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Intravenous quinidine: Relations among concentration, tachyarrhythmia suppression and electrophysiologic actions with inducible sustained ventricular tachycardia
Intravenous Quinidine: Relations Among Concentration, Tachyarrhythmia Suppression and Electrophysiologic Actions with Inducible Sustained Ventricular Tachycardia HENRY J. DUFF, MD, D. GEORGE WYSE, MD, PhD, DANTE MANYARI,
MD,
and L. BRENT MITCHELL, MD
A computer simulation was used to devise quinidine sulfate infusions to produce pseudo-steady-state concentrations in the low (8 @W/liter) and high (14 @W/liter) therapeutic ranges, avoiding high peak concentrations. Using this infusion, efficacy and electrophysiologic actions of quinidine sulfate were assessed in 21 patients with sustained inducible ventricular tachycardia (VT) when concentrations were 12.8 f 11 @f/liter (mean f standard deviation) and 18 f 9 @f/liter. Although mean concentrations approximated target levels, there was substantial individual variation. A reciprocal linear relation (r = 0.8, p
to intravenous quinidine, 17 patients received gradually increasing oral quinidine dosages adjusted to reproduce plasma levels that had been effective during intravenous administration, or to maximal well-tolerated dosage (if side effects occurred). VT was still inducible during oral treatment in 4 of 5 patients in whom VT had been suppressed during the intravenous infusion. Side effects frequently limited oral dosage to less than that required to reproduce effective concentrations. However, 2 patients did not respond to oral quinidine even when concentrations were equal to those which had been effective during intravenous treatment. in contrast, 11 of 12 patients who did not respond to intravenous quinidine also did not respond to its oral preparation. Response to intravenous quinidine also accurately predicted whether response would ultimately occur to any oral antiarrhythmic agent. In conclusion, acute drug testing to quinidine is safe and efficacious. The discrepancy between antiarrhythmic response to oral and intravenous quinidine is due, at least in part, to poor patient tolerance of large doses of quinidine given orally. (Am J Cardiol 1985;55:92-97)
Although quinidine is effective treatment for some patients with atria1 and ventricular tachyarrhythmias, intravenous use of quinidine has been traditionally considered hazardous because of frequent adverse side
effects,l-3 particularly hypotension at peak concentrations. Recent reports have suggested that the use of intravenous quinidine gluconate is not as troublesome as was alleged,4-6 although hypotension continued to occur frequently in the study of Swerdlow et a1.6The ability to administer intravenous quinidine safely and achieve a range of therapeutic plasma concentrations would allow a rapid and systematic evaluation of its antiarrhythmic efficacy in individual patients. A computer-simulated infusion was devised to produce pseudo-steady-state concentrations in the low and high therapeutic range with little overshoot. Using this
From the Cardiology Division, Department of Medicine, University of the Foothills General Hospital, Calgary, Alberta, Canada. This study WAS Supported by grants from the Alberta Heritage Foundation for Medical Research, the Alberta Heart Foundation and the Medical Research Council of Canada. Manuscript received March 19, 1984; revised manuscript received and accepted September 6, 1984. Address for reprints: Henry J. Duff, MD, Department of Medicine, Division of Cardiology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N 1.
Calgary,and
92
January 1, 1985
infusion protocol, safety, efficacy and electrophysiologic actions of quinidine sulfate were assessed in 21 patients with sustained, inducible ventricular tachycardia (VT).
Methods Standard infusion: Published pharmacokinetic parameters of quinidine gluconate in normal humans7-s were used to design a standard series of infusions producing serum concentrations which gradually increased after an exponential growth pattern to minimize early peaks and troughs. This objective was achieved by giving a series of infusions at decremental rates (Fig. 1). The first series of infusions was designed to produce plasma concentrations in the low therapeutic range (approximately 8 /.&f/liter). If efficacy was not seen with these low-dose infusions, a second series of infusions was given to produce concentrations in the high therapeutic range (approximately 14 PM/liter). Because volume of distribution of a number of antiarrhythmic drugs, including quinidine,s is altered in the presence of congestive heart failure, radionuclide angiograms were performed in a drug-free state so that observed pseudo-steady-state plasma concentrations could be related to baseline ejection fraction (EF). Protocol: Twenty-one patients with sustained, inducible VT were candidates for this study. These patients were referred for treatment due to: (1) sustained VT, (2) documented nonsustained VT (more than 5 consecutive ventricular ectopic depolarizations at a cycle length of less than 500 ms) that was associated with unmonitored outpatient syncope or that required cardiopulmonary resuscitation; or (3) syncope of obscure origin in patients in whom sustained unimorphic VT could be induced at electrophysiologic study. Sustained VT was defined as consecutive ventricular premature complexes at a cycle length of less than 500 ms lasting longer than 30
FIGURE 1. A decremental series of infusions produce concentrations that increase in a slow exponential pattern. Low therapeutic plasma Concentrations are produced by infusion rates (pg/ kg/min, each for 25 minutes) of 0.22, 0.11,0.06 and higher concentrations by rates of 0.17, 0.14, 0.08.
5 F a g
THE AMERICAN
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OF CARDIOLOGY
Volume 55
seconds, or producing hemodynamic compromise requiring termination of the tachyarrhythmia within 30 seconds. Each patient gave written, informed consent. After withdrawal of all antiarrhythmic medications (for at least 4 halflives), programmed electrical stimulation studies were done in a drug-free state. The standard quinidine sulfate infusion was then administered and blood pressure, pulse and clinical status were evaluated every 5 minutes throughout the infusion. Programmed electrical stimulation studies during the first series of infusions were not begun until the infusions had been under way for at least 40 minutes. Blood samples for quinidine assay were obtained just before and after electrophysiologic measurements. When VT induction was not suppressed with the first series of infusions, the higher dose infusion protocol was administered and electrophysiologic studies were repeated no sooner than 30 minutes after beginning the second series of infusions. Independent of response to intravenous quinidine, consenting patients subsequently received gradually increasing oral dosagesof quinidine. The dosage was adjusted to reproduce the serum levels that had been effective during the intravenous quinidine electrophysiologic study or to the maximal tolerated oral dose, whichever was lower. Electrophysiologic testing was then repeated on oral quinidine therapy. Electrophysiologic studies: The ventricular origin of the patient’s arrhythmia was confirmed by His bundle recordings. Programmed electrical stimulation techniques used in the study included introduction of single, double and, if necessary, triple extrastimuli (3 mA or twice diastolic threshold, whichever was greater, and a 2-ms pulse width) at ventricular drive cycle lengths of 600,500 and 400 ms with the electrode catheter at the apex of the right ventricle.lO Ventricular burst pacing (4 to 12 beats at cycle lengths of 300 to 240 ms) was subsequently used if VT was not induced by,the extrastimulus
8 t
30
93
60
90 MINUTES
120
150
94
INTRAVENOUS
QUINIDINE
FOR INDUCIBLE
VENTRICULAR
TACHYCARDIA
technique. During the drug-free study the endpoint of programmed electrical stimulation was induction of VT on at least 2 occasions with at least 1 of these being sustained (defined above). During subsequent quinidine studies, the ability to induce at least 5 consecutive ventricular ectopic depolarizations at a cycle length of less than 500 ms was considered to be drug failure. Concentration-dependent change in other electrophysiologic parameters were also evaluated. Surface electrocardiographic leads I, aVF and Vi were recorded at baseline and during quinidine treatments, and the PR, QRS, QT and RR intervals were measured. Rate-corrected QT (QTc) was calculated from the formula QTc = QT/a Ventricular effective refractory periods (VERPs) of the beats induced by the first and second extrastimuli (Ss, Ss) were also measured using the extrastimulus technique and conventional definitions. Concentration-dependent changes in rate and morphologic pattern of the induced VT were also assessed. Analytical: Samples were assayed, using an enzymatic immunoassay (EMIT@) method. The therapeutic range for quinidine has been reported to be 7 to 14 PMiliter. Little cross-reactivity to quinidine’s major metabolite has been found using this assay.11J2 Statistics: One-way analysis of variance was used to assess the significance of changes in electrophysiologic measurements during the quinidine infusions. Chi-square analysis was used for discrete data. The null hypothesis was rejected at the p <0.05 level. Continuous data are presented as mean f standard deviation. Results
Patients: Four of the 21 patients had 1 or more episodes of ventricular fibrillation, 9 had spontaneous sustained VT, 5 had nonsustained VT and recurrent outpatient syncopal episodes and 3 were evaluated for syncope of obscure origin. Six of the 21 patients had
required 1 or more transthoracic cardioversions for VT and 4 of the patients had required cardiopulmonary resuscitation out of hospital. Seventeen of the patients had ischemic heart disease with a global EF of 42 f 10%. Quinidine infusion: The first series of quinidine infusions achieved pseudo-steady-state concentrations of 12.6 f 11 PM/liter while the second series of infusions produced serum concentrations of 18 f 9 j&/liter. Mean observed plasma levels were somewhat in excess of the target concentration (7 and 14 PM/liter), and there was substantial interindividual variation. Figure 2 shows a reciprocal linear relation between the drugfree EF and the observed plasma concentrations at electrophysiologic testing (r = 0.8, p
of quinidine
sulfate (as assessed by its ability to
preclude induction of VT) increased with increasing serum concentrations (Fig. 3). Forty-three percent of the patients responded to intravenous quinidine, and little additional benefit was observed with serum concentrations
in excess of 18 PM/liter.
Induction
of VT
with a stimulation protocol which was less aggressive than that required at baseline occurred in 7 patients during the quinidine infusions. VT was easier to induce l
.. .
. .
l *o
.
.
r=oa1 slope
= -52
intercept
= 104
p <0.03
I
I
I
I
20
40
60
60
DRUG
FREE
EJECTION
FRACTION
FIGURE 2. A reciprocal relation between plasma concentrations duced and the drug-free ejection fraction.
pro-
I
I
I
I
3
10
20
30
CONCENTRATION
(FM/L)
FIGURE 3. Cumulative proportion of patients responding to quinidine with suppression of induced ventricular tachycardia relative to plasma concentration.
January 1, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY
TABLE I
lnducibility (I) or Noninducibility (NI) of Tachycardia with Intravenous and Oral Quinidine lnducibility with Intravenous Quinidine
lnducibility with oral quinidine Difference
not significant
NI
I
NI
I
1
I
4
11
= cl L
Volume
55
95
80
7 0 0
(x2). ji f
in 4 of the 7 patients at low concentrations, while high-dose quinidine enhanced VT induction in 3 patients. Of interest, 2 of 4 patients in whom VT was easier to induce after low-dose quinidine infusion responded to the larger dose infusion with suppression of inducibility. There was no simple relation between extent of QTc prolongation or VERP change and easeof inducibility. While inducibility of VT was occasionally enhanced by quinidine, paradoxical acceleration of VT rate was not seen. Figure 4 illustrates concentrationdependent changes in electrophysiologic measurements. The VERP of Ss was increased only to a small degree in these patients and there was little increase in this measurement at concentrations beyond 7 PM/liter. However, the VERP of the beat induced by Sa progressively increased throughout the concentration range tested and paralleled antiarrhythmic efficacy. The relation between quinidine concentration and change in QRS was linear (r = 0.62, p <0.05). A plateau in the concentration-dependent increase in QTc interval occurred at approximately 14 @f/liter. Although the cycle length of induced VT was slowed by quinidine (245 f 53 ms at baseline; 313 f 80 ms with low-dose quinidine, and 364 f 62 with high-dose quinidine) the extent of its slowing did not correlate with serum concentration. Response to intravenous quinidine as a predictor of response to oral treatment: Independent, of the response to intravenous quinidine, 17 consenting patients received gradually increasing oral dosages of quinidine and electrophysiologic studies were repeated. Table I illustrates the relation between inducibility during intravenous quinidine treatment to inducibility during its oral administration. Four of 5 patients who responded to intravenous quinidine did not respond during oral treatment. In 2 of these 4 patients the oral quinidine dose was limited by side effects and the effective concentrations achieved with intravenous quinidine could not be reached. However, VT continued to be inducible during oral therapy in 2 patients who had equal plasma levels during intravenous and oral treatments (Table II). In contrast, the absence of antiarrhythmic response to intravenous quinidine accurately predicted a lack of response to oral quinidine in 11 of 12 patients. We also assessed whether the antiarrhythmic response to intravenous quinidine would predict eventual response to any oral antiarrhythmic therapy (Tables II and III). Eight of 9 patients who responded to intravenous quinidine finally responded to oral antiarrhythmic medication (Table II). Nine of 12 patients who did not have an adequate antiarrhythmic response to in-
w
01
I
I
6-S
9-12
LlUUUL
A
QUINIDINE
B
-
i 13-18
6-S
(S3)
VERP
(S2)
I 20-30
>30
(uM/L)
UUUUI 3-5
S.E.
VERP
9-1213-18
20-30
>30
QUINIDINE (@4/L) FIGURE 4. Concentration-dependent change in electrophysiologic measurements. A, ventricular effective refractory period (VERP) of Sp and S3. 6, QRS duration. S.E. = standard error.
travenous quinidine medication.
did not respond to any oral
Discussion Acute electrophysiologic effects of intravenous quinidine have been previously investigated after stopping a rapid infusion of quinidine.6J3J4 However, concentration-response relations measured during the rapid distribution phase may not be reliable.15 Furthermore, in previous studies no attempt was made to systematically evaluate antiarrhythmic efficacy over the entire therapeutic range.6 The rapid infusion technique also increases the likelihood of side effects by producing early high peak levels. Symptomatic hypotension occurred frequently in the study of Swerdlow et a1,6but it was infrequently seen in the present study. Rapid evaluation of efficacy and pharmacologic actions of intravenous antiarrhythmic agents can be improved when infusions produce pseudo-steady-state serum
INTRAVENOUS
96
TABLE II
QUINtDINE
FOR INDUCIBLE
VENTRICULAR
Individual Patient Responses to Programmed Medications Given Intravenous Quinidine
Pt
Cont. *
PES
TACHYCARDIA
Electrical
Stimulation
Cont.
PES NI ;’ It It It I I
ft 2:
I
if 53
I
: NA
LA NA I
6
NA
I I I
6
21
7
NI
NA
and to
Discharge Medications
Oral Quinidine
2:
in Relation to Serum Concentration
NA
Meds Quinidine Quinidine Amiodarone Quinidine, propranolol Sotalol Quinidine, tocainide Sotalol Quinidine, mexiletine Amiodarone Amiodarone Disopyramide Amiodarone Surgery Amiodarone Amiodarone Amiodarone Mexiletine Propranolol Mexiletine, quinidine Quinidine, verapamil Propranolol
Cont.
l
Induc.
36.0 :7 1:3 Iii NA 0.8 1.1 2.1 0.7 39 0.8 7.5 NA 67
NI
Concentration; the units for each medication are: quinidine, PM/liter; amiodarone, pg/ml; propranolol, rig/ml; sotalol, pg/ml; tocainide pglml; disoovramide. u&f/liter: mexiletine. uo/ml. t Patients in’whom dkcordant r&l% were noted between intravenous and oral quinidine. I = inducible; I+ = inducible, but optimal treatment; NA = not available; NI = not inducible; PES = programmed electrical stimulation. l
concentrations which explore concentration response relations over the entire therapeutic range without side effects. The quinidine infusion devised for this study did achieve a range of therapeutic concentrations; however, other problems of acute drug testing limit its overall value. Antiarrhythmic effects seen during the acute drug infusion did not predict the response with oral quinidine treatment. Such discrepancies may relate to several factors, including: (1) side effects during chronic oral therapy, which limit dosage increments so that effective concentrations seen with the intravenous quinidine are not reached; (2) a difference in the relation between tissue levels and plasma levels when these are measured under pseudo-steady-state and steady-state conditions; and (3) the presence of’active metabolites, which may contribute to pharmacologic actions and side effects. The relative inefficacy of oral quinidine in this study was primarily a result of side effects that limited our ability to reproduce effective plasma concentrations during the infusion. Side effects seenwith oral quinidine treatment may reflect local gastrointestinal irritation. Cho@ evaluated the relation between plasma concentrations and ventricular tissue concentrations of quinidine during a constant infusion in dogs. In that study, there was little discrepancy between intravenous and myocardial concentrations after 90 minutes, suggesting that there is little difference in tissue levels under pseudo-steady-state and steady-state conditions. Two patients did not respond to oral quinidine, even though their plasma levels reproduced concentrations
that had been effective during intravenous quinidine therapy. Hypothetically, active metabolites of quinidine could accumulate during long-term oral therapy and as the metabolites are electrophysiologically active17Js they could alter antiarrhythmic efficacy. The infusions designed for this study allowed an evaluation of concentration-related changes in electrophysiologic parameters and their relation to antiarrhythmic activity. No single electrophysiologic change or combination thereof clearly discriminated between patients who would or would not respond to quinidine. However, we noted that change in the VERP of the beat induced by Se had a concentration-response relation that paralleled antiarrhythmic activity. Although parallel concentration-response curves do not indicate a cause and effect relation, such observations do suggest potentially fruitful areas of future research. Few other studies in man have systematically evaluated the concentration-response relations of electrophysiologic changes with quinidine. The present data, like previous data from human studies by Heissenbuttel and Bigger,lg show concentration-dependent changes in QRS duration, QTc interval. Unlike Heissenbuttel’s studyI we evaluated change in VERP (Ss) and observed that its increase occurs at low plasma concentrations (7 PM/liter) with little increase in this measurement at higher concentration. The QTc interval however progressively prolonged and only then plateaued at approximately 12 &f/liter, while QRS increases linearly with concentration. Varying concentration-response relations suggest that quinidine may mediate its elec-
January 1, 1985
TABLE III
lnducibility (I) or Noninducibility (NI) of Tachycardia with Quinidine Compared with Any Oral Antiarrhythmic Agent lnducibility with I.V. Quinidine NI
lnducibility with any oral antiarrhythmic
THE AMERICAN
a
3
I
1
9
p -Co.01 (x2).
trophysiologic actions at a number of different active sites. These results are in keeping with in vitro data20 that suggests that quinidine’s effects on various phases of the action potential are mediated at a number of active sites. The results obtained with intravenous quinidine in this study are similar to those seen with procainamide. As with procainamide,21922 high concentrations of quinidine achieved control of ventricular arrhythmias resistant to more conventional concentrations and acute toxicity at high concentrations was not a major problem.22y23Despite the limitation of use of acute intravenous quinidine testing to predictive response to oral quinidine, such testing may be of value in predicting eventual response to any oral antiarrhythmic agent. A similar predictive value 22123has been seen relating antiarrhythmic response to procainamide and response to any oral antiarrhythmic agent. Differences are also apparent between quinidine and procainamide. In this study, oral quinidine therapy was not well tolerated, unlike results reported with high-dose oral procainamide. This infusion was designed from pharmacokinetic parameters derived from administration of intravenous quinidine gluconate. The administered dosagewas then adjusted to reflect the relative proportion of the quinidine sulfate molecule, which is base (rather than salt). Theoretically, if the present quinidine infusion were modified so that quinidine gluconate was to be given, the serial intravenous rates would be increased by a factor of 1.34. In conclusion, an infusion protocol for the administration of quinidine sulfate was devised that permits a rapid and safe assessment of antiarrhythmic efficacy at both low and high therapeutic concentrations in man. Response to intravenous quinidine predicts the likeli-
OF CARDIOLOGY
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97
hood of a response to any oral antiarrhythmic agent. However, this infusion has a major limitation relating to a discrepancy between tolerance to intravenous and oral medication. References
I
NI
JOURNAL
1. Rakov HL. Ventricular fibrillation in acute coronary thrombosis during intravenous ouinidine sulfate infusion: reoort .- of a fatal case. Ann Intern Med 1942;16:541-576. 2. Armburst CA, Levine SA. Paroxysmal ventricular tachycardia: a study of one hundred and seven cases. Circulation 1950;1:28-40. 3. Acierno LJ, Gabner R. Utility and limitations of intravenous quinidine in arrhythmias. Am Heart J 1957;41:733-741. 4. Woo E, Greenbiatt DJ. A reevaluation of intravenous quinidine. Am Heart J 1978;96:829-832. 5. Och SHR, Grube DJ, Greenbiatt DJ, Arndt R. Intravenous quinidine in congestive cardiomyopathy. Eur J Clin Pharmacol 1981;19:173-176. 6. Swerdlow CD, Yu JO, Jacobson E, Winkle RA, Mason JW. Safety and efficacy of intravenous quinidine. Am J Med 1983;75:36-42. 7. Uyeda CT, Hirschfield DS, Scheinman MM, Rowland M, Williamson BJ, Dzinrio BS. Disposition kinetics of quinldine. Clin Pharmacol Ther 1976; ,0.9”-?R a. Conrad KA, Molik BL, Chidsey CA. Pharmacokinetic studies of quinidine in patients with arrhythmias. Circulation 1977;55:1-7. 9. Guenter llW, Haiford NHG, Goates P, Upton RA, Riegeimans. Quinidine pharmacodiuretics in man: choice of disposition model and absolute availability. J Pharmacokinet Biopharm 1979;7:315-331. 10. Josephson ME, Seides SK. Clinical Cardiac Electrophysiology. Techniques and Interpretation. Philadelphia: Lea & Febiger, 1979:41. 11. Dextrose PG, Foreman J, Griffiths WC, Diamond I. Comparison of an enzyme immunologic and a high performance liquid chromatographic method for quantitation of quinidine in serum. Clin Toxic01 1981;18:291-297. 12. Drayer DE, Lorenzo B, Riedenberg MM. Liquid chromatography and fluorescence spectroscopy compared to a homogeneous enzyme immunoassay technique for determining quinidine in serum. Clin Chem 1981;27:308310. 13. Mason JW, Winkle RA, Rider AK, Stlnson EB, Harrison DC. The electrophysiologic effects of quinidine in the transplanted human heart. J Clin Invest 1977;39:487-489. arrhythmia induction in the se14. Mason JW, Winkle RA. Electrode-catheter lection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachvcardia. Circulation 1978:58:971-985. 15. Melmon KL,* Morreiii HF. Clinical Pharmacology. New York: Macmillan, 1978:71-108. 16. Chou YW. Quantitative correlation of plasma and myocardial quinidine concentration with biochemical and electrocardiographic changes. Am Heart J 1973;85:648-654. 17. Drayer DE, Lowenthal DT, Restivo KM, Schwartz A, Cook CK, Reidenberg MM. Steady state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function. Clin Pharmacol Ther 1978;24:31-39. 16. Holford NHG, Coates PE, Guentert TW, Riegetman S, Shelner LB. The effect of quinidine and its metabolltes on the electrocardiogram and systolic time intervals: concentration-effect relationships. Br J Clin Pharmacol 1981;11:187-195. Heissenbuttei RH, Bigger JT. The effect of oral quinidine on intraventricular 19. conduction in man: correlation of plasma quinidine with changes in QRS duration. Am Heart J 1970;80:453-462. 20. Nattel S, Bailey JC. Time course of the electrophysiological effective quinidine canine purkinje fibers: concentration dependence and comparison with lidocaine and disopyramide. J Pharmacol Exp Ther 1983;225:176180. 21. Engel TR, Meister SG, Luck JC. Modification of ventricular tachycardia by procainamide in patients with coronary artery disease. Am J Cardiol 1980;46:1033-1038. 22. Greenspan AM, Horowitz LN, Speilman SR, Josephson ME. Large dose procainamide therapy for ventricular tachyarrhythmia. Am J Cardiol 1980:46:453-462. 23. Waxman HL, Buxton AE, Sadowski LM, Josephson ME. The response to procainamide during electrophysioiogic study for sustained ventricular tachyarrhythmias predicts the response to other medications. Circulation 1983;67:30-36. .“..,”
“-.
MD,
and L. BRENT MITCHELL, MD
A computer simulation was used to devise quinidine sulfate infusions to produce pseudo-steady-state concentrations in the low (8 @W/liter) and high (14 @W/liter) therapeutic ranges, avoiding high peak concentrations. Using this infusion, efficacy and electrophysiologic actions of quinidine sulfate were assessed in 21 patients with sustained inducible ventricular tachycardia (VT) when concentrations were 12.8 f 11 @f/liter (mean f standard deviation) and 18 f 9 @f/liter. Although mean concentrations approximated target levels, there was substantial individual variation. A reciprocal linear relation (r = 0.8, p
to intravenous quinidine, 17 patients received gradually increasing oral quinidine dosages adjusted to reproduce plasma levels that had been effective during intravenous administration, or to maximal well-tolerated dosage (if side effects occurred). VT was still inducible during oral treatment in 4 of 5 patients in whom VT had been suppressed during the intravenous infusion. Side effects frequently limited oral dosage to less than that required to reproduce effective concentrations. However, 2 patients did not respond to oral quinidine even when concentrations were equal to those which had been effective during intravenous treatment. in contrast, 11 of 12 patients who did not respond to intravenous quinidine also did not respond to its oral preparation. Response to intravenous quinidine also accurately predicted whether response would ultimately occur to any oral antiarrhythmic agent. In conclusion, acute drug testing to quinidine is safe and efficacious. The discrepancy between antiarrhythmic response to oral and intravenous quinidine is due, at least in part, to poor patient tolerance of large doses of quinidine given orally. (Am J Cardiol 1985;55:92-97)
Although quinidine is effective treatment for some patients with atria1 and ventricular tachyarrhythmias, intravenous use of quinidine has been traditionally considered hazardous because of frequent adverse side
effects,l-3 particularly hypotension at peak concentrations. Recent reports have suggested that the use of intravenous quinidine gluconate is not as troublesome as was alleged,4-6 although hypotension continued to occur frequently in the study of Swerdlow et a1.6The ability to administer intravenous quinidine safely and achieve a range of therapeutic plasma concentrations would allow a rapid and systematic evaluation of its antiarrhythmic efficacy in individual patients. A computer-simulated infusion was devised to produce pseudo-steady-state concentrations in the low and high therapeutic range with little overshoot. Using this
From the Cardiology Division, Department of Medicine, University of the Foothills General Hospital, Calgary, Alberta, Canada. This study WAS Supported by grants from the Alberta Heritage Foundation for Medical Research, the Alberta Heart Foundation and the Medical Research Council of Canada. Manuscript received March 19, 1984; revised manuscript received and accepted September 6, 1984. Address for reprints: Henry J. Duff, MD, Department of Medicine, Division of Cardiology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N 1.
Calgary,and
92
January 1, 1985
infusion protocol, safety, efficacy and electrophysiologic actions of quinidine sulfate were assessed in 21 patients with sustained, inducible ventricular tachycardia (VT).
Methods Standard infusion: Published pharmacokinetic parameters of quinidine gluconate in normal humans7-s were used to design a standard series of infusions producing serum concentrations which gradually increased after an exponential growth pattern to minimize early peaks and troughs. This objective was achieved by giving a series of infusions at decremental rates (Fig. 1). The first series of infusions was designed to produce plasma concentrations in the low therapeutic range (approximately 8 /.&f/liter). If efficacy was not seen with these low-dose infusions, a second series of infusions was given to produce concentrations in the high therapeutic range (approximately 14 PM/liter). Because volume of distribution of a number of antiarrhythmic drugs, including quinidine,s is altered in the presence of congestive heart failure, radionuclide angiograms were performed in a drug-free state so that observed pseudo-steady-state plasma concentrations could be related to baseline ejection fraction (EF). Protocol: Twenty-one patients with sustained, inducible VT were candidates for this study. These patients were referred for treatment due to: (1) sustained VT, (2) documented nonsustained VT (more than 5 consecutive ventricular ectopic depolarizations at a cycle length of less than 500 ms) that was associated with unmonitored outpatient syncope or that required cardiopulmonary resuscitation; or (3) syncope of obscure origin in patients in whom sustained unimorphic VT could be induced at electrophysiologic study. Sustained VT was defined as consecutive ventricular premature complexes at a cycle length of less than 500 ms lasting longer than 30
FIGURE 1. A decremental series of infusions produce concentrations that increase in a slow exponential pattern. Low therapeutic plasma Concentrations are produced by infusion rates (pg/ kg/min, each for 25 minutes) of 0.22, 0.11,0.06 and higher concentrations by rates of 0.17, 0.14, 0.08.
5 F a g
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 55
seconds, or producing hemodynamic compromise requiring termination of the tachyarrhythmia within 30 seconds. Each patient gave written, informed consent. After withdrawal of all antiarrhythmic medications (for at least 4 halflives), programmed electrical stimulation studies were done in a drug-free state. The standard quinidine sulfate infusion was then administered and blood pressure, pulse and clinical status were evaluated every 5 minutes throughout the infusion. Programmed electrical stimulation studies during the first series of infusions were not begun until the infusions had been under way for at least 40 minutes. Blood samples for quinidine assay were obtained just before and after electrophysiologic measurements. When VT induction was not suppressed with the first series of infusions, the higher dose infusion protocol was administered and electrophysiologic studies were repeated no sooner than 30 minutes after beginning the second series of infusions. Independent of response to intravenous quinidine, consenting patients subsequently received gradually increasing oral dosagesof quinidine. The dosage was adjusted to reproduce the serum levels that had been effective during the intravenous quinidine electrophysiologic study or to the maximal tolerated oral dose, whichever was lower. Electrophysiologic testing was then repeated on oral quinidine therapy. Electrophysiologic studies: The ventricular origin of the patient’s arrhythmia was confirmed by His bundle recordings. Programmed electrical stimulation techniques used in the study included introduction of single, double and, if necessary, triple extrastimuli (3 mA or twice diastolic threshold, whichever was greater, and a 2-ms pulse width) at ventricular drive cycle lengths of 600,500 and 400 ms with the electrode catheter at the apex of the right ventricle.lO Ventricular burst pacing (4 to 12 beats at cycle lengths of 300 to 240 ms) was subsequently used if VT was not induced by,the extrastimulus
8 t
30
93
60
90 MINUTES
120
150
94
INTRAVENOUS
QUINIDINE
FOR INDUCIBLE
VENTRICULAR
TACHYCARDIA
technique. During the drug-free study the endpoint of programmed electrical stimulation was induction of VT on at least 2 occasions with at least 1 of these being sustained (defined above). During subsequent quinidine studies, the ability to induce at least 5 consecutive ventricular ectopic depolarizations at a cycle length of less than 500 ms was considered to be drug failure. Concentration-dependent change in other electrophysiologic parameters were also evaluated. Surface electrocardiographic leads I, aVF and Vi were recorded at baseline and during quinidine treatments, and the PR, QRS, QT and RR intervals were measured. Rate-corrected QT (QTc) was calculated from the formula QTc = QT/a Ventricular effective refractory periods (VERPs) of the beats induced by the first and second extrastimuli (Ss, Ss) were also measured using the extrastimulus technique and conventional definitions. Concentration-dependent changes in rate and morphologic pattern of the induced VT were also assessed. Analytical: Samples were assayed, using an enzymatic immunoassay (EMIT@) method. The therapeutic range for quinidine has been reported to be 7 to 14 PMiliter. Little cross-reactivity to quinidine’s major metabolite has been found using this assay.11J2 Statistics: One-way analysis of variance was used to assess the significance of changes in electrophysiologic measurements during the quinidine infusions. Chi-square analysis was used for discrete data. The null hypothesis was rejected at the p <0.05 level. Continuous data are presented as mean f standard deviation. Results
Patients: Four of the 21 patients had 1 or more episodes of ventricular fibrillation, 9 had spontaneous sustained VT, 5 had nonsustained VT and recurrent outpatient syncopal episodes and 3 were evaluated for syncope of obscure origin. Six of the 21 patients had
required 1 or more transthoracic cardioversions for VT and 4 of the patients had required cardiopulmonary resuscitation out of hospital. Seventeen of the patients had ischemic heart disease with a global EF of 42 f 10%. Quinidine infusion: The first series of quinidine infusions achieved pseudo-steady-state concentrations of 12.6 f 11 PM/liter while the second series of infusions produced serum concentrations of 18 f 9 j&/liter. Mean observed plasma levels were somewhat in excess of the target concentration (7 and 14 PM/liter), and there was substantial interindividual variation. Figure 2 shows a reciprocal linear relation between the drugfree EF and the observed plasma concentrations at electrophysiologic testing (r = 0.8, p
of quinidine
sulfate (as assessed by its ability to
preclude induction of VT) increased with increasing serum concentrations (Fig. 3). Forty-three percent of the patients responded to intravenous quinidine, and little additional benefit was observed with serum concentrations
in excess of 18 PM/liter.
Induction
of VT
with a stimulation protocol which was less aggressive than that required at baseline occurred in 7 patients during the quinidine infusions. VT was easier to induce l
.. .
. .
l *o
.
.
r=oa1 slope
= -52
intercept
= 104
p <0.03
I
I
I
I
20
40
60
60
DRUG
FREE
EJECTION
FRACTION
FIGURE 2. A reciprocal relation between plasma concentrations duced and the drug-free ejection fraction.
pro-
I
I
I
I
3
10
20
30
CONCENTRATION
(FM/L)
FIGURE 3. Cumulative proportion of patients responding to quinidine with suppression of induced ventricular tachycardia relative to plasma concentration.
January 1, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY
TABLE I
lnducibility (I) or Noninducibility (NI) of Tachycardia with Intravenous and Oral Quinidine lnducibility with Intravenous Quinidine
lnducibility with oral quinidine Difference
not significant
NI
I
NI
I
1
I
4
11
= cl L
Volume
55
95
80
7 0 0
(x2). ji f
in 4 of the 7 patients at low concentrations, while high-dose quinidine enhanced VT induction in 3 patients. Of interest, 2 of 4 patients in whom VT was easier to induce after low-dose quinidine infusion responded to the larger dose infusion with suppression of inducibility. There was no simple relation between extent of QTc prolongation or VERP change and easeof inducibility. While inducibility of VT was occasionally enhanced by quinidine, paradoxical acceleration of VT rate was not seen. Figure 4 illustrates concentrationdependent changes in electrophysiologic measurements. The VERP of Ss was increased only to a small degree in these patients and there was little increase in this measurement at concentrations beyond 7 PM/liter. However, the VERP of the beat induced by Sa progressively increased throughout the concentration range tested and paralleled antiarrhythmic efficacy. The relation between quinidine concentration and change in QRS was linear (r = 0.62, p <0.05). A plateau in the concentration-dependent increase in QTc interval occurred at approximately 14 @f/liter. Although the cycle length of induced VT was slowed by quinidine (245 f 53 ms at baseline; 313 f 80 ms with low-dose quinidine, and 364 f 62 with high-dose quinidine) the extent of its slowing did not correlate with serum concentration. Response to intravenous quinidine as a predictor of response to oral treatment: Independent, of the response to intravenous quinidine, 17 consenting patients received gradually increasing oral dosages of quinidine and electrophysiologic studies were repeated. Table I illustrates the relation between inducibility during intravenous quinidine treatment to inducibility during its oral administration. Four of 5 patients who responded to intravenous quinidine did not respond during oral treatment. In 2 of these 4 patients the oral quinidine dose was limited by side effects and the effective concentrations achieved with intravenous quinidine could not be reached. However, VT continued to be inducible during oral therapy in 2 patients who had equal plasma levels during intravenous and oral treatments (Table II). In contrast, the absence of antiarrhythmic response to intravenous quinidine accurately predicted a lack of response to oral quinidine in 11 of 12 patients. We also assessed whether the antiarrhythmic response to intravenous quinidine would predict eventual response to any oral antiarrhythmic therapy (Tables II and III). Eight of 9 patients who responded to intravenous quinidine finally responded to oral antiarrhythmic medication (Table II). Nine of 12 patients who did not have an adequate antiarrhythmic response to in-
w
01
I
I
6-S
9-12
LlUUUL
A
QUINIDINE
B
-
i 13-18
6-S
(S3)
VERP
(S2)
I 20-30
>30
(uM/L)
UUUUI 3-5
S.E.
VERP
9-1213-18
20-30
>30
QUINIDINE (@4/L) FIGURE 4. Concentration-dependent change in electrophysiologic measurements. A, ventricular effective refractory period (VERP) of Sp and S3. 6, QRS duration. S.E. = standard error.
travenous quinidine medication.
did not respond to any oral
Discussion Acute electrophysiologic effects of intravenous quinidine have been previously investigated after stopping a rapid infusion of quinidine.6J3J4 However, concentration-response relations measured during the rapid distribution phase may not be reliable.15 Furthermore, in previous studies no attempt was made to systematically evaluate antiarrhythmic efficacy over the entire therapeutic range.6 The rapid infusion technique also increases the likelihood of side effects by producing early high peak levels. Symptomatic hypotension occurred frequently in the study of Swerdlow et a1,6but it was infrequently seen in the present study. Rapid evaluation of efficacy and pharmacologic actions of intravenous antiarrhythmic agents can be improved when infusions produce pseudo-steady-state serum
INTRAVENOUS
96
TABLE II
QUINtDINE
FOR INDUCIBLE
VENTRICULAR
Individual Patient Responses to Programmed Medications Given Intravenous Quinidine
Pt
Cont. *
PES
TACHYCARDIA
Electrical
Stimulation
Cont.
PES NI ;’ It It It I I
ft 2:
I
if 53
I
: NA
LA NA I
6
NA
I I I
6
21
7
NI
NA
and to
Discharge Medications
Oral Quinidine
2:
in Relation to Serum Concentration
NA
Meds Quinidine Quinidine Amiodarone Quinidine, propranolol Sotalol Quinidine, tocainide Sotalol Quinidine, mexiletine Amiodarone Amiodarone Disopyramide Amiodarone Surgery Amiodarone Amiodarone Amiodarone Mexiletine Propranolol Mexiletine, quinidine Quinidine, verapamil Propranolol
Cont.
l
Induc.
36.0 :7 1:3 Iii NA 0.8 1.1 2.1 0.7 39 0.8 7.5 NA 67
NI
Concentration; the units for each medication are: quinidine, PM/liter; amiodarone, pg/ml; propranolol, rig/ml; sotalol, pg/ml; tocainide pglml; disoovramide. u&f/liter: mexiletine. uo/ml. t Patients in’whom dkcordant r&l% were noted between intravenous and oral quinidine. I = inducible; I+ = inducible, but optimal treatment; NA = not available; NI = not inducible; PES = programmed electrical stimulation. l
concentrations which explore concentration response relations over the entire therapeutic range without side effects. The quinidine infusion devised for this study did achieve a range of therapeutic concentrations; however, other problems of acute drug testing limit its overall value. Antiarrhythmic effects seen during the acute drug infusion did not predict the response with oral quinidine treatment. Such discrepancies may relate to several factors, including: (1) side effects during chronic oral therapy, which limit dosage increments so that effective concentrations seen with the intravenous quinidine are not reached; (2) a difference in the relation between tissue levels and plasma levels when these are measured under pseudo-steady-state and steady-state conditions; and (3) the presence of’active metabolites, which may contribute to pharmacologic actions and side effects. The relative inefficacy of oral quinidine in this study was primarily a result of side effects that limited our ability to reproduce effective plasma concentrations during the infusion. Side effects seenwith oral quinidine treatment may reflect local gastrointestinal irritation. Cho@ evaluated the relation between plasma concentrations and ventricular tissue concentrations of quinidine during a constant infusion in dogs. In that study, there was little discrepancy between intravenous and myocardial concentrations after 90 minutes, suggesting that there is little difference in tissue levels under pseudo-steady-state and steady-state conditions. Two patients did not respond to oral quinidine, even though their plasma levels reproduced concentrations
that had been effective during intravenous quinidine therapy. Hypothetically, active metabolites of quinidine could accumulate during long-term oral therapy and as the metabolites are electrophysiologically active17Js they could alter antiarrhythmic efficacy. The infusions designed for this study allowed an evaluation of concentration-related changes in electrophysiologic parameters and their relation to antiarrhythmic activity. No single electrophysiologic change or combination thereof clearly discriminated between patients who would or would not respond to quinidine. However, we noted that change in the VERP of the beat induced by Se had a concentration-response relation that paralleled antiarrhythmic activity. Although parallel concentration-response curves do not indicate a cause and effect relation, such observations do suggest potentially fruitful areas of future research. Few other studies in man have systematically evaluated the concentration-response relations of electrophysiologic changes with quinidine. The present data, like previous data from human studies by Heissenbuttel and Bigger,lg show concentration-dependent changes in QRS duration, QTc interval. Unlike Heissenbuttel’s studyI we evaluated change in VERP (Ss) and observed that its increase occurs at low plasma concentrations (7 PM/liter) with little increase in this measurement at higher concentration. The QTc interval however progressively prolonged and only then plateaued at approximately 12 &f/liter, while QRS increases linearly with concentration. Varying concentration-response relations suggest that quinidine may mediate its elec-
January 1, 1985
TABLE III
lnducibility (I) or Noninducibility (NI) of Tachycardia with Quinidine Compared with Any Oral Antiarrhythmic Agent lnducibility with I.V. Quinidine NI
lnducibility with any oral antiarrhythmic
THE AMERICAN
a
3
I
1
9
p -Co.01 (x2).
trophysiologic actions at a number of different active sites. These results are in keeping with in vitro data20 that suggests that quinidine’s effects on various phases of the action potential are mediated at a number of active sites. The results obtained with intravenous quinidine in this study are similar to those seen with procainamide. As with procainamide,21922 high concentrations of quinidine achieved control of ventricular arrhythmias resistant to more conventional concentrations and acute toxicity at high concentrations was not a major problem.22y23Despite the limitation of use of acute intravenous quinidine testing to predictive response to oral quinidine, such testing may be of value in predicting eventual response to any oral antiarrhythmic agent. A similar predictive value 22123has been seen relating antiarrhythmic response to procainamide and response to any oral antiarrhythmic agent. Differences are also apparent between quinidine and procainamide. In this study, oral quinidine therapy was not well tolerated, unlike results reported with high-dose oral procainamide. This infusion was designed from pharmacokinetic parameters derived from administration of intravenous quinidine gluconate. The administered dosagewas then adjusted to reflect the relative proportion of the quinidine sulfate molecule, which is base (rather than salt). Theoretically, if the present quinidine infusion were modified so that quinidine gluconate was to be given, the serial intravenous rates would be increased by a factor of 1.34. In conclusion, an infusion protocol for the administration of quinidine sulfate was devised that permits a rapid and safe assessment of antiarrhythmic efficacy at both low and high therapeutic concentrations in man. Response to intravenous quinidine predicts the likeli-
OF CARDIOLOGY
Volume 55
97
hood of a response to any oral antiarrhythmic agent. However, this infusion has a major limitation relating to a discrepancy between tolerance to intravenous and oral medication. References
I
NI
JOURNAL
1. Rakov HL. Ventricular fibrillation in acute coronary thrombosis during intravenous ouinidine sulfate infusion: reoort .- of a fatal case. Ann Intern Med 1942;16:541-576. 2. Armburst CA, Levine SA. Paroxysmal ventricular tachycardia: a study of one hundred and seven cases. Circulation 1950;1:28-40. 3. Acierno LJ, Gabner R. Utility and limitations of intravenous quinidine in arrhythmias. Am Heart J 1957;41:733-741. 4. Woo E, Greenbiatt DJ. A reevaluation of intravenous quinidine. Am Heart J 1978;96:829-832. 5. Och SHR, Grube DJ, Greenbiatt DJ, Arndt R. Intravenous quinidine in congestive cardiomyopathy. Eur J Clin Pharmacol 1981;19:173-176. 6. Swerdlow CD, Yu JO, Jacobson E, Winkle RA, Mason JW. Safety and efficacy of intravenous quinidine. Am J Med 1983;75:36-42. 7. Uyeda CT, Hirschfield DS, Scheinman MM, Rowland M, Williamson BJ, Dzinrio BS. Disposition kinetics of quinldine. Clin Pharmacol Ther 1976; ,0.9”-?R a. Conrad KA, Molik BL, Chidsey CA. Pharmacokinetic studies of quinidine in patients with arrhythmias. Circulation 1977;55:1-7. 9. Guenter llW, Haiford NHG, Goates P, Upton RA, Riegeimans. Quinidine pharmacodiuretics in man: choice of disposition model and absolute availability. J Pharmacokinet Biopharm 1979;7:315-331. 10. Josephson ME, Seides SK. Clinical Cardiac Electrophysiology. Techniques and Interpretation. Philadelphia: Lea & Febiger, 1979:41. 11. Dextrose PG, Foreman J, Griffiths WC, Diamond I. Comparison of an enzyme immunologic and a high performance liquid chromatographic method for quantitation of quinidine in serum. Clin Toxic01 1981;18:291-297. 12. Drayer DE, Lorenzo B, Riedenberg MM. Liquid chromatography and fluorescence spectroscopy compared to a homogeneous enzyme immunoassay technique for determining quinidine in serum. Clin Chem 1981;27:308310. 13. Mason JW, Winkle RA, Rider AK, Stlnson EB, Harrison DC. The electrophysiologic effects of quinidine in the transplanted human heart. J Clin Invest 1977;39:487-489. arrhythmia induction in the se14. Mason JW, Winkle RA. Electrode-catheter lection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachvcardia. Circulation 1978:58:971-985. 15. Melmon KL,* Morreiii HF. Clinical Pharmacology. New York: Macmillan, 1978:71-108. 16. Chou YW. Quantitative correlation of plasma and myocardial quinidine concentration with biochemical and electrocardiographic changes. Am Heart J 1973;85:648-654. 17. Drayer DE, Lowenthal DT, Restivo KM, Schwartz A, Cook CK, Reidenberg MM. Steady state serum levels of quinidine and active metabolites in cardiac patients with varying degrees of renal function. Clin Pharmacol Ther 1978;24:31-39. 16. Holford NHG, Coates PE, Guentert TW, Riegetman S, Shelner LB. The effect of quinidine and its metabolltes on the electrocardiogram and systolic time intervals: concentration-effect relationships. Br J Clin Pharmacol 1981;11:187-195. Heissenbuttei RH, Bigger JT. The effect of oral quinidine on intraventricular 19. conduction in man: correlation of plasma quinidine with changes in QRS duration. Am Heart J 1970;80:453-462. 20. Nattel S, Bailey JC. Time course of the electrophysiological effective quinidine canine purkinje fibers: concentration dependence and comparison with lidocaine and disopyramide. J Pharmacol Exp Ther 1983;225:176180. 21. Engel TR, Meister SG, Luck JC. Modification of ventricular tachycardia by procainamide in patients with coronary artery disease. Am J Cardiol 1980;46:1033-1038. 22. Greenspan AM, Horowitz LN, Speilman SR, Josephson ME. Large dose procainamide therapy for ventricular tachyarrhythmia. Am J Cardiol 1980:46:453-462. 23. Waxman HL, Buxton AE, Sadowski LM, Josephson ME. The response to procainamide during electrophysioiogic study for sustained ventricular tachyarrhythmias predicts the response to other medications. Circulation 1983;67:30-36. .“..,”
“-.