obstruction. This unusual presentation of aortic dissection serves to highlight the myriad clinical manifestations of this disease process. ACKNOWLEDGMENT: The authors thank Louise Funke for preparation of the manuscript and Dr. M. Bourke for supplying the photograph of the patient.
REFERENCES
2
3
4
5
6
7
Eagle KA, DeSanctis RW Aortic dissection. Current Prob Card 1989; May:229-78 Banker Vp, Maddison FE. Superior vena cava syndrome secondary to aortic disease: report of two cases and review of the literature. Dis Chest 1967; 51;656-62 Strax TE, Ryvicker MJ, Elguezabal A: Superior vena cava syndrome due to a mediastinal hematoma secondary to a dissecting aortic aneurysm. Dis Chest 1969; 55:338-41 Spitzer S, Blanco G, Adam A, Spyrou PG, Mason D. Superior vena cava obstruction and dissecting aortic aneurysm. JAMA 1975; 233:164-65 Kahn SE, Kolter MN, Goldman Ap,Ablaza S. Superior vena cava obstruction secondary to acute dissecting aneurysm of the aorta. Am Heart J 1986; 111:606-08 Stone DL, Petch MC, Verney GI, Dixon AK. Superior mediastinal obstruction with aortic dissection after aortic valve replacement. Br Heart J 1984; 51:565-67 Calenda DG, Uricchio JF. Superior vena cava syndrome, differentiation between simple obstruction and aorticocaval communication. Arch Intern Med 1953; 91:800
Noncardiogenic Pulmonary Edema Complicating Massive Diltiazem Overdose· \emon H. Humbert, Jr., M.D., F.C.C.P.;t Nancy j. Munn, M.D.;* and Randall F. Hawkins, M.D.
misuse' have generally ascribed the condition to negative inotropy related to the drug or to fluid resuscitation during overdose-induced hypotension. CASE REPORT A 30-year-old nurse was hospitalized after having been found apathetic and unable to ambulate. She was known to be taking diltiazem for migraine headaches and had a long history of stress disorder and depression and had previously been evaluated for anorexia nervosa. On examination, she was lethargic but responsive to noxious stimuli. The blood pressure varied from 58132mm Hg to 90160mm Hg and the pulse from 35 to 45 per minute. The respiratory rate was 18. She had warm skin and full pulses distally. The initial chest radiograph showed a very small heart, no infiltration, and a paucity of vascular markings. The electrocardiogram showed atrial inactivity with a slow ventricular escape rhythm. Arterial blood gases on a 100 percent rebreathing mask revealed a blood pH of 7.23, Pco, of 27 mm Hg, and a Po. of 308 mm Hg, The initial serum albumin level was normal. Initial therapy with atropine, isoproterenol and calcium glueonate raised the heart rate to 45 to 50 per minute; sinus bradycardia alternated with ventricular escape rhythm. Infusions of saline solution (totaling 4L during the first 24 hours) and dopamine gradually raised the blood pressure to a consistent 90160 mm Hg over several hours. Urine Rowremained copious, After 24 hours of steady improvement, the patient developed shortness of breath and suffered respiratory arrest. Endotracheal intubation and mechanical ventilation were promptly instituted. Repeat chest radiograph showed uniformly dilJuse pulmonary infiltrates without change in heart size (Fig 1). Mechanical ventilation with 100 percent oxygen and positive end-expiratory pressure of 15 cm H 20 was needed to elevate the Po. to 67 mm Hg. Hemodynamic measurements from a Row-directed catheter revealed a pulmonary artery pressure of 32112 mm Hg and a pulmonary capillary wedged pressure of 9 mm Hg. Cardiac output by thermodilution was 6.50 Umin (5.07 Umin/m·). Although extensive bacterial cultures later proved negative, she developed a fever of38.3°-38.6°C36 hours after intubation. Therapy with broad
Non-cardiogenic pulmonary edema has not been previously described in calcium channel blocker overdose. We describe a case of non-cardiogenic pulmonary edema occurring during the course of therapy for massive diltiazem overdose in a young patient with anorexia nervosa. Review of the current literature suggests that major and minor pulmonary complications occur with some frequency in the setting of calcium channel blocker overdose although tbeir exact incidence remains unclear. (Chen 1991; 99:258-60) ,llthough mild arterial desaturation is common after cal~ cium channel blocker overdose, l.2 no well-documented case of non-cardiogenic pulmonary edema in this setting has previously been reported. Prior reports of pulmonary edema occurring after calcium channel blocker use" or -From the Department of Medicine, Divisions of tCardiology and *Pulmonary Medicine, Marshall University School of Medicine, Huntington, WVA. Supported in part by the Marshall University Foundation. Presented in part at the 1989 Scientific Meeting, Pennsylvania and West Virginia Regions, American College of Physicians, Pittsburgh, October 6, 1989. Reprint requests: Dr. Munn, 1801 Sixth Avenue, Huntington, WVA 25755-9410
258
FIGURE 1. Chest radiograph shortly after endotracheal intubation showing dilJuse, uniform pulmonary infiltration and a small cardiac silhouette compatible with non-eardiogenic pulmonary edema. Noncardiogenic PulmonaryEdema (Humbert. Munn. Hawkins)
spectrum antibiotics was begun, With continuous ventilatory support and diuretic therapy, the chest radiograph and arterial blood gas levels gradually returned to normal and fever subsided. A transient major rise in creatine kinase with negative MB isoenzyme fraction was noted with lesser elevations of total lactic dehydrogenase and alanine aminotransferase. Urine drug screens were tracepositive for barbiturates and tricyclic anti-depressants. Diltiazem was present in "massive" quantity by semi-quantitative thin layer chromatography DISCUSSION
We present a c1earcut case of noncardiogenic pulmonary edema occurring in association with a massive ingestion of diltiazem. We can only speculate as to the relative effects of the drug itself and of the patient's rather prolonged shock-like state on the genesis of the pulmonary edema. Hypotension of similar severity and duration has been reported after verapamil overdose without development of overt pulmonary edema. 1 The pulmonary artery pressure values and normal cardiac index exclude myocardial depression as an etiologic factor. Fluid resuscitation alone probably could not explain the profound arterial desaturation and pulmonary infiltration in the absence of unusual pulmonary capillary leakiness. There was no suggestion that aspiration pneumonia played a role in the patient's pulmonary deterioration. There are few reports of diltiazem overdose in the English language. Of ten prior cases of diltiazem overdose with adequate data available,"? all had bradycardic rhythms (sinus bradycardia and/or heart block), nine had hypotension, and one who died had "cyanosis." Calcium infusion, anticholinergics, and catecholamine infusions have been used with variable success in restoring unstable hemodynamics in calcium channel blocker overdose, commonly failing to restore blood pressure and pulse rate adequately for some hours,'···7.' as in our patient. Pulmonary edema has previously been noted after nifedipine overdose in a patient whose clinical picture and response to initial therapy approximated our patient's but whose duration of sustained hypotension was probably somewhat less.' Pulmonary edema has also been noted at autopsy after verapamil overdose" and "pneumonia" requiring mechanical ventilation (for 11 days) and positive endexpiratory pressure was required on the second day of a diltiazem overdose complicated by a short period of hypotension." Arterial desaturation presumably due to ventilation-perfusion mismatch appears relatively common in the setting of verapamil overdose.'> the possibility that these episodes of modest desaturation may represent incipient or subclinical pulmonary capillary leak has never been addressed. Multiple mechanisms appear to underlie the various forms of drug-induced noncardiogenic pulmonary edema." Mechanisms implicated in drug overdose pulmonary edema include inhibition of prostacyclin synthesis (aspirin) and mast cell degranulation (opiate overdose). Reported effects
of calcium entry blockers on prostacyclin synthesis are contradictory. Although nifedipine has been reported to suppress calcium infusion-mediated increases in prostacyclin metabolism, 11 diltiazem has been reported to increase vascular prostacyclin synthesis." Mast cell membranes appear to be stabilized by calcium entry blockers," Calcium entry blockers are well known to cause selective systemic pre-capillary vasodilation with associated peripheral edema." A similar mechanism may contribute to excessive pulmonary capillary transudation in calcium blocker overdose. Serious pulmonary embarrassment may result in the course ofcalcium channel blocker overdose, although attention has not previously been drawn to this possibility and its potential frequency remains to be established. We recommend prompt institution ofcardiac pacing if catecholamines, anticholinergics, and calcium infusion fail to quickly improve bradycardic rhythms in this setting. Hypotensive but well perfused patients probably should not be overly challenged with crystalloid in the absence of c1earcut pre-existent volume depletion. REFERENCES
2
3
4 5 6 7 8
9 10
II
12
13
14
Passal DB, Crespin FH Jr. Verapamil poisoning in an infant. Pediatrics 1984; 73:543-45 Enyeart JJ, Price WA, Hoffman DA, Woods L. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coli Cardioll983; 2:1228-31 Epstein SE, Rosing DR. Verapamil: its potential hlr causing serious complications in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:437-41 Herrington DM, Insley BM, Weinmann GG: Nifedipine overdose. Am J Med 1986; 81:344-46 Jakubowski AT, Mizgala HF. Effect of diltiazem overdose. Am J Cardioll987; 60:932-33 Data on file, Marion Laboratories, Kansas City, Missouri Snover S\v, Bocchino V. Massive diltiazem overdose. Ann Emerg Med 1986; 15:1221-24 Crump BJ, Holt D\v, Vale JA. Lack of response to intravenous calcium in severe verapamil poisoning [letter]. Lancet 1982; 2:939-40 Gelbke Hp, Schlicht HJ, Schmidt C. Fatal poisoning with verapamil. Arch Toxico11977; 37:89-94 Allen J, Cooper D, White DA, Matthay RA. Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis 1986; 133:488-505 Nadler JL, McKay M, Campese V, Vrbanac J, Horton R. Evidence that prostacyclin modulates the vascular actions of calcium in man. J Clin Inves 1986; 77:1278-84 Mehta J, Mehta P, Ostrowski N. Calcium blocker diltiazem inhibits platelet activation and stimulates vascular prostacyclin synthesis. Am J Med Sci 1986; 291:20-4 Lofdahl C-G, Barnes PJ. Calcium, calcium channel blockade and airways function. Acta Pharmacol et 'Ioxieol 1986; 5(Suppl 2):91-IIl Low RI, Takeda P, Mason DT, DeMaria AN. The effects of calcium channel blocking agents on cardiovascular function. Am J Cardioll982; 49:547-53
CHEST 1991 1 I JANUARY, 1991
259
REFERENCES
2
3
4
5
6
7
Eagle KA, DeSanctis RW Aortic dissection. Current Prob Card 1989; May:229-78 Banker Vp, Maddison FE. Superior vena cava syndrome secondary to aortic disease: report of two cases and review of the literature. Dis Chest 1967; 51;656-62 Strax TE, Ryvicker MJ, Elguezabal A: Superior vena cava syndrome due to a mediastinal hematoma secondary to a dissecting aortic aneurysm. Dis Chest 1969; 55:338-41 Spitzer S, Blanco G, Adam A, Spyrou PG, Mason D. Superior vena cava obstruction and dissecting aortic aneurysm. JAMA 1975; 233:164-65 Kahn SE, Kolter MN, Goldman Ap,Ablaza S. Superior vena cava obstruction secondary to acute dissecting aneurysm of the aorta. Am Heart J 1986; 111:606-08 Stone DL, Petch MC, Verney GI, Dixon AK. Superior mediastinal obstruction with aortic dissection after aortic valve replacement. Br Heart J 1984; 51:565-67 Calenda DG, Uricchio JF. Superior vena cava syndrome, differentiation between simple obstruction and aorticocaval communication. Arch Intern Med 1953; 91:800
Noncardiogenic Pulmonary Edema Complicating Massive Diltiazem Overdose· \emon H. Humbert, Jr., M.D., F.C.C.P.;t Nancy j. Munn, M.D.;* and Randall F. Hawkins, M.D.
misuse' have generally ascribed the condition to negative inotropy related to the drug or to fluid resuscitation during overdose-induced hypotension. CASE REPORT A 30-year-old nurse was hospitalized after having been found apathetic and unable to ambulate. She was known to be taking diltiazem for migraine headaches and had a long history of stress disorder and depression and had previously been evaluated for anorexia nervosa. On examination, she was lethargic but responsive to noxious stimuli. The blood pressure varied from 58132mm Hg to 90160mm Hg and the pulse from 35 to 45 per minute. The respiratory rate was 18. She had warm skin and full pulses distally. The initial chest radiograph showed a very small heart, no infiltration, and a paucity of vascular markings. The electrocardiogram showed atrial inactivity with a slow ventricular escape rhythm. Arterial blood gases on a 100 percent rebreathing mask revealed a blood pH of 7.23, Pco, of 27 mm Hg, and a Po. of 308 mm Hg, The initial serum albumin level was normal. Initial therapy with atropine, isoproterenol and calcium glueonate raised the heart rate to 45 to 50 per minute; sinus bradycardia alternated with ventricular escape rhythm. Infusions of saline solution (totaling 4L during the first 24 hours) and dopamine gradually raised the blood pressure to a consistent 90160 mm Hg over several hours. Urine Rowremained copious, After 24 hours of steady improvement, the patient developed shortness of breath and suffered respiratory arrest. Endotracheal intubation and mechanical ventilation were promptly instituted. Repeat chest radiograph showed uniformly dilJuse pulmonary infiltrates without change in heart size (Fig 1). Mechanical ventilation with 100 percent oxygen and positive end-expiratory pressure of 15 cm H 20 was needed to elevate the Po. to 67 mm Hg. Hemodynamic measurements from a Row-directed catheter revealed a pulmonary artery pressure of 32112 mm Hg and a pulmonary capillary wedged pressure of 9 mm Hg. Cardiac output by thermodilution was 6.50 Umin (5.07 Umin/m·). Although extensive bacterial cultures later proved negative, she developed a fever of38.3°-38.6°C36 hours after intubation. Therapy with broad
Non-cardiogenic pulmonary edema has not been previously described in calcium channel blocker overdose. We describe a case of non-cardiogenic pulmonary edema occurring during the course of therapy for massive diltiazem overdose in a young patient with anorexia nervosa. Review of the current literature suggests that major and minor pulmonary complications occur with some frequency in the setting of calcium channel blocker overdose although tbeir exact incidence remains unclear. (Chen 1991; 99:258-60) ,llthough mild arterial desaturation is common after cal~ cium channel blocker overdose, l.2 no well-documented case of non-cardiogenic pulmonary edema in this setting has previously been reported. Prior reports of pulmonary edema occurring after calcium channel blocker use" or -From the Department of Medicine, Divisions of tCardiology and *Pulmonary Medicine, Marshall University School of Medicine, Huntington, WVA. Supported in part by the Marshall University Foundation. Presented in part at the 1989 Scientific Meeting, Pennsylvania and West Virginia Regions, American College of Physicians, Pittsburgh, October 6, 1989. Reprint requests: Dr. Munn, 1801 Sixth Avenue, Huntington, WVA 25755-9410
258
FIGURE 1. Chest radiograph shortly after endotracheal intubation showing dilJuse, uniform pulmonary infiltration and a small cardiac silhouette compatible with non-eardiogenic pulmonary edema. Noncardiogenic PulmonaryEdema (Humbert. Munn. Hawkins)
spectrum antibiotics was begun, With continuous ventilatory support and diuretic therapy, the chest radiograph and arterial blood gas levels gradually returned to normal and fever subsided. A transient major rise in creatine kinase with negative MB isoenzyme fraction was noted with lesser elevations of total lactic dehydrogenase and alanine aminotransferase. Urine drug screens were tracepositive for barbiturates and tricyclic anti-depressants. Diltiazem was present in "massive" quantity by semi-quantitative thin layer chromatography DISCUSSION
We present a c1earcut case of noncardiogenic pulmonary edema occurring in association with a massive ingestion of diltiazem. We can only speculate as to the relative effects of the drug itself and of the patient's rather prolonged shock-like state on the genesis of the pulmonary edema. Hypotension of similar severity and duration has been reported after verapamil overdose without development of overt pulmonary edema. 1 The pulmonary artery pressure values and normal cardiac index exclude myocardial depression as an etiologic factor. Fluid resuscitation alone probably could not explain the profound arterial desaturation and pulmonary infiltration in the absence of unusual pulmonary capillary leakiness. There was no suggestion that aspiration pneumonia played a role in the patient's pulmonary deterioration. There are few reports of diltiazem overdose in the English language. Of ten prior cases of diltiazem overdose with adequate data available,"? all had bradycardic rhythms (sinus bradycardia and/or heart block), nine had hypotension, and one who died had "cyanosis." Calcium infusion, anticholinergics, and catecholamine infusions have been used with variable success in restoring unstable hemodynamics in calcium channel blocker overdose, commonly failing to restore blood pressure and pulse rate adequately for some hours,'···7.' as in our patient. Pulmonary edema has previously been noted after nifedipine overdose in a patient whose clinical picture and response to initial therapy approximated our patient's but whose duration of sustained hypotension was probably somewhat less.' Pulmonary edema has also been noted at autopsy after verapamil overdose" and "pneumonia" requiring mechanical ventilation (for 11 days) and positive endexpiratory pressure was required on the second day of a diltiazem overdose complicated by a short period of hypotension." Arterial desaturation presumably due to ventilation-perfusion mismatch appears relatively common in the setting of verapamil overdose.'> the possibility that these episodes of modest desaturation may represent incipient or subclinical pulmonary capillary leak has never been addressed. Multiple mechanisms appear to underlie the various forms of drug-induced noncardiogenic pulmonary edema." Mechanisms implicated in drug overdose pulmonary edema include inhibition of prostacyclin synthesis (aspirin) and mast cell degranulation (opiate overdose). Reported effects
of calcium entry blockers on prostacyclin synthesis are contradictory. Although nifedipine has been reported to suppress calcium infusion-mediated increases in prostacyclin metabolism, 11 diltiazem has been reported to increase vascular prostacyclin synthesis." Mast cell membranes appear to be stabilized by calcium entry blockers," Calcium entry blockers are well known to cause selective systemic pre-capillary vasodilation with associated peripheral edema." A similar mechanism may contribute to excessive pulmonary capillary transudation in calcium blocker overdose. Serious pulmonary embarrassment may result in the course ofcalcium channel blocker overdose, although attention has not previously been drawn to this possibility and its potential frequency remains to be established. We recommend prompt institution ofcardiac pacing if catecholamines, anticholinergics, and calcium infusion fail to quickly improve bradycardic rhythms in this setting. Hypotensive but well perfused patients probably should not be overly challenged with crystalloid in the absence of c1earcut pre-existent volume depletion. REFERENCES
2
3
4 5 6 7 8
9 10
II
12
13
14
Passal DB, Crespin FH Jr. Verapamil poisoning in an infant. Pediatrics 1984; 73:543-45 Enyeart JJ, Price WA, Hoffman DA, Woods L. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coli Cardioll983; 2:1228-31 Epstein SE, Rosing DR. Verapamil: its potential hlr causing serious complications in patients with hypertrophic cardiomyopathy. Circulation 1981; 64:437-41 Herrington DM, Insley BM, Weinmann GG: Nifedipine overdose. Am J Med 1986; 81:344-46 Jakubowski AT, Mizgala HF. Effect of diltiazem overdose. Am J Cardioll987; 60:932-33 Data on file, Marion Laboratories, Kansas City, Missouri Snover S\v, Bocchino V. Massive diltiazem overdose. Ann Emerg Med 1986; 15:1221-24 Crump BJ, Holt D\v, Vale JA. Lack of response to intravenous calcium in severe verapamil poisoning [letter]. Lancet 1982; 2:939-40 Gelbke Hp, Schlicht HJ, Schmidt C. Fatal poisoning with verapamil. Arch Toxico11977; 37:89-94 Allen J, Cooper D, White DA, Matthay RA. Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis 1986; 133:488-505 Nadler JL, McKay M, Campese V, Vrbanac J, Horton R. Evidence that prostacyclin modulates the vascular actions of calcium in man. J Clin Inves 1986; 77:1278-84 Mehta J, Mehta P, Ostrowski N. Calcium blocker diltiazem inhibits platelet activation and stimulates vascular prostacyclin synthesis. Am J Med Sci 1986; 291:20-4 Lofdahl C-G, Barnes PJ. Calcium, calcium channel blockade and airways function. Acta Pharmacol et 'Ioxieol 1986; 5(Suppl 2):91-IIl Low RI, Takeda P, Mason DT, DeMaria AN. The effects of calcium channel blocking agents on cardiovascular function. Am J Cardioll982; 49:547-53
CHEST 1991 1 I JANUARY, 1991
259
