Background: Epinephrine administered by low umbilical venous catheter ( UVC ) or endotracheal tube ( ETT ) is indicated in neonates who fail to respond to positive pressure ventilation and chest compressions at birth. Pharmacokinetics of ETT epinephrine via fluid‐filled lungs or UVC epinephrine in the presence of fetal shunts is unknown. We hypothesized that epinephrine administered by ETT or low UVC results in plasma epinephrine concentrations and rates of return of spontaneous circulation ( ROSC ) similar to right atrial ( RA ) epinephrine. Methods and Results: Forty‐four lambs were randomized into the following groups: RA epinephrine (0.03 mg/kg), low UVC epinephrine (0.03 mg/kg), postcompression ETT epinephrine (0.1 mg/kg), and precompression ETT epinephrine (0.1 mg/kg). Asystole was induced by umbilical cord occlusion. Resuscitation was initiated following 5 minutes of asystole. Thirty‐eight of 44 lambs achieved ROSC (10/11, 9/11, and 12/22 in the RA , UVC , and ETT groups, respectively; subsequent RA epinephrine resulted in a total ROSC of 19/22 in the ETT groups). Median time (interquartile range) to achieve ROSC was significantly longer in the ETT group (including those that received RA epinephrine) compared to the intravenous group (4.5 [2.9–7.4] versus 2 [1.9–3] minutes; P =0.02). RA and low UVC epinephrine administration achieved comparable peak plasma epinephrine concentrations (470±250 versus 450±190 ng/mL) by 1 minute compared to ETT values of 130±60 ng/mL at 5 minutes; P =0.03. Following ROSC with ETT epinephrine alone, there was a delayed peak epinephrine concentration (652±240 ng/mL). Conclusions: The absorption of ETT epinephrine is low and delayed at birth. RA and low UVC epinephrine rapidly achieve high plasma concentrations resulting in ROSC .

Birth asphyxia accounts for about 23% of the approximately 4 million neonatal deaths each year worldwide (Black et al., Lancet, 2010, 375(9730):1969-87). The majority of newborn infants require little assistance to undergo physiologic transition at birth and adapt to extrauterine life. Approximately 10% of infants require some assistance to establish regular respirations at birth. Less than 1% need extensive resuscitative measures such as chest compressions and approximately 0.06% require epinephrine (Wyllie et al. Resuscitation, 2010, 81 Suppl 1:e260–e287). Transition at birth is mediated by significant changes in circulatory and respiratory physiology. Ongoing research in the field of neonatal resuscitation has expanded our understanding of neonatal physiology enabling the implementation of improved recommendations and guidelines on how to best approach newborns in need for intervention at birth. Many of these recommendations are extrapolated from animal models and clinical trials in adults. There are many outstanding controversial issues in neonatal resuscitation that need to be addressed. This article provides a comprehensive and critical literature review on the most relevant and current research pertaining to evolving new strategies in neonatal resuscitation. The key elements to a successful neonatal resuscitation include ventilation of the lungs while minimizing injury, the judicious use of oxygen to improve pulmonary blood flow, circulatory support with chest compressions, and vasopressors and volume that would hasten return of spontaneous circulation. Several exciting new avenues in neonatal resuscitation such as delayed cord clamping, sustained inflation breaths, and alternate vasopressor agents are briefly discussed. Finally, efforts to improve resuscitative efforts in developing countries through education of basic steps of neonatal resuscitation are likely to decrease birth asphyxia and neonatal mortality.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy disproportionately affects low- and middle-income countries, where ≈96% of affected infants reside. The current standard of care, therapeutic hypothermia, is frequently ineffective in this setting, likely because injury may be occurring earlier during labor. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally. METHODS: Ewes were randomly assigned to receive either 1 g IV caffeine citrate or placebo before delivery and placental transport assessed. Near-term lambs (141–143 days) of both sexes were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Lambs that received caffeine in utero also received 20 mg/kg IV caffeine citrate following resuscitation and 10 mg/(kg·d) IV for 2 days. An additional cohort received 60 mg/kg followed by 30 mg/(kg·d) (low dose versus high dose) postnatally. Biochemical, histological, and neurological outcome measures in lambs were assessed over a 6-day period. RESULTS: Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with lamb plasma levels comparable to those targeted in neonates with apnea of prematurity. Caffeine administration resulted in a systemic immunomodulatory effect, evidenced by significant reductions in proinflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes, while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex. This neuroprotective effect was greater and via a different mode of action than we previously reported for azithromycin. A higher caffeine dosing regimen demonstrated significant toxicity. CONCLUSIONS: Perinatal caffeine administration is well tolerated, attenuates systemic and brain inflammation, and contributes to improvements in histological and neurological outcomes in an ovine model of neonatal hypoxic-ischemic encephalopathy.