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The Management of Acute Quinidine Intoxication
The Management of Acute Quinidine Intoxication* Clarence Shub, M.D.; Gerald T. Gau, M.D., F.C.C.P.; Peter M. Sidell, M.D.; and Leonard A. Brennan, ]r., M.D.
A 16-year-old patient survived severe intoxication with quinidine. Hypotension, rapidly progressing to oliguria and shock, was resistant to the usual therapeutic interventions but responded favorably to the use of an intraaortic balloon pump. Some hemodynamic implications are discussed. Pulmonary edema occurred and was treated
The management of acute intoxication with quinidine poses a complex and challenging clinical problem. In toxic doses, quinidine causes various poorly understood multisystem abnormalities. 1 For editorial comment, see page 129
Among the most deleterious effects are profound cardiac depression and refractory peripheral vasodilation, both of which contribute to significant hypotension and can ultimately lead to cardiovascular collapse and death.2 •3 Because the renal excretion of quinidine is rapid, 4 a proposed therapeutic goal in the management of intoxication with quinidine has been support and maintenance of cardiovascular and renal function, thereby allowing the kidneys time to excrete the drug; 1 however, in severe intoxication, hypotension and oliguria tend to negate this approach. Although various specific therapeutic approaches to intoxication with quinidine have been suggested, 1.2.5 no single regimen is widely accepted. A 16-year-old girl without prior heart disease ingested 8 gm of quinidine sulfate in an attempt at suicide. Severe hypotension, various cardiac arrhythmias, and oliguria rapidly occurred and were refractory to the usual therapeutic maneuvers. In order to improve systemic and renal perfusion, and thereby facilitate elimination of quinidine, the cardiovascular assistance of an intra-aortic balloon pump was employed. A striking, salutary hemodynamic response occurred, which reversed the hypotension and the oliguric state. Subsequent management was facilitated, and the patient survived an otherwise fulminating and potentially lethal course. °From the Mayo Clinic and Mayo Foundation, Rochester, Minn. Manuscript received February 21 ; revision accepted June 7. Reprint requests: Section of Publications, Mayo Clinic, Rochester Minnesota 55901
CHEST, 73: 2, FEBRUARY, 1978
with positive end-expiratory pressure. Electrocardiographic disturbances in conduction, transient bradycardia, and recurrent ventricular arrhythmias characterized the initial 36-hour critical period. Unexplained electrolyte abnormalities occurred and further complicated management.
CAsE REPORT
On July 6, 1976, a previo~sly healthy 16-year-old girl was evaluated in the emergency room at 6 : 10 PM, approximately two hours after consuming 8 gm of quinidine sulfate ( 117 mg of quinidine base per kilogram of body weight) in an attempt at suicide. She also had ingested a small but unknown quantity of propoxyphene and acetaminophen. Upon arrival, the patient was awake and oriented, but diaphoretic and nauseated. Gastric lavage was performed. During the next 30 minutes, the patient's respirations became shallow, and she became progressively obtunded. Her limbs became flaccid and areflexic. Babinski signs were elicited bilaterally. The patient's blood pressure decreased, but her skin remained warm and dry. Her chest was clear to auscultation, and the findings from cardiac examination were normal. Cardiac monitoring demonstrated changing rhythms, consisting primarily of accelerated idioventricular rhythm with varied morphologic appearance of the QRS complexes and intermittent sinus capture beats, as well as frequent paroxysms of wide-complex tachycardia ( Fig 1A) . The Q-T interval was prolonged. Generalized convulsions occurred, and diazepam was administered intravenously. Endotracheal intubation was performed, and respiration was assisted with a mechanical volume ventilator. The patient was oliguric. A solution of dopamine (concentration, 800 ~o~g/ml) was administered intravenously, initially at a rate of 5 ugl/ min; the dose was increased over a one-hour period to rates exceeding 50 ~o~g/ min, without any noticeable improvement in blood pressure or urinary output ( Fig 2). Intravenous administration of first a solution of isoproterenol ( 4 ~o~g/ml) at doses up to 4 ~o~g/min and then a solution of norepinephrine ( 8 ~o~g/ml) at doses up to 32 ~o~g/min had no significant effect as well. By 6 :45 PM, the patient's systolic blood pressure was barely palpable, and she was in profound coma. An antigravity pressure suit (Armstrong M.A.S.T . II) was applied, and the patient's systolic blood pressure increased transiently. Deep coma persisted and was interrupted by intermittent generalized convulsions. The patient remained oliguric despite the administration of 6,000 ml of physiologic saline solution, furosemide, and mannitol over a four-hour period. Initial laboratory data became available (Table 1 ) . The serum level of creatinine was normal. Sodium bicarbonate and potassium chloride were administered. An attempt to deflate the body pressure suit led to a further decline in blood pressure ( Fig 2) .
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 173
At 8 :00 P.\1 , an x-ray film of the chest showed diffuse pulmonary edema. With hemodynamic monitoring, an intraarterial blood pressure of 70/ 40 mm Hg was recorded . The mean pulmonary arterial wedge pressure was 11 mm Hg. Positive end-expiratory pressure (PEEP) was added to the respiratory assistance device. A temporary intravenous pacemaker was inserted. Further laboratory data became available (Table 1) . Calcium Gluceptate was administered by repeated intravenous bolus injections. Dopamine was readministered without any effect. Further administration of potassium was temporarily withheld. Because of persistent refractory hypotension and oliguria, an intra-aortic balloon pump (A VCO trisegment balloon with 30-ml volume) was inserted, and circulatory assistance was begun. With this, the blood pressure increased and significant urinary Bow began (Fig 2). A Scribner arteriovenous cannula was implanted, and hemodetoxification was subsequently attempted using a column of uncoated activated charcoal ( Becton-Dickinson Co. ). The procedure was terminated after one hour because of clotting within the canisters of charcoal; however, prior to this, blood was sampled simultaneously from the arterial and venous lines in order to determine the binding capacity of the charcoal for quinidine. The arterial concentration of quinidine was 19.8 mg/ L, and the venous concentration was 1.8 mg/L, which suggested adequate adsorption of the quinidine by the charcoal. From midnight (July 7, 1976) to 6 :00 AM, control of blood pressure and urinary output continued to be satisfactory. The patient remained comatose. The electrocardiographic monitor showed a transient narrowing of the QRS complex, and the patient's intrinsic heart rate slowed to 40 beats per minute, causing periodic activation of the demand pacemaker. The Q-T interval remained prolonged (Fig 1B) . At 6:00 AM, widening of the QRS complex recurred (Fig
F1 . RE 1. rial e l ctr ardi grap hic tracings from patient with intoxica tion ' ith q uinidin , howing I ad Y ( Frank v to r stem) nd pr cordia l I ad 1 • rrow indic t paced beats. P waves can be seen in panel labelled C-VI ·
Admission
BP mm Hg
80 60 40 20
Oliguria 6 pm
7 pm
8 pm
Urine flow 9 pm
10 pm
11 pm
12mid
Intra-aortic balloon pump FIGURE 2. Response of blood pressure ( BP) to various therapeutic interventions in patient with intoxication with quinidine. X indicates systolic blood pressure (cuff), open circles indicate diastolic blood pressure (cuff), asterisks indicate systolic blood pressure (arterial cannula), and solid circles indicate diastolic blood pressure (arterial cannula). For a brief period after starting therapy with intra-aortic balloon pump (indicated by vertical interruption of lines in curves), diastolic pressure exceeded systolic; thereafter, systolic-diastolic phase relationships were normal. Note response of blood pressure and urinary output to intra-aortic balloon pump.
174 SHUB ET AL
CHEST, 73: 2, FEBRUARY, 1978
Table 1--Cour•e of Seleeted Laboratory Data in a Patient lflitla lnto%ication 111itla Quinidine* 7 / 8/76
7/7/ 76
7 / 6/76
~
Data and Serum Levels••
7 :00 7 :30 8:00 9 :00 11:00 2:00 6 :00 1:00 5 :00 9 :00 7 :00 1:00 6 :00 PM PM PM PM PM AM AM PM PM PM AM PM PM 7 / 9/76
Quinidine, mg/ L
14.3
Sodium, mEq / L
140
Potassium, mEq / L
2.7
Calcium, mg/ 100 ml Phosphorus, mg/100 ml
21.4 17.7 11.5 9.6 152
...
149 151
8.7
6 .3
7 / 10 / 76 7 / 12 / 76 7 / 15 / 76
3 .2
1.6
1.6
148
140
144
139
146
142
142
142
142
. . . 2.9
2.6
2.6
3.2
3.7
3 .8
4 .4 4.5
4.0
3.7
4.5
4.0
4.5
... . . .
. . . 6.0
7.6
8.2
7.7
.. .
9.3
. . . 8.6
8.6
8 .5
8.3
8.2
9.1
. ..
..
. . . 1.1 .. .
...
Magnesium, mg/ 100 ml
. 1.3
4.3
3.7 1.3
1.3
2.1
2.0
2.4
2.3
PaO,, mm Hg
210
498
336
144
133 214 85
101
139
150 80
173
151
82
PaCOt, mm Hg
32
39
36
36
33
31
34
33
38
41
39
Arterial pH
7.26 7.08 7.33
7.48
7.44
Bicarbonate, mEq / L
14
Respiratory rate, breaths per minute
20
33
37
7.44 7.46 7.48 7.53 7.59 7.54 7.47 7.44 7.48 . . . 25
24
27
28
30
39
25
25
29
30
27
14
16
16
14
20
12
10
10
30
18
22
Tidal volume, L
0.8
0.9
0.8
0.8
0.8
0.8
0.6
0.8
Fl<>t
1.0
1.0
1.0
0.50 0.50 0.50 0.50 0.30
7
10
10
5
PEEP, em HtO
. ..
11
19
36
. . . . .. . ..
5
5
0
1.7
Room air
0
*Treatment consisted of the following : (1) anesthesia bag (100 percent oxygen) from 7 PM to 9 PM on July 6; (2 ) volume ventilator from 9 PM on July 6, with period of weaning from T piece (70 percent oxygen) to closed face mask (40 percent oxygen) beginning at 7 AM and concluding at 1 PM on July 8; (3) closed face mask (40 percent oxygen) from 1 PM on July 8 through July 9 (no therapy thereafter) ; and (4) addition of 50 ml of dead space from 1 PM on July 7 to 5 PM on July 7 (increased to 75 ml from 5 PM to 9 PM). **PaO,, Arterial oxygen pressure; PaC02 , arterial carbon dioxide tension ; and Fl<>t, fractional concentration of oxygen in inspired gas. IC) . The appearance of P waves suggested that a sinus mechanism had recurred. The cardiac index ( dye-dilution method) was 4.0 L/min/sq m. During the next several hours, the patient's level of consciousness improved. By 4:00PM, the intra-aortic balloon pump assistance ratio was reduced, without adverse effect. Ventricular irritability recurred, with several episodes of paroxysmal ventricular tachycardia. Cardioversion was achieved with the administration of lidocaine and electroshock. Calcium supplementation was continued, administration of potassium was resumed, and magnesium replacement (magnesium sulfate) was begun. Paroxysmal ventricular tachycardia recurred and was treated successfully with lidocaine ( 4 mgj min) and pacemaker "overdrive" suppression. At 3 :00 AM on July 8, ventricular irritability recurred, necessitating readministration of lidocaine. By 8 :00 AM, the electrocardiogram showed normal sinus rhythm with a prolonged Q-T interval ( Fig 1D) . The cardiac index was 3. 7 L/min sq m. The intra-aortic balloon pump was removed. The patient was awake, and the findings from neurologic examination were normal. Respiratory support was discontinued .. During the next 24 hours the patient remained alert and
CHEST, 73: 2, FEBRUARY, 1978
had no residual neurologic deficit. Ventricular irritability had ceased. An x-ray film of the chest showed gradual clearing over several days. The ECC continued to manifest nonspecific ST-T abnormalities for another week. Administration of all medications was stopped over the ensuing 48 hours. The patient was transferred to the psychiatric section for further evaluation and treabnent. She was fully ambulatory and asymptomatic. DISCUSSION
Currently, there is no consistent approach to the treatment of intoxication with quinidine. To treat the hypotension, the use of various sympathomimetic agents has been suggested, u-s but resistance to these agents has been reported. 1·u Administration of sodium lactate has been suggested as a therapeutic intervention, 5 •10 but this has not been uniformly effective. 2•9 The case presented illustrates many of the therapeutic difficulties inherent in the management of
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 175
intoxication with quinidine. Although survival has been reported after ingestion of large doses of the drug, 11 •12 death has also occurred. 3 In our case the rapidity of the onset of symptoms within a few hours after ingestion of a large dose, as well as the fulminating progression to shock and coma, c~ntrasts to the delayed and more gradual course of intoxication with quinidine described by Woie and Audun; 11 however, in the latter case a long-acting preparation containing quinidine was ingested, presumably delaying and attenuating its effects. The possible potentiating effects of the simultaneously ingested propoxyphene and acetaminophen were considered to be negligible because of the small amounts taken. The severe hypotension and oliguria failed to respond to full therapeutic doses of the usually employed sympathomimetic agents. Quinidine-induced peripheral vasodilation that is refractory to pharmacologic treatment has been previously reported 4 and has been attributed to a functional antagonistic effect on peripheral aadrenergic receptors. The warm, dry, and pink skin observed clinically in our patient in the presence of severe hypotension supports this theory. In contrast to previous reports, 2 •7 •8 • 13 the sympathomimetic agents given to our patient had no significant effects on the disturbances in cardiac conduction. The use of the antigravity suit ( M.A.S.T.) was the only initial maneuver that provided any improvement in blood pressure, possibly by preventing the pooling of blood in the lower extremities; however, the effect was minimal and transient and had no effect on the How of urine. The therapeutic maneuver that reversed the oliguria and abnormal hemodynamic state (Fig 2) was the use of the intra-aortic balloon pump. Although this maneuver has been employed experimentally in dogs with drug-induced cardiovascular intoxication, 14 to our knowledge, this is the first reported use of an intra-aortic balloon pump in druginduced cardiac depression in humans. The normal cardiac index and stroke volume while the patient was receiving assistance with the pump, even in the presence of widened QRS complexes and high serum levels of quinidine, suggest that cardiac depression, at least in the normal heart, is amenable to therapeutic intervention. After an initial brief period during which diastolic pressure exceeded systolic, both systolic and diastolic pressures increased. This contrasts to previously described hemodynamic effects of the intra-aortic balloon pump, 15 in which diastolic pressures increased but systolic pressures decreased slightly. If one assumes that quinidineinduced vasodilation persisted because of its long-
176 SHUB ET AL
lasting peripheral effects, 2 then the immediate increase in blood pressure that occurred (Fig 2) , despite decreased peripheral resistance, implies a very significant increase in cardiac output. The expanded intravascular volume, the decreased diastolic runoff (as a result of the intra-aortic balloon pump), and the pump-related improved coronary perfusion all may have been contributory to the improved hemodynamic state. In contrast to the case described herein, the intra-aortic balloon pump caused only modest increases in cardiac output in experiments in animals in which cardiac depression was induced by administration of procainamide and propranolol. 14 The previously reported difficulties with the timing of the intra-aortic balloon pump in the presence of cardiac arrhythmias 15 were not observed in our case. The usefulness of the intra-aortic balloon pump in our patient suggests a possible role for this device in future cases of drug-induced cardiac depression and may be another indication for its use. 15 The disturbances in cardiac conduction and rhythm that were noted were typical for intoxication with quinidine. 1•4 •8 • 16 Most prominent were widened, bizarre QRS complexes associated with prolonged Q-T intervals and representing either ventricular tachycardia or supraventricular tachycardia with aberrant conduction (Fig IA). An interesting temporal pattern of changing rhythms and QRS morphologic appearance was identified. Initially, there was tachycardia with widened QRS complexes (Fig IA) . Several hours later, as serum levels of quinidine declined, the QRS complexes narrowed, and the heart rate slowed enough to cause periodic activation of the pacemaker (Fig IB ). This, in tum, was followed by reappearance of abnormal QRS morphologic appearances (Fig IC). The appearance of P waves (Fig. IC) implied resumption of sinus activity. Rivers and Boyd 16 described a similar temporal sequence of intoxication with quinidine in a child. Although the mechanism underlying this effect is unknown, a second effect on the depolarization of membranes could have occurred because of a delayed appearance of an active product of the degradation of quinidine.4 Another major therapeutic problem was recurrent ventricular dysrhythmias. Ventricular irritability persisted for 36 hours after the patient's admission to the hospital, despite improvement in hemodynamic status. Quinidine-induced ventricular ectopy has been described; 8 •16•17 its precise mechanism remains unclear. 5 Lidocaine was administered repeatedly and effectively for this problem without any obvious untoward effects. Therapy with lidocaine had been used previously in a patient with intoxication with quinidine,18 and, thus, we disagree CHEST, 73: 2, FEBRUARY, 1978
with the waming 1to avoid all antifibrillatory drugs in treating intoxication with quinidine. A temporary transvenous pacemaker was used to maintain the cardiac rate during a transient bradycardiac phase (Fig 1B), as well as to provide socalled overdrive suppression of ventricular irritability. The previously described problems with an elevated threshold for capture by the pacemaker in the presence of intoxication with quinidine 12 were not observed is our patient. Intriguing, but unexplained, effects on various electrolytes (Table 1) added further to the complexity of the clinical problem. Quinidine-associated hypokalemia has been described previously. 4·12·17 The mechanism for this effect is unknown. Experimental data4·19 have suggested that hypokalemia will reverse the cardiotoxicity of quinidine and prolong survival. These empiric observations have been supported by limited clinical experience.U We therefore elected to prolong the spontaneous hypokalemia by temporarily limiting replacement of potassium. Systemic acidosis, although previously reported in intoxication with quinidine, 10·12 also has not been well characterized. Our data suggest that the cause of the acidosis was primarily metabolic (Table 1). On an empiric basis, by the use of sodium bicarbonate, as well as by adjusting respiratory control, we attempted to keep the pH in the mildly alkalotic range; however, when the pH increased beyond 7.59, especially since ventricular ectopy persisted, we elected to reverse the trend via the addition of dead space to the respiratory assistance device (Table 1). An even more perplexing occurrence was persistent hypocalcemia. This was considered to be significant, despite a slightly decreased serum level of albumin ( 3.0 gm/ 100 ml). The dilutional effect of saline solution, which was administered intravenously during the first several hours after admission, may have been responsible. The level of ionized calcium was not measured, and, therefore, the significance of the observed hypocalcemia remains uncertain. To our knowledge, this has not been previously reported in either experimental or clinical intoxication with quinidine. Decreased serum levels of phosphate and magnesium also were observed. The hypophosphatemia may have been related to the intravenous administration of glucose.20 Interestingly, quinidine has been reported to act as a chelating agent of heavy metals.4 Although speculative, it is conceivable that quinidine chelation of calcium and magnesium occurred at intracellular sites where the drug is bound at high tissue-to-serum concentrations.4 Various interactions of quinidine, calcium, CHEST, 73: 2, FEBRUARY, 1978
and protein have been described;21 ·22 their exact significance is unclear. Coma and convulsions previously have been described in intoxication with quinidine 1·12·17 and have been attributed to a direct effect of the drug on the central nervous system; however, there is a delay in transfer of the agent across the blood-brain barrier.4 Therefore, the convulsions that occurred early in our patient's course may have been due to metabolic causes. Quinidine-related respiratory failure has been described1·8 and has been attributed to a central mechanism. The pulmonary edema seen in our patient was associated with normal pulmonary wedge pressures and probably had many causes. Ingestion of propoxyphene23 may have added to the pulmonary toxicity. Quinidine has not been included in previous reviews 23 of drug-induced pulmonary syndromes. In our patient the use of PEEP was helpful in the management of the pulmonary edema. Hemodialysis has been suggested as a useful adjunct in the treatment of intoxication with quinidine; however, Reimold et aP 7 and Woie and Audun 11 found relatively poor clearances of the drug. During an eight-hour dialysis performed in an intoxicated child, Reimold et aP 7 calculated that 145 mg of quinidine had been removed. Woie and Audun 11 calculated that only 78 mg were removed during a 6~-hour hemodialysis in an adult. Unfortunately, the procedure of hemoperfusion with charcoal that we employed had to be abandoned after only one hour. This invalidates any comparison of hemodialysis with hemoperfusion with charcoal; however, the rate of extraction for quinidine would seem to be as high as 320 mg/ hr during the first hour of perfusion. Diminishing rates of clearance would be expected as the column of charcoal became saturated, and, therefore, further experience would be required to allow any further comparison between the two methods. Nonetheless, hemoperfusion with charcoal should be considered in future cases of intoxication with quinidine associated with oliguria. ACKNOWLEDGMENT: We gratefully acknowledge the assistance of Drs. James A. Prentice, Ross M. Tucker, Lawrence A. Solberg, Jr. and Geoffrey 0. Hartzler in the management of this case and that of Ms. Eileen A. Andrist in the preparation of this manuscript. REFERENCES
1 Gosselin RE, Hodge HC, Smith RP, et al: Clinical Toxicology of Commercial Products : Acute Poisoning (4th ed). Baltimore, Williams and Wilkins Co, 1976, pp 282289 2 Luchi RJ, Helwig J Jr, Conn HL Jr : Quinidine toxicity and its treatment. Am Heart J 65 :340-348, 1963
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 177
3 Winek CL, Davis ER, Collom WD, et al: Quinine fatality : case report. Clin Toxicol7: 129-132, 1974 4 Conn HL Jr: Some considerations of quinidine and procaine amide action at the cellular level. In Briller SA, Conn HL Jr ( eds): The Myocardial Cell: Structure, Function, and Modification by Cardiac Drugs. Philadelphia, University of Pennsylvania Press, 1966, pp 269296 5 Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias: 7. Cardiac effects of quinidine and procaine amide B. Am Heart J 90:117122,1975 6 Bailey DJ Jr: Cardiotoxic effects of quinidine and their treatment : Review and case reports. Arch Intern Med 105 :13-22, 1960 7 Nickel SN, Thibaudeau Y: Quinidine intoxication treated by isoproterenol (lsuprel) . Can Med Assoc J 85 :81-83, 1961 8 Finnegan TRL, Trounce JR : Depression of the heart by quinidine and its treatment. Br Heart J 16:341-350, 1954 9 Rainier-Pope CR, Schrire V, Beck W, et al : The treatment of quinidine-induced ventricular fibrillation by closed-chest resuscitation and external defibrillation. Am Heart J 63 :582-590, 1962 10 Wasserman F, Brodsky L. Dick MM, et al: Successful treatment of quinidine and procaine amide intoxication. N Engl J Med 259 :797-802, 1958 11 Woie L, Audun 0: Quinidine intoxication treated with hemodialysis. Acta Med Scand 195:237-239, 1974 12 Kerr F, Kenoyer G, Bilitch M: Quinidine overdose: Neurological and cardiovascular toxicity in a normal person. Br Heart J 33:629-631, 1971
178 SHUB ET AL
13 Gottsegen G, Ostor E : Prevention of the cardiotoxic effect of quinidine by isoproterenol. Am Heart J 65 : 102109, 1963 14 Grossman Jl, Furman S: Intra-aortic balloon augmentation during drug-induced myocardial depression. Surgery 70:304-310, 1971 15 Weber KT, Janicki JS : Intraaortic balloon counterpulsation : A review of physiological principles, clinical results, and device safety. Ann Thorac Surg 17:602-636,1974 16 Rivers RPA, Boyd RDH: Quinidine toxicity in a normal heart. Acta Paediatr Scand 62:391-395, 1973 17 Reirnold EW, Reynolds WJ, Fixler DE, et al : Use of hemodialysis in the treatment of quinidine poisoning. Pediatrics 52 :111-115, 1973 18 Kaplinsky E, Yahini JH, Barzilai J, et al : Quinidine syncope: Report of a case succe.ssfully treated with lidocaine. Chest 62 :764-766, 1972 19 Brandfonbrener M, Kronholm J, Jones HR: The effect of serum potassium concentration on quinidine toxicity. J Pharmacol Exp Ther 154:250-254, 1966 20 Guillou PJ, Morgan DB, Hill GL: Hypophosphataemia: A complication of "innocuous dextrose-saline." Lancet 2 :710 712, 197ft 21 Conn HL Jr, Luchi RJ : Ionic inHuences on quinidinealbumin interaction. J Pharmacol Exp Ther 133:76-83, 1961 22 Fuchs F, Gertz EW, Briggs FN: The effect of quinidine on calcium accumulation by isolated sarcoplasmic reticulum of skeletal and cardiac muscle. J Gen Physiol 52:955-968, 1968 23 Rosenow EC Ill : The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, 1972
CHEST, 73: 2, FEBRUARY, 1978
A 16-year-old patient survived severe intoxication with quinidine. Hypotension, rapidly progressing to oliguria and shock, was resistant to the usual therapeutic interventions but responded favorably to the use of an intraaortic balloon pump. Some hemodynamic implications are discussed. Pulmonary edema occurred and was treated
The management of acute intoxication with quinidine poses a complex and challenging clinical problem. In toxic doses, quinidine causes various poorly understood multisystem abnormalities. 1 For editorial comment, see page 129
Among the most deleterious effects are profound cardiac depression and refractory peripheral vasodilation, both of which contribute to significant hypotension and can ultimately lead to cardiovascular collapse and death.2 •3 Because the renal excretion of quinidine is rapid, 4 a proposed therapeutic goal in the management of intoxication with quinidine has been support and maintenance of cardiovascular and renal function, thereby allowing the kidneys time to excrete the drug; 1 however, in severe intoxication, hypotension and oliguria tend to negate this approach. Although various specific therapeutic approaches to intoxication with quinidine have been suggested, 1.2.5 no single regimen is widely accepted. A 16-year-old girl without prior heart disease ingested 8 gm of quinidine sulfate in an attempt at suicide. Severe hypotension, various cardiac arrhythmias, and oliguria rapidly occurred and were refractory to the usual therapeutic maneuvers. In order to improve systemic and renal perfusion, and thereby facilitate elimination of quinidine, the cardiovascular assistance of an intra-aortic balloon pump was employed. A striking, salutary hemodynamic response occurred, which reversed the hypotension and the oliguric state. Subsequent management was facilitated, and the patient survived an otherwise fulminating and potentially lethal course. °From the Mayo Clinic and Mayo Foundation, Rochester, Minn. Manuscript received February 21 ; revision accepted June 7. Reprint requests: Section of Publications, Mayo Clinic, Rochester Minnesota 55901
CHEST, 73: 2, FEBRUARY, 1978
with positive end-expiratory pressure. Electrocardiographic disturbances in conduction, transient bradycardia, and recurrent ventricular arrhythmias characterized the initial 36-hour critical period. Unexplained electrolyte abnormalities occurred and further complicated management.
CAsE REPORT
On July 6, 1976, a previo~sly healthy 16-year-old girl was evaluated in the emergency room at 6 : 10 PM, approximately two hours after consuming 8 gm of quinidine sulfate ( 117 mg of quinidine base per kilogram of body weight) in an attempt at suicide. She also had ingested a small but unknown quantity of propoxyphene and acetaminophen. Upon arrival, the patient was awake and oriented, but diaphoretic and nauseated. Gastric lavage was performed. During the next 30 minutes, the patient's respirations became shallow, and she became progressively obtunded. Her limbs became flaccid and areflexic. Babinski signs were elicited bilaterally. The patient's blood pressure decreased, but her skin remained warm and dry. Her chest was clear to auscultation, and the findings from cardiac examination were normal. Cardiac monitoring demonstrated changing rhythms, consisting primarily of accelerated idioventricular rhythm with varied morphologic appearance of the QRS complexes and intermittent sinus capture beats, as well as frequent paroxysms of wide-complex tachycardia ( Fig 1A) . The Q-T interval was prolonged. Generalized convulsions occurred, and diazepam was administered intravenously. Endotracheal intubation was performed, and respiration was assisted with a mechanical volume ventilator. The patient was oliguric. A solution of dopamine (concentration, 800 ~o~g/ml) was administered intravenously, initially at a rate of 5 ugl/ min; the dose was increased over a one-hour period to rates exceeding 50 ~o~g/ min, without any noticeable improvement in blood pressure or urinary output ( Fig 2). Intravenous administration of first a solution of isoproterenol ( 4 ~o~g/ml) at doses up to 4 ~o~g/min and then a solution of norepinephrine ( 8 ~o~g/ml) at doses up to 32 ~o~g/min had no significant effect as well. By 6 :45 PM, the patient's systolic blood pressure was barely palpable, and she was in profound coma. An antigravity pressure suit (Armstrong M.A.S.T . II) was applied, and the patient's systolic blood pressure increased transiently. Deep coma persisted and was interrupted by intermittent generalized convulsions. The patient remained oliguric despite the administration of 6,000 ml of physiologic saline solution, furosemide, and mannitol over a four-hour period. Initial laboratory data became available (Table 1 ) . The serum level of creatinine was normal. Sodium bicarbonate and potassium chloride were administered. An attempt to deflate the body pressure suit led to a further decline in blood pressure ( Fig 2) .
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 173
At 8 :00 P.\1 , an x-ray film of the chest showed diffuse pulmonary edema. With hemodynamic monitoring, an intraarterial blood pressure of 70/ 40 mm Hg was recorded . The mean pulmonary arterial wedge pressure was 11 mm Hg. Positive end-expiratory pressure (PEEP) was added to the respiratory assistance device. A temporary intravenous pacemaker was inserted. Further laboratory data became available (Table 1) . Calcium Gluceptate was administered by repeated intravenous bolus injections. Dopamine was readministered without any effect. Further administration of potassium was temporarily withheld. Because of persistent refractory hypotension and oliguria, an intra-aortic balloon pump (A VCO trisegment balloon with 30-ml volume) was inserted, and circulatory assistance was begun. With this, the blood pressure increased and significant urinary Bow began (Fig 2). A Scribner arteriovenous cannula was implanted, and hemodetoxification was subsequently attempted using a column of uncoated activated charcoal ( Becton-Dickinson Co. ). The procedure was terminated after one hour because of clotting within the canisters of charcoal; however, prior to this, blood was sampled simultaneously from the arterial and venous lines in order to determine the binding capacity of the charcoal for quinidine. The arterial concentration of quinidine was 19.8 mg/ L, and the venous concentration was 1.8 mg/L, which suggested adequate adsorption of the quinidine by the charcoal. From midnight (July 7, 1976) to 6 :00 AM, control of blood pressure and urinary output continued to be satisfactory. The patient remained comatose. The electrocardiographic monitor showed a transient narrowing of the QRS complex, and the patient's intrinsic heart rate slowed to 40 beats per minute, causing periodic activation of the demand pacemaker. The Q-T interval remained prolonged (Fig 1B) . At 6:00 AM, widening of the QRS complex recurred (Fig
F1 . RE 1. rial e l ctr ardi grap hic tracings from patient with intoxica tion ' ith q uinidin , howing I ad Y ( Frank v to r stem) nd pr cordia l I ad 1 • rrow indic t paced beats. P waves can be seen in panel labelled C-VI ·
Admission
BP mm Hg
80 60 40 20
Oliguria 6 pm
7 pm
8 pm
Urine flow 9 pm
10 pm
11 pm
12mid
Intra-aortic balloon pump FIGURE 2. Response of blood pressure ( BP) to various therapeutic interventions in patient with intoxication with quinidine. X indicates systolic blood pressure (cuff), open circles indicate diastolic blood pressure (cuff), asterisks indicate systolic blood pressure (arterial cannula), and solid circles indicate diastolic blood pressure (arterial cannula). For a brief period after starting therapy with intra-aortic balloon pump (indicated by vertical interruption of lines in curves), diastolic pressure exceeded systolic; thereafter, systolic-diastolic phase relationships were normal. Note response of blood pressure and urinary output to intra-aortic balloon pump.
174 SHUB ET AL
CHEST, 73: 2, FEBRUARY, 1978
Table 1--Cour•e of Seleeted Laboratory Data in a Patient lflitla lnto%ication 111itla Quinidine* 7 / 8/76
7/7/ 76
7 / 6/76
~
Data and Serum Levels••
7 :00 7 :30 8:00 9 :00 11:00 2:00 6 :00 1:00 5 :00 9 :00 7 :00 1:00 6 :00 PM PM PM PM PM AM AM PM PM PM AM PM PM 7 / 9/76
Quinidine, mg/ L
14.3
Sodium, mEq / L
140
Potassium, mEq / L
2.7
Calcium, mg/ 100 ml Phosphorus, mg/100 ml
21.4 17.7 11.5 9.6 152
...
149 151
8.7
6 .3
7 / 10 / 76 7 / 12 / 76 7 / 15 / 76
3 .2
1.6
1.6
148
140
144
139
146
142
142
142
142
. . . 2.9
2.6
2.6
3.2
3.7
3 .8
4 .4 4.5
4.0
3.7
4.5
4.0
4.5
... . . .
. . . 6.0
7.6
8.2
7.7
.. .
9.3
. . . 8.6
8.6
8 .5
8.3
8.2
9.1
. ..
..
. . . 1.1 .. .
...
Magnesium, mg/ 100 ml
. 1.3
4.3
3.7 1.3
1.3
2.1
2.0
2.4
2.3
PaO,, mm Hg
210
498
336
144
133 214 85
101
139
150 80
173
151
82
PaCOt, mm Hg
32
39
36
36
33
31
34
33
38
41
39
Arterial pH
7.26 7.08 7.33
7.48
7.44
Bicarbonate, mEq / L
14
Respiratory rate, breaths per minute
20
33
37
7.44 7.46 7.48 7.53 7.59 7.54 7.47 7.44 7.48 . . . 25
24
27
28
30
39
25
25
29
30
27
14
16
16
14
20
12
10
10
30
18
22
Tidal volume, L
0.8
0.9
0.8
0.8
0.8
0.8
0.6
0.8
Fl<>t
1.0
1.0
1.0
0.50 0.50 0.50 0.50 0.30
7
10
10
5
PEEP, em HtO
. ..
11
19
36
. . . . .. . ..
5
5
0
1.7
Room air
0
*Treatment consisted of the following : (1) anesthesia bag (100 percent oxygen) from 7 PM to 9 PM on July 6; (2 ) volume ventilator from 9 PM on July 6, with period of weaning from T piece (70 percent oxygen) to closed face mask (40 percent oxygen) beginning at 7 AM and concluding at 1 PM on July 8; (3) closed face mask (40 percent oxygen) from 1 PM on July 8 through July 9 (no therapy thereafter) ; and (4) addition of 50 ml of dead space from 1 PM on July 7 to 5 PM on July 7 (increased to 75 ml from 5 PM to 9 PM). **PaO,, Arterial oxygen pressure; PaC02 , arterial carbon dioxide tension ; and Fl<>t, fractional concentration of oxygen in inspired gas. IC) . The appearance of P waves suggested that a sinus mechanism had recurred. The cardiac index ( dye-dilution method) was 4.0 L/min/sq m. During the next several hours, the patient's level of consciousness improved. By 4:00PM, the intra-aortic balloon pump assistance ratio was reduced, without adverse effect. Ventricular irritability recurred, with several episodes of paroxysmal ventricular tachycardia. Cardioversion was achieved with the administration of lidocaine and electroshock. Calcium supplementation was continued, administration of potassium was resumed, and magnesium replacement (magnesium sulfate) was begun. Paroxysmal ventricular tachycardia recurred and was treated successfully with lidocaine ( 4 mgj min) and pacemaker "overdrive" suppression. At 3 :00 AM on July 8, ventricular irritability recurred, necessitating readministration of lidocaine. By 8 :00 AM, the electrocardiogram showed normal sinus rhythm with a prolonged Q-T interval ( Fig 1D) . The cardiac index was 3. 7 L/min sq m. The intra-aortic balloon pump was removed. The patient was awake, and the findings from neurologic examination were normal. Respiratory support was discontinued .. During the next 24 hours the patient remained alert and
CHEST, 73: 2, FEBRUARY, 1978
had no residual neurologic deficit. Ventricular irritability had ceased. An x-ray film of the chest showed gradual clearing over several days. The ECC continued to manifest nonspecific ST-T abnormalities for another week. Administration of all medications was stopped over the ensuing 48 hours. The patient was transferred to the psychiatric section for further evaluation and treabnent. She was fully ambulatory and asymptomatic. DISCUSSION
Currently, there is no consistent approach to the treatment of intoxication with quinidine. To treat the hypotension, the use of various sympathomimetic agents has been suggested, u-s but resistance to these agents has been reported. 1·u Administration of sodium lactate has been suggested as a therapeutic intervention, 5 •10 but this has not been uniformly effective. 2•9 The case presented illustrates many of the therapeutic difficulties inherent in the management of
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 175
intoxication with quinidine. Although survival has been reported after ingestion of large doses of the drug, 11 •12 death has also occurred. 3 In our case the rapidity of the onset of symptoms within a few hours after ingestion of a large dose, as well as the fulminating progression to shock and coma, c~ntrasts to the delayed and more gradual course of intoxication with quinidine described by Woie and Audun; 11 however, in the latter case a long-acting preparation containing quinidine was ingested, presumably delaying and attenuating its effects. The possible potentiating effects of the simultaneously ingested propoxyphene and acetaminophen were considered to be negligible because of the small amounts taken. The severe hypotension and oliguria failed to respond to full therapeutic doses of the usually employed sympathomimetic agents. Quinidine-induced peripheral vasodilation that is refractory to pharmacologic treatment has been previously reported 4 and has been attributed to a functional antagonistic effect on peripheral aadrenergic receptors. The warm, dry, and pink skin observed clinically in our patient in the presence of severe hypotension supports this theory. In contrast to previous reports, 2 •7 •8 • 13 the sympathomimetic agents given to our patient had no significant effects on the disturbances in cardiac conduction. The use of the antigravity suit ( M.A.S.T.) was the only initial maneuver that provided any improvement in blood pressure, possibly by preventing the pooling of blood in the lower extremities; however, the effect was minimal and transient and had no effect on the How of urine. The therapeutic maneuver that reversed the oliguria and abnormal hemodynamic state (Fig 2) was the use of the intra-aortic balloon pump. Although this maneuver has been employed experimentally in dogs with drug-induced cardiovascular intoxication, 14 to our knowledge, this is the first reported use of an intra-aortic balloon pump in druginduced cardiac depression in humans. The normal cardiac index and stroke volume while the patient was receiving assistance with the pump, even in the presence of widened QRS complexes and high serum levels of quinidine, suggest that cardiac depression, at least in the normal heart, is amenable to therapeutic intervention. After an initial brief period during which diastolic pressure exceeded systolic, both systolic and diastolic pressures increased. This contrasts to previously described hemodynamic effects of the intra-aortic balloon pump, 15 in which diastolic pressures increased but systolic pressures decreased slightly. If one assumes that quinidineinduced vasodilation persisted because of its long-
176 SHUB ET AL
lasting peripheral effects, 2 then the immediate increase in blood pressure that occurred (Fig 2) , despite decreased peripheral resistance, implies a very significant increase in cardiac output. The expanded intravascular volume, the decreased diastolic runoff (as a result of the intra-aortic balloon pump), and the pump-related improved coronary perfusion all may have been contributory to the improved hemodynamic state. In contrast to the case described herein, the intra-aortic balloon pump caused only modest increases in cardiac output in experiments in animals in which cardiac depression was induced by administration of procainamide and propranolol. 14 The previously reported difficulties with the timing of the intra-aortic balloon pump in the presence of cardiac arrhythmias 15 were not observed in our case. The usefulness of the intra-aortic balloon pump in our patient suggests a possible role for this device in future cases of drug-induced cardiac depression and may be another indication for its use. 15 The disturbances in cardiac conduction and rhythm that were noted were typical for intoxication with quinidine. 1•4 •8 • 16 Most prominent were widened, bizarre QRS complexes associated with prolonged Q-T intervals and representing either ventricular tachycardia or supraventricular tachycardia with aberrant conduction (Fig IA). An interesting temporal pattern of changing rhythms and QRS morphologic appearance was identified. Initially, there was tachycardia with widened QRS complexes (Fig IA) . Several hours later, as serum levels of quinidine declined, the QRS complexes narrowed, and the heart rate slowed enough to cause periodic activation of the pacemaker (Fig IB ). This, in tum, was followed by reappearance of abnormal QRS morphologic appearances (Fig IC). The appearance of P waves (Fig. IC) implied resumption of sinus activity. Rivers and Boyd 16 described a similar temporal sequence of intoxication with quinidine in a child. Although the mechanism underlying this effect is unknown, a second effect on the depolarization of membranes could have occurred because of a delayed appearance of an active product of the degradation of quinidine.4 Another major therapeutic problem was recurrent ventricular dysrhythmias. Ventricular irritability persisted for 36 hours after the patient's admission to the hospital, despite improvement in hemodynamic status. Quinidine-induced ventricular ectopy has been described; 8 •16•17 its precise mechanism remains unclear. 5 Lidocaine was administered repeatedly and effectively for this problem without any obvious untoward effects. Therapy with lidocaine had been used previously in a patient with intoxication with quinidine,18 and, thus, we disagree CHEST, 73: 2, FEBRUARY, 1978
with the waming 1to avoid all antifibrillatory drugs in treating intoxication with quinidine. A temporary transvenous pacemaker was used to maintain the cardiac rate during a transient bradycardiac phase (Fig 1B), as well as to provide socalled overdrive suppression of ventricular irritability. The previously described problems with an elevated threshold for capture by the pacemaker in the presence of intoxication with quinidine 12 were not observed is our patient. Intriguing, but unexplained, effects on various electrolytes (Table 1) added further to the complexity of the clinical problem. Quinidine-associated hypokalemia has been described previously. 4·12·17 The mechanism for this effect is unknown. Experimental data4·19 have suggested that hypokalemia will reverse the cardiotoxicity of quinidine and prolong survival. These empiric observations have been supported by limited clinical experience.U We therefore elected to prolong the spontaneous hypokalemia by temporarily limiting replacement of potassium. Systemic acidosis, although previously reported in intoxication with quinidine, 10·12 also has not been well characterized. Our data suggest that the cause of the acidosis was primarily metabolic (Table 1). On an empiric basis, by the use of sodium bicarbonate, as well as by adjusting respiratory control, we attempted to keep the pH in the mildly alkalotic range; however, when the pH increased beyond 7.59, especially since ventricular ectopy persisted, we elected to reverse the trend via the addition of dead space to the respiratory assistance device (Table 1). An even more perplexing occurrence was persistent hypocalcemia. This was considered to be significant, despite a slightly decreased serum level of albumin ( 3.0 gm/ 100 ml). The dilutional effect of saline solution, which was administered intravenously during the first several hours after admission, may have been responsible. The level of ionized calcium was not measured, and, therefore, the significance of the observed hypocalcemia remains uncertain. To our knowledge, this has not been previously reported in either experimental or clinical intoxication with quinidine. Decreased serum levels of phosphate and magnesium also were observed. The hypophosphatemia may have been related to the intravenous administration of glucose.20 Interestingly, quinidine has been reported to act as a chelating agent of heavy metals.4 Although speculative, it is conceivable that quinidine chelation of calcium and magnesium occurred at intracellular sites where the drug is bound at high tissue-to-serum concentrations.4 Various interactions of quinidine, calcium, CHEST, 73: 2, FEBRUARY, 1978
and protein have been described;21 ·22 their exact significance is unclear. Coma and convulsions previously have been described in intoxication with quinidine 1·12·17 and have been attributed to a direct effect of the drug on the central nervous system; however, there is a delay in transfer of the agent across the blood-brain barrier.4 Therefore, the convulsions that occurred early in our patient's course may have been due to metabolic causes. Quinidine-related respiratory failure has been described1·8 and has been attributed to a central mechanism. The pulmonary edema seen in our patient was associated with normal pulmonary wedge pressures and probably had many causes. Ingestion of propoxyphene23 may have added to the pulmonary toxicity. Quinidine has not been included in previous reviews 23 of drug-induced pulmonary syndromes. In our patient the use of PEEP was helpful in the management of the pulmonary edema. Hemodialysis has been suggested as a useful adjunct in the treatment of intoxication with quinidine; however, Reimold et aP 7 and Woie and Audun 11 found relatively poor clearances of the drug. During an eight-hour dialysis performed in an intoxicated child, Reimold et aP 7 calculated that 145 mg of quinidine had been removed. Woie and Audun 11 calculated that only 78 mg were removed during a 6~-hour hemodialysis in an adult. Unfortunately, the procedure of hemoperfusion with charcoal that we employed had to be abandoned after only one hour. This invalidates any comparison of hemodialysis with hemoperfusion with charcoal; however, the rate of extraction for quinidine would seem to be as high as 320 mg/ hr during the first hour of perfusion. Diminishing rates of clearance would be expected as the column of charcoal became saturated, and, therefore, further experience would be required to allow any further comparison between the two methods. Nonetheless, hemoperfusion with charcoal should be considered in future cases of intoxication with quinidine associated with oliguria. ACKNOWLEDGMENT: We gratefully acknowledge the assistance of Drs. James A. Prentice, Ross M. Tucker, Lawrence A. Solberg, Jr. and Geoffrey 0. Hartzler in the management of this case and that of Ms. Eileen A. Andrist in the preparation of this manuscript. REFERENCES
1 Gosselin RE, Hodge HC, Smith RP, et al: Clinical Toxicology of Commercial Products : Acute Poisoning (4th ed). Baltimore, Williams and Wilkins Co, 1976, pp 282289 2 Luchi RJ, Helwig J Jr, Conn HL Jr : Quinidine toxicity and its treatment. Am Heart J 65 :340-348, 1963
MANAGEMENT OF ACUTE QUINIDINE INTOXICATION 177
3 Winek CL, Davis ER, Collom WD, et al: Quinine fatality : case report. Clin Toxicol7: 129-132, 1974 4 Conn HL Jr: Some considerations of quinidine and procaine amide action at the cellular level. In Briller SA, Conn HL Jr ( eds): The Myocardial Cell: Structure, Function, and Modification by Cardiac Drugs. Philadelphia, University of Pennsylvania Press, 1966, pp 269296 5 Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias: 7. Cardiac effects of quinidine and procaine amide B. Am Heart J 90:117122,1975 6 Bailey DJ Jr: Cardiotoxic effects of quinidine and their treatment : Review and case reports. Arch Intern Med 105 :13-22, 1960 7 Nickel SN, Thibaudeau Y: Quinidine intoxication treated by isoproterenol (lsuprel) . Can Med Assoc J 85 :81-83, 1961 8 Finnegan TRL, Trounce JR : Depression of the heart by quinidine and its treatment. Br Heart J 16:341-350, 1954 9 Rainier-Pope CR, Schrire V, Beck W, et al : The treatment of quinidine-induced ventricular fibrillation by closed-chest resuscitation and external defibrillation. Am Heart J 63 :582-590, 1962 10 Wasserman F, Brodsky L. Dick MM, et al: Successful treatment of quinidine and procaine amide intoxication. N Engl J Med 259 :797-802, 1958 11 Woie L, Audun 0: Quinidine intoxication treated with hemodialysis. Acta Med Scand 195:237-239, 1974 12 Kerr F, Kenoyer G, Bilitch M: Quinidine overdose: Neurological and cardiovascular toxicity in a normal person. Br Heart J 33:629-631, 1971
178 SHUB ET AL
13 Gottsegen G, Ostor E : Prevention of the cardiotoxic effect of quinidine by isoproterenol. Am Heart J 65 : 102109, 1963 14 Grossman Jl, Furman S: Intra-aortic balloon augmentation during drug-induced myocardial depression. Surgery 70:304-310, 1971 15 Weber KT, Janicki JS : Intraaortic balloon counterpulsation : A review of physiological principles, clinical results, and device safety. Ann Thorac Surg 17:602-636,1974 16 Rivers RPA, Boyd RDH: Quinidine toxicity in a normal heart. Acta Paediatr Scand 62:391-395, 1973 17 Reirnold EW, Reynolds WJ, Fixler DE, et al : Use of hemodialysis in the treatment of quinidine poisoning. Pediatrics 52 :111-115, 1973 18 Kaplinsky E, Yahini JH, Barzilai J, et al : Quinidine syncope: Report of a case succe.ssfully treated with lidocaine. Chest 62 :764-766, 1972 19 Brandfonbrener M, Kronholm J, Jones HR: The effect of serum potassium concentration on quinidine toxicity. J Pharmacol Exp Ther 154:250-254, 1966 20 Guillou PJ, Morgan DB, Hill GL: Hypophosphataemia: A complication of "innocuous dextrose-saline." Lancet 2 :710 712, 197ft 21 Conn HL Jr, Luchi RJ : Ionic inHuences on quinidinealbumin interaction. J Pharmacol Exp Ther 133:76-83, 1961 22 Fuchs F, Gertz EW, Briggs FN: The effect of quinidine on calcium accumulation by isolated sarcoplasmic reticulum of skeletal and cardiac muscle. J Gen Physiol 52:955-968, 1968 23 Rosenow EC Ill : The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, 1972
CHEST, 73: 2, FEBRUARY, 1978