Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.

Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial.

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation. Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial. Design, Setting, and Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020. Exposure: Parental choice of enrollment in neonatal clinical trial. Main Outcomes and Measures: Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers. Results: Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment. Conclusions and Relevance: In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.

Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial.

OBJECTIVE: To determine if preterm infants with moderate respiratory distress syndrome on continuous positive airway pressure (CPAP) who received surfactant via a laryngeal mask airway (LMA) would have a decreased rate of intubation and mechanical ventilation compared with those on CPAP who did not receive surfactant. STUDY DESIGN: In this prospective, multicenter, randomized controlled trial, 103 premature infants 280/7-356/7 weeks gestation, ≥1250 g and ≤36 hours old on CPAP requiring fraction of inspired oxygen 0.30-0.40 were assigned to receive surfactant administered through an LMA then placed back on CPAP (LMA group) or maintained on CPAP with no surfactant administered (control group). The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. RESULTS: Surfactant administration through an LMA (n = 50) significantly decreased the rate of intubation and mechanical ventilation compared with controls (n = 53): 38% vs 64%, respectively, OR 0.30 (95% CI 0.13, 0.70), P = .006, number needed to treat: 4). There were no serious adverse events associated with placement of the LMA or surfactant administration. CONCLUSIONS: In premature neonates with moderate respiratory distress syndrome, surfactant administered through an LMA decreased the rate of intubation and mechanical ventilation. This intervention may have significant impact on clinical care in both high and low resource settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01116921.

Bi-level CPAP does not improve gas exchange when compared with conventional CPAP for the treatment of neonates recovering from respiratory distress syndrome.

AIM: We hypothesised that short-term application of bi-level nasal continuous positive airway pressure CPAP (SiPAP) compared with conventional nasal CPAP (nCPAP) at the same mean airway pressure in infants with persistent oxygen need recovering from respiratory distress syndrome would improve CO2 removal with no change in oxygen requirement. DESIGN: Non-blinded, randomised, observational four-period crossover study. SETTING/POPULATION: Level III NICU; low-birthweight infants requiring CPAP and oxygen while recovering from respiratory distress syndrome. METHODS: Infants requiring nasal CPAP for >24 h prior to study enrolment, and fraction of inspired oxygen requirement (FiO2) of 0.25-0.5, were randomised to either nCPAP or SiPAP. A crossover design with four 1 h treatment periods was used such that each infant received both treatments twice. Oxygen saturations (SaO2), transcutaneous CO2 (tcCO2) and vital signs were monitored continuously. Polysomnographic recordings were analysed for apnoea, bradycardia and oxygen desaturation. RESULTS: Twenty low-birthweight infants receiving 0.3±0.04% supplemental oxygen on CPAP of 6 cm H2O were studied at an average of 33 days of age (±23 days, SD). There were no differences in tcCO2 or other physiological parameters except mean blood pressure, which was lower during nCPAP (52.3±8.3 vs 54.4±9.1 mm Hg; ±SD; p<0.01). No differences in short or prolonged apnoea, bradycardia or significant desaturation events were observed. CONCLUSIONS: At similar mean airway pressures, SiPAP does not improve CO2 removal, oxygenation or other studied physiological parameters with the exception of mean blood pressure, which was not clinically significant. TRIAL REGISTRATION NUMBER: NCT01053455.

Aerosolized KL4 surfactant improves short-term survival and gas exchange in spontaneously breathing newborn pigs with hydrochloric acid-induced acute lung injury.

BACKGROUND: Surfactant therapy may be beneficial in acute lung injury (ALI). In spontaneously breathing newborn pigs with ALI supported with continuous positive airway pressure (CPAP), we evaluated the hypothesis that aerosolized KL4 surfactant (AERO KL4 S) would provide a similar therapeutic effect as intratracheal KL4 surfactant (ETT KL4 S) when compared to controls. METHODS: We randomized pigs with HCl-induced ALI to: (1) 175 mg/kg KL4 surfactant via endotracheal tube (ETT); (2) AERO KL4 S (22.5 mg/min phospholipid) for 60 min via continuous positive airway pressure (CPAP); or (3) sham procedure on CPAP. We obtained physiologic data and arterial blood gases throughout the 3-hr study. At study end, lungs were excised for analysis of interleukin-8 (IL-8), myeloperoxidase (MPO) levels and histomorphometric data. RESULTS: Pigs treated with ETT KL4 S and AERO KL4 S had improved survival and sustained pO2 compared to controls. The AERO KL4 S group had higher pH compared to controls. Lung IL-8 levels were lower in the AERO KL4 S group compared to controls. Histomorphometric analysis showed less hemorrhage in the ETT and AERO KL4 S groups compared to controls. The AERO KL4 S group had more open lung units per fixed-field than the ETT KL4 S or controls. CONCLUSIONS: AERO KL4 S produced similar improvements in survival, physiology, inflammatory markers, and morphology as ETT KL4 S in an ALI model.

Improved gas exchange and survival after KL-4 surfactant in newborn pigs with severe acute lung injury.

OBJECTIVE: To determine the effectiveness of artificial surfactant therapy using KL-4 surfactant in newborn pigs with hydrochloric acid (HCl)-induced acute lung injury (ALI). DESIGN: After induction of ALI via intratracheal HCl instillation, pigs were randomized to receive 5.8 ml/kg KL-4 surfactant or no surfactant prior to extubation to bubble CPAP. SETTING: Clinical laboratory. SUBJECTS: Spontaneously breathing newborn pigs (<1 week of age). INTERVENTIONS: Treatment with KL-4 surfactant on bubble CPAP with PEEP of 6 cmH(2)O for 3.5 hr after extubation compared with controls. MEASUREMENTS: Physiologic parameters and arterial blood gases were measured every 15 min. At the conclusion of the study, the lungs were excised for the analysis of histopathology and morphometric data. MAIN RESULTS: Pigs treated with KL-4 surfactant had arterial blood gases with less acidosis (P < 0.001), higher P(a)O(2) levels (P < 0.001), and lower P(a)CO(2) levels (P < 0.001). Pigs treated with KL-4 surfactant had improved survival compared with controls (6/12 KL-4, 2/12 control, P < 0.05). Postmortem morphometric data demonstrated that pigs treated with KL-4 surfactant had larger (P < 0.05) exchange units in the caudal-dorsal lung as compared to relatively atelectatic region in the control animals. CONCLUSIONS: In newborn pigs with severe HCl-induced ALI, treatment with KL-4 surfactant resulted in improved respiratory parameters, less dependent atelectasis, and improved short-term survival.

Laryngeal mask airway for surfactant administration in a newborn animal model.

Premature infants are subjected to adverse effects of intubation to benefit from surfactant. We hypothesized that administration of surfactant through a laryngeal mask airway (LMA) is as effective as administration through an endotracheal tube (ETT) and that time and physiologic changes during instrumentation will be less in the LMA group. This study is a randomized, controlled trial using newborn pigs. Lung injury was induced via surfactant washout. Animals were randomized into groups: 1) LMA placed, no surfactant administered (control; n = 8); 2) surfactant via an LMA (LMA group; n = 8); and 3) surfactant via an ETT (ETT group; n = 8). We demonstrated that partial pressure of oxygen in arterial blood (Pao2) levels of the LMA and ETT groups were not statistically different. Time for successful placement of LMA was 19 ± 1 s versus ETT 123 ± 35 s (mean ± SEM); number of attempts for successful LMA placement was 1.1 (1-2) versus ETT 1.9 (1-7) [mean (range)]. Administration of surfactant via an LMA compared with an ETT resulted in similar improvements in oxygenation. Placement of the device required less time and fewer attempts. These data suggest that further study in human neonates is justified. If proven effective, some infants with respiratory distress may be able to receive surfactant while avoiding intubation.

Observational study of humidified high-flow nasal cannula compared with nasal continuous positive airway pressure.

OBJECTIVES: To conduct an in vitro evaluation of a humidified high-flow nasal cannula (HFNC) system at different flows, cannula sizes, and air leaks and also an in vivo analysis of mean end-expiratory esophageal pressure (EEEP) from nasal continuous positive airway pressure at 6 cm H(2)O (NCPAP+6) versus HFNC. STUDY DESIGN: In the in vitro study, we measured HFNC system pressure and flow, with varying degrees of leak and with and without the use of a pressure-limiting valve. In the in vivo study, we measured EEEP in 15 newborns on NCPAP+6 and then on HFNC at 6 L/minute, with flow decreased by 1 L/minute every 30 minutes. Heart rate, respiratory rate, fraction of inspired oxygen, arterial oxygen saturation, respiratory distress syndrome score, and EEEP were recorded for each intervention. Data analysis was done using repeated-measures analysis of variance and linear regression. RESULTS: In the in vitro study, in the absence of leaks, the pressures were limited by the pressure-limiting valve only at flows > or = 2 L/minute. With leaks of 30% and 50%, delivered pressures were always < 3 cm H(2)O. In the in vivo study, respiratory rate increased from baseline (NCPAP+6) as flow decreased (P < .02). Intrapatient and interpatient coefficients of variation were always high. CONCLUSIONS: A pressure-limiting valve is necessary in a HFNC system. Although mean EEEP levels were similar in NCPAP+6 and HFNC, tachypnea developed as flow diminished. This system apparently cannot predict EEEP, because of interpatient and intrapatient variation.

Gas exchange and lung inflammation using nasal intermittent positive-pressure ventilation versus synchronized intermittent mandatory ventilation in piglets with saline lavage-induced lung injury: an observational study.

OBJECTIVE: Physiologic and pathologic comparison of two modes of assisted ventilation, nasal intermittent positive-pressure ventilation (NIPPV) and synchronized intermittent mandatory ventilation (SIMV), in spontaneously breathing term newborn piglets with saline lavage-induced lung injury. DESIGN: After inducing acute lung injury via repetitive saline lavage, piglets were randomized to NIPPV (n = 12) or SIMV (n = 11) and treated for 6 hrs. SETTING: Clinical laboratory. SUBJECTS: Spontaneously breathing term newborn piglets. INTERVENTIONS: Invasive (SIMV) or noninvasive (NIPPV) assisted ventilation for 6 hrs. MEASUREMENTS: Physiologic parameters and arterial blood gases were continuously monitored. At the conclusion of the study, lung tissue was obtained to analyze for evidence of inflammation, including myeloperoxidase, interleukin-8, and hydrogen peroxide levels, as well as for evidence of pathologic injury. MAIN RESULTS: Piglets treated with NIPPV demonstrated higher arterial blood gas pH (p < .001), lower PaCO2 (p < .05), and a lower set respiratory rate (p < .0001) as compared with the SIMV-treated piglets. The piglets in the SIMV group had higher PaO2/PaO2 ratio than those in the NIPPV group (p = .001). There was significantly more interstitial inflammation (p = .04) in the SIMV-treated piglets compared with the NIPPV-treated piglets. Total respiratory rate, heart rate, blood pressure, oxygen saturation, and biochemical markers of lung inflammation were not different between the groups. CONCLUSION: In surfactant-deficient term newborn piglets, NIPPV offers an effective and noninvasive ventilatory strategy with the potential for less pathologic lung inflammation.

The role of high-frequency ventilation in neonates: evidence-based recommendations.

High-frequency ventilation (HFV) uses small tidal volumes and extremely rapid ventilator rates. Despite the wealth of laboratory and clinical research on HFV, there are no established guidelines for prioritizing the use of HFV versus conventional mechanical ventilation (CMV) in neonatal respiratory failure. Examination of the currently available randomized controlled trials and meta-analysis of HFV versus CMV does not demonstrate any clear benefit of HFV either as a primary mode or as a "rescue" mode of ventilation in neonates who have respiratory insufficiency. The current literature does support the preferential use of HFV over CMV in conjunction with inhaled nitric oxide to maximize oxygenation in hypoxemic respiratory failure, in particular, as a result of persistent pulmonary hypertension.