for Dysrhythmia and Hypotension in Tricyclic - NCBI

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Refer to: Hoffman JR, McElroy CR: Bicarbonate therapy for dysrhythmia and hypotension in tricyclic antidepressant overdose. West J Med 134:60-64, Jan 1981

Bicarbonate Therapy for Dysrhythmia and Hypotension in Tricyclic Antidepressant Overdose JEROME R. HOFFMAN, MD CHARLES R. McELROY, MD Los Angeles SUICIDE IS THE fourth leading cause of death in persons 5 to 40 years of age in the United States.' Unfortunately, people attempting suicide with tricyclic antidepressants are often successful.2-4 These drugs are prescribed largely for persons suffering depression. They have a delayed onset of maximal therapeutic effect, thus allowing time for persons still in a depressed state to take a suicidal overdose before the desired mood elevation supravenes. Tricyclic drugs have devastating pharmacological effects on the heart, as well as on the brain, gastrointestinal tract and neurovascular system.4-28 While the potentially life-threatening dysrhythmias associated with tricyclic drug overdose are well known, the value of alkalinization therapy has been appreciated only recently.29-34 We present a case that dramatically demonstrates the effectiveness of such therapy for treating tricyclic drug overdose.

Report of a Case The patient was a 25-year-old woman transferred to the UCLA (University of California, Los Angeles) Emergency Medicine Center from a local hospital with a presumptive diagnosis of overdose with unknown medications. The patient From the Department of Medicine, Division of Emergency Medicine, University of California, Los Angeles, Center for the Health Sciences. Submitted, revised, Februiary 11, 1980. Reprint requests to: Jerome R. Hoffman, MD, Emergency Medicine Center, UCLA Hospital and Clinics, Center for the Health Sciences, 10833 Le Conte, Los Angeles, CA'90024.

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had a history of six previous suicide attempts, five times with drug overdose and once with a self-inflicted gunshot wound. At the time of admission she was being treated at the UCLA Neuropsychiatric Institute for depression, and was on a therapeutic regimen of imipramine (Tofranil). She had left her house at 2:00 AM on the morning of her admission, and when she returned four hours later, her mother found her to be mumbling incoherently. She was taken to a local emergency room where she was noted to be combative and incoherent. She was treated with gastric lavage, magnesium citrate and activated charcoal and was transferred to the UCLA Emergency Medicine Center. On arrival, the patient exhibited bizarre behavior, alternately screaming paraphrasically and swinging her arms and legs violently and then lying very still. She was placed in a quiet room and the lights were turned down, at which time she lay still on her bed. However, whenever any sensory input was provided, she began to scream and rage again. Further examination showed sluggishly reactive dilated pupils and bidirectional nystagmus. Examination showed that her chest, heart and abdomen were all normal with the exception of a regular tachycardia. Her neurological examination was entirely within normal limits with the exception of the mental status decribed above. Her skin was dry and warm. An electrocardiogram (EKG) taken at the time of admission to the Emergency Medicine Center detected a tachycardia with wide bizarre QRS complexes (Figure 1). The underlying rhythm appeared to be regular but had occasional apparently premature complexes. At this time the patient's blood pressure was 90/50 mm of mercury. Arterial blood gas measurements showed a pH of 7.29 and a carbon dioxide tension (Pco2) of 29 mm of mercury and intravenous alkalinization therapy was instituted with 88 mEq of sodium bicarbonate. The patient's QRS complexes narrowed towards normal almost immediately, and the QRS duration became 0.12 seconds. The rhythm became clearly regular (Figure 2). A second blood gas determination was made, which showed a pH of 7.40 and Pco., of 35 mm of mercury. At this time the patient's blood pressure

CASE REPORTS was 1 10/70 mm of mercury

and her pulse rate remained 108 per minute. She was given a third ampule of 44 mEq of sodium bicarbonate, and her EKG again showed dramatic narrowing of her QRS complexes to within normal limits (Figure 3). A third blood gas determination was done, which showed a pH of 7.47 and a Pco2 of 34.5

of mercury. The patient's blood pressure was stable at 130/90 mm of mercury and her pulse was 84 per minute and regular. She was admitted to the coronary care unit (ccu) for observation and monitoring. The patient's hospital course was entirely unremarkable. At no time during her stay in the ccu

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However, while toxic effects, including even fatal dysrhythmias, may occur with routine doses and "normal" levels of the drug in the blood,4 8 9 3o 35 there is some evidence to suggest that the degree of toxicity increases in proportion to increases in levels of the drug in the blood, and that blood levels equal to or greater than 1,000 ng per ml in particular put the patient at a much higher risk for dysrhythmias, conduction abnormalities, seizures and cardiac arrest.31'36-38 It has also been observed that blood levels of greater than 1,000 ng per ml likewise correlate with QRS durations of greater than 0.10 seconds.36 Following a review of 254 tricyclic drug overdoses, investigators from the Colorado Poison Control Center made two important observations: (1) The latest onset of dysrhythmia occurred 19 hours after admission and (2) a tachycardia of 110 or more per minute was associated with a risk of subsequent dysrhythmia and was considered to require 24 hours of monitoring. Their criteria for treating tricyclic overdoses were (1) if dysrhythmia was present on admission, the patient was considered to require 24 hours of monitoring and (2) any dysrhythmia present after the time of admission was considered to require 24 hours of monitoring from that time.39 The above are useful criteria, although we have seen a case at UCLA in which potentially lifethreatening dysrhythmia first occurred 36 hours following admission. The literature also includes numerous isolated reports of late cardiac deaths. 25'26'40-42 The most significant cardiac manifestations of tricyclic drug overdose are dysrhythmia and hypotension. The hypotension associated with such an overdose can be difficult to manage, both because of its poor response to pressor agents and because of theoretical objections to the use of pressors in this circumstance.5'6'3' The cardiovas-

did she show any cardiac dysrhythmias, and at no time did she have prolongation of her QRS complexes. A urine drug screen showed the presence of salicylate and imipramine, as well as qualitatively but not quantitatively detectable amounts of barbiturate and diazepam. The level of imipramine in the patient's blood at admission was 1,000 ng per ml. All of the laboratory test results (including electrolytes and complete blood count, liver function, renal function, calcium and magnesium) were within normal limits. The patient's mental state became stable during the first 24 hours, and she was discharged after psychiatric consultation during which psychiatric follow-up was recommended.

Discussion Our patient's acute psychosis was strongly suggestive of either phencyclidine or scopolamine overdose, although neither of these drugs was found in the patient's blood or urine. However, the test for urine salicylate was positive. Scopolamine is often difficult to identify in drug overdose, but it is frequently suggested by the presence of salicylamide with which it is combined in numerous preparations. While we cannot be certain that this was the basis for the patient's acute psychotic behavior, we suspect that this may well have been the case. The initial rhythm of the patient's heart was, in retrospect, most likely a supraventricular tachycardia with widened QRS complexes secondary to direct tricyclic toxicity, with occasional premature ventricular contractions. An initial consideration of ventricular tachycardia, suggested in part by the hypotension, appears quite unlikely, particularly in light of the response seen with therapy. Clinical guidelines are generally used to recognize serious tricyclic antidepressant overdose.35

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Figure 3.-Supraventricular tachycardia with normal QRS, associated with normotension and arterial pH of 7.47, following subsequent bicarbonate therapy.

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cular system in the presence of tricyclic antidepressant overdose may well show increased sensitivity to catecholamines.43-51 Because the amine pump has' been blocked, there is bioamine depletion at the neuroeffector sites, but there is also nonhomogeneous pharmacological activity that can then sensitize the person to a nonuniform response to exogenous catecholamines. Vasopressors may also enhance ectopic dysrhythmic activity, further complicating an already difficult situation. It is for this reason that the general initial treatment for hypotension should be intravenous infusion of fluid.5'6'31 If the hypotension does not respond to simple volume expansion, management of arterial pH with alkalinization therapy will often be successful in reversing hypotension. Brown and others have reported that alkalinization of patients with tricyclic drug overdose to pH's of 7.50 to 7.55 is routinely accompanied by a reversal of hypotension.29-37 This is explained on the basis of changes in tricyclic protein binding, which then makes these agents less available to the tissues and reduces their toxic effect.52-54 The value of alkalinization in tricyclic antidepressant overdose may well have a precedent in the efficacy of such therapy in cases of quinidine overdose. Quinidine has effects on cardiac electrical activity similar to those of tricyclic antidepressants."6-"8 This is true at both therapeutic and toxic levels. These include, most notably, prolongation of PR interval and rate-corrected QTc interval, and progressive broadening of the QRS complex.556-0 Furthermore, quinidine toxicity can produce hypotension, cardiac dysrhythmias and metabolic acidosis.57 -60 Alkalinization therapy has been advocated with quinidine overdose to decrease serum drug levels by increasing protein binding, as well as to lower serum potassium (because increased potassium levels are associated with increased toxicity) and increase urinary

excretion.58-63 The use of physostigmine, often enthusiastically recommended for the treatment of both hypotension and dysrhythmia, has failed to show consistently a reversal of hypotension.5.32'39'64-68 It may, however, play an important role in treating patients who remain hypotensive after both volume expansion and alkalinization. Various pharmacological agents have been used to treat tricyclic-induced cardiac dysrhythmias. Physostigmine has generated much inte-rest but is a less than optimal therapeutic drug for several

reasons. Most important is that it is not uniformly successful. It also can cause such severe side effects as seizures, hyperperistalsis, hypersalivation and bradycardia.5'32'39'64- 8 Finally, it produces an increase in vagal tone, which theoretically could increase the degree of heart block in severe cases. Lidocaine would appear to work in theory because it increases, or at worst has no effect on, the speed of atrioventricular conduction. However, it has met with limited clinical success. Furthermore, it may potentiate the hypotensive effect of the tricyclic drugs.2'32'69 Diaphenylhydantoin similarly makes theoretical sense, but has been shown to work poorly, if at all, in the treatment of tricyclic antidepressant overdose.32 Propranolol is contraindicated because of its potent negative inotropic effect, as well as its tendency to increase heart block.2'32 Despite the availability of numerous antidysrhythmic drugs, there is no current consensus concerning the best therapeutic regimen. There may be, nevertheless, a possible unifying concept allowing a rational approach to both hypotension and cardiac dysrhythmias secondary to tricyclic drug overdose. In most patients suffering from shock and dysrhythmias pronounced acidosis occurs. In the case of tricyclic-induced overdose, it is generally a combined metabolic and respiratory acidosis. As pH falls, more drug may become unbound from serum proteins and, hence, be available to tissues for biologic activity. Thus, a vicious circle occurs. Various investigators have reported great success in managing both the hypotension and cardiac dysrhythmias associated with tricyclic drug overdose through alkalinization therapy. This should be combined with optimal ventilation to produce a Pco, of approximately 40 mm of mercury, as well as supplemental oxygen to reduce any concomitant tissue hypoxia, along with the administration of bicarbonate to bring arterial pH to between 7.50 and 7.55. As our case dramatically shows, this will often obviate the need to use physostigmine-a drug with significant morbidity-or other agents.

Conclusion Tricyclic antidepressant overdoses are often associated with life-threatening hypotension and cardiac dysrhythmias. We present a patient with tricyclic drug overdose accompanied by an unusual tachycardia with wide, bizarre QRS complexes and associated hypotension who responded dramatically to alkalinization therapy. We believe THE WESTERN JOURNAL OF MEDICINE

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that along with volume expansion, as necessary, alkalinization should be the therapy of first choice for hypotension and dysrhythmia secondary to tricyclic antidepressant overdose. REFERENCES 1. Facts of Life and Death, Publication No. (PHS) 79-1222, US Dept of Health, Education and Welfare, Nov 1978, pp 39-47 2. Byck R: Chap 12, In Goodman LS, Gilman A (Eds): Pharmacological Basis of Therapeutics. 5th Ed. New York, Macmillan Publishing Co, 1975, pp 174-179 3. Noble J, Matthew H: Acute poisoning by TCA's: Clinical features and management of 100 patients. Clin Tox 2:403, 1969 4. Thorstrand C: Cardiovascular effects of poisoning with TCA's. Acta Med Scand 195:505-514, 1974 5. Manoguerra AS: Poisoning with tricyclic antidepressant drugs. Clin Tox 10:149-158, 1977 6. Wood CA, Brown JR, Coleman JH, et al: Management of tricyclic antidepressant toxicities. Dis Nervous System 37:459461, Jul/Dec 1976 7. Fowler NO, McCall D, Te-Chuan C, et al: Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol 37:223-230, Feb 1976 8. Robinson DS, Barker E: Tricyclic antidepressant cardiotoxicity. JAMA 236:2089-2090, Nov 1, 1976 9. Vohra J, Burrows G, Hunt D, et al: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Europ J Cardiol 3:219-227, 1975 10. Kristiansen ES: Cardiac complications during treatment with imipramine (Tofranil). Acta Psychiat Neurol Scand 36:427442, 1961 11. Moir DC: Tricyclic antidepressants and cardiac disease. Am Heart J 86:841-842, Dec 1973 12. Vohra J, Burrows GD, Sloman G: Assessment of cardiovascular side effects of therapeutic doses of tricyclic antidepressant drLugs. Aust N Z J 5:7-11, 1975 13. Coull DC, Dingwall-Fordyce I, Crooks J, et al: Amitriptyline and cardiac disease-Risk of sudden death identified by monitoring system. Lancet 2:590-591, Sep 19, 1970 14. Kantor SJ, Bigger JT, Glassman AH, et al: Imipramineinduced heart block-A longitudinal case study. JAMA 231: 1364-1366, Mar 31, 1975 15. Nymark M, Rasmussen J: Effect of certain drugs upon amitriptyline induced electrocardiographic changes. Acta Pharmacol Toxicol 24:148-156, 1966 16. Dumovic P, Burrows GD, Vohra J, et al: The effect of tricyclic antidepressant drugs on the heart. Arch Toxicol 35:255262, 1976 17. Vohra J, Hunt D, Burrows G, et al: Intracardiac conduction defects following overdose of tricyclic antidepressant drugs. Europ J Cardiol 2:453-458, 1975 18. Moir DC, Cornwell WB, Dingwall-Fordyce I, et al: Cardiotoxicity of amitriptyline. Lancet 2:561-564, Sep 16, 1972 19. Thorstrand C: Cardiovascular effects of poisoning with tricyclic antidepressants. Acta Med Scand 195:505-514, 1974 20. Sigg EB, Osborn M, Korol B: Cardiovascular effects of imipramine. J Pharmacol Exp Ther 141:237-243, Aug 1963 21. Cocco G, Ague C: Interactions between cardioactive drugs and antidepressants. Europ J Clin Pharmacol 11:389-393, 1977 22. Surawicz B, Lasseter KC: Effect of drugs on the electrocardiogram. Prog in Cardiovasc Dis 8:26-55, Jul 1970 23. Jandhyala BS, Steenberg ML, Perel JM ,et al: Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthesized dogs. Europ J Pharmacol 42:403-410, 1977 24. Fouron JC, Chicoine R: ECG changes in fatal imipramine (Tofranil) intoxication. Pediatrics 48:777-781, Nov 1971 25. Freeman JW, Mundy GR, Beattie RR, et al: Cardiac abnormalities in poisoning with tricyclic antidepressants. Br Med J 2:610-611, 1969 26. Brackenridge RG, Peters TJ, Watson JM: Myocardial damage in amitriptyline and mortriptyline poisoning. Scot Med J 13:208, 1968 27. Roberts RJ, Mueller S, Lauer RM: Propranolol in the treatment of cardiac arrhythmias associated with amitriptyline intoxication. J Pedr 82:65-67, 1973 28. Heimiian EM: Cardiac toxicity and thioridazine tricyclic antidepressant combination. J Nerv Dis 165:139-143, 1977 29. Brown TCK: Sodiunm bicarbonate treatment for tricyclic antidepressant arrhythmias in children. Med J Aust 2:380-383, 1976 30. Brown TCK: Tricyclic antidepressant overdosage: Experimental studies on the management of circulatory complications. Clin Tox 9:255-272, 1976 31. Brown TCK, Barker GA, Dunlop ME, et al: The use of sodium bicarbonate in the treatment of TCA-induced arrhythmias: Anaesth Intens Care 1:203-210, 1976 32. Slovis TL, Ott JE, Teitelbaum DT, et al: Physostigmine therapy of acute tricyclic antidepressant poisoning. Clin Tox 4: 451-459, Sep 1971 33. Bismuth C, Pebay-Peyroula F, Frejaville J: Present day therapy of toxic cardiomyopathies. Concours Med 91 (Suppl 21): 4453-4470, 1969 34. NaHCO3 and TCA poisoning (Editorial). Lancet 2:838, Oct 1976 35. Moir DC, Cornwell WB, Dingwall-Frodyce 1. et al: Cardiotoxicity of amitriptyline. Lanicet 2:561-564, Sep 16, 1972 36. Biggs JT, Spiker DG, Petit JM: Tricyclic antidepressant overdose. JAMA 238:135-138, Jul 11, 1977

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37. Petit JM, Spiker DG, Ruwitch JF, et al: Tricyclic antidepressant plasma levels in adverse effects after overdose. Clin Pharmacol and Ther 21:47-51, 1977 38. Glassinan AH, Jurwic MJ, Perel JM: Plasma binding of imipramine and clinical outcome. Am J Psych 130:1367-1369, Dec 1973 39. Physostigmine: Rational use (Editorial). JACEP 5:541, Jul 1976 40. Sedal L, Korman MG, William PO, et al: Overdosage of tricyclic antidepressants: A report of two deaths and a prospective study of 24 patients. Med J Aust 2:74-79, 1972 41. Spiker DG, Biggs JT: Tricyclic antidepressants: Prolonged plasma levels after overdose. JAMA 236:1711-1712, Oct 11, 1976 42. Masters AB: Delayed death in imipramine poisoning. Br Med J 3:866-867, Sep 30, 1967 43. Noble J: Acute poisoning by TCA's. Clin Tox 4:451, 1971 44. George AJ: The effects of three tricyclic antidepressants on arterial 3HNA uptake and arterial responsiveness to noradrenaline (NA). Br J Pharmacol 57:432-433, 1976 45. Filczewski M, Szymanska-Kosmala M, Oledzka K: Biosynthesis of catecholamines, uptake of 3H-noradrenaline, and reactivity of cardiovascular system of the rat after chronic and acute treatment with a new antidepressant agent, IPF C-45. Pol J Pharmacol 29:23-29, 1977 46. Kabes J, Poschlova N, Krsiak TD, et al: Tricyclic antidepressants and depletion of brain catecholamines: Preclinical and clinical studies with L-dopa. Activitas Nervosa Superior 18: 242, 1976 47. Nakamura M, Fukushima H: The effect of tricyclic antidepressants and neLuroleptics on the peripheral and central action of norepinephrine in reserpine-treated mice. Europ J Pharmacol 38:342-348, 1976 48. Axelrod J, Whitby LG, Hertting G: Effect of psychotropic drugs on the uptake of 3H-norephinephrine by tissues. Science 133:383-384, Feb 1961 49. Axelrod J, Hertting G, Potter L: Effect of drugs on the uptake and release of 3H-norepinephrine in the rat heart. Nature 194:297, Apr 21, 1962 50. Franco R, Bonaccorsi A, Castelli MG, et al: Relationships between chronotropic effect, 1-3H-noradrenaline uptake and tissue concentrations of desirpramine, protriptyline and doxepin in rat isolated atria. Arch Int Pharmacodyn 224:55-65, 1976 51. Boakes AJ, Laurence DR, Teoh PC, et al: Interactions between sympathomimetic amines and antidepressant agents in man. Br Med J 1:311-315, 1973 52. Borga 0, Hamberger B, Malmfors T, et al: The role of plasma protein binding in the inhibitory effect of nortriptyline on the neuronal uptake of norepinephrine. Clin Pharmacol Ther 11:581-588, 1970 53. Borga 0, Azarnoff DL, Forshell GP, et al: Plasma protein binding of tricyclic antidepressants in man. Biochem Pharmacol 18:2135-2138, 1969 54. Glassman AH, Hurwic MJ, Perel JM: Plasma binding of imipramine and clinical outcome. Am J Psych 130:1367-1369, Dec 1973 55. Bigger JT Jr, Giardina EGV, Perel JM, et al: Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engl J Med 296:206, 1977 56. Kantor SJ, Glassman AH, Bigger JT Jr, et al: The cardiac effects of therapeutic plasma concentrations of imipramine. Am J Psychiatry 135:534, 1978 57. Vohra J, Burrows G, Hunt D, et al: The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. ELur J Cardiol 3:219, 1975 58. Kerr F, Kenoyer G, Bilitch M: Quinidine overdose-Neurologic and cardiovascuLlar toxicity in a normal person. Br Heart J 33:629, 1971 59. Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrythmias-VII. Cardiac effects of quinidine anid procaine amide. B Am Heart J 90:117, 1975 60. Shub C, Gau GT, Sidell PM, et al: The management of acute quinidine intoxication. Chest 73:173, 1978 61. Sizyer RB, Clark JK, Barker ES, et al: The acute effects in man of rapid intravenotus infusion of hypertonic sodium bicarbonate solution. Medicine 34:51, 1955 62. Conn HL, Luchi RJ: Some quantitative aspects of the binding of quinidine and related quinoline compounds by human serum albumin. J Clin Invest 40:509, 1961 63. Gerhardt RE, Knouss RF, Thyrum PT, et al: Quinidine excretion in aciduria and alkaluria. Ann Intern Med 71:927-933, Nov 1969 64. Burks JS, Walker JE, Rumack BH, et al: Tricyclic antidepressant poisoning: Reversal of coma, choreoathetosis, and myoclonus by physostigmine. JAMA 230:1405-1407, Dec 4, 1974 65. Snyder BD, Blonde L, McWhirter WR: Reversal of amitryptiline intoxication by physostigmine. JAMA 230:1433-1434, Dec 4, 1974 66. Newton RW: Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA 231:942-943, Mar 3, 1975 67. Katz RL, Katz GJ: Clinical experience with parasympathomimetics and anticholinesterases in anesthesia, In Nahas GC, Salamagne JC, Vears P, et al (Eds): Le Systeme Cholinergique. Paris, Librarie Arnette, 1972 68. Chin LS, Havill JH, Rothwell RP, et al: Use of physostigmine in tricyclic antidepressant poisoning. Anesth Intensive Care 4:138-140, May 1976 69. Langslet A, Johansen WG, Ryg M, et al: Effects of dibenzepine and imipramine on the isolated rat heart. Europ J Pharmacol 14:333-339, May 1971