Elsevier

Resuscitation

Volume 65, Issue 1, April 2005, Pages 21-39
Resuscitation

Review article
A systematic review of currently available pharmacological neuroprotective agents as a sole intervention before anticipated or induced cardiac arrest

https://doi.org/10.1016/j.resuscitation.2004.11.004Get rights and content

Abstract

We conducted a Medline search for controlled studies evaluating currently available drugs for pharmacological neuroprotection. They had to be administered prior to transient global cerebral ischaemia without further non-pharmacological measures. We deliberately excluded focal ischaemia since its pathophysiology is substantially different from global ischaemia. A total of 45 articles conducted exclusively in laboratory animals met these criteria. The following classes of agents were evaluated: anaesthetics, GABAergic drugs, calcium-antagonists, anticonvulsives, sodium-channel blockers, potassium-channel activators, NMDA-receptor antagonists, hormones, vasodilators, dopamine- and α2-agonists, magnesium, xanthine oxidase- and cyclooxygenase inhibitors, a nootropic, a protease inhibitor, and immunosuppressants. Some of them were applied chronically and others administered via clinically impracticable routes. The available literature favours isoflurane, phenytoin, lamotrigine, magnesium, and potentially, nimodipine, and flunarizine. If factors like costs, toxicity, side effects, route and mode of application are considered, isoflurane and MgSO4 that have also been safely applied to patients with compromised left ventricular pump function are advantageous but their true role in human neuroprotection remains unclear.

Introduction

Transient global cerebral ischaemia is a devastating event that is associated with great morbidity and prolonged and intensive medical treatment [1]. Transient global cerebral ischaemia can occur during asphyxiation, shock, brain injury, during extracorporeal circulation, and cardiac arrest. In certain clinical situations transient global cerebral ischaemia can either be anticipated or is even induced iatrogenically. The latter is the case during surgical repair of the thoracic aorta, complex congenital heart lesions and also during implantable cardiac defibrillator (ICD) testing in patients with drug resistant ventricular fibrillation. Furthermore, intraoperative hypothermia during cardiac or thoracic surgery with its proven neuroprotective effect is employed less frequently nowadays and is thus less often instituted during intraoperative emergencies so that pharmacologic neuroprotection remains the only alternative.

In the course of cardiac arrest, global cerebral blood flow is severely impaired with the consequent risk of ischaemic damage of brain cells. After reinstitution of the cerebral circulation, much greater damage may ensue. We could recently demonstrate that even brief recurrent cerebral hypoperfusions during implantation of ICD devices lead to NSE and S100 release post-operatively [2]. The magnitude of the rise of NSE, a serum markers of cerebral injury, was associated with the cumulative time in cardiac arrest.

Brain injury due to transient global cerebral ischaemia potentially could be mitigated by pharmacological means. A great number of neuroprotective pharmacological agents only prove effective when applied before the ischaemic insult and are less effective or not effective at all when given later in time, i.e. during ischaemia or reperfusion [3], [4]. Thus, we conducted a Medline search to find pharmacological agents that proved to be neuroprotective and can be administered before common clinical situations that result in cardiac arrest without the necessity to establish complex non-pharmacological measures.

As global and focal cerebral ischaemia have a substantially different pathophysiology, findings determined in hemispheric cerebral ischaemia cannot necessarily be applied to situations with global cerebral ischaemia [5]. This is underlined by the observation that ketamine was neuroprotective in focal ischaemia but not in global ischaemia in rats [6], [7]. Therefore, we restricted our literature search to studies investigating pharmacological measures applied prior to transient global cerebral ischaemia.

Section snippets

Methods and results

A Medline search was performed in June 2004 with the following combination of key words: “cerebral protection and global cerebral ischaemia”, “brain protection and global cerebral ischaemia”, “neuronal protection and global cerebral ischaemia”, “neuroprotection and global cerebral ischaemia”, “brain protection and cardiac arrest”, “neuronal protection and cardiac arrest”, “cerebral protection and cardiac arrest”, “neuroprotection and cardiac arrest” as well as “cerebral protection and

Discussion and conclusion

Unfortunately, despite its clinical relevance, only a limited number of studies investigated pharmacological neuroprotection when given as a pre-treatment before transient global cerebral ischaemia without the additional aid of non-pharmacological measures. Using a broad combination of terms listed in Section 2 we only came across 45 articles that dealt with this topic. As with all reviews that use specific terms to search the literature there is always a certain selection bias that prevents

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    A Spanish and Portuguese translated version of the Abstract and Keywords of this article appears at 10.1016/j.resuscitation.2004.11.004.

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