tiple doses of oral charcoal, and charcoal hemoperfusion. The patient's ECG and hemodynamic status returned to normal within 24 hours. Despite an apparent ...
CASE REPORT drug overdose, tricyclics, late death; overdose, tricyclics, late death; tricyclics, and late death; tricyctics, charcoal hemoperfusion; tricyclics, myocardial depressant effect
Late Death in Tricyclic Antidepressant Overdose Revisited We report a late death following the ingestion of amitriptyline. A 46-year-old woman presented to the emergency department with coma, hypotension, tachycardia, and a prolonged QRS interval after the ingestion of a large Cludii~i~f
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tiple doses of oral charcoal, and charcoal hemoperfusion. The patient's ECG and hemodynamic status returned to normal within 24 hours. Despite an apparent total recov~y, she suddenly sustained a cardiorespiratory arrest and died 33 hours after ECG normalization (at 57 hours after admission). This case brings into question the feasibiffty of ceasing ECG monitoring in tricyclic antidepressant overdoses once the ECG has stabilized, especially in patients with a history of chronic usage. A possible explanation for late sequelae is the myocardial cell binding and depressant effect of preexisting therapeutic TCA medication. [McAlpine SB, Calabro JJ, Robinson MD, Burkle FM: Late death in tricyclic antidepressant overdose revisited. Ann Emerg Med November 1986;15:1349-I352.] INTRODUCTION Tricyclic antidepressant (TCA) overdose has received much-deserved attention in the medical literature. It is estimated that 5,000 to 10,000 people poison themselves every year with TeAs. 1 A recent report stated that all patients who die of direct TCA toxicity do so within 24 hours of ingestion. 2 We report an appropriately managed TCA overdose patient who sustained late sudden death.
CASE REPORT
Steven B McAIpine, MD Joseph J Calabro, DO Mel D Robinson, MD, FACEP Frederick M Burkle, Jr, MD, MPH, FAAP, FACEP Tacoma, Washington From the Department of Emergency Medicine, Madigan Army Medical Center, Tacoma, Washington. Received for publication October 21, 1985. Revision received December 30, 1985. Accepted for publication January 15, 1986. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of Defense. Address for reprints: Joseph J Calabro, DO, Emergency Medicine Service, Letterman Army Medical Center, Presidio of San Francisco, California 94129.
A 46-year-old woman known to have been on therapeutic doses of amitriptyline for several months was found with the empty bottle nearby two hours after a family quarrel. Paramedics found her to be comatose with the following vital signs: blood pressure, 110/74 mm Hg; pulse, 110; and respirations, four. The patient was intubated, a 16-gauge IV line was started, and 0.8 mg naloxone and 25 g dextrose IV were administered without improvement. On arrival, vital signs were as follows: blood pressure, 100/70 m m Hg; pulse, 110; respirations, none to one; temperature, 37 C; and Glasgow Coma Score, 3. General examination revealed no evidence of trauma. The skin was warm and dry without cyanosis. Pupils were mid-range and nonreactive. Breath sounds were equal and the cardiac monitor revealed a sinus tachycardia. Bowel sounds were hypoactive and the stool was negative for blood. The remainder of the physical examination was unremarkable. Medical records revealed a history of chronic depression, five prior suicide attempts, and maintenance dosage of Elavil ®. She reportedly was free of cardiovascular disease.
The ECG exhibited a sinus tachycardia with a QRS interval of 0.14 second (Figure 1). Initial arterial blood gases were as follows: pH, 7.37; PO2, 167 m m Hg; and PCO2, 37 m m Hg on 100% FIO 2 with mechanical ventilations. The chest radiograph was clear with a properly positioned endotracheal tube. Further laboratory values were as follows: sodium, 141 mEq/L; potassium, 2.9 mEq/L; chloride, 135 mEq/L; bicarbonate, 16 mM/L; glucose, 111 mg/dL; creatinine, 0.5 mg/dL; calcium, 7.8 mg/dL; WBC, 15,400 cells/mm3; hemoglobin, 9.9 g; hematocrit, 29.4%; platelets, 174,000; and ethanol, 100 mg/dL. Urine and serum toxicology analysis were pending; the working diagnosis 15:11 November 1986
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-[CA OVERDOSE McAIpine et al
was coma secondary to TCA overdose. Initial therapy included administration of 44 mEq NaHCO s and an additional 1.2 mg naloxone IV A second large-bore IV line, a Foley catheter, and a large-bore orogastric tube were placed. Gastric lavage with normal saline solution produced multiple pill fragments consistent in color with amitriptyline. Charcoal 100 g and magnesium citrate 240 mL were instilled following lavage. The patient's blood pressure suddenly dropped to 70/0 m m Hg. Rapid infusion of 1,500 mL 0.9% NaC1 and a dopamine infusion at 20 p~g/kg/min failed to improve the patient's hemodynamic status. A right subclavian central venous catheter was placed with an initial measurement of 12 cm H20. Titration of bicarbonate and norepinephrine drips achieved a systolic blood pressure of 100 to 110 m m Hg. One gram of phenytoin was administered IV without i m p r o v e m e n t in the QRS duration. The patient was transferred to the ICU. A Swan-Ganz catheter and arterial line were inserted. Arterial pH was maintained at 7.5 using a continuous NaHCO 3 drip. Two 1-mg doses of IV p h y s o s t i g m i n e produced only brief improvement in the patient's mental status. Repeated doses of 100 g charcoal were administered every two hours. Lumbar puncture and cranial computed tomography scan were normal. Initial serum levels of amitriptyline were more than 1,000 ng. Nine hours after her admission, charcoal hemoperfusion (CHP) with system XR-010 (Extracorporeal Systems, ® Extracorporeal Medical Specialty Systems, Inc, King of Prussia, Pennsylvania) was used. After two hours the amitriptyline level fell to 540 ng/mL with a n o r t r i p t y l i n e level of 161 ng/mL. Glasgow Coma Score improved to 8. After three and one-half hours of treatment, the amitriptyline level fell to 260 n g / m L with a nortriptyline level of 112 ng/mL. Subsequently the endotracheal tube dislodged, and during readjustment epistaxis that required nasal packing occurred. Due to the risks of continued heparinization, CHP was discontinued. The patient's clinical response deteriorated to a Glasgow Coma Score of 3. The levels of amitriptyline and nortriptyline at 1V2 hours after CHP were 430 and 168 ng/mL, respectively. Post-CHP platelets were 105,000; calcium was un120/1350
changed at 7.8 mg/dL; h e m a t o c r i t was 30.5%; and p o t a s s i u m was 4.1 mEq/dL. Twenty-four hours after admission, the ECG showed narrowing of the QRS to 0.08 seconds (Figure 2). Pressor support was no longer required to maintain blood pressure. Cardiac enzymes were normal. Orogastric charcoal doses w e r e c o n t i n u e d , and therapeutic levels of phenytoin were maintained. The protein binding of TCAs by sodium bicarbonate continuous IV infusion maintained the arterial pH at 7.5. Levels of amitriptyline and nortriptyline decreased to 220 and 117 ng/dL, r e s p e c t i v e l y . Throughout the next 24 hours, the patient gradually awakened; vital signs were as follows: blood p r e s s u r e , 122/70 m m Hg; pulse, 82; and .respirations, 20. At 51 hours after admission she was weaned from the ventilator, central monitoring devices, bicarbonate, phenytoin, and orogastric tube. No v e n t r i c u l a r e c t o p y or o t h e r dysrhythmias were reported during the patient's course. Laboratory results at this time included hematocrit, 35.5%; sodium, 141 mEq/dL; p o t a s s i u m , 3.6 mEq/dL; chloride, 114 mEq/dL; bicarbonate, 23 mM/L~ glucose, 157 mg/dL; and BUN, 7 mg/ dL. The patient became alert and conversed with her family. Arrangements were made to transfer her to the psychiatric ward the following day. Charcoal therapy was discontinued once the patient passed multiple charcoal stools. Fifty-six hours after admission she became slightly agitated and in rapid succession developed a bradycardia with decreased respirations and hypotension. Advanced cardiac life support protocol was instituted immediately. Electromechanical dissociation was unresponsive to appropriate therapy, including venous pacing. The patient was pronounced dead 57 hours after admission. Levels drawn the morning of death (48 hours after admission) subsequently were reported as amitriptyline, 240 ng/dL, and nortriptyline, 139 ng/mL. A u t o p s y findings revealed o n l y long-standing arteriosclerotic cardiovascular disease without evidence of acute myocardial infarction.
DISCUSSION The physiological or clinical effects of the TCAs are in large part conAnnals of Emergency Medicine
centration dependent. 3,4 TCAs are associated with a high risk of toxicity because they have a low therapeutic index. 5 As little as 20 m s / k s has proven to be lethal. 6 Doses of 35 mg/ kg provide an approximate LD50, and doses of more than 50 mg/kg are almost uniformly fatal. 7 Due to large variations in individual metabolism of TCAs, some patients with identical serum concentrations survive overdoses while others do not. These differences may result in differences in steady-state therapeutic plasma levels from 11- to 40-fold. 8 Tissue levels run about ten times that of plasma, and myocardial levels may be another ten times greater.3 T h e p a t h o p h y s i o l o g i c a l consequences of TCA overdose occur by three mechanisms: anticholinergic, adrenergic, and quinidine-like. 9 The anticholinergic effects of TCAs can precipitate central nervous s y s t e m confusion, agitation, hallucinations, seizures, or coma depending on the stage of a n e s t h e s i a reached. 1° Peripheral manifestations include mydriasis, vasodilatation, hyperpyrexia, tachycardia, decreased salivation, decreased intestinal motility, and urinary retention. Adrenergic effects result from the block of norepinephrine reuptake into adrenergic neurons.7, u This results in an expected sympathomimetic effect of tachycardia, hypertension, and increased cardiac output. The cardiac toxicity associated with TCA overdoses does not, however, correlate with the degree of adrenergic stimulus. 7 The final major physiologic effect, the quinidine-like action of the TCAs, is responsible for the most acute serious cardiac toxicities seen in overdoses.5, ~1q4 Glassman states that the logical approach is to treat TCA-induced arrythmias like any other class I antiarrhythmic overdose with sodium lactate and pacing. 7 Others argue that TCA-induced cardiac abnormalities can be reversed by phenytoin - - as much as 1 g IV at 50 mg/kg in adults or in children at 15 to 20 mg/kg over 30 minutes#2,13 Several overall s c h e m e s for the t r e a t m e n t of TCA overdoses have been outlined, including an airway, ECG and cardiac monitoring, bladder catheterization, gastric lavage, activated charcoal, arterial blood gases, diazepam or p h e n y t o i n for seizures, fluids or dopamine for hypotension, 15:11 November 1986
digoxin and diuretics for heart failure, sodium bicarbonate and potassium and/or lidocaine or propranolol for ventricular dysrhythmias, and rarely, physostigmine.4, is Haddad recommends increasing protein binding of TCAs by sodium bicarbonate continuous IV infusion maintaining the arterial pH at 7.50. u Spector 16 recommends both serial doses of activated charcoal and an initial cathartic; more support has been echoed for multiple doses of activated charcoal to ensure binding of unabsorbed drug hours after ingestion, i6-1s Controversy still exists regarding the use of CHP.19 Pharmacokinetic data on CHP show that rapid declines in serum TCA concentrations may be appreciated during treatment, ao This correlates with a more rapid rate of drug removal from the central compartment relative to the rate of drug removal from the peripheral to the central c o m p a r t m e n t . 2o This slow movement of drug from the tissue compartment to the central compartment is postulated to be the limiting factor of the CHP procedure, ao The total a m o u n t of TCA removed by CHP is relatively small, often less than 1% of the ingested dose. 2o CHP is also not without risk because it requires heparinization and c annulization of major vessels. Transient decreases in both serum calcium and platelet count occur. 2o Rebound increases in serum TCA levels frequently are observed subsequent to CHP.2O The clinical benefits of transiently lowered serum TCA c o n c e n t r a t i o n s m u s t be weighed against the risks of CHE To date, no large clinical trials have been conducted. Sporadic case reports and experimental data in the literature have produced conflicting results.IS, ~o-22 15:11 November 1986
Our patient was treated using all c u r r e n t l y r e c o m m e n d e d modes of therapy, including serial charcoal lavage, systemic alkalinization, and CHP. The patient appeared clinically. to have cleared all signs and symptoms of TCA toxicity. She sustained a cardiac dysrhythmia and died after having a documented normal ECG for 33 hours. Goldberg et al reported that no patient with a normal ECG for 24 h o u r s developed a d y s r h y t h m i a . 1 Fasoli and Glauser, in their report of 38 cases found no dysrhythmias more than 24 hours after ingestion, a4 In reviews of 141 and 62 TCA overdoses, no unexpected late sequelae were found.aa, a3 Tricyclics are highly concentrated by the myocardium and contribute to direct myocardial depressant activity even at therapeutic levels, as Cardiovascular side effects have been demonstrated at therapeutic levels.a6, ¢7 The incidence of cardiac side effects in the elderly given T C A in the u s u a l therapeutic dosages for a prolonged period is great enough to warrant frequent careful monitoring of cardiac status during therapy, aa This has been attributed to a possible prolonged TCA half-life secondary to decreased hepatic metabolic breakdown, a variation in the blood levels despite identical dosage, and decreased protein binding. ¢8 Similar concerns arise in patients with prior organic heart disease.a9 Studies have investigated the influence of TCA on cardiac rhythm and myocardial contractility after prolonged administration, concluding that no a r r h y t h m o g e n i c or antiarrhythmic effect exists, a9 Other studies have shown that the ECG changes caused by TCA return toward normal despite one year's treatment. 31 The Annals of Emergency Medicine
FIGURE 1. Initial ECG with wide
QRS complexes. FIGURE 2. ECG 24 hours after admis-
sion. QRS complexes narrowed. one exception is a raised heart rate that remains elevated. A persistent impairment of myocardial function exists w i t h c h r o n i c use for four years. 31 We are not aware of any reports that distinguish between overdoses in subjects already on prescribed therapeutic TCA doses and overdoses in subjects without prior TCA medication. One might speculate that anticholinergic and sympathomimetic activity would be similar in contributing to the acute cardiovascular effects. However, it is not clear whether the direct myocardial depressant activity from myocardial cell binding with ordinary and chronic use would contribute to more rapid cardiovascular failure or remain a contributing factor to the risk of late sequelae.
SUMMARY Sudden death may occur as a late sequela of TCA overdose. Despite appropriate aggressive management, including serial charcoal lavage, systemic alkalinization, phenytoin therapy, and charcoal hemoperfusion, our patient sustained sudden cardiorespiratory arrest and death 57 hours after admission (33 hours after ECG normalization) secondary to apparent TCA overdose. All currently prognostic indicators had resolved. The efficacy and potential complication of charcoal h e m o p e r f u s i o n are underscored as is the renewed consideration of length of monitoring, especially in the patient on chronic TCAs. 1351/121
TCA OVERDOSE McAIpine et al
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Annals of Emergency Medicine
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