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. 2010 Dec 21;2010:0216.

Ventricular tachyarrhythmias (out-of-hospital cardiac arrests)

Eddy S Lang 1,#, Kim Browning 2,#
PMCID: PMC3217818  PMID: 21418694

Abstract

Introduction

Pulseless ventricular tachycardia and ventricular fibrillation are the main causes of sudden cardiac death, but other ventricular tachyarrhythmias can occur without haemodynamic compromise. Ventricular arrhythmias occur mainly as a result of myocardial ischaemia or cardiomyopathies, so risk factors are those of cardiovascular disease.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of electrical therapies for out-of-hospital cardiac arrest associated with ventricular tachycardia or ventricular fibrillation? What are the effects of antiarrhythmic drug treatments for use in out-of-hospital cardiac arrest associated with shock-resistant ventricular tachycardia or ventricular fibrillation? What are the effects of treatments for comatose survivors of out-of-hospital cardiac arrest associated with ventricular tachycardia or ventricular fibrillation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 15 systematic reviews and RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: amiodarone, bretylium, defibrillation, lidocaine, procainamide, and therapeutic hypothermia.

Key Points

Pulseless ventricular tachycardia and ventricular fibrillation are the main causes of sudden cardiac death, but other ventricular tachyarrhythmias can occur without haemodynamic compromise.

  • Ventricular arrhythmias occur mainly as a result of myocardial ischaemia or cardiomyopathies, so risk factors are those of CVD.

Cardiac arrest associated with ventricular tachyarrhythmias is managed with cardiopulmonary resuscitation and electrical defibrillation, where available.

  • Adrenaline is given once intravenous access is obtained or endotracheal intubation has been performed.

  • Delivering electrical shocks to the heart (defibrillation) in an effort to terminate the fatal arrhythmias of ventricular tachycardia, and ventricular fibrillation in an effort to restore sinus, together form a mainstay of treatment in cardiac arrest. Biphasic shock is more effective than monophasic shock in restoring people to organised rhythm and spontaneous circulation but it is unclear how different waveforms compare for reducing mortality and increasing neurological recovery.

Amiodarone may increase the likelihood of arriving alive at hospital in people with ventricular tachyarrhythmia that has developed outside hospital, compared with placebo or with lidocaine, but has not been shown to increase longer-term survival.

  • Amiodarone is associated with hypotension and bradycardia.

We don't know whether lidocaine or procainamide improve survival in people with ventricular tachyarrhythmias in out-of-hospital settings, as we found few studies.

  • Procainamide is given by slow infusion, which may limit its usefulness to people with recurrent ventricular tachyarrhythmias.

We don't know whether bretylium improves survival compared with placebo or lidocaine, and it may cause hypotension and bradycardia. It is no longer recommended for use in ventricular fibrillation or pulseless ventricular tachycardia.

Controlled induction of moderate hypothermia after cardiac arrest has been shown to improve both survival and neurological outcomes in a population that typically carries a very poor prognosis.

About this condition

Definition

Ventricular tachyarrhythmias are defined as abnormal patterns of electrical activity originating within ventricular tissue. The most commonly encountered ventricular tachyarrhythmias of greatest clinical importance to clinicians, and those that will be the focus of this review, are ventricular tachycardia and ventricular fibrillation. Ventricular tachycardia is further classified as monomorphic when occurring at a consistent rate and amplitude, and polymorphic when waveforms are more variable and chaotic. Torsades de pointes is a specific kind of polymorphic ventricular tachycardia associated with a prolonged QT interval and a characteristic twisting pattern to the wave signal. It is often associated with drug toxicity and electrolyte disturbances, and is commonly treated with intravenous magnesium. Torsades de pointes will not be specifically covered in this review. Pulseless ventricular tachycardia results in similar clinical manifestations, but is diagnosed by a QRS width complex of greater than 120 milliseconds and electrical rhythm of 150 to 200 beats a minute. Waveforms in ventricular fibrillation are characterised by an irregular rate, usually exceeding 300 beats a minute as well as amplitudes generally exceeding 0.2 mV. Ventricular fibrillation usually fades to asystole (flat line) within 15 minutes. Ventricular fibrillation and ventricular tachycardia associated with cardiac arrest and sudden cardiac death (SCD) are abrupt pulseless arrhythmias. Non-pulseless (stable) ventricular tachycardia has the same electrical characteristics as ventricular tachycardia, but without haemodynamic compromise. The treatment of stable ventricular tachycardia is not covered in this review. Ventricular fibrillation is characterised by irregular and chaotic electrical activity and ventricular contraction in which the heart immediately loses its ability to function as a pump. Pulseless ventricular tachycardia and ventricular fibrillation are the primary causes of SCD. Population: In this review we focus on drug treatments and defibrillation, given generally by paramedics, for ventricular tachycardia and ventricular fibrillation associated with cardiac arrest in an out-of-hospital setting.

Incidence/ Prevalence

The annual incidence of SCD is believed to approach 2/1000 population, but can vary depending on the prevalence of CVD in the population. It is estimated that 400,000 to 450,000 SCDs are recorded annually in the US, representing 60% of all cardiovascular mortality in that country. Data from Holter monitor studies suggest that about 85% of SCDs are the result of ventricular tachycardia/ventricular fibrillation.

Aetiology/ Risk factors

Ventricular arrhythmias occur as a result of structural heart disease arising primarily from myocardial ischaemia or cardiomyopathies. In resource-rich countries, ventricular tachycardia- or ventricular fibrillation-associated cardiac arrest is believed to occur most typically in the context of myocardial ischaemia. As a result, major risk factors for SCD reflect those that lead to progressive coronary artery disease. Specific additional risk factors attributed to SCD include dilated cardiomyopathy (especially with ejection fractions of <30%), age (peak incidence 45–75 years), and male sex.

Prognosis

Ventricular fibrillation and ventricular tachycardia associated with cardiac arrest result in lack of oxygen delivery and major ischaemic injury to vital organs. If untreated this condition is uniformly fatal within minutes.

Aims of intervention

In conjunction with defibrillation, to restore sinus rhythm or a sufficiently organised electrical rhythm that will support the systemic circulation with minimal adverse effects.

Outcomes

Survival/mortality including survival to hospital discharge, survival to hospital admission; functional neurological recovery; return of spontaneous circulation (ROSC); defibrillation efficacy (number of shocks to defibrillation); quality of life; adverse effects of treatment

Methods

Clinical Evidence search and appraisal February 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2010, Embase 1980 to February 2010, and The Cochrane Database of Systematic Reviews 2010, Issue 1 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. For the RCTs in questions 1 and 2 (defibrillation and drug treatment options), at least clinicians and outcome assessors had to be blinded. For questions 1 and 2 we excluded all studies described as "open", "open label", or not blinded. For the therapeutic hypothermia option in question 3, open and blinded studies were acceptable. RCTs had to contain 20 or more individuals, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Glossary

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Eddy S Lang, McGill University, Quebec, Canada.

Kim Browning, University of Calgary, Calgary, Canada.

References

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BMJ Clin Evid. 2010 Dec 21;2010:0216.

Defibrillation

Summary

DEFIBRILLATION EFFICACY Biphasic shock compared with monophasic shock: Biphasic shock is more effective at returning people to organised rhythm after an out-of-hospital ventricular cardiac arrest ( high-quality evidence ). RETURN TO SPONTANEOUS CIRCULATION Biphasic shock compared with monophasic shock: Biphasic shock may be more effective in returning people to spontaneous circulation after an out-of-hospital ventricular cardiac arrest ( low-quality evidence ). SURVIVAL TO HOSPITAL ADMISSION/DISCHARGE Biphasic shock compared with monophasic shock: We don't know if biphasic shock is more effective at increasing the proportion of people who survive to hospital admission or discharge after an out-of-hospital ventricular cardiac arrest ( moderate-quality evidence ). FUNCTIONAL NEUROLOGICAL RECOVERY Biphasic shock compared with monophasic shock: We don't know if biphasic shock is more effective in improving neurological recovery in people after an out-of-hospital ventricular cardiac arrest (low-quality evidence).

Benefits

Biphasic versus monophasic defibrillation:

We found 5 high-quality RCTs comparing biphasic versus monophasic shock.

The first RCT (115 people with ventricular fibrillation) compared biphasic shocks (150-J) versus monophasic shocks (200–360-J) using an automated external defibrillator (AED). The primary outcome for this RCT was success of defibrillation within the first 3 shocks. The RCT found that biphasic shock significantly increased the proportion of people successfully defibrillated within the first 3 shocks compared with monophasic shock (53/54 [98%] with biphasic v 42/61 [69%] with monophasic; P <0.0001). The RCT also found that biphasic shock significantly increased the proportion of people successfully defibrillated with the initial shock compared with monophasic shock (96% with biphasic v 59% with monophasic; P <0.0001; RR, CI, and absolute numbers not reported). The RCT found that biphasic shock significantly increased the proportion of people who achieved return of spontaneous circulation (ROSC; 76% with biphasic shock v 54% with monophasic shock; P = 0.01; absolute numbers not reported). The RCT also found that biphasic shock significantly improved cerebral status at discharge from hospital compared with monophasic shock (87% with biphasic v 53% with monophasic; P = 0.04; absolute numbers not reported). The RCT found no significant difference between groups in rates of survival to hospital admission or to hospital discharge (reported as not significant, no further data reported). However, the RCT was statistically powered to show differences in defibrillation efficacy, not in survival.

A subsequent analysis compared biphasic truncal exponential (BTE) versus either monophasic truncated exponential (MTE) or monophasic damped sine (MDS) AEDs. The RCT found that BTE significantly increased the proportion of people who achieved ROSC compared with MTE (41/54 [76%] with BTE v 26/48 [54%] with MTE; P = 0.024; CI not reported). It found no significant difference for ROSC with BTE compared with MDS (41/54 [76%] with BTE v 7/13 [54%] with MDS; P = 0.17; CI not reported).

The second RCT (120 people with ventricular fibrillation) compared biphasic shock (low-energy BTE) versus monophasic shock (MDS). The primary outcome for the RCT was success of first shock defibrillation with return of organised rhythm at 1 minute. The RCT found that biphasic shock significantly increased the proportion of people with organised rhythm at 1 minute compared with monophasic shock (35/51 [69%] with biphasic v 31/69 [45%] with monophasic; RR 1.53, 95% CI 1.11 to 2.10; P = 0.01). The RCT found no significant difference between biphasic shock and monophasic shock in termination of ventricular fibrillation 5 seconds after first shock, admission to hospital, or discharge from hospital (termination of ventricular fibrillation 5 seconds after first shock: 50/51 [98%] with biphasic v 63/69 [91%] with monophasic; RR 1.07, 95% CI 0.99 to 1.14; P = 0.12; admission to hospital: 20/51 [40%] with biphasic v 33/69 [48%] with monophasic; RR 0.82, 95% CI 0.54 to 1.25; P = 0.35; discharge from hospital: 7/51 [14%] with biphasic v 13/69 [19%] with monophasic; RR 0.73, 95% CI 0.31 to 1.70; P = 0.46). However, this RCT was not powered to detect clinically important differences in these outcomes.

The third RCT (167 people with ventricular fibrillation) compared biphasic shock (120-J rectilinear biphasic waveform [RLB]) versus monophasic shock (200-J MDS). The primary outcome for this RCT was shock success, defined as conversion to an organised rhythm at 5 seconds after one to 3 shocks. Secondary outcomes were: conversion to an organised rhythm with first, second, or third shocks; 24-hour survival; survival to hospital discharge; cerebral performance at discharge; and 30-day survival. The RCT found that biphasic shock significantly improved the rate of conversion to organised rhythm at 5 seconds compared with monophasic shock (45/87 [52%] with biphasic v 28/83 [34%] with monophasic; P = 0.01). The RCT found no significant difference between biphasic and monophasic shock in conversion to organised rhythm after first or second shock, but found that biphasic shock significantly increased conversion after third shock compared with monophasic shock (conversion to organised rhythm after first shock: 48/161 [30%] with biphasic v 35/146 [24%] with monophasic; P = 0.25; after second shock: 24/116 [21%] with biphasic v 24/116 [21%] with monophasic; reported as not significant; after third shock: 18/92 [20%] with biphasic v 8/91 [9%] with monophasic; P = 0.06). The RCT found no significant difference between biphasic and monophasic shock in 24-hour survival, survival to hospital discharge, cerebral performance at discharge, and 30-day survival (24-hour survival: 31/163 [19%] with biphasic v 26/147 [18%] with monophasic; reported as not significant; survival to hospital discharge: 8/163 [5%] with biphasic v 6/147 [4%] with monophasic; reported as not significant; cerebral performance at discharge: 57% with biphasic v 50% with monophasic; reported as not significant; absolute numbers not reported; 30-day survival: 7/162 [4%] with biphasic v 6/147 [4%] with monophasic; reported as not significant).

The fourth RCT (168 people with non-traumatic out-of-hospital ventricular fibrillation cardiac arrest) compared biphasic shock (BTE) versus monophasic shock (MDS). The primary outcome for this RCT was survival to hospital admission. The secondary outcomes included survival to hospital discharge and neurological outcome. The RCT found no significant difference in survival to hospital admission between biphasic shock compared with monophasic shock (52/68 [68%] with biphasic v 58/80 [73%] with monophasic; P = 0.58). The RCT found no significant difference between biphasic and monophasic shock in survival to hospital discharge or neurological outcomes at hospital discharge (survival to discharge: 28/68 [41%] with biphasic v 27/80 [34%] with monophasic; P = 0.35; neurological outcomes at discharge: P = 0.4, no further data reported).

The fifth RCT (120 people with out-of-hospital ventricular fibrillation) compared biphasic shock (BTE) versus monophasic shock (MDS). The primary outcome for this RCT was the return to organised rhythm defined as two QRS complexes: <5 seconds apart, and <60 seconds after defibrillation. The RCT found that biphasic shock significantly increased the proportion of people returned to organised rhythm compared with monophasic shock (35/51 [69%] with biphasic v 31/69 [45%] with monophasic; RR 1.53, 95% CI 1.11 to 2.10).

Harms

The RCTs gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Dec 21;2010:0216.

Amiodarone

Summary

SURVIVAL TO HOSPITAL ADMISSION/DISCHARGE Compared with placebo: Amiodarone is more effective at increasing the proportion of people (with cardiac arrest and shock-resistant ventricular fibrillation or pulseless ventricular fibrillation developing at some point during resuscitation) who survive to hospital admission, but not hospital discharge ( moderate-quality evidence ). Compared with lidocaine: Amiodarone is more effective at increasing the proportion of people (with cardiac arrest and shock-resistant ventricular fibrillation or pulseless ventricular fibrillation developing at some point during resuscitation) who survive to hospital admission, but not to hospital discharge ( high-quality evidence ). QUALITY OF LIFE Compared with placebo: Amiodarone may be no more effective at increasing the proportion of people who survive to discharge from hospital who return to independent living or work ( low-quality evidence ). NOTE Amiodarone has been associated with hypotension and bradycardia.

Benefits

We found no systematic review.

Amiodarone versus placebo:

One RCT (504 people with cardiac arrest and shock-resistant ventricular fibrillation or pulseless ventricular fibrillation developing at some point during resuscitation) found that a significantly greater proportion of people survived to admission to hospital when given amiodarone compared with placebo (108/246 [44%] with amiodarone v 89/258 [34%] with placebo; P = 0.03) (see table 1 ). However, it found no significant difference in survival to hospital discharge between amiodarone and placebo (33/246 [13.4%] with amiodarone v 34/258 [13.2%] with placebo; reported as not significant). The RCT also found similar results between amiodarone and placebo in the proportion of the people who survived to discharge from hospital who returned to independent living or work (18/33 [55%] with amiodarone v 17/34 [50%] with placebo; significance not reported).

Table 1.

Resuscitation protocols as reported in the included RCTs*

Intervention Initial treatment* Further treatment* Inclusion/exclusion criteria Survival to hospital discharge
Amiodarone or placebo Basic life support including shocks by automated external defibrillator; then: advanced life-support measures including adrenaline 1 mg after tracheal intubation Amiodarone 300 mg or placebo while CPR continued. Single dose only Included: 504 adults with non-traumatic out-of-hospital cardiac arrest, with VF or VT (at any time in the resuscitation attempt) after at least 3 pre-cordial shocks, iv access, and paramedics present with drug/placebo 33/246 (13.4%) with amiodarone v 34/258 (13.2%) with placebo; P = NS
         
Amiodarone or lidocaine 3 shocks, 1 dose of iv adrenaline, fourth shock (further details not reported) Amiodarone 5 mg/kg or lidocaine 1.5 mg/kg plus further shocks and ACLS. If VF persisted, same drug given (amiodarone 2.5 mg/kg; lidocaine 1.5 mg/kg) and attempts at resuscitation (American Heart Association guidelines for ACLS) Included: 347 adults with out-of-hospital VF tested electrocardiographically. VF resistant to initial treatment (see left) 9/180 (5%) with amiodarone v 5/167 (3%) with lidocaine; P = 0.34
         
Bretylium or placebo Basic cardiac life support In emergency department: bretylium (5–10 mg/kg) or placebo plus American Heart Association guidelines for ACLS. If person in cardiopulmonary arrest after 20 minutes, a second dose of same drug given Included: 29 people presenting with cardiopulmonary arrest and assessed by study investigator Survival to discharge from emergency department: 7/18 (39%) with bretylium v 1/11 (9%) with placebo; P = 0.13
         
Lidocaine or bretylium CPR, then basic life support, 320-J defibrillatory shock, ET tube, iv catheter 10 mL bolus of bretylium 500 mg or lidocaine 100 mg. If persistent VF after second shock or fibrillation recurrence, second bolus of same drug plus routine resuscitation measures Included: 100 people aged at least 13 years whose rhythm became organised or remained in VF. Excluded: people converting to asystole or profound bradycardia with initial shock 10/44 (23%) with lidocaine v 12/56 (21%) with bretylium; P >0.1
         
Lidocaine or bretylium Countershocks to people in VF twice at 200 Ws, iv line of D5W and ET tube; sodium bicarbonate 1 mEq/kg and adrenaline 0.5–1.0 mg if VF persists Bretylium (10–30 mg/kg total) or lidocaine (2–3 mg/kg total). If failure to convert, other drug given. If further failure to convert procainamide given (100 mg over 5 minutes, up to 1000 mg). Countershock and resuscitation by ACLS protocols given after each intervention Included: 91 adults with "refractory ventricular fibrillation" –  failure to convert from VF with the initial American Heart Association protocol, or return to VF before antiarrhythmics were given. Excluded: drugs given out of sequence; not fulfilling definition of refractory VF 5/48 (10%) with lidocaine v 2/43 (5%) with bretylium; P = NS
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*Treatments in out-of-hospital settings unless otherwise specified. ACLS, advanced cardiac life support; ET, endotracheal; iv, intravenous; NS, not significant; VF, ventricular fibrillation; VT, ventricular tachyarrhythmia.

Amiodarone versus lidocaine:

One RCT (347 people with cardiac arrest and shock-resistant ventricular tachycardia or ventricular fibrillation developing at some point during their resuscitation) found that a significantly larger proportion of people survived to hospital admission with amiodarone compared with lidocaine (41/180 [23%] with amiodarone v 20/167 [12%] with lidocaine; OR 2.17, 95% CI 1.21 to 3.83; P = 0.009) (see table 1 ). However, it found no significant difference in survival to discharge from hospital between amiodarone and lidocaine (9/180 [5%] with amiodarone v 5/167 [3%] with lidocaine; P = 0.34) (see table 1 ). (Both groups also received placebo.)

Amiodarone versus bretylium:

We found no RCTs.

Amiodarone versus procainamide:

We found no RCTs. See comment on procainamide.

Harms

Amiodarone versus placebo:

The RCT found significantly more hypotension and bradycardia in people who took amiodarone compared with placebo, and who had either a transient or a sustained return of spontaneous circulation (hypotension: 91/153 [59%] with amiodarone v 69/145 [48%] with placebo; P = 0.04; bradycardia: 63/153 [41%] with amiodarone v 36/145 [25%] with placebo; P = 0.004).

Amiodarone versus lidocaine:

The RCT reported that people who took amiodarone and people who took lidocaine required pressor drugs (13/180 [7%] with amiodarone v 6/167 [4%] with lidocaine; reported as not significant). The RCT also reported that treatment for bradycardia was required in both groups (43/180 [24%] with amiodarone v 38/167 [23%] with lidocaine; reported as not significant).

Comment

As neither study found an advantage with regard to either hospital discharge or meaningful neurological recovery, it is possible that amiodarone use might simply lead to increased consumption of hospital intensive care unit (ICU) resources without patient benefit. Although methodologically sound, the selection of admission to hospital ICU as the study's primary outcome is problematic. However, important developments in post-resuscitative care (i.e., therapeutic hypothermia) might actually allow the increased ICU admission rate associated with amiodarone to translate into a clinical benefit as it relates to neurological recovery from cardiac arrest (see comment on procainamide).

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Dec 21;2010:0216.

Bretylium

Summary

SURVIVAL TO HOSPITAL ADMISSION/DISCHARGE Compared with placebo: Bretylium is no more effective at increasing survival to discharge from emergency department ( low-quality evidence ). Compared with lidocaine: We don’t know whether bretylium is more effective at increasing the proportion of people (with out-of-hospital ventricular fibrillation, or persistent ventricular fibrillation after initial shock, or in people with refractory ventricular fibrillation) who survive to hospital discharge ( very low-quality evidence ). NOTE We found no clinically important results from RCTs about bretylium compared with amiodarone or procainamide in people with out-of-hospital cardiac arrest. NOTE Bretylium has been associated with hypotension and bradycardia and is now rarely used in clinical practice.

Benefits

We found no systematic review.

Bretylium versus placebo:

One small RCT (59 people presenting to an emergency department, as opposed to the pre-hospital setting, with cardiopulmonary arrest, 29 of whom had ventricular fibrillation) found no significant difference in survival to discharge from emergency department between bretylium compared with placebo (see table 1 ). The RCT did not report on survival to discharge from hospital.

Bretylium versus lidocaine:

See benefits of lidocaine.

Bretylium versus procainamide or amiodarone:

We found no RCTs.

Harms

Bretylium versus placebo:

One RCT found significantly more adverse events in survivors with bretylium compared with placebo (reported adverse events with bretylium: tachycardia 5/8 [63%], hypotension 4/8 [50%], bradycardia 1/8 [13%], hypertension 1/8 [13%] v reported adverse events with placebo: hypotension 1/3 [33%]; P <0.05).

Comment

Although the RCT found no significant difference between bretylium and placebo in survival to discharge from emergency department in people with ventricular fibrillation, there was a significant difference when a population with either ventricular fibrillation or asystole was taken into consideration (8/23 [35%] with bretylium v 1/16 [6%] with placebo; P <0.05).

Clinical guide:

The absence of evidence showing benefit of bretylium use in clinical trials, compounded with adverse effects such as refractory hypotension, and the lack of availability of this compound from 1998–2000, led the American Heart Association to remove bretylium from the Advanced Cardiac Life Support (ACLS) algorithm for ventricular fibrillation/pulseless ventricular tachycardia in 2000.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Dec 21;2010:0216.

Lidocaine

Summary

SURVIVAL TO HOSPITAL ADMISSION/DISCHARGE Compared with bretylium: We don't know whether lidocaine is more effective at increasing the proportion of people (with out-of-hospital ventricular fibrillation, or persistent ventricular fibrillation after initial shock, or in people with refractory ventricular fibrillation) who survive to hospital discharge ( very low-quality evidence ). Compared with amiodarone: Lidocaine is less effective at increasing the proportion of people (with cardiac arrest and shock-resistant ventricular fibrillation or pulseless ventricular fibrillation developing at some point during resuscitation) who survive to hospital admission, but not to hospital discharge ( high-quality evidence ). NOTE We found no direct information about whether lidocaine is better than no active treatment in an out-of-hospital setting.

Benefits

We found no systematic review.

Lidocaine versus placebo:

We found no RCTs.

Lidocaine versus bretylium:

We found two small RCTs. The first RCT (100 people with out-of-hospital ventricular fibrillation, with persistent ventricular fibrillation after initial shock) found no significant difference between lidocaine and bretylium given after the first shock in survival to discharge from hospital (10/44 [23%] with lidocaine v 12/56 [21%] with bretylium; P >0.1) (see table 1 ).

The second RCT (91 people with refractory ventricular fibrillation) found no significant difference between lidocaine and bretylium in the proportion of people who survived to hospital discharge (5/48 [10%] with lidocaine v 2/43 [5%] with bretylium; reported as not significant; P value not reported). However, in this RCT, people were given the alternative drug if they did not respond to the first drug (see table 1 ).

Lidocaine versus procainamide:

We found no RCTs.

Lidocaine versus amiodarone:

See benefits of amiodarone.

Harms

Lidocaine versus bretylium:

The first RCT reported that people who took lidocaine and people who took bretylium required pressor drugs (14/43 [33%] with lidocaine v 16/43 [37%] with bretylium; P >0.1). The second RCT did not report on adverse events.

Lidocaine versus amiodarone:

See harms of amiodarone.

Comment

Although methodologically sound, the selection of admission to hospital intensive care unit (ICU) as the study's primary outcome is problematic. With the effect of amiodarone as compared with lidocaine uncertain with regard to functional neurological recovery, it is possible that use of amiodarone can simply increase resource consumption through ICU and nursing home facilities without achieving any meaningful clinical benefit. However, important developments in post-resuscitative care (i.e., therapeutic hypothermia) might actually allow the increased ICU admission rate associated with amiodarone to translate into a clinical benefit as it relates to neurological recovery from cardiac arrest.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Dec 21;2010:0216.

Procainamide

Summary

We found no direct information from RCTs about whether procainamide is better than no active treatment or other antiarrhythmics (lidocaine, bretylium, or amiodarone) in people with out-of-hospital cardiac arrest.

Benefits

We found no systematic review or RCTs comparing procainamide versus placebo or the other antiarrhythmic drugs included in this review (lidocaine, bretylium, amiodarone) for the clinical outcomes of interest. Procainamide is an important option in managing ventricular tachyarrhythmias in contexts other than cardiac arrest.

Harms

We found no RCTs.

Comment

One RCT (CASCADE [Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation]) showed better results for amiodarone by comparison with procainamide for the secondary prevention of cardiac arrest.

Clinical guide:

The time required to infuse procainamide is usually long (slow infusion over several minutes) and this would make it a less favourable choice as a preferred drug in acute or unstable conditions. It might be considered an option for recurrent ventricular tachycardia/ventricular fibrillation.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Dec 21;2010:0216.

Therapeutic hypothermia with or without antiarrhythmics

Summary

SURVIVAL TO HOSPITAL ADMISSION/DISCHARGE Therapeutic hypothermia compared with control/normothermia: Conventional cooling during hospital stay given within 6 hours of hospital arrival may be more effective than control (defined as standard treatment at the time the trials were undertaken, which may include antiarrhythmics) at increasing the proportion of people who survive to hospital discharge, but we don't know whether haemofiltration as a specific method to achieve hypothermia improves survival ( low-quality evidence ). Pre-hospital hypothermia compared with in-hospital hypothermia: We don't know whether pre-hospital cooling is more effective than no pre-hospital cooling plus standard care (which may include in-hospital cooling and antiarrhythmics) at increasing the proportion of people who survive to hospital discharge ( very low-quality evidence ). NEUROLOGICAL RECOVERY Therapeutic hypothermia compared with control/normothermia: Conventional cooling during hospital stay given within 6 hours of hospital arrival may be more effective than control (defined as standard treatment at the time the studies were undertaken, which include antiarrhythmics) at increasing the proportion of people with neurological improvement (defined as achieving cerebral performance categories [CPC] grade 1/2), but we don't know whether haemofiltration improves neurological outcomes (low-quality evidence).

Benefits

We found one systematic review (search date 2007) and two subsequent RCTs assessing the effects of therapeutic hypothermia on comatose survivors of out-of-hospital cardiac arrest.

Therapeutic hypothermia versus control/normothermia:

The review (5 RCTs, 481 adults who suffered from cardiac arrest in or out of hospital and were successfully resuscitated) compared therapeutic hypothermia given within 6 hours of hospital arrival (target temperature 35 °C or below) versus control (defined as standard treatment after cardiac arrest at the time of the trial, which may have included antiarrhythmics). The review noted that only 3 of the 5 trials used conventional cooling methods and were deemed to have been of good quality. Of the remaining two RCTs, one used haemofiltration and the other used an unknown method of cooling. The primary outcome of the review was neurological recovery; this was assessed using the cerebral performance categories (CPC) grade 1 (good) to 5 (death). The review found that conventional cooling during hospital stay significantly increased the proportion of people who achieved CPC grade 1/2 compared with control (3 RCTs; 104/195 [53%] with cooling v 65/188 [34%] with control; RR 1.53, 95% CI 1.22 to 1.96; P = 0.002). The review found no significant difference in the proportion of people who achieved CPC grade 1/2 at 6 months with haemofiltration compared with control (1 RCT; 7/22 [32%] with haemofiltration v 9/20 [45%] with control; RR 0.71, 95% CI 0.32 to 1.54; P = 0.38). The review also reported one RCT with unknown method of cooling. It found that cooling significantly increased the proportion of people who achieved CPC grade 1/3 at 1 month compared with control (1 RCT; 18/36 [50%] with cooling v 2/18 [11%] with control; RR 4.5, 95% CI 1.17 to 17.3; P = 0.02).

The review also found that conventional cooling significantly increased the proportion of people who survived to hospital discharge compared with control (3 RCTs; 110/195 [56%] with cooling v 79/188 [42%] with control; RR 1.35, 95% CI 1.10 to 1.65; P = 0.003). The review found no significant difference in survival at 6 months between cooling with haemofiltration and control (1 RCT; 7/22 [32%] with haemofiltration v 9/20 [45%] with control; RR 0.71, 95% CI 0.32 to 1.54; P = 0.38). The review performed two subgroup analyses to assess the effects of cooling in out-of-hospital arrests and those arrests with initial ventricular fibrillation (VF)/ventricular tachycardia (VT) rhythms with the end point being the best reached CPC during hospital stay. The review found that for those people who had an out-of-hospital arrest, the effect size for cooling was similar to that of the whole study population (365 people; RR 1.56, 95% CI 1.23 to 1.99) and for people that had a VF/VT rhythm the effect size was again similar to that of the whole study population (330 people; RR 1.47, 95% CI 1.15 to 1.88). Only conventional cooling methods were found to improve survival to discharge (individual patient data; 383 people; RR 1.35, 95% CI 1.10 to 1.65).

The first subsequent RCT (70 adults resuscitated from out-of-hospital VF cardiac arrest) compared therapeutic hypothermia (33 °C for 24 hours using external cooling) versus normothermia. The RCT found no significant difference in survival at 3 month follow-up after cardiac arrest with hypothermia compared with normothermia (28/36 [77%] with hypothermia v 22/34 [65%] with normothermia; P = 0.22). Three people, one in the hypothermia group and two in the normothermia group, were unconscious at 3 months, and two people in the normothermia group did not attend the neurological study because of distance, but were living independently. Therefore, 45 people (27 in the hypothermia group and 18 in the normothermia group) were assessed for neuropsychological outcomes. The outcomes were assessed using several tests including Pittsburgh Outcome Scale — this is a 5 category scale of CPC; CPC 1, conscious and alert with normal cerebral function; CPC 2, conscious and alert with moderate cerebral function; CPC 3, conscious with severe cerebral disability; CPC 4, comatose or in persistent vegetative state; CPC 5, dead; and a battery of cognitive function tests. The RCT found that a higher proportion of people achieved a good standard of cerebral performance (CPC 1 or 2) with hypothermia compared with normothermia at 3 months after cardiac arrest (25/27 [93%] with hypothermia v 14/18 [78%] with normothermia; P value not reported). The RCT found no significant difference between hypothermia and normothermia in any of the cognitive functions; however, a lower proportion of people were found to have severe cognitive deficits with hypothermia compared with normothermia (4/27 [15%] with hypothermia v 5/18 [28%] with normothermia; P value not reported).

Neurophysiological testing also included observations of both the quantitative EEG (Q-EEG) and P300 potential for both groups. The Q-EEG amplitude is a marker of brain activity and the P300 amplitue is a marker of cognitive function. They are commonly used to predict neurological outcome after injury, especially after low perfusion states (i.e., cardiac arrest). The RCT found no significant difference in Q-EEG potential between the hypothermic group (26 people) and the normothermic group (16 people), reported as not significant, no further data reported. However, the RCT reported that while there was no significant difference between groups, the Q-EEGs of the hypothermic group included consistently more fast and less slow frequency activity in all the brain regions. While the Q-EEG parameters were better with hypothermia compared with control, they did not reach significance. The RCT found latency to the P300 potential response was not significant between the hypothermic and normothermic groups (374.4 ± 42.5 with hypothermia v 385.6 ± 43.4 with normothermia; P = 0.45). However, the RCT found that the amplitude of the P300 response was found to be significantly higher with hypothermia compared with normothermia (7.91 ± 5.12 with hypothermia v 4.99 ± 2.99 with normothermia; P = 0.02; see comment).

Pre-hospital hypothermia versus in-hospital hypothermia:

The second subsequent RCT (125 people with out-of-hospital cardiac arrest) compared pre-hospital cooling (63 people; after return of spontaneous circulation [ROSC], intravenous infusion of 2 L of saline fluid at 4 °C temperature) versus standard inpatient care (62 people; with or without in-hospital intravenous cooling and antiarrhythmics). The RCT reported that in the 62 people randomised to standard inpatient care alone, no cooling was performed pre-hospital; however, of the 63 people randomised to pre-hospital cooling, in fact 8 people received no fluid, 6 people received <500 mL, 37 people received between 500 mL and 2 L, and 12 people received 2 L. This variation in the pre-hospital cooling protocol occurred because of death pre-hospital arrival, rearrest, and lack of time before hospital arrival. The RCT reported that pre-hospital cooling increased the proportion of people that had VF rhythm arrests who survived to hospital discharge compared with standard inpatient care; however, this difference did not reach significance (proportion who had VF arrests who survived: 19/29 [66%] with cooling v 10/22 [45%] with control; P value not reported; reported as not significant).

Of the 97/125 (78%) people admitted to hospital, 60/97 (62%) were treated at the discretion of the attending physician with hypothermia induced by surface cooling. The RCT hypothesised that the interaction of pre-hospital cooling and in-hospital cooling could impact on survival to hospital discharge. The RCT found no significant difference for survival to hospital discharge between pre-hospital cooling alone and standard inpatient care (OR 1.25, 95% CI 0.55 to 2.82; absolute data not reported). Additionally, when the odds ratio was adjusted for hospital cooling and the interaction term (using a multiple logistic regression model) in those who received pre-hospital cooling alone, the likelihood of survival to discharge remained non-significant (adjusted OR 1.92, 95% CI 0.46 to 8.0; absolute data not reported); for those receiving hospital cooling alone there was also no significant difference in survival to hospital discharge compared with standard care (OR 0.91, 95% CI 0.28 to 2.96, adjusted for pre-hospital cooling and interaction term; absolute data not reported). The RCT found no significant interaction variable between in pre-hospital and hospital cooling. The RCT also reported a non-significant trend in favour of pre-hospital cooling in the proportion of people who awakened (proportion who had VF arrests: 20/29 (69%) with cooling v 10/22 (45%) with standard care; P = 0.15).

Harms

Therapeutic hypothermia versus control:

The review reported no significant difference in adverse effects for therapeutic hypothermia compared with control. The two subsequent RCTs gave no information on adverse effects.

Comment

The results of this RCT are interesting because the P300 is an event-related stimulus elicited by the clinician that measures a person's reaction to a stimulus. In those who have cognitive impairment there is often an increased latency and decreased amplitude. These results suggest that those who received hypothermia treatment had an increased reaction to the P300 stimulus and thus perhaps better neurological prognostic indicators.

Clinical guide:

The body of literature surrounding hypothermia as a cardiac arrest therapy after return of spontaneous circulation supports its use in the clinical setting. Specifically, it has been demonstrated, mainly by two large RCTs, that controlled mild hypothermia aids in improving neurological outcomes and survival to discharge. The two RCTs (the largest to date directed at this topic) included primarily patients with a cardiac cause of cardiac arrest and who had an out-of-hospital arrest with an initial VF/VT rhythm (studies included in the Cochrane review). Because inducing hypothermia in the setting of cardiac arrest is relatively new, there may be hesitance towards applying the therapy in general but especially to sub-populations of cardiac arrest patients (i.e., those who arrested from rhythms other than VF/VT). However, in principle the mechanisms by which hypothermia works to improve neurological outcomes should be relevant and effective in other arrest situations (e.g., asystole, pulseless electrical activity); however, there is not an extensive body of literature to support this claim. Therefore, while keeping in mind that the evidence is strongest for VF/VT rhythm cardiac arrests, it is our view that controlled mild hypothermia (32–34 °C for 12–24 h) should be attempted in any clinical scenario for which a cardiac cause of cardiac arrest is suspected and where its application is feasible and warranted. In fact, the European Resuscitation Council in their recent update to their recommended guidelines state that therapeutic hypothermia should be used in comatose survivors of cardiac arrest resulting from both shockable and non-shockable rhythms (although the lower level of evidence is acknowledged for the latter scenario). Therapeutic hypothermia is now considered the standard of care for these patient populations. For formal therapeutic guidelines, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation has a formal publication statement for reference.

Substantive changes

Therapeutic hypothermia: New option added with one systematic review and two subsequent RCTs assessing the effects of hypothermia compared with no cooling/standard care (which may have included antiarrhythmics). The review found that most therapeutic techniques improved neurological recovery and survival to hospital discharge compared with standard care. The first subsequent RCT found no difference in rates of survival at 3 months between hypothermia and normothermia, but reported that a higher proportion of people achieved good neurological recovery with hypothermia. The second subsequent RCT reported that a high proportion of people survived to hospital discharge with pre-hospital cooling compared with no pre-hospital cooling, but the result did not reach significance. Categorised as likely to be beneficial.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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