Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: A systematic review and network meta-analysis.

BACKGROUND: Despite their wide use in the prehospital setting, randomized control trials (RCTs) have failed to demonstrate that any antiarrhythmic agent improves survival to hospital discharge following out-of-hospital cardiac arrest. OBJECTIVE: To assess the use of antiarrhythmic drugs for patients experiencing out-of-hospital cardiac arrest (OHCA). METHODS: Electronic searches of Medline, EMBASE and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand-searched. Randomized controlled trials (RCTs) investigating the use of antiarrhythmic agents administered during resuscitation for adult (≥18years) patients suffering non-traumatic OHCA were included. Direct and indirect evidence were combined in a network meta-analysis (NMA) using a frequentist approach with fixed-effects models and reported as relative risks (RR) with 95% confidence intervals (CIs). For each pairwise comparison, the certainty of direct, indirect, and network evidence was assessed using the GRADE approach. RESULTS: 8 RCTs involving 4464 patients were combined to compare the effectiveness of 5 antiarrhythmic agents and placebo administered during resuscitation following OHCA. Lidocaine was associated with a statistically significant increase in ROSC compared to placebo (1.15; 95% CI: 1.03-1.28) and was also superior to bretylium (1.61; 95% CI: 1.00-2.60) for ROSC. When compared to placebo, both amiodarone (1.18; 95% CI: 1.08-1.30) and lidocaine (1.18; 95% CI: 1.07-1.30) were associated with a statistically significant increase in survival to hospital admission. However, no antiarrhythmic was statistically more effective than placebo for survival to hospital discharge or neurologically intact survival, and no antiarrhythmic was convincingly superior to any other for any outcome. CONCLUSIONS: Amiodarone and lidocaine were the only agents associated with improved survival to hospital admission in the NMA. For the outcomes most important to patients, survival to hospital discharge and neurologically intact survival, no antiarrhythmic was convincingly superior to any other or to placebo.

Amiodarone supplants lidocaine in ACLS and CPR protocols.

Amiodarone is an antiarrhythmic medication used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias. Amiodarone gained slow acceptance outside the specialized field of cardiac antiarrhythmic surgery because the side-effects are significant. Recent adoption of amiodarone in the ACLS (Advanced Cardiac Life Support) protocol has somewhat popularized this class of antiarrhythmics. Its use is slowly expanding in the acute medicine setting of anesthetics. This article summarizes the use of Amiodarone by anesthesiologists in the operating room and during cardiopulmonary resuscitation.

Survival after prolonged resuscitation with 99 defibrillations due to Torsade De Pointes cardiac electrical storm: a case report.

A 48-year-old previously healthy woman suffered witnessed cardiac arrest in hospital. She achieved return of spontaneous circulation and was transferred to the intensive care unit. During the following 3 hours, she suffered a cardiac electrical storm with 98 episodes of Torsade de Pointes ventricular tachycardia rapidly degenerating to ventricular fibrillation. She was converted with a total of 99 defibrillations. There was no response to the use of any recommended anti arrhythmic drugs. However, the use of bretylium surprisingly stabilized her heart rhythm and facilitated placing of a temporary pacemaker. Overdrive pacing prevented further arrhythmias and was life saving. A number of beneficial factors may have contributed to the good neurological outcome. Further investigations gave no explanation for her cardiac electrical storm.

Arrhythmia and acute coronary syndrome suppression and cardiac resuscitation management with bretylium.

It is well known that electric shock can both initiate and terminate ventricular fibrillation. Refractory ventricular fibrillation (RVF) may often be an iatrogenic paradoxical result of early, frequent, excessive salvos of DC current countershocks and inappropriate off-label drug use, particularly aggressive epinephrine administration. Evidence suggests that the current advanced cardiac life support pharmacology protocol for cardiac resuscitation may contribute to disappointing survival in patients with out-of-hospital cardiac arrest. Controlled studies and new theoretical consideration suggest the protocol may induce RVF. In contrast, studies suggest that immediate adequate intravenous bretylium administration therapy together with sustained effective chest compressions can induce chemical defibrillation or facilitate electrical defibrillation as well as reduce the intensity, or even need for potentially heart-damaging countershock, where early frequent excessive current shocks are likely to increase refractory arrhythmia as demonstrated in animals and in humans. Salvos of shocks do not allow time between shocks for uniform recovery of normal electrical parameters needed to restore a stable heart rhythm. This may occur by inadvertently administering shock during the vulnerable period of the cardiac cycle. There are compelling existing data to demonstrate that bretylium and cardiopulmonary resuscitation (CPR) delivered before initiating shock therapy is likely to provide the best outcome in cardiac arrest. But, most importantly, adequate CPR chest compressions administered while bretylium is being infused also provide the opportunity to wash out electrically destabilizing electrolytes that have leaked from or are abnormally transported by functionally damaged membranes of fibrillation-induced ischemic myocytes. This may cause abnormal compartment redistribution of electrolytes that may facilitate RVF by heterogeneously partially depolarizing ischemic myocytes. Although efforts have been made to provide hard science for advanced life support, the guidelines are a product of consensus, the give and take of collegiality and intuition rather than rigorous controlled studies. Bretylium has a direct antifibrillatory action normalizing myocyte membrane currents, which restores intracompartmental normal electrolyte balance. In addition, adrenergic blockade by bretylium dilates coronary arteries, increasing effective O2 delivery by CPR. The free and aggressive use of epinephrine is toxic. Catechalomines cause coronary spasm and puts myocardial metabolism into damaging hypermetabolic overdrive to support the "fight or flight reflex" rapidly depleting adenosine triphosphate needed for cardiac electrical and mechanical recovery. Moreover, the value of epinephrine to resuscitation has never been demonstrated in a controlled human study, whereas its potential damage has been largely ignored. Epinephrine's potential deleterious actions that might compromise resuscitation are well established and reviewed here.

Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease?

It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD by catecholamine-induced metabolic actions on lipid mobilization by activation of phospholipases. This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like propranolol, reserpine, and guanethidine all inhibit arteriosclerosis induced by hypercholesterolemia in experimental animals and prevent carotid vascular disease (associated with stroke) in humans. The concomitant development of myocardiopathy and coronary vascular lesions or coronary and carotid artery intimal medial thickening by catecholamine toxicity is reflected by the frequent primary presentation of patients with catecholamine-secreting pheochromocytoma with cardiovascular disease, ie, hypertension arrhythmias, AMI, SCD, CHF, and vascular disease, which represents a clear example of the primary deleterious impact of catecholamines on the entire cardiovascular system causing adrenergic cardiovascular disease. Thus, like myocardiopathy, CAD and atherosclerosis in general may be the consequences of or a complication of catecholamine actions rather than its putative cause. This report shows how prophylactic bretylium not only prevents arrhythmias but prevents myocardial necrosis, shock, CHF, maintains or restores normal contractility, and lowers mortality in AMI patients by inducing adrenergic blockade.

Strategies for reversing shock-resistant ventricular fibrillation.

PURPOSE OF REVIEW: Shock-resistant ventricular fibrillation is defined as ventricular fibrillation persisting after three defibrillation attempts. In approximately 10 to 25% of all cardiac arrests, shock-resistant ventricular fibrillation develops, and 87 to 98% of these patients die. RECENT FINDINGS: In the treatment of shock-resistant ventricular fibrillation, defibrillation using biphasic waveforms is considered as an intervention of choice. Intravenous amiodarone is also acceptable, safe, and useful, based on evidence from two randomized clinical trials. Intravenous vasopressin is acceptable and probably safe and useful, but the evidence supporting this recommendation is coming from a small, randomized clinical trial. Procainamide is acceptable but not recommended. In the presence of acute myocardial infarction and recurrent ventricular fibrillation, if all other therapies fail, beta-blockers can be considered. Magnesium, lidocaine, and bretylium are not recommended in the treatment of shock-resistant ventricular fibrillation. SUMMARY: Biphasic defibrillation and intravenous amiodarone are useful in shock-resistant ventricular fibrillation.

Potentially significant drug interactions of class III antiarrhythmic drugs.

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin. Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug. Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions. Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism. Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide. It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism. Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically. If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.

Amiodarone and bretylium in the treatment of hypothermic ventricular fibrillation in a canine model.

UNLABELLED: Refractory ventricular fibrillation (VF) is a complication of severe hypothermia. Despite mixed experimental data, some authors view bretylium as the drug of choice in hypothermic VF. Bretylium was removed from Advanced Cardiac Life Support guidelines, and, to date, efficacy of amiodarone in hypothermia is unknown. OBJECTIVES: To compare defibrillation rates from hypothermic VF after drug therapy with amiodarone, bretylium, and placebo. METHODS: This was a randomized, blinded, and placebo-controlled laboratory experiment. Thirty anesthetized dogs were mechanically ventilated and instrumented to monitor coronary perfusion pressure (CPP), rectal core temperature, and electrocardiogram (ECG). Animals were cooled to 22 degrees C or the onset of spontaneous VF. Ventricular fibrillation was induced as needed with a transthoracic AC current. Cardiopulmonary resuscitation (CPR) was initiated and animals were randomized (n = 10 each group) to receive amiodarone 10 mg/kg (A), bretylium 5 mg/kg (B), or placebo (P) intravenously. CPR was continued while monitoring for chemical defibrillation. Rewarming was limited to removal from the cold environment. After 10 minutes, up to three escalating defibrillatory shocks were administered. Hemodynamic monitoring continued after resuscitation. Return of spontaneous circulation (ROSC) was defined as a sustainable ECG rhythm generating a corresponding arterial pressure tracing lasting a minimum of 15 minutes. Sample size permitted 80% power to detect a 60% difference in conversion rate between groups. RESULTS: CPR was adequate based on CPP > 15 mm Hg in all animals. Mean (+/-SD) CPP was 35.3 +/- 18.8 mm Hg with an overall lower trend in the amiodarone group (p = 0.06). Baseline variables were similar between groups. No instance of chemical defibrillation was noted. There was no significant difference in ROSC rates between groups. Resuscitation rates were: amiodarone = 1/10, bretylium = 4/10, and placebo = 3/10 (p = 0.45). CONCLUSIONS: In this model of severe hypothermic VF, neither amiodarone nor bretylium was significantly better than placebo in improving the resuscitation rate.

Preventing ventricular fibrillation by flattening cardiac restitution.

Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the previous diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.

Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged ventricular fibrillation.

OBJECTIVE: To test the hypothesis that combination pharmacotherapy with delayed countershock would produce higher rates of return of spontaneous circulation (ROSC) and one-hour survival when compared with standard Advanced Cardiac Life Support (ACLS) therapy. METHODS: A prospective, block-randomized, blinded, laboratory experiment was conducted in an established swine model of prolonged ventricular fibrillation (VF). Fifty-six female domestic swine were anesthetized, instrumented, and shocked into VF with a bipolar pacing catheter. The VF was untreated for 8 minutes, then basic CPR was done mechanically for 1 minute. At 9 minutes of VF, the animals were randomized to treatment with one of seven therapies: group 1, combination pharmacotherapy with epinephrine (0.20 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), propranolol (1.0 mg), and U-74389G (3.0 mg/kg); group 2, epinephrine (0.20 mg/kg); group 3, lidocaine (1.0 mg/kg) and bretylium (5.0 mg/kg); group 4, propranolol (1.0 mg); group 5, U-74389G (3.0 mg/kg); group 6, normal saline solution (volume equal to that for group 1); and group 7, standard ACLS (first countershock at 9 minutes of VF). Initial countershocks for groups 1-6 were given after 11 minutes of VF. Data were analyzed with two-tailed Fisher's exact test, with alpha set at 0.05. RESULTS: Return of spontaneous circulation occurred in group 1 = 8/8 (100%); group 2 = 7/8 (88%); group 3 = 3/8 (38%); group 4 = 3/8 (38%); group 5 = 5/8 (63%); group 6 = 4/8 (50%); and group 7 = 3/8 (38%). One-hour survival occurred in group 1 = 8/8 (100%); group 2 = 5/8 (63%); group 3 = 2/8 (25%); group 4 = 2/8 (25%); group 5 = 3/8 (38%); group 6 = 2/8 (25%); and group 7 = 1/8 (13%). CONCLUSIONS: Combination pharmacotherapy with delayed countershock (group 1) produced significantly higher rates of ROSC (p = 0.03) and one-hour survival (p = 0.001) when compared with standard ACLS in this porcine model of prolonged VF.

Pharmacologic and pharmacokinetic profile of class III antiarrhythmic drugs.

Cardiac arrhythmias frequently respond only to drugs that have as their predominant electrophysiologic effect the prolongation of repolarization and refractoriness. According to the Singh-Vaughan Williams classification, these drugs are known as class III agents. In the last few years, interest has increased in the development of class III antiarrhythmic drugs as alternatives to sodium channel blocking agents, which mainly affect cardiac conduction. Much of this interest results from a perceived danger of using drugs with sodium channel blocking properties, particularly in patients with ischemic heart disease, based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) and several other trials. This article is a review of the pharmacology, including the pharmacokinetics and pharmacodynamics, of the most commonly used and investigated class III antiarrhythmic drugs. As will be seen from the discussion, each of these drugs has novel pharmacology that makes it applicable in specific clinical situations. Their putative effects on various arrhythmogenic mechanisms and their efficacy in treating specific target arrhythmias will be addressed.

Advanced cardiac life support controversy: where do antiarrhythmic agents fit in?

Approximately half of all cardiovascular fatalities are attributable to sudden cardiac death, and the majority of sudden cardiac deaths result from ventricular fibrillation (VF). Antiarrhythmic agents are needed to manage refractory VF and ventricular tachycardia (VT); the primary reason for their administration is to prevent recurrence of VF and to abolish VT. The American Heart Association recommends lidocaine hydrochloride as a first-line antiarrhythmic agent in the advanced cardiac life support (ACLS) setting, followed by bretylium tosylate. Although the newly approved intravenous antiarrhythmic agent, amiodarone hydrochloride, may potentially be effective in ACLS, studies are needed to document its clinical benefit in this setting. Such studies are currently under way to document this potential use.

Prophylactic treatment of swine with bretylium for experimental cardiac catheterization.

We evaluated a cryothermic ablation catheter for potential use in treating supraventricular tachycardia by cardiac catheterization in miniature swine. Cardiac catheterization was performed on anesthetized miniature swine by using multiple catheters that were inserted bilaterally by either percutaneous or cutdown techniques into the femoral veins. We performed electrophysiologic tests according to standard atrial and ventricular electrical stimulation protocols. Manipulation of catheters in the tricuspid valve area and right ventricle was an essential part of the study. During an initial study of five swine, catheter manipulation produced sustained and nonsustained ventricular tachycardia and ventricular fibrillation. To prevent arrhythmias, bretylium (5 mg/kg) was administered intravenously 10 minutes before catheter manipulation and repeated every 30 minutes throughout the procedure. Since the use of bretylium was instituted, there have been no cases of ventricular fibrillation in a series of 20 animals. We determined that bretylium is effective in the suppression of ventricular arrhythmias in swine undergoing cardiac catheterization.

An experimental algorithm versus standard advanced cardiac life support in a swine model of out-of-hospital cardiac arrest.

STUDY OBJECTIVE: To compare an experimental algorithm with standard advanced cardiac life support in a swine model of out-of-hospital cardiac arrest. DESIGN: Randomized, controlled experimental trial. SETTING/TYPE OF PARTICIPANT: Animal laboratory using swine. INTERVENTIONS: Eighteen swine (17.8 to 23.7 kg) were sedated, intubated, anesthetized, and instrumented for monitoring of arterial and central venous pressures and ECG. Ventricular fibrillation was induced using a bipolar pacing catheter. Animals were randomized to treatment with the experimental algorithm or standard advanced cardiac life support therapy after eight minutes of untreated ventricular fibrillation. The experimental algorithm consisted of starting CPR; giving high-dose epinephrine (0.20 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), and propranolol (0.5 to 1.0 mg) by peripheral IV; hyperventilating (20 to 25 breaths per minute); and delaying countershock (5 J/kg) 60 seconds after completion of drug delivery. Data were analyzed with the Student's t-test and Fisher's exact test. MEASUREMENTS AND MAIN RESULTS: Outcome variables were arterial and central venous pressures, return of spontaneous circulation, and one-hour survival. Hemodynamics were not different between groups during CPR. Return of spontaneous circulation occurred in seven of nine swine (77%) in the experimental algorithm group versus two of nine swine (22%) in the advanced cardiac life support group (P = .057). Four of nine swine (44%) in the experimental algorithm group survived to one hour versus none of the animals in the advanced cardiac life support group (P = .041). CONCLUSION: In this swine model of out-of-hospital cardiac arrest, animals treated with an experimental algorithm had a significant improvement in one-hour survival compared with those treated with advanced cardiac life support.