299 - Effects of Epinephrine on Hemodynamics and Vasculature in an Asphyxiated Term and Preterm Ovine Models

Publication Number: 299.4903

Justin Helman, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States; Sylvia Gugino, SUNY at Buffalo, Buffalo, NY, United States; Mausma I. Bawa, University At Buffalo, Buffalo, NY, United States; Nicole Bradley, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States; Lori Nielsen, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Clarence Center, NY, United States; Hamza Abbasi, John R. Oishei Children’s Hospital, East Amherst, NY, United States; Mary Divya Kasu, University of Maryland Children's Hospital, Baltimore, MD, United States; Munmun Rawat, University at Buffalo, Buffalo, NY, United States; Praveen Chandrasekharan, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States

Background: American Academy of Pediatrics Neonatal Resuscitation Program (AAP NRP) recommends epinephrine (EPI) intravenously (IV) at a dose of 0.02mg/kg/dose followed by a 3 ml flush during extensive resuscitation, with an increase in dose to 0.03mg/kg/dose. These doses and the need for flush have been evaluated in lambs and extrapolated to newborns. The response to EPI could differ between term and preterm infants, and has not been evaluated.

Objective: To evaluate the response to 0.03mg/kg/dose of IV EPI followed by flush using both term and preterm models requiring resuscitation on:
i) hemodynamics - carotid (CaF), pulmonary blood flows (PBF), systemic blood pressures (BP) during pre & post-EPI (in vivo) before return of spontaneous circulation (ROSC)
ii) vascular response - to advancing doses of EPI on carotid (Ca) & coronary artery (Co) vessels - in a vessel bath (in vitro).

Design/Methods: After IACUC approval, both near-term (139-142d) and preterm (125-127d) lambs were instrumented to measure CaF, PBF, Systolic (SBP) & Diastolic (DBP). In vivo evaluation of hemodynamic parameters before and after IV EPI were compared using unpaired t-tests during resuscitation alone. In vitro, assessment of the vascular response was evaluated in a Kreb's solution by isolating Ca & Co vessel rings from both term & preterm lambs. The data is presented as a percentage response to thromboxane mimetic (U46619) with increasing concentrations of EPI (ug/cc). Propranolol (PROP) was used for the beta-blocking effect.

Results: Characteristics of lambs are shown in Fig1. ROSC rates were 100% in term and 60% in preterm lambs.
i) In vivo - Pre & post-EPI, there was a significant increase in CaF, PBF, SBP & DBP in term, as shown in Fig2a,2b,2c,2d. There was an increase in hemodynamic parameters in preterm, as shown in Fig2, but not statistically different.
ii) In vitro - at a therapeutic dose of EPI - a) Ca response - Fig 3a&3b - the term Ca vessel constriction was 300% of U46619 contraction and decreased with PROP (Fig3a), while the preterm Ca (Fig3b) was ~200% with similar response to PROP, b) Co response - Fig 3c & 3d - the term vessel constriction was 120% of U46619 compared to preterm 100% and relaxation observed with PROP in both.

Conclusion(s): Response to EPI was robust in term lambs. The difference in response to EPI, both in vivo and in vitro, in term and preterm lambs suggests that higher doses may be needed to resuscitate preterm infants. This could be due to drug-receptor immaturity and reduced sensitivity. Further studies, both translational and clinical, are needed to validate our findings.

Figure 1.
Characteristics of Term and Preterm Lambs

Figure 2
Shows the blood flow & pressures pre & post EPI in term & preterm lambs during resuscitation. 2a: Shows a significant increase in carotid blood flow in term lambs but not preterm lambs. 2b: A significant increase in pulmonary blood flow was noted in term but not in preterm lambs. 2c&2d: Show a significant increase in systolic and diastolic blood pressure in term lambs but not preterm lambs during resuscitation. Data – average & SEM. * unpaired t-test.

Figure 3
Shows the vascular response in term & preterm lambs as a % of thromboxane mimetic contraction (U46619 – y-axis) with advancing doses of EPI (x-axis). Propranolol was used to assess the effect after the beta-blockade. 3a & 3b shows the carotid artery response, which was higher in term than preterm lambs. 3c & 3d shows the coronary artery response, which was higher in term compared to preterm lambs. Preterm relaxation to EPI showed reduced sensitivity to the drug compared to term coronary artery.
Propranolol did block the relaxation but no additional increase in tone was seen in preterm gestation.
This may be pertinent to appropriate epi doses at earlier gestation Data – average & SD. Error bars are shown in one direction for clarity.