BRIEF CLINICAL
treatment for ventricular tachyarrhythmias complicating astemizole poisoning. The precise mechanism of this phenomenon awaits further study. JONATHAN LEOR, MICHAL HARMAN, BABETH RABINOWITZ, BENJAMIN MOZES,
M.D. M.D. M.D. M.D.
Chaim Sheba Medical Center Tel-Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel 1. Craft TM. Torsade de pointes after astemizole overdose. BMJ 1986; 292: 660. 2. Bishop RO. Gaudry PL. Prolonged Q-T interval following astemizole overdose. Arch Emerg Med 1989; 6: 63-5. 3. Snook J, Boothman-Burrell D. Watkins J, ColinJones D. Torsade de pointes ventricular tachycardia associated with astemizole overdose. Br J Clin Pratt 1988; 42: 257-9. 4. Simons FE, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet 1988: 2: 624. 5. Jackman WM. Friday KJ. Anderson JL. Aliot EM, Clark M. Lauara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31: 115-72. 6. Kaseda S, Gilmour RF, Zipes DP. Depressant effect of magnesium on early after-depolarizations and triggered activity induced by cesium, quinidine. and 4aminopyridine in canine cardiac Purkinje fibers. Am Heart J 1989; 118: 458-66. 7. Wolf AA, Levi R. Histamine and cardiac arrhythmias. Circ Res 1986; 58: 1-16. 8. Richards DM. Brogden RC, Heel RC, Speight TM, Avery GS. Astemizole: a review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 23: 38-61. 9. Tzivoni D. Banai S. Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988; 77: 392-7. Submitted
November
7.1990,
and accepted February 5, 1991
REVERSIBLEPULMONARY HYPERTENSIONASSOCIATED WITH ANOREXIGENUSE Primary pulmonary hypertension is a disease of unknown etiology that typically affects young women and results in death within several years of the onset of symptoms [1,2]. The clinical diagnosis of primary pulmonary hypertension requires the exclusion of other conditions that may
produce pulmonary hypertension, such as chronic thromboembolic disease, congenital heart disease, and left ventricular dysfunction. An association between exogenous factors and severe pulmonary hypertension in the absence of other causes has been reported. Gurtner et al [3] described an outbreak of pulmonary hypertension in western Europe that appeared to be related to the use of the anorexic agent aminorex. A relationship between the development of pulmonary hypertension and the use of other anorectic agents has also been found [4,5]. However, reversible pulmonary hypertension associated with the use of anorexigens has not been reported in the United States. We describe a case of anorexigen-induced severe pulmonary hypertension that was confirmed by both hemodynamic and pathologic findings and was reversible upon discontinuation of the offending agent. A 41-year-old woman had been in good health until she developed dyspnea in the summer of 1989. Her past medical history was unremarkable. She denied using oral contraceptives and had stopped smoking 2 years previously. However, she reported that she had begun using a diet suppressant, phendimetrazine tartrate (Bontril), approximately 6 months before the onset of her symptoms. The patient was initially treated for pneumonia and asthma without relief of her symptoms. In October 1989, she underwent emergency admission due to cardiogenic shock. Right heart catheterization was performed with the patient receiving dopamine 10 pg/kg/minute and dobutamine 10 pg/kg/minute (Table I). An echocardiogram revealed a moderate-sized pericardial effusion, a dilated and poorly contracting right ventricle, a mildly enlarged July
1991 The American
OBSERVATIONS
right atrium, and abnormal septal wall motion believed to be due to the right heart abnormalities. The left atrium and the left ventricle were normal in size and function. A ventilation-perfusion lung scan was normal, and results of serologic screening studies for the presence of a collagen vascular disease were negative. An open-lung biopsy was performed and demonstrated grade 2 to 3 vascular lesions consistent with primary pulmonary hypertension (Figure 1). A pericardial biopsy showed nonspecific inflammation. She was discharged and treated as an outpatient with digoxin, Dyazide, and warfarin. In December 1989, she was referred to the University of Maryland Medical Center. Although she still had exertional dyspnea, her symptoms had improved since discharge. Physical examination was remarkable for moderate obesity, a mild right ventricular lift, and an intermittent right-sided Sd gallop. An electrocardiogram revealed mild right ventricular hypertrophy with strain pattern. In January 1990, approximately 3 months after she had discontinued use of the anorexigen, subsequent echocardiography revealed no evidence of a pericardial effusion and resolution of the right heart abnormalities. Right heart catheterization was again performed (Table I). Although the cause of primary pulmonary hypertension remains unknown, there is evidence to suggest that pulmonary hypertension can occur in patients using appetite suppressant medications. Gurtner was among the first investigators to note an association between pulmonary hypertension and ingestion of aminorex, an appetite suppressant that is structurally similar to amphetamine. Between 1967 and 1968, a large number of patients relating a history of aminorex use Journal
of Medicine
Volume
91
97
BRIEF CLINICAL OBSERVATIONS
TABLE I HemcdynamicData October1989 Mean systemic artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Central venous pressure (mm Hg) Cardiac output (L/minute) Systemic vascular resistance (ml/minute/mm Hg) Pulmonary vascular resistance (ml/minute/mm Hg)
presented with exertional dyspnea, syncope,reduced exercise tolerance,and signsof right ventricular failure. The increase in the incidence of pulmonary hypertensionoccurredonly in those countries where aminorex was commercially available (Austria, Switzerland, and Germany), and a decline in its incidencewasnoted when aminorex was removed from the market in 1968. Although laboratory animals failed to develop pulmonary hypertension after the administration of aminorex, the epidemiologic evidencesuggestinga cause-and-effect relationship between this drug and the disease appears strong [6]. The exact mechanism causingpulmonary hypertension in patients using amphetaminerelated diet suppressantsis un-
:Ei
Januav 1990 ;;
3
:; 3.1
18
7.1
i.2
14.4 3.1
clear,but by blocking cellular uptake of serotoninin the lungsand by inhibiting monoamine oxidase, aminorex may potentiate the vasoconstrictoraction of serotonin [7,8].The vasoconstrictor effects of other anorectic drugs may be related to their ability to release norepinephrine and dopamine from nerve endings [7]. Other appetite depressants have also been implicated in causingpulmonary hypertension. Douglas et al [4] reported two casesof pulmonary hypertension associatedwith the useof fenfluramine. Both women improved physiologically and symptomatically upon withdrawal of the drug. One woman who was rechallengedwith fenfluramine developed a recurrenceof her diseasethat again improved upon
discontinuation of the drug. Atia and Sonnex[9] reported a caseof irreversiblepulmonary hypertension in a patient who used fenfluramine intermittently for several years.Cameron et al [5] reported a possiblerelationship of pulmonary hypertensionwith another anorecticdrug, propylhexedrine hydrochloride (Eventin), in a 39-year-old woman who had beentaking this medication orally for a period of 8 years. Although a definite relationship was not established,her symptoms of dyspnea and signs of right ventricular hypertrophy resolved 1 year after discontinuation of propylhexedrine hydrochloride and oral contraceptives. The development of pulmonary hypertensionin our patient wastemporally related to the use of an anorecticagent,phendimetrazine tartrate. Her symptoms, electrocardiographic abnormalities, and pulmonary hemodynamics improved severalmonths after discontinuation of the drug. Although we cannot exclude spontaneous remission of primary pulmonary hypertension, this is a rare phenomenon [lo]. Our findings suggest that patients using this drug should be closelymonitored, and that clini-
Figure 1. Pulmonary hypertension, grade 2. There is cellular intimal proliferation in addition to the medial hypertrophy (Verhoeff-van Gieson stain; original magnification X250, reduced by 35%).
98
July 1991 The American Journal of Medicine
Volume 91
BRIEF CLINICAL
cians evaluating patients with signs and symptoms suggestive of pulmonary hypertension should inquire regarding a history of anorexigen use, since this may be a reversible cause of this fatal disease. KENNYC.NALL,M.D. LEWISJ.RUBIN,M.D. University of Maryland School of Medicine Baltimore, Maryland STUARTLIPSKIND,M.D. Manasses, Virginia JOELD.SENNESH,M.D. Fairfax Hospital Falls Church, Virginia
ACKNOWLEDGMENT We would like to thank Seena Aisner. M.D., Department of Pathology, University of Maryland, for assistance with the photomicrographs. 1. Hughes JD, Rubin IJ. Primary pulmonary hypertension-an analysis of 28 cases and a review of the literature. Medicine (Baltimore) 1986; 65: 56-72. 2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension-a national prospective study. Ann Intern Med 1987; 107: 216-23. 3. Gurtner HP, Gertsch M. Salzman C. Scherrer M, Stricki P, Wyss F. Hanfensich die primar vascular formen des chronischen car pulmonale? Schweiz Med Wochenschr 1968; 4. Douglas JG, Munro Proudfoot AT. Pulmonary amine. BMJ 1981; 283: 5. Cameron J. Waugh L.
98: 1579. JF, Kitchin AH, Muir AL, hypertension and fenflur881-3. Loadsman T. White P, Rad-
July 1991
OBSERVATIONS
ford DJ. Possible association of pulmonary hypertension with an anorectic drug. Med J Aust 1984; 140: 595-7. 6. Kay JM, Smith P, Heath D. Amrnorex and the pulmonary circulation. Thorax 1971; 26: 262-70. 7. Bowman WC, Rand MJ. Textbook of pharmacology. 2nd ed. Oxford: Blackwell. 1980: 43.41-2. 8. Seiler KU, Wasserman 0. MAO-inhibiting properties of anorectic drugs. J Pharm Pharmacol 1973; 25: 576-8. 9. Atia W, Sonnex C. Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ 1986; 292: 239-40. 10. Bourdillon PDV, Oakley CM. Regression of primary pulmonary hypertension. Br Heart J 1976; 38: 264-70. Submitted
The American
Journal
November
7, 1990, and accepted in revised form February 5. 1991
of Medicine
Volume
91
99
treatment for ventricular tachyarrhythmias complicating astemizole poisoning. The precise mechanism of this phenomenon awaits further study. JONATHAN LEOR, MICHAL HARMAN, BABETH RABINOWITZ, BENJAMIN MOZES,
M.D. M.D. M.D. M.D.
Chaim Sheba Medical Center Tel-Hashomer, Israel and Sackler School of Medicine Tel Aviv University Tel Aviv, Israel 1. Craft TM. Torsade de pointes after astemizole overdose. BMJ 1986; 292: 660. 2. Bishop RO. Gaudry PL. Prolonged Q-T interval following astemizole overdose. Arch Emerg Med 1989; 6: 63-5. 3. Snook J, Boothman-Burrell D. Watkins J, ColinJones D. Torsade de pointes ventricular tachycardia associated with astemizole overdose. Br J Clin Pratt 1988; 42: 257-9. 4. Simons FE, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet 1988: 2: 624. 5. Jackman WM. Friday KJ. Anderson JL. Aliot EM, Clark M. Lauara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31: 115-72. 6. Kaseda S, Gilmour RF, Zipes DP. Depressant effect of magnesium on early after-depolarizations and triggered activity induced by cesium, quinidine. and 4aminopyridine in canine cardiac Purkinje fibers. Am Heart J 1989; 118: 458-66. 7. Wolf AA, Levi R. Histamine and cardiac arrhythmias. Circ Res 1986; 58: 1-16. 8. Richards DM. Brogden RC, Heel RC, Speight TM, Avery GS. Astemizole: a review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 23: 38-61. 9. Tzivoni D. Banai S. Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988; 77: 392-7. Submitted
November
7.1990,
and accepted February 5, 1991
REVERSIBLEPULMONARY HYPERTENSIONASSOCIATED WITH ANOREXIGENUSE Primary pulmonary hypertension is a disease of unknown etiology that typically affects young women and results in death within several years of the onset of symptoms [1,2]. The clinical diagnosis of primary pulmonary hypertension requires the exclusion of other conditions that may
produce pulmonary hypertension, such as chronic thromboembolic disease, congenital heart disease, and left ventricular dysfunction. An association between exogenous factors and severe pulmonary hypertension in the absence of other causes has been reported. Gurtner et al [3] described an outbreak of pulmonary hypertension in western Europe that appeared to be related to the use of the anorexic agent aminorex. A relationship between the development of pulmonary hypertension and the use of other anorectic agents has also been found [4,5]. However, reversible pulmonary hypertension associated with the use of anorexigens has not been reported in the United States. We describe a case of anorexigen-induced severe pulmonary hypertension that was confirmed by both hemodynamic and pathologic findings and was reversible upon discontinuation of the offending agent. A 41-year-old woman had been in good health until she developed dyspnea in the summer of 1989. Her past medical history was unremarkable. She denied using oral contraceptives and had stopped smoking 2 years previously. However, she reported that she had begun using a diet suppressant, phendimetrazine tartrate (Bontril), approximately 6 months before the onset of her symptoms. The patient was initially treated for pneumonia and asthma without relief of her symptoms. In October 1989, she underwent emergency admission due to cardiogenic shock. Right heart catheterization was performed with the patient receiving dopamine 10 pg/kg/minute and dobutamine 10 pg/kg/minute (Table I). An echocardiogram revealed a moderate-sized pericardial effusion, a dilated and poorly contracting right ventricle, a mildly enlarged July
1991 The American
OBSERVATIONS
right atrium, and abnormal septal wall motion believed to be due to the right heart abnormalities. The left atrium and the left ventricle were normal in size and function. A ventilation-perfusion lung scan was normal, and results of serologic screening studies for the presence of a collagen vascular disease were negative. An open-lung biopsy was performed and demonstrated grade 2 to 3 vascular lesions consistent with primary pulmonary hypertension (Figure 1). A pericardial biopsy showed nonspecific inflammation. She was discharged and treated as an outpatient with digoxin, Dyazide, and warfarin. In December 1989, she was referred to the University of Maryland Medical Center. Although she still had exertional dyspnea, her symptoms had improved since discharge. Physical examination was remarkable for moderate obesity, a mild right ventricular lift, and an intermittent right-sided Sd gallop. An electrocardiogram revealed mild right ventricular hypertrophy with strain pattern. In January 1990, approximately 3 months after she had discontinued use of the anorexigen, subsequent echocardiography revealed no evidence of a pericardial effusion and resolution of the right heart abnormalities. Right heart catheterization was again performed (Table I). Although the cause of primary pulmonary hypertension remains unknown, there is evidence to suggest that pulmonary hypertension can occur in patients using appetite suppressant medications. Gurtner was among the first investigators to note an association between pulmonary hypertension and ingestion of aminorex, an appetite suppressant that is structurally similar to amphetamine. Between 1967 and 1968, a large number of patients relating a history of aminorex use Journal
of Medicine
Volume
91
97
BRIEF CLINICAL OBSERVATIONS
TABLE I HemcdynamicData October1989 Mean systemic artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Central venous pressure (mm Hg) Cardiac output (L/minute) Systemic vascular resistance (ml/minute/mm Hg) Pulmonary vascular resistance (ml/minute/mm Hg)
presented with exertional dyspnea, syncope,reduced exercise tolerance,and signsof right ventricular failure. The increase in the incidence of pulmonary hypertensionoccurredonly in those countries where aminorex was commercially available (Austria, Switzerland, and Germany), and a decline in its incidencewasnoted when aminorex was removed from the market in 1968. Although laboratory animals failed to develop pulmonary hypertension after the administration of aminorex, the epidemiologic evidencesuggestinga cause-and-effect relationship between this drug and the disease appears strong [6]. The exact mechanism causingpulmonary hypertension in patients using amphetaminerelated diet suppressantsis un-
:Ei
Januav 1990 ;;
3
:; 3.1
18
7.1
i.2
14.4 3.1
clear,but by blocking cellular uptake of serotoninin the lungsand by inhibiting monoamine oxidase, aminorex may potentiate the vasoconstrictoraction of serotonin [7,8].The vasoconstrictor effects of other anorectic drugs may be related to their ability to release norepinephrine and dopamine from nerve endings [7]. Other appetite depressants have also been implicated in causingpulmonary hypertension. Douglas et al [4] reported two casesof pulmonary hypertension associatedwith the useof fenfluramine. Both women improved physiologically and symptomatically upon withdrawal of the drug. One woman who was rechallengedwith fenfluramine developed a recurrenceof her diseasethat again improved upon
discontinuation of the drug. Atia and Sonnex[9] reported a caseof irreversiblepulmonary hypertension in a patient who used fenfluramine intermittently for several years.Cameron et al [5] reported a possiblerelationship of pulmonary hypertensionwith another anorecticdrug, propylhexedrine hydrochloride (Eventin), in a 39-year-old woman who had beentaking this medication orally for a period of 8 years. Although a definite relationship was not established,her symptoms of dyspnea and signs of right ventricular hypertrophy resolved 1 year after discontinuation of propylhexedrine hydrochloride and oral contraceptives. The development of pulmonary hypertensionin our patient wastemporally related to the use of an anorecticagent,phendimetrazine tartrate. Her symptoms, electrocardiographic abnormalities, and pulmonary hemodynamics improved severalmonths after discontinuation of the drug. Although we cannot exclude spontaneous remission of primary pulmonary hypertension, this is a rare phenomenon [lo]. Our findings suggest that patients using this drug should be closelymonitored, and that clini-
Figure 1. Pulmonary hypertension, grade 2. There is cellular intimal proliferation in addition to the medial hypertrophy (Verhoeff-van Gieson stain; original magnification X250, reduced by 35%).
98
July 1991 The American Journal of Medicine
Volume 91
BRIEF CLINICAL
cians evaluating patients with signs and symptoms suggestive of pulmonary hypertension should inquire regarding a history of anorexigen use, since this may be a reversible cause of this fatal disease. KENNYC.NALL,M.D. LEWISJ.RUBIN,M.D. University of Maryland School of Medicine Baltimore, Maryland STUARTLIPSKIND,M.D. Manasses, Virginia JOELD.SENNESH,M.D. Fairfax Hospital Falls Church, Virginia
ACKNOWLEDGMENT We would like to thank Seena Aisner. M.D., Department of Pathology, University of Maryland, for assistance with the photomicrographs. 1. Hughes JD, Rubin IJ. Primary pulmonary hypertension-an analysis of 28 cases and a review of the literature. Medicine (Baltimore) 1986; 65: 56-72. 2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension-a national prospective study. Ann Intern Med 1987; 107: 216-23. 3. Gurtner HP, Gertsch M. Salzman C. Scherrer M, Stricki P, Wyss F. Hanfensich die primar vascular formen des chronischen car pulmonale? Schweiz Med Wochenschr 1968; 4. Douglas JG, Munro Proudfoot AT. Pulmonary amine. BMJ 1981; 283: 5. Cameron J. Waugh L.
98: 1579. JF, Kitchin AH, Muir AL, hypertension and fenflur881-3. Loadsman T. White P, Rad-
July 1991
OBSERVATIONS
ford DJ. Possible association of pulmonary hypertension with an anorectic drug. Med J Aust 1984; 140: 595-7. 6. Kay JM, Smith P, Heath D. Amrnorex and the pulmonary circulation. Thorax 1971; 26: 262-70. 7. Bowman WC, Rand MJ. Textbook of pharmacology. 2nd ed. Oxford: Blackwell. 1980: 43.41-2. 8. Seiler KU, Wasserman 0. MAO-inhibiting properties of anorectic drugs. J Pharm Pharmacol 1973; 25: 576-8. 9. Atia W, Sonnex C. Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ 1986; 292: 239-40. 10. Bourdillon PDV, Oakley CM. Regression of primary pulmonary hypertension. Br Heart J 1976; 38: 264-70. Submitted
The American
Journal
November
7, 1990, and accepted in revised form February 5. 1991
of Medicine
Volume
91
99
