Renewed Impact of Lidocaine on Refractory Ventricular Arrhythmias in the Amiodarone Era Koji Yoshie, Takeshi Tomita, Takahiro Takeuchi, Ayako Okada, Takashi Miura, Hirohiko Motoki, Uichi Ikeda PII: DOI: Reference:

S0167-5273(14)01635-0 doi: 10.1016/j.ijcard.2014.08.090 IJCA 18711

To appear in:

International Journal of Cardiology

Received date: Accepted date:

13 August 2014 15 August 2014

Please cite this article as: Yoshie Koji, Tomita Takeshi, Takeuchi Takahiro, Okada Ayako, Miura Takashi, Motoki Hirohiko, Ikeda Uichi, Renewed Impact of Lidocaine on Refractory Ventricular Arrhythmias in the Amiodarone Era, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2014.08.090

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Renewed Impact of Lidocaine on Refractory Ventricular Arrhythmias

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in the Amiodarone Era

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Koji Yoshie M.D.a, Takeshi Tomita M.D.a, Takahiro Takeuchi M.D.a, Ayako Okada M.D.a, Takashi Miura M.D.a, Hirohiko Motoki M.D.a, Uichi Ikeda M.D.a Department of Cardiovascular medicine, Shinshu University School of Medicine

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This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation

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Address for Correspondence: Koji Yoshie M.D.

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Department of Cardiovascular medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan Tel: 81-263-37-3486 Fax: 81-263-37-2573 E-mail: [email protected]

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There are no grants, contracts, financial support, or relationships with industry.

Key words: Lidocaine, Amiodarone, LVEF, Ventricular arrhythmia

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Abstract

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Background

Recent guidelines for treating ventricular fibrillation (VF) and ventricular tachycardia

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(VT) stress class III antiarrhythmic drugs, but some malignant arrhythmias refractory to

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these agents still occur in clinical practice. The possibility of a new treatment strategy involving lidocaine and amiodarone combination therapy was evaluated. Methods

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From September 2008 to September 2013, 62 patients were treated at our hospital with

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lidocaine. The medical records were retrospectively reviewed. Twenty inappropriate

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patients were excluded. The remaining 42 patients were analyzed. Patients were divided into two groups according to the effectiveness of lidocaine in terminating refractory

Results

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ventricular arrhythmias: the effective group.

LVEF was significantly higher in the lidocaine effective (E) group compared to the ineffective (I) group (44±16% vs. 32±10%, p=0.027). There were more patients already on amiodarone at the start of lidocaine therapy in the E group compared to the I group (11/26 vs. 1/16, p=0.012). Furthermore, patients receiving lidocaine without amiodarone were re-analyzed to estimate the actual effect of lidocaine. Of the 30 patients not

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receiving amiodarone, 15 were in the effective without amiodarone(E w/o A) group and

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15 were in the ineffective without amiodarone(I w/o A) group. LVEF was significantly higher in the E w/o A group than in the I w/o A group (51±16% vs. 32±9%, p=0.001).

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Conclusions

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This retrospective study suggests that combination therapy with lidocaine and amiodarone can terminate most refractory ventricular arrhythmias. Even in patients with a sufficient LVEF not receiving amiodarone, it is possible that lidocaine can contribute

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to a favorable outcome.

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Introduction

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Since the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that sodium channel blockers worsened the prognosis of patients with structural heart disease (1,2)

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class III antiarrhythmic drugs such as amiodarone have been recommended for

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ventricular arrhythmias instead (3,4,5). Cairns and others reported a decrease in the mortality rate in patients with myocardial infarction suffering from non-sustained ventricular tachycardia (NSVT) or premature ventricular complexes (PVCs) with the

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use of amiodarone (6). In their study of chronic heart failure, Singh et al. found that the

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mortality rate due to nonischemic cardiomyopathy also decreased with the use of oral

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amiodarone (7). Furthermore, Kasanuki et al. reported the effectiveness of amiodarone as secondary prevention for malignant arrhythmias; they also observed an increase in

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the survival rate (8). However, despite these studies mentioned above, there are no firm conclusions about the reliability of amiodarone therapy and the optimal treatment for refractory malignant arrhythmias (9,10). Nowadays, implantation of an implantable cardioverter defibrillator (ICD) is recommended in patients on amiodarone therapy because of the poor prognosis with medical therapy alone (11,12). There is no doubt that amiodarone is one of the mainstream drugs for treating malignant arrhythmias (13,14). But a further treatment strategy for malignant arrhythmias including electrical

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storm after ICD implantation is urgently needed.

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In such situations, lidocaine combined with other antiarrhythmic drugs is considered to treat malignant arrhythmias. Lidocaine is often used as first line treatment

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because it has little effect on cardiac function (15) and the proarrhythmic risk is low

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when used at an appropriate dose. Since its release in 1955, lidocaine has been widely used in clinical practice and it is effective in many patients. However, several reports have cast doubt on the effectiveness of lidocaine for eliminating ventricular arrhythmias

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(16,17,18,19). Therefore, lidocaine has been excluded from emergency treatment

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guidelines in recent years (20,21). In this context, we conducted a retrospective study to

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evaluate the efficacy of lidocaine in patients with refractory ventricular arrhythmias, most of who were already receiving a potassium channel blocker. We evaluated the

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effectiveness of lidocaine and amiodarone combination therapy.

Methods Patients. We retrospectively reviewed the clinical data of 62 patients who were treated with lidocaine from September 2008 to September 2013 at Shinshu University Hospital. The protocol for this study was approved by the ethical committee of Shinshu University Hospital and informed consent was obtained from the patients as much as

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possible because of the limit of the retrospective study. Cases that were inappropriate

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for analysis (used for other indications [n=9], already on other potassium channel blockers [n=5], used to treat accelerated idioventricular rhythm (AIVR) related to acute

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coronary revascularization [n=5], or concurrent high-rate pacing [n=1]) were excluded

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from this study. The remaining 42 patients were analyzed in the present study. The following baseline clinical characteristics were evaluated: type of ventricular arrhythmia, amiodarone and β-blocker therapy, left ventricular ejection fraction (LVEF) measured

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by cardiac ultrasound or left ventriculography, brain natriuretic peptide (BNP) levels,

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history of heart failure, and history of intervention for underlying heart disease. In

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patients who were not able to undergo LVEF measurements on admission because of life-threatening ventricular tachycardia (VT) / ventricular fibrillation (VF), we obtained

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the most recent available data before and after the arrhythmic events. Evaluation of lidocaine. We reviewed medical records to determine the dose of lidocaine and whether it was given as a quick or continuous intravenous infusion. The effectiveness of lidocaine was defined as follows. In patients with VT, lidocaine was considered effective if triggering PVCs resolved or decreased in frequency and sustained VT was resolved. In patients with VF, lidocaine was considered effective when VF was terminated after administration of lidocaine or cardioversion and no

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further episodes of VF occurred during lidocaine therapy. In patients with NSVT and

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frequent PVCs affecting the hemodynamic status or presenting a risk of life-threatening arrhythmic events, treatment was considered effective if those events decreased after

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initiation of the medication or no shift to VT or VF was observed.

Statistical analysis

Analysis was performed using SPSS statistical software (SPSS version 21 for Windows).

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Quantitative variables were expressed as means ± 2SD and categorical data were

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expressed as frequencies or percentages. For categorical data, the chi-squared test and

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Fisher’s exact test were used to compare groups. Student’s t test was used for continuous variables. A p value < 0.05 was considered statistically significant. The

curve.

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cut-off point for LVEF was calculated from a receiver operating characteristic (ROC)

Results Patient Characteristics. The clinical characteristics of the study patients are summarized in Table 1. The median age was 68±15 years (range, 28 to 90 years). Of the 42 patients, 32 were men (76.1%). The distribution of ventricular arrhythmias was as

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follows: VT in 24 patients, VF in 4, NSVT in 10, and frequent PVCs threatening to

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develop into VT/VF in 4. Mean LVEF was 40±15%, and the mean BNP concentration was 1028±1110 pg/ml. There were 27 patients (64.3%) with heart failure (HF), and 30

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(71.4%) of the 42 patients underwent interventions for their underlying heart disease.

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Underlying heart disease consisted of ischemic heart disease in 21 patients, cardiomyopathy in 9, valvular heart disease in 4, and other in 8. The study patients were divided into two groups according to their response to lidocaine: the lidocaine effective

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group (E group, n=26) and the lidocaine ineffective group (I group, n=16). Among the

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patients in the E group, 15 had VT, 3 had VF, 8 had NSVT and frequent PVCs causing

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hemodynamic deterioration.

Method of lidocaine and amiodarone administration and adverse effects. For

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continuous intravenous infusion, the mean dose of lidocaine was 40.8±17.1 mg/day (range, 8 mg/hour to 60 mg/hour), compared to 75.0±35.4 mg (range, 50 mg to 100 mg) for bolus dosing. Bolus injections alone, continuous intravenous infusion after a bolus dose, or continuous intravenous infusion were used from the beginning of this therapy. The adverse effects of lidocaine (shock, altered level of consciousness, tremors, convulsions, malignant hyperthermia, gastrointestinal symptoms, and hives) were searched for but did not find any documentation of these change in the medical records

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of the study patients.

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The amiodarone regimen was also reviewed. There were three patterns: oral administration prior to admission, intravenous injection after admission, or both. In the

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E group, oral or intravenous injection of amiodarone had already been administered in

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11 of 26 patients, whereas there was just one patient who received amiodarone in the I group. The mean dose of oral amiodarone was 177.8±97.2 mg/day (range, 100 mg/day to 400 mg/day) and that of continuous intravenous infusion was 20.8±8.9 mg/hour

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(range, 10.5 mg/hour to 26.3 mg/hour). In the 11 E group patients who received

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amiodarone, 8 were on oral amiodarone, for 7 days up to more than 10 years. In contrast,

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3 of the 11 patients received continuous intravenous administration of amiodarone upon admission. In all patients, treatment efficacy was confirmed from the medical record

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within 1 day of starting lidocaine and amiodarone combination therapy. Amiodarone had already been given when lidocaine was first administered. The occurrence of side effects associated with amiodarone (interstitial pneumonia, aggravation of arrhythmias, HF, complete atrioventricular block, hypotension, liver dysfunction, thyroid dysfunction, and syndrome of inappropriate secretion of antidiuretic hormone) was also evaluated in the study patients; none were observed in the review of their medical records.

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Effect of lidocaine in patients with prior amiodarone use (combination therapy). Compared to the I group, there were more patients in the E group who received

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amiodarone before lidocaine infusion (I group 1/16 vs. E group 11/26; p=0.012; Table

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1). Furthermore, the influence of LVEF was compared. Combination therapy with lidocaine and amiodarone was significantly more effective in the high LVEF group than in the low LVEF group (44±16% vs. 32±10%; p=0.027; Table 1). The maximum LVEF

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in the E group was 49.5%.

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Effect of lidocaine in patients without prior amiodarone administration (lidocaine

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monotherapy). Next, the effect of lidocaine alone on VT/VF was evaluated. There were 30 patients who did not receive either oral or intravenous amiodarone. Of these 30

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patients, 23 (76.7%) were male, and the median age was 69±14 years. LVEF was 41±16%, and the BNP level was 994±857 pg/ml. The underlying heart disease was ischemic heart disease in 15 patients, cardiomyopathy in 6, valvular heart disease in 4, and other in 5. There were 15 patients with VT, 2 with VF, 9 with NSVT, and 4 with frequent PVCs threatening to deteriorate into VT/VF. The mean dose of lidocaine was 48.0±18.4 mg/day (range, 10 mg/hour to 100 mg/hour) with continuous intravenous infusion and 62.5±25.0 mg (range, 50 mg to 100 mg) with bolus therapy. Patients were

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divided into the lidocaine effective group without amiodarone (E w/o A group, n=15)

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and lidocaine ineffective group without amiodarone (I w/o A group, n=15). The same methods used in the main analysis were used in this subset analysis (Table 2). LVEF

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was significantly higher in the E w/o A group compared to the I w/o A group (51±16%

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vs. 32±9%; p=0.001). The cut-off point for LVEF calculated from the ROC curve was 46.85% (area under curve(AUC), 0.809). The dose of lidocaine in the E w/o A group was lower than the dose in the I w/o A group, for those receiving continuous

Discussion

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mg vs. 75.0±25.0 mg).

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intravenous infusion (47.3±22.0 mg vs. 49.2±16.8 mg) as well as bolus therapy (50.0±0

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The present study demonstrated two important effects of lidocaine on refractory ventricular arrhythmias in clinical practice. The first was that the effect of lidocaine depends on cardiac function. In the patients with a normal LVEF, lidocaine monotherapy could eliminate electrical storms. The second is that lidocaine could potentially control malignant arrhythmias more effectively when combined with amiodarone, even in patients with impaired cardiac function. In this study, lidocaine alone tended to be effective in patients with LVEF >50% (the cut-off point calculated

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from the ROC curve was 46.85%) and combination therapy with lidocaine and

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amiodarone was effective in all but one patient with LVEF 50%, fast-acting lidocaine is recommended (in this study, the cut-off point for the effectiveness of lidocaine alone was 46.85%). If the treatment fails, termination of fatal arrhythmias could be achieved in almost all cases

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with the combination of amiodarone. In this study, all patients with LVEF 46.85% (AUC 0.801). On the other hand, there were some patients with LVEF