Safety and efficacy of intravenous quinidine

Safety and Efficacy of Intravenous Quinidine

CHARLES D. SWERDLOW, M.D. JEANETTE 0. YU ERIC JACOBSON, B.S. SUSAN MANN, R.N. ROGER A. WINKLE, M.D. JERRY C. GRIFFIN, M.D. DAVID L. ROSS, M.D., B.S., F.R.A.C.P. JAY W. MASON, M.D. Stanford, California

From the Cardiac Arrhythmia Study Unit, Cardiology Division, Stanford University Medical Center, Stanford, California. Dr. Ross was supported by Grants 79N 111 OA and 80N 114 from the American Heart Association, California affiliate. Dr. Mason was supported by a scholarship from the Erotman Foundation, Los Angeles, California. Dr. Mason is an Established Investigator of the American Heart Association. Requests for reprints should be addressed to Dr. Jay W. Mason, Cardiac Arrhythmia Study Unit, Cardiology Division, Stanford University Medical Center, Stanford, California 94305. Manuscript accepted August 31, 1982.

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The safety and efficacy of intravenous quinidine were evaluated in a patient population with a high prevalence of left ventricular dysfunction and intraventricular conduction delays. Dulnidlne gluconate (mean dose 9.1 f 1.6 mg/kg) was administered during electrophysiologic study to 100 patients with ventricular or supraventrlcular tachyarrhythmias. Clinical heart failure was present in 66 percent of the patients. Left ventricular end-diastolic pressure, cardiac Index, and left ventricular ejection fraction were abnormal in 62, 46, and 70 percent, respectively. Major intraventricular conduction delays (QRS of 120 msec or more) were present in 27 percent, and the H-V interval was prolonged (over 55 msec) in 26 percent. Despite the prevalence of these abnormalities, quinidine was discontinued because of hypotension in only 10 patients. Saline solution was infused to maintain preioad in 37 percent, and hypotenslon responded promptly to saline solution infusion or discontinuation of quinldine infusion in ail subjects. Hypotension was not more common in patients with more severe left ventricular dysfunction. QRS duration, H-V interval, QTc, and right ventricular effective refractory period increased significantly (p
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PATIENTS AND METHODS

RESULTS

We performed pharmacologic trials of intravenous quinidine gluconate during electrophysiologic study in 100 patients with spontaneous and inducible ventricular or supraventricular tachyarrhythmias. Studies were performed to identify effective antiarrhythmic therapy. At least 24 hours before initial electrophysiologic study, all antiarrhythmic medicines, excluding digoxin, were discontinued. During the initial study, three to five multipolar electrode catheters were used for pacing and recording. Follow-up studies were performed with a single multipolar electrode catheter. Three to six surface electrocardiogram leads were recorded simultaneously with intracardiac electrograms. Femoral arterial pressure was monitored continuously during 96 studies. Cardiac stimulation was performed using rectangular pulses with 2 msec duration and constant current strength twice the diastolic capture threshold. A strict programmed stimulation protocol was followed [ 14,151. If tachyarrhythmia could be induced reliably and repeatedly, drug trials were performed according to a previously described schedule [ 151. In patients with inducible, sustained ventricular tachycardia or ventricular fibrillation, an antiarrhythmic drug was considered effective if no more than five repetitive ventricular beats could be initiated. In patients with inducible, unsustained ventricular tachycardia (six beats to 15 seconds), an antiarrhythmic drug was considered effective if no more than two repetitive beats could be initiated. Partial efficacy was defined as conversion of a sustained tachyarrhythmia to an unsustained tachyarrhythmia or induction of a hemodynamically more stable arrhythmia as judged by elimination of requirement for cardioversion. Initial trials of quinidine were performed in the absence of other antiarrhythmic drugs. Quinidine gluconate was infused at an initial rate of 0.4 to 0.5 mg/kg per minute. The infusion rate was slowed or normal saline solution was infused, or both, if systolic blood pressure decreased by 20 percent. A mean dose of 9.6 f 1.2 mg/kg was administered to the 87 patients who received the full intended dose. Eleven patients received lower doses because hypotension persisted (10 patients) or arrhythmia recurred (one patient) during quinidine infusion. In two patients, the quinidine infusion was discontinued because sustained arrhythmia ceased after doses of 5.9 mg/kg and 7.1 mg/kg, respectively. For the entire group of 100 patients, the mean dose was 9.1 f 1.6 mg/kg. Quinidine plasma concentrations were measured by the doubleextraction technique [ 161 at the end of induction attempts, 10 to 30 minutes after termination of the infusion. Data were displayed on a switched-beam oscilloscope and recorded on magnetic tape and photographic paper at a speed of 100 mm per second. Blood pressure, A-H interval, H-V interval, effective refractory periods, and surface electrocardiographic intervals were determined at baseline and at the termination of quinidine infusion. Differences between values before and after quinidine administration were analyzed by the two-tailed Student t test for paired data. Clinical characteristics of patients who had persistent hypotension during quinidine infusion were compared with those of the other patients using the chi-square test with Yates’ correction and the two-tailed Student t test for independent means.

Patient Characteristics.

Table I summarizes the clinical, electrocardiographic, angiographic, and hemodynamic characteristics of the group. Sixty-eight patients had clinical evidence of heart failure (New York Heart Association Functional Class II, Ill, or IV). Left ventricular end-diastolic pressure, cardiac index, and left ventricular ejection fraction were abnormal in 62 percent (44 of 71) 48 percent (30 of 63), and 70 percent (45 of 64) respectively, of those patients for whom recent measurements were available. Twenty-seven patients had electrocardiographic evidence of bundle branch block or significant intraventricular conduction

TABLE I

Characteristics of 100 Patients Receiving Intravenous Quinidine

Age (years)

Male:Female Diagnosis’ Coronary artery disease Myocardial disease Valvular heart disease No structural heart disease New York Heart Association Class I II III IV Left ventricular end-diastolic pressure (mm Hg, n = 71) Cardiac index (liter/minute/m2, n = 63) Left ventricular ejection fraction+ (n = 64) H-V Interval* 155 msec with IVCD no IVCD 56-70 msec with IVCD no IVCD >70 msec with IVCD no IVCD

51 f 17 5.3:l 59 14 4 23 32 33 30 5 17f6 2.5 * 0.7 0.38 f 0.14

8 (9) 54 (63) 6 7 7 2

(9) (6) (6) (2)

Variables are expressed as mean f standard deviation. Numbers in parentheses are percentages. Coronary artery disease was diagnosed if the diameter of at least one major coronary artery was narrowed by 70% or more or if a l

myocardial infarction had occurred. Valvular heart disease was diagnosed if hemodynamically significant stenosis or insufficiency of one or more cardiac valves were present, or if the patient had undergone previous valve replacement. Myocardial disease was diagnosed if cardiac enlargement, congestive heart failure, or left ventricular hypertrophy or dilatation were documented by echocardiography or contrast angiography in the absence of coronary artery disease or valvular heart disease. The presence of hypertrophy and fibrosis on endomyocardial biopsy was used as confirmatory evidence of myocardial disease. t Determined by contrast ventriculography. T Values for H-V interval are shown for 23 of 27 patients with intraventricular conduction defects (IVCD) and 63 of 73 patients without intraventricular conduction defects. Patients were excluded because the resting electrocardiogram showed ventricular preexcitation (eight patients), ventricular tachycardia (two patients), or ventricular paced rhythm (two patients). The H-V interval could not be accurately measured in two patients with atrial fibrillation.

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INTRAVENOUS

TABLE II

QUINIDINE-SWERDLOW

ET AL

Influence of Left Ventricular Function on Qulnldlne-Induced Hypotension Patients in Whom Quinidine was Okcontinued Because ot Hvootension

Patients Receiving Complete Dose Patients* New York Hear-t Association Class I II Ill IV Left ventricular end-diastolic pressure (mm Hg) Cardiac index (liter/ minute/m*) Left ventricular ejection fraction Digoxin therapy

Normal saline solution (885 f 497 ml) was infused to maintain preload in 37 patients. Twelve patients received less than 500 ml, 16 patients received from 500 to 1,000 ml, and nine patients received more than 1,000 ml. The infusion was discontinued in 10 patients after a mean of 6.1 f 1.O mg/kg of quinidine gluconate had been administered because of hypotension that persisted despite a decreased quinidine infusion rate and saline solution administration. In an additional 14 patients, the infusion rate was slowed because of hypotension. Hypotension responded promptly to saline solution administration or discontinuation of the quinidine infusion in all patients. Severe or sustained hypotension did not occur. Mean arterial pressure decreased by a similar magnitude in patients who required discontinuation of the infusion (from 89 f 9 to 73 f 18 mm Hg) and those who received the entire dose (from 90 f 14 to 76 f 13 mm Hg). No patient required administration of a vasopressor. Three of the 10 patients who required discontinuation of the infusion received atropine (0.5 mg) for apparent vasovagal reactions, and one had angina while hypotensive. In seven additional patients, mild, transient nausea or light-headedness developed during the infusion. As shown in Table II, quinidine-induced hypotension was not more common in patients with more severe degrees of heart failure (judged by New York Heart Association Functional Class), more severe left ventricular dysfunction (judged by left ventricular ejection fraction, left ventricular enddiastolic pressure, and cardiac index), or in those taking digoxin. Electrophysiologic Effects. The electrophysiologic effects of quinidine observed in this study are shown in Table Ill. Quinidine produced statistically significant increases in heart rate, QRS duration, H-V interval, Q-T interval, and right ventricular effective refractory period. P-R and A-H intervals did not change significantly. Patients with prolonged H-V intervals or electrocardiographic evidence of intraventricular conduction defects had increases in H-V interval similar in magnitude to those observed in patients with normal intraventricular conduction. Heart block or QRS widening of 50 percent or more did not occur. Ventricular tachycardia cycle length increased in all 41 patients in whom identical forms of ventricular tachycardia were induced before and after quinidine. Efficacy. Complete or partial antiarrhythmic efficacy was observed in 40 of 76 patients with ventricular arrhythmias (53 percent) and in three of 11 patients with supraventricular arrhythmias (27 percent) who received the full intended dose. Quinidine prevented arrhythmia induction in three of 11 patients with supraventricular arrhythmias (27 percent), including one of four patients with Wolff-Parkinson-White syndrome, one of two patients with a concealed accessory atrioventricular

87

10

28 28 28 5

5 (50%) 4 (40%) 1 (10%) O(O%)

(30%) (32%) (32%) (8%)

17 f 8(n = 83)

16 f

7 (n = 7)

2.5 f 0.7 (n = 55)

3.0 f 0.9 (n = 7)

0.38 f

0.40 f 0.21 (n = 6)

0.13 (n = 58)

23 (28%)

2 (20%)

There are no statistically significant differences between any of the listed variables. Values are shown for 97 patients. Two patients received lower doses because their spontaneous arrhythmias terminated and couM not be reinduced after a partial dose had been administered. In one patient, quinidine infusion was stopped because ventricular tachycardia spontaneously recurred during the infusion. l

delay (QRS duration of 120 msec or more): left bundle branch block (12 patients), right bundle branch block (three patients), right bundle branch block and left anterior hemiblock (one patient), and nonspecific intraventricular conduction delay (11 patients). Nine additional patients had isolated left anterior hemiblock. The H-V interval was prolonged (over 55 msec) in 28 percent (24 of 86) of the patients in whom it was measured. Eighty-five patients had ventricular arrhythmias, including 77 patients with sustained ventricular tachycardia, four patients with unsustained ventricular tachycardia, and four patients with ventricular fibrillation. Fifteen patients had supraventricular arrhythmias: circus movement tachycardia or atrial fibrillation associated with the Wolff-Parkinson-White syndrome (eight patients), circus movement tachycardia associated with a concealed accessory atrioventricular pathway (three patients), paroxysmal atrial flutter (two patients), intra-atrial reentrant tachycardia (one patient), and automatic atrial tachycardia (one patient). Hemodynamlc Effects. Mean arterial pressure decreased in all 100 patients after quinidine administration.

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INTRAVENOUS

TABLE III

OUINIDINE-SWERDLOW

ET AL

ElectrophysloloQlc Effects of Quinidine BeforeQuinidine

R-R P-R QRS QTc A-H H-V+ RVERPi VT cycle§ length l

783 f 177 184 111 422 108 51 250 310

=t rt f f f f f

100 30 55

38 13 36 65

After Quinidine 689 f 187 f 124 f 505 f 102 f 60f 270 f 392 f

173 100 36 62 33 17 51 98

Change -94

f 15, p
Measured variables are expressed in milliseconds as mean f standard deviation. Change is expressed in milliseconds as mean f standard error of the mean. Values are shown for 78 patients in sinus rhythm. Patients were excluded because the resting electrocardiogram showed ventricular preexcitation (eight patients), ventricular tachycardia (two patients), ventricular paced rhythm (two patients), atrial fibrillation (six patients), atrial flutter (two patients), and atrial tachycardia (two patients). t Values are shown for 86 patients as in Table I. t The right ventricular effective refractory period (RVERP) was determined in ventricular paced rhythm at a cycle length of 600 msec. 5 The ventricular tachycardia (VT) cycle length was compared in 41 patients in whom the same morphology of ventricular tachycardia was induced before and after quinidine administration. l

pathway, and one of two patients with paroxysmal atrial flutter. Similarly, quinidine alone prevented arrhythmia induction in 15 of 76 patients with ventricular arrhythmias (20 percent): 12 of 66 patients with sustained ventricular tachycardia (18 percent), two of six patients with unsustained ventricular tachycardia (33 percent), and one of four patients with ventricular fibrillation (25 percent). For comparison, the incidence of complete efficacy for other drugs evaluated in the 85 patients with ventricular arrhythmias were: lidocaine seven of 64 (11 percent), encainide two of 23 (9 percent), procainamide two of 23 (9 percent), amiodarone one of 15 (7 percent), propranolol two of 10 (20 percent), other single agents two of 27 (7 percent). In an additional five patients with ventricular arrhythmias (7 percent), arrhythmia induction was prevented by quinidine in combination with lidoCaine (three patients) or propranolol (two patients). Partial antiarrhythmic efficacy occurred in 20 patients with ventricular arrhythmias (26 percent) who received the entire intended dose. These effects included conversion of sustained ventricular tachycardia to unsustained ventricular tachycardia (eight patients, 11 percent) and induction of better tolerated arrhythmias as judged by elimination of requirement for cardioversion (12 patients, 16 percent). Quinidine may have exacerbated induced arrhythmias in four patients. Spontaneous ventricular tachycardia with the same morphology as the arrhythmia induced in the baseline state occurred in one patient, and cardioversion was required only after quinidine in three patients. Arrhythmia exacerbation was not more common in patients taking digoxin (one patient with new requirement for cardioversion), nor did digitalis toxicity occur. Quinidine-induced pleomorphic ventricular tachycardia or ventricular fibrillation was not observed during this study.

Quinidine Plasma Levels. The mean quinidine plasma concentration determined at the end of the study in 73 patients who received full doses of quinidine was 3.2 f 2.1 pg/ml. Quinidine plasma concentrations were higher in patients in whom quinidine prevented arrhythmia induction than in those in whom quinidine failed to prevent arrhythmia induction (4.4 f 3.0 pg/ml versus 2.7 f 1.5 pg/ml, p = 0.01). Quinidine levels in the 10 patients whose infusions were discontinued because of hypotension were lower than those in patients who received the furl dose (1.9 f 1.6 versus 3.2 f 2.1, p <0.02). COMMENTS Intravenous quinidine is used infrequently because of early reports of its adverse effects. Current recommendations against intravenous use of quinidine are based on clinical experience that accrued before the hemodynamic and electrophysiologic properties of quinidine were fully elucidated. In 17 series dating from 1932 to 195 1 [ 17-2 11, serious adverse reactions occurred in 17 of 142 patients (12 percent), including 9 deaths (6 percent). As shown in Table IV, analysis of these fatal cases reveals that deaths occurred only when intravenous quinidine was administered to critically ill patients during tachyarrhythmias, with no effort made to maintain adequate preload ] 17-l 91. Controversy regarding the hemodynamic effects of quinidine arose among previous investigators because of failure to distinguish myocardial from peripheral vascular effects, failure to control for variations in autonomic tone, and use of different study populations and quinidine concentrations. Studies in dogs with denervated hearts [22] and human cardiac transplant recipients [23] have demonstrated that intravenous quinidine has no direct effect on normal myocardial

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TABLE IV

Pllsllt

Deaths Reported after Intravenous Adminlstration of Qulnidlne Arrhythmia Diagnosis

Clinical Diagnosis

VT VT

AMI VHD

VT VT VT VT

AMI, uremia AMI VHD HTN, heart disease

7

VT

8

VT

9

VT

HTN, heart disease, “coronary insufficiency” HTN, heart disease, chronic CHF HTN, heart disease

COlldHlsll

Excessive Doss

Rate Too Fast

DigHalls Toxicity

+

t

0

0

0

0

0 + 0 0

+ + Possible 0

0 0 0 +

Not stated

0

0

Possible

Not stated

0

Possible

+

Pulmonary edema, coma

0

+

Possible

Cardiogenic shock Pulmonary edema, cardiogenic shock Pulmonary edema, coma Cardiogenic shock Cardiogenic shock Pulmonary edema

ECG at De&h

Reference

NA NA

17 18

NA NA NA AVB asystole AVB -+ asystole

18 18 18 19

AVB -

19

VF

AVB asystole

19

19

The quinidine dose was excessive in Patient 1 (650 mg of quinidine sulfate as a bolus equivalent to 860 mg of quinidine gluconate, after administration of 1,760 mg of quinidine sulfate in the previous 24 hours) and Patient 4 (1,200 mg of quinidine base, equivalent to 1,935 mg of quinkline gluconate, over 30 minutes). Quinidine was administered as a bolus in Patients 1,3, and 9. Digitalis toxicity was definitely present in two patients (Patients 6 and 8) and may have been present in two others (Patients 7 and 9). Additional quinidlne was given after the QRS duration increased by 100 percent in Patient 7. In Patient 6, the fatal arrhythmia occurred 75 minutes after quinidine was administered and may not have been caused by quinidine. AMI = acute myocardial infarction; AVB = atrioventricular block; CHF = congestive heart failure; ECG = electrocardiogram; HTN = hypertension; NA = not available: VF = ventricular fibrillaton; VHD = valvular heart disease; VT = ventricular tachycardia.

contractility when administered in doses producing therapeutic plasma concentrations. Rather, it causes hypotension by direct vasodilation and interference with alpha-adrenergically mediated vasoconstriction in both arteries and veins. The hemodynamic effects of oral quinkfine are similar but less pronounced [24]. Quinidine-induced hypotension is related to dose and rate of administration. In normal human volunteers [l-4] and patients without heart failure [5,6], 4 to 8 mg/kg of quinidine gluconate (or an equivalent dose of quinidine lactate) infused at rates of 0.2 to 0.5 mg/kg per minute was well tolerated. When administered at the more rapid rate of 0.8 mg/kg per minute, 4 mg/kg of quinidine gluconate caused marked symptomatic hypotension in five of six patients without heart failure

[71.

Two previous studies have examined the hemodynamic effects of,quinidine in patients with heart failure. Ochs et al [8] found that intravenous quinidine was well tolerated by eight patients with compensated, congestive cardiomyopathy and did not impair left ventricular function as assessed by echocardiography. Hirschfeld et al [9] administered intravenous quinldine to 20 patients, 13 of whom had heart failure. Asymptomatic hypotension occurred in five patients (25 percent), and symptomatic hypotension requiring discontinuation of infusion occurred in two (10 percent). These investigators did not comment on the prevalence of heart failure in patients in whom hypotension developed.

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In our study, the incidence of hypotension requiring slowing of infusion (14 percent) or discontinuation of infusion (10 percent) was similar. We observed no association between initial arterial pressure or degree of heart failure and occurrence of hypotension. Vigorous volume expansion was usually effective in maintaining blood pressure. Severe or sustained hypotension did not occur. Despite the prevalence of left ventricular dysfunction in our patient population, saline solution infusion to reverse hypotension did not produce clinical evidence of volume overload. Thus, loading doses of quinidine can be safely administered intravenously to most patients, provided quinidine’s prominent vasodilator properties are appreciated and care is taken to maintain adequate preload. The electrophysiologic effects of quinidine have been established in various isolated tissue preparations and clinical studies. It prolongs the QRS duration, Q-T interval, and atrial and ventricular effective refractory periods [25]. In the denervated heart of human cardiac transplant recipients, it slows sinus rate and prolongs the A-H and H-V intervals [ 261. In clinical studies, quinidine’s effect on sinus rate, A-H interval, and H-V interval has varied [9,27]. Observed results depend on the relative contribution of its direct effect, its vagolytic effect, and the degree of hypotension-induced reflex sympathetic discharge. Potentially deleterious effects include slowed conduction in the His-Purkinje system and possible exacerbation of ventricular tachycardia. Quinidine-induced prolongation of infranodal con-

INTRAVENOUS QUINIDINE-SWERDLOW ET AL

duction has led some investigators to caution against its use in patients with intraventricular conduction delays [ 10,281. Hirschfeld et al [9] reported transient, asymptomatic, complete infranodal block in one patient with right bundle branch block and left anterior fascicular block who had a resting H-V interval of 80 msec and a split His potential. lnfranodal block did not occur in our study, despite the high prevalence of intraventricular conduction defects and prolonged H-V intervals in our patient population. However, we believe it would be prudent to initiate quinidine therapy with a lower dose in patients known to have extreme degrees of infranodal conduction system disease. Some authors recommend discontinuing quinidine administration if the QRS duration increases by more than 50 percent in patients with normal QRS duration or by more than 25 percent in patients with major intraventricular conduction delays [ 13,201. We cannot comment specifically on these recommendations because excessive QRS widening during quinidine infusion did not occur in our study. Quinidine may exacerbate ventricular tachycardia in at least three ways: (1) it may facilitate tachycardia initiation [29]; (2) it may cause tachycardias that are hemodynamically stable in the baseline state to become hemodynamically unstable: (3) it may induce pleomorphic ventricular tachycardia or ventricular fibrillation. Exacerbation of ventricular tachycardia by the first two mechanisms was rare in this study. Vasodilator effects may in part exlain why ventricular tachycardia induced after quinidine administration was not always better tolerated, despite uniformly slower rates. In this and previous studies [l-9,23,26], quinidine was infused while patients were in their usual cardiac rhythms. If quinidine is administered during a tachyarrhythmia in which vasoconstriction is required to maintain arterial pressure, adequate cardiac compensation may not be possible, especially in patients with abnormal ventricular function further compromised by tachycardia. Quinidine-induced ventricular fibrillation or pleomorphic

ventricular tachycardia, often demonstrating torsade de pointes morphology, may occur as an idiosyncratic reaction or as a result of quinidine overdose [30-321. This complication did not occur in any patient in our study, nor was there any association between digoxin therapy and arrhythmia exacerbation during or after electrophysiologic study. Efficacy rates for individual antiarrhythmic drugs are low when evaluated by electrophysiologic studies using up to three programmed extrastimuli [33,34]. When assessed in this manner, quinidine compares favorably with other standard and experimental antiarrhythmic agents. Although quinidine is one of the oldest antiarrhythmic agents, it remains one of the most effective. Loading doses of intravenous quinidine can be safely administered to patients with moderate heart failure or infranodal conduction system disease if preload is adequately maintained and continuous electrocardiographic monitoring is performed, preferably in an intensive care setting. This study did not evaluate maintenance therapy with intravenous quinidine, and its results might not apply in that setting. Up to 10 mg/kg of quinidine gluconate may be administered as a loading dose at a rate not exceeding 0.5 mg/kg per minute. Blood pressure should be measured by cuff at least every three minutes or continuously by an arterial catheter. Most patients, even those with significant heart failure, will tolerate 500 ml of normal saline solution during quinidine administration if hypotension occurs. Others will require more. The quinidine infusion should be stopped or slowed if significant, symptomatic hypotension persists despite administration of saline solution. We suggest that intravenous quinidine may be indicated in the acute treatment of arrhythmias when first-line agents have proved ineffective or are contraindicated, or in patients who require intravenous therapy and in whom quinidine is known to have been effective orally.

REFERENCES 1. Greenblatt DJ, Pfeifer HJ, Ochs HR, et al: Pharmacokinetics

2.

3.

4.

5.

of quinidine in humans after intravenous, intramuscular and oral administration. J Pharmacol Exp Ther 1977; 202: 365378. Ochs HR, Greenblatt DJ, Woo E, Smith TW: Reduced quinidine clearance in elderly persons. Am J Cardiol 1978; 42: 481-485. Ochs HR, Greenblatt DJ, Woo E, Franke K, Smith TW: Effects of propranolol on pharmacokinetics and acute electrocardiographic changes following intravenous quinidine in humans. Pharmacology 1978; 17: 303-306. Ochs HR, Grube E, Greenblatt DJ, Woo E. Boden G: Intravenous quinidine: pharmacokinetic properties and effects on left ventricular performance in humans. Am Heart J 1980; 99: 468-475. Ueda CT, Hirschfeld DS, Scheinman MM, Rowland M, Wil-

6.

7.

8.

9.

10.

July 1993

liamson BJ, Dzinzio 6s: Disposition kinetics of quinidine. Clin Pharmacol Ther 1976; 19: 30-36. Conrad KA, Molik BL, Chidsey CA: Pharmacokinetic studies of quinidine in patients with arrhythmias. Circulation 1977; 55: 1-7. Wellens HJJ, Durrer D: Effect of procainamide, quinidine, and amjaline in the Wolff-Parkinson-White syndrome. Circulation 1974; 50: 114-120. Ochs HR. Grube E, Greenblatt DJ, Arendt R: Intravenous quinidine in congestive cardiomyopathy. Eur J Clin Pharmacol 1981; 19: 173-176. Hirschfeld DS, Ueda CT, Rowland M, Scheinman MM: Clinical and elecfrophysiologic effects of quinidine in man. Br Heart J 1977; 39: 309-316. Feldman MS, Helfant RH: Antiarrhythmic agents. In: Helfant RH, ed. Essentials of cardiac arrhythmias. Philadelphia: WB

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11.

12.

13.

14.

15.

16. 17.

16.

19.

20.

21. 22.

23.

42

Saunders, 1960; 308-329. Arnsdorf MF, Hsieh YY: Antiarrhythmic agents. In: Hurst JW, Logue RB, Schlant RC, Wenger NK, eds. The heart arteries and veins, 4th ed. New York: McGraw-Hill, 1978; 19411963. Fowler NO: Clinical pharmacology of selected cardiovascular drugs. In: Fowler NO, ed. Cardiac diagnosis and treatment, 3rd ed. Hagerstown, Maryland: Harper & Row, 1980; 1253-1257. Jaffe AS: Cardiac arrhythmias. In: Freitag JJ, Miller LW, eds. Manual of medical therapeutics. Boston: Little, Brown, 1980: 99-132. Mason JW, Winkle RA: Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978; 58: 971-985. Mason JW, Winkle RA: Accuracy of the ventricular tachycardia-induction study for predicting long-term efficacy and inefficacy of antiirhythmic drugs. N Engl J Med 1980; 303: 1073-1077. Cramer G. lsaksson 8: Quantitative determination of quinidine in plasma. Stand J Lab Invest 1963; 15: 553-556. Rakov HL: Ventricular fibrillation in acute coronary artery thrombosis during the intravenous administration of quinidine sulphate; report of a fatal case. Ann Intern Med 1942; 16: 571-576. Armburst CA, Levine SA: Paroxysmal ventricular tachycardia: a study of one hundred and seven cases. Circulation 1950; 1: 28-40. Acierno LJ, Gubner R: Utility and limitations of intravenous quinidine in arrhythmias. Am Heart J 1951; 41: 733741. Clagett AH: Intravenous use of quinidine with particular reference to ventricular tachycardii. Am J Med Sci 1950; 220: 381-388. Woo E, Greenblatt DJ: A reevaluation of intravenous quinidine. Am Heart J 1978; 96: 829-831. Markiewicz W. Winkle RA, Binetti G, Kernoff R, Harrison DC: Normal myocardial contractile state in the presence of quinidine. Circulation 1976; 53: 101-106. Mason JW, Winkle RA, lngels NB, Daughters GT, Harrison DC, Stinson EB: Hemodynamic effects of intravenously ad-

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Volume 75

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

ministered quinldine on the transplanted heart. Am J Cardiol 1977; 40: 99-104. Ferrer MI, Harvey RM, Werko L, Dresdale DT, Courant A, Richards DW: Some effects of quinidine sulfate on the heart and circulation in man. Am Heart J 1948; 36: 816-837. Conn HL Jr, Luchi RJ: Some cellular and metabolic considerations relating to the action of quinidine as a prototype antiarrhythmic agent. Am J Med 1964; 37: 685-699. Mason JW. Winkle RA, Rider AK, Stinson EB, Harrison DC: The electrophysiologic effects of quinidine in the transplanted human heart. J Clin Invest 1977; 59: 481489. Josephson ME, Seides SF, Batsford WP, et al: The electrophysiological effects of intramuscular quinidine on the atrioventricular conduction system in man. Am Heart J 1974; 87: 55-64. Sokolow M, Perloff DB: The clinical pharmacology and use of quinidine in heart disease. Prog Cardiovasc Dis 1961; 3: 316-330. Horowitz LN. Josephson ME, Farshidi A, Spielman SR, Michaelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978; 58: 986-997. Seizer A, Wray HW: Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1959; 17: 17-26. Jenze HR, ltagemeijer F: Quinidine syncope: torsade de pointes with low quinidine plasma concentrations. Eur J Cardiol 1976; 4: 447-451. Reynolds EW, Van der Ark CR: Guinldine syncope and delayed repolarization syndromes. Mod Concepts Cardiovasc Dis 1976; 45: 117-122. Swerdlow CD, Echt DS, Winkle RA, Griffin JC, Ross DL, Mason JW: Incidence of acute antiarrhythmic drug efficacy at electrophysiologic study (abstr). Circulation 1981; 82(Suppl IV): IV-137. Swerdlow CD, Blum J, Winkle RA, Griffin JC, Ross DL, Mason JW: Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with use of a third extrastimulus. Am Heart J 1982; 104: 1004-1011.