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Cardiovascular Effects of Carbamazepine Toxicity
TOXICOLOGY/ORIGINAL
CONTRIBUTION
Cardiovascular Effects of Carbamazepine Toxicity From the Division of Emergency
Jonathan D Apfelbaum, MD*
Study objective: To evaluate the cardiovascular effects of
Medicine, Universityof Utah School of Medicine*, and Utah Poison Control Center~, Salt Lake City,
E Martin CaraVati, MD, MPH *~
carbamazepine in patients presenting to the emergency department.
Utah; Department of Emergency
Medicine, CarolinasMedical Center s ,
William P Kerns II, MD e'' Philip J Bossart, MD* Gordon Larsen, MD ~
and Carolinas Poison Center II, Charlotte, North Carolina; and Department of Emergency Medicine,
Design: A retrospective case series from February 1, 1985, to July 30, 1993.
Setting: Six urban EDs.
St. FrancisMedical Center, Peoria, Illinois~.
Participants: Seventy-two adult and pediatric patients with
Receivedfor publication September 1, 1993. Revisions received
serum carbamazepine concentrations greater than 12 pg/mL and concurrent 12-lead ECGs.
July 18, 1994 and October31, 1994. Acceptedfor publication November 22, 1994. Preliminary data presented at the American Academy of Clinical ToxicologyAnnual Meeting, Toronto, Ontario, Canada, October 1991;final data presented at the Western Student Medical Research Forum, Monterey, California, February 1994, and at ACEP Research Forum, San Diego,
California, March 1994. Copyright © by the American College of Emergency Physicians.
Results: The mean carbamazepine level was 24 pg/mL (range, 12.6 to 55 t~g/mL). Minor ECG abnormalities were noted but no clinically significant arrhythmias were found. No correlation was found between carbamazepine concentration and heart rate or PR, QRS, or corrected QT intervals. Four adult patients had transient hypotension. Conclusion: Clinically significant cardiovascular toxicity occurs rarely in patients with toxic carbamazepine concentrations. ECG findings do not correlate with serum carbamazepine concentration. [Apfelbaum JD, Caravati EM, Kerns WP II, Bossart PJ, Larsen G: Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med May 1995;25:631-635.]
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C A R B A M A Z E P I N E TOXICITY Apfelbaum et al
INTRODUCTION
Carbamazepine (Tegretol) is an iminostilbene derivative with a tricyclic structure. It is a drug of choice for the treatment of simple and complex partial seizures, trigeminal and glossopharyngeal neuralgias, and certain affective disorders. Carbamazepine toxicity has been associated with cardiac effects, including sinus bradycardia, varying degrees of atrioventricular block, sinus tachycardia, and possibly QRS-interval and corrected QT (QTc) interval prolongations.i-3 Carbamazepine overdose may also induce central nervous system depression with concurrent respiratory depression, seizures, and hypothermia.4 Hospitalization and 24-hour continuous cardiac monitoring has been recommended for all patients with toxic carbamazepine levels. 5 This study was designed to evaluate the frequency and severity of cardiovascular effects associated with carbamazepine toxicity. MATERIALS AND METHODS
Hospital records of patients admitted to six urban teaching hospitals for carbamazepine toxicity between February 1985 and July 1993 were evaluated as a retrospective case series. Patients were identified on the basis of hospital computerized discharge diagnosis for anticonvulsant toxicity (ICD-9 codes at all participating facilities), Regional Poison Control Centers listing of overdoses in Utah and North Carolina, and the Drug Abuse Warning network at Carolinas Medical Center. This study was approved by the institutional review boards of all participating facilities.
Inclusion criteria were a serum carbamazepine concentration greater than 12 gg/mL and a 12-lead ECG performed concurrently in the emergency department. Exclusion criteria were the presence of medications known to affect the ECG such as tricyclic antidepressants, digoxin, ~-blockers, or type I antiarrhythmic drugs (eg, quinidine). Patients were included in the cardiac data evaluation but excluded from the Glasgow Coma Scale (GCS) group if they had either a serum ethanol concentration of greater than 100 mg/dL (21.7 mmol/L) or the presence of other drug ingestions (eg, opiates) known to alter the sensorium. Patient data included age, sex, acute or chronic exposure, dose, method of decontamination (ipecac, gastric lavage, activated charcoal), other drugs ingested, GCS score in the ED, serum carbamazepine concentration, duration of cardiac monitoring, and ECG. ECGs were evaluated for rate; rhythm; PR, QRS, and QTc intervals (calculated with an ECG computer); frontal plane QRS axis; and frontal plane terminal 40-milfiseconds QRS axis (T40-milliseconds axis). In addition, episodes of arrhythmias, hypotension, respiratory compromise, and death were recorded. Patients were categorized as adult (older than 12 years) or pediatric (younger than 13 years). Patients were further categorized as having acute (single episode of ingestion) or chronic (routine ingestion of supratherapeutic dose) exposure. The basis for categorizing a patient was the presenting histo~ An acute overdose superimposed on longterm carbamazepine therapy was considered an acute exposure.
Table 1.
Demographics, exposure, and complications in carbamazepine toxicity. Pediatric Group
Adult Group Features No. of patients M/F Age (yr)* Serum carbamazepine (gg/mL)* GCS* Intubation Sinus tachycardia Conduction delays Prolonged QTc interval Prolonged QRS interval Bundle-branch block Prolonged PR interval * Mean_+SD(range).
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Acute 42 23:19 30_+11 (13-57) 25+10 (12.6-55) 11_+4(3-15) 4 (9%) 12 (27%) 22 (50%) 5 (11%) I (2%) 2 (5%)
Chronic
Acute
16 5:11 39+16 (t9-66) 20-+7 (14-40) 14+2 (6-15) O 2 (12%)
7 4:3 5_+4(2-12) 25+9 (14-38) 10+_4(5-15) 3 (43%) 1 (14%)
7 (38%) 4 (25%) 0 0
2 (29%) 1 (14%) 0 0
Chronic 7 5:2 9+4 (3-11) 22_+4(16-28) 12+_3(9-15) 1 (14%) 3 (43%) 4 (57%) 0 0 0
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Standard descriptive analysis was performed. Correlation coefficients were determined for linear relationships among ECG parameters, GCS, and carbamazepine concentration. Statistical significance was accepted if P was less than .05. Values are expressed as mean&+SD. RESULTS
Seventy-two patients met the inclusion criteria. This group comprised 58 adults (mean age, 32+13 years), of whom 42 had acute ingestion and 16 had chronic toxicity. Fourteen pediatric patients were enrolled (mean age, 7_+4 years); 7 in the acute and 7 in the chronic category In 60% of patients the amount of carbamazepine ingested was unknown, in 27% it was less than 5 g, in 5% it was between 5.1 and 10 g, in 1% it was between 10.1 and 15 g, and in 7% it was between 15.1 and 20 g. The times between ingestion and presentation could not be reliably determined. Twenty-five patients had repeat carbamazepine assays. In 4 patients, carbamazepine levels were higher than the initial levels found in the ED. Toxicology screening revealed one patient with stimulant amines (heart rate, 99), one patient with a therapeutic thorazine level (heart rate, 148, QT c, 426), one patient with cocaine (heart rate, 140), two patients with amantidine (heart rates, 70 and 76), and one patient with a dilantin level of 1.7 btg/ml. Forty-five percent of adults (57% of acute ingestions, 13% with chronic toxicity) and 36 % of children (57% acute, 13% chronic) underwent gastric emptying. Seventyfive percent of adults (84% in the acute category, 50% in the chronic group) and 50% of children (57% acute, 43% chronic) received activated charcoal in the ED. Ages, maximum carbamazepine concentrations, GCS scores, acute versus chronic ingestion, and complications are listed in Table 1. Fifty percent of adult and 67% of
pediatric patients had mental status changes. GCS score was correlated inversely with carbamazepine concentration (P=.000E, r=.584). Four adults (7%) and four children (29%) underwent endotracheal intubation, one adult underwent hemoperfusion filtration for high serum carbamazepine concentration, one adult had a generalized tonic-clonic seizure thought to be a result of carbamazepine toxicity, four adults exhibited transient hypotension in the ED (range, 100170 mm Hg to 80/60 mm Hg) that responded to fluid bolus, and one patient's hospitalization was complicated by pneumomediastinum. There were no deaths. ECG parameters showed multiple minor abnormalities (Table 2). Of the adults, 14 patients (23%) had sinus tachycardia (heart rate greater than 100) on presentation. Two patients had first-degree atrioventricular block (PR greather than 200 milliseconds). No other ECGs were available for these two patients. Nine adults (15%) had QRS-interval prolongation (normal, less than 100 milliseconds). 6 In three cases the QRS-interval prolongation was known to be preexisting, and in the other six cases no prior ECGs were available. Twenty-nine adult cases (50%) had prolonged QT intervals, with our series mean at the upper limit of the normal range (normal, less than 420 milliseconds). 6 One patient had a left bundle-branch block (no prior ECG available). No statistical correlation was found between serum carbamazepine concentration and heart rate (P=.278, r=.257), PR interval (P=.514, r=.179), QRS interval (P=.979, r=.003), QT c interval (P=. 126, r=. 179), T40 milliseconds axis (P=.860, r=.023), or QRS axis (P=. 100, r=.215). Only three adult patients had previous ECGs available for comparisons, and only nine patients had repeat ECGs after admission to the hospital. In the pediatric population, five patients had sinus tachycardia (36%), defined as heart rate greater than 160 in patients 2 years old, greater than 130 in patients 2 to 5
Table 2.
ECG parameters in carbarnazepine-toxicity patients. Adult Group Parameters Heart rate PR interval (milliseconds) QRS complex duration (milliseconds) QTc interval (milliseconds) QRS axis (degrees) T40-milliseconds axis (degrees) Dataexpressedas mean_+SD(range).
Acute 90+_16(64-148) 163+_28(120-240) 89+12 (60-116) 420_+31 (340-487) 53+_27(-17-93) 98+_82(-60-270)
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Pediatric Group Chronic 80+14 (60-102) 163+_17(124-180) 92_+12(80-112) 418_+22(380-460) 43_+32(~49-94) 58+67 (-30-220)
Acute 104_+16(85-130) 141_+23(103-105) 83_+18(70-120) 405_+30(363-452) 65_+31 (30-119) 79+_67(0-210)
Chronic 106_+23(75-140) 155_+24(113-176) 82+_7(70-92) 420+_11 (400-436) 41_+33(-18-80) 95+_100(-30-270)
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years old, and greater than 100 if over 5 years of age. The PR intervals were within normal limits. QRS width was prolonged in one patient with known preexisting cardiac conduction defect. The QRS axis was normal, with the exception of right axis deviation in one patient. The QT C interval was prolonged in four cases (29%). As in the adult population, no statistical correlation was found between serum carbamazepme concentration and heart rate (P=.181, r=.379), PR interval (P=.363, r=.263), QRS width (P=.233, r=.341), QRS axis (P=.539, r=.180), QT c interval (P=.67, r=. 125) or T40-ms axis P=. 102, r=.445). Only one pediatric patient had a previous ECG, and only two patients had repeat ECG after admission. Continuous cardiac monitoring was performed in 66% of cases for periods of up to 168 hours (mean 32+35 hours), but no arrhythmias or ectopy was found. All cardiac conduction defects were discovered on the initial ECG obtained in the ED. DISCUSSION
The exact frequency and severity of cardiovascular toxicity in patients with carbamazepine overdose are unknown. Acute intoxication with carbamazepine may cause many of the symptoms (central nervous system depression, anticholinergic effects, cardiovascular effects, and, possibly, seizures) caused by acute tricydic antidepressant toxicity. Because the structure of carbamazepme is very similar to those of the tricyclic antidepressants, it is reasonable to assume that cardiovascular toxicity may develop in patients with carbamazepine overdose, leading some authors to recommend 24-hour cardiac monitoring in patients with CBZ ingestion. 5 In vitro and in vivo studies in dogs have demonstrated impaired AV conduction from CBZ. r In addition, many case reports have described carbamazepine-induced sinus bradycardia and heart block m patients with supratherapeutic and even therapeutic drug levels, s-> However, most of these case reports involve elderly patients with underlying heart disease. Puletti et al evaluated 92 patients with therapeutic carbamazepine concentrations and concluded that clinically significant conduction disorders do not occur m younger patients receiving carbamazepine. 15 The few published series of patients with toxic ingestions of carbamazepine have demonstrated only sinus tachycardia as a frequent cardiovascular effect. Spiller et al reported 62 cases of CBZ overdoseJ 6 They found sinus tachycardia in 35% of the patients, one case of asymptomatic second-degree heart block, and no cases
634
of hypotension or arrhythmias. Seymor reported 33 cases of carbamazepine overdose} This investigator found four cases of transient first-degree heart block and no cases of hypotension. Hojer et al reported 28 cases of massive carbamazepine poisoning. 17 They found that 36% of the patients had sinus tachycardia. In addition, in four patients AV block, transient QRS prolongation, life-threatening arrhythmias, or all three developed. Because all four of these patients were comatose and had respiratory failure and seizures, it is unclear whether their cardiovascular toxicity was due to carbamazepine alone or was the result of hypoxemia and acidemia. Tibballs reported 82 pediatric patients with CBZ ingestion, and noted several cases of hypotension and some conduction defects, but the frequency and severity of these cases were not reported. ~s Our study is one of the largest series of carbamazepine overdose cases. The low frequency of significant cardiovascular toxicity in this study is in agreement with other, smaller series. No patient in our study had arrhythmia noted other than sinus tachycardia. There were four cases of mild transient hypotension; none of these patients was symptomatic or required therapy other than IV fluid. The large number of patients with QRS and QT c prolongation is surprising; carbamazepine is not known to affect QRS or QT c intervals. 2,r However, the vast majority of these cases had QRS or QT c intervals (or both) only slightly above normal. Very few patients had previous ECG or repeat ECGs. Therefore we were unable to determine whether the prolongation was due to carbamazepine. No correlation was found in this study between CBZ levels and heart rate or PR, QRS, and QT c intervals. This is further evidence that carbamazepine does not have a frequent or consistent effect on the cardiac conduction system. Because tricyclic antidepressant ingestion has been associated with rightward rotation of the T40 milliseconds, we determined whether CBZ ingestion had a similar association. 19,2° No correlation between carbamazepine concentration and the ]740 milliseconds axis was found. A greater percentage of pediatric than adult patients (29% versus 7%) underwent intubation on admission. The sample size, however, was too small in this retrospective series for us to reliably analyze these data. There are several limitations to this study. Because it was a retrospective, sampling bias existed. Missing data from the medical record could lead to underreporting of cardiovascular complications. Furthermore, our study population was relatively young and without apparent underlying cardiac disease. Elderly patients and those
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with known heart disease would be expected to have more frequent cardiac toxicity from carbamazepine ingestion. Many of our patients had minimally increased serum carbamazepine concentrations. One might expect the incidence of cardiovascular effects to be more severe in patients with higher carbamazepine levels. Finally, this was a descriptive study without a control population. It is impossible to know, therefore, whether the ECG abnormalities were truly caused by carbamazepine. The only reliable control population for this study would be the pretoxicity and posttoxicity ECGs from this same group of patients. Unfortunately, these data are not available. Other control groups would be unsatisfactory because they would introduce new biases into the study.
16. Spiller HA, KrenzelokEP, CooksonE: Carbamazepineoverdose:A prospective study of serum levels and toxicity. J Toxicol Clio Toxico11990;28:445-458. 17. Hajar J, Malmlund HO, Borg A: Clinical features in 28 consecutive cases of laboratory-confirmed massive poisoning with carbamazepinealone. Clin Toxico11993;31:449-458. 18. Tibballs J: Acute toxic reaction to carbamazepine:Clinical effects and serum concentrations. J Pediatr 1992;121:295-299. 19. Wolfe TR, Caravati EM, Rollins DE: Terminal 40-ms frontal plane QRSaxis as a marker for tricyclic antidepressant overdose.Ann EmergMeal 1989;18:348-351. 20. Caravati EM, Bossart PJ: Demographicand electrocardiographicfactors associated with severe tricyclic antidepressant toxicity. J Toxicol Clio Toxico11991;29:31-43.
Reprint no. 47/1/63146 Address for reprints: E Martin Caravati, MD, MPH Division of Emergency Medicine University of Utah Health Science Center 1150 Moran Building
CONCLUSION
75 North Medical Drive
Patients with toxic carbamazepine concentrations have a low incidence of clinically significant cardiovascular toxicity. ECG findings are not correlated with serum carbamazepine concentrations.
Salt Lake City, Utah 84132 801-581-2417 Fax 801-585-6699
REFERENCES 1. Fisher RS, CysykB: A fatal overdose of carbamazepine:Case report and review of literature. J Toxicot Clin Toxicol 1988;26:477-486. 2. SeymourJF: Carbamazepineoverdose: Featuresof 33 cases. Drug Safety 1993;8:81-88. 3. Weaver DF, Camfield P, FraserA: Massive carbamazepineoverdose: Clinical and pharmacologic observations in five episodes. Neuro/ogy1988;38:755q59. 4. Goldfrank LR, Osborn H, Brenitz EA: Phenytoin and other anticonvulsants, in Goldfrank LR (ed): Toxicological Emergencies, ed 4. East No~alk, Connecticut, Appleton and Lange, 1990, p 333. 5. Sulfivan JB, RumackBH, Petersen RG: Acute carbamazepinetoxicity resulting from overdose. Neurology 1981;31:621-624. 6. GoldbergerAL: Electrocardiography,in Goldberger E (ed): Textbookof Clinical Cardiology.St. Louis, CV Mesby, 1982, p 129-184. 7. Steiner C, Wit AL, Weiss MB, et ah The antiarrhythmic actions of carbamazepine(Tegretol). J PharmaeolExp Thor1970;173:323-325. 8. BeermannB, EdhagO, Vallin H: Advanced heart block aggravated by carbamazepine.Br Heart J 1975;37:668-671. 9. Kasarskis EJ, Kue CS, Berger R, et al: Carbamazepine-inducedcardiac dysfunction: Characterizationof two distinct clinical syndromes. Arch Intern Me(/1992;152:186-191. 10. LabrecqueJ, Cote MA, Vincent P: Carbamazepine-inducedatrioventricular block. Am J Psychiatr 1992;149:572-573. 11. Leslie PJ, Heyworth R, Prescott LF: Cardiaccomplications of carbamazepineintoxication: Treatment by haemoperfusion.BMJ 1983;286:1018. 12. Maenab A, RobinsonJ, Adderly R, et ah Heart block secondaryto erythremycin-inducedcarbamazepinetoxicity. Pediatrics 1987;80:951-953. 13. Hewetson KA, Ritch AES, Watson RDS: Sick sinus syndrome aggravated by carbamazepine therapy for epilepsy. Postgrad Meal J 1986;62:497-498. 14. Durelli L. Mutani R, Sechi G, et al: Cardiacside effects of phenytoin and carbamazepine:A dose-related phenomenon?Arch Neural 1985;42:1057-1058. 15. Pufetti M, lani C, Curione M, et ah Carbamazepineand the heart. Ann Neural 1991;29:575576.
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CONTRIBUTION
Cardiovascular Effects of Carbamazepine Toxicity From the Division of Emergency
Jonathan D Apfelbaum, MD*
Study objective: To evaluate the cardiovascular effects of
Medicine, Universityof Utah School of Medicine*, and Utah Poison Control Center~, Salt Lake City,
E Martin CaraVati, MD, MPH *~
carbamazepine in patients presenting to the emergency department.
Utah; Department of Emergency
Medicine, CarolinasMedical Center s ,
William P Kerns II, MD e'' Philip J Bossart, MD* Gordon Larsen, MD ~
and Carolinas Poison Center II, Charlotte, North Carolina; and Department of Emergency Medicine,
Design: A retrospective case series from February 1, 1985, to July 30, 1993.
Setting: Six urban EDs.
St. FrancisMedical Center, Peoria, Illinois~.
Participants: Seventy-two adult and pediatric patients with
Receivedfor publication September 1, 1993. Revisions received
serum carbamazepine concentrations greater than 12 pg/mL and concurrent 12-lead ECGs.
July 18, 1994 and October31, 1994. Acceptedfor publication November 22, 1994. Preliminary data presented at the American Academy of Clinical ToxicologyAnnual Meeting, Toronto, Ontario, Canada, October 1991;final data presented at the Western Student Medical Research Forum, Monterey, California, February 1994, and at ACEP Research Forum, San Diego,
California, March 1994. Copyright © by the American College of Emergency Physicians.
Results: The mean carbamazepine level was 24 pg/mL (range, 12.6 to 55 t~g/mL). Minor ECG abnormalities were noted but no clinically significant arrhythmias were found. No correlation was found between carbamazepine concentration and heart rate or PR, QRS, or corrected QT intervals. Four adult patients had transient hypotension. Conclusion: Clinically significant cardiovascular toxicity occurs rarely in patients with toxic carbamazepine concentrations. ECG findings do not correlate with serum carbamazepine concentration. [Apfelbaum JD, Caravati EM, Kerns WP II, Bossart PJ, Larsen G: Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med May 1995;25:631-635.]
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C A R B A M A Z E P I N E TOXICITY Apfelbaum et al
INTRODUCTION
Carbamazepine (Tegretol) is an iminostilbene derivative with a tricyclic structure. It is a drug of choice for the treatment of simple and complex partial seizures, trigeminal and glossopharyngeal neuralgias, and certain affective disorders. Carbamazepine toxicity has been associated with cardiac effects, including sinus bradycardia, varying degrees of atrioventricular block, sinus tachycardia, and possibly QRS-interval and corrected QT (QTc) interval prolongations.i-3 Carbamazepine overdose may also induce central nervous system depression with concurrent respiratory depression, seizures, and hypothermia.4 Hospitalization and 24-hour continuous cardiac monitoring has been recommended for all patients with toxic carbamazepine levels. 5 This study was designed to evaluate the frequency and severity of cardiovascular effects associated with carbamazepine toxicity. MATERIALS AND METHODS
Hospital records of patients admitted to six urban teaching hospitals for carbamazepine toxicity between February 1985 and July 1993 were evaluated as a retrospective case series. Patients were identified on the basis of hospital computerized discharge diagnosis for anticonvulsant toxicity (ICD-9 codes at all participating facilities), Regional Poison Control Centers listing of overdoses in Utah and North Carolina, and the Drug Abuse Warning network at Carolinas Medical Center. This study was approved by the institutional review boards of all participating facilities.
Inclusion criteria were a serum carbamazepine concentration greater than 12 gg/mL and a 12-lead ECG performed concurrently in the emergency department. Exclusion criteria were the presence of medications known to affect the ECG such as tricyclic antidepressants, digoxin, ~-blockers, or type I antiarrhythmic drugs (eg, quinidine). Patients were included in the cardiac data evaluation but excluded from the Glasgow Coma Scale (GCS) group if they had either a serum ethanol concentration of greater than 100 mg/dL (21.7 mmol/L) or the presence of other drug ingestions (eg, opiates) known to alter the sensorium. Patient data included age, sex, acute or chronic exposure, dose, method of decontamination (ipecac, gastric lavage, activated charcoal), other drugs ingested, GCS score in the ED, serum carbamazepine concentration, duration of cardiac monitoring, and ECG. ECGs were evaluated for rate; rhythm; PR, QRS, and QTc intervals (calculated with an ECG computer); frontal plane QRS axis; and frontal plane terminal 40-milfiseconds QRS axis (T40-milliseconds axis). In addition, episodes of arrhythmias, hypotension, respiratory compromise, and death were recorded. Patients were categorized as adult (older than 12 years) or pediatric (younger than 13 years). Patients were further categorized as having acute (single episode of ingestion) or chronic (routine ingestion of supratherapeutic dose) exposure. The basis for categorizing a patient was the presenting histo~ An acute overdose superimposed on longterm carbamazepine therapy was considered an acute exposure.
Table 1.
Demographics, exposure, and complications in carbamazepine toxicity. Pediatric Group
Adult Group Features No. of patients M/F Age (yr)* Serum carbamazepine (gg/mL)* GCS* Intubation Sinus tachycardia Conduction delays Prolonged QTc interval Prolonged QRS interval Bundle-branch block Prolonged PR interval * Mean_+SD(range).
632
Acute 42 23:19 30_+11 (13-57) 25+10 (12.6-55) 11_+4(3-15) 4 (9%) 12 (27%) 22 (50%) 5 (11%) I (2%) 2 (5%)
Chronic
Acute
16 5:11 39+16 (t9-66) 20-+7 (14-40) 14+2 (6-15) O 2 (12%)
7 4:3 5_+4(2-12) 25+9 (14-38) 10+_4(5-15) 3 (43%) 1 (14%)
7 (38%) 4 (25%) 0 0
2 (29%) 1 (14%) 0 0
Chronic 7 5:2 9+4 (3-11) 22_+4(16-28) 12+_3(9-15) 1 (14%) 3 (43%) 4 (57%) 0 0 0
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Standard descriptive analysis was performed. Correlation coefficients were determined for linear relationships among ECG parameters, GCS, and carbamazepine concentration. Statistical significance was accepted if P was less than .05. Values are expressed as mean&+SD. RESULTS
Seventy-two patients met the inclusion criteria. This group comprised 58 adults (mean age, 32+13 years), of whom 42 had acute ingestion and 16 had chronic toxicity. Fourteen pediatric patients were enrolled (mean age, 7_+4 years); 7 in the acute and 7 in the chronic category In 60% of patients the amount of carbamazepine ingested was unknown, in 27% it was less than 5 g, in 5% it was between 5.1 and 10 g, in 1% it was between 10.1 and 15 g, and in 7% it was between 15.1 and 20 g. The times between ingestion and presentation could not be reliably determined. Twenty-five patients had repeat carbamazepine assays. In 4 patients, carbamazepine levels were higher than the initial levels found in the ED. Toxicology screening revealed one patient with stimulant amines (heart rate, 99), one patient with a therapeutic thorazine level (heart rate, 148, QT c, 426), one patient with cocaine (heart rate, 140), two patients with amantidine (heart rates, 70 and 76), and one patient with a dilantin level of 1.7 btg/ml. Forty-five percent of adults (57% of acute ingestions, 13% with chronic toxicity) and 36 % of children (57% acute, 13% chronic) underwent gastric emptying. Seventyfive percent of adults (84% in the acute category, 50% in the chronic group) and 50% of children (57% acute, 43% chronic) received activated charcoal in the ED. Ages, maximum carbamazepine concentrations, GCS scores, acute versus chronic ingestion, and complications are listed in Table 1. Fifty percent of adult and 67% of
pediatric patients had mental status changes. GCS score was correlated inversely with carbamazepine concentration (P=.000E, r=.584). Four adults (7%) and four children (29%) underwent endotracheal intubation, one adult underwent hemoperfusion filtration for high serum carbamazepine concentration, one adult had a generalized tonic-clonic seizure thought to be a result of carbamazepine toxicity, four adults exhibited transient hypotension in the ED (range, 100170 mm Hg to 80/60 mm Hg) that responded to fluid bolus, and one patient's hospitalization was complicated by pneumomediastinum. There were no deaths. ECG parameters showed multiple minor abnormalities (Table 2). Of the adults, 14 patients (23%) had sinus tachycardia (heart rate greater than 100) on presentation. Two patients had first-degree atrioventricular block (PR greather than 200 milliseconds). No other ECGs were available for these two patients. Nine adults (15%) had QRS-interval prolongation (normal, less than 100 milliseconds). 6 In three cases the QRS-interval prolongation was known to be preexisting, and in the other six cases no prior ECGs were available. Twenty-nine adult cases (50%) had prolonged QT intervals, with our series mean at the upper limit of the normal range (normal, less than 420 milliseconds). 6 One patient had a left bundle-branch block (no prior ECG available). No statistical correlation was found between serum carbamazepine concentration and heart rate (P=.278, r=.257), PR interval (P=.514, r=.179), QRS interval (P=.979, r=.003), QT c interval (P=. 126, r=. 179), T40 milliseconds axis (P=.860, r=.023), or QRS axis (P=. 100, r=.215). Only three adult patients had previous ECGs available for comparisons, and only nine patients had repeat ECGs after admission to the hospital. In the pediatric population, five patients had sinus tachycardia (36%), defined as heart rate greater than 160 in patients 2 years old, greater than 130 in patients 2 to 5
Table 2.
ECG parameters in carbarnazepine-toxicity patients. Adult Group Parameters Heart rate PR interval (milliseconds) QRS complex duration (milliseconds) QTc interval (milliseconds) QRS axis (degrees) T40-milliseconds axis (degrees) Dataexpressedas mean_+SD(range).
Acute 90+_16(64-148) 163+_28(120-240) 89+12 (60-116) 420_+31 (340-487) 53+_27(-17-93) 98+_82(-60-270)
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Pediatric Group Chronic 80+14 (60-102) 163+_17(124-180) 92_+12(80-112) 418_+22(380-460) 43_+32(~49-94) 58+67 (-30-220)
Acute 104_+16(85-130) 141_+23(103-105) 83_+18(70-120) 405_+30(363-452) 65_+31 (30-119) 79+_67(0-210)
Chronic 106_+23(75-140) 155_+24(113-176) 82+_7(70-92) 420+_11 (400-436) 41_+33(-18-80) 95+_100(-30-270)
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years old, and greater than 100 if over 5 years of age. The PR intervals were within normal limits. QRS width was prolonged in one patient with known preexisting cardiac conduction defect. The QRS axis was normal, with the exception of right axis deviation in one patient. The QT C interval was prolonged in four cases (29%). As in the adult population, no statistical correlation was found between serum carbamazepme concentration and heart rate (P=.181, r=.379), PR interval (P=.363, r=.263), QRS width (P=.233, r=.341), QRS axis (P=.539, r=.180), QT c interval (P=.67, r=. 125) or T40-ms axis P=. 102, r=.445). Only one pediatric patient had a previous ECG, and only two patients had repeat ECG after admission. Continuous cardiac monitoring was performed in 66% of cases for periods of up to 168 hours (mean 32+35 hours), but no arrhythmias or ectopy was found. All cardiac conduction defects were discovered on the initial ECG obtained in the ED. DISCUSSION
The exact frequency and severity of cardiovascular toxicity in patients with carbamazepine overdose are unknown. Acute intoxication with carbamazepine may cause many of the symptoms (central nervous system depression, anticholinergic effects, cardiovascular effects, and, possibly, seizures) caused by acute tricydic antidepressant toxicity. Because the structure of carbamazepme is very similar to those of the tricyclic antidepressants, it is reasonable to assume that cardiovascular toxicity may develop in patients with carbamazepine overdose, leading some authors to recommend 24-hour cardiac monitoring in patients with CBZ ingestion. 5 In vitro and in vivo studies in dogs have demonstrated impaired AV conduction from CBZ. r In addition, many case reports have described carbamazepine-induced sinus bradycardia and heart block m patients with supratherapeutic and even therapeutic drug levels, s-> However, most of these case reports involve elderly patients with underlying heart disease. Puletti et al evaluated 92 patients with therapeutic carbamazepine concentrations and concluded that clinically significant conduction disorders do not occur m younger patients receiving carbamazepine. 15 The few published series of patients with toxic ingestions of carbamazepine have demonstrated only sinus tachycardia as a frequent cardiovascular effect. Spiller et al reported 62 cases of CBZ overdoseJ 6 They found sinus tachycardia in 35% of the patients, one case of asymptomatic second-degree heart block, and no cases
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of hypotension or arrhythmias. Seymor reported 33 cases of carbamazepine overdose} This investigator found four cases of transient first-degree heart block and no cases of hypotension. Hojer et al reported 28 cases of massive carbamazepine poisoning. 17 They found that 36% of the patients had sinus tachycardia. In addition, in four patients AV block, transient QRS prolongation, life-threatening arrhythmias, or all three developed. Because all four of these patients were comatose and had respiratory failure and seizures, it is unclear whether their cardiovascular toxicity was due to carbamazepine alone or was the result of hypoxemia and acidemia. Tibballs reported 82 pediatric patients with CBZ ingestion, and noted several cases of hypotension and some conduction defects, but the frequency and severity of these cases were not reported. ~s Our study is one of the largest series of carbamazepine overdose cases. The low frequency of significant cardiovascular toxicity in this study is in agreement with other, smaller series. No patient in our study had arrhythmia noted other than sinus tachycardia. There were four cases of mild transient hypotension; none of these patients was symptomatic or required therapy other than IV fluid. The large number of patients with QRS and QT c prolongation is surprising; carbamazepine is not known to affect QRS or QT c intervals. 2,r However, the vast majority of these cases had QRS or QT c intervals (or both) only slightly above normal. Very few patients had previous ECG or repeat ECGs. Therefore we were unable to determine whether the prolongation was due to carbamazepine. No correlation was found in this study between CBZ levels and heart rate or PR, QRS, and QT c intervals. This is further evidence that carbamazepine does not have a frequent or consistent effect on the cardiac conduction system. Because tricyclic antidepressant ingestion has been associated with rightward rotation of the T40 milliseconds, we determined whether CBZ ingestion had a similar association. 19,2° No correlation between carbamazepine concentration and the ]740 milliseconds axis was found. A greater percentage of pediatric than adult patients (29% versus 7%) underwent intubation on admission. The sample size, however, was too small in this retrospective series for us to reliably analyze these data. There are several limitations to this study. Because it was a retrospective, sampling bias existed. Missing data from the medical record could lead to underreporting of cardiovascular complications. Furthermore, our study population was relatively young and without apparent underlying cardiac disease. Elderly patients and those
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with known heart disease would be expected to have more frequent cardiac toxicity from carbamazepine ingestion. Many of our patients had minimally increased serum carbamazepine concentrations. One might expect the incidence of cardiovascular effects to be more severe in patients with higher carbamazepine levels. Finally, this was a descriptive study without a control population. It is impossible to know, therefore, whether the ECG abnormalities were truly caused by carbamazepine. The only reliable control population for this study would be the pretoxicity and posttoxicity ECGs from this same group of patients. Unfortunately, these data are not available. Other control groups would be unsatisfactory because they would introduce new biases into the study.
16. Spiller HA, KrenzelokEP, CooksonE: Carbamazepineoverdose:A prospective study of serum levels and toxicity. J Toxicol Clio Toxico11990;28:445-458. 17. Hajar J, Malmlund HO, Borg A: Clinical features in 28 consecutive cases of laboratory-confirmed massive poisoning with carbamazepinealone. Clin Toxico11993;31:449-458. 18. Tibballs J: Acute toxic reaction to carbamazepine:Clinical effects and serum concentrations. J Pediatr 1992;121:295-299. 19. Wolfe TR, Caravati EM, Rollins DE: Terminal 40-ms frontal plane QRSaxis as a marker for tricyclic antidepressant overdose.Ann EmergMeal 1989;18:348-351. 20. Caravati EM, Bossart PJ: Demographicand electrocardiographicfactors associated with severe tricyclic antidepressant toxicity. J Toxicol Clio Toxico11991;29:31-43.
Reprint no. 47/1/63146 Address for reprints: E Martin Caravati, MD, MPH Division of Emergency Medicine University of Utah Health Science Center 1150 Moran Building
CONCLUSION
75 North Medical Drive
Patients with toxic carbamazepine concentrations have a low incidence of clinically significant cardiovascular toxicity. ECG findings are not correlated with serum carbamazepine concentrations.
Salt Lake City, Utah 84132 801-581-2417 Fax 801-585-6699
REFERENCES 1. Fisher RS, CysykB: A fatal overdose of carbamazepine:Case report and review of literature. J Toxicot Clin Toxicol 1988;26:477-486. 2. SeymourJF: Carbamazepineoverdose: Featuresof 33 cases. Drug Safety 1993;8:81-88. 3. Weaver DF, Camfield P, FraserA: Massive carbamazepineoverdose: Clinical and pharmacologic observations in five episodes. Neuro/ogy1988;38:755q59. 4. Goldfrank LR, Osborn H, Brenitz EA: Phenytoin and other anticonvulsants, in Goldfrank LR (ed): Toxicological Emergencies, ed 4. East No~alk, Connecticut, Appleton and Lange, 1990, p 333. 5. Sulfivan JB, RumackBH, Petersen RG: Acute carbamazepinetoxicity resulting from overdose. Neurology 1981;31:621-624. 6. GoldbergerAL: Electrocardiography,in Goldberger E (ed): Textbookof Clinical Cardiology.St. Louis, CV Mesby, 1982, p 129-184. 7. Steiner C, Wit AL, Weiss MB, et ah The antiarrhythmic actions of carbamazepine(Tegretol). J PharmaeolExp Thor1970;173:323-325. 8. BeermannB, EdhagO, Vallin H: Advanced heart block aggravated by carbamazepine.Br Heart J 1975;37:668-671. 9. Kasarskis EJ, Kue CS, Berger R, et al: Carbamazepine-inducedcardiac dysfunction: Characterizationof two distinct clinical syndromes. Arch Intern Me(/1992;152:186-191. 10. LabrecqueJ, Cote MA, Vincent P: Carbamazepine-inducedatrioventricular block. Am J Psychiatr 1992;149:572-573. 11. Leslie PJ, Heyworth R, Prescott LF: Cardiaccomplications of carbamazepineintoxication: Treatment by haemoperfusion.BMJ 1983;286:1018. 12. Maenab A, RobinsonJ, Adderly R, et ah Heart block secondaryto erythremycin-inducedcarbamazepinetoxicity. Pediatrics 1987;80:951-953. 13. Hewetson KA, Ritch AES, Watson RDS: Sick sinus syndrome aggravated by carbamazepine therapy for epilepsy. Postgrad Meal J 1986;62:497-498. 14. Durelli L. Mutani R, Sechi G, et al: Cardiacside effects of phenytoin and carbamazepine:A dose-related phenomenon?Arch Neural 1985;42:1057-1058. 15. Pufetti M, lani C, Curione M, et ah Carbamazepineand the heart. Ann Neural 1991;29:575576.
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