Lidocaine as an anti‐arrhythmic drug: Are there any indications left?

Abstract

Lidocaine is classified as a class Ib anti‐arrhythmic that blocks voltage‐ and pH‐dependent sodium channels. It exhibits well investigated anti‐arrhythmic effects and has been the anti‐arrhythmic of choice for the treatment of ventricular arrhythmias for several decades. Lidocaine binds primarily to inactivated sodium channels, decreases the action potential duration, and increases the refractory period. It increases the ventricular fibrillatory threshold and can interrupt life‐threatening tachycardias caused by re‐entrant mechanisms, especially in ischemic tissue. Its use was pushed into the background in the era of amiodarone and modern electric device therapy. Recently, lidocaine has come back into focus for the treatment of acute sustained ventricular tachyarrhythmias. In this brief overview, we review the clinical pharmacology including possible side effects, the historical course, possible indications, and current Guideline recommendations for the use of lidocaine.

INTRODUCTION

Lidocaine was synthesized as a local anesthetic in 1943 ¹ by Loefgren and initially administered as an anti‐arrhythmic drug by Southworth et al. ² Over the last 70 years, the indication has undergone many changes – once the drug of choice for ventricular arrhythmias (VAs), the indication has increasingly receded into the background. Recently, lidocaine has come back into focus for the treatment of acute sustained VA. ³ Are there arguments for a renaissance of the drug in the clinical setting of VA? In this brief overview, we review the clinical pharmacology including possible side effects, the historical course, possible indications, and actual recommendations for the use of lidocaine.

HISTORY OF THE USE OF LIDOCAINE AS AN ANTI‐ARRHYTHMIC DRUG

Lidocaine was first synthetized in 1943 ⁴ as an anesthetic agent and first used in 1950 as an anti‐arrhythmic drug. ¹ , ⁵ Up to the late 1980s, it has been the anti‐arrhythmic of choice for VA, mostly due to lack of alternatives. There was a theoretical and experimental basis for its routine use. In 1988, MacMahon et al. ⁶ published an overview of results from randomized, controlled trials investigating the effectiveness of lidocaine. In summary, lidocaine was associated with a reduction of ventricular fibrillation (VF) of about one third, but there was a lack of evidence for any beneficial effect on mortality. In addition, the analyzed trials had small numbers of reported events and relatively short follow‐up periods. ⁶ Reports on side effects, especially sinus arrest, also led to questioning the use of lidocaine. ⁷ The use of external defibrillators was not widespread up to the late 1970s. However, with improving defibrillation technology their use became more common. Due to an increase in lidocaine's affinity to sodium channel receptors in an acidotic environment, lidocaine may increase defibrillation thresholds. Therefore, lidocaine's effects on defibrillation were questioned because of a possible reduction of shock efficacy of ventricular tachyarrhythmias.

CLINICAL PHARMACOLOGY AND EXPERIMENTAL DATA

Lidocaine blocks voltage‐ and pH‐dependent sodium channels which results in a decrease in conduction velocity. ⁸ The electrophysiological effects have been studied extensively in experimental studies and are summarized as follows: lidocaine has got dose‐dependent effects on the automaticity of pacemaker cells as it decreases automaticity by slowing the rate of spontaneous phase 4 depolarization. ⁹ It prolongs the effective refractory period relatively compared to the action potential duration. Sodium channels have got three different states: a closed conformation (resting), an open conformation (activated), and a non‐conduction conformation (inactivated). The resting state occurs during phase 4 of the action potential. Membrane depolarization opens the activation gate and sodium ions move into the cell (phase 0), the inward sodium movement is terminated with maintained depolarization and closing of the inactivation gate. As the membrane potential repolarizes during phase III, the cell is refractory. At the end of phase III, the sodium channels begin to transition back into their resting state. ¹⁰ Lidocaine binds, not exclusively, but primarily to inactivated sodium channels and therefore effects the action potential duration. Because of this blockade, the recovery of the fast sodium channels is prolonged and by that the effective refractory period is increased. Of note, lidocaine exerts a negligible effect on voltage‐gated potassium channels. ¹¹ In summary, lidocaine binds primarily to inactivated sodium channels, decreases action potential duration, and increases the refractory period (Figure 1). Decreasing the action potential duration and increasing the effective refractory period can interrupt tachycardias caused by re‐entrant mechanisms. ¹² Besides, the ventricular fibrillatory threshold is increased at therapeutic perfusion concentrations, in acutely ischemic hearts at even lower doses. The therapeutic levels in humans range between 1.5 and 5 μg/mL. ⁹ According to experimental data, the most prominent effect is noted on Purkinje fibers, followed by ventricular cells. The effect on atrial tissue is rather low and seen only at higher levels of perfusion concentration. ¹³

FIGURE 1.

Cellular mechanisms of lidocaine.

Pharmacokinetics

The plasma concentration of lidocaine can be described in a biphasic curve model that can be fitted in two exponential components: early fall, followed by a later slower decrease in plasma concentration. The first rapid phase is due to changes in distribution of lidocaine within the two compartments. The first compartment is the central compartment, including the intravascular space, and the second compartment is the peripheral compartment. ¹⁴ Approximately 70% of lidocaine is extracted in the liver. The second slow phase is dependent on the slower net transfer of drug from the larger peripheral compartment to the smaller central compartment. VA have been observed to return within 15 to 20 min after a lidocaine injection and a constant infusion alone may not provide effective blood levels in life‐threatening VA. ¹⁵ Thus, the clinical approach is to give a bolus dose with constant infusion simultaneously. To maintain therapeutic blood levels, a bolus of 1–2 mg/kg is recommended, followed by a 55 μg/kg/min infusion. Because lidocaine is mainly eliminated via the liver and the hepatic blood flow is related to the cardiac output, the dosing should be adjusted in special populations. In acute myocardial infarction with moderately to severely reduced cardiac output, the initial injection should, for example, be 1.5 mg/kg, followed by a 30 μg/kg/min infusion. Patients with cardiogenic shock should be managed with an initial injection of 0.75 mg/kg, followed by 10–20 μg/kg/min. In this patient group, monitoring of lidocaine plasma levels is highly recommended. ¹⁶ The average half‐life of lidocaine is about 8 to 17 min for the early rapid fall and the half‐life for the slow decrease is about 90 to 110 min. After discontinuing an infusion at a steady‐state level, the dominant elimination half‐life is ~1.5 to 2 h. ¹⁷ This implies that reduction of possible toxic effects may take several hours. On the other hand, reaching higher plasma levels requires repetitive bolus injection, for example, in case of an incessant ventricular tachyarrhythmia. ⁹ , ¹⁴ , ¹⁸

Effects on atrial tissue

Several experimental data demonstrated that lidocaine is most effective on Purkinje fibers in the presence of ischemia. Kostis et al. ¹⁹ investigated the effects of lidocaine (applicated in a dosage of 2 and 3 mg/kg) on the threshold of atrial fibrillation in anesthetized dogs. Lidocaine confirmed effects on atrial tissue, but only on higher than usual doses of 3 mg/kg, which on the other hand were accompanied by a higher rate of side effects. Due to well‐established alternatives, lidocaine's use on atrial tachyarrhythmias is therefore not recommended ²⁰ and it appears no longer in the European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines for the treatment of atrial fibrillation. ²¹ , ²²

Effects on ischemic tissue

Several studies demonstrated that the effect on the maximum rate of depolarization and membrane responsiveness is not only dose‐dependent but also depends of the extracellular potassium concentration. ¹³ , ²³ , ²⁴ At physiological potassium concentrations, the maximum rate of depolarization and membrane responsiveness is decreased in the presence of recommended therapeutic lidocaine concentrations. In hypokalemia, up to tenfold of the recommended lidocaine concentrations are needed due to hyperpolarization of the cell membrane. ²³ , ²⁵ During acute ischemia there is an anaerobic metabolism with intracellular and interstitial acidosis and potassium efflux leading to increase in extracellular potassium. These effects result in progressive loss of resting membrane potential, reduction of action potential upstroke velocity and refractoriness, and a transient increase followed by a decrease in excitability leading to heterogeneities in refractoriness. This may consequently enable re‐entrant mechanisms. In addition, Purkinje fibers surviving in an infarcted area may give rise to abnormal automaticity. The release of endogenous catecholamine may also trigger activity secondary to delayed afterdepolarizations. In this setting, lidocaine binds to sodium channels, inactivates them during a low membrane potential of the plateau phase, and dissociates from channel receptors after repolarization. The metabolic effects of ischemia with increased potassium levels lead to an increase of the affinity of lidocaine to sodium channels and the acidosis potentiates the action of lidocaine. ²⁶

Effects on the atrioventricular node and intraventricular conduction time

In experimental animal studies, no significant changes on the conduction time were demonstrated with therapeutic doses between 1 and 2 mg/kg. In the presence of higher doses of 5–20 mg/kg, an increased atrioventricular node conduction time in dogs was reported. ²⁷ , ²⁸ Weaver et al. ²⁹ observed a 25% occurrence rate of asystole with repeated lidocaine administration for VF after a first defibrillation shock. In a randomized trial, Haynes et al. ³⁰ reported an increased incidence of asystole after the administration of lidocaine compared with bretylium, a potent potassium channel blocker. The respective drug was administered after the initial shock unless the post shock rhythm was asystole. Possible mechanisms of asystole after lidocaine administration include decreases in conduction and automaticity and the simultaneous use of other cardio depressant drugs. ³¹ Mechanisms other than direct electrophysiologic depression are also discussed: In anesthetized dogs, Aidonidis et al. ³² demonstrated that lidocaine induced asystole after defibrillation was associated with decrease in quantitative postganglionic cardiac sympathetic nerve activity. Previous studies have also shown that defibrillation in the absence of lidocaine was associated with enhanced activation of the sympathetic nervous system. ³³

Hemodynamic effects

In animal experiments, lidocaine depresses ventricular contractility. Rapidly applied doses of 4 and 8 mg/kg produced dose‐dependent, significant transient depression of ventricular contractility, arterial pressure, heart rate, and cardiac output in anesthetized dogs with myocardial infarction. In contrast, given continuous infusion, the circulatory changes are described as minimal and bolus doses of lidocaine up to 2 mg/kg were shown to be safe with minimal changes in arterial pressure or heart rate. ³⁴ , ³⁵ , ³⁶

Effects on defibrillation

Chow et al. ³⁷ investigated the effect of lidocaine (2 mg/kg) and bretylium (5 mg/kg) on defibrillation thresholds in anesthetized dogs undergoing cardiopulmonary resuscitation (CPR). In these experiments, lidocaine acutely elevated the defibrillation threshold. Echt et al. ³⁸ investigated the pH dependence of lidocaine on internal defibrillation energy requirements in dogs and demonstrated that the effects of increasing the energy required for termination of ventricular defibrillation were exacerbated in acidosis. ³⁸ Therefore, the use of lidocaine in the presence of ischemia‐related acidosis may have unwanted effects on shock efficacy.

CLINICAL DATA

Regarding prophylactic use of lidocaine on VA, lidocaine suppressed ventricular ectopy in the setting of acute myocardial infarction in a historic meta‐analysis of clinical studies. ³⁹ Of note, in contrast to, for example, flecainide it does not alter QRS duration in sinus rhythm. In a double‐blinded randomized study in 1974, it was shown that the effectiveness was related to the dosage used; the use of a high dosage of 3 mg/min preceded by an i.v. bolus of 100 mg was effective in preventing VF but was also associated with high rates of side effects in 15% in the patients receiving lidocaine in that dosage, more common in the older age group (>60 years). Of note, patients older than 69 years were excluded. ⁴⁰ There is a lack of randomized studies investigating the effect of prophylactic use of lidocaine on mortality. In contrast, Cairns et al. ⁴¹ reported in the randomized, double‐blinded CAMIAT trial a decrease in mortality in patients with myocardial infarction with non‐sustained ventricular tachycardia (VT) or premature ventricular complexes with the use amiodarone. Yoshie et al. ⁴² investigated the role of lidocaine on refractory VA in a retrospective study. This study suggested that combining lidocaine and amiodarone might be effective in terminating refractory ventricular tachyarrhythmias in patients with reduced cardiac output. Forty‐four percent of the 42 studied patients were effectively treated with lidocaine, 28.6% of these were already treated with amiodarone at the start of the lidocaine therapy. With or without amiodarone, the left ventricular function was higher in the effective group. In conclusion, in patients with preserved cardiac output, the administration of lidocaine even without amiodarone was suggested. In a recent, randomized, double‐blinded trial amiodarone, lidocaine, and placebo along with standard care were investigated in adults with out‐of‐hospital cardiac arrest, shock‐refractory ventricular defibrillation or pulseless VT with regard to survival to hospital discharge, and favorable neurologic function at discharge. ⁴³ Both anti‐arrhythmic drugs failed to increase long‐term survival or survival with favorable neurological outcome. However, administration of lidocaine (60–180 mg) compared to placebo showed a higher level of survival at hospital admission without an effect on hospital discharge. Amiodarone compared to lidocaine showed no difference in survival to hospital admission and discharge (Table 1).

TABLE 1.

Clinical studies of role of lidocaine in cardiac arrest.

	Design	End points	Results
Wagner et al. 2022 60	Retrospective cohort study, 14,630 patients were enrolled. Patients receiving amiodarone or lidocaine for VF/VT in‐hospital cardiac arrest refractory to CPR were analyzed.	Primary end point: ROSC, secondary outcomes: 24 h survival, survival to hospital discharge and favorable neurologic outcome	Compared with amiodarone, lidocaine was associated with significantly higher odds of ROSC (OR: 1.15), 24 h survival (OR: 1.16), survival to discharge (OR: 1.19)
Kudenchuk et al. 2016 43	Randomized, double‐blind trial, 3026 patients were enrolled. In patients with out‐of‐hospital cardiac arrest, shock‐refractory VF or pulseless VT after at least one shock, amiodarone, lidocaine, and placebo were compared.	Primary end point: Survival to hospital discharge. Secondary end point: Favorable neurologic function	Amiodarone had a survival rate compared to placebo by 3.2 percentage points. For lidocaine versus placebo, the difference survival rate was 2.6 percentage points. For amiodarone versus lidocaine, the difference survival rate was 0.7 percentage points. None of the differences were statistically significant. Neurologic outcome at discharge was similar in the three groups.
Yoshie et al. 2014 42	Retrospective cohort study, 42 patients were enrolled. Clinical data of patients receiving lidocaine for the treatment of VF/VT were analyzed.	Primary end point: Effectiveness in terminating refractory ventricular arrhythmias	LVEF was significantly higher in the effective group (51 ± 16% vs. 32 ± 9%). Regardless of the LVEF, combination of amiodarone and lidocaine was more effective than admission of lidocaine only.
Kudenchuck et al. 2013 61	Retrospective cohort study, 1721 patients were enrolled. Patients with witnessed out‐of‐hospital‐cardiac‐arrest and VT/VF who did or did not receive prophylactic lidocaine at first ROSC were analyzed.	Primary end point: Frequency of re‐arrest from recurrent VF/VT after initial ROSC, admission alive to hospital, survival to hospital discharge	Prophylactic lidocaine was associated with reduced odds of re‐arrest from VF/VT (OR: 0.34) and from nonshockable arrhythmias (0.47), a higher hospital admission rate (1.88) and improved survival to discharge (1.49).
Shiga et al. 2010 62	Prospective, observational study, 55 patients were enrolled. Patients with in‐hospital VF or VT resistant to at least two shocks were analyzed after participating hospitals were pre‐registered either to nifekalant or lidocaine.	Primary end point: Termination of VF or VT with/without additional shock. Secondary endpoints: ROSC, 1‐month survival, and survival to hospital discharge	Patients with nifekalant therapy showed significantly higher termination rates of VF or VT as compared with patients treated with lidocaine (OR: 3.8). There was no difference in 1‐month survival between the two groups. There was a higher incidence of asystole with lidocaine (7 of 28 patients) than with nifekalant (0 of 27 patients).
Rea et al. 2006 63	Multicenter retrospective study, 194 patients were enrolled. Hospitalized patients who received amiodarone, lidocaine, or a combination for pulseless VT/VF were analyzed.	Primary end point: Proportion of patients alive 24 h post‐cardiac arrest	Among the lidocaine group, the amiodarone‐group, and the combination‐group, there were no differences in the proportion of patients alive 24 hs post‐cardiac arrest (p = 0.39). The likelihood of survival in patients who received amiodarone was decreased as compared with lidocaine.
Dorian et al. 2002 64	Randomized, double‐blinded study, 347 patients were enrolled. Patients with out‐of‐hospital VF resistant to three shocks, i.v. epinephrine, and a further shock, or recurrent VF after initially successful defibrillation, were assigned to receive amiodarone + lidocaine placebo or i.v. lidocaine + amiodarone placebo.	Primary end point: Proportion of patients who survived to be admitted to the hospital	22.8% of the patients treated with amiodarone survived to hospital admission as compared with 12% of the patients treated with lidocaine (p = 0.009)
Herlitz et al. 1997 65	Retrospective cohort study, 1212 patients were enrolled. Patients with out‐of‐hospital‐cardiac arrest found in VF, with and without lidocaine treatment, were analyzed.	Primary end point: Survival to hospital discharge	In case of sustained VF, as well as after conversion to a pulse‐generating rhythm, patients treated with lidocaine had a higher rate of ROSC and were more likely to hospitalized alive (p < 0.01 for ROSC and being hospitalized alive). The proportion of patients being discharged did not significantly defer between the lidocaine and the no lidocaine groups.

Abbreviations: CPR, cardiopulmonary resuscitation; LVEF, left ventricular ejection fraction; OR, odds ratio; ROSC, return of spontaneous circulation; VF, ventricular fibrillation; VT, ventricular tachycardia.

ROLE OF LIDOCAINE IN CURRENT INTERNATIONAL GUIDELINES

In current ESC, AHA/American College of Cardiology (ACC)/ Heart Rhythm Society (HRS), and Canadian Cardiovascular Society (CCS) guidelines for the management of patient with VA recommendations for the use of lidocaine differ ⁴⁴ , ⁴⁵ but similar to mexiletine ⁴⁶ the role of lidocaine is very limited (Table 2): The recent ESC Guideline ⁴⁷ considers lidocaine solely as second‐line therapy for the treatment of VA associated with an acute coronary syndrome (class IIb). In addition, the 2017 AHA/ACC/HRS ⁴⁸ guideline gives a class IIa recommendation for the use of lidocaine in case of a witnessed cardiac arrest due to VF or polymorphic VT that is unresponsive to CPR, defibrillation, and vasopressor therapy. Similarly, the 2020 CCS/Canadian Heart Rhythm Society (CHRS) ⁴⁹ position statement suggests a strong recommendation for the use of lidocaine in patients with shock refractory VT/VF or recurrent polymorphic VT/VF and additionally considers lidocaine as second‐line alternative to procainamide for the acute treatment of stable monomorphic VT in patients with structural heart disease. All guidelines agree on initial bolus followed by continuous maintenance infusion or repeat bolus in case of shock refractory arrhythmias, although recommended doses differ. ⁴⁷

TABLE 2.

Indications for the use of lidocaine as an antiarrhythmic drug in the current international guidelines.

	2022 ESC guideline	2017 AHA/ACC/HRS guideline	2020 CCS/CHRS position statement
General indication	Polymorphic VT/VF associated with ACS	VT/VF	monomorphic VT, polymorphic VT/VF
Specific recommendations for the use of i.v. lidocaine (class of recommendation)	Recurrent PVT/VF not responding to beta‐blockers or amiodarone, or if amiodarone is contraindicated during the acute phase of ACS (II b)	Witnessed cardiac arrest due to VF or polymorphic VT that is unresponsive to CPR, defibrillation, and vasopressor therapy (class IIa) Prophylactic administration of lidocaine […] for the prevention of VT in patients with suspected acute myocardial infarction is potentially harmful (class III)	Acute treatment of patients with shock refractory VT/VF (failure of at least 1 attempt at defibrillation) or patients with recurrent polymorphic VT/ VF, unless there is a strong suspicion of torsade de pointes (strong recommendation) Second‐line alternative to procainamide for acute treatment of stable monomorphic VT in patients with SHD (strong recommendation)
Dose (i.v.)	50–200 mg bolus, then 2–4 mg/min	1 mg/kg bolus, 1–3 mg/min 1–1.5 mg/kg, repeat 0.5–0.75 mg/kg bolus every 5–10 min (max. cumulative dose 3 mg/kg) Maintenance infusion is (0.5)‐1–4 mg/min	Shock refractory VT/VF: 100 mg bolus (50 mg if <45 kg) with a subsequent dose of 50 mg bolus in the event of failure of another shock Acute treatment of sustained monomorphic VT: 1 mg/kg bolus, followed by 1–2 mg/min infusion
Recommendations for pregnancy	Use only if potential benefit outweighs potential risks	–	–

Abbreviations: ACC, American College of Cardiology; ACS, American Community Survey; AHA, American Heart Association; CCS, Canadian Cardiovascular Society; CHRS, Canadian Heart Rhythm Society; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; PVT, portal vein thrombosis; SHD, structural heart disease; VF, ventricular fibrillation; VT, ventricular tachycardia.

SIDE EFFECTS OF LIDOCAINE

Side effects mostly occur when plasma concentrations rise to toxic levels. They mainly include effects on the central nervous system and on intraventricular conduction. Sinus bradycardia may be further slowed or induced, and sinus arrest related to lidocaine is discussed in several case reports. ⁶ , ⁵⁰ , ⁵¹ , ⁵² Focal and grand mal seizures, psychosis, respiratory arrests, drowsiness, decreased hearing, paraesthesia, disorientation, muscle twitching, and agitation are additional side effects. ⁵³ The metabolites of lidocaine (N‐dealkylation metabolites, monoethylglycerine‐xylidide, and glycine‐xylidide) may be responsible for central nervous system symptoms. ⁵⁴ , ⁵⁵ The therapy of these neurological side effects consists of lidocaine withdrawal and therapy with sedatives, for example, barbiturates and/or diazepam. An increased incidence of lidocaine toxicity, including central nervous system disturbances, is seen in patients with severe liver disease and congestive heart failure as the clearance of lidocaine is limited by hepatic blood flow, resulting in elevated blood concentrations. Thus, depressed cardiac output with the consequence of reduced hepatic blood flow in patients with acute myocardial infarction must also be considered while applying lidocaine. ¹⁵

CONCLUSION

Lidocaine has got well investigated anti‐arrhythmic effects, especially on ischemic tissue. It has been the anti‐arrhythmic of choice for the treatment of VA in acute myocardial infarction for several decades. According to the Vaughan Williams classification, it is classified as a class Ib anti‐arrhythmic drug ⁵⁶ that blocks voltage‐ and pH‐dependent sodium channels, resulting in decreased conduction. The ventricular fibrillatory threshold is increased. Tachycardias caused by re‐entrant mechanisms can be interrupted by decreasing action potential duration and increasing the effective refractory period. This effect is most prominent in the presence of myocardial ischemia. Due to controversial experimental and clinical data, reporting both efficacy ³⁹ , ⁵⁷ , ⁵⁸ and ineffectiveness ⁵⁹ of lidocaine in preventing life‐threatening VA during acute myocardial infarction, the use of lidocaine has declined and the era of amiodarone has emerged at the same time. As pointed out by MacMahon et al., ⁶ in an overview of randomized, controlled trials of prophylactic lidocaine use in suspected myocardial infarction, “there was no evidence of any beneficial effect on early mortality.” Thus, a prophylactic use of lidocaine is no longer recommended. However, lidocaine has returned as an alternative to amiodarone or as second‐line therapy for refractory VT. But more trials are needed to investigate the role of lidocaine in the era of amiodarone and modern electric device therapy.

FUNDING INFORMATION

No funding was received for this work.

CONFLICT OF INTEREST STATEMENT

The authors declared no competing interests for this work.

Güler S, Könemann H, Wolfes J, et al. Lidocaine as an anti‐arrhythmic drug: Are there any indications left? Clin Transl Sci. 2023;16:2429‐2437. doi: 10.1111/cts.13650