Bioavailability of endotracheal epinephrine in an ovine model of neonatal resuscitation

Abstract

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.

Keywords: Endotracheal epinephrine; Epinephrine concentration; Lung liquid; Neonatal resuscitation.

Figure 1:

Cumulative percentage of lambs attaining ROSC (return of spontaneous circulation) following each dose of epinephrine (epi). Lambs received initial ET epi (n=15 newborn, n= 6 postnatal), 2^nd ET (n=9 newborn, n=3 postnatal) and a 3^rd dose IV (n=5 newborn, n=1 postnatal) prior to ROSC.

Figure 2:. Highest plasma epinephrine levels in the study groups

A. after first dose ETT epinephrine and prior to administration of the second dose in some lambs (highest level achieved between minute 1-4 after onset of positive pressure ventilation - n=15 newborn, n= 6 postnatal) B. after second dose ETT epinephrine and prior to IV epinephrine in some lambs (highest level achieved between minutes 4-7 after onset of positive pressure ventilation ● Newborn group (n=9) Postnatal group (n=3). * p<0.01 vs newborn by Mann Whitney U test

Figure 3:

Pattern of rise in plasma epinephrine concentrations over time following each dose of Epinephrine cumulatively in all lambs. ●Newborn group (n=15) Postnatal group (n=6) ▴ Historical newborn lambs receiving only IV epinephrine (dose, 0.03 mg/kg - n=8)

Figure 4:

Plasma epinephrine concentrations in relation to time of ROSC in lambs receiving only 1 dose epinephrine prior to achieving ROSC ● ET Newborn group (n=6) ET Postnatal group (n=3)▴ Historical newborn lambs receiving only IV epinephrine (n=8). The vertical grey bar depicts time of ROSC.

Figure 5:

Hemodynamic parameters in the study groups at various time points in lambs that received only ET epinephrine- baseline prior to resuscitation, during chest compressions, epinephrine administration and 2min and 5-10min after ROSC. A. Heart rate changes B. Carotid blood flow C. Systolic blood pressure and D. Diastolic blood pressure. ● Newborn group (n=10) Postnatal group (n=5) * p<0.01 by Mann Whitney U test vs newborn at the same time point.