A randomized and blinded trial of inhaled nitric oxide in a piglet model of pediatric cardiopulmonary resuscitation

Abstract

Aim: Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA.

Methods: After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology.

Results: During CPR, the iNO group had higher mean aortic pressure (41.6 ± 2.0 vs. 36.0 ± 1.4 mmHg; p = 0.005); diastolic BP (32.4 ± 2.4 vs. 27.1 ± 1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ± 2.6 vs. 19.1 ± 1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ± 54.1 vs. 115.5 ± 37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O₂/s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O₂/s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups.

Conclusions: Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model.

Keywords: Cardiopulmonary resuscitation; Cerebral blood flow; Hemodynamics; In-hospital cardiac arrest; Inhaled nitric oxide; Laboratory; Pediatrics; Physiology; Pulmonary hypertension; Shock.

Figure 1:. Hemodynamics during Cardiopulmonary Resuscitation.

Graphs represent: A, aortic diastolic blood pressure (DBP); B, mean aortic blood pressure (MAP); C, coronary perfusion pressure (CoPP); D, mean pulmonary artery pressure (PAP); E, cerebral perfusion pressure (CePP); and F, relative cerebral blood flow (rCBF) during the first ten minutes of cardiopulmonary resuscitation (CPR). Values are 15-second means for each variable with standard error of the mean depicted with error bars. Blue squares = hemodynamic-directed CPR (HD-CPR) with inhaled nitric oxide (iNO). Gray circles = HD-CPR without iNO. All pressures are mmHg. rCBF is % baseline relative to the first minute (pre-iNO) of CPR. Values from minutes 1–10 compared between groups using a generalized estimating equation accounting for clustering within subjects. *Indicates statistically significant (p<0.05) difference between groups.

Figure 2:. Cerebral Mitochondrial Respiration and Reactive Oxygen Species Generation.

Box plots represent measurements from cerebral cortex (top panel) and hippocampus (bottom panel): A and E, Complex I oxidative phosphorylation; B and F, maximal oxidative phosphorylation (Complex I + Complex II); C and G, leak respiration; and D and H, mitochondrial reactive oxygen species (Complex I + Complex II). Respiration values are provided in pmol O2/s*mg. Reactive oxygen species are provided in pmol H2O2/s*mg. Displayed values were normalized to citrate synthase content and were compared between groups using the Wilcoxon rank-sum test. *Indicates statistically significant (p<0.05) difference between groups.