Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance resulting in right-to-left shunting of blood and hypoxemia. PPHN is often secondary to parenchymal lung disease (such as meconium aspiration syndrome, pneumonia or respiratory distress syndrome) or lung hypoplasia (with congenital diaphragmatic hernia or oligohydramnios) but can also be idiopathic. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis. The diagnosis is confirmed by the echocardiographic demonstration of - (a) right-to-left or bidirectional shunt at the ductus or foramen ovale and/or, (b) flattening or leftward deviation of the interventricular septum and/or, (c) tricuspid regurgitation, and finally (d) absence of structural heart disease. Management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation and pulmonary vasodilator therapy. Failure of these measures would lead to consideration of extracorporeal membrane oxygenation (ECMO); however decreased need for this rescue therapy has been documented with advances in medical management. While trends also note improved survival, long-term neurodevelopmental disabilities such as deafness and learning disabilities remain a concern in many infants with severe PPHN. Funded by: 1R01HD072929-0 (SL).

Epinephrine is the only medication recommended by the International Liaison Committee on Resuscitation for use in newborn resuscitation. Strong evidence from large clinical trials is lacking owing to the infrequent use of epinephrine during neonatal resuscitation. Current recommendations are weak as they are extrapolated from animal models or pediatric and adult studies that do not adequately depict the transitioning circulation and fluid-filled lungs of the newborn in the delivery room. Many gaps in knowledge including the optimal dosing, best route and timing of epinephrine administration warrant further studies. Experiments on a well-established ovine model of perinatal asphyxial cardiac arrest closely mimicking the newborn infant provide important information that can guide future clinical trials.

BACKGROUND: Over half a million newborn deaths are attributed to intrapartum related events annually, the majority of which occur in low resource settings. While progress has been made in reducing the burden of asphyxia, novel approaches may need to be considered to further decrease rates of newborn mortality. Administration of intravenous, intraosseous or endotracheal epinephrine is recommended by the Newborn Resuscitation Program (NRP) with sustained bradycardia at birth. However, delivery by these routes requires both advanced skills and specialized equipment. Intramuscular (IM) epinephrine may represent a simple, low cost and highly accessible alternative for consideration in the care of infants compromised at birth. At present, the bioavailability of IM epinephrine in asphyxia remains unclear. METHODS: Four term fetal lambs were delivered by cesarean section and asphyxiated by umbilical cord occlusion with resuscitation after 5 min of asystole. IM epinephrine (0.1 mg/kg) was administered intradeltoid after 1 min of positive pressure ventilation with 30 s of chest compressions. Serial blood samples were obtained for determination of plasma epinephrine concentrations by ELISA. RESULTS: Epinephrine concentrations failed to increase following administration via IM injection. Delayed absorption was observed after return of spontaneous circulation (ROSC) in half of the studies. CONCLUSIONS: Inadequate absorption of epinephrine occurs with IM administration during asphyxial cardiac arrest, implying this route would be ineffective in infants who are severely compromised at birth. Late absorption following ROSC raises concerns for risks of side effects. However, the bioavailability and efficacy of intramuscular epinephrine in less profound asphyxia may warrant further evaluation.

Objective

Continuous chest compressions are more effective during resuscitation in adults. Sustained inflation rapidly establishes functional residual capacity in fluid-filled lungs at birth. We sought to compare the hemodynamics and success in achieving return of spontaneous circulation in an asphyxial cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs between subjects receiving continuous chest compressions during sustained inflation and those receiving conventional 3:1 compression-to-ventilation resuscitation.

Design

Prospective, randomized, animal model study.

Setting

An experimental laboratory.

Subjects

Fourteen newborn term gestation lambs.

Interventions

Lambs were randomized into two groups: 3:1 compression-to-ventilation (control) and continuous chest compressions during sustained inflation. The umbilical cord was occluded to induce asphyxia and asystole. The control group was resuscitated per NRP guidelines. In the sustained inflation + continuous chest compressions group, sustained inflation at 35 cm H2O was provided for 30 seconds with 1-second interruptions before another sustained inflation was provided. One hundred twenty chest compressions/min started after the initial sustained inflation. The first dose of IV epinephrine was given at 6 minutes if return of spontaneous circulation was not achieved and then every 3 minutes until return of spontaneous circulation or for a total of four doses.

Measurement and results

All lambs achieved return of spontaneous circulation in a comparable median time (interquartile range) of 390 seconds (225-405 s) and 345 seconds (204-465 s) in the sustained inflation + continuous chest compressions and control groups, respectively. Four of seven (sustained inflation + continuous chest compressions) and three of six (control) lambs required epinephrine to achieve return of spontaneous circulation. Diastolic blood pressures were lower in the sustained inflation + continuous chest compressions (4 ± 2 mm Hg) compared to the control group (7 ± 2 mm Hg), p < 0.05. PaCO2, PaO2, and lactate were similar between the groups during the study period.

Conclusion

In this perinatal cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs, sustained inflation + continuous chest compressions is as effective as 3:1 compression-to-ventilation resuscitation in achieving return of spontaneous circulation. Half the lambs achieved return of spontaneous circulation without epinephrine. continuous chest compressions during sustained inflation reduced diastolic pressures but did not alter gas exchange or carotid blood flow compared to 3:1 compression-to-ventilation resuscitation.

Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.

The optimal timing of cord clamping in asphyxia is not known. Our aims were to determine the effect of ventilation (sustained inflation-SI vs. positive pressure ventilation-V) with early (ECC) or delayed cord clamping (DCC) in asphyxiated near-term lambs. We hypothesized that SI with DCC improves gas exchange and hemodynamics in near-term lambs with asphyxial bradycardia. A total of 28 lambs were asphyxiated to a mean blood pressure of 22 mmHg. Lambs were randomized based on the timing of cord clamping (ECC-immediate, DCC-60 s) and mode of initial ventilation into five groups: ECC + V, ECC + SI, DCC, DCC + V and DCC + SI. The magnitude of placental transfusion was assessed using biotinylated RBC. Though an asphyxial bradycardia model, 2-3 lambs in each group were arrested. There was no difference in primary outcomes, the time to reach baseline carotid blood flow (CBF), HR ≥ 100 bpm or MBP ≥ 40 mmHg. SI reduced pulmonary (PBF) and umbilical venous (UV) blood flow without affecting CBF or umbilical arterial blood flow. A significant reduction in PBF with SI persisted for a few minutes after birth. In our model of perinatal asphyxia, an initial SI breath increased airway pressure, and reduced PBF and UV return with an intact cord. Further clinical studies evaluating the timing of cord clamping and ventilation strategy in asphyxiated infants are warranted.

Background

In neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO₂) or saturations (SpO₂) to determine return of spontaneous circulation (ROSC) until more evidence becomes available.

Methods

We evaluated the role of monitoring ETCO₂ during resuscitation in a lamb model of cardiac arrest induced by umbilical cord occlusion (n = 21). Lambs were resuscitated as per NRP guidelines. Systolic blood pressure (SBP), carotid and pulmonary blood flows along with ETCO₂ and blood gases were continuously monitored. Resuscitation was continued for 20 min or until ROSC (whichever was earlier). Adequate CC was arbitrarily defined as generation of 30 mmHg SBP during resuscitation. ETCO₂ thresholds to predict adequacy of CC and detect ROSC were determined.

Results

Significant relationship between ETCO₂ and adequate CC was noted during resuscitation (AUC-0.735, P < 0.01). At ROSC (n = 12), ETCO₂ rapidly increased to 57 ± 20 mmHg with a threshold of ≥32 mmHg being 100% sensitive and 97% specific to predict ROSC.

Conclusion

In a large mammalian model of perinatal asphyxia, continuous ETCO₂ monitoring predicted adequacy of CC and detected ROSC. These findings suggest ETCO₂ in conjunction with other devices may be beneficial during CC and predict ROSC.

Background

Distressed infants in the delivery room and those that have completed postnatal transition are both resuscitated according to established neonatal resuscitation guidelines, often with endotracheal (ET) epinephrine at the same dose. We hypothesized that ET epinephrine would have higher bioavailability in a post-transitional compared to transitioning newborn model due to absence of fetal lung liquid and intra-cardiac shunts.

Methods

15 term fetal (transitioning newborn) and 6 postnatal lambs were asphyxiated by umbilical cord and ET tube occlusion respectively. Lambs were resuscitated after 5 min of asystole. ET epinephrine (0.1 mg/kg) was administered after 1 min of positive pressure ventilation (PPV) and chest compressions, and repeated 3 min later, followed by intravenous (IV) epinephrine (0.03 mg/kg) every 3 min until return of spontaneous circulation (ROSC). Serial plasma epinephrine concentrations were measured.

Results

Peak plasma epinephrine concentrations were lower in transitioning newborns as compared to postnatal lambs: after a single ET dose (145.36 ± 135.5 ng/ml vs 553.54 ± 215 ng/ml, p < 0.01) and after two ET doses (443 ± 192.49 ng/ml vs 1406 ± 420.8 ng/ml, p < 0.01). The rates of ROSC with a single ET dose were similar in both groups (40% vs 50% in newborn and postnatal respectively, p > 0.99). There was a higher incidence of post-ROSC tachycardia and increased carotid blood flow in the postnatal group.

Conclusions

In the postnatal period, ET epinephrine at currently recommended doses resulted in higher peak epinephrine concentrations, post-ROSC tachycardia and cerebral reperfusion without significant differences in incidence of ROSC. Further studies evaluating the optimal dose of ET epinephrine during the postnatal period are warranted.

The current guidelines recommend the use of 100% O₂ during resuscitation of a neonate requiring chest compressions (CC). Studies comparing 21% and 100% O₂ during CC were conducted in postnatal models and have not shown a difference in incidence or timing of return of spontaneous circulation (ROSC). The objective of this study is to evaluate systemic oxygenation and oxygen delivery to the brain during CC in an ovine model of perinatal asphyxial arrest induced by umbilical cord occlusion. Pulseless cardiac arrest was induced by umbilical cord occlusion in 22 lambs. After 5 min of asystole, lambs were resuscitated with 21% O₂ as per Neonatal Resuscitation Program (NRP) guidelines. At the onset of CC, inspired O₂ was either increased to 100% O₂ (n = 25) or continued at 21% (n = 9). Lambs were ventilated for 30 min post ROSC and FiO₂ was gradually titrated to achieve preductal SpO₂ of 85-95%. All lambs achieved ROSC. During CC, PaO₂ was 21.6 ± 1.6 mm Hg with 21% and 23.9 ± 6.8 mm Hg with 100% O₂ (p = 0.16). Carotid flow was significantly lower during CC (1.2 ± 1.6 mL/kg/min in 21% and 3.2 ± 3.4 mL/kg/min in 100% oxygen) compared to baseline fetal levels (27 ± 9 mL/kg/min). Oxygen delivery to the brain was 0.05 ± 0.06 mL/kg/min in the 21% group and 0.11 ± 0.09 mL/kg/min in the 100% group and was significantly lower than fetal levels (2.1 ± 0.3 mL/kg/min). Immediately after ROSC, lambs ventilated with 100% O₂ had higher PaO₂ and pulmonary flow. It was concluded that carotid blood flow, systemic PaO₂, and oxygen delivery to the brain are very low during chest compressions for cardiac arrest irrespective of 21% or 100% inspired oxygen use during resuscitation.

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. 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). The absorption of ETT epinephrine is low and delayed at birth. RA and low UVC epinephrine rapidly achieve high plasma concentrations resulting in ROSC.