Brain Stem Death as the Vital Determinant for Resumption of Spontaneous Circulation after Cardiac Arrest in Rats

Alice Y W Chang,Yao-Chung Chuang,Christoph Kleinschnitz,Samuel H H Chan,Julie Y H Chan

doi:10.1371/journal.pone.0007744

Abstract

BackgroundSpontaneous circulation returns to less than half of adult cardiac arrest victims who received in-hospital resuscitation. One clue for this disheartening outcome arises from the prognosis that asystole invariably takes place, after a time lag, on diagnosis of brain stem death. The designation of brain stem death as the point of no return further suggests that permanent impairment of the brain stem cardiovascular regulatory machinery precedes death. It follows that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences. Here, we evaluated the hypothesis that maintained functional integrity of the rostral ventrolateral medulla (RVLM), a neural substrate that is intimately related to brain stem death and central circulatory regulation, holds the key to the vital time-window between cardiac arrest and resumption of spontaneous circulation.Methodology/Principal FindingsAn animal model of brain stem death employing the pesticide mevinphos as the experimental insult in Sprague-Dawley rats was used. Intravenous administration of lethal doses of mevinphos elicited an abrupt cardiac arrest, accompanied by elevated systemic arterial pressure and anoxia, augmented neuronal excitability and enhanced microvascular perfusion in RVLM. This period represents the vital time-window between cardiac arrest and resumption of spontaneous circulation in our experimental model. Animals with restored spontaneous circulation exhibited maintained neuronal functionality in RVLM beyond this critical time-window, alongside resumption of baseline tissue oxygen and enhancement of local blood flow. Intriguingly, animals that subsequently died manifested sustained anoxia, diminished local blood flow, depressed mitochondrial electron transport activities and reduced ATP production, leading to necrotic cell death in RVLM. That amelioration of mitochondrial dysfunction and bioenergetic failure in RVLM by coenzyme Q10, the mobile electron carrier in mitochondrial respiratory chain, or oxygenation restored spontaneous circulation further established a causal relationship between functionality of RVLM and resumed spontaneous circulation after cardiac arrest.Conclusions/SignificanceWe conclude that whereas necrotic cell death because of bioenergetic failure triggered by anoxia in RVLM, which precipitates brain stem death, negates resuscitation of an arrested heart, maintained functional integrity of this neural substrate holds the key to resumption of spontaneous circulation after cardiac arrest in rats.

Highlights

Two most daunting and unresolved medical enigmas in contemporary medicine are resumption of spontaneous circulation after cardiac arrest and brain stem death
In comatose patients who succumbed to systemic inflammatory response syndrome [8], severe brain injury [9] or organophosphate poisoning [10], we found that the sequence of cardiovascular events before death invariably entails a dramatic reduction or loss of the low-frequency component (LF; 0.004 to 0.15 Hz) in the power spectrum of their systemic arterial pressure (SAP) signals, which reflects brain stem death [7], followed progressively by hypotension and eventually asystole
An immediate corollary that arises from these clinical observations is that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences

Summary

Introduction

Two most daunting and unresolved medical enigmas in contemporary medicine are resumption of spontaneous circulation after cardiac arrest and brain stem death. On intravenous administration of Mev, this animal model allowed us to determine the temporal relationship between the elicited cardiac arrest, alterations in SAP, the life-anddeath signal and tissue oxygen level, blood flow or temperature in the RVLM. It allowed for biochemical analyses of the cellular events that took place in the RVLM during the vital time-window that interposes between cardiac arrest and resumption of spontaneous circulation. In addition to validating this hypothesis, our results revealed that the repertoire of cellular events that underlies the loss of functional integrity in the RVLM, which underpins the failure of resumption of spontaneous circulation after cardiac arrest because of the precipitated brain stem death, entails progression towards sustained anoxia, cessation of local blood flow, dysfunction of mitochondrial electron transport chain and reduction in ATP production, leading to necrotic cell death

Materials and Methods

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Discussion