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Acute hydralazine overdose: Marked ECG abnormalities in a young adult
CASE REPORT
hydralazine, overdose
Acute Hydralazine Overdose: Marked ECG Abnormalities in a Young Adult
From the Departments of Emergency Medicine, Wilford Hall Medical Center, Lackland Air Force Base, Texas:* and Darnall Army Community Hospital, Fort Hood, Texas. t Recei,vedfor publication February 12, 1991. Revision received July 18, 1991. Accepted for publication September 6, 1991. The opinions and assertions contained herein are those of the authors and should not be construed as official or as representing the opinions of the Department of the
Brent A Smith, MD, CPT, MC, USA* Douglas B Ferguson, MD t
Although hydralazine is a commonly prescribed antihypertensive agent, reports of acute human poisoning are uncommon. Most of the literature focuses on chronic toxicity, most notably, the drug-induced systemic lupus erythematosus syndrome. A case of acute hydralazine overdose associated with marked ECG ST segment depression in a young adult is presented. Although the patient also had mild hypotension, acidemia, and ethanol intoxication, the ECG abnormality was alarming and suggestive of myocardial ischemia. The patient was managed conservatively in an tCU setting, and the metabolic and ECG abnormalities resolved. No reports of such marked ECG changes associated with acute hydralazine poisoning in a young adult could be found. Clinical and experimental data on acute hydralazine exposure suggest that the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury, should be considered. [Smith BA, Ferguson DB: Acute hydralazine overdose: Marked ECG abnormalities in a young adult. Ann Emerg Med March 1992;21:326-330.]
Army, the Department of the Air Force, or the Department of Defense.
INTRODUCTION Although hydralazine hydroehloride is a commonly prescribed antihypertensive agent, reports of acute poisoning are uncommon. Most of the literature relating to adverse effects of this agent focuses on effects associated with chronic therapy, most notably, the drug-induced systemic lupus erythematosus syndrome. Furthermore, reported acute sequelae of hydralazine administration have usually been restricted to the possibility of reflex tachycardia-induced myocardial ischemia in older patients with known ischemic heart disease. A case of acute hydralazine overdose in a young woman that was associated with ethanol intoxication is presented. The patient's emergency department course was notable for a markedly abnormal ECG as well as mild hypotension, tachycardia, and acidemia. No other reports of acute hydralazine overdose associated with such marked ECG abnormalities in a young adult have been found. Possible pathophysiologic mechanisms involved in acute overdose of hydralazine and the implications for treatment are discussed.
126/326
ANNALS OF EMERGENCY MEDICINE 21:3
MARCH1992
HYDRALAZINE
OVERDOSE
Smith & Ferguson
CASE REPORT A 27-year-old woman was brought to the ED by ambulance after ingesting ethanol and a total of 2,000 mg hydralazine two hours before arrival during a suicide attempt. According to paramedics, the patient was alert and cooperative at the scene, and vital signs were systolic blood pressure, 85 mm Hg; pulse, 130; and respirations, 20. There was no evidence of trauma, and the only empty pill bottle found was a recent prescription for hydralazine (100 tablets, 25 mg each). Prehospital treatment directed by the on-line base station physician was limited to establishment of an IV line of 0.9% NaC1, cardiac monitoring, supplemental oxygen, and code III (emergency) transport. Prehospital time was approximately ten minutes. The patient's husband stated that the couple had argued earlier in the day and that his wife had no history of suicide, chronic alcohol abuse, or psychiatric disorders. The patient's medical history was significant only for essential hypertension since she was about 20 years old. Her only regular medication was 25 mg hydralazine twice daily, which she had taken for several years. She had undergone surgical sterilization by tubal ligation in the past. Evaluation in the ED revealed an intoxicated but cooperative woman in no distress. She was oriented to
person, place, and date. The patient denied the presence of chest pain, shortness of breath, dyspnea, loss of consciousness, vomiting, abdominal pain, injury, or any other complaints. She admitted the ingestion of a total of 80 hydralazine tablets (25 mg each) and ethanol but denied other ingestions, including illicit drugs. Initial vital signs were blood pressure, 90/48 mm Hg; pulse, 132; respirations, 24; and temperature, 37 C. The patient's body weight was 71 kg. Physical examination of the head, neck, chest, abdomen, extremities, and skin was unremarkable except for the presence of tachycardia and symmetric lateral gaze nystagmus (attributed to ethanol intoxication). There was no stigmata of chronic alcoholism or IV drug abuse. After the rapid IV administration of 2 L of 0.9% NaCI, the patient's blood pressure increased to 115/48 mm Hg, and the pulse decreased to 120. She underwent orogastric lavage followed by the administration of 50 g of activated charcoal and 300 mL of magnesium citrate solution through an orogastric tube. An ECG done in the ED demonstrated sinus tachycardia and diffuse, marked ST segment depression (Figure I). Initial serum chemistries were sodium, 144 mmol/L; chloride, 110 retool/L; potassium, 3.2 mmol/L; bicarbonate, 17 mmol/L (anion gap, 17); urea
MARCH 1992 21:3 ANNALS OF EMERGENCY MEDICINE
nitrogen, 3.0 retool/L; creatinine, 124 pmol/L; and glucose, 9.3 mmol/L (range, 3.9 to 6.1). The serum calcium was 2.2 mmol/L (range, 2.2 to 2.5), the serum magnesium was 1.0 mmol/L (range, 0.8 to 1.2), and quantitative levels for salicylate and acetaminophen were negative. A urine toxicology screen was negative for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and tetrahydrocannabinols. A blood ethanol level was 66 mmol/L (306 mg/dL). The measured and calculated osmolalities (including ethanol) were 368 nmol/kg and 366 nmol/kg, respectively. A test for serum ketones was negative. The initial arterial blood gas on 2 L nasal oxygen was pH, 7.30; PCO2, 24 mm Hg; PO2, 123 mm Hg; and Hco 3, 11.6 mmol/L. The WBC count was 15.2 x 109/L, and the hemoglobin was 110.1 g/L. The patient was admitted to the ICU with a persistent sinus tachycardia averaging 120. Her blood pressure was maintained with IV crystalloid and did not require vasopressors. Further laboratory evaluation after admission included serial cardiac enzymes every eight hours.
Although serial creatine phosphokinase levels were elevated (278, 368, and 268 units/L; normal values, 21 to 215 units/L), the MB-isoenzyme fraction was less than 3%, and serial lactate dehydrogenase and aspartate aminotransferase levels remained normal. Although no potassium supplementation was given, a repeat potassium level three hours after admission was 4.4 mmol/L, and ECG and arterial blood gas were essentially unchanged. A lactate level drawn five hours after admission was elevated at 3.0 mmol/L (range, 0.5 to 2.0 mmol/L). The urine was normal without evidence of myoglobinuria. The patient remained stable without cardiac arrhythmias, chest pain, or other systemic complaints; by 24 hours after ingestion, her arterial blood gas, electrolytes, complete blood count, and ECG (Figure 2) had returned to normal. After psychiatric evaluation, she was discharged home without any apparent sequelae. A graded exercise test done in follow-up was normal. The patient subsequently moved to another state and was lost to follow-up. •
Figure 1. ECG demonstrating sinus tachycardia.
Figure 2. ECG 24 hours after ingestion.
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DISCUSSION Hydralazine is a commonly prescribed agent that is used to treat essential hypertension, heart failure, and the preeclampsia/eclampsia syndrome. In the most recent annual report of the American Association of Poison Control Centers, a total 404 exposures were reported, with only three patients experiencing major sequelae.1 A specific toxic dose is undefined, and an adult allegedly survived acute ingestion of l0 g hydralazine. 2 Gastrointestinal absorption of hydralazine is excellent (50% to 90%) with peak plasma levels occurring within approximately 1 to 2 hours. Protein binding is high (85%), 3 and peak clinical effects occur in about 2 to 4 hours. ¢ The metabolism of hydralazine is not straightforward. The drug is subject to first-pass metabolism by the intestinal wall and liver, the extent of which is genetically determined by the patient's acetylator phenotype. Slow acetylators have higher steady-state plasma levels of hydralazine, and patients who are rapid aeetylators appear to require higher doses of the drug for efficacy.S,6 The plasma elimination half-life of hydralazine reported in the literature has been variable, and the duration of the hypotensive effects exceeds that predicted from the rate of elimination of the parent compound. No clear-cut correlation exists between plasma
128/328
levels and the drug's clinical effects. 5 Approximately 10% of a single oral dose is recovered from the urine as the parent drug, but the validity of assays used in the past has been questioned because the drug is unstable in biological fluids. 5 The drug accumulates in renal failure. The antihypertensive effects of hydralazine are thought to be secondary to direct relaxation of arteriolar vascular smooth muscle and may involve cyclic GMP. The prominent effects of therapeutic doses include decreases in peripheral vascular resistance, decreased blood pressure, and tachycardia. 6 Adverse effects of chronic hydralazine administration are often reported. Attention has focused largely on the lupuslike syndrome that occurs in as many as 10% to 20% of patients receiving total daily doses exceeding 400 rag. The syndrome is uncommon if daily doses are limited to less than 200 mg and has a higher incidence in slow acetylators.S, 7 Published reports of acute toxicity from hydralazine are uncommon. Adverse sequelae of acute hydralazine exposure usually focus on the possibility of indirect mechanisms such as baroreeeptor-mediated reflex taehyeardia with resultant myocardial ischemia (in patients with underlying ischemie heart disease), hypotension, and shock.3,4 Although the cardiovascular
toxicity mentioned in the literature reflects such assumptions of the pathophysiology, this may not be the case. There is evidence, both clinically and experimentally, that there may be direct organ toxicity from acute hydralazine overdose. In a study with rats, a single subcutaneous injection of hydralazine (10 mg/kg) was associated with evidence of fresh microscopic myocardial necrosis. This finding was more pronounced when animals were injected with both hydralazine and prenalterol (a ~-adrenergic receptor agonist). 8 In mice, a single oral overdose of hydralazine manifested as tonic-clonic convulsions within ten minutes, whereas in dogs, a subacute toxicity model using a modified hydralazine compound produced marked tachycardia but no ECG changes. 9 Other evidence of a direct myocardial effect include in vivo experimentation in which hydralazine produced both positive chronotropic and inotropic effects in isolated animal hearts. 10 These inotropic effects were inhibited by the addition of a calcium channel blocker (verapamil) and a ~-blocker (propranolol). Finally, hydralazine-induced myocardial necrosis in rats was prevented by pretreatment with verapamil or propranolol, n These data suggest that augmentation of myocardial slow calcium Channels and [~-adrenergic receptors
may- play a role in the pathophysiology of acute hydralazine toxicity, perhaps leading directly to tachycardia, occult myocardial damage, and ECG changes. The notion of tachycardiainduced myocardial ischemia may also be more obtuse than the literature suggests. After an oral dose of hydralazine, a temporary reduction in the coronary perfusion pressure gradient (a major correlate of subendocardial blood flow) was found in patients with ischemic cardiomyopathy that corresponded temporally with episodes of myocardial ischemia. This occurred in the absence of tachycardia.12 The coingestion of alcohol in acute hydralazine overdose has not been studied, and its contribution to the marked ECG abnormality seen in our patient is speculative. The acute cardiovascular effects of ethanol are variable and include increased atrial and ventricular arrhythmias, 13 as well as tachycardia, vasodilatation, and decreased blood pressure. 1¢ Although chronic alcoholic cardiomyopathy is a well-known entity that may be associated with ECG ST-T abnormalities,iS, 16 no specific reports of acute intoxication associated with marked ST segment depression such as that seen in our patient could be found in a computerized literature search. Altered electrolyte homeostasis may have been responsible for the marked ECG •
ANNALS 0F EMERGENCY MEDICINE 2 1 : 3 MARCH1992
H Y D R A L A Z I N E OVERDOSE
Smith & Ferguson
abnormalities. Hypokalemia is a well-known cause of ECG changes, but these changes are not usually seen until
gestive of a lactic acidosis secondary to circulatory shock. 2o Other known causes of increased anion gap
potassium concentrations fall below 3.0 retool/L, and they consist of flattening or inversion of T waves and the presence of U waves. ST segment depression, PR interval prolongation, and slight prolongation of the QRS complex may also occur. These changes are probably mediated through hyperpolarization of myocardial cell membranes. 17 In addition, potassium shifts to the extracellular compartment with decreases in serum pH by approximately 0.6 mmol/L per 0.1 pH unit. 18 In the setting of systemic acidosis and an initial serum potassium of 3.2 mmol/L such as was seen in our patient, normalization of pH should have been manifested by a more severe hypokalemia, but this was not observed. This inconsistency, coupled with the lack of data on acute hydralazine overdose, makes the etiology of the marked ECG
metabolic acidosis were not present. Under conditions of tissue hypoperfusion, there is an increase in reduced nicotinamide adenine dinucleotide (NADH) relative to NAD that favors the formation of lactate. Although rarely sufficient by itself to cause significant lactic acidosis, heavy ethanol intake may also increase NADH favoring the formation of lactate. 21 A direct drug effect on myocardial cell membranes from acute hydralazine overdose as a cause of the ECG abnormalities has not been reported, and such a mechanism is speculative. The management of acute hydralazine overdose is usually reported as straightforward with emphasis on correction of the arteriolar vasodilatadon-induced hypotension with IV crystalloid and gut decontamination.3 Vasopressors such as dopamine are recom-
abnormality seen in our patient uncertain, but hypokalemia may have been a factor. Other explanations for the ECG abnormalities are plau-
mended as secondary agents if crystalloid fails to reverse hypotension. Laboratory levels of hydralazine are not clinically useful in acute overdose. 3 Although data are not abundant, there is some evidence that one should consider the following theoretical concerns based on reported clinical and experimental data. First, direct myocardial damage in both healthy and diseased hearts may result
sible. Circulatory shock and tissue hypoperfusion may be a cause of ST segment abnormalities. 19 The increased anion gap metabolic acidosis, elevated lactate level, and relative hypotension manifested by our patient are all sug-
MARCH 1992 21:3
ANNALS OF EMERGENCY MEDIOINE
from acute hydralazine overdose. Second, hydralazine may have direct chronotropic and inotropic effects, and tachycardia associated with hydralazine overdose may not be just a simple baroreceptormediated mechanism. Third, acute cardiovascular toxicity of hydralazine overdose may be mediated through slow calcium channels and J~adrenergic receptor augmentation. The administration of calcium channel and/or J3-blocking agents may be considered in addition to IV fluids in the management of tachycardia or ischemia. Last, the use of vasopressors with prominent J3-adrenergic agonist effects should be used with caution in managing hypotension unresponsive to IV crystalloid.
SUMMARY A case of acute hydralazine overdose in a young adult associated with marked ECG ST segment depression is presented. The patient was managed conservatively in an ICU setting, and the ECG and metabolic abnormalities returned to normal within 24 hours. Clinical and experimental data on acute hydralazine exposure suggest that consideration be given to the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury. These data also suggest that vasopressors with prominent 13-agonist effects
should be used with caution and that calcium channel blockers and J3-antagonists may have a role in the management of acute hydralazine overdose. IN
REFERENCES 1. Litovitz TL, Schmitz BF, Bailey KM: 1989 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am J ErnergMed 1990;8:394-442. 2. POISINBEX,Denver, Micromedix, 1991, p 67. 3. E[lenhorn M J, Barceloux DG (eds): Medical Toxicology:Diagnosis and Treatmentof Human Poisoning. New York, Elsevier Science Publishing Co, 1988, p 312313. 4. Keene JG, Dunne ML: Antihypertensive agents, in Noji EK, Kelen GD (eds): Manual of ToxicologicEmergencies. Chicago, Year Book Medical Publishers, 1989, p 477-478. 5. Talseth T: Clinical pharmacokinetics of hydralazine. Clio Pharmacokinet 1977;2:317-329. 6. Goodman LS, Gilman AG, Rail TW, et al {eds): The PharmacologicalBasis of Therapeutics. New York, Macmillan, 1985, p 795-796. 7. Kock-Weser J: Hydralazine. N Engl J Med 1976;295:320-323, 8. Joseph X, Balazs T: Enhanced myocardial necrosis induced in rats by the combined administration of hydralazine and prenalterol. J PharmPharmaco11986;38:895-697. 9. Yeary RA, Brahm CA, MNler DL: Acute and subacute toxicity of an adduct of hydralazine and a ketealkylthiazide. TexicelAppl Pharmecol1965;7:598-605. 10. Azuma J, Sawamura A, Harada H, et ah Mechanism of direct cardiostimulating actions of hydralazine. Eur J Pharmacel 1987;139:137-144. 1I. Balazs T, Ferrans VJ, EI-Hage A, et ah Study of the mechanism of hydralazineinduced myocardial necrosis in the rat. ToxicolAppl Pharmacol1981;59: 524-634. 12. Packer M, Meller J, Gorlin R, et ah Hydralazine-induced ischemia without tachycardia: The importance of coronary perfusion pressure gradients, Am J Cardiof 1978;41:398. 13. Kentala E, Luurila O, Salaspuro MP: Effects of alcohol ingestion on cardiac rhythm in patients with ischemic heart disease. Ann Clin Res 1976;8:408-414. 14. Welch RD, Todd K: Nifedipine overdose accompanied by ethanol intoxication in a patient with congenital heart disease. J Emerg Med 1990;8:169-172. 15. Sokolow M, Mollroy MB: Clinical Cardiology,ed 4. No~alk, Connecticut, Appleton-Century-Crofts, 1986, p 553-554.
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16. Urbano-MarquezA, Estruch R, NavarroLopezF, et al: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 1989;320:409-415. 17. Janson CL: Fluid and electrolyte balance, in RosenP, et al (eds): EmergencyMedicine: Conceptsand Clinical Practice, ed 2. St. Louis, CV Mosby Co, 1988, p 1981-1991. 18. Tyler DS: Fluids and electrolytes, in Lyerly HK (ed):The Handbookof Surgical Intensive Care."Practices of the Surgery Residents at the Duke University Medical Center, ed 2. Chicago,Year Book Medical Publishers, 1989, p 239-241 19. Dunn MI, Upman BS: Lipman-Massie Clinical Electrocardiology,ed 8. Chicago, Year Book Publishers, 1989, p 307-316. 20. McCall D, O'RourkeRA: Hypotensionand cardiegenic shock, in Stein JH (ed): Internal Medicine, ed 3. Boston, Little, Brown & Co, 1990, p 97-102. 21. Kurtzman NA, Laski ME: Disordersof acid-base balance, in Stein JH (ed): Internal Medicine, ed 3. Boston, Little, Brown & Co, 1990. p 864-871.
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Address for reprints: Brent A Smith, MD, CPT, MC, USA, Department of Emergency Medicine-SGHAE, Wilferd Hall Medical Center, Lackland Air Force Base, Texas 78236.
ANNALS OF EMERGENCY MEDICINE
21:3
MARCH 1992
hydralazine, overdose
Acute Hydralazine Overdose: Marked ECG Abnormalities in a Young Adult
From the Departments of Emergency Medicine, Wilford Hall Medical Center, Lackland Air Force Base, Texas:* and Darnall Army Community Hospital, Fort Hood, Texas. t Recei,vedfor publication February 12, 1991. Revision received July 18, 1991. Accepted for publication September 6, 1991. The opinions and assertions contained herein are those of the authors and should not be construed as official or as representing the opinions of the Department of the
Brent A Smith, MD, CPT, MC, USA* Douglas B Ferguson, MD t
Although hydralazine is a commonly prescribed antihypertensive agent, reports of acute human poisoning are uncommon. Most of the literature focuses on chronic toxicity, most notably, the drug-induced systemic lupus erythematosus syndrome. A case of acute hydralazine overdose associated with marked ECG ST segment depression in a young adult is presented. Although the patient also had mild hypotension, acidemia, and ethanol intoxication, the ECG abnormality was alarming and suggestive of myocardial ischemia. The patient was managed conservatively in an tCU setting, and the metabolic and ECG abnormalities resolved. No reports of such marked ECG changes associated with acute hydralazine poisoning in a young adult could be found. Clinical and experimental data on acute hydralazine exposure suggest that the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury, should be considered. [Smith BA, Ferguson DB: Acute hydralazine overdose: Marked ECG abnormalities in a young adult. Ann Emerg Med March 1992;21:326-330.]
Army, the Department of the Air Force, or the Department of Defense.
INTRODUCTION Although hydralazine hydroehloride is a commonly prescribed antihypertensive agent, reports of acute poisoning are uncommon. Most of the literature relating to adverse effects of this agent focuses on effects associated with chronic therapy, most notably, the drug-induced systemic lupus erythematosus syndrome. Furthermore, reported acute sequelae of hydralazine administration have usually been restricted to the possibility of reflex tachycardia-induced myocardial ischemia in older patients with known ischemic heart disease. A case of acute hydralazine overdose in a young woman that was associated with ethanol intoxication is presented. The patient's emergency department course was notable for a markedly abnormal ECG as well as mild hypotension, tachycardia, and acidemia. No other reports of acute hydralazine overdose associated with such marked ECG abnormalities in a young adult have been found. Possible pathophysiologic mechanisms involved in acute overdose of hydralazine and the implications for treatment are discussed.
126/326
ANNALS OF EMERGENCY MEDICINE 21:3
MARCH1992
HYDRALAZINE
OVERDOSE
Smith & Ferguson
CASE REPORT A 27-year-old woman was brought to the ED by ambulance after ingesting ethanol and a total of 2,000 mg hydralazine two hours before arrival during a suicide attempt. According to paramedics, the patient was alert and cooperative at the scene, and vital signs were systolic blood pressure, 85 mm Hg; pulse, 130; and respirations, 20. There was no evidence of trauma, and the only empty pill bottle found was a recent prescription for hydralazine (100 tablets, 25 mg each). Prehospital treatment directed by the on-line base station physician was limited to establishment of an IV line of 0.9% NaC1, cardiac monitoring, supplemental oxygen, and code III (emergency) transport. Prehospital time was approximately ten minutes. The patient's husband stated that the couple had argued earlier in the day and that his wife had no history of suicide, chronic alcohol abuse, or psychiatric disorders. The patient's medical history was significant only for essential hypertension since she was about 20 years old. Her only regular medication was 25 mg hydralazine twice daily, which she had taken for several years. She had undergone surgical sterilization by tubal ligation in the past. Evaluation in the ED revealed an intoxicated but cooperative woman in no distress. She was oriented to
person, place, and date. The patient denied the presence of chest pain, shortness of breath, dyspnea, loss of consciousness, vomiting, abdominal pain, injury, or any other complaints. She admitted the ingestion of a total of 80 hydralazine tablets (25 mg each) and ethanol but denied other ingestions, including illicit drugs. Initial vital signs were blood pressure, 90/48 mm Hg; pulse, 132; respirations, 24; and temperature, 37 C. The patient's body weight was 71 kg. Physical examination of the head, neck, chest, abdomen, extremities, and skin was unremarkable except for the presence of tachycardia and symmetric lateral gaze nystagmus (attributed to ethanol intoxication). There was no stigmata of chronic alcoholism or IV drug abuse. After the rapid IV administration of 2 L of 0.9% NaCI, the patient's blood pressure increased to 115/48 mm Hg, and the pulse decreased to 120. She underwent orogastric lavage followed by the administration of 50 g of activated charcoal and 300 mL of magnesium citrate solution through an orogastric tube. An ECG done in the ED demonstrated sinus tachycardia and diffuse, marked ST segment depression (Figure I). Initial serum chemistries were sodium, 144 mmol/L; chloride, 110 retool/L; potassium, 3.2 mmol/L; bicarbonate, 17 mmol/L (anion gap, 17); urea
MARCH 1992 21:3 ANNALS OF EMERGENCY MEDICINE
nitrogen, 3.0 retool/L; creatinine, 124 pmol/L; and glucose, 9.3 mmol/L (range, 3.9 to 6.1). The serum calcium was 2.2 mmol/L (range, 2.2 to 2.5), the serum magnesium was 1.0 mmol/L (range, 0.8 to 1.2), and quantitative levels for salicylate and acetaminophen were negative. A urine toxicology screen was negative for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and tetrahydrocannabinols. A blood ethanol level was 66 mmol/L (306 mg/dL). The measured and calculated osmolalities (including ethanol) were 368 nmol/kg and 366 nmol/kg, respectively. A test for serum ketones was negative. The initial arterial blood gas on 2 L nasal oxygen was pH, 7.30; PCO2, 24 mm Hg; PO2, 123 mm Hg; and Hco 3, 11.6 mmol/L. The WBC count was 15.2 x 109/L, and the hemoglobin was 110.1 g/L. The patient was admitted to the ICU with a persistent sinus tachycardia averaging 120. Her blood pressure was maintained with IV crystalloid and did not require vasopressors. Further laboratory evaluation after admission included serial cardiac enzymes every eight hours.
Although serial creatine phosphokinase levels were elevated (278, 368, and 268 units/L; normal values, 21 to 215 units/L), the MB-isoenzyme fraction was less than 3%, and serial lactate dehydrogenase and aspartate aminotransferase levels remained normal. Although no potassium supplementation was given, a repeat potassium level three hours after admission was 4.4 mmol/L, and ECG and arterial blood gas were essentially unchanged. A lactate level drawn five hours after admission was elevated at 3.0 mmol/L (range, 0.5 to 2.0 mmol/L). The urine was normal without evidence of myoglobinuria. The patient remained stable without cardiac arrhythmias, chest pain, or other systemic complaints; by 24 hours after ingestion, her arterial blood gas, electrolytes, complete blood count, and ECG (Figure 2) had returned to normal. After psychiatric evaluation, she was discharged home without any apparent sequelae. A graded exercise test done in follow-up was normal. The patient subsequently moved to another state and was lost to follow-up. •
Figure 1. ECG demonstrating sinus tachycardia.
Figure 2. ECG 24 hours after ingestion.
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DISCUSSION Hydralazine is a commonly prescribed agent that is used to treat essential hypertension, heart failure, and the preeclampsia/eclampsia syndrome. In the most recent annual report of the American Association of Poison Control Centers, a total 404 exposures were reported, with only three patients experiencing major sequelae.1 A specific toxic dose is undefined, and an adult allegedly survived acute ingestion of l0 g hydralazine. 2 Gastrointestinal absorption of hydralazine is excellent (50% to 90%) with peak plasma levels occurring within approximately 1 to 2 hours. Protein binding is high (85%), 3 and peak clinical effects occur in about 2 to 4 hours. ¢ The metabolism of hydralazine is not straightforward. The drug is subject to first-pass metabolism by the intestinal wall and liver, the extent of which is genetically determined by the patient's acetylator phenotype. Slow acetylators have higher steady-state plasma levels of hydralazine, and patients who are rapid aeetylators appear to require higher doses of the drug for efficacy.S,6 The plasma elimination half-life of hydralazine reported in the literature has been variable, and the duration of the hypotensive effects exceeds that predicted from the rate of elimination of the parent compound. No clear-cut correlation exists between plasma
128/328
levels and the drug's clinical effects. 5 Approximately 10% of a single oral dose is recovered from the urine as the parent drug, but the validity of assays used in the past has been questioned because the drug is unstable in biological fluids. 5 The drug accumulates in renal failure. The antihypertensive effects of hydralazine are thought to be secondary to direct relaxation of arteriolar vascular smooth muscle and may involve cyclic GMP. The prominent effects of therapeutic doses include decreases in peripheral vascular resistance, decreased blood pressure, and tachycardia. 6 Adverse effects of chronic hydralazine administration are often reported. Attention has focused largely on the lupuslike syndrome that occurs in as many as 10% to 20% of patients receiving total daily doses exceeding 400 rag. The syndrome is uncommon if daily doses are limited to less than 200 mg and has a higher incidence in slow acetylators.S, 7 Published reports of acute toxicity from hydralazine are uncommon. Adverse sequelae of acute hydralazine exposure usually focus on the possibility of indirect mechanisms such as baroreeeptor-mediated reflex taehyeardia with resultant myocardial ischemia (in patients with underlying ischemie heart disease), hypotension, and shock.3,4 Although the cardiovascular
toxicity mentioned in the literature reflects such assumptions of the pathophysiology, this may not be the case. There is evidence, both clinically and experimentally, that there may be direct organ toxicity from acute hydralazine overdose. In a study with rats, a single subcutaneous injection of hydralazine (10 mg/kg) was associated with evidence of fresh microscopic myocardial necrosis. This finding was more pronounced when animals were injected with both hydralazine and prenalterol (a ~-adrenergic receptor agonist). 8 In mice, a single oral overdose of hydralazine manifested as tonic-clonic convulsions within ten minutes, whereas in dogs, a subacute toxicity model using a modified hydralazine compound produced marked tachycardia but no ECG changes. 9 Other evidence of a direct myocardial effect include in vivo experimentation in which hydralazine produced both positive chronotropic and inotropic effects in isolated animal hearts. 10 These inotropic effects were inhibited by the addition of a calcium channel blocker (verapamil) and a ~-blocker (propranolol). Finally, hydralazine-induced myocardial necrosis in rats was prevented by pretreatment with verapamil or propranolol, n These data suggest that augmentation of myocardial slow calcium Channels and [~-adrenergic receptors
may- play a role in the pathophysiology of acute hydralazine toxicity, perhaps leading directly to tachycardia, occult myocardial damage, and ECG changes. The notion of tachycardiainduced myocardial ischemia may also be more obtuse than the literature suggests. After an oral dose of hydralazine, a temporary reduction in the coronary perfusion pressure gradient (a major correlate of subendocardial blood flow) was found in patients with ischemic cardiomyopathy that corresponded temporally with episodes of myocardial ischemia. This occurred in the absence of tachycardia.12 The coingestion of alcohol in acute hydralazine overdose has not been studied, and its contribution to the marked ECG abnormality seen in our patient is speculative. The acute cardiovascular effects of ethanol are variable and include increased atrial and ventricular arrhythmias, 13 as well as tachycardia, vasodilatation, and decreased blood pressure. 1¢ Although chronic alcoholic cardiomyopathy is a well-known entity that may be associated with ECG ST-T abnormalities,iS, 16 no specific reports of acute intoxication associated with marked ST segment depression such as that seen in our patient could be found in a computerized literature search. Altered electrolyte homeostasis may have been responsible for the marked ECG •
ANNALS 0F EMERGENCY MEDICINE 2 1 : 3 MARCH1992
H Y D R A L A Z I N E OVERDOSE
Smith & Ferguson
abnormalities. Hypokalemia is a well-known cause of ECG changes, but these changes are not usually seen until
gestive of a lactic acidosis secondary to circulatory shock. 2o Other known causes of increased anion gap
potassium concentrations fall below 3.0 retool/L, and they consist of flattening or inversion of T waves and the presence of U waves. ST segment depression, PR interval prolongation, and slight prolongation of the QRS complex may also occur. These changes are probably mediated through hyperpolarization of myocardial cell membranes. 17 In addition, potassium shifts to the extracellular compartment with decreases in serum pH by approximately 0.6 mmol/L per 0.1 pH unit. 18 In the setting of systemic acidosis and an initial serum potassium of 3.2 mmol/L such as was seen in our patient, normalization of pH should have been manifested by a more severe hypokalemia, but this was not observed. This inconsistency, coupled with the lack of data on acute hydralazine overdose, makes the etiology of the marked ECG
metabolic acidosis were not present. Under conditions of tissue hypoperfusion, there is an increase in reduced nicotinamide adenine dinucleotide (NADH) relative to NAD that favors the formation of lactate. Although rarely sufficient by itself to cause significant lactic acidosis, heavy ethanol intake may also increase NADH favoring the formation of lactate. 21 A direct drug effect on myocardial cell membranes from acute hydralazine overdose as a cause of the ECG abnormalities has not been reported, and such a mechanism is speculative. The management of acute hydralazine overdose is usually reported as straightforward with emphasis on correction of the arteriolar vasodilatadon-induced hypotension with IV crystalloid and gut decontamination.3 Vasopressors such as dopamine are recom-
abnormality seen in our patient uncertain, but hypokalemia may have been a factor. Other explanations for the ECG abnormalities are plau-
mended as secondary agents if crystalloid fails to reverse hypotension. Laboratory levels of hydralazine are not clinically useful in acute overdose. 3 Although data are not abundant, there is some evidence that one should consider the following theoretical concerns based on reported clinical and experimental data. First, direct myocardial damage in both healthy and diseased hearts may result
sible. Circulatory shock and tissue hypoperfusion may be a cause of ST segment abnormalities. 19 The increased anion gap metabolic acidosis, elevated lactate level, and relative hypotension manifested by our patient are all sug-
MARCH 1992 21:3
ANNALS OF EMERGENCY MEDIOINE
from acute hydralazine overdose. Second, hydralazine may have direct chronotropic and inotropic effects, and tachycardia associated with hydralazine overdose may not be just a simple baroreceptormediated mechanism. Third, acute cardiovascular toxicity of hydralazine overdose may be mediated through slow calcium channels and J~adrenergic receptor augmentation. The administration of calcium channel and/or J3-blocking agents may be considered in addition to IV fluids in the management of tachycardia or ischemia. Last, the use of vasopressors with prominent J3-adrenergic agonist effects should be used with caution in managing hypotension unresponsive to IV crystalloid.
SUMMARY A case of acute hydralazine overdose in a young adult associated with marked ECG ST segment depression is presented. The patient was managed conservatively in an ICU setting, and the ECG and metabolic abnormalities returned to normal within 24 hours. Clinical and experimental data on acute hydralazine exposure suggest that consideration be given to the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury. These data also suggest that vasopressors with prominent 13-agonist effects
should be used with caution and that calcium channel blockers and J3-antagonists may have a role in the management of acute hydralazine overdose. IN
REFERENCES 1. Litovitz TL, Schmitz BF, Bailey KM: 1989 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am J ErnergMed 1990;8:394-442. 2. POISINBEX,Denver, Micromedix, 1991, p 67. 3. E[lenhorn M J, Barceloux DG (eds): Medical Toxicology:Diagnosis and Treatmentof Human Poisoning. New York, Elsevier Science Publishing Co, 1988, p 312313. 4. Keene JG, Dunne ML: Antihypertensive agents, in Noji EK, Kelen GD (eds): Manual of ToxicologicEmergencies. Chicago, Year Book Medical Publishers, 1989, p 477-478. 5. Talseth T: Clinical pharmacokinetics of hydralazine. Clio Pharmacokinet 1977;2:317-329. 6. Goodman LS, Gilman AG, Rail TW, et al {eds): The PharmacologicalBasis of Therapeutics. New York, Macmillan, 1985, p 795-796. 7. Kock-Weser J: Hydralazine. N Engl J Med 1976;295:320-323, 8. Joseph X, Balazs T: Enhanced myocardial necrosis induced in rats by the combined administration of hydralazine and prenalterol. J PharmPharmaco11986;38:895-697. 9. Yeary RA, Brahm CA, MNler DL: Acute and subacute toxicity of an adduct of hydralazine and a ketealkylthiazide. TexicelAppl Pharmecol1965;7:598-605. 10. Azuma J, Sawamura A, Harada H, et ah Mechanism of direct cardiostimulating actions of hydralazine. Eur J Pharmacel 1987;139:137-144. 1I. Balazs T, Ferrans VJ, EI-Hage A, et ah Study of the mechanism of hydralazineinduced myocardial necrosis in the rat. ToxicolAppl Pharmacol1981;59: 524-634. 12. Packer M, Meller J, Gorlin R, et ah Hydralazine-induced ischemia without tachycardia: The importance of coronary perfusion pressure gradients, Am J Cardiof 1978;41:398. 13. Kentala E, Luurila O, Salaspuro MP: Effects of alcohol ingestion on cardiac rhythm in patients with ischemic heart disease. Ann Clin Res 1976;8:408-414. 14. Welch RD, Todd K: Nifedipine overdose accompanied by ethanol intoxication in a patient with congenital heart disease. J Emerg Med 1990;8:169-172. 15. Sokolow M, Mollroy MB: Clinical Cardiology,ed 4. No~alk, Connecticut, Appleton-Century-Crofts, 1986, p 553-554.
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16. Urbano-MarquezA, Estruch R, NavarroLopezF, et al: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 1989;320:409-415. 17. Janson CL: Fluid and electrolyte balance, in RosenP, et al (eds): EmergencyMedicine: Conceptsand Clinical Practice, ed 2. St. Louis, CV Mosby Co, 1988, p 1981-1991. 18. Tyler DS: Fluids and electrolytes, in Lyerly HK (ed):The Handbookof Surgical Intensive Care."Practices of the Surgery Residents at the Duke University Medical Center, ed 2. Chicago,Year Book Medical Publishers, 1989, p 239-241 19. Dunn MI, Upman BS: Lipman-Massie Clinical Electrocardiology,ed 8. Chicago, Year Book Publishers, 1989, p 307-316. 20. McCall D, O'RourkeRA: Hypotensionand cardiegenic shock, in Stein JH (ed): Internal Medicine, ed 3. Boston, Little, Brown & Co, 1990, p 97-102. 21. Kurtzman NA, Laski ME: Disordersof acid-base balance, in Stein JH (ed): Internal Medicine, ed 3. Boston, Little, Brown & Co, 1990. p 864-871.
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Address for reprints: Brent A Smith, MD, CPT, MC, USA, Department of Emergency Medicine-SGHAE, Wilferd Hall Medical Center, Lackland Air Force Base, Texas 78236.
ANNALS OF EMERGENCY MEDICINE
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MARCH 1992