Ventilatory Assist in a Healthy and a Lung-Injured Piglet Model.

BACKGROUND: Noninvasive ventilation (NIV) is commonly used in neonates. A mode of NIV called neurally adjusted ventilatory assist (NAVA) offers patient-ventilator interactions by using electrical activity of the diaphragm to control mechanical breaths. We hypothesized that the work of breathing (WOB) would decrease with NIV-NAVA. Secondary objectives evaluated the impact of NIV-NAVA on arterial blood gases and respiratory parameters. METHODS: We compared WOB between synchronized breaths in NIV-NAVA and NIV in piglets with healthy lungs and then with surfactant-depleted lungs. Neonatal pigs (median, 2.0 [range, 1.8-2.4] kg) with healthy and then surfactant depleted lungs were sedated and ventilated with NIV-NAVA and NIV in random order. Airway flow and pressure waveforms were acquired. Waveforms were analyzed for the pressure-time product that reflected WOB. The primary outcome between modes was assessed with repeated measurement analysis of variance. RESULTS: The pressure-time product was significantly decreased for NIV-NAVA in both healthy and injured lungs (P < .001). PaO2 , PaCO2 , inspiratory tidal volume, and peak inspiratory flow were not different in either model. CONCLUSIONS: Synchronized breaths during NIV-NAVA resulted in decreased WOB compared with synchronized breaths during NIV.