Cardiotoxic manifestations of mesoridazine overdose

CASE REPORT mesoridazine, overdose; overdose, mesoridazine

Cardiotoxic Manifestations of Mesoridazine Overdose We present a case of malignant arrhythmias associated with hypocalcemia and subsequent cardiac arrest in a 20-year-old woman due to ingestion of 3.1 g mesoridazine in a suicide attempt. There were unexplained alterations in serum electrolytes preceding the cardiac arrest. The patient subsequently recovered and was transferred to a psychiatric hospital. Despite the paucity of data on the potential cardiotoxicity associated with mesoridazine overdose, this case demonstrates that malignant arrhythmias and cardiac arrest occur; consequently, these patients probably require constant ECG monitoring. [Marrs-Simon PA, Zell-Kanter M, Kendzierski DL, Leikin JB: Cardiotoxic manifestations of mesoridazine overdose. A n n Emerg M e d October 1988;17:1074-1078.]

Pamela A Marrs-Simon, PharmD* Michelle ZelI-Kanter, PharmD* Donald L Kendzierski, Pharmb* Jerrold B Leikin, MD, FACP, FACEPt Chicago, Illinois

INTRODUCTION Mesoridazine besylate is the besylate salt of a sufoxidized active metabolite of thioridazine. Both drugs are categorized as piperidine phenothiazines and are used therapeutically as antipsychotic agents.1 Therapeutic and toxic serum levels for these drugs have not been defined. The cardiovascular effects of the phenothiazines have been described previously.2-4 Thioridazine has the most significant effects on the ECG of all phenothiazines. 2 These ECG changes occur in both the therapeutic use of thioridazine and in the overdose situation. While mesoridazine also has been shown to alter the ECG at therapeutic or even subtherapeutic doses, s much of its cardiotoxicity has been implied from data generated through study of thioridazine. Only one case of documented potentially lethal ventricular arrhythmias due to mesoridazine overdose has been reported. 6 A second case of fatal mesoridazine overdose with documentation of the clinical course after presentation to the emergency department recently has been reported; however, specific electrocardiographic details were not included.7 Ten other fatal cases of mesoridazine poisoning have been recorded post-mortem.8, 9 We present the case of a patient with malignant arrhythmias associated with hypocafcemia and subsequent cardiac arrest secondary to ingestion of a toxic amount of mesoridazine in a suicide attempt.

Received for publication April 11, 1988. Accepted for publication July 1, 1988.

From the Department of Pharmacy Practice, College of Pharmacy;* and Department of Medicine, Section of Emergency Medicine, College of Medicine,t University of Illinois at Chicago.

Presented at the Annual Scientific Meeting of AACT/AAPCC/ABMT/CAPCC in Vancouver, British Columbia, Canada, ©ctober 1987. Address for reprints: Pamela A MarrsSimon, PharmD, Department of Pharmacy Practice, College of Pharmacy, The University of Illinois at Chicago, Room 244, 833 S Wood Street, Chicago, Illinois 60612.

CASE PRESENTATION A 20-year-old woman with a history of schizophrenia presented to the emergency department approximately two and one-half hours after ingesting an unknown quantity of mesoridazine besylate 50 mg tablets. A tablet count on the prescription bottle revealed that the patient had ingested an estimated 3.1 g mesoridazine (40.1 mg/kg). She denied ingestion of any other substances,

On presentation, the patient's blood pressure was 140/100 mg Hg; pulse, 80; respirations, 20; and temperature, 37.4 C. Physical examination revealed equal, round, and reactive pupils. Mucous membranes were dry, the cardiac examination was normal, and bowel sounds were present. The patient was alert and oriented with a somewhat flattened affect and was hyperreflexic. Gag reflex was intact. Laboratory analyses (including chemistries, hematology, liver enzymes, and urinalysis) were normal. Urine toxicology screen was positive only for phenothiazines. Mesoridazine level was not obtained. The ECG (Figure 1) 17:10October 1988

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MESORIDAZINE OVERDOSE Marrs-Simon et al

FIGURE 1. ECG at two and one-half hours after ingestion. FIGURE 2. ECG at eight hours after ingestion.

showed prolonged QT¢ (0.52 seconds} calculated by the method of Bazett, increased QRS duration (0.12 seconds), first-degree heart block (PR interval 0.22 seconds), and right axis deviation

(+ 135°1. Gastric lavage returned many tablet fragments. Activated charcoal 50 g with sorbitol was administered. Over the next hour, the patient had a marked decline in mental status, eventually becoming unresponsive. Vital signs r e m a i n e d u n c h a n g e d throughout this period. Shortly thereafter, she vomited approximately 100 mL of charcoal-laden emesis and had difficulty clearing the vomitus. The blood pressure dropped to 80/50 m m Hg. ECG at that time (Figure 2) revealed further increase in the QRS complex duration (0.28 seconds) and further prolongation of the QT¢ (0.65 seconds). Nasotracheal intubation was performed. Despite Trendelenburg positioning and fluid bolus, the blood pressure r e m a i n e d 9 0 / 6 0 m m Hg. N o r epinephrine infusion of 6 t~g/min was required for refractory hypotension. The patient was transferred to the medical ICU. Lidocaine 100 mg IV push and an infusion of 2 mg/min was administered without change in the EGG. Repeat laboratory tests sent at the time of transfer revealed a decrease in total serum calcium from 10.0 mg/dL on admission to 7.7 mg/dL and a decrease in serum potassium from 4.1 mEq/L to 3.7 mEq/L despite systemic acidosis (pH, 7.20; pCO2, 33; pO2, 348; base excess, -14.4). In addition, blood glucose had increased from 94 mg/dL on admission to 204 mg/dL. Within 30 minutes of being transfered to the medical ICU, the patient developed m o n o m o r p h i c ventricular tachycardia at a rate of 95 to 120, which then degenerated to ventricular fibrillation. CPR was started. Epinephrine 1 mg IV push was administered, and a precordial thump converted the cardiac rhythm back to the slow ventricular tachycardia with a blood pressure of 60/40 m m Hg. Direct current cardioversion with 300 J restored the 120/1075

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original wide QRS sinus rhythm with a blood pressure of 130/70 m m Hg. The patient also experienced two generalized tonic-clonic seizures during the cardiac arrest that responded to a total of 10 mg IV diazepam. The lidocaine infusion was increased to 4 mg/min, and 1 g phenytoin was infused over the ensuing 45 minutes. The EGG the following morning (Figure 3) revealed a persistent prolongation of the QTc (0.42 seconds), continued increase in the QRS duration (0.12 seconds), first-degree heart block, right axis deviation (+ 105°), and widening of the QRS complex, but the patient was alert and was maintaining adequate blood pressure without pressors. Serum chemistries Annals of Emergency Medicine

at that time revealed serum calcium, 8.9 mg/dL; s e r u m p o t a s s i u m , 3.5 mEq/L; and blood glucose, 96 mg/dL. On ECG 41 hours after the ingestion (Figure 4), QRS complex duration and QT c were within normal limits, but first-degree heart block and right axis deviation persisted. The patient's electrolytes and blood glucose were normal. The patient recovered fully. On the third hospital day, she was transferred to a psychiatric hospital where she was treated for schizophrenia. DISCUSSION T h e p h e n o t h i a z i n e s c a u s e distinctive effects on the ECG. Disturbances in ventricular repolarization 17:10 October 1988

FIGURE 3. ECG at 16 hours after ingestion. FIGURE 4. ECG at 41 hours after ingestion.

manifested by prolongation of the QT interval are the earliest ECG changes seen. 4 Atrioventricular conduction abnormalities are noted with the occurrence of first-degree heart block. Also, widening of the QRS complex and marked right axis deviation are present due to intraventricutar conduction delay. These electrophysiologic properties of the phenothiazines have been likened to those of qninidine (socalled "quinidine-like" effects). 4 The arrhythmogenicity of the phenothiazines also has been reviewed previously. 2-4 Supraventricular and ventricular tachyarrhythmias, as well as sudden death, have been reported in patients being treated therapeutically with the phenothiazines and in cases 17:10 October 1988

of overdose. 4 The ECG abnormalities seen in our patient are strikingly similar to those seen in the mesoridazine overdose patient reported by Niemann et al 6 (Table). They noted ventricular repolarization a b n o r m a l i t i e s (QT c of 0.55 seconds), atrioventricular conduction abnormalities manifested by first-degree heart block (PR interval, 0.30 seconds), and intraventricular conduction delay (QRS duration, 0.24 seconds and right axis deviation, + 185°). Also, in the previously reported case, the patient demonstrated Supraventricular tachycardia and a relatively slow ventricular tachycardia (rate of 130 to 140). 6 We also observed a slow ventricular tachycardia that eventually Annals of Emergency Medicine

degenerated to ventricular fibrillation in this patient. The electrolyte changes observed in our patient also were seen in Niemann's patient. In that case, the authors noted a serum potassium of 2.9 mEq/L on admission and stated that they believed that the bypokalemia contributed to, but did not cause; the arrhythmias they observed. 6 We also noted a significant decrease in both serum potassium and calcium from the initial laboratory analyses to repeat analyses approximately 5.5 hours later. Chouinard and Annable 10 proposed that the ECG changes induced by the phenothiazines at therapeutic doses are caused and/or aggravated by an alteration in intracellular-to-extracellular ratio of potassium induced by a glucose load. The increased glucose s t i m u l a t e s an e n d o g e n o u s insulin bolus that causes a shift of potassium intracellularly. This would explain the reduction in serum potassium seen in our patient. Whether this increase in blood glucose and subsequent decrease in serum potassium was due to the mesoridazine ingestion alone, or in part to the administration of the norepinephrine infusion, cannot be determined. The calcium channel-blocking properties of the antipsychotic drugs (esp e c i a l l y t h i o r i d a z i n e and m e s o ridazine) have been the subject of recent discussions.Xl, 12 While these effects have been d e m o n s t r a t e d in vitro, their implications in vivo are not clear. Still, the theorized calcium c h a n n e l - b l o c k i n g effects of these agents can neither explain the reduction in serum calcium seen in our case nor can they fully explain the ECG abnormalities. Even the classiCally used calcium channel blockers (eg, verapamil, diltiazem, nifedipine) do not alter serum calcium in therapeutic doses13,14 or overdose situations.lSA 6 The phenothiazines that have been investigated for their cal: cium channel-blocking properties have not been shown to aker serum calcium c o n c e n t r a t i o n s either. Although c a l c i u m c h a n n e l blockade 1076/121

MESORIDAZINE OVERDOSE Marrs-Simon et al

TABLE. E l e c t r o l y t e c h a n g e s a n d progression o f E C G a b n o r m a l i t i e s Hours After Ingestion

Glucose (mg/dL)

K+ (mEq/L)

Ca + + (mg/dL)

Figure

ECG

2.5

94

4.1

10.0

1

pulse, 87 QT e, 0.52 sec PR, 0.22 sec QRS, 0.12 sec axis, + 135 °

8

204

3.7

7.7

2

pulse, 65 QTo, 0.65 sec PR, 0.24 sec QRS, 0.28 sec axis, + 135 °

16

96

3.5

8.9

3

pulse, 115 QT c, 0.42 sec PR, 0.22 sec QRS, 0.12 sec axis, + 105 °

41

109

3.9

4

pulse, 85 QT c, 0.47 sec PR, 0.16 sec QRS, 0.10 sec axis, + 105 °

Previously reported case s 1

m a y explain t h e alterations in atrioventricular conduction seen w i t h phenothiazines, it cannot explain the observed ECG changes associated w i t h prolonged ventricular repolarization. While the total serum calcium decreased in our patient, m a r k e d acidosis also was seen. Therefore, it is likely that the ionized calcium probably did not change as significantly as the total serum calcium. The decrease in serum calcium m a y be a t t r i b u t e d to systemic acidosis. While the total serum calcium decreased, it is likely t h a t t h e i o n i z e d c a l c i u m was unchanged in light of the patient's pH.

SUMMARY Despite the paucity of data on the cardiotoxicity associated w i t h mesoridazine overdose, these cases demonstrate that malignant arthythmias and cardiac arrest occur and consequently these p a t i e n t s require c o n s t a n t E C G monitoring. As N i e m a n n et al 6 noted, the ECG also m a y be a useful diagnostic tool in the m a n a g e m e n t of pa122/1077

pulse, 110 QT c, 0.55 sec PR, 0.30 sec QRS, 0.24 sec axis, + 185 °

2.9

t i e n t s w i t h i n g e s t i o n s of u n k n o w n substances. T h e striking s i m i l a r i t i e s in cardiotoxic manifestations between our case and theirs support this notion. We w o u l d , h o w e v e r , c a r r y t h i s thought one step further. T h e m o s t n o t a b l e s i m i l a r i t i e s in t h e E C G s of these two patients were the Q T c prolongation and the m a r k e d right axis deviation on presentation. Based on these two case reports, it is interesting to theorize that these findings on initial evaluation serve as predictors of t h e d e v e l o p m e n t of m a l i g n a n t arrhythmias, including ventricular tachycardia and/or fibrillation. The significance of the e l e c t r o l y t e a b n o r m a l i t i e s observed in t h e s e patients is unclear. As N e i m a n n et a16 previously noted, hypokalemia may further aggrevate cardiac a r t h y t h m i a s due to the mesoridazine intoxication. In a d d i t i o n , t h e s e findings of h y p o k a l e m i a or h y p e r g l y c e m i a also m a y add supportive evidence in a t t e m p t i n g to identify a mesoridazine overdose in Annals of Emergency Medicine

the case of an u n k n o w n ingestion.

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1982;307:1618-1627. 14. Zsoter TT, C h u r c h JG: Calcium antagonists: Pharmacodynamic effects and mechanisms of action. Drugs 1983;25:93-112. 15. Morris DL, Goldschlager N: Calcium infusion for reversal of adverse effects of intravenous verapamil. JAMA 1983;249:3212-3913. 16. Shover SW, Bocchino V: Massive diltiazem overdose. Ann Emerg Med 1986;15:1221-1224.

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