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Anesthesia & Analgesia:
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The Comparative Effects of Methohexital, Propofol, and Etomidate for Electroconvulsive Therapy

Avramov, Michail N. MD PhD; Husain, Mustafa M. MD; White, Paul F. PhD MD, FANZCA

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Departments of Anesthesiology and Pain Management (Avramov, White) and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas (Husain).

Accepted for publication May 3, 1995.

Address correspondence and reprint requests to Paul F. White, PhD, MD, FANZCA, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5161 Harry Hines Blvd., CS 2.126, Dallas TX.

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Abstract

The intravenous anesthetics which are commonly used for electroconvulsive therapy (ECT) possess dosedependent anticonvulsant properties.Since the clinical efficacy of ECT depends on the induction of a seizure of adequate duration, it is important to determine the optimal dose of the hypnotic for use during ECT. We compared the duration of seizure activity and cognitive recovery profiles after different doses of methohexital, propofol, and etomidate administered to induce hypnosis prior to ECT. Ten outpatients with major depressive disorders receiving maintenance ECT participated in this prospective, randomized, cross-over study. Patients were premedicated with glycopyrrolate, 0.2 mg intravenously (IV), and labetalol, 20-30 mg IV, and hypnosis was induced with an IV bolus injection of methohexital or propofol (0.75, 1.0, and 1.5 mg/kg), or etomidate (0.15, 0.2, and 0.3 mg/kg), administered over 10-15 s. Adequate muscle paralysis was achieved with succinylcholine, 1.0-1.4 mg/kg IV. Each patient's seizure threshold was determined prior to enrollment in the study and the electrical stimulus variables were kept constant throughout the study period. After delivery of a bilateral electrical stimulus, the duration of the resulting electroencephalographic (EEG) and motor seizures were recorded. A total of 90 ECT treatments were evaluated. The durations of EEG and motor seizures were longest after etomidate and shortest after propofol. There were no significant dose-related differences in motor and EEG seizure durations (means +/- SD) after the low, intermediate, and high doses of etomidate of 44 +/- 11 and 77 +/- 19, 43 +/- 10 and 76 +/- 34, 42 +/- 16 and 78 +/- 56 s, respectively. Conversely, both methohexital and propofol, 0.75, 1.0, and 1.5 mg/kg, produced dosedependent decreases in motor and EEG seizure durations (i.e., 37 +/- 10 and 58 +/- 12, 36 +/- 8 and 62 +/- 24, and 29 +/- 13 and 48 +/- 20 for methohexital; 34 +/- 15 and 56 +/- 29, 31 +/- 8 and 50 +/- 17, and 20 +/- 6 and 33 +/- 12 for propofol, respectively). The awakening times were similar, regardless of the hypnotic or dose administered. The rate of cognitive recovery was prolonged after ECT treatments with a longer duration of seizure activity. Discharge time was 5-7 min longer after etomidate than methohexital or propofol. Etomidate, 0.15-0.3 mg/kg, has minimal effect on the duration of ECT-induced seizure activity. However, recovery of cognitive functions was prolonged after etomidate because of the longer period of seizure activity. Propofol and methohexital, at doses more than 1 mg/kg, lead to 35%-45% decreases in ECT-induced seizure duration compared to etomidate. We conclude that etomidate may be a useful alternative to propofol and methohexital for ECT therapy.

(Anesth Analg 1995;81:596-602)

Electroconvulsive therapy (ECT) is a well-established treatment for severe depression in patients who have not responded to pharmacotherapy [1]. Maintenance therapy is usually required to sustain remission of the symptoms of depression. The safety of the procedure has improved with the use of succinylcholine to produce a brief period of neuromuscular blockade, thereby preventing muscle contractions and protecting against bone fractures. A brief period of unconsciousness is required to avoid recall of muscle paralysis, especially in the event of a "missed" or incomplete seizure [2].

The ideal hypnotic drug for ECT would have a rapid onset and short duration of action without adversely affecting the efficacy of the seizure treatment. Since most short-acting anesthetics possess anticonvulsant properties, they can increase the threshold and inhibit the spread of seizure, thus modifying the seizure activity and shortening its duration. Large doses of these anesthetics can abort the ECT-induced seizure. To the extend that the seizure duration is related to the therapeutic outcome [3-5], hypnotic doses of anesthetic drugs can presumably counteract the therapeutic effects of ECT.

Methohexital has been the drug of choice for ECT [2]. However, because of the well-known anticonvulsant properties of barbiturates [6], other intravenous (IV) anesthetics have been evaluated. Propofol has a very favorable recovery profile for outpatients undergoing ambulatory surgery procedures [7]. However, decreased ECT-induced seizure duration has been demonstrated even after propofol dose as small as 0.75 mg/kg [8-11]. A retrospective comparative study of etomidate and thiopental for ECT reported longer ECT-induced seizures after etomidate [12]. However, etomidate also possesses anticonvulsant activity [13] and has been used to treat refractory status epilepticus [14].

Previous comparative studies of anesthetics for ECT have compared only single doses of the different hypnotics. Since the central nervous system (CNS) depressant effects of hypnotic drugs are dose-dependent [15,16], and the dose-response curves for hypnotic and anticonvulsant actions may not be the same, comparative studies should evaluate the effects of multiple doses. The ideal hypnotic for ECT would reliably produce a loss of consciousness without interfering with the duration of the ECT-induced seizure. In this comparative study, we evaluated seizure duration, hemodynamic stability and recovery characteristics when three different doses of methohexital, propofol, or etomidate were administered prior to ECT in outpatients undergoing maintenance therapy for major depressive disorders.

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Methods

Ten consenting patients undergoing maintenance ECT treatment for chronic depression were enrolled in this prospective, randomized, study approved by the institutional review board. Noninvasive arterial blood pressure, electrocardiogram (ECG), heart rate, and oxygen saturation were measured at 1- to 5-min intervals during the study period. Glycopyrrolate, 0.2 mg IV and labetalol, 20-30 mg IV, were given 3-5 min prior to induction of anesthesia to attenuate the acute hemodynamic responses to the ECT.

Each patient received one of three different doses of methohexital (0.75, 1.0, or 1.5 mg/kg), propofol (0.75, 1.0, or 1.5 mg/kg), or etomidate (0.15, 0.2, or 0.3 mg/kg) in a randomized order using a double-blind cross-over study design during consecutive ECT treatments at 2- to 4-wk intervals. Prior to entering the study, each patient's ECT-induced seizure threshold was determined by administering successive stimuli of increasing intensity at 30-s intervals until a generalized motor and electroencephalogram (EEG) seizure was induced (i.e., a threshold stimulus) [5]. A suprathreshold stimulus (i.e., an intensity one level higher than the threshold stimulus) was used throughout the study and was maintained at a constant level for each patient. The hypnotics were administered as a bolus dose over 10-15 s. After loss of responsiveness to verbal command, a blood pressure cuff applied to the lower leg was inflated to isolate the circulation to the foot and permit an accurate assessment of the motor seizure. Succinylcholine, 1.0-1.4 mg/kg IV, was then administered and ventilation was assisted using a face mask and 100% oxygen.

A suprathreshold electrical stimulus was delivered within 4 min of induction of anesthesia via bifrontotemporal electrodes using a MECTA-SR1 Trademark machine (MECTA Corp., Portland, OR). The stimulus variables (level, dynamic energy, intensity) were recorded. The EEG was recorded continuously during each treatment from two frontal electrodes, and the duration of the EEG seizure activity (i.e., the time from stimulus to post-ictal EEG suppression) was noted. The duration of the motor seizure was recorded as the time from the ECT stimulus to cessation of tonic-clonic motor activity in the "isolated" foot.

Psychomotor recovery was assessed as the time from delivering of the electrical stimulus until eye opening, ability to follow simple commands, and to orientation to person, place, and time by a blinded observer. A simple questionnaire (Appendix) was administered prior to ECT, upon awakening, and at 5-min intervals in the recovery room. Anxiety, confusion, fatigue, clumsiness, and drowsiness were evaluated using a four-level verbal self-assessment scale (none, mild, moderate, and severe) prior to the ECT and upon discharge from the recovery room. The time to "fitness for discharge" from the posttreatment recovery room was determined by a nurse who was blinded to the anesthetic used.

Relative potency for methohexital and propofol was calculated from the data for the smallest and the largest doses using the "2 and 2" procedure (two drugs and two doses) [17]. The mean durations of the motor and EEG seizure activity were the response end-points used to determine the relative anticonvulsant potency of the hypnotic drugs.

Data were analyzed using repeated-measures analysis of variance (Friedman's test) followed by multiple Wilcoxon matched-pairs tests, with Bonferroni's correction and one-way analysis of variance with post-hoc Student-Newman-Keuls multiple range tests, where appropriate. P values <0.05 were considered statistically significant. Data are presented as mean values (+/- SD or +/- SEM) or as median values (ranges).

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Results

The 10 patients, five male and five female, with a mean age of 54 yr (range 27-81 yr) and weight of 72.5 kg (range 50-100), received a total of 90 ECT study treatments. The doses of glycopyrrolate, labetalol, and succinylcholine were similar for each treatment group. The durations of EEG and motor seizures were longest after etomidate and shortest after propofol Figure 1. There were no differences in seizure duration between the three doses of etomidate. Conversely, both methohexital and propofol produced dose-dependent decreases in both motor and EEG seizure duration, and these differences were significant at the highest (versus lowest) doses. The dose-response relationship for seizure duration was steepest for propofol [with a 9% and 40% decrease at the 1.0 and 1.5 mg/kg doses (vs 0.75 mg/kg), respectively]. The anticonvulsant effect of methohexital was less profound (17% and 22% decrease, for EEG and motor seizures, respectively) at the highest dosage. Thus, at the 1.5 mg/kg dose, both propofol and methohexital failed to provide a consistent motor seizure duration lasting >30 s. The relative potency of the anticonvulsant actions of methohexital and propofol, based on the dose-response data for seizure durations at the 0.75 mg/kg and 1.5 mg/kg doses, according to the "2 and 2"-type assay [17] was 1.5:1.0 and 1.4:1.0 for motor and EEG seizures, respectively.

Figure 1
Figure 1
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All patients received the same premedication to blunt the autonomic response to ECT. However, there were differences in the hemodynamic response with the three different drugs Figure 2. The mean arterial pressure decreased significantly after the administration of propofol and did not change in the methohexital and etomidate groups. Immediately after ECT, propofol was associated with a reduced acute hemodynamic response compared to methohexital and etomidate.

Figure 2
Figure 2
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The emergence times were similar regardless of the administered dose of the hypnotic Table 1. However, the times to eye opening and following simple commands were significantly longer after etomidate. In contrast to the effect of the hypnotics on the length of seizure activity, the emergence times (eye opening, following simple commands) were not found to be dose-related. The recovery of cognitive function, determined by the ability to correctly answer simple questions, did not differ significantly between the three doses of etomidate, and exhibited a negative dose-response relationship with propofol and methohexital (i.e., recovery was fastest at the highest doses) Figure 3. The recovery room discharge times were 6-8 min longer after etomidate (44-46 min) compared to methohexital (37-39 min) and propofol (37-39 min). However, patient self-assessment of the level of anxiety, confusion, fatigue, clumsiness, and drowsiness at the time of discharge was not significantly different from pretreatment baseline values. At the time of discharge, no patient reported recall of the onset of neuromuscular block, the ECT treatment, or residual muscle weakness after the treatment.

Table 1
Table 1
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Figure 3
Figure 3
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Discussion

This clinical investigation suggests that not only the dose, but also the type of hypnotic drug, is important in determining the duration of ECT-induced seizure activity. We compared a range of IV doses from minimally hypnotic to anesthetic induction doses of methohexital, propofol, and etomidate. In a preliminary pilot study, we determined that 0.75 mg/kg was the lowest dose of propofol or methohexital that reliably induced hypnosis in this patient population [11]. On the other hand, induction doses of propofol exceeding 2 mg/kg had profound depressant effects on seizure duration, frequently aborting the ECT-induced seizure. Therefore, we studied methohexital and propofol doses ranging from 0.75 to 1.5 mg/kg. In our study, the minimal hypnotic dose of etomidate was 0.15 mg/kg and in order to achieve a similar dose ratio to propofol and methohexital, etomidate doses of 0.2 and 0.3 mg/kg were studied. In contrast to previous studies [9,18,19], we used only a single bolus dose of each drug to induce anesthesia.

Although approximately "equihypnotic" doses (on the basis of their induction doses) of the three anesthetics were used, their effect on ECT-induced seizures differed significantly. Methohexital and propofol induced a similar pattern of dose-dependent depression in the duration of ECT-induced seizures, while the different doses of etomidate produced no significant changes in the duration of ECT-induced seizure activity. Of the three anesthetics, propofol exerted the most profound anticonvulsant effect. The difference between propofol and methohexital was small and not statistically significant at the smallest dose (0.75 mg/kg), but it was clearly evident at the intermediate and high doses. Thus, compared to an "equihypnotic" dose of etomidate, the use of methohexital and propofol led to significant reductions in the duration of EEG seizure activity (18%-39% and 27%-58%, respectively).

Previous studies comparing propofol with methohexital have consistently demonstrated that propofol, 1.3-2.0 mg/kg, reduces seizure duration compared to methohexital 1.0-1.4 mg/kg [8-10,18,19]. The studies which did not find significantly shorter seizures after propofol (versus methohexital) used lower doses of propofol, 1.0-1.2 mg/kg [20,21]. However, we have previously demonstrated that propofol, even at doses as low as 0.75 mg/kg, may significantly shorten seizure duration in comparison with methohexital [11]. The use of equal doses of propofol and methohexital, provided an opportunity to compare their anticonvulsant potency [17]. The anticonvulsant potency ratio for propofol:methohexital of 1:1.4 and 1:1.5, for motor and EEG seizures, respectively, is similar to their hypnotic potency ratio of 1:1.46 [22]. Since both propofol and the barbiturates are CNS depressant drugs [16], the fact that their anticonvulsant actions parallel other CNS actions suggests that similar neurophysiologic mechanisms may be involved.

Our findings of significantly longer seizure durations after etomidate differ from previous comparative studies with methohexital [23,24] which reported no difference in ECT-induced seizure durations. These previous studies used only single doses of etomidate or methohexital given alternatively to each patient for unilateral ECT at 2- to 3-day intervals. Etomidate antagonizes pentylenetetrazol and maximal electroshock-induced convulsions [13], and has been used successfully to control refractory status epilepticus [14]. The dose-response data from the present study, however, suggest that in contrast to methohexital and propofol, the anticonvulsant activity of etomidate does not parallel its hypnotic action.

The rate of recovery from the hypnotic effects of these IV anesthetics is usually dose-dependent. However, in the present study, this relationship was not observed. In fact, an inverse relationship between dose and rate of recovery of cognitive function was found for both propofol and methohexital. The apparent discrepancies in the predicted course of early recovery can be attributed to the effect of the seizure itself (i.e., smaller anesthetic doses allowed longer seizures and were associated with a more prolonged recovery). Thus, the duration of the ECT-induced seizure is the primary determinant of early recovery rather than the dose of the hypnotic drug. The more rapid and pleasant recovery after propofol in comparison with methohexital and etomidate has made it a drug of choice for short diagnostic and surgical procedures. However, under the circumstances of ECT, this advantage is no longer apparent.

Recently, the importance of seizure duration for the therapeutic efficacy of ECT has been questioned [5]. Nevertheless, poor therapeutic outcomes in controlled trial of ECT [25] have been attributed to shorter seizures associated with the use of larger doses of methohexital [26]. Methohexital doses of 1.2 mg/kg have also been found to increase the number of ECT treatments required per course [27]. Similarly, the use of standard induction doses of propofol has been discouraged due to its depressant effects on seizure duration. Our results confirm that propofol and methohexital, at doses more than 1.0 mg/kg have a significant anticonvulsant effect during ECT. Given the short duration of propofol's CNS effects after a dose of 0.75 mg/kg, good coordination between the anesthesia and psychiatry ECT teams is required. Conversely, etomidate even at an anesthetic induction dose of 0.3 mg/kg is not associated with a significant depression of ECT-induced seizures and it appears to be an useful alternative to methohexital or propofol in patients achieving suboptimal therapeutic responses to ECT.

The hemodynamic changes during ECT involve sequential increases in parasympathetic and sympathetic nervous system activity. The use of a combination of vagolytic and beta-adrenergic blocking drugs to blunt the cardiovascular effects of ECT is well accepted. In addition, the anesthetic used during ECT has an important impact on the hemodynamic response. These results confirm that propofol provides the best protection against an untoward hypertensive response to ECT, while etomidate was the least effective in blunting the hyperdynamic response.

In conclusion, the clinically significant anticonvulsant potency of propofol and methohexital closely parallels their hypnotic effects. The optimal dose of propofol and methohexital is <1.0 mg/kg. Hypnotic doses in excess of 1.0 mg/kg have adverse effects on seizure duration and possibly, on the therapeutic efficacy of ECT. Finally, etomidate was associated with comparatively longer seizures and should be considered the drug of choice in patients who have inadequate seizure durations with other IV anesthetics.

The author gratefully acknowledges the help of the nursing staff in the Zale Lipshy University Hospital Psychiatric Unit, as well as the residents in the Departments of Anesthesiology and Psychiatry. The support of Doctors Clair Callan and William Houghton of the Hospital Products Division of Abbott Laboratories (Abbott Park, IL) was greatly appreciated.

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Appendix

1. What is your name?

2. What is your full name?

3. What is your birthdate?

4. Do you know where you are?

5. Do you know the name of the hospital?

6. Do you know what city you are in?

7. Do you know what county you are in?

8. Do you know what state you are in?

9. Do you know the month?

10. Do you know the year?

11. Do you know the date today?

12. Do you know the day of the week?

13. Why are you here?

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5. Sackheim HA, Devanad DP, Prudic J. Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy. Psychiatr Clin North Am 1991;14:803-43.

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