Antidysrhythmic Toxicity Workup
- Author: Nidhish Sasi, MD; Chief Editor: Asim Tarabar, MD more...
Laboratory tests for patients with antidysrhythmic toxicity vary according to the individual agent.
The role of drug concentration testing for acute toxicity in the emergency department is extremely limited. Serum concentrations of quinidine and lidocaine may be measured in the acute care setting, but treatment for presumed toxicity should be based on clinical grounds rather than serum concentrations.
Therapeutic concentrations for quinidine are 2-6 mg/mL, and toxic concentrations are greater than 8 mg/mL. Concentrations above 14 mg/mL are associated with cause cardiac toxicity in most patients.
Tests for levels of lidocaine and its metabolite, monoethylglycinexylidide (MEGX), are available. Effective plasma concentrations are 1.5-5 mg/mL. CNS toxicity is seen with 7 mg/mL, and fatal concentrations are greater than 15 mg/mL for an adult and at least 3.8 mg/mL for a child.
Electrolyte assays, including potassium and magnesium levels, are appropriate for patients taking drugs that can prolong the corrected QT (QTc) interval.
An electrocardiogram (ECG) should be performed on every patient with suspected antidysrhythmic toxicity. Physicians should look out for features such as QRS widening and QTc prolongation. QRS widening is most likely to be present in patients taking drugs with sodium-channel blocking effects (class I antidysrhythmics, amiodarone, dronedarone). QTc prolongation can occur with any drug that delays repolarization (class IA, IC, and III drugs).
Monitoring and evaluation of individual agents
Cardiac monitoring, serial ECGs and blood pressure measurements should be performed regularly. Vital signs should be monitored to assess for excessive anticholenergic effects and any evidence of worsening heart failure or dysrhythmias. Serum mono-N-dealkyldisopyramide concentration can be measured and if it is over approximately 1 microg/mL, the dose should be decreased or discontinued. Blood glucose should be regularly monitored.
Renal function and hepatic function should be assessed and monitored throughout therapy. ECGs and blood pressure measurements should be performed regularly. Agranulocytosis and pancytopenia can occur at therapeutic doses; a complete blood cell count (CBC) with differential should be obtained regularly during the first 3 months of therapy and then periodically checked. Antineutrophil antibody (ANA) and anti-histones may be monitored for rising levels to evaluate for drug-induced systemic lupus erythematosus (SLE). Unlike drug-induced lupus, idiopathic SLE will be positive for anti-double stranded DNA antibodies and hypocomplementemia.[17, 34]
Cardiac monitoring, ECGs, and frequent vital sign reassessments are indicated. Serum creatinine should be checked and the quinidine dosage reduced if the patient has renal insufficiency. A CBC should be checked for hematologic reactions.
Lidocaine toxicity is primarily assessed clinically. Lidocaine should be administered under ECG monitoring during cardiac arrest events. If the clinician is concerned about local anesthetic toxicity, IV access and cardiac monitoring should be instituted. In severe toxicity, blood gases may be obtained.
Drug initiation should take place in a monitored hospital setting, given the potential for ventricular dysrhythmias.
Blood pressure, renal function, and hepatic function should be assessed before drug administration. Serum concentrations can be followed in patients with hepatic or renal insufficiency. Electrolytes should be monitored.
ECG, blood pressure, and hepatic function tests should be performed at baseline. Agranulocytosis can occur, so a CBC with differential should be periodically checked.
Amiodarone toxicity is cumulative, with increased dosage and length of treatment time as the largest factors. Patients at highest risk of amiodorone toxicity include those taking 400 mg/day for longer than 2 months or 200 mg/day for 2 years.
Patients taking amiodarone should have baseline pulmonary function tests, chest radiography, thyroid function tests, and liver function tests performed, and should have these tests repeated on a regular basis while taking the drug.
In patients presenting with pulmonary symptoms suggestive of pneumonitis, a positive gallium scan may help to differentiate amiodarone pneumonitis from other processes, such as pulmonary embolism and congestive heart failure .
Fatal hepatotoxicity from amiodarone occurs in 1-3% of patients. Toxicity is dose and duration dependent. Liver function tests are recommended every 3-6 months.
Patients with an implanted cardioverter-defibrillator (ICD) who have been loaded with amiodarone should have an ICD evaluation or an electrophysiology study to evaluate for drug-device interactions, according to North American Society of Pacing and Electrophysiology (NASPE) guidelines. [35, 36]
Patients on dronedarone should have regular ECGs to look for evidence of QTc prolongation. Transaminase levels and electrolytes should periodically checked throughout treatment. Serum creatinine levels should be checked periodically. Concomitant medications that are renally cleared should be monitored for adverse reactions.
Patients should have a baseline creatinine clearance and QTc interval measured before initiating therapy. QTc intervals should be checked regularly during long-term oral use. QTc interval greater than 450 milliseconds is a contraindication to therapy. Sotalol should be discontinued or reduced if the QTc exceeds 500 milliseconds or if there is a change in QTc interval exceeeding 15% from a baseline wide QRS (>120 ms).
Patients should have a baseline ECG. Ibutilide is not recommended if the baseline QTc is greater than 440 milliseconds. Serum potassium and magnesium levels should be measured, and potassium and magnesium should be repleted before administering sotalol. Continued ECG monitoring should be performed during the dosing period and for at least 4-6 hours, given the risk for ventricular arrhythmias. Ibutilde should be used with cautions in patients with structurally abnormal hearts, depressed left ventricular function, or a history of ischemia or myocardial infarction, because ibutilde-induced torsade de pointes may be difficult to treat in such patients.[37, 14]
Initiation of dofetilide should be conducted under continued cardiac monitoring in a hospital setting for several days, to ensure that significant QTc prolongation does not occur and to avoid torsade de pointes. Dofetilide should not be given to patients with a creatinine clearance of less than 20 mL/min or a baseline QTc greater than 440 milliseconds. The initiation and prescription of dofetilide should be restricted to physicians who have trained in the monitoring of this medicatio,n due to its prodysrhythmic effects.
Rhythm monitoring should be performed during administration of adenosine, ideally with a continuous 12-lead rhythm strip.
Duncan WJ, Tyrrell MJ, Bharadwaj BB. Disopyramide as a negative inotrope in obstructive cardiomyopathy in children. Can J Cardiol. 1991 Mar. 7 (2):81-6. [Medline].
Atkinson AJ Jr, Krumlovsky FA, Huang CM, del Greco F. Hemodialysis for severe procainamide toxicity: clinical and pharmacokinetic observations. Clin Pharmacol Ther. 1976 Nov. 20(5):585-92. [Medline].
Mok NS, Chan NY, Chiu AC. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004 Jun. 27 (6 Pt 1):821-3. [Medline].
Collinsworth KA, Kalman SM, Harrison DC. The clinical pharmacology of lidocaine as an antiarrhythymic drug. Circulation. 1974 Dec. 50 (6):1217-30. [Medline].
Napolitano C, Bloise R, Priori SG. Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacol Ther. 2006 Apr. 110 (1):1-13. [Medline].
Kusumoto M, Ueno K, Oda A, Takeda K, Mashimo K, Takaya K, et al. Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men. Clin Pharmacol Ther. 2001 Mar. 69 (3):104-7. [Medline].
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21. 324 (12):781-8. [Medline].
Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000 Aug 29. 102 (9):945-7. [Medline].
Siu CW, Wong MP, Ho CM, Lam CL, Tse HF. Fatal lung toxic effects related to dronedarone use. Arch Intern Med. 2012 Mar 26. 172 (6):516-7. [Medline].
Tschuppert Y, Buclin T, Rothuizen LE, Decosterd LA, Galleyrand J, Gaud C, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007 Dec. 64 (6):785-91. [Medline].
Saarimaa H. Combination of clonidine and sotalol in hypertension. Br Med J. 1976 Apr 3. 1 (6013):810. [Medline].
Frick M, Darpö B, Ostergren J, Rosenqvist M. The effect of oral magnesium, alone or as an adjuvant to sotalol, after cardioversion in patients with persistent atrial fibrillation. Eur Heart J. 2000 Jul. 21 (14):1177-85. [Medline].
Somberg JC, Preston RA, Ranade V, Cvetanovic I, Molnar J. Gender differences in cardiac repolarization following intravenous sotalol administration. J Cardiovasc Pharmacol Ther. 2012 Mar. 17(1):86-92. [Medline].
Nair M, George LK, Koshy SK. Safety and efficacy of ibutilide in cardioversion of atrial flutter and fibrillation. J Am Board Fam Med. 2011 Jan-Feb. 24 (1):86-92. [Medline].
Singh S, Zoble RG, Yellen L, Brodsky MA, Feld GK, Berk M, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation. 2000 Nov 7. 102 (19):2385-90. [Medline].
Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].
Zitnik, RJSO. Drug-induced lung disease: Antiarrhythmic agents. J Respir Dis. 1996. 17:254.
Venkayya RV, Poole RM, Pentz WH. Respiratory failure from procainamide-induced myopathy. Ann Intern Med. 1993 Aug 15. 119 (4):345-6. [Medline].
Godley PJ, Morton TA, Karboski JA, Tami JA. Procainamide-induced myasthenic crisis. Ther Drug Monit. 1990 Jul. 12 (4):411-4. [Medline].
Cohen IS, Jick H, Cohen SI. Adverse reactions to quinidine in hospitalized patients: findings based on data from the Boston Collaborative Drug Surveillance Program. Prog Cardiovasc Dis. 1977 Sep-Oct. 20 (2):151-63. [Medline].
Mintzer J, Burns A. Anticholinergic side-effects of drugs in elderly people. J R Soc Med. 2000 Sep. 93 (9):457-62. [Medline].
Somberg JC, Timar S, Bailin SJ, Lakatos F, Haffajee CI, Tarjan J, et al. Lack of a hypotensive effect with rapid administration of a new aqueous formulation of intravenous amiodarone. Am J Cardiol. 2004 Mar 1. 93 (5):576-81. [Medline].
Lindquist DE, Rowe AS, Heidel E, Fleming T, Yates JR. Evaluation of the Hemodynamic Effects of Intravenous Amiodarone Formulations During the Maintenance Phase Infusion. Ann Pharmacother. 2015 Dec. 49 (12):1317-21. [Medline].
Nacca N, Bhamidipati CM, Yuhico LS, Pinnamaneni S, Szombathy T. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012 Dec. 4 (6):667-70. [Medline].
Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008 Jul. 66 (1):82-7. [Medline].
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997 Sep. 30 (3):791-8. [Medline].
Orr CF, Ahlskog JE. Frequency, characteristics, and risk factors for amiodarone neurotoxicity. Arch Neurol. 2009 Jul. 66 (7):865-9. [Medline].
Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008 Jun 19. 358(25):2678-87. [Medline].
Danielly J, DeJong R, Radke-Mitchell LC, Uprichard AC. Procainamide-associated blood dyscrasias. Am J Cardiol. 1994 Dec 1. 74 (11):1179-80. [Medline].
Hudson CJ, Whitner TE, Rinaldi MJ, Littmann L. Brugada electrocardiographic pattern elicited by inadvertent flecainide overdose. Pacing Clin Electrophysiol. 2004 Sep. 27(9):1311-3. [Medline].
Thevenin J, Da Costa A, Roche F, Romeyer C, Messier M, Isaaz K. Flecainide induced ventricular tachycardia (torsades de pointes). Pacing Clin Electrophysiol. 2003 Sep. 26 (9):1907-8. [Medline].
Odeh M, Seligmann H, Oliven A. Propafenone-induced ataxia: report of three cases. Am J Med Sci. 2000 Aug. 320 (2):151-3. [Medline].
MacNeil DJ, Davies RO, Deitchman D. Clinical safety profile of sotalol in the treatment of arrhythmias. Am J Cardiol. 1993 Aug 12. 72(4):44A-50A. [Medline].
Merola JF. Lupus-like syndromes related to drugs. Schur PH, Massarotti E. Lupus Erythematosus: Clinical Evaluation and Treatment. New York: Springer; 211-221.
[Guideline] Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med. 2000 Jun 26. 160 (12):1741-8. [Medline].
Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother. 1995 Jun. 29 (6):582-6. [Medline].
Gowda RM, Khan IA, Wilbur SL, Vasavada BC, Sacchi TJ. Torsade de pointes: the clinical considerations. Int J Cardiol. 2004 Jul. 96 (1):1-6. [Medline].
Tzivoni D, Keren A, Stern S, Gottlieb S. Disopyramide-induced Torsade de Pointes. Arch Intern Med. 1981 Jun. 141 (7):946-7. [Medline].
Arimori K, Kawano H, Nakano M. Gastrointestinal dialysis of disopyramide in healthy subjects. Int J Clin Pharmacol Ther Toxicol. 1989 Jun. 27 (6):280-4. [Medline].
Holt DW, Helliwell M, O'Keeffe B, Hayler AM, Marshall CB, Cook G. Successful management of serious disopyramide poisoning. Postgrad Med J. 1980 Apr. 56 (654):256-60. [Medline].
Neal JM, Mulroy MF, Weinberg GL, American Society of Regional Anesthesia and Pain Medicine. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg Anesth Pain Med. 2012 Jan-Feb. 37 (1):16-8. [Medline].
Mazoit JX, Le Guen R, Beloeil H, Benhamou D. Binding of long-lasting local anesthetics to lipid emulsions. Anesthesiology. Feb 2009. 110(2):380-6. [Medline].
Akinci E, Yüzbasioglu Y, Coskun F. Hemodialysis as an alternative treatment of mexiletine intoxication. Am J Emerg Med. 2011 Nov. 29(9):1235.e5-6. [Medline].
Ellsworth H, Stellpflug SJ, Cole JB, Dolan JA, Harris CR. A life-threatening flecainide overdose treated with intravenous fat emulsion. Pacing Clin Electrophysiol. 2013 Mar. 36(3):e87-9. [Medline].
Auzinger GM, Scheinkestel CD. Successful extracorporeal life support in a case of severe flecainide intoxication. Crit Care Med. 2001 Apr. 29(4):887-90. [Medline].
Qamar S, Hassan W, Sra J, Akhtar M, Mortada ME. Abstract 14890: Hyponatremia Associated with Flecainide: Case Series. Circulation. 2012. 126.21:[Full Text].
Khavandi A, Walker. Flecainide cardiotoxicity precipitated by electrolyte imbalance. Caution with thiazide diuretics. Emerg Med J. 2007. 24(5):[Medline].
Wozakowska-Kaplon B, Stepien-Walek A. Propafenone overdose: cardiac arrest and full recovery. Cardiol J. 2010. 17(6):619-22. [Medline].
Ovaska H, Ludman A, Spencer EP, Wood DM, Jones AL, Dargan PI. Propafenone poisoning--a case report with plasma propafenone concentrations. J Med Toxicol. 2010 Mar. 6 (1):37-40. [Medline].
Patsilinakos S, Christou A, Kafkas N, Nikolaou N, Antonatos D, Katsanos S, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol. 2010 Sep 1. 106 (5):673-6. [Medline].
Jovic-Stosic J, Gligic B, Putic V, Brajkovic G, Spasic R. Severe propranolol and ethanol overdose with wide complex tachycardia treated with intravenous lipid emulsion: a case report. Clin Toxicol (Phila). 2011 Jun. 49(5):426-30. [Medline].
Montiel V, Gougnard T, Hantson P. Diltiazem poisoning treated with hyperinsulinemic euglycemia therapy and intravenous lipid emulsion. Eur J Emerg Med. 2011 Apr. 18(2):121-3. [Medline].
French D, Armenian P, Ruan W, Wong A, Drasner K, Olson KR, et al. Serum verapamil concentrations before and after Intralipid® therapy during treatment of an overdose. Clin Toxicol (Phila). 2011 Apr. 49(4):340-4. [Medline].
French D, Smollin C, Ruan W, Wong A, Drasner K, Wu AH. Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies. Clin Toxicol (Phila). 2011 Nov. 49(9):801-9. [Medline].
Martindale JL, Brown DFM. Rapid Interpretation of ECGs in Emergency Medicine: A Visual Guide. Lippincott Williams and Wilkins; 2012.
EM Williams. Classifying antiarrhythmic actions: by facts or speculation. The Journal of Clinical Pharmacology. 1992 Nov. 32:964–77. [Medline].
Lim YP, Lin CL, Lin YN, Ma WC, Chen WC, Hung DZ, et al. Antiarrhythmic agents and the risk of malignant neoplasm of liver and intrahepatic bile ducts. PLoS One. 2015. 10 (1):e0116960. [Medline].
Benowitz NL. Antiarrhythmic Drugs. Olson KR. Poisoning & Drug Overdose. 6th. Mcgraw-Hill; 2012.
Piña IL, Oghlakian G. Adverse Cardiovascular Drug Interactions and Complications. Fuster V, Walsh RA, Harrington RA. Hurst's The Heart. 13th. Mcgraw-Hill; 2011.
Benowitz NL. Quinidine and Other Type Ia Antiarrhythmic Drugs. Olson KR. Poisoning & Drug Overdose. 6th ed. McGraw-Hill; 2012.
Trevor AJ, Katzung BG, Kruidering-Hall. Antiarrhythmic Drugs. Trevor AJ, Katzung BG, Kruidering-Hall. Katzung & Trevor's Pharmacology: Examination & Board Review,. 11th ed. McGraw-Hill; 2015.
Frishman WH, Alwarshetty M. Beta-adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the current guidelines. Clin Pharmacokinet. 2002. 41 (7):505-16. [Medline].
Ting SM, Lee D, Maclean D, Sheerin NS. Paranoid psychosis and myoclonus: flecainide toxicity in renal failure. Cardiology. 2008. 111 (2):83-6. [Medline].
Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide. Am J Cardiol. 1984 Feb 27. 53 (5):101B-105B. [Medline].
Tsuchishita Y, Fukumoto K, Kusumoto M, Ueno K. Effects of serum concentrations of disopyramide and its metabolite mono-N-dealkyldisopyramide on the anticholinergic side effects associated with disopyramide. Biol Pharm Bull. 2008 Jul. 31 (7):1368-70. [Medline].