The use of anti-arrhythmic agents incardiopulmonary resuscitation

Colin Robertson MBChB, MRCP(UK), FRCPEd, FRCSEd, FFAEM, FSAScot

Consultant

Ian R. Summers MBBS(Hons), DRACOG

Registrar

Department of Accident and Emergency Medicine and Surgery, Royal In®rmary, Lauriston Place, Edinburgh,EH3 9YW Scotland

Cardiac arrest is a major cause of unexpected sudden death in adults. In the majority of casesan arrhythmia is the primary cause. A multitude of agents have been used in the treatment ofventricular ®brillation and asystole during cardiac arrest. At present there is no evidence toindicate that any of these agents ultimately improve the ®nal outcome in humans. Prevention,competent basic life support and rapid de®brillation for patients in ventricular ®brillationremain the mainstays of treatment for cardiac arrest.

Key words: cardiac arrest; cardiopulmonary resuscitation; ventricular ®brillation; asystole;anti-arrhythmic drugs; lidocaine; bretylium; procainamide; amiodarone; magnesium; epine-phrine; atropine; aminophylline.

INTRODUCTION

Sudden cardiac death continues to be the major cause of unanticipated death forpatients out of hospital. Despite ®ve decades of research into this area and numerousattempts at improving the systems of delivering resuscitation treatments, resuscitationrates worldwide remain depressingly low. The great majority of sudden cardiac deathsoccur in the community and, given the extremely low rates of success, the primaryemphasis must always be on prevention. Modi®cation of the major risk factors thatpotentially can be changed, in particular smoking, hypertension, blood lipid abnorm-alities, diabetes mellitus and obesity, together with life-style changes relating toexercise and stress, are, and will continue to be, by far the most cost-e�ectiveapproaches to the problem of sudden cardiac death.

It is often forgotten that, once cardiac arrest has actually taken place, there are onlytwo interventions that have been shown to improve survival unequivocally. The ®rst ofthese is basic life support, the second, de®brillation. This is not to say that othertreatment modalities, for example aspects relating to ventilation, di�ering techniques

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of producing antegrade blood ¯ow in the arrested circulation, drugs to modify orreduce the myocardial and cerebral injury associated with cardiac arrest etc, do notshow promise. But, at the present time, the e�cacy of all of these interventions inde®nitively improving outcome is still open to conjecture.

Pharmacological treatments for cardiac arrest have been advocated ever since theclinical condition was ®rst recognized. Many agents have ben used, but unfortunatelymany of the preceding comments apply to their use in this situation. This chapter aimsto present an overview of the anti-arrhythmic drugs that have been used previously incardiopulmonary resuscitation (CPR), together with the newer agents for whichevidence is still being accrued.

ANTI-ARRHYTHMIC AGENTS AND VENTRICULAR FIBRILLATION

The overwhelming majority of patients who survive cardiac arrest have ventricular®brillation/pulseless ventricular tachycardia as their primary rhythm.1 For theseindividuals, the major determinant of success is the speed with which electricalde®brillation can be achieved following collapse. Eventual survivors usually requirethree or fewer direct current (DC) shocks to achieve a spontaneously generatedrhythm with output.1,2 Anti-arrhythmic agents have been advocated in shock-refractory situations. This is normally de®ned as persistent ventricular ®brillationdespite the application of three or more DC shocks.

At ®rst glance, this pragmatic approach sounds both reasonable and logical.Ventricular ®brillation is an arrhythmia and in experimental situations and clinicaltrials a multitude of pharmacological agents have been demonstrated to be of bene®tin the treatment, or prevention, of a variety of atrial and (perfusing) ventriculararrhythmias. Unfortunately, this extrapolation of clinical e�cacy from the situation ofa beating (albeit arrhythmic) heart to one which is in cardiac arrest with ventricular®brillation, has not proved simple or accurate.

The chemical nature of anti-arrhythmic drugs and the mechanism by which theiractions are manifested at the cellular level, underpins their electrophysiologicalproperties. The Vaughan Williams classi®cation is of value in categorizing their actions(see Table 1).

Class I drugs reduce the rate of depolarization of the action potential by blockingsodium channels and can be subdivided (Ia, Ib etc) on the basis of the magnitude of thisblockade and the subsequent changes in ventricular repolarisation. The Class III drugs

Table 1. Anti-arrhythmic drugs used for ventricular®brillation by their Vaughan Williams classi®cation.

Class

I III

Electrophysiological actionsNa� channel blockade K� channel blockade

AgentsProcainamide (Ia) BretyliumLidocaine (Ib) Amiodarone

568 C. Robertson and I. R. Summers

block potassium channels and act to prolong the duration of the action potential. Forthe past 30 years, two drugs, lidocaine and bretylium have dominated anti-arrhythmictherapy for refractory ventricular ®brillation.

Lidocaine

The story of lidocaine illustrates the di�culties of extrapolating from the experimentalto the clinical situation, and the problem of deciding upon which end-points thedecisions of e�cacy and use should be made.

Twenty-®ve years ago, lidocaine was shown to produce a highly signi®cant reductionin the incidence of ventricular ®brillation when given prophylactically to patients inthe early phases of acute myocardial infarction.3 Unfortunately, subsequent meta-analyses showed that while lidocaine did indeed reduce the frequency of ventricular®brillation in this group of patients, there was no bene®t in terms of overall survival.4,5

Similar results were obtained when other Class I anti-arrhythmic drugs were givenprophylactically.6,7

Nevertheless, the electrophysiological e�ects of lidocaine (particularly in ischaemicenvironments) were such as to merit consideration that it could facilitate de®brillationby reducing the chance of subsequent re-entrant arrhythmias.8 Concerns that, inanimals, lidocaine could increase the ventricular de®brillation threshold (the amountof energy required to successfully achieve de®brillation)9±11 may have been a�ected bythe experimental technique used, and in humans evidence of an adverse e�ect on thede®brillation threshold is lacking.12

Accordingly, lidocaine has featured in the guidelines of the European ResuscitationCouncil and the American Heart Association in the treatment of refractory ventricular®brillation for the past two decades. But evidence of its clinical e�cacy is absent. Anearly retrospective study by Harrison13 failed to show an improved likelihood ofde®brillation success, although no adverse outcomes were noted. A later randomizedcomparison of patients with out-of-hospital ventricular ®brillation who failed torespond to the ®rst shock and were then assigned to receive epinephrine or lidocaineshowed that the group of patients receiving lidocaine had a threefold greater chance(25% versus 7%, P5 0.02) of developing post-shock asystole. There was, however, nodi�erence in the rates of return of spontaneous circulation between the two groups,or their eventual outcomes.14 More recently, Stiell et al15 could ®nd no evidence ofbene®t from the use of lidocaine for in-hospital ventricular ®brillation arrests, whileHerlitz et al16 reported that when lidocaine was given to patients with out-of-hospitalsustained ventricular ®brillation, these individuals were more likely to be admitted tohospital alive (38% versus 18%, P5 0.01) but this di�erence did not persist, andhospital discharge rates showed no di�erence.

Overall, therefore, there is little evidence to support the continuing routine use oflidocaine. Perhaps fortunately, it appears to be a relatively `safe' agent. At conventionaldoses in patients who achieve a perfusing rhythm, it has little negative inotropic orchronotropic activity and, provided it is not given by continuous infusion, has arelatively short half-life and plasma levels tend to remain in the therapeutic range evenafter 30 minutes of CPR.17,18

Bretylium tosylate

Bretylium was initially used as an anti-hypertensive agent, and its anti-arrhythmicactions were only described in 1965.19 Although given a Class III categorization, it has

Use of anti-arrhythmic agents in CPR 569

complex electrophysiological actions. These include direct myocardial e�ects, withprolongation of the action potential and refractory period and adrenergic e�ects.Initially, bretylium causes norepinephrine release from adrenergic nerves, but laterproduces inhibition of release and uptake of both epinephrine and norepinephrine.

Experimentally, bretylium increases the threshold for developing ventricular®brillation, with no signi®cant e�ect upon de®brillation threshold20, and in casereports has been described as acting as a `chemical' de®brillator.21 It does, however,have signi®cant adverse e�ects. Post-resuscitation hypotension, which may be severeand require volume/pressor support, is the most serious of these.

Evidence for the clinical e�cacy of bretylium is sparse. Nowak et al22, in anemergency department randomized placebo-controlled trial, showed a bene®t inpatients given bretylium, but this applied to the whole of the treated population withcardiac arrest of all rhythms. When the groups were studied on the basis of rhythm,paradoxically, bretylium seemed to be only of bene®t to those patients who were notin ventricular ®brillation.

To date, two randomized trials have been published comparing bretylium withlidocaine in the management of ventricular ®brillation.23,24 Both studies were out-of-hospital studies, but while one showed a trend towards better outcomes in patientsgiven bretylium, in the other the situation was reversed. The results of the Europeanmulticentre trial of lidocaine versus bretylium (CALIBRE) are currently awaited.

Procainamide

Procainamide is a typical Class I agent, with useful actions in ventricular arrhythmias.The clinical e�cacy of procainamide in the context of ventricular ®brillation has beenstudied only indirectly. Stiell et al15 reported its use in 20 patients who formed part ofa larger study group looking at the overall e�ect of drug therapy in cardiac arrest.They found a strong association between the administration of procainamide andsubsequent survival in patients with ventricular ®brillation. This related to bothhospital admission and discharge outcomes, but since this was a non-randomizedobservational study, and involved so few patients, further interpretation or extra-polation of these results is at present unwarranted.

Amiodarone

Although amiodarone is classi®ed as a Class III agent, it has complex electrophysio-logical actions, including e�ects on calcium channel blockade and alpha and betaadrenergic blocking activities, all of which are likely to contribute to its anti-arrhythmic actions.25

Amiodarone has been shown to signi®cantly reduce the incidence of arrhythmicdeath in high risk patients26, and has been shown to be e�ective in treating a widerange of both ventricular and supraventricular arrhythmias. A number of case seriesreports have also suggested e�cacy in the context of ventricular ®brillation.27,28

Two randomized studies have suggested that amiodarone is at least as e�ective asbretylium29 or lidocaine30 and with possibly fewer adverse e�ects such as hypotension.

The ARREST trial studied the use of amiodarone in a large (4500 patients),randomized, placebo-controlled, double-blind, out-of-hospital study. Patients wereincluded if they had ventricular ®brillation/pulseless ventricular tachycardia that wasrefractory to the ®rst three DC shocks.31 The group that received amiodarone weresigni®cantly more likely to be admitted alive to hospital (44% versus 34%, P � 0.03),

570 C. Robertson and I. R. Summers

but the proportion of patients who survived to be discharged alive from hospital didnot di�er signi®cantly (13.4% versus 13.2%) and the trial did not have su�cientstatistical power to detect any such di�erence.

This study is an important contribution to the study of anti-arrhythmic therapy inventricular ®brillation, but does have a number of aspects that should prevent over-enthusiastic extrapolation. It must be remembered that the out-of-hospital Seattle/King County emergency system is highly sophisticated and regularly produces survivalresults that are unmatched either in the USA or elsewhere. The study groups werewell matched, but a mean of 5(+2) (median 4) shocks had been administered beforethe study drug or placebo was given. Subsequently, 4(+3) (median 3) shocks wereadministered before return of spontaneous circulation was achieved. For 44% of theamiodarone treated group then to survive to be admitted to hospital is extraordinary,while the comparative ®gure of 34% for the placebo group is itself exceptionallyhigh.1,2,32 Finally, the chosen end-point of hospital admission has inherent limitations. Itmay be relevant that hypotension and bradycardia were more frequently observed inthe amiodarone treated group, and may have contributed to in-hospital mortality.Clearly the return of spontaneous circulation and survival to hospital admission areprerequisites for eventual success, but as the experience with lidocaine has demon-strated, unless a treatment can be shown to improve the ultimate end-point of hospitaldischarge with survivors who are neurologically intact, then its bene®t must beconsidered to be guarded.

Magnesium

There are several theoretical reasons to suggest why magnesium could have a role inthe treatment of cardiac arrest in general, and ventricular ®brillation in particular.After potassium, magnesium is the most common intracellular cation, and has a crucialrole in maintaining the function of membrane associated ionic channels and intra-cellular calcium homeostasis. Acting as a sarcolemmal calcium channel blocker and byactivating an enzyme that is involved in the active extrusion of calcium ions frommyocardial cells, magnesium may prevent the intracellular calcium overload thatoccurs in ischaemic conditions.

Magnesium de®ciency is certainly linked with adverse outcomes in conditionsassociated with acute cardiovascular disease33, and several medications, in particulardiuretics, produce magnesium depletion.34 It should, however, be noted that plasmalevels do not correlate closely with intracellular values.35 Furthermore, althoughpreliminary reports have suggested that magnesium administration improvedmortality and reduced the incidence of arrhythmias in acute myocardial infarction,the results of the very large ISIS-4 trial failed to con®rm this.36

Two case reports, both with dramatic outcomes, suggested that magnesium couldhave a role in refractory ventricular ®brillation37,38 and intravenous magnesiumsulphate had been noted to produce `chemical de®brillation' in patients being re-warmed following cardiac surgery.39 Interestingly, a characteristic ECG pattern wasdocumented in this study with magnesium producing a conversion from ®ne to coarseventricular ®brillation prior to the return to a normal perfusing rhythm.

An initial pilot study failed to show any improvement in overall neurologicalrecovery or survival to hospital discharge, although non-statistically signi®cant trendstowards an improvement in post-arrest neurological status and a return ofspontaneous circulation occurred in the patients who were given magnesium.40 The`magic' trial, a prospective, randomized, double-blind, placebo-controlled trial in an

Use of anti-arrhythmic agents in CPR 571

emergency department environment, failed to show any bene®t from the use of highdose (5 g) magnesium as a ®rst line drug therapy.41 A second study with a lower initialdose (2 g) followed by 8 g over the subsequent 24 hours, which recruited in-hospitalintensive care unit (ICU) and general ward patients, likewise found no evidence tosupport claims of e�cacy irrespective of the end-point (return of spontaneouscirculation, survival to 24 hours, or hospital discharge) chosen.42

ASYSTOLE

If the pharmacological response and outcomes of cardiac arrest with ventricular®brillation as the primary rhythm are disappointing, then those for asystolic arrest aresimply bleak. To a certain extent, this re¯ects the meaning in clinical terms of asystole.As a primary rhythm in adults, the reported incidence of asystole in cardiac arrest isapproximately 25±50%, but with increasing time from collapse to the institution ofelectrocardiographic monitoring, this incidence increases rapidly and, irrespectiveof the primary rhythm, asystole is the ®nal electrocardiographic manifestation ofdeath.43,44 Survival rates are consistently reported as less than 4%.44±46

The well-recognized role of the parasympathetic nervous system in the innervationof the sino-atrial and atrioventricular nodes led to the hypothesis that asystolic arrestsmay be related primarily to, or as a secondary consequence of, excessive or unantag-onized increases in parasympathetic tone. Certainly, vagal stimulation with or withoutassociated myocardial ischaemia, or hypoxia, can induce profound bradyarrhthymiasand even cardiac standstill.47

Atropine blocks the depressant e�ect of acetylcholine on both sinu-atrial andatrioventricular nodes and Chamberlain et al48 demonstrated that, in ®t young adults,a dose of 3 mg atropine was su�cient to completely block para-sympathetic activity.The use of atropine in the treatment of asystole thus appeared reasonable.

Isolated case reports, occasionally with dramatic responses, have been pub-lished.44,47,49 These initial case reports were followed by observational studies. In aprospective prehospital study, Coon et al50 could not show any bene®t from the use ofatropine in asystole refractory to epinephrine and bu�er agents, although thesepatients had, by de®nition, a very poor prognosis. Stueven et al52 retrospectivelyreported on a series of 84 prehospital patients with asystole who had also failed torespond to epinephrine and bicarbonate. Forty-three were given atropine and six(14%) had return of spontaneous circulation. Of the patients who did not receiveatropine, none had return of spontaneous circulation. Nevertheless, no patient ineither group survived to hospital discharge. Therefore, the e�cacy of the routine useof atropine in brady-asystolic arrest is unproven, and at best it does not appear to beharmful.52

Epinephrine has been used in the treatment of asystole since early last century.53

Epinephrine in standard dose (1 mg every 3±5 minutes) is well-established in relationto improvements of blood ¯ow delivered to organs such as the brain and the heartduring conventional CPR. There is, however, no evidence to indicate that epinephrine,or indeed, any other adrenergic agent, possesses speci®c actions to restore a perfusingrhythm in patients with asystole, and there is no evidence of bene®t in this situation.54

In conditions of myocardial ischaemia, endogenously released adenosine may havesigni®cantly depressant e�ects on both electrical conduction within the heart andinotropic activity.55 Aminophylline acts as a competitive adenosine antagonist, and anintriguing initial report by Visken et al56 reported that in 15 patients with refractory

572 C. Robertson and I. R. Summers

asystole, a perfusing rhythm developed in 11 patients within 30 seconds of intravenousaminophylline administration. Nevertheless, only one patient survived to hospitaldischarge.

Prompted by this, a pilot study of 22 patients by Mader and Gibson57 comparedstandard drug therapy for asystole with the addition of aminophylline in a prospective,randomized, double-blind, placebo-controlled trial (Bart-1). Encouragingly, half of thepatients in the treatment group had return of organized cardiac electrical activity.Unfortunately, when extended to a trial of 82 patients the authors could not showsigni®cant improvement in terms of return of spontaneous circulation, survival tohospital admission or discharge.58

SUMMARY

There are many theoretical reasons why pharmacotherapy for patients with cardiacarrest should be of bene®t. It is, however, apparent that the extrapolation of resultsfrom cellular electrophysiological investigations, animal studies or human clinicalstudies where spontaneous cardiac activity is present, is of extremely limited value.Furthermore, the situation is clouded by the choice of end-point used. It is not enoughmerely to demonstrate improvements in short-term goals such as return ofspontaneous circulation or hospital admission, although these are useful as a startingpoint. To date, in humans, no single anti-arrhythmic agent has been proven to improvehospital discharge rates for resuscitation of cardiac arrest. The importance of theaspects of prevention, competent basic life support and rapid de®brillation for patientsin ventricular ®brillation cannot be overemphasized.

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Practice points

. prevention of cardiac arrest is preferable to treating the situation

. of all possible interventions, only two, basis life support and de®brillation, havebeen demonstrated to improve outcome

. anti-arrhythmic agents may have pro-arrhythmic actions

. no single drug has been shown to be superior in the treatment of ventricular®brillation

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