360 - Norepinephrine is more selective to systemic than pulmonary arteries and dopamine is non-selective in ovine persistent pulmonary hypertension of the newborn.

Publication Number: 1344.360

Nuria Daghbouche-Rubio, PhD, University of California, Davis, School of Medicine, Davis, CA, United States; Evan M. Giusto, UC Davis Health, Sacramento, CA, United States; Michelle J. Lim, University of California, Davis, School of Medicine, Sacramento, CA, United States; Jocelyn Livezey, University of California, Davis, School of Medicine, Davis, CA, United States; Rebecca Valdez, University of California Davis Children's Hospital, Sacramento, CA, United States; Evan Maher, University of California, Davis, School of Medicine, Woodland, CA, United States; Amy Lesneski, UC Davis, Davis, CA, United States; Victoria Hammitt, UC Davis Stem Cell Research, Davis, CA, United States; Maryann K. Ferrara, University of California, Davis, School of Medicine, Vacaville, CA, United States; Paulina Hume, University of California Davis Children's Hospital, Sacramento, CA, United States; Sylvia Bowditch, University of California Davis Children's Hospital, Sacramento, CA, United States; Luna Khanal, University of California Davis Children's Hospital, Sacramento, CA, United States; Payam Vali, University of California, Davis, School of Medicine, sacramento, CA, United States; Yogen Singh, UC Davis Children’s Hospital, Sacramento, CA, United States; Elena Goncharova, University of California, Davis, School of Medicine, Davis, CA, United States; Manuel F. Navedo, University of California, Davis, School of Medicine, Davis, CA, United States; Madeline Nieves-Cintron, University of California, Davis, School of Medicine, Davis, CA, United States; Satyan Lakshminrusimha, UC Davis, Sacramento, CA, United States; Deepika Sankaran, University of California Davis Children's Hospital, Sacramento, CA, United States

Background: Systemic hypotension resulting in poor end-organ perfusion is a frequent complication of persistent pulmonary hypertension of the newborn in meconium aspiration syndrome (MAS). The vasopressor that is relatively selective to systemic circulation, increases systemic vascular resistance (SVR) without increasing pulmonary vascular resistance (PVR) and increases systemic arterial constriction without increasing pulmonary arterial constriction is not known.

Objective: To determine the effect of dopamine and norepinephrine on cerebral SVR and PVR in vivo and systemic and pulmonary vascular contraction ex vivo in an ovine model of asphyxia, MAS and PPHN with systemic hypotension.

Design/Methods: Asphyxia was induced by umbilical cord occlusion followed by meconium instillation into the tracheal tube to induce MAS and PPHN in 14 fetal lambs (134-141 d gestation). Lambs were resuscitated per neonatal resuscitation program guidelines and ventilated, cooled to 33.5˚C and started on inhaled nitric oxide. When the lambs developed systemic hypotension defined as SAP < 50 mm Hg despite two fluid boluses of 10-mL/kg, they received either norepinephrine (0.2-0.8 mcg/kg/min) or dopamine infusion (5-13 mcg/kg/min). Left carotid artery blood flow (CaF), SAP, and main pulmonary artery pressure (PAP) were monitored, and cerebral SVR and PVR were calculated. Vascular contractile response ex vivo to dopamine and norepinephrine were compared using wire myography in 3rd generation systemic (mesenteric/gastric) and 5th generation pulmonary arteries isolated from twin control lambs without PPHN and dose-response curves were plotted.

Results: In vivo studies: The baseline characteristics were not different (Table). Mean CaF was higher with dopamine compared to norepinephrine (figure 1a). PAP and PVR were not different, but SAP was higher with dopamine and cerebral SVR was higher with norepinephrine (figures 1b & c and 2a & b).
Ex vivo studies: Norepinephrine elicited higher contractile response in systemic arteries compared to pulmonary arteries isolated from control lambs, whereas dopamine was nonselective with similar contractility in both systemic and pulmonary arteries (figure 3a & c). Non-receptor mediated contractile response to 118 mM KCl was higher with systemic arteries compared to pulmonary arteries (figures 3b & d).

Conclusion(s): In vivo data showed higher SVR with norepinephrine, and the ex vivo vascular reactivity testing showed that norepinephrine is more selective to systemic arteries than dopamine in ovine MAS, PPHN and systemic hypotension. Further studies are warranted to determine the ideal vasopressor in PPHN.

Figure 1. Comparison of left carotid artery blood flow (1a), mean systemic artery pressure (SAP, 1b) and mean pulmonary artery pressure (PAP, 1c) between lambs with asphyxia, MAS, PPHN and systemic hypotension that received dopamine and norepinephrine, respectively.
Carotid artery blood flow and SAP were higher with dopamine whereas the PAP was not different. When comparing carotid blood flow with lower doses (dopamine <10 mcg/kg/min and norepinephrine < 0.4 mcg/kg/min), p=0.01, and when comparing carotid blood flow with higher doses (dopamine > or equal to 10 mcg/kg/min and norepinephrine > or equal to 0.6 mcg/kg/min), p <0.0001. Similarly for left pulmonary artery blood flow, comparison of dopamine vs norepinephrine at lower doses had p=0.005, and comparison of higher doses had p= 0.02. On the contrary, the PAP was not different at lower (p= 0.67) or higher doses (p=0.34). Data presented as mean and standard error of mean, compared using ANOVA repeated measures. The peach shaded area represents comparison between lower doses and gray shaded area represents comparison between higher doses.

Table and Figure 2.
Table and Figure 2. Table shows baseline characteristics for lambs with asphyxia, MAS and PPHN that received dopamine and norepinephrine, respectively, to treat systemic hypotension. Comparison of cerebral systemic vascular resistance (figure 2a) and pulmonary vascular resistance (PVR, figure 2b) between dopamine and norepinephrine showed higher cerebral SVR with norepinephrine (p < 0.01) and PVR was not different. When comparing cerebral SVR at lower doses (dopamine <10 mcg/kg/min and norepinephrine < 0.4 mcg/kg/min), p=0.005, and when comparing cerebral SVR with higher doses (dopamine > or equal to 10 mcg/kg/min and norepinephrine > or equal to 0.6 mcg/kg/min), p< 0.0001. On the contrary, for pulmonary vascular resistance, comparison of dopamine vs norepinephrine at lower doses and higher doses respectively were not different. Data presented as mean and standard error of mean, compared using ANOVA repeated measures. The peach shaded area represents comparison between lower doses and gray shaded area represents comparison between higher doses.

Figure 3. Ex vivo studies using wire myography to compare contractile response of systemic and pulmonary arteries to norepinephrine and dopamine, respectively.
Ex vivo receptor-mediated contraction to norepinephrine was greater in 3rd generation systemic arteries compared to 5th generation pulmonary arteries suggesting that norepinephrine is relatively selective to systetmic circulation. On the contrary, the receptor-mediated contraction to dopamine was similar in systemic and pulmonary arteries, suggesting that dopamine is a non-selective agent. The non-receptor-mediated constriction to 118 mM KCl indicating the inherent ability to constrict was higher in systemic arteries than in pulmonary arteries. Data presented as raw tension in mN and compared using two-way ANOVA for dose response curves to norepinephrine and dopamine and unpaired t-test for contraction to 118 mM KCl.