Journal of Toxicology: Clinical Toxicology
ISSN: 0731-3810 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx19
Intravenous Propranolol Reverses Hypertension after Sympathomimetic Overdose: Two Case Reports Keith K. Burkhart To cite this article: Keith K. Burkhart (1992) Intravenous Propranolol Reverses Hypertension after Sympathomimetic Overdose: Two Case Reports, Journal of Toxicology: Clinical Toxicology, 30:1, 109-114, DOI: 10.3109/15563659208994450 To link to this article: http://dx.doi.org/10.3109/15563659208994450
Published online: 25 Sep 2008.
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Date: 15 March 2016, At: 22:58
CLINICAL TOXICOLOGY, 30(1), 109-114 (1992)
Downloaded by [RMIT University Library] at 22:58 15 March 2016
INTRAVENOUS PROPRANOLOL REVERSES HYPERTENSION A F E R SYMPATHOMIMETIC OVERDOSE: TWO CASE REPORTS
Keith K. Burkhart, M.D. Central Pennsylvania Poison Center The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, Pennsylvania
ABSTRACT Hypertension is a potential complication following ephedrine and pseudoephedrine overdoses. Treatment with propranolol, a beta blocker, is not recommended since it may produce be an alpha agonist with the potential for further elevated blood pressure. Two patients who developed hypertension following sympathomimetic overdoses were treated with propranolol. After ingesting 4500 mg of pseudoephedrine, a 24 year-old male developed a blood pressure of 220/108. Five min after intravenous propranolol 1 mg BP was 153/88. After ingesting 17 500 mg of ephedrine a 29 year-old female developed a BP of 1681106. Her BP was 124/90 five min after intravenous propranolol. Further study is needed to investigate the potential therapeutic benefit of propranolol in the treatment of sympathomimetic-induced hypertension. (Key Words: ephedrine; pseudoepidrine; poisoning, humun; propranolol; hypertension, therapy.)
Address reprint requests to: Dr. Keith Burkhart, The Milton S. Hershey Medical Center, The Pennsylvania State University, 500 University Drive, Hershey, PA 17033. 109 Copyright
@
1992 by Marcel Dekker, Inc.
110
BURKHART
Downloaded by [RMIT University Library] at 22:58 15 March 2016
INTRODUCTION Ephedrine and pseudoephedrine are sympathomimetic drugs that possess both beta and alpha agonist properties (1). These drugs are also indirect-acting sympathomimetics that cause the release of neuronal norepinephrine (1). Hypertension and arrhythmias have been reported following overdoses of these drugs (2,3). Hypertension has been complicated by intracerebral and subarachnoid hemorrhages (2). Propranolol, a beta-blocker, has not been recommended for the treatment of sympathomimetic overdoses, because unopposed alpha agonist may aggravate hypertension (4). Intravenous propranolol was administered as treatment for hypertension and agitation in the following two cases of sympathomimetic overdose. Case ReDort 1 A 24 year-old male ingested by history 150 30 mg pseudoephedrine
tablets and approximately 200 325 mg aspirin tablets. When he began vomiting, he called for medical assistance. The medics reported finding an empty bottle of pseudoephedrine and a partially empty bottle of aspirin near the patient. In the Emergency Department 2 h after the overdose the patient was agitated and tremulous. He would slowly follow commands, but would not answer questions. He did shake his head "no," when asked if he had medical problems, allergies, or if he was taking prescribed medications or was using "street" drugs. His vital signs in the emergency department were: HR 125, RR 22, BP 195/92, T 37.2OC. Gastric lavage returned pink fluid, but no pill fragments. Fifty grams of activated charcoal and 70 mL 70% sorbitol were instilled. After lavage: HR 154, BP 220/108. Labetalol was not readily available that day in the emergency department, therefore propranolol 1 mg was administered intravenously over 2 min. Nitroprusside was available, if needed. Three minutes later: HR 96, BP 153/88. His tremulousness resolved and he quickly followed commands and answered questions. His ECG demonstrated normal sinus rhythm, but an ECG was not obtained prior to therapy. Laboratory data after propranolol administration included sodium 143 mmol/L, potassium 4.1 mmol/L, bicarbonate 27
Downloaded by [RMIT University Library] at 22:58 15 March 2016
PROPRANOLOL AND SYMPATHOMIMETIC OVERDOSE
111
mmol/L, chloride 107 mmol/L, blood sugar 128 mg/dL, and CPK 184 IU/L. Additional therapy included activated charcoal 25 g by nasogastric tube every 2 h. One hundred mEq of sodium bicarbonate was added to one liter D5W. This fluid was administered at 250 mL/h. His salicylate level peaked at 47 mg/dL and his bicarbonate level never fell below 24 mEq/L. His urinary pH remained above seven during his hospitalization. His hypertension recurred and additional doses of propranolol 1 mg were administered (Table 1). His recovery was otherwise uneventful. His BP at discharge was 120/80. Comprehensive drug analyses were not obtained. Case ReDort 2 A 29 year-old female drank eight beers and then ingested 700 25 mg ephedrine tablets. She walked into the ED 1.5 h later at which time: HR 100, RR 20, BP 150/100. Gastric lavage contained a large number of pills and undigested food. Activated charcoal and sorbitol were administered. Post lavage: HR 120, BP 168/106. Her physical exam was remarkable for intoxication and mild agitation. Her blood alcohol level was 245 mg/dL. A urine drug screen was positive for amphetamines. d,l-Ephedrine in a concentration of 1.0 mcg/mL will produce a false positive on the U AMP pack analyzed in a Dupont ACA discrete clinical analyzer (Product Information, E.I. Du Pont de Nemours and Company, Wilmington, DE). Gas chromatography-mass spectrometry analysis of the urine was negative for amphetamines, but further identification was not performed. She was given propranolol 1 mg IV. Four minutes later her HR was 96 and her BP was 124/90. Over the next 24 h her BP never exceeded 130/90. At discharge her BP was 110/70.
DISCUSSION
Many investigators have studied the effect of propranolol administration on blood pressure changes induced by epinephrine and norepinephrine. In one study of human volunteers an infusion of epinephrine was administered after 10 mg of intravenous propranolol (5). In the control
BURKHART
112 TABLE 1
Blood Pressure and Heart Rate Measurements Before and After Propranolol 1 mg IV in Case 1 Time 1225
1230 1730 1800
Downloaded by [RMIT University Library] at 22:58 15 March 2016
m 0005
Heart Rate
154 96 138 106 112 99
Blood Pressure 2201108
153/88 178/106 160/94 170/110 164/104
limb epinephrine alone was given. When compared to the control phase propranolol preadministration resulted in a significant increase in arterial pressure (5). Chronic oral propranolol therapy, 240 mglday , potentiated the blood pressure response to infusions of both epinephrine and norepinephrine (6). In another human volunteer study norepinephrine-inducedblood pressure elevations were blunted by chronic oral propranolol therapy, 160 mg/day (7). These study designs do not mimic overdose treatment, because direct-acting catecholamines were continuously infused after high dose or chronic dose propranolol administration. Propranolol may potentially improve hemodynamics following overdoses by suppression of the sympathetic nervous system. Rosen et al. demonstrated that propranolol decreased the release of norepinephrine in a human volunteer study (8). Kelliher et al. also demonstrated a central hypotensive effect of propranolol in a cat model that was not dependent on its beta-blocking property (9). Brain catecholamines were redistributed. Overall brain epinephrine ievels increased, while brain norepinephrine levels decreased. Propranolol, in contrast to other beta-blocking drugs, is lipophilic and quickly penetrates the central nervous system, where it may exert its chief antihypertensive effect. Propranolol administration did not aggravate hypertension produced by indirect acting sympathomimetics that demonstrate predominantly alpha agonist (10,ll).Propranolol, 0.3 mg/kg, in a human volunteer study antagonized the pressor effect of phenylpropanolamine that lacks beta-2
Downloaded by [RMIT University Library] at 22:58 15 March 2016
PROPRANOLOL AND SYMPATHOMIMETIC OVERDOSE
113
agonist properties (10). Chronic propranolol therapy, 160 or 320 mg/day, did not enhance alpha-adrenoreceptor activity following phenylephrine (1 1). There are only a few case reports detailing treatment of ephedrine and pseudoephedrine overdoses. In one case the intravenous administration of propranolol 1 mg following an overdose of an OTC stimulant containing ephedrine, caffeine and phenylpropanolamine successfully reversed ventricular tachycardia (3). In a pseudoephedrine overdose of 840 mg, labetalol was administered to treat a BP of 200/160 mm Hg (12). Two doses, 25 and 40 mg, decreased BP to 150/110,but this required 30 to 40 min. In our cases adequate blood pressure reduction occurred in minutes. This rapidity of action for propranolol compared to labetalol may be explained by the high lipid solubility of propranolol that may enhance CNS penetration. Our patient’s agitation also quickly resolved after propranolol administration. In our first case propranolol was safely readministered. Aggressive urinary alkalinization to treat the salicylate ingestion probably prolonged the half-life of pseudoephedrine, normally only 3 to 6 h in an acid urine (4). Propranolol readministration lowered the blood pressure below our target treatment range, systolic pressure less than 170 mm Hg and diastolic less than 110 mm Hg. It is uncertain why there was less blood pressure and heart rate reduction following the readministration of propranolol. The most recent edition of Poisindexm suggests propranolol as a treatment consideration for oral sympathomimetic overdoses that develop tachyarrythmias and severe symptomatic palpitations, tremor and agitation (13). For the treatment of moderate hypertension (diastolic pressure < 115 mm Hg) sublingual nifedipine is a proposed treatment, while for the treatment of severe hypertension nitroprusside remains a first line agent (13). CONCLUSION A small dose of propranolol rapidly corrected hemodynamic and CNS derangements following overdoses of two indirect-acting sympathomimetics.
Further study is needed to evaluate the potential therapeutic benefit for propranolol compared to the other numerous antihypertensive agents available for the treatment of symptomatic sympathomimetic overdoses.
114
BURKHART
REFERENCES 1. 2.
Downloaded by [RMIT University Library] at 22:58 15 March 2016
3. 4.
5. 6.
7.
8. 9. 10. 11. 12.
13.
Chua S S , Benrimoj SI. Non-prescription sympathomimeticagents and hypertension. Med Toxic01 Adverse Drug Exp 1988;3:387-417. Stoessl AJ, Young GB, Feasby TE. Intracerebral haemorrhage and angiographic beading following ingestion of catecholaminergics. Stroke 1985 ;16:734-73 6. Weesner KM, Denison M, Roberts RJ. Cardiac arrhythmias in an adolescent following ingestion of an over-the-counter stimulant. Clin Pediutr 1982;21:700-701. Aaron CK. Sympathomimetics. Emerg Med Clin North Am 1990;8:513-526. Harris WS, Schoenfeld CD, Brooks RH, Weissler AM. Effect of beta adrenergic blockade on the hemodynamic responses to epinephrine in man. Am J Cardiol 1966;17:484-492. Reeves RA, Boer WHY DeLeve L, Leenen FHH. Nonselective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine, and angiotensin 11 in normal man. Clin Phurmacol Ther 1984;35:461-466. Vlachakis ND, DeGuia D, Mendlowitz M. Blood pressure responses to catecholamines during beta adrenergic blockade with propranolol in hypertensive subjects. Chesr 1977;71:38-43. Rosen SG, Supiano MA, Perry TJ, et al. Beta-adrenergic blockade decreases norepinephrine release in humans. Am J Physiol 1990;258:E999-E1005. Kelliher GJ, Buckley JP. Central hypotensive activity of dl- and d-propranolol. J Pharm Sci 1970;59:1276-1280. Pentel PR, Asinger RW, Benowitz NL. Propranolol antagonism of phenylpropanolamine-induced hypertension. Clin Pharmacol Ther 1985;37:488-494. Myers MG. Beta adrenoceptor antagonism and pressor response to phenylephrine. Clin Pharmacol Ther 1984;36:57-63. Mariani PJ. Pseudoephedrine-induced hypertensive emergency: Treatment with Iabetalol. Am J Emerg Med 1986;4:141-142. Sawyer DR. Sympathomimetics, Oral (Management/Treatment Protocol). In: Poisindex@ Information Systems. Rumack BH , Spoerke DG, eds. , Denver, CO: Micromedex, Inc., (Edition expires September 199 1).
ISSN: 0731-3810 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx19
Intravenous Propranolol Reverses Hypertension after Sympathomimetic Overdose: Two Case Reports Keith K. Burkhart To cite this article: Keith K. Burkhart (1992) Intravenous Propranolol Reverses Hypertension after Sympathomimetic Overdose: Two Case Reports, Journal of Toxicology: Clinical Toxicology, 30:1, 109-114, DOI: 10.3109/15563659208994450 To link to this article: http://dx.doi.org/10.3109/15563659208994450
Published online: 25 Sep 2008.
Submit your article to this journal
Article views: 20
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx19 Download by: [RMIT University Library]
Date: 15 March 2016, At: 22:58
CLINICAL TOXICOLOGY, 30(1), 109-114 (1992)
Downloaded by [RMIT University Library] at 22:58 15 March 2016
INTRAVENOUS PROPRANOLOL REVERSES HYPERTENSION A F E R SYMPATHOMIMETIC OVERDOSE: TWO CASE REPORTS
Keith K. Burkhart, M.D. Central Pennsylvania Poison Center The Milton S. Hershey Medical Center The Pennsylvania State University Hershey, Pennsylvania
ABSTRACT Hypertension is a potential complication following ephedrine and pseudoephedrine overdoses. Treatment with propranolol, a beta blocker, is not recommended since it may produce be an alpha agonist with the potential for further elevated blood pressure. Two patients who developed hypertension following sympathomimetic overdoses were treated with propranolol. After ingesting 4500 mg of pseudoephedrine, a 24 year-old male developed a blood pressure of 220/108. Five min after intravenous propranolol 1 mg BP was 153/88. After ingesting 17 500 mg of ephedrine a 29 year-old female developed a BP of 1681106. Her BP was 124/90 five min after intravenous propranolol. Further study is needed to investigate the potential therapeutic benefit of propranolol in the treatment of sympathomimetic-induced hypertension. (Key Words: ephedrine; pseudoepidrine; poisoning, humun; propranolol; hypertension, therapy.)
Address reprint requests to: Dr. Keith Burkhart, The Milton S. Hershey Medical Center, The Pennsylvania State University, 500 University Drive, Hershey, PA 17033. 109 Copyright
@
1992 by Marcel Dekker, Inc.
110
BURKHART
Downloaded by [RMIT University Library] at 22:58 15 March 2016
INTRODUCTION Ephedrine and pseudoephedrine are sympathomimetic drugs that possess both beta and alpha agonist properties (1). These drugs are also indirect-acting sympathomimetics that cause the release of neuronal norepinephrine (1). Hypertension and arrhythmias have been reported following overdoses of these drugs (2,3). Hypertension has been complicated by intracerebral and subarachnoid hemorrhages (2). Propranolol, a beta-blocker, has not been recommended for the treatment of sympathomimetic overdoses, because unopposed alpha agonist may aggravate hypertension (4). Intravenous propranolol was administered as treatment for hypertension and agitation in the following two cases of sympathomimetic overdose. Case ReDort 1 A 24 year-old male ingested by history 150 30 mg pseudoephedrine
tablets and approximately 200 325 mg aspirin tablets. When he began vomiting, he called for medical assistance. The medics reported finding an empty bottle of pseudoephedrine and a partially empty bottle of aspirin near the patient. In the Emergency Department 2 h after the overdose the patient was agitated and tremulous. He would slowly follow commands, but would not answer questions. He did shake his head "no," when asked if he had medical problems, allergies, or if he was taking prescribed medications or was using "street" drugs. His vital signs in the emergency department were: HR 125, RR 22, BP 195/92, T 37.2OC. Gastric lavage returned pink fluid, but no pill fragments. Fifty grams of activated charcoal and 70 mL 70% sorbitol were instilled. After lavage: HR 154, BP 220/108. Labetalol was not readily available that day in the emergency department, therefore propranolol 1 mg was administered intravenously over 2 min. Nitroprusside was available, if needed. Three minutes later: HR 96, BP 153/88. His tremulousness resolved and he quickly followed commands and answered questions. His ECG demonstrated normal sinus rhythm, but an ECG was not obtained prior to therapy. Laboratory data after propranolol administration included sodium 143 mmol/L, potassium 4.1 mmol/L, bicarbonate 27
Downloaded by [RMIT University Library] at 22:58 15 March 2016
PROPRANOLOL AND SYMPATHOMIMETIC OVERDOSE
111
mmol/L, chloride 107 mmol/L, blood sugar 128 mg/dL, and CPK 184 IU/L. Additional therapy included activated charcoal 25 g by nasogastric tube every 2 h. One hundred mEq of sodium bicarbonate was added to one liter D5W. This fluid was administered at 250 mL/h. His salicylate level peaked at 47 mg/dL and his bicarbonate level never fell below 24 mEq/L. His urinary pH remained above seven during his hospitalization. His hypertension recurred and additional doses of propranolol 1 mg were administered (Table 1). His recovery was otherwise uneventful. His BP at discharge was 120/80. Comprehensive drug analyses were not obtained. Case ReDort 2 A 29 year-old female drank eight beers and then ingested 700 25 mg ephedrine tablets. She walked into the ED 1.5 h later at which time: HR 100, RR 20, BP 150/100. Gastric lavage contained a large number of pills and undigested food. Activated charcoal and sorbitol were administered. Post lavage: HR 120, BP 168/106. Her physical exam was remarkable for intoxication and mild agitation. Her blood alcohol level was 245 mg/dL. A urine drug screen was positive for amphetamines. d,l-Ephedrine in a concentration of 1.0 mcg/mL will produce a false positive on the U AMP pack analyzed in a Dupont ACA discrete clinical analyzer (Product Information, E.I. Du Pont de Nemours and Company, Wilmington, DE). Gas chromatography-mass spectrometry analysis of the urine was negative for amphetamines, but further identification was not performed. She was given propranolol 1 mg IV. Four minutes later her HR was 96 and her BP was 124/90. Over the next 24 h her BP never exceeded 130/90. At discharge her BP was 110/70.
DISCUSSION
Many investigators have studied the effect of propranolol administration on blood pressure changes induced by epinephrine and norepinephrine. In one study of human volunteers an infusion of epinephrine was administered after 10 mg of intravenous propranolol (5). In the control
BURKHART
112 TABLE 1
Blood Pressure and Heart Rate Measurements Before and After Propranolol 1 mg IV in Case 1 Time 1225
1230 1730 1800
Downloaded by [RMIT University Library] at 22:58 15 March 2016
m 0005
Heart Rate
154 96 138 106 112 99
Blood Pressure 2201108
153/88 178/106 160/94 170/110 164/104
limb epinephrine alone was given. When compared to the control phase propranolol preadministration resulted in a significant increase in arterial pressure (5). Chronic oral propranolol therapy, 240 mglday , potentiated the blood pressure response to infusions of both epinephrine and norepinephrine (6). In another human volunteer study norepinephrine-inducedblood pressure elevations were blunted by chronic oral propranolol therapy, 160 mg/day (7). These study designs do not mimic overdose treatment, because direct-acting catecholamines were continuously infused after high dose or chronic dose propranolol administration. Propranolol may potentially improve hemodynamics following overdoses by suppression of the sympathetic nervous system. Rosen et al. demonstrated that propranolol decreased the release of norepinephrine in a human volunteer study (8). Kelliher et al. also demonstrated a central hypotensive effect of propranolol in a cat model that was not dependent on its beta-blocking property (9). Brain catecholamines were redistributed. Overall brain epinephrine ievels increased, while brain norepinephrine levels decreased. Propranolol, in contrast to other beta-blocking drugs, is lipophilic and quickly penetrates the central nervous system, where it may exert its chief antihypertensive effect. Propranolol administration did not aggravate hypertension produced by indirect acting sympathomimetics that demonstrate predominantly alpha agonist (10,ll).Propranolol, 0.3 mg/kg, in a human volunteer study antagonized the pressor effect of phenylpropanolamine that lacks beta-2
Downloaded by [RMIT University Library] at 22:58 15 March 2016
PROPRANOLOL AND SYMPATHOMIMETIC OVERDOSE
113
agonist properties (10). Chronic propranolol therapy, 160 or 320 mg/day, did not enhance alpha-adrenoreceptor activity following phenylephrine (1 1). There are only a few case reports detailing treatment of ephedrine and pseudoephedrine overdoses. In one case the intravenous administration of propranolol 1 mg following an overdose of an OTC stimulant containing ephedrine, caffeine and phenylpropanolamine successfully reversed ventricular tachycardia (3). In a pseudoephedrine overdose of 840 mg, labetalol was administered to treat a BP of 200/160 mm Hg (12). Two doses, 25 and 40 mg, decreased BP to 150/110,but this required 30 to 40 min. In our cases adequate blood pressure reduction occurred in minutes. This rapidity of action for propranolol compared to labetalol may be explained by the high lipid solubility of propranolol that may enhance CNS penetration. Our patient’s agitation also quickly resolved after propranolol administration. In our first case propranolol was safely readministered. Aggressive urinary alkalinization to treat the salicylate ingestion probably prolonged the half-life of pseudoephedrine, normally only 3 to 6 h in an acid urine (4). Propranolol readministration lowered the blood pressure below our target treatment range, systolic pressure less than 170 mm Hg and diastolic less than 110 mm Hg. It is uncertain why there was less blood pressure and heart rate reduction following the readministration of propranolol. The most recent edition of Poisindexm suggests propranolol as a treatment consideration for oral sympathomimetic overdoses that develop tachyarrythmias and severe symptomatic palpitations, tremor and agitation (13). For the treatment of moderate hypertension (diastolic pressure < 115 mm Hg) sublingual nifedipine is a proposed treatment, while for the treatment of severe hypertension nitroprusside remains a first line agent (13). CONCLUSION A small dose of propranolol rapidly corrected hemodynamic and CNS derangements following overdoses of two indirect-acting sympathomimetics.
Further study is needed to evaluate the potential therapeutic benefit for propranolol compared to the other numerous antihypertensive agents available for the treatment of symptomatic sympathomimetic overdoses.
114
BURKHART
REFERENCES 1. 2.
Downloaded by [RMIT University Library] at 22:58 15 March 2016
3. 4.
5. 6.
7.
8. 9. 10. 11. 12.
13.
Chua S S , Benrimoj SI. Non-prescription sympathomimeticagents and hypertension. Med Toxic01 Adverse Drug Exp 1988;3:387-417. Stoessl AJ, Young GB, Feasby TE. Intracerebral haemorrhage and angiographic beading following ingestion of catecholaminergics. Stroke 1985 ;16:734-73 6. Weesner KM, Denison M, Roberts RJ. Cardiac arrhythmias in an adolescent following ingestion of an over-the-counter stimulant. Clin Pediutr 1982;21:700-701. Aaron CK. Sympathomimetics. Emerg Med Clin North Am 1990;8:513-526. Harris WS, Schoenfeld CD, Brooks RH, Weissler AM. Effect of beta adrenergic blockade on the hemodynamic responses to epinephrine in man. Am J Cardiol 1966;17:484-492. Reeves RA, Boer WHY DeLeve L, Leenen FHH. Nonselective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine, and angiotensin 11 in normal man. Clin Phurmacol Ther 1984;35:461-466. Vlachakis ND, DeGuia D, Mendlowitz M. Blood pressure responses to catecholamines during beta adrenergic blockade with propranolol in hypertensive subjects. Chesr 1977;71:38-43. Rosen SG, Supiano MA, Perry TJ, et al. Beta-adrenergic blockade decreases norepinephrine release in humans. Am J Physiol 1990;258:E999-E1005. Kelliher GJ, Buckley JP. Central hypotensive activity of dl- and d-propranolol. J Pharm Sci 1970;59:1276-1280. Pentel PR, Asinger RW, Benowitz NL. Propranolol antagonism of phenylpropanolamine-induced hypertension. Clin Pharmacol Ther 1985;37:488-494. Myers MG. Beta adrenoceptor antagonism and pressor response to phenylephrine. Clin Pharmacol Ther 1984;36:57-63. Mariani PJ. Pseudoephedrine-induced hypertensive emergency: Treatment with Iabetalol. Am J Emerg Med 1986;4:141-142. Sawyer DR. Sympathomimetics, Oral (Management/Treatment Protocol). In: Poisindex@ Information Systems. Rumack BH , Spoerke DG, eds. , Denver, CO: Micromedex, Inc., (Edition expires September 199 1).
