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Effects of nicardipine and labetalol on the acute hemodynamic response to electroconvulsive therapy
Original Contribution Effects of Nicardipine and Labetalol on the Acute Hemodynamic Response to Electroconvulsive Therapy Michail N. Avramov, MD, PhD,* Louis A. Stool, MD, Paul F. White, PhD, MD,‡ Mustafa M. Husain, MD,§ Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, TX USA
*Assistant Instructor in Anesthesiology †Assistant Professor of Anesthesiology ‡Professor and Holder of the Margaret Milam McDermott Distinguished Chair of Anesthesiology §Assistant Professor of Psychiatry Address correspondence and reprint requests to Dr. White at the Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5161 Harry Hines Blvd., CS2.202, Dallas, TX 75235-9068, USA. Received for publication July 10, 1997; revised manuscript accepted for publication March 24, 1998.
Study Objective: To examine the acute hemodynamic effects of intravenous (IV) nicardipine and its ability to attenuate the hyperdynamic response to electroconvulsive therapy (ECT), when used alone or in combination with labetalol. Design: Prospective, randomized, double-blind, positive-control, clinical investigation. Setting: University hospital. Patients: 36 patients undergoing ECT. Interventions: In a series of three studies, the hemodynamic effects of nicardipine were assessed prior to, during, and after ECT. After administration of glycopyrrolate 0.1 mg IV, placebo (saline) or nicardipine was administered by rapid infusion (1, 2.5, 5, 10, and 15 mg) or bolus injection (1.25, 2.5, and 5 mg), either alone or in combination with labetalol 10 mg IV. Unconsciousness was induced with methohexital 1 mg/kg IV; succinylcholine 1.2 to 1.5 mg/kg IV was administered for muscle relaxation. A bilateral electrical stimulus was delivered and the durations of motor and electroencephalographic (EEG) seizures were noted. Measurements and Main Results: Mean arterial pressure (MAP) and heart rate (HR) values were recorded at 1- to 5-minute intervals throughout the study period. When administered as a rapid infusion, nicardipine 5 mg IV produced a significant decrease in MAP; however, nicardipine dosages of 10 to 15 mg IV did not produce a significantly greater decrease in MAP than 5 mg. Bolus administration of nicardipine 1.25 to 5 mg produced a rapid onset of its hemodynamic effects without exacerbating the cardiovascular depressant effects of methohexital. However, the decrease in MAP was accompanied by an increase in HR after administration of the 5 mg IV bolus dose. The acute hyperdynamic response to ECT was most effectively controlled by nicardipine 2.5 to 5 mg IV bolus, in combination with labetalol 10 mg IV. Seizure duration was not significantly altered by the use of nicardipine as part of the anesthetic regimen for ECT. Conclusion: Nicardipine 2.5 mg IV bolus in combination with labetalol 10 mg IV was the most effective pretreatment regimen for preventing the acute hyperdynamic response to ECT. However, this combination produced a 20% decrease in MAP immediately prior to ECT and a lower MAP at the time of discharge. © 1998 by Elsevier Science Inc. Keywords: Calcium antagonist; nicardipine; calcium-channel blockers; electroconvulsive therapy (ECT); hypertension; labetalol; seizures.
Journal of Clinical Anesthesia 10:394 – 400, 1998 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/98/$19.00 PII S0952-8180(98)00052-X
Nicardipine, Labetalol, and ECT: Avramov et al.
Introduction Electroconvulsive therapy (ECT) is frequently associated with significant hypertension (systolic blood pressure increases of 30 –70 mmHg, diastolic blood pressure increases of 10 –50 mmHg) and tachycardia [HR . 130 beats per minute (bpm)].1 A cardiovascular mortality of 0.03% has been reported with ECT.2,3 In patients with preexisting cardiovascular disease, the acute hyperdynamic response to ECT may increase the risks of myocardial ischemia. A wide variety of antihypertensive drugs, including trimethaphan,4 nitroprusside,5 nitroglycerin,6 clonidine,7 propranolol,7,8 esmolol,9 –12 and labetalol,11,12 have been administered in an attempt to attenuate the acute circulatory response to ECT. However, the ideal pretreatment regimen to reliably attenuate the acute hemodynamic response following ECT without producing preinduction hypotension has not been identified. Although the calcium-channel blocker nifedipine was evaluated during ECT,13 it is not available for parenteral administration. Nicardipine (Cardenet), is a dihydropyridine calcium antagonist which was recently introduced into clinical practice for use by intravenous (IV) infusion. To date, the efficacy and safety of nicardipine for ECT have not been established. Furthermore, to our knowledge, the acute hemodynamic effects of nicardipine when administered as an IV bolus versus infusion have not been studied previously. In addition, the acute hemodynamic effects of nicardipine when administered prior to an IV induction drug has not been investigated. Finally, determining the effect of different dosages of nicardipine on the ECTinduced seizure duration is important because the therapeutic efficacy of ECT depends on the induction of an adequate seizure,14 and some calcium antagonists have been found to possess anticonvulsant properties.15 Therefore, a prospective, randomized, positive-control, clinical investigation was designed to examine the acute cardiovascular effects of nicardipine as well as its ability to attenuate the hyperdynamic response to ECT. In a series of three studies, the hemodynamic effects of nicardipine were assessed prior to, during, and after ECT. Nicardipine was administered as a rapid infusion (1, 2.5, 5, 10, and 15 mg) or bolus injection (1.25, 2.5, and 5 mg), either alone or in combination with labetalol 10 mg as part of a standard anesthetic regimen for ECT.
Materials and Methods After University of Texas Southwestern Medical Center at Dallas Institutional Review Board approval, informed consent was obtained from 36 patients undergoing ECT treatments for severe chronic depression. Patients with clinically significant cardiovascular, respiratory, or hepatic disease; with a history of prior adverse reactions to any of the study medications; or receiving concurrent antihypertensive medications were excluded from the study. Patients were prospectively enrolled to receive different antihypertensive pretreatment regimens including labetalol, nicardipine, or a combination of the two drugs. This
prospective clinical investigation consisted of three sequential study protocols. 1. Rapid infusion: Nine patients received six randomly assigned (via random numbers table) treatments over a period of 3 to 6 weeks, consisting of a combination of labetalol, 10 mg, with a placebo (100 ml of saline) or nicardipine 1, 2.5, 5, 10, or 15 mg in 100 ml of saline. Labetalol was administered as a bolus injection and nicardipine (or saline) as an infusion in 100 ml saline over 5 to 7 minutes, immediately followed by induction of anesthesia with methohexital. 2. Bolus administration: Fifteen patients received four treatments in random order (random numbers table) consisting of labetalol 10 mg IV bolus in combination with placebo (saline) or nicardipine 1.25, 2.5, or 5 mg administered as a 5 ml bolus injection over 10 to 15 seconds four minutes prior to induction of anesthesia with methohexital. 3. Interaction between nicardipine and labetalol: Twelve patients received four consecutive treatments in random order (random numbers table) consisting of nicardipine 2.5 or 5 mg IV bolus, with or without labetalol 10 mg IV administered 4 minutes prior to induction of anesthesia with methohexital. Noninvasive mean arterial pressure (MAP), electrocardiogram (ECG), heart rate (HR), and hemoglobin oxygen saturation (SpO2) values were measured at one-minute intervals during the study treatment period and at fiveminute intervals during the recovery. Baseline hemodynamic values were averaged from two to three readings at 1-minute intervals prior to the administration of any medications. Glycopyrrolate 0.1 mg IV was followed by labetalol and/or nicardipine according to one of the above three study protocols. Unconsciousness was induced with methohexital 1 mg/kg IV administered as a bolus injection over 10 to 15 seconds. After loss of responsiveness to verbal commands, a BP cuff applied to the lower leg was inflated to isolate the circulation to the foot so as to assess the duration of the motor seizure. Succinylcholine 1.2 to 1.5 mg/kg IV was then administered and ventilation was controlled using a face mask and 100% oxygen. The succinylcholine dose requirement was established for each patient during prestudy treatment sessions, and the same dose was used for all study treatments. The prestimulation MAP and HR values were measured two minutes after induction of anesthesia, and the incremental changes in MAP and HR values from baseline were calculated. A suprathreshold electrical stimulus was delivered two to three minutes following induction of anesthesia via bifrontotemporal electrodes using a MECTA-SR1™ machine (MECTA Corp., Portland, OR). The seizure threshold of each patient was determined during ECT treatment sessions prior to enrollment in the study, and the stimulus variables were maintained constant for the duration of each study. The electroencephalogram (EEG) was recorded continuously from two frontal electrodes. The times from the ECT stimulus to the cessation of the J. Clin. Anesth., vol. 10, August 1998
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Table 1 Demographic Characteristics of Patients in the Three Nicardipine Study Protocols
Number (n) ASA physical status I, II, III (n) Age (yrs)
Protocol 1: Rapid Infusion
Protocol 2: Bolus Administration
Protocol 3: Interaction study
9 0/5/4 67 (45–81)
15 1/8/6 67 (44–86)
12 1/7/4 73 (61–83)
Note: Data are numbers, or means and ranges in parentheses. No significant difference was seen among the three groups.
clonic-tonic motor activity in the “isolated” foot (i.e., motor seizure duration) and to postictal EEG suppression (i.e., EEG seizure duration), determined by a blinded observer (MMH), were noted. The peak MAP and HR values during the five-minute period immediately following the seizure, as well as the incremental changes in MAP (DMAP) and HR (DHR) values (i.e., the increment from prestimulus-to-peak values) were noted. The time from delivering the electrical stimulus until eye opening, ability to follow simple commands, and “fitness for discharge” from the recovery room (i.e., alert, oriented, able to take oral fluids without nausea, and ambulate without assistance) were recorded by a nurse who was blinded to the medications administered during the procedure. Data were analyzed using repeated measures analysis of variance (Friedman’s test) followed by multiple Wilcoxon matched-pairs tests, with Bonferroni’s correction and oneway analysis of variance (ANOVA) followed by post hoc Tukey’s pairwise comparisons where appropriate. P-values less than 0.05 were considered statistically significant. Data
are presented as mean values (6SD) or as median values (and ranges).
Results A total of 36 patients participated in this series of studies. Demographic characteristics were similar in the three study groups (Table 1). There were no significant differences in the durations of seizure activity between the different pretreatment regimens used in the three study protocols (Table 2). These data show that the use of nicardipine does not result in a shorter duration of either motor or EEG seizure activity. Similarly, there were no significant differences in the recovery times among the different pretreatment groups (Table 2). In the first study (Protocol 1), a rapid infusion of nicardipine 5 to 15 mg produced a 19% to 24% decrease in MAP during the prestimulation period (Figure 1). Compared with nicardipine 5 mg IV, increasing the nicardipine dosage to 10 mg or 15 mg did not lead to a
Table 2 Seizure Durations and Recovery Times for Patients in the Three Nicardipine Study Protocols Duration of seizures (s)
Protocol 1: Rapid infusion Labetalol 10 mg Nicardipine 1 mg 1 Labetalol 10 mg Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 5 mg 1 Labetalol 10 mg Nicardipine 10 mg 1 Labetalol 10 mg Nicardipine 15 mg 1 Labetalol 10 mg Protocol 2: Bolus Administration Labetalol 10 mg Nicardipine 1.25 mg 1 Labetalol 10 mg Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 5 mg 1 Labetalol 10 mg Protocol 3: Interaction Study Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 2.5 mg alone Nicardipine 5 mg 1 Labetalol 10 mg Nicardipine 5 mg alone Note: Data are means 6 SD. No significant difference was noted. EEG 5 electroencephalogram. 396
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Recovery times (min)
Motor
EEG
Opens eyes
Obeys commands
Discharge
28 6 8 45 6 15 36 6 19 28 6 10 31 6 10 28 6 10
44 6 11 68 6 29 58 6 22 43 6 16 46 6 9 42 6 12
16 6 5 19 6 4 16 6 7 14 6 4 14 6 7 14 6 2
18 6 4 20 6 4 21 6 7 16 6 3 16 6 6 17 6 2
32 6 4 33 6 4 34 6 8 29 6 4 30 6 5 30 6 4
47 6 16 43 6 22 42 6 16 48 6 21
78 6 30 61 6 19 59 6 20 71 6 34
18 6 4 17 6 3 16 6 4 17 6 5
20 6 4 18 6 4 20 6 5 20 6 5
33 6 4 32 6 5 35 6 3 37 6 7
35 6 16 33 6 11 35 6 17 32 6 14
61 6 40 50 6 17 53 6 22 52 6 19
16 6 5 19 6 5 14 6 6 16 6 5
21 6 7 25 6 9 17 6 5 18 6 4
33 6 7 39 6 5 29 6 4 34 6 6
Nicardipine, Labetalol, and ECT: Avramov et al.
Figure 1. A. Mean arterial pressure (MAP) values and B. heart rate (HR) values following labetalol 10 mg and a 100 ml infusion containing saline alone (L 10), or nicardipine 1 mg (N 1), 2.5 mg (N 2.5), 5 mg (N 5), 10 mg (N 10), and 15 mg (N 15) in saline. Mean and standard deviation data are presented for the baseline (open circles), prestimulation period (closed circles), and the peak values following induction of seizure (closed diamonds). *Significant differences versus baseline values. #Significant differences versus labetalol 10 mg alone (control group) (p , 0.05).
significantly greater decrease in MAP. The transient hypertensive response after ECT was effectively blocked with 2.5 mg and higher doses of nicardipine. Conversely, labetalol 10 mg IV, alone or in combination with nicardipine 1 mg IV, was associated with significant increases in MAP values following ECT (p , 0.05) (Figure 1). However, there were no significant differences among the six
treatment groups with respect to the magnitude of the incremental changes in MAP (16% to 27%) and HR (4% to 14%) values following ECT. When administered as a bolus dose over 10 to 15 seconds (Protocol 2), nicardipine 1.25 to 5 mg produced a significant (20% to 30%) decrease from the baseline MAP values within 1 to 3 minutes following the injection
Figure 2. A. Mean arterial pressure (MAP) values and B. heart rate (HR) values following bolus administration of labetalol 10 mg (L 10) alone (circles), and in combination with nicardipine 1.25 mg (N 1.25; diamonds), 2.5 mg (N 2.5; triangles), and 5 mg (N 5; squares). Mean and standard deviation data are presented for the baseline (BL), prestimulation period (Pre-stim), and the peak values following induction of seizure (Peak MAP or HR). *Significant differences versus baseline values (p , 0.05). J. Clin. Anesth., vol. 10, August 1998
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Figure 3. Heart rate (HR) following bolus administration of nicardipine 2.5 mg (triangles) or 5 mg (squares) alone (open symbols), or in combination with labetalol 10 mg (closed symbols). Mean and standard deviation data are presented for the baseline (BL), prestimulation period (Pre-stim), and the peak values following induction of seizure (Peak HR). *Significant differences versus baseline values (p , 0.05).
(p , 0.01) (Figure 2). In the nicardipine 1.25 and 5 mg group, HR increased by 10% above the baseline value (p , 0.01) (Figure 2). The peak MAP values after ECT-induced seizures were decreased by nicardipine 2.5 to 5 mg in combination with labetalol 10 mg IV. In contrast, the peak post-ECT increase in MAP was greater than baseline values following labetalol 10 mg IV, alone or in combination with nicardipine 1.25 mg IV (p , 0.05)
(Figure 2). The peak HR values following ECT were significantly increased from baseline values in all four treatment groups. However, the incremental changes in prestimulus MAP and HR to peak MAP and HR values following the seizure [i.e., DMAP (23–37 mmHg) and DHR (2–18 bpm)] were similar among the four treatment groups. When nicardipine 2.5 mg or 5 mg IV were administered alone (Protocol 3), adequate control of MAP after ECT was achieved. However, there was a significant increase in HR prior to, during, and after the treatment when the calcium-channel blocker was administered without labetalol (p , 0.05) (Figure 3). Pretreatment with nicardipine alone or in combination with labetalol produced similar cardiovascular depressant effects after methohexital 1 mg/kg IV, compared with labetalol alone (DMAP: 25 to 242 mmHg and 29 to 233 mmHg, respectively). The MAP values following induction of anesthesia were not significantly different from the immediate preinduction values in any of the three study protocols (Table 3). In the two nicardipine bolus protocols (Protocols 2 and 3), comparable increases in MAP values were noted following ECT stimulation (21–37 mmHg). Similarly, the incremental increase in HR after ECT (2–18 bpm) did not differ significantly among the different nicardipine-labetalol treatment regimens. Following nicardipine 2.5 mg IV bolus alone or nicardipine 1.25 mg IV in combination with labetalol 10 mg IV, patients remained hemodynamically stable without significant changes from their baseline MAP and HR values during the recovery period and at the time of discharge. However, a significant hypotensive effect (MAP values of 87 6 15 to 95 6 7 mmHg) was noted during the recovery period following pretreatment with nicardipine 5 mg IV boluses in combination with labetalol 10 mg IV (Table 3). Furthermore, the two groups of patients who received
Table 3 Hemodynamic Changes Prior to, During, and after Electroconvulsive Therapy (ECT) with intravenous Bolus Administration of Nicardipine (N) and Labetalol (L), Alone and in Combination Protocol 2: Bolus Administration
MAP (mmHg) at: Baseline Preinduction Prestimulus Peak MAP Discharge HR (bpm) at: Baseline Preinduction Prestimulus Peak MAP Discharge
Protocol 3: Interaction Study
L10
N1.25 1 L10
N2.5 1 L10
N5 1 L10
N2.5 1 L10
N2.5 alone
N5 1 L10
N5 alone
107 6 19 102 6 24* 102 6 17 129 6 17* 98 6 21
104 6 12 83 6 11* 86 6 11* 120 6 25* 91 6 12
105 6 17 80 6 13* 90 6 14* 106 6 14 93 6 13*
109 6 14 78 6 9* 81 6 11* 111 6 21 92 6 21*
112 6 17 84 6 9* 90 6 12* 121 6 21 103 6 15
107 6 9 89 6 9* 98 6 16 131 6 14* 100 6 11
115 6 18 81 6 9* 79 6 12* 108 6 18 89 6 15*
108 6 12 83 6 8* 85 6 15* 117 6 17 96 6 12*
78 6 14 76 6 10 86 6 13 95 6 17* 76 6 10
76 6 9 76 6 10 86 6 15* 98 6 16* 79 6 9
78 6 13 79 6 10 86 6 13 95 6 23* 80 6 11
77 6 9 86 6 13* 89 6 16* 106 6 22* 80 6 11
75 6 14 77 6 11 81 6 15 94 6 20* 82 6 11
79 6 13 92 6 17* 104 6 20* 120 6 23* 90 6 7*
82 6 12 82 6 16 82 6 18 99 6 21 78 6 8
82 6 14 88 6 16 99 6 13* 113 6 17* 92 6 13
Data are mean values 6 SD MAP 5 mean arterial pressure, L10 5 Labetalol 10 mg; N1.25 5 Nicardipine 1.25 mg; N2.5 5 Nicardipine 2.5 mg; N5 5 Nicardipine 5 mg, HR 5 heart rate. *p , 0.05 vs. baseline values. 398
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Nicardipine, Labetalol, and ECT: Avramov et al.
nicardipine alone remained tachycardic (HR . 90 bpm) at the time of discharge. However, none of the patients receiving nicardipine by either bolus injection or rapid infusion required any pharmacologic treatment for persistent hypotension in the recovery room, nor did they experience a delayed discharge.
Discussion Pretreatment with IV nicardipine significantly decreased the peak MAP values following ECT without decreasing the duration of seizure activity. Consistent with the recent findings of Song et al.,16 bolus administration of nicardipine was found to produce a rapid onset of its BP lowering effect (1 to 3 min). When nicardipine 2.5 to 5 mg was combined with labetalol 10 mg IV, it effectively protected against ECT-induced hypertension. Use of nicardipine alone resulted in an increase in HR both prior to and immediately after ECT treatment. The BP lowering effect of nicardipine persisted into the early recovery period when nicardipine doses of 2.5 mg and higher were used. However, none of the patients required treatment of hypotension in the post-ECT period, and discharge times were similar in all treatment groups. Nicardipine, which is a dihydropyridine calcium antagonist, produces selective coronary and peripheral vasodilatation.17,18 Effective control of intraoperative hypertension has been previously demonstrated during both cardiac19 and non-cardiac20 surgery. IV bolus doses of nicardipine 0.5 to 5 mg21,22 produced 17% to 35% decreases in systemic BP. Although higher dosages of nicardipine were used in the present investigation, similar reductions in MAP were observed prior to and following induction of anesthesia with methohexital. When administered by an infusion over five to seven minutes, increasing the nicardipine dose from 5 mg to 15 mg did not further decrease MAP values (Figure 1). Even though a rapid infusion of high doses of nicardipine did not produce clinically significant cardiovascular depression, the use of nicardipine doses in excess of 5 mg did not provide additional protection against ECT-induced hypertension. Although the hypertensive response to ECT was effectively blocked with nicardipine dosages of 2.5 mg and higher, HR was significantly increased both prior to and following ECT treatment when larger doses of nicardipine (5–15 mg) were used, suggesting activation of the baroreflex mechanism. Moreover, when used without labetalol, nicardipine actually accentuated the HR response to ECT. Thus, the beta-blocking action provided by labetalol 10 mg in combination with the lower dosages of nicardipine provided the most effective control of the acute hemodynamic responses to ECT. The cardiovascular responses during ECT also can be influenced by the anticholinergic (e.g., glycopyrrolate), which was administered to decrease oral secretions and to prevent the transient bradycardia that results from the brief, intense parasympathetic discharge that accompanies the electrical stimulus. In order to minimize the influence of glycopyrrolate on the cardiovascular response, a stan-
dardized dose of 0.1 mg IV was administered in all three studies.23 Although it is not a universal practice, use of an anticholinergic is included in the American Psychiatric Association Task Force Report on “standard” clinical anesthetic practice guidelines for ECT.24 Pretreatment with nicardipine did not adversely affect the duration of ECT-induced seizure activity. Dihydropyridine antagonists modulate the action of a subtype of voltage-dependent calcium channels, the L-channel, which is a high-threshold slowly inactivating current. Although anticonvulsant properties of dihydropyridine calcium antagonists have been demonstrated in animal models of electrocortical shock-induced seizure,25,26 nicardipine was a notable exception in that it was devoid of anticonvulsant properties.25–27 Our findings in the ECT population are in agreement with the previous observations in animals. Because nicardipine is a partially charged molecule, its failure to decrease ECT-evoked seizure activity may be related to its limited ability to penetrate the blood-brain barrier in humans. These clinical findings suggest that, inasmuch as seizure duration is one of the important determinants of the quality of the ECT treatment,14 the use of nicardipine should not adversely affect the efficacy of ECT in patients with depressive disorders. The ideal antihypertensive pretreatment for ECT would involve the use of only one medication to blunt the ECT-induced hyperdynamic response, without producing hypotension during the pretreatment and posttreatment periods and without decreasing the duration of seizure activity. Although it may appear that nicardipine attenuated the hypertensive response induced by ECT, its use was accompanied by a significant decrease in MAP immediately prior to the ECT treatment. The present study suggests that the use of nicardipine decreases the hyperdynamic response to ECT by lowering the pre-ECT MAP values. Thus, the incremental change in MAP values in response to the ECT stimulus was unchanged by nicardipine pretreatment. Furthermore, consistent with the effects of other calcium-channel antagonists, the hypotensive effect of nicardipine was accompanied by tachycardia. Therefore, nicardipine must be administered in combination with labetalol or esmolol to minimize the nicardipineinduced increase in HR. In conclusion, nicardipine 2.5 mg IV bolus in combination with a beta-blocker (labetalol 10 mg IV), administered four minutes prior to induction of anesthesia with methohexital, was the most effective combination in preventing the acute hypertensive responses immediately after ECT without adversely affecting the duration of seizure activity. However, as with other antihypertensive pretreatment regimens for ECT, nicardipine was unable to decrease the magnitude of the incremental rise in MAP values in response to the ECT stimulus, even when administered in combination with labetalol.
Acknowledgments The authors would like to acknowledge John A. Thomas, B.A., Steven J. Luke, M.D., Carl E. Adkins, M.D., and the nursing personnel at the Psychiatry Unit of Zale-Lipshy University Hospital, Dallas, TX. J. Clin. Anesth., vol. 10, August 1998
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References 1. Brown ML, Huston PE, Heinz HM, Brown GW: Cardiovascular changes associated with electroconvulsive therapy in the man. Arch Neurol 1953;69:601– 8. 2. Fink M: Convulsive therapy—theory and practice. New York: Raven Press, 1979:P42. 3. Selvin BL: Electroconvulsive therapy—1987. Anesthesiology 1987; 67:367– 85. 4. Tewfik GI, Wells BG: The use of Arfonad for the alleviation of cardiovascular stress following electroconvulsive therapy. J Ment Sci 1975;10:636 – 44. 5. Ciraulo D, Lind L, Salzman C, Pilon R, Elkins R: Sodium nitroprusside treatment of ECT-induced blood pressure elevations. Am J Psychiatry 1978;135:1105– 6. 6. Lee JT, Erbguth PH, Stevens WC, Sack RL: Modification of electroconvulsive therapy induced hypertension with nitroglycerin ointment. Anesthesiology 1985;62:793– 6. 7. Liu WS, Petty WC, Jeppsen A, Wade EJ, Pace NL: Attenuation of hemodynamic and hormonal responses to ECT with propranolol, xylocaine, sodium nitroprusside or clonidine. Anesth Analg 1984; 63:244. 8. London SW, Glass DD: Prevention of electroconvulsive therapyinduced dysrhythmias with atropine and propranolol. Anesthesiology 1985;62:819 –22. 9. Kovac AL, Goto H, Pardo MP, Arakawa K: Comparison of two esmolol bolus doses on the haemodynamic response and seizure duration during electroconvulsive therapy. Can J Anaesth 1991; 38:204 –9. 10. Howie MB, Black HA, Zvara D, McSweeney TD, Martin DJ, Coffman JA: Esmolol reduces autonomic hypersensitivity and length of seizures induced by electroconvulsive therapy. Anesth Analg 1990;71:384 – 8. 11. Weinger MB, Partridge BL, Hauger R, Mirow A: Prevention of the cardiovascular and neuroendocrine response to electroconvulsive therapy: I. Effectiveness of pretreatment regimens on hemodynamics. Anesth Analg 1991;73:556 – 62. 12. Castelli I, Steiner LA, Kaufman MA, et al: Comparative effects of esmolol and labetalol to attenuate hyperdynamic states after electroconvulsive therapy. Anesth Analg 1995;80:557– 61. 13. Wells DG, Davies GG, Rosewarne F: Attenuation of electroconvulsive therapy induced hypertension with sublingual nifedipine. Anaesth Intensive Care 1989;17:31–3. 14. Maletzki BM: Seizure duration and clinical effect in electroconvulsive therapy. Compr Psychiatry 1987;19:541–50.
400
J. Clin. Anesth., vol. 10, August 1998
15. Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW: Selective central nervous system calcium channel blockers—a new class of anticonvulsants. Mayo Clin Proc 1986;61:239 – 47. 16. Song D, Singh H, White PF, Gadhiali M, Griffin JD, Klein KW: Optimal dose of nicardipine for maintenance of hemodynamic stability after tracheal intubation and skin incision. Anesth Analg 1997;85:1247–51. 17. Lambert CR, Hill JA, Nichols WW, Feldman RL, Pepine CJ: Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652– 6. 18. IV Nicardipine Study Group. Efficacy and safety of intravenous nicardipine in the control of postoperative hypertension. Chest 1991;99:393– 8. 19. van Wezel HB, Koolen JJ, Visser CA, et al: Antihypertensive and anti-ischemic effects of nicardipine and nitroprusside in patients undergoing coronary artery bypass grafting. Am J Cardiol 1989; 64:22H–27H. 20. Goto F, Kato S, Sudo I: Treatment of intraoperative hypertension with enflurane, nicardipine, or human atrial natriuretic peptide: haemodynamic and renal effects. Can J Anaesth 1992;39:932–7. 21. Kishi Y, Okumura F, Furuya H: Hemodynamic effects of nicardipine hydrochloride. Studies during its use to control acute hypertension in anaesthetized patients. Br J Anaesth 1984;56: 1003–7. 22. Begon C, Dartayet B, Edouard A, David D, Samii K: Intravenous nicardipine for treatment of intraoperative hypertension during abdominal surgery. J Cardiothorac Anesth 1989;3:707–11. 23. Mirakhur RK: Anticholinergic drugs. Br J Anaesth 1979;51:671–9. 24. American Psychiatric Association Task Force Report: The practice of Electroconvulsive therapy. Recommendations for treatment, training and privileging. Washington, DC: American Psychiatric Association, 1990. 25. Czuczwar SJ, Gasior M, Janusz W, Kleinrok Z: Influence of flunarizine, nicardipine and nimodipine on the anticonvulsant activity of different antiepileptic drugs in mice. Neuropharmacology 1992;31:1179 – 83. 26. Meyer FB, Anderson RE, Sundt TM Jr: Anticonvulsant effects of dihydropyridine Ca21 antagonists in electrocortical shock seizures. Epilepsia 1990;31:68 –74. 27. Palmer GC, Stagnitto ML, Ray RK, Knowles MA, Harvey R, Garske GE: Anticonvulsant properties of calcium channel blockers in mice: N-methyl-D-, L-aspartate-and Bay K 8644-induced convulsions are potently blocked by the dihydropyridines. Epilepsia 1993;34:372– 80.
*Assistant Instructor in Anesthesiology †Assistant Professor of Anesthesiology ‡Professor and Holder of the Margaret Milam McDermott Distinguished Chair of Anesthesiology §Assistant Professor of Psychiatry Address correspondence and reprint requests to Dr. White at the Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5161 Harry Hines Blvd., CS2.202, Dallas, TX 75235-9068, USA. Received for publication July 10, 1997; revised manuscript accepted for publication March 24, 1998.
Study Objective: To examine the acute hemodynamic effects of intravenous (IV) nicardipine and its ability to attenuate the hyperdynamic response to electroconvulsive therapy (ECT), when used alone or in combination with labetalol. Design: Prospective, randomized, double-blind, positive-control, clinical investigation. Setting: University hospital. Patients: 36 patients undergoing ECT. Interventions: In a series of three studies, the hemodynamic effects of nicardipine were assessed prior to, during, and after ECT. After administration of glycopyrrolate 0.1 mg IV, placebo (saline) or nicardipine was administered by rapid infusion (1, 2.5, 5, 10, and 15 mg) or bolus injection (1.25, 2.5, and 5 mg), either alone or in combination with labetalol 10 mg IV. Unconsciousness was induced with methohexital 1 mg/kg IV; succinylcholine 1.2 to 1.5 mg/kg IV was administered for muscle relaxation. A bilateral electrical stimulus was delivered and the durations of motor and electroencephalographic (EEG) seizures were noted. Measurements and Main Results: Mean arterial pressure (MAP) and heart rate (HR) values were recorded at 1- to 5-minute intervals throughout the study period. When administered as a rapid infusion, nicardipine 5 mg IV produced a significant decrease in MAP; however, nicardipine dosages of 10 to 15 mg IV did not produce a significantly greater decrease in MAP than 5 mg. Bolus administration of nicardipine 1.25 to 5 mg produced a rapid onset of its hemodynamic effects without exacerbating the cardiovascular depressant effects of methohexital. However, the decrease in MAP was accompanied by an increase in HR after administration of the 5 mg IV bolus dose. The acute hyperdynamic response to ECT was most effectively controlled by nicardipine 2.5 to 5 mg IV bolus, in combination with labetalol 10 mg IV. Seizure duration was not significantly altered by the use of nicardipine as part of the anesthetic regimen for ECT. Conclusion: Nicardipine 2.5 mg IV bolus in combination with labetalol 10 mg IV was the most effective pretreatment regimen for preventing the acute hyperdynamic response to ECT. However, this combination produced a 20% decrease in MAP immediately prior to ECT and a lower MAP at the time of discharge. © 1998 by Elsevier Science Inc. Keywords: Calcium antagonist; nicardipine; calcium-channel blockers; electroconvulsive therapy (ECT); hypertension; labetalol; seizures.
Journal of Clinical Anesthesia 10:394 – 400, 1998 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/98/$19.00 PII S0952-8180(98)00052-X
Nicardipine, Labetalol, and ECT: Avramov et al.
Introduction Electroconvulsive therapy (ECT) is frequently associated with significant hypertension (systolic blood pressure increases of 30 –70 mmHg, diastolic blood pressure increases of 10 –50 mmHg) and tachycardia [HR . 130 beats per minute (bpm)].1 A cardiovascular mortality of 0.03% has been reported with ECT.2,3 In patients with preexisting cardiovascular disease, the acute hyperdynamic response to ECT may increase the risks of myocardial ischemia. A wide variety of antihypertensive drugs, including trimethaphan,4 nitroprusside,5 nitroglycerin,6 clonidine,7 propranolol,7,8 esmolol,9 –12 and labetalol,11,12 have been administered in an attempt to attenuate the acute circulatory response to ECT. However, the ideal pretreatment regimen to reliably attenuate the acute hemodynamic response following ECT without producing preinduction hypotension has not been identified. Although the calcium-channel blocker nifedipine was evaluated during ECT,13 it is not available for parenteral administration. Nicardipine (Cardenet), is a dihydropyridine calcium antagonist which was recently introduced into clinical practice for use by intravenous (IV) infusion. To date, the efficacy and safety of nicardipine for ECT have not been established. Furthermore, to our knowledge, the acute hemodynamic effects of nicardipine when administered as an IV bolus versus infusion have not been studied previously. In addition, the acute hemodynamic effects of nicardipine when administered prior to an IV induction drug has not been investigated. Finally, determining the effect of different dosages of nicardipine on the ECTinduced seizure duration is important because the therapeutic efficacy of ECT depends on the induction of an adequate seizure,14 and some calcium antagonists have been found to possess anticonvulsant properties.15 Therefore, a prospective, randomized, positive-control, clinical investigation was designed to examine the acute cardiovascular effects of nicardipine as well as its ability to attenuate the hyperdynamic response to ECT. In a series of three studies, the hemodynamic effects of nicardipine were assessed prior to, during, and after ECT. Nicardipine was administered as a rapid infusion (1, 2.5, 5, 10, and 15 mg) or bolus injection (1.25, 2.5, and 5 mg), either alone or in combination with labetalol 10 mg as part of a standard anesthetic regimen for ECT.
Materials and Methods After University of Texas Southwestern Medical Center at Dallas Institutional Review Board approval, informed consent was obtained from 36 patients undergoing ECT treatments for severe chronic depression. Patients with clinically significant cardiovascular, respiratory, or hepatic disease; with a history of prior adverse reactions to any of the study medications; or receiving concurrent antihypertensive medications were excluded from the study. Patients were prospectively enrolled to receive different antihypertensive pretreatment regimens including labetalol, nicardipine, or a combination of the two drugs. This
prospective clinical investigation consisted of three sequential study protocols. 1. Rapid infusion: Nine patients received six randomly assigned (via random numbers table) treatments over a period of 3 to 6 weeks, consisting of a combination of labetalol, 10 mg, with a placebo (100 ml of saline) or nicardipine 1, 2.5, 5, 10, or 15 mg in 100 ml of saline. Labetalol was administered as a bolus injection and nicardipine (or saline) as an infusion in 100 ml saline over 5 to 7 minutes, immediately followed by induction of anesthesia with methohexital. 2. Bolus administration: Fifteen patients received four treatments in random order (random numbers table) consisting of labetalol 10 mg IV bolus in combination with placebo (saline) or nicardipine 1.25, 2.5, or 5 mg administered as a 5 ml bolus injection over 10 to 15 seconds four minutes prior to induction of anesthesia with methohexital. 3. Interaction between nicardipine and labetalol: Twelve patients received four consecutive treatments in random order (random numbers table) consisting of nicardipine 2.5 or 5 mg IV bolus, with or without labetalol 10 mg IV administered 4 minutes prior to induction of anesthesia with methohexital. Noninvasive mean arterial pressure (MAP), electrocardiogram (ECG), heart rate (HR), and hemoglobin oxygen saturation (SpO2) values were measured at one-minute intervals during the study treatment period and at fiveminute intervals during the recovery. Baseline hemodynamic values were averaged from two to three readings at 1-minute intervals prior to the administration of any medications. Glycopyrrolate 0.1 mg IV was followed by labetalol and/or nicardipine according to one of the above three study protocols. Unconsciousness was induced with methohexital 1 mg/kg IV administered as a bolus injection over 10 to 15 seconds. After loss of responsiveness to verbal commands, a BP cuff applied to the lower leg was inflated to isolate the circulation to the foot so as to assess the duration of the motor seizure. Succinylcholine 1.2 to 1.5 mg/kg IV was then administered and ventilation was controlled using a face mask and 100% oxygen. The succinylcholine dose requirement was established for each patient during prestudy treatment sessions, and the same dose was used for all study treatments. The prestimulation MAP and HR values were measured two minutes after induction of anesthesia, and the incremental changes in MAP and HR values from baseline were calculated. A suprathreshold electrical stimulus was delivered two to three minutes following induction of anesthesia via bifrontotemporal electrodes using a MECTA-SR1™ machine (MECTA Corp., Portland, OR). The seizure threshold of each patient was determined during ECT treatment sessions prior to enrollment in the study, and the stimulus variables were maintained constant for the duration of each study. The electroencephalogram (EEG) was recorded continuously from two frontal electrodes. The times from the ECT stimulus to the cessation of the J. Clin. Anesth., vol. 10, August 1998
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Table 1 Demographic Characteristics of Patients in the Three Nicardipine Study Protocols
Number (n) ASA physical status I, II, III (n) Age (yrs)
Protocol 1: Rapid Infusion
Protocol 2: Bolus Administration
Protocol 3: Interaction study
9 0/5/4 67 (45–81)
15 1/8/6 67 (44–86)
12 1/7/4 73 (61–83)
Note: Data are numbers, or means and ranges in parentheses. No significant difference was seen among the three groups.
clonic-tonic motor activity in the “isolated” foot (i.e., motor seizure duration) and to postictal EEG suppression (i.e., EEG seizure duration), determined by a blinded observer (MMH), were noted. The peak MAP and HR values during the five-minute period immediately following the seizure, as well as the incremental changes in MAP (DMAP) and HR (DHR) values (i.e., the increment from prestimulus-to-peak values) were noted. The time from delivering the electrical stimulus until eye opening, ability to follow simple commands, and “fitness for discharge” from the recovery room (i.e., alert, oriented, able to take oral fluids without nausea, and ambulate without assistance) were recorded by a nurse who was blinded to the medications administered during the procedure. Data were analyzed using repeated measures analysis of variance (Friedman’s test) followed by multiple Wilcoxon matched-pairs tests, with Bonferroni’s correction and oneway analysis of variance (ANOVA) followed by post hoc Tukey’s pairwise comparisons where appropriate. P-values less than 0.05 were considered statistically significant. Data
are presented as mean values (6SD) or as median values (and ranges).
Results A total of 36 patients participated in this series of studies. Demographic characteristics were similar in the three study groups (Table 1). There were no significant differences in the durations of seizure activity between the different pretreatment regimens used in the three study protocols (Table 2). These data show that the use of nicardipine does not result in a shorter duration of either motor or EEG seizure activity. Similarly, there were no significant differences in the recovery times among the different pretreatment groups (Table 2). In the first study (Protocol 1), a rapid infusion of nicardipine 5 to 15 mg produced a 19% to 24% decrease in MAP during the prestimulation period (Figure 1). Compared with nicardipine 5 mg IV, increasing the nicardipine dosage to 10 mg or 15 mg did not lead to a
Table 2 Seizure Durations and Recovery Times for Patients in the Three Nicardipine Study Protocols Duration of seizures (s)
Protocol 1: Rapid infusion Labetalol 10 mg Nicardipine 1 mg 1 Labetalol 10 mg Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 5 mg 1 Labetalol 10 mg Nicardipine 10 mg 1 Labetalol 10 mg Nicardipine 15 mg 1 Labetalol 10 mg Protocol 2: Bolus Administration Labetalol 10 mg Nicardipine 1.25 mg 1 Labetalol 10 mg Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 5 mg 1 Labetalol 10 mg Protocol 3: Interaction Study Nicardipine 2.5 mg 1 Labetalol 10 mg Nicardipine 2.5 mg alone Nicardipine 5 mg 1 Labetalol 10 mg Nicardipine 5 mg alone Note: Data are means 6 SD. No significant difference was noted. EEG 5 electroencephalogram. 396
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Recovery times (min)
Motor
EEG
Opens eyes
Obeys commands
Discharge
28 6 8 45 6 15 36 6 19 28 6 10 31 6 10 28 6 10
44 6 11 68 6 29 58 6 22 43 6 16 46 6 9 42 6 12
16 6 5 19 6 4 16 6 7 14 6 4 14 6 7 14 6 2
18 6 4 20 6 4 21 6 7 16 6 3 16 6 6 17 6 2
32 6 4 33 6 4 34 6 8 29 6 4 30 6 5 30 6 4
47 6 16 43 6 22 42 6 16 48 6 21
78 6 30 61 6 19 59 6 20 71 6 34
18 6 4 17 6 3 16 6 4 17 6 5
20 6 4 18 6 4 20 6 5 20 6 5
33 6 4 32 6 5 35 6 3 37 6 7
35 6 16 33 6 11 35 6 17 32 6 14
61 6 40 50 6 17 53 6 22 52 6 19
16 6 5 19 6 5 14 6 6 16 6 5
21 6 7 25 6 9 17 6 5 18 6 4
33 6 7 39 6 5 29 6 4 34 6 6
Nicardipine, Labetalol, and ECT: Avramov et al.
Figure 1. A. Mean arterial pressure (MAP) values and B. heart rate (HR) values following labetalol 10 mg and a 100 ml infusion containing saline alone (L 10), or nicardipine 1 mg (N 1), 2.5 mg (N 2.5), 5 mg (N 5), 10 mg (N 10), and 15 mg (N 15) in saline. Mean and standard deviation data are presented for the baseline (open circles), prestimulation period (closed circles), and the peak values following induction of seizure (closed diamonds). *Significant differences versus baseline values. #Significant differences versus labetalol 10 mg alone (control group) (p , 0.05).
significantly greater decrease in MAP. The transient hypertensive response after ECT was effectively blocked with 2.5 mg and higher doses of nicardipine. Conversely, labetalol 10 mg IV, alone or in combination with nicardipine 1 mg IV, was associated with significant increases in MAP values following ECT (p , 0.05) (Figure 1). However, there were no significant differences among the six
treatment groups with respect to the magnitude of the incremental changes in MAP (16% to 27%) and HR (4% to 14%) values following ECT. When administered as a bolus dose over 10 to 15 seconds (Protocol 2), nicardipine 1.25 to 5 mg produced a significant (20% to 30%) decrease from the baseline MAP values within 1 to 3 minutes following the injection
Figure 2. A. Mean arterial pressure (MAP) values and B. heart rate (HR) values following bolus administration of labetalol 10 mg (L 10) alone (circles), and in combination with nicardipine 1.25 mg (N 1.25; diamonds), 2.5 mg (N 2.5; triangles), and 5 mg (N 5; squares). Mean and standard deviation data are presented for the baseline (BL), prestimulation period (Pre-stim), and the peak values following induction of seizure (Peak MAP or HR). *Significant differences versus baseline values (p , 0.05). J. Clin. Anesth., vol. 10, August 1998
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Figure 3. Heart rate (HR) following bolus administration of nicardipine 2.5 mg (triangles) or 5 mg (squares) alone (open symbols), or in combination with labetalol 10 mg (closed symbols). Mean and standard deviation data are presented for the baseline (BL), prestimulation period (Pre-stim), and the peak values following induction of seizure (Peak HR). *Significant differences versus baseline values (p , 0.05).
(p , 0.01) (Figure 2). In the nicardipine 1.25 and 5 mg group, HR increased by 10% above the baseline value (p , 0.01) (Figure 2). The peak MAP values after ECT-induced seizures were decreased by nicardipine 2.5 to 5 mg in combination with labetalol 10 mg IV. In contrast, the peak post-ECT increase in MAP was greater than baseline values following labetalol 10 mg IV, alone or in combination with nicardipine 1.25 mg IV (p , 0.05)
(Figure 2). The peak HR values following ECT were significantly increased from baseline values in all four treatment groups. However, the incremental changes in prestimulus MAP and HR to peak MAP and HR values following the seizure [i.e., DMAP (23–37 mmHg) and DHR (2–18 bpm)] were similar among the four treatment groups. When nicardipine 2.5 mg or 5 mg IV were administered alone (Protocol 3), adequate control of MAP after ECT was achieved. However, there was a significant increase in HR prior to, during, and after the treatment when the calcium-channel blocker was administered without labetalol (p , 0.05) (Figure 3). Pretreatment with nicardipine alone or in combination with labetalol produced similar cardiovascular depressant effects after methohexital 1 mg/kg IV, compared with labetalol alone (DMAP: 25 to 242 mmHg and 29 to 233 mmHg, respectively). The MAP values following induction of anesthesia were not significantly different from the immediate preinduction values in any of the three study protocols (Table 3). In the two nicardipine bolus protocols (Protocols 2 and 3), comparable increases in MAP values were noted following ECT stimulation (21–37 mmHg). Similarly, the incremental increase in HR after ECT (2–18 bpm) did not differ significantly among the different nicardipine-labetalol treatment regimens. Following nicardipine 2.5 mg IV bolus alone or nicardipine 1.25 mg IV in combination with labetalol 10 mg IV, patients remained hemodynamically stable without significant changes from their baseline MAP and HR values during the recovery period and at the time of discharge. However, a significant hypotensive effect (MAP values of 87 6 15 to 95 6 7 mmHg) was noted during the recovery period following pretreatment with nicardipine 5 mg IV boluses in combination with labetalol 10 mg IV (Table 3). Furthermore, the two groups of patients who received
Table 3 Hemodynamic Changes Prior to, During, and after Electroconvulsive Therapy (ECT) with intravenous Bolus Administration of Nicardipine (N) and Labetalol (L), Alone and in Combination Protocol 2: Bolus Administration
MAP (mmHg) at: Baseline Preinduction Prestimulus Peak MAP Discharge HR (bpm) at: Baseline Preinduction Prestimulus Peak MAP Discharge
Protocol 3: Interaction Study
L10
N1.25 1 L10
N2.5 1 L10
N5 1 L10
N2.5 1 L10
N2.5 alone
N5 1 L10
N5 alone
107 6 19 102 6 24* 102 6 17 129 6 17* 98 6 21
104 6 12 83 6 11* 86 6 11* 120 6 25* 91 6 12
105 6 17 80 6 13* 90 6 14* 106 6 14 93 6 13*
109 6 14 78 6 9* 81 6 11* 111 6 21 92 6 21*
112 6 17 84 6 9* 90 6 12* 121 6 21 103 6 15
107 6 9 89 6 9* 98 6 16 131 6 14* 100 6 11
115 6 18 81 6 9* 79 6 12* 108 6 18 89 6 15*
108 6 12 83 6 8* 85 6 15* 117 6 17 96 6 12*
78 6 14 76 6 10 86 6 13 95 6 17* 76 6 10
76 6 9 76 6 10 86 6 15* 98 6 16* 79 6 9
78 6 13 79 6 10 86 6 13 95 6 23* 80 6 11
77 6 9 86 6 13* 89 6 16* 106 6 22* 80 6 11
75 6 14 77 6 11 81 6 15 94 6 20* 82 6 11
79 6 13 92 6 17* 104 6 20* 120 6 23* 90 6 7*
82 6 12 82 6 16 82 6 18 99 6 21 78 6 8
82 6 14 88 6 16 99 6 13* 113 6 17* 92 6 13
Data are mean values 6 SD MAP 5 mean arterial pressure, L10 5 Labetalol 10 mg; N1.25 5 Nicardipine 1.25 mg; N2.5 5 Nicardipine 2.5 mg; N5 5 Nicardipine 5 mg, HR 5 heart rate. *p , 0.05 vs. baseline values. 398
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Nicardipine, Labetalol, and ECT: Avramov et al.
nicardipine alone remained tachycardic (HR . 90 bpm) at the time of discharge. However, none of the patients receiving nicardipine by either bolus injection or rapid infusion required any pharmacologic treatment for persistent hypotension in the recovery room, nor did they experience a delayed discharge.
Discussion Pretreatment with IV nicardipine significantly decreased the peak MAP values following ECT without decreasing the duration of seizure activity. Consistent with the recent findings of Song et al.,16 bolus administration of nicardipine was found to produce a rapid onset of its BP lowering effect (1 to 3 min). When nicardipine 2.5 to 5 mg was combined with labetalol 10 mg IV, it effectively protected against ECT-induced hypertension. Use of nicardipine alone resulted in an increase in HR both prior to and immediately after ECT treatment. The BP lowering effect of nicardipine persisted into the early recovery period when nicardipine doses of 2.5 mg and higher were used. However, none of the patients required treatment of hypotension in the post-ECT period, and discharge times were similar in all treatment groups. Nicardipine, which is a dihydropyridine calcium antagonist, produces selective coronary and peripheral vasodilatation.17,18 Effective control of intraoperative hypertension has been previously demonstrated during both cardiac19 and non-cardiac20 surgery. IV bolus doses of nicardipine 0.5 to 5 mg21,22 produced 17% to 35% decreases in systemic BP. Although higher dosages of nicardipine were used in the present investigation, similar reductions in MAP were observed prior to and following induction of anesthesia with methohexital. When administered by an infusion over five to seven minutes, increasing the nicardipine dose from 5 mg to 15 mg did not further decrease MAP values (Figure 1). Even though a rapid infusion of high doses of nicardipine did not produce clinically significant cardiovascular depression, the use of nicardipine doses in excess of 5 mg did not provide additional protection against ECT-induced hypertension. Although the hypertensive response to ECT was effectively blocked with nicardipine dosages of 2.5 mg and higher, HR was significantly increased both prior to and following ECT treatment when larger doses of nicardipine (5–15 mg) were used, suggesting activation of the baroreflex mechanism. Moreover, when used without labetalol, nicardipine actually accentuated the HR response to ECT. Thus, the beta-blocking action provided by labetalol 10 mg in combination with the lower dosages of nicardipine provided the most effective control of the acute hemodynamic responses to ECT. The cardiovascular responses during ECT also can be influenced by the anticholinergic (e.g., glycopyrrolate), which was administered to decrease oral secretions and to prevent the transient bradycardia that results from the brief, intense parasympathetic discharge that accompanies the electrical stimulus. In order to minimize the influence of glycopyrrolate on the cardiovascular response, a stan-
dardized dose of 0.1 mg IV was administered in all three studies.23 Although it is not a universal practice, use of an anticholinergic is included in the American Psychiatric Association Task Force Report on “standard” clinical anesthetic practice guidelines for ECT.24 Pretreatment with nicardipine did not adversely affect the duration of ECT-induced seizure activity. Dihydropyridine antagonists modulate the action of a subtype of voltage-dependent calcium channels, the L-channel, which is a high-threshold slowly inactivating current. Although anticonvulsant properties of dihydropyridine calcium antagonists have been demonstrated in animal models of electrocortical shock-induced seizure,25,26 nicardipine was a notable exception in that it was devoid of anticonvulsant properties.25–27 Our findings in the ECT population are in agreement with the previous observations in animals. Because nicardipine is a partially charged molecule, its failure to decrease ECT-evoked seizure activity may be related to its limited ability to penetrate the blood-brain barrier in humans. These clinical findings suggest that, inasmuch as seizure duration is one of the important determinants of the quality of the ECT treatment,14 the use of nicardipine should not adversely affect the efficacy of ECT in patients with depressive disorders. The ideal antihypertensive pretreatment for ECT would involve the use of only one medication to blunt the ECT-induced hyperdynamic response, without producing hypotension during the pretreatment and posttreatment periods and without decreasing the duration of seizure activity. Although it may appear that nicardipine attenuated the hypertensive response induced by ECT, its use was accompanied by a significant decrease in MAP immediately prior to the ECT treatment. The present study suggests that the use of nicardipine decreases the hyperdynamic response to ECT by lowering the pre-ECT MAP values. Thus, the incremental change in MAP values in response to the ECT stimulus was unchanged by nicardipine pretreatment. Furthermore, consistent with the effects of other calcium-channel antagonists, the hypotensive effect of nicardipine was accompanied by tachycardia. Therefore, nicardipine must be administered in combination with labetalol or esmolol to minimize the nicardipineinduced increase in HR. In conclusion, nicardipine 2.5 mg IV bolus in combination with a beta-blocker (labetalol 10 mg IV), administered four minutes prior to induction of anesthesia with methohexital, was the most effective combination in preventing the acute hypertensive responses immediately after ECT without adversely affecting the duration of seizure activity. However, as with other antihypertensive pretreatment regimens for ECT, nicardipine was unable to decrease the magnitude of the incremental rise in MAP values in response to the ECT stimulus, even when administered in combination with labetalol.
Acknowledgments The authors would like to acknowledge John A. Thomas, B.A., Steven J. Luke, M.D., Carl E. Adkins, M.D., and the nursing personnel at the Psychiatry Unit of Zale-Lipshy University Hospital, Dallas, TX. J. Clin. Anesth., vol. 10, August 1998
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References 1. Brown ML, Huston PE, Heinz HM, Brown GW: Cardiovascular changes associated with electroconvulsive therapy in the man. Arch Neurol 1953;69:601– 8. 2. Fink M: Convulsive therapy—theory and practice. New York: Raven Press, 1979:P42. 3. Selvin BL: Electroconvulsive therapy—1987. Anesthesiology 1987; 67:367– 85. 4. Tewfik GI, Wells BG: The use of Arfonad for the alleviation of cardiovascular stress following electroconvulsive therapy. J Ment Sci 1975;10:636 – 44. 5. Ciraulo D, Lind L, Salzman C, Pilon R, Elkins R: Sodium nitroprusside treatment of ECT-induced blood pressure elevations. Am J Psychiatry 1978;135:1105– 6. 6. Lee JT, Erbguth PH, Stevens WC, Sack RL: Modification of electroconvulsive therapy induced hypertension with nitroglycerin ointment. Anesthesiology 1985;62:793– 6. 7. Liu WS, Petty WC, Jeppsen A, Wade EJ, Pace NL: Attenuation of hemodynamic and hormonal responses to ECT with propranolol, xylocaine, sodium nitroprusside or clonidine. Anesth Analg 1984; 63:244. 8. London SW, Glass DD: Prevention of electroconvulsive therapyinduced dysrhythmias with atropine and propranolol. Anesthesiology 1985;62:819 –22. 9. Kovac AL, Goto H, Pardo MP, Arakawa K: Comparison of two esmolol bolus doses on the haemodynamic response and seizure duration during electroconvulsive therapy. Can J Anaesth 1991; 38:204 –9. 10. Howie MB, Black HA, Zvara D, McSweeney TD, Martin DJ, Coffman JA: Esmolol reduces autonomic hypersensitivity and length of seizures induced by electroconvulsive therapy. Anesth Analg 1990;71:384 – 8. 11. Weinger MB, Partridge BL, Hauger R, Mirow A: Prevention of the cardiovascular and neuroendocrine response to electroconvulsive therapy: I. Effectiveness of pretreatment regimens on hemodynamics. Anesth Analg 1991;73:556 – 62. 12. Castelli I, Steiner LA, Kaufman MA, et al: Comparative effects of esmolol and labetalol to attenuate hyperdynamic states after electroconvulsive therapy. Anesth Analg 1995;80:557– 61. 13. Wells DG, Davies GG, Rosewarne F: Attenuation of electroconvulsive therapy induced hypertension with sublingual nifedipine. Anaesth Intensive Care 1989;17:31–3. 14. Maletzki BM: Seizure duration and clinical effect in electroconvulsive therapy. Compr Psychiatry 1987;19:541–50.
400
J. Clin. Anesth., vol. 10, August 1998
15. Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW: Selective central nervous system calcium channel blockers—a new class of anticonvulsants. Mayo Clin Proc 1986;61:239 – 47. 16. Song D, Singh H, White PF, Gadhiali M, Griffin JD, Klein KW: Optimal dose of nicardipine for maintenance of hemodynamic stability after tracheal intubation and skin incision. Anesth Analg 1997;85:1247–51. 17. Lambert CR, Hill JA, Nichols WW, Feldman RL, Pepine CJ: Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652– 6. 18. IV Nicardipine Study Group. Efficacy and safety of intravenous nicardipine in the control of postoperative hypertension. Chest 1991;99:393– 8. 19. van Wezel HB, Koolen JJ, Visser CA, et al: Antihypertensive and anti-ischemic effects of nicardipine and nitroprusside in patients undergoing coronary artery bypass grafting. Am J Cardiol 1989; 64:22H–27H. 20. Goto F, Kato S, Sudo I: Treatment of intraoperative hypertension with enflurane, nicardipine, or human atrial natriuretic peptide: haemodynamic and renal effects. Can J Anaesth 1992;39:932–7. 21. Kishi Y, Okumura F, Furuya H: Hemodynamic effects of nicardipine hydrochloride. Studies during its use to control acute hypertension in anaesthetized patients. Br J Anaesth 1984;56: 1003–7. 22. Begon C, Dartayet B, Edouard A, David D, Samii K: Intravenous nicardipine for treatment of intraoperative hypertension during abdominal surgery. J Cardiothorac Anesth 1989;3:707–11. 23. Mirakhur RK: Anticholinergic drugs. Br J Anaesth 1979;51:671–9. 24. American Psychiatric Association Task Force Report: The practice of Electroconvulsive therapy. Recommendations for treatment, training and privileging. Washington, DC: American Psychiatric Association, 1990. 25. Czuczwar SJ, Gasior M, Janusz W, Kleinrok Z: Influence of flunarizine, nicardipine and nimodipine on the anticonvulsant activity of different antiepileptic drugs in mice. Neuropharmacology 1992;31:1179 – 83. 26. Meyer FB, Anderson RE, Sundt TM Jr: Anticonvulsant effects of dihydropyridine Ca21 antagonists in electrocortical shock seizures. Epilepsia 1990;31:68 –74. 27. Palmer GC, Stagnitto ML, Ray RK, Knowles MA, Harvey R, Garske GE: Anticonvulsant properties of calcium channel blockers in mice: N-methyl-D-, L-aspartate-and Bay K 8644-induced convulsions are potently blocked by the dihydropyridines. Epilepsia 1993;34:372– 80.