Pyruvate Intervention for Brain Injury Inflicted by Cardiac Arrest-Resuscitation

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2016-05

Authors

Nguyen, Anh Q.

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Abstract

Fewer than 10% of the 360,000 people who suffer out-of-hospital cardiac arrest annually in the U.S. survive to hospital discharge. Many suffer brain injuries that greatly affect their daily activities and quality of life. Despite improvements in clinical outcomes from cardiac arrest as a result of therapeutic hypothermia, survival rates are still dismal. Additional interventions to be used alone or in combination with therapeutic hypothermia could potentially save many lives. The intermediate metabolite pyruvate has been proven to be neuroprotective when given acutely. The goal of this investigation is to examine the neuroprotective capabilities and mechanisms of pyruvate in a large animal model of cardiac arrest, closed-chest cardiopulmonary resuscitation (CPR) and countershock induced defibrillation. The central hypothesis is that pyruvate therapy suppresses matrix metalloproteinase (MMP) activity and thereby preserves blood-brain barrier (BBB) integrity, increases expression and content of the cytoprotective cytokine erythropoietin (EPO), and dampens inflammation following cardiac arrest, and, thus, improves neurobehavioral recovery from cardiac arrest. Experiments were conducted in Yorkshire swine, subjected to cardiac arrest, closed-chest cardiocerebral resuscitation (CCR), defibrillation by trans-thoracic countershock, and recovery. The project was divided into two studies with different durations of cardiac arrest, producing different intensities of brain damage. In the first study, swine were subjected to 6 min of untreated cardiac arrest and 4 min of CCR, following by defibrillation and recovery of spontaneous circulation (ROSC). In the second study, untreated cardiac arrest was extended to 10 min before 4 min CCR. Animals were euthanized at 1, 4, and 72 h ROSC, and the brain was biopsied for histological and biochemical analyses. For animals in 72 h ROSC groups, neurological assessment and testing were performed at 24, 48, and 72 h ROSC. At 3 d ROSC, the number of viable cerebellar Purkinje cells fell by 30% vs. Sham control, but pyruvate infusion during CCR and the first 60 min ROSC preserved these neurons. EPO mRNA abundance was sharply increased at 4 h ROSC and in the non-arrest Sham, indicating the surgical protocol, hyperoxic ventilation and anesthesia induced neuroprotective EPO, which may have limited brain injury. There were no differences in neurological scores among Sham, CPR, and CPR+Pyruvate, prompting study of more prolonged cardiac arrest to intensify brain injury. At 4 h ROSC in 10 min untreated cardiac arrest group, cardiac arrest unexpectedly decreased hippocampal and cerebellar MMP-2 activities and cerebellar EPO content, regardless of treatment. 72 h survival rate fell from 100% in study one (6 min pretreatment arrest) to only 2 of 6 pigs in study two (10 min pretreatment arrest), which wide disparity in neurological function among the 2 survivors. Collectively, these results indicate the prolonging pre-intervention arrest from 6 to 10 min sharply intensified brain injury, depleted cytoprotective EPO, and inactivated oxyradical-sensitive enzymes. Pyruvate treatment did not exert favorable effects on these variables, indicating that pyruvate may have had limited ability to traverse the blood brain barrier and protect the brain parenchyma in this large animal model of cardiac arrest and CCR.

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