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Original Articles – Cardiovascular

Prophylactic amiodarone versus lidocaine for prevention of reperfusion ventricular fibrillation after release of aortic cross-clamp

Ayoub, Chakib Ma; Sfeir, Pierre Mb; Bou-Khalil, Pierrec; Azar, Mireillea; Haddadin, Ala' Sd; Harfouch, Dialaa; Nasr, Viviane Ga; El-Khatib, Mohamad Fa

Author Information
European Journal of Anaesthesiology: December 2009 - Volume 26 - Issue 12 - p 1056-1060
doi: 10.1097/EJA.0b013e32832f0dfb

Abstract

Introduction

Ventricular fibrillation, which can be precipitated after the release of the aortic cross-clamp (ACC) in patients undergoing cardiac surgery, is reported to occur in 74–96% of cases [1]. Ventricular fibrillation is considered to be secondary to the combination of myocardial ischaemia and reperfusion injury after release of the ACC despite adequate myocardial protection by hypothermic potassium cardioplegia [1,2]. Upon resumption of blood flow, released substances exert a transient, yet potent, arrhythmogenic effect [3–6]. Reperfusion ventricular fibrillation and the ensuing needed electric defibrillation counter shocks (DCSs) can be deleterious to the myocardium by adding an insult to injury [7,8]. Hence, preventing reperfusion ventricular fibrillation at the time of release of the ACC can be beneficial in the preservation of the overall myocardial function following cardiopulmonary bypass (CPB) [9,10].

Although defibrillation remains the standard practice, various methods are used in an attempt to prevent and/or treat reperfusion ventricular fibrillation. The addition of lidocaine to cardioplegic solutions decreased the incidence of ventricular fibrillation to 42% [11,12], whereas a bolus of 100 mg lidocaine, administered by way of the pump 2 min before release of the ACC, reduced ventricular fibrillation occurrence from 70 to 11% [1].

Previous studies have reported several benefits for the use of amiodarone in treating ventricular fibrillation. Amiodarone, a class III antiarrhythmic agent, with systemic/coronary vasodilation, phospholipase inhibition and selective inhibition of the thyroid hormone metabolism effects, has been recognized as the drug of choice in shock-resistant ventricular fibrillation [13,14]. The two independent and simultaneously published Amiodarone versus Lidocaine in Prehospital Ventricular Fibrillation Evaluation (ALIVE) [15] and ARREST [16] trials have shown a clear superiority of amiodarone over lidocaine in terms of survival rates to hospital admission. Furthermore, amiodarone has been shown to be effective in the treatment of ventricular fibrillation refractory to other antiarrhythmic medications after CPB [17,18].

The aim of the current study is to evaluate the efficacy of the prophylactic administration of 150 mg amiodarone versus lidocaine and placebo, by way of the pump 2 min before release of ACC, in preventing ventricular fibrillation in adult patients undergoing cardiac surgery.

Methods

The present prospective, randomized and blinded study was conducted at a tertiary care teaching hospital in Beirut, Lebanon between January 2007 and September 2008. The Investigative and Research Board approved the study protocol and written informed consent was obtained 1–2 days prior to surgery from all participating patients. After obtaining written informed consent, 120 patients scheduled to undergo elective coronary artery bypass graft (CABG) surgery were included in the study. Exclusion criteria included contraindications to amiodarone (sick sinus syndrome, atrioventricular conduction abnormalities, thyroid disease, interstitial lung disorders, renal or liver disease, known allergic or toxic reactions to amiodarone), need for concomitant cardiac surgical procedure, emergency surgery, history of chronic or intermittent arrhythmias and pretreatment with digoxin or amiodarone.

Patient characteristics were obtained and included age, sex, weight, preoperative medications, electrocardiogram, echocardiography and coronary angiography results.

All patients were premedicated with valium 5 mg orally and robinul 0.2 mg intramuscularly. Induction of anaesthesia consisted of midazolam 0.03 mg kg−1, sufentanil 0.6 μg kg−1, thiopentone 2.5 mg kg−1 and rocuronium 0.6 mg kg−1. Following tracheal intubation, patients were mechanically ventilated with 100% oxygen. Anaesthesia was maintained with midazolam (0.1 μg kg−1 min−1), sufentanil (1 μg kg−1 h−1) and cisatracurium (1–2 μg kg−1 h−1). Patients were continuously monitored with ECG (leads II and V5), radial artery catheter and a thermodilution pulmonary artery catheter.

After achieving adequate anticoagulation with heparin, CPB was initiated using a membrane oxygenator (Univox spiral gold, Baxter Deutschland, Unterschleißheim, Germany) and patients were perfused by a nonpulsatile roller pump (SARNS 800 modular perfusion system; Sarns 8000, 3M Health Group, Ann Arbor, Michigan, USA) at a flow rate of 2.4 l min−1 m−2. The circuit was primed with 1500 ml of lactated Ringer's solution. Moderate systemic hypothermia around 29°C was induced during CPB. The heart in all patients was arrested with antegrade perfusion of 20 ml kg−1 of cold (4°C) crystalloid hyperkalemic cardioplegia (St Thomas' solution) at a pressure of 120 mmHg and cardioplegia was repeated every 20 min throughout the ACC period.

Before ACC release, patients were randomly assigned by a member of the research team to either of three groups by way of a random number table to receive the assigned treatment by way of the pump 2 min before release of the ACC. Group A received 150 mg of amiodarone (50 mg ml−1) added to 2 ml of isotonic saline, group L received 5 ml of 2% lidocaine (100 mg), whereas group P received the same volume (5 ml) as saline and served as control group. The assigned drug was prepared by a member of the research team. All members of the medical team, including perfusionists, anaesthesiologists and surgeons were blinded to the drug given.

Intraoperative data collected included the number of grafts, CPB time, ACC time, total volume of cardioplegia used, arterial blood gas (ABG) values, haematocrit, electrolytes, rectal and body temperatures at the time of ACC release. The cardiac rhythm after unclamping the aorta was recorded until sinus rhythm resumed. The incidence of ventricular fibrillation in the amiodarone, lidocaine and control group was noted. Whenever ventricular fibrillation occurred, DCSs were applied until resolution of the ventricular fibrillation. The number of DCSs needed as well as the energy used were recorded. The occurrence of atrioventricular block and the need for a pacemaker were also noted. The haemodynamic parameters [heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP) and cardiac output] were monitored in all groups for 15 min after weaning from CPB. Inotropic support was provided by dobutamine whenever needed as deemed necessary by the surgical and anaesthesia teams providing care to the patients.

Statistical analysis

The present study was powered on the basis of historical results showing around 50% incidence of post-ACC release ventricular fibrillation in the control group. A sample size of at least 39 patients in each group was calculated to detect a decrease in the incidence of ventricular fibrillation down to 18–20% with a power of 80% (i.e. β = 0.2). All values were reported as means ± SD and percentages. Data were analysed using the one-way analysis of variance (ANOVA) test with the Scheffe's test for post-hoc analysis and the Fisher's exact test for testing proportions. A P value less than 0.05 will be considered statistically significant.

Results

The patient characteristics, preoperative medications, operative conditions and conditions at ACC release for patients in the amiodarone (n = 40 patients), lidocaine (n = 40 patients) and saline groups (n = 40 patients) are presented in Table 1. There were no statistically significant differences in any of the variables among the three groups. Furthermore, there were no statistically significant changes in the mean arterial blood pressure among the three groups following release of the ACC.

Table 1
Table 1:
Comparison of control, lidocaine-treated and amiodarone-treated groups

The flow chart of the study is presented in Fig. 1. The frequency of occurrence of ventricular fibrillation was significantly higher in both the amiodarone [19/40; 48%; 95% confidence interval (CI) 33–63%; P = 0.0172] and the control group (18/40; 45%; 95% CI 31–60%) (P = 0.031) as compared with the lidocaine group (8/40; 20%; CI 11–35%) with no statistically significant difference between the amiodarone and the control groups (Table 2). Furthermore, whenever ventricular fibrillation occurred, the percentage of patients requiring DCS for reversal of the ventricular fibrillation was significantly higher in both the amiodarone (11/19; 58%; 95% CI 36–77%; P = 0.043) and control (11/18; 61%; 95% CI 36–82%; P = 0.036) groups as compared with the lidocaine group (1/8; 13%; 95% CI 2–47%) with no difference between the amiodarone and the control groups (Table 2).

Fig. 1
Fig. 1
Table 2
Table 2:
Incidence of ventricular fibrillation and requirements for direct current shocks in the three groups

Also, for those patients receiving DCS, although there were no statistically significant differences in the required energy between the lidocaine group (18 ± 9 J) and either the amiodarone or control groups, the DCS energy required in the amiodarone group (16 ± 7 J) was significantly lower than that for the control group (25 ± 8 J; P = 0.023; Table 2).

Discussion

The present study showed no difference between 150 mg amiodarone and placebo given by way of pump 2 min before release of the ACC in preventing ventricular fibrillation, despite a significant decrease in the direct current shocks energy requirements in the amiodarone group. Furthermore, our study confirmed the efficacy of lidocaine in preventing reperfusion ventricular arrhythmias as compared with amiodarone 150 mg and placebo.

Our data did not show a statistically significant difference in the incidence of ventricular fibrillation between the amiodarone and the placebo groups, making the proarrhythmic potential of amiodarone in the setting of cardiac surgery questionable. These observed results pertaining to the effect of 150 mg amiodarone in comparison with control are somewhat unexpected. However, these findings can be explained based on the dosing regimen utilized, the pharmacokinetics of the drugs administered on CPB, as well as the proinflammatory and potential proarrhythmogenic effects of amiodarone. Amiodarone is a class III antiarrhythmic drug that was proved effective in the prevention and treatment of atrial fibrillation as well as refractory ventricular arrhythmias [15,16,18]. It has also class I, class II and antiadrenergic effects. Amiodarone blocks potassium channels and prolongs repolarization and increases the refractory period of atrial and ventricular muscle as well as the atrioventricular node. It has a mild β-blocker and calcium channel blocker activity in addition to its class III antiarrhythmic activity. However, amiodarone's negative inotropic effect is controversial [13,14]. The acute circulatory actions of 150 mg of amiodarone in cardiac surgical patients have been studied by Cheung et al. [19]. They showed that transient hypotension, the most frequent adverse event (15–26%), is primarily caused by a selective arterial vasodilation with preservation of myocardial contractility. In our study, we elected to administer 150 mg of amiodarone in order to decrease the incidence of such reported hypotension and consequently, the need for increased vasopressor requirements. Furthermore, various doses of intravenous amiodarone (125, 500 and 1000 mg per day) were previously evaluated by Scheinman et al.[20]. The low-dose regimen did not prove to be equally effective as the higher doses in reducing the median 24-h recurrence rates of ventricular arrhythmias (1.68, 0.96 and 0.48 events per 24 h, respectively). It, thus, showed a trend towards a direct relationship between the intended amiodarone dose and ventricular arrhythmias recurrence rates.

Although the electrophysiological effects and antiarrhythmic efficacy of amiodarone depend on the myocardial concentration of the drug, previous pharmacokinetics observations have suggested a rather rapid myocardial amiodarone uptake. Nanas and Mason [21] showed that the peak concentration of amiodarone in the myocardium was reached 10–30 min after a 5 mg kg−1 intravenous bolus administration, nearly reaching the peak plasma concentration, even though the latter poorly correlates with clinical effects. Thus, the larger the initial bolus is, the greater the myocardial concentration and the faster its effect on conduction. The dose of amiodarone used in our study is comparable to the low dose used by Scheinman et al. [20], which is around 2 mg kg−1. This is well below the dose of 5 mg kg−1 that made a clinical impact in both the ALIVE [15] and ARREST [16] trials. In the current study, although this dose did not decrease the frequency of occurrence of ventricular fibrillation (48%) in the amiodarone group as compared with the control group (45%), it did, however, reduce the requirements of direct current shocks energy in the amiodarone group (16 ± 7 J) as compared with the control group (25 ± 8 J), which might prove beneficial in this setting.

Furthermore, amiodarone-induced ventricular arrhythmia, in the form of torsades de pointes, though rare, has been described in the setting of prolonged QT interval and severe bradycardia, as well as in cardiac patients in the absence of any other predisposing factors [22,23]. Such a ventricular arrhythmia induced by amiodarone toxicity is rather unlikely in view of the known poor bioavailability of amiodarone and its large volume of distribution [24]. However, CPB with its associated hypothermia, haemodilution, potential acidosis and electrolytes imbalance may alter the pharmacokinetics of any drug given into the venous reservoir in a very unpredictable manner [25].

Finally, although amiodarone is not known to induce an inflammatory response, various studies have shown that it may enhance the inflammatory cycle caused by other triggers such as atherosclerosis or surgery [26]. Delle Karth et al.[27] showed that in the setting of cardiac surgery and CPB, amiodarone treatment was associated with a significantly higher fibrinogen formation and a trend towards higher monocyte chemoattractant protein-1 (MCP-1) generation compared with placebo-treated patients. Although none of the cytokines produced is known to have a proarrhythmic activity, the proinflammatory potential in the setting of an acute ischaemic insult to the heart and CPB could explain the lack of efficacy of the drug in preventing ventricular fibrillation.

Lidocaine, an amide local anaesthetic, has been shown to increase the threshold for ventricular fibrillation. It belongs to the class IB antiarrhythmic drugs, binds to sodium channels, decreases the slope of phase 4 depolarization and increases the diastolic electric current threshold in Purkinje fibres. Rinne and Kaukinen [28] studied the effect of an intravenous bolus of lidocaine given before clamping the aorta, to be followed by a continuous infusion for 20 h. They reported neither an increase in cardiac protection nor a decrease in the incidence of reperfusion ventricular fibrillation. Baraka et al.[1] showed that the administration of a bolus of 100 mg of lidocaine by way of the pump 2 min before releasing the ACC can significantly decrease the incidence of reperfusion ventricular fibrillation, without increasing the incidence of atrioventricular block. The beneficial effects of lidocaine in our study were not only limited to reducing the incidence of reperfusion ventricular fibrillation to 20% but also in a trend towards reducing the direct current shock energy required (18 ± 9 J) compared with the control group (25 ± 8 J).

In conclusion, the present study shows that although the administration of 150 mg of amiodarone by way of the pump 2 min before release of ACC did not affect the incidence of reperfusion ventricular fibrillation, it did, however, prove beneficial in reducing the number of direct current shocks needed to treat the arrhythmia. Furthermore, the administration of lidocaine is recommended as more data are accumulating favouring its efficacy in reducing the occurrence of ventricular fibrillation post-ACC release.

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Keywords:

amiodarone; antiarrhythmic drug; cardiac surgery; cardiopulmonary bypass; coronary artery bypass graft; lidocaine; local anaesthetic; reperfusion ventricular fibrillation

© 2009 European Society of Anaesthesiology