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The 7th edition of the Textbook ofNeonatal Resuscitation recommends administration of epinephrine via an umbilical venous catheter (UVC) inserted 2–4 cm below the skin, followed by a 0.5-mL to 1-mL flush for severe bradycardia despite effective ventilation and chest compressions (CC). This volume of flush may not be adequate to push epinephrine to the right atrium in the absence of intrinsic cardiac activity during CC. The objective of our study was to evaluate the effect of 1-mL and 2.5-mL flush volumes after UVC epinephrine administration on the incidence and time to achieve return of spontaneous circulation (ROSC) in a near-term ovine model of perinatal asphyxia induced cardiac arrest. After 5 min of asystole, lambs were resuscitated per Neonatal Resuscitation Program (NRP) guidelines. During resuscitation, lambs received epinephrine through a UVC followed by 1-mL or 2.5-mL normal saline flush. Hemodynamics and plasma epinephrine concentrations were monitored. Three out of seven (43%) and 12/15 (80%) lambs achieved ROSC after the first dose of epinephrine with 1-mL and 2.5-mL flush respectively (p = 0.08). Median time to ROSC and cumulative epinephrine dose required were not different. Plasma epinephrine concentrations at 1 min after epinephrine administration were not different. From our pilot study, higher flush volume after first dose of epinephrine may be of benefit during neonatal resuscitation. More translational and clinical trials are needed.

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy (CP) and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near term lambs (n=27) are resuscitated after the induction of 5 minutes of asystole. Following recovery, lambs are assessed to define neurodevelopmental outcomes. At the end of this period, lambs are euthanized, and brains harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enables identification of animals that recover significant neurological function. Approximately 35 % of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matter, oligodendrocyte loss, and neuronal loss and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex and demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

BACKGROUND:The neonatal resuscitation program (NRP) recommends interrupted chest compressions (CCs) with ventilation in the severely bradycardic neonate. The conventional 3:1 compression-to-ventilation (C:V) resuscitation provides 90 CCs/min, significantly lower than the intrinsic newborn heart rate (120-160 beats/min). Continuous CC with asynchronous ventilation (CCCaV) may improve the success of return of spontaneous circulation (ROSC). METHODS: Twenty-two near-term fetal lambs were randomized to interrupted 3:1 C:V (90 CCs + 30 breaths/min) or CCCaV (120 CCs + 30 breaths/min). Asphyxiation was induced by cord occlusion. After 5 min of asystole, resuscitation began following NRP guidelines. The first dose of epinephrine was given at 6 min. Invasive arterial blood pressure and left carotid blood flow were continuously measured. Serial arterial blood gases were collected. RESULTS: Baseline characteristics between groups were similar. Rate of and time to ROSC was similar between groups. CCCaV was associated with a higher PaO 2 (partial oxygen tension) (22 ± 5.3 vs. 15 ± 3.5 mmHg, p < 0.01), greater left carotid blood flow (7.5 ± 3.1 vs. 4.3 ± 2.6 mL/kg/min, p < 0.01) and oxygen delivery (0.40 ± 0.15 vs. 0.13 ± 0.07 mL O 2 /kg/min, p < 0.01) compared to 3:1 C:V. CONCLUSIONS: In a perinatal asphyxiated cardiac arrest lamb model, CCCaV showed greater carotid blood flow and cerebral oxygen delivery compared to 3:1 C:V resuscitation.

Background: The Neonatal Resuscitation Program (NRP) recommends using 100% O 2 during chest compressions and adjusting FiO 2 based on SpO 2 after return of spontaneous circulation (ROSC). The optimal strategy for adjusting FiO 2 is not known. Methods: Twenty-five near-term lambs asphyxiated by umbilical cord occlusion to cardiac arrest were resuscitated per NRP. Following ROSC, lambs were randomized to gradual decrease versus abrupt wean to 21% O 2 followed by FiO 2 titration to achieve NRP SpO 2 targets. Carotid blood flow and blood gases were monitored. Results: Three minutes after ROSC, PaO 2 was 229±32 mmHg in gradual wean group compared to 57±13 following abrupt wean to 21% O 2 (p<0.001). PaO 2 remained high in the gradual wean group at 10 min after ROSC (110±10 vs. 67±12, p <0.01) despite similar FiO 2 (~0.3) in both groups. Cerebral O 2 delivery (C-DO 2 ) was higher above physiological range following ROSC with gradual wean (p<0.05). Lower blood oxidized/reduced glutathione ratio (suggesting less oxidative stress) was observed with abrupt wean. Conclusion: Weaning FiO 2 abruptly to 0.21 with adjustment based on SpO 2 prevents surge in PaO 2 and C-DO 2 and minimizes oxidative stress compared to gradual weaning from 100% O 2 following ROSC. Clinical trials with neurodevelopmental outcomes comparing post-ROSC FiO 2 weaning strategies are warranted.

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