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Comparison of methohexital and etomidate as anesthetic agents for electroconvulsive therapy in affective and psychotic disorders
Journal of Psychiatric Research 47 (2013) 686e693
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Comparison of methohexital and etomidate as anesthetic agents for electroconvulsive therapy in affective and psychotic disorders H. Janouschek a, b, *, T. Nickl-Jockschat a, M. Haeck a, B. Gillmann c, M. Grözinger a a
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany Department of Neurology, RWTH Aachen University, Germany c Department of Anesthesiology, RWTH Aachen University, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 June 2012 Received in revised form 3 December 2012 Accepted 14 December 2012
Background: ECT is a well-established treatment for severe depression. The available data on psychosis are limited, but reliable. Its therapeutic potential relies on the induction of a generalized seizure. Besides other narcotics, methohexital and etomidate are used for general anesthesia in ECT. Since prolonged seizures have been reported following the use of etomidate, it can be deduced that the substances might differ in their anticonvulsant properties, resulting in a lower increase in stimulus intensity during the course of treatment under etomidate. Besides this hypothesis, we aimed to investigate the differential effects of etomidate and methohexital on clinical features, ECT parameters and side effects of the treatment. Methods: We performed a retrospective analysis of treatment data of patients with affective and psychotic diagnosis who received general anesthesia for ECT either with etomidate or with methohexital. Results: ECT with etomidate and methohexital was equally effective. During the course of therapies the administered electric charge increased significantly and equally in both treatment groups. In the methohexital group, but not in the etomidate group, electroencephalographic seizure duration had a declining trend during the course of therapies. We observed more side effects during and immediately after ECT in the methohexital group than in the etomidate group. Limitations: The limitations of this study are that the patients received various psychotropic comedications, which influence ictal parameters differently, and, secondly, the study is based on a retrospective analysis. Conclusion: The results of our analysis suggest that etomidate and methohexital affect ictal parameters to different extents. Longer seizure duration and fewer side effects are in favor of etomidate. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Electroconvulsive therapy Narcotics Etomidate Methohexital
1. Introduction Electroconvulsive therapy (ECT) is a well-established, highly effective treatment for severe depression. The available data on psychosis are limited, but reliable (The UK ECT Review Group, 2003; Zervas et al., 2012). Although the exact therapeutic mechanisms remain to be clarified, repeated induction of a generalized seizure is viewed as decisive for a therapeutic response (Sackeim et al., 1991). General anesthesia and muscular relaxation are performed in order to prevent injuries during the seizure.
* Corresponding author. Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. Tel.: þ49 241 8035986; fax: þ49 241 8082582. E-mail address: [email protected] (H. Janouschek). 0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2012.12.019
Cognitive-mnestic impairments are the most frequent severe side effects (The UK ECT Review Group, 2003). Although these impairments have been shown to be fully reversible (The UK ECT Review Group, 2003), they are usually perceived by patients as being very defacing, and sometimes to such an extent as to render a further administration of ECT impossible. Besides electrode placement, the electric charge needed for seizure induction has been shown to be a pivotal parameter influencing cognitive side effects (Weiner et al., 1986). Thus, all measures that lead to a reduction of the electric charge might also help reduce cognitive side effects. There is widespread consensus that a generalized seizure of sufficient duration is necessary for the therapeutic effect of the treatment (American Psychiatric Association, 2001), but this alone is likely not sufficient (Robin and De Tissera, 1982; Sackeim et al., 2000). While recent studies have sought to identify EEG measures that are able to predict ECT outcome (Perera et al., 2007),
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the notion that ictal parameters influence therapeutic properties of ECT continues to persist. Higher amplitudes of the ictal EEG, especially in the d-band, greater ictal coherence, stronger postictal suppression and a higher peak seizure heart rate are associated with greater success of the treatment (Perera et al., 2004; Folkerts, 1996). There is no relationship between seizure duration and ECTeffectiveness (Swartz, 2001). Since seizures are longer under the influence of etomidate than under the influence of methohexital (Eranti et al., 2009), it can be assumed that the anticonvulsant effect seen by the gain of electric charge necessary to elicit a sufficient seizure is smaller after etomidate than after methohexital. One of the aims of this study was to test this hypothesis. Besides this, we wanted to test if the choice of the narcotic had an effect on other ictal and treatment parameters. Since the choice of the narcotic might influence both the main effect and the side effects induced by ECT, a better characterization of the narcotics used in ECT is needed for further optimization of this treatment. Here we present a retrospective study with subjects who underwent ECT for clinical reasons in order to treat their affective disorder or their schizophrenia. One part of the patients received general anesthesia with methohexital, a short acting barbiturate, while the other part of the patients received etomidate, a non barbiturate. We sought to evaluate if these two patient groups differed in electric stimulation dose, main effect and the treatment’s side effects. Moreover, we examined whether the group that improved better during ECT differed from the one that improved less in any other aspect. 2. Methods 2.1. Study design This is a retrospective analysis of ECT treatments performed in our clinical institution from 2005 to 2007. All patients received general anesthesia. Originally, we performed ECT with methohexital as a narcotic. Then, with methohexital not being available in the market for some time, we resorted to using etomidate. None of the patients who received methohexital was included in the etomidate group. One reason for the choice of etomidate was that we thought the seizure parameters could be improved by this narcotic agent. In this analysis, 21 patients received methohexital and 47 patients received etomidate. Muscle relaxation was performed with the depolarizing muscle relaxant succinylcholine. Besides the use of two narcotic agents, all other treatment parameters stayed the same. The patients were suffering from major depression (n ¼ 51; ICD-10: F32.x, F33.x), schizoaffective disorder (n ¼ 6; F25.x) or treatment-resistant schizophrenia (n ¼ 11; F20.x). 2.2. ECT treatment Preoxygenation and post-seizure ventilation were performed by face mask until the patient’s own ventilation was sufficient again. Before and immediately after the ECT noninvasive arterial blood pressure was measured. Oxygen saturation, heart rate and electrocardiogram (ECG) were monitored. ECT treatment was performed using the Thymatron IV (SOMATICS, INC, Lake Bluff, IL) device. The treatment was started with right unilateral (RUL) stimulation as described by D’Elia et al. (1983). If a generalized EEG seizure of sufficient length could not be elicited even after raising the electric charge, or if no clinical response was seen, treatment was switched to left anterior right temporal (LART) stimulations (Swartz and Nelson, 2005). The seizures were monitored by two-channel EEG recording, with the EEG electrodes positioned bifrontally and over the mastoids. The energy administered during the first treatment was determined by the age
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method, which is frequently used in Germany (Loh et al., 2012). If the seizure quality was poor, the administered electric charge was raised by 10e30% for the following stimulation; in most cases the electric charge was raised by 20%. At very low stimulus doses, i.e. below 252 mC, the electric charge was raised only by 10%. At very high stimulus doses, i.e. above 756 mC, the charge was raised by 30% where applicable. A seizure of sufficient length was classified as of poor quality if the amplitudes of the ictal EEG were low due to visual classification of an experienced clinician, or if the postictal suppression was poor, as the latter finding suggests that the stimulus was not high enough supra-threshold (Nobler et al., 1993; Suppes et al., 1996; Krystal et al., 1995, 1998; Perera et al., 2004; Riddle et al., 1993). If the electroencephalographic seizure was below 20 s, or if no seizure could be elicited, a restimulation was performed. If the seizure as detected by the electroencephalogram was between 20 and 24 s, a restimulation was only performed if the ictal EEG had low amplitudes (Folkerts, 1996). No restimulation was performed above 25 s. In order to avoid restimulation during the refractory period of the brain, we performed restimulation 2 min after termination of the insufficient seizure. The energy administered is referred to in mC. Pulse duration was 0.5 ms for electric charges of 504 mC and below, while it was 1 ms for higher electric charges. ECT was performed twice a week. 2.3. Data acquisition We performed a retrospective analysis of treatment data of 68 patients who had been receiving ECT for clinical reasons. They were suffering from unipolar depression, bipolar depression, schizoaffective disorder or schizophrenia according to ICD-10. 21 patients received methohexital and 47 patients received etomidate as narcotic agent for ECT. For induction, 0.2e0.3 mg etomidate per kg body weight (20 4 mg) or 1e1.5 mg methohexital per kg body weight (117 28 mg) were administered. During and after each treatment session side effects were monitored. Pharmacological intervention was performed when necessary. The presence of cognitive side effects was assessed by the physician responsible for the patients’ treatment on the ward and by the supervisor. Cognitive deficits caused by ECT were labeled as mild, if they were observable, but not disabling in every-day life. They were labeled as intermediate, if they were disabling in every-day life, but a sufficient level of daily functioning was not impossible due to ECTinduced cognitive deficits. ECT-induced cognitive deficits were labeled as severe, if they were so disabling that they extensively impaired daily functioning. In these cases ECT was stopped. Information about the duration of the current episode, the duration of illness calculated from the first episode on, and history of hypertension or cardiac damage were gained from the patient’s medical records. GAF is a global parameter for daily functioning, which is applicable to severely ill patients not only with unipolar depression, but also schizoaffective disorder and schizophrenia. In order to compare the ECT-induced improvements of daily functioning of the etomidate and the methohexital group, GAF values were independently estimated before and after the course of ECT treatments by two psychiatrists responsible for the patients’ treatment on the ward. The mean of these GAF values was used for the analysis. The patients were treated with antidepressants, high-potency antipsychotics, low-potency antipsychotics, mood stabilizers and benzodiazepines. 2.4. Statistical analysis The following parameters of both treatment groups were compared by two-sided t-test: age, duration of illness, time from the first ECT treatment to discharge from hospital, GAF and alteration of
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H. Janouschek et al. / Journal of Psychiatric Research 47 (2013) 686e693
GAF, number of ECT treatments, electric charge at the first treatment, number of LART stimulations and restimulations, and total number of side effects. Fisher’s exact-test (two-sided) was used for the following parameters: sex, prevalence of the respective psychiatric illness, cognitive deficits, ECG abnormalities at admission, history of cardiac damage or hypertension and frequency of prescription of certain psychiatric medications. Repeated measurement was used to determine if seizure duration, time to peak power or administered electric charge changed significantly during the course of therapies. Analysis of variance was used to determine if age or the given narcotic had a significant influence on the change of the GAF value. A subsample analysis was done for the patients suffering from unipolar depression. The subsample analysis was performed with respect to the following parameters: age, duration of illness, time from the first ECT treatment to discharge from hospital, GAF and alteration of GAF, number of ECT treatments, electric charge at the first and the 13th treatments, number of LART stimulations and restimulations, total number of side effects, sex, cognitive deficits, ECG abnormalities at admission, history of cardiac damage or hypertension and frequency of prescription of certain psychiatric medications, development of seizure duration and time to peak power during the course of therapies. A p-value below 0.05 was regarded as significant. 3. Results 3.1. Demographic and clinical features In each treatment group, most patients were suffering from unipolar depression (etomidate: n ¼ 31; methohexital n ¼ 12). 8 patients receiving etomidate were suffering from schizophrenia, 5 from bipolar disorder and 3 from schizoaffective disorder. In the methohexital group, 3 patients were suffering from schizophrenia, bipolar disorder and schizoaffective disorder respectively (Table 1). The groups didn’t differ significantly in the distribution of illnesses (Fisher’s exact-test unipolar depression: p ¼ 0.59; Fisher’s exacttest bipolar depression: p ¼ 0.70; Fisher’s exact-test schizophrenia: p ¼ 1.0; Fisher’s exact-test schizoaffective disorder: p ¼ 0.36), sexes (etomidate: 18 male, 29 female; methohexital: 10 male, 11 female; Fisher’s exact-test: p ¼ 0.60), age (etomidate: 56 12 years, methohexital 54 15 years, t-test: p ¼ 0.56) or duration of disease calculated from the first episode (etomidate: 15.8 13.3 years, methohexital 13.3 10.3 years, t-test: p ¼ 0.52). The period of time
from the first ECT until discharge from hospital was similar for patients receiving etomidate or methohexital (etomidate: 61.9 33.2 days, methohexital 63.9 35.2 days, t-test: p ¼ 0.83). From the subgroup of patients with unipolar depression, analogous results were obtained for sex, age, duration of disease calculated from the first episode and the period between the first ECT and discharge from hospital (see Table 1). The groups didn’t differ significantly in terms of the prevalence of ECG alterations at admission (etomidate: 12 patients, methohexital: 7 patients; Fisher’s exacttest: p ¼ 0.57), the number of patients having a history of hypertension (etomidate: 11 patients, methohexital: 2 patients; Fisher’s exact-test: p ¼ 0.32) or in the number of cases with a history of cardiac damage (etomidate: 5 patients, methohexital: no patient; Fisher’s exact-test: p ¼ 0.31). The subgroup of patients suffering from unipolar depression exhibited comparable results for the prevalence of ECG alterations at admission, the number of patients having a history of hypertension and the number of cases with a history of cardiac damage (see Table 1). Treatment effectiveness was measured by the alteration of GAF values before and after the course of ECT. Although the groups differed significantly in pretreatment GAF values (etomidate: 28.1 10.6 vs. methohexital: 21.4 8.3; t-test: p < 0.01), no difference could be seen in the improvement of GAF (etomidate: 31.2 18.1 vs. methohexital: 30.9 16.5; t-test: p ¼ 0.94). This is also true for the subgroup of patients with unipolar depression (see Table 1). Analysis of variance revealed a significant influence of age (p ¼ 0.03), but not the chosen narcotic (p ¼ 0.94) on the change of the GAF value. The older the people were, the better they responded to the treatment. In the etomidate group, low-potency neuroleptics were given significantly more often than in the methohexital group (etomidate: 20 patients vs. methohexital one patient; Fisher’s exact-test: p < 0.01). The subgroup of patients with unipolar depression showed a similar result (see Table 1). For the other psychotropic medications, no significant difference between the groups could be seen. Analogous results were obtained from the subgroup of unipolar depressed patients (see Table 1). Table 1 presents demographic and clinical features of each treatment group. 3.2. ECT and ictal parameters A total of 524 treatment sessions were performed with etomidate as a narcotic agent and 212 treatment sessions were
Table 1 Demographic and clinical features.
Agea Genderb ECG alterations at admissionb History of hypertensionb History of cardiac damageb Time since first episodea Unipolar depressionb Bipolar depressionb Schizophreniab Schizoaffective disorderb Antidepressantsb High-potency antipsychoticsb Low-potency antipsychoticsb Mood stabilizerb Benzodiazepinesb Time to discharge from hospitala GAF before ECTa Improvement of GAFa *Statistically significant. a Two-sided t-test. b Fisher’s exact test two-sided.
Etomidate all diagnoses
Methohexital all diagnoses
p value all diagnoses
p value unipolar depression
56 12 y. 38% male 12 (26%) 11 (23%) 5 (11%) 15.8 13.3 y. 31 (66%) 5 (11%) 8 (17%) 3 (6%) 41 (87%) 27 (57%) 20 (43%) 12 (26%) 10 (21%) 61.9 33.2 days 28.1 10.6 31.2 18.1
54 15 y. 48% male 7 (33%) 2 (10%) 0 (0%) 13.3 10.3 y. 12 (57%) 3 (14%) 3 (14%) 3 (14%) 16 (76%) 14 (67%) 1 (5%) 3 (14%) 6 (29%) 63.9 35.2 days 21.4 8.3 30.9 16.5
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. p < 0.01* n.s. n.s. n.s. p < 0.01* n.s.
n.s. n.s. n.s. n.s. n.s. n.s. e e e e e n.s. p ¼ 0.03* n.s. n.s. n.s. p < 0.01* n.s.
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performed with methohexital. The number of ECT sessions per patient didn’t differ significantly in either treatment group (etomidate: 11.1 4.2 vs. methohexital: 10.1 3.7; t-test: p ¼ 0.33). Similar results were derived from the subgroup of patients with unipolar depression (see Table 2). In the group of patients receiving etomidate, 423 treatment sessions were performed with right unilateral ECT as described by D’Elia et al. (1983), while 101 treatment sessions (19.3%) were performed with left anterior right temporal ECT. With etomidate, the average number of treatment sessions with LART stimulations was 2.15 3.37 per patient. In this group, a restimulation was necessary in 64 treatment sessions (15.6%) with an average number of 1.36 1.54 restimulations per patient. In the group of patients receiving methohexital, 179 treatment sessions were performed with RUL ECT, while 33 treatment sessions (15.6%) were performed with the LART technique. In this group the average number of treatment sessions with LART stimulations was 1.57 3.33 per patient. With methohexital, 28 restimulations (13.2%) were necessary with an average number of 1.33 2.18 restimulations per patient. There was no significant difference in the number of LART treatments and restimulations per patient between the treatment groups (t-test: p ¼ 0.95 for restimulations and p ¼ 0.52 for LART treatments). The subgroup of unipolar depressed patients showed equivalent results (see Table 2). Due to the use of the age method, the administered electric charge during the first treatment session didn’t differ significantly for patients receiving etomidate or methohexital (etomidate: 283.1 99.5 mC vs. methohexital: 309.6 112.2 mC; t-test: p ¼ 0.33). In both groups the applied energy rose significantly from the 1st to the 13th treatment session (etomidate: repeated measurement p < 0.01; methohexital: repeated measurement p < 0.01). During the 13th treatment session the groups didn’t differ significantly in the administered electric charge (etomidate: 639.5 241.9 mC vs. methohexital 655.2 274.2 mC; t-test: p ¼ 0.90). Fig. 1 illustrates the gain of electric charge during the course of therapies with all diagnoses included and with patients suffering from unipolar depression. Table 2 presents the dosages of the narcotic agents and treatment parameters. There was no significant difference in electroencephalographic seizure duration between the first and the 13th treatment sessions in the etomidate group (1st treatment: 55.8 24.7 s, 13th treatment 50.9 30.1 s; repeated measurement p ¼ 0.27). The unipolar depressed subgroup showed a similar result (see Table 2). With methohexital, however, a declining trend was observed in the electroencephalographic seizure duration during the course of electroconvulsive therapies (methohexital 1st treatment: 58.9 31.9 s, methohexital 13th treatment 32.7 10.1 s; repeated measurement p ¼ 0.10). For patients suffering from unipolar depression, the results were not significant (repeated measurement: p ¼ 0.21). Fig. 2 illustrates the development of the EEG seizure duration during the course of therapies. In both treatment groups, the TPP (time to peak power) in the ictal EEG was also declining during the course of ECT treatments.
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However, the differences in TPP between the first and the 13th treatments did not reach statistical significance in either group. While peak power was reached after 21.0 18.0 s at the first treatment in the ictal EEG, it was reached in 13.4 10.8 s during treatment number 13 with etomidate (repeated measurement p ¼ 0.44). For patients suffering from unipolar depression, too, there was no significant decline in peak power from the first to the 13th treatment session (repeated measurement p ¼ 0.64). With methohexital, peak power in the ictal EEG was reached after 25.5 26.0 s at the first treatment and after 14.0 5.1 s at treatment number 13 (repeated measurement p ¼ 0.33). Here, too, the subgroup analysis with patients suffering from unipolar depression didn’t show any significant result (repeated measurement p ¼ 0.48). (Fig. 3 illustrates the decrease of time to peak power in the ictal EEG.) 3.3. Side effects Side effects observed during and immediately after each treatment session (peri-treatment side effects) were evaluated separately from accumulating cognitive side effects (which developed following several treatment sessions). Peri-treatment side effects occurred during 27 treatments out of the 524 treatments (5.2%) performed with etomidate and during 34 out of the 212 treatments (16%) performed with methohexital. During some treatment sessions different types of side effects occurred. The total number of peri-treatment side effects per patient was significantly lower in the etomidate group than in the methohexital group (etomidate: 0.57 0.95 vs. methohexital 1.62 1.86; t-test: p ¼ 0.02). An analogous result was derived from the unipolar depressed subgroup (see Table 3). With etomidate, peri-treatment side effects were detected in 4.7% of all treatments with restimulation. With methohexital, these side effects were detected in 10.7% of all treatments with restimulation. In 4% of all LART treatments under etomidate, peri-treatment side effects were seen while under methohexital; 30% of all LART treatments showed these side effects. The most frequent side effects of the electroconvulsive therapy were cognitive deficits which occurred in 11 patients of the etomidate group (23.4%) and in 5 patients of the methohexital group (23.8%). Here, statistical analysis revealed no difference between the treatment groups (Fisher’s exact-test: p ¼ 1.0). The same pvalue was achieved in the subgroup analysis involving patients suffering from unipolar depression. While the course of ECTs needed to be stopped due to severe cognitive deficits in 6 patients from the etomidate group, this wasn’t necessary in the methohexital group (Fisher’s exact-test: p ¼ 0.17). In the subgroup of patients suffering from unipolar depression, the treatment groups didn’t differ significantly in the prevalence of severe cognitive deficits (Fisher’s exact-test: p ¼ 0.56). Postictal restlessness and confusion were observed twelve times in each treatment group (5.7% of the treatments with methohexital, 2.3% of the treatments with etomidate). It was seen in 10 patients receiving etomidate (21.3% of all patients of this group) and in 6
Table 2 Treatment parameters. Etomidate all diagnoses Narcotic dosage Number of ECTs per patient Dosage of 1st stimulation Dosage of 13th stimulation Number of bilateral treatments per patient Number of restimulations per patient Two-sided t-test was used for statistics.
20 11.1 283.1 639.5 2.15 1.36
4 mg 4.2 99.5 mC 241.9 mC 3.37 1.54
Methohexital all diagnoses 117 10.1 309.6 655.2 1.57 1.33
28 mg 3.7 112.2 mC 274.2 mC 3.33 2.18
p value all diagnoses
p value unipolar depression
e n.s. n.s. n.s. n.s. n.s.
e n.s. n.s. n.s. n.s. n.s.
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H. Janouschek et al. / Journal of Psychiatric Research 47 (2013) 686e693 60
1000
50
800
Etomidate all diagnoses
700 600
Methohexital all diagnoses
500 400
Etomidate + Methohexital unipolar depression
300 200 100
TPP in seconds
Electric charge in mC
900
40 Etomidate
30
Methohexital
20 10 0
0
1 1
2
3
4
5
6
7
8
9
2
3
Fig. 1. Increase of the electric charge during the course of the therapies.
EEG seizure duration in seconds
patients receiving methohexital (28.6% of all patients of this group). Statistical analysis showed no difference in the number of patients developing this side effect (Fisher’s exact-test: p ¼ 0.55). The unipolar depressed subgroup showed a similar result (see Table 3). One patient receiving etomidate developed delirium after ECT, while this side effect didn’t occur in the methohexital group. Bradycardia and cardiac arrhythmia were seen during 9 ECTs with etomidate (1.7%) and during 11 ECTs with methohexital (5.2%). These side effects were seen in 6 patients of the etomidate group (12.8%) and 8 patients of the methohexital group (38.1%). Statistical analysis revealed a higher rate of patients from the methohexital group with these side effects (Fisher’s exact-test: p ¼ 0.03). In the subgroup of patients suffering from unipolar depression, there was a trend toward a higher rate of bradycardia and cardiac arrhythmia in the methohexital group (Fisher’s exact-test: p ¼ 0.08). Severe events of hypertension, which required acute intervention, were seen during 3 treatments with etomidate, and in 9 treatments with methohexital. This side effect occurred in 3 patients (6.4%) receiving etomidate and in 4 patients (19%) receiving methohexital. This difference however didn’t reach statistical significance (Fisher’s exact-test: p ¼ 0.19). An analogous result was derived from the subgroup of patients with unipolar depression (see Table 3). The treatment groups didn’t differ significantly in average postictal systolic (etomidate: 166 13 mmHg vs. methohexital: 169 18 mmHg; t-test p ¼ 0.57) or diastolic (etomidate: 90 8 mmHg vs. methohexital: 91 10 mmHg; t-test p ¼ 0.53) blood pressure of each patient. No significant difference in the average systolic (t-test p ¼ 0.96) or diastolic (t-test p ¼ 0.70) blood pressure of each patient was observed in the group with unipolar depression. There was also no significant change in postictal systolic or diastolic blood pressure of the respective group during the course of therapies. With etomidate, systolic blood pressure was 162 24 mmHg during the first treatment session and 177 26 mmHg during the 13th treatment session (repeated
90 80 70 60 50
Etomidate
40
Methohexital
30 20 10 0 2
3
4
5
6
7
8
5
6
7
8
9
10
11
12
13
Number of ECT sessions
Number of ECTsessions
1
4
10 11 12 13
9
10
11
12
13
Number of ECT sessions
Fig. 2. Development of EEG seizure duration during the course of therapies.
Fig. 3. Decrease of time to peak power during the course of therapies.
measurement p ¼ 0.65). Diastolic blood pressure was 88 16 mmHg during the first treatment session and 89 15 mmHg during the 13th treatment session in this group (repeated measurement p ¼ 0.74). In the etomidate group, the unipolar depressed subgroup also did not reveal any significant alteration of systolic (repeated measurement p ¼ 0.66) or diastolic blood pressure (repeated measurement p ¼ 0.67) during the course of therapies. With methohexital, systolic blood pressure was 164 18 mmHg at the first treatment and 176 22 mmHg at the 13th treatment (repeated measurement p ¼ 0.51). Diastolic blood pressure was 90 13 mmHg during the first treatment session and 103 10 mmHg during the 13th session in this group (repeated measurement p ¼ 0.57). In the methohexital group, the unipolar depressed patients exhibited no significant alteration of systolic (repeated measurement p ¼ 0.95) or diastolic blood pressure (repeated measurement p ¼ 0.63). With etomidate, we saw hyperhidrosis and a prolonged wakeup time following ECT in one patient and prolonged tachycardia in another patient. Two patients of each group developed hypomania as a side effect of the ECT. One patient of the methohexital group complained about newly developed tinnitus during the course of treatments. Table 3 presents the most frequent side effects in absolute and relative frequencies. 4. Discussion Etomidate and methohexital didn’t differ in treatment effectiveness. However, with both narcotics older patients had a greater benefit. Due to the anticonvulsive effect, there was a significant increase in charge during the course of ECTs with no difference between the treatment groups. While the electroencephalographic seizure duration in the first and the 13th therapies was in the same range with etomidate, it declined with methohexital, although without reaching statistical significance. Another finding of this study was that the time to peak power of the ictal electroencephalogram declined in both groups during the treatment course. We observed significantly more peri-treatment side effects (hypertension, bradycardia, arrhythmia, restlessness and confusion) with methohexital than with etomidate. We also found significantly more patients with bradycardia and arrhythmia, and a tendency toward more patients with serious hypertension, in the methohexital group compared to the etomidate group. As an effect of diagnosis could not be excluded, a subsample analysis of the patients suffering from unipolar depression was performed. However, the results of the subsample analysis and the analysis of the whole group were comparable. Conforming to our results, Eranti et al. (2009) couldn’t find any significant difference in ECT treatment effectiveness between
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Table 3 Most common side effects in absolute and relative frequencies.
Peri-treatment side effects per patienta Cognitive deficits in totalb Severe cognitive deficitsb Intermediate cognitive deficitsb Mild cognitive deficitsb Postictal restlessness/confusionb Bradycardia/arrhythmiab Serious hypertensionb
Etomidate all diagnoses
Methohexital all diagnoses
p value all diagnoses
p value unipolar depression
0.57 0.95 11 (23%) patients 6 (13%) patients 1 (2%) patients 1 (2.1%) patients 10 (21%) patients 6 (13%) patients 3 (6%) patients
1.62 1.86 5 (24%) patients 0 (0%) patients 2 (10%) patients 2 (10%) patients 6 (29%) patients 8 (38%) patients 4 (19%) patients
p ¼ 0.02* n.s. n.s. n.s. n.s. n.s. p ¼ 0.03* n.s.
p ¼ 0.03* n.s. n.s. n.s. n.s. n.s. n.s. n.s.
*Statistically significant. a Two-sided t-test. b Fisher’s exact test two-sided.
etomidate and methohexital. Our findings support the notion that older age can be seen as a positive predictor of response. In agreement with this, Wilkinson et al. (1993) reported a superior response rate to ECT for elderly subjects. In a retrospective analysis by Black et al. (1993), the average age of responders to ECT was also slightly higher than the age of nonresponders. In line with these results, Tew et al. (1999) saw a lower rate of response to ECT in patients aged 59 years and younger compared to those aged 60e74 years. Moreover, younger age was a predictor of non remission under ECT in a study by Dombrovski et al. (2005). However, in some studies greater patient age wasn’t associated with better response. While in one study by Krystal et al. (1998) older subjects were more likely to be nonresponders to ECT, another study by the same authors didn’t find any significant relationship between age and response (Krystal et al., 2000). Based on the available data, we suggest that higher patient age should be regarded as an argument for, not against, the use of ECT. The significant gain in electric charge in both groups during the treatment course can be explained by the anticonvulsant effect of ECT (Sackeim et al., 1983; Sackeim, 1999), which has been shown to be mediated by GABAergic mechanisms, endogenous opioids (Coffey et al., 1995; Krystal et al., 1998; Krueger et al., 1993; Shapira et al., 1996; Sackeim et al., 1987; Sackeim, 1999) and the GABAagonistic properties of etomidate and methohexital (Kendall and Minchin, 1982; Rudolph and Antkowiak, 2004). Since the treatment groups didn’t differ in the electric charge administered during the 1st and the 13th treatment sessions, the anticonvulsant effect of the two narcotic agents isn’t different either. Based on these findings, the initial assumption that the anticonvulsive effect is smaller with etomidate than with methohexital has to be rejected. In our study, a non-significant reduction of seizure duration was observed in the methohexital group compared to the etomidate group. Supporting our data, Avramov et al. (1995) also found longer mean seizure durations with etomidate compared to methohexital. Going along with this, Eranti et al. (2009) reported a trend toward longer seizure durations under the influence of etomidate than under methohexital. Compared to other narcotics, like propofol (Stadtland et al., 2002; Gábor et al., 2007) or thiopentone (Christensen et al., 1986; Saffer and Berk, 1998; Conca et al., 2003), longer seizure durations have also been shown with etomidate. Since the study is a retrospective analysis of clinical data, both treatment groups received different kinds of psychotropic medications. The patients’ co-medications probably affected the seizure duration. Higher doses of lorazepam, for example, are associated with shorter EEG seizure duration (Krueger et al., 1993; Boylan et al., 2000). It was during the course of our evaluation that we realized exactly how high was the number of different psychotropic medications that patients had received during ECT. This, however, is a common practice, with most German medical centers
continuing to administer antidepressants and antipsychotics in the same dosage during the course of ECT (Loh et al., 2012), although it is unclear if psychotropic medication is necessary during ECT. Whether the administration of psychotropic agents should be continued during the course of ECTs is a question that needs to be addressed in future research. Neither the etomidate group nor the methohexital group showed any significant increase in postictal systolic or diastolic blood pressure during the course of therapies. The groups didn’t differ significantly in average systolic and diastolic blood pressure of each patient. Supporting our data, Kovac and Pardo (1992) reported no differences in blood pressure while comparing patients who received methohexital with those given etomidate for ECT. In our study, the treatment groups didn’t differ significantly in the prevalence of ECG alterations at admission to hospital or in history of hypertension or cardiac damage. In absolute numbers, however, more cases with ECG alterations at admission to hospital and a history of hypertension could be seen in the etomidate group. In light of this, the more than 3-fold higher rate of cardiac side effects, like hypertension, bradycardia and cardiac arrhythmia, under methohexital compared to etomidate is surprising. Significantly more patients receiving methohexital suffered from bradycardia and arrhythmia. Based on our data, it can be concluded that methohexital causes more cardiovascular side effects than etomidate. Contradicting our results, however, Kovac and Pardo (1992) reported no difference in the occurrence of cardiac arrhythmias in their crossover study involving 20 patients receiving 2 treatments with etomidate and 2 treatments with methohexital respectively. But in this study, only the frequency of arrhythmias is reported, without any reference to whether the number of patients developing this side effect differed between the two narcotics. Regarding the transient cardiovascular side effects, a retrospective study by Eser et al. (2010) couldn’t find significant differences between etomidate and methohexital. This study also didn’t test if the number of patients who developed this kind of side effect differed between the treatment groups. This question, however, might be of importance, because although ECT is regarded as a relatively safe treatment even for patients with severe cardiac diseases, a study examining the prevalence of cardiovascular complications with ECT proved that patients with cardiac diseases experienced significantly more cardiovascular complications than those without any cardiac disease. The type of such ECT complications was strongly associated with the nature of the preexisting cardiac disease (Zielinski et al., 1993). Postictal restlessness and confusion are often seen after ECT. We found a higher proportion of postictal restlessness and confusion with methohexital while Eranti et al. (2009) couldn’t find significant differences between etomidate and methohexital with respect to these side effects.
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5. Limitations This was a retrospective study without randomization of the patients to one anesthetic. Since the sample size of the methohexital group is much smaller than the one of the etomidate group, the capacity of the study to demonstrate differences between the two hypnotic agents might have been reduced. A serious limitation of this study is that the treatment groups differ significantly in pretreatment GAF values. 6. Conclusion Acknowledging the caveats listed above, our study was able to show that ECT with etomidate and methohexital is equally effective. However, there were significantly fewer side effects with etomidate than with methohexital. In particular, there were fewer cardiovascular side effects, like bradycardia, cardiac arrhythmia and hypertension, requiring acute intervention. This aspect is of clinical relevance, especially with regard to the treatment of the elderly, who suffer from cardiovascular comorbidities more frequently. For these patients, etomidate should be preferred as a narcotic. Funding No funding was received for this study. Contributors H. Janouschek, T. Nickl-Jockschat, M. Haeck and M. Grözinger conducted the ECT treatments. B. Gillmann provided Anesthesia for the ECT treatments. H. Janouschek and M. Grözinger undertook the statistical analysis. H. Janouschek wrote the first draft of the manuscript. T. Nickl-Jockschat and M. Grözinger looked over the first draft and made their comments. After consideration of these comments in a first revision the manuscript was given to B. Gillmann and M. Haeck for further contribution. All authors contributed to and have approved the final manuscript. Conflict of interest H. Janouschek, MD, T. Nickl-Jockschat, MD, M. Haeck, MD., B. Gillmann, MD and M. Grözinger MD do not have any financial disclosures. There is no conflict of interest. Acknowledgments None. References American Psychiatric Association. The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging: a task force report of the American Psychiatric Association. 2nd ed.; 2001. Washington, D.C. Avramov MN, Husain MH, White PF. The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy. Anesthesia & Analgesia 1995;81:596e602. Black DW, Winokur G, Nasrallah A. A multivariante analysis of the experience of 423 depressed inpatients treated with electroconvulsive therapy. Convulsive Therapy 1993;9:112e20. Boylan LS, Haskett RF, Mulsant BH, Greenberg RM, Prudic J, Spicknall K, et al. Determinants of seizure threshold in ECT: benzodiazepine use, anesthetic dosage, and other factors. The Journal of ECT 2000;16:3e18. Christensen P, Kragh-Sørensen P, Sørensen C, Thomsen HY, Iversen AD, Christensen KS, et al. EEG-monitored ECT: a comparison of seizure duration under anesthesia with etomidate and thiopentone. Convulsive Therapy 1986;2:145e50.
Coffey CE, Lucke J, Weiner RD, Krystal AD, Aque M. Seizure threshold in electroconvulsive therapy (ECT) ii. the anticonvulsant effect of ECT. Biological Psychiatry 1995;37:777e88. Conca A, Germann R, König P. Etomidate vs. thiopentone in electroconvulsive therapy. an interdisciplinary challenge for anaesthesiology and psychiatry. Pharmacopsychiatry 2003;36:94e7. D’Elia GO, Ottosson JO, Strömgren LS. Present practice of convulsive therapy in Scandinavia. Archives of General Psychiatry 1983;40:577e81. Dombrovski AY, Mulsant BH, Haskett RF, Prudic J, Begley AE, Sackeim HA. Predictors of remission after electroconvulsive therapy in unipolar major depression. The Journal of Clinical Psychiatry 2005;66:1043e9. Eranti SV, Mogg AJ, Pluck GC, Landau S, McLoughlin DM. Methohexitone, propofol and etomidate in electroconvulsive therapy for depression: a naturalistic comparison study. Journal of Affective Disorders 2009;113:165e71. Eser D, Nothdurfter C, Schüle C, Damm J, Steng Y, Möller HJ, et al. The influence of anaesthetic medication on safety, tolerability and clinical effectiveness of electroconvulsive therapy. World Journal of Biological Psychiatry 2010;11: 447e56. Folkerts H. The ictal electroencephalogram as a marker for the efficacy of electroconvulsive therapy. European Archives of Psychiatry and Clinical Neuroscience 1996;246:155e64. Gábor G, Judit T, Zsolt I. Comparison of propofol and etomidate regarding impact on seizure threshold during electroconvulsive therapy in patients with schizophrenia. Neuropsychopharmacologia Hungarica 2007;9:125e30. Kendall TJ, Minchin MC. The effects of anaesthetics on the uptake and release of amino acid neurotransmitters in thalamic slices. British Journal of Pharmacology 1982;75:219e27. Kovac AL, Pardo M. A comparison between etomidate and methohexital for anaesthesia in ECT. Convulsive Therapy 1992;8:118e25. Krueger RB, Fama JM, Devanand DP, Prudic J, Sackeim HA. Does ECT permanently alter seizure threshold? Biological Psychiatry 1993;33:272e6. Krystal AD, Weiner RD, Coffey CE. The ictal EEG as a marker of adequate stimulus intensity with unilateral ECT. Journal of Neuropsychiatry and Clinical Neurosciences 1995;7:295e303. Krystal AD, Coffey CE, Weiner RD, Holsinger T. Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings. Journal of Neuropsychiatry and Clinical Neurosciences 1998;10:178e86. Krystal AD, Holsinger T, Weiner RD, Coffey CE. Prediction of the utility of a switch from unilateral to bilateral ECT in the elderly using treatment 2 ictal EEG indices. The Journal of ECT 2000;16:327e37. Loh N, Nickl-Jockschat T, Sheldrick AJ, Grözinger M. Accessibility, standards and challenges of electroconvulsive therapy in western industrialized countries: a German example. World Journal of Biological Psychiatry 2012 [Epub ahead of print]. Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: effects of electrode placement and stimulus intensity. Biological Psychiatry 1993;34:321e30. Perera TD, Luber B, Nobler MS, Prudic J, Anderson C, Sackeim HA. Seizure expression during electroconvulsive therapy: relationships with clinical outcome and cognitive side effects. Neuropsychopharmacology 2004;29:813e25. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, et al. Antidepressantinduced neurogenesis in the hippocampus of adult nonhuman primates. The Journal of Neuroscience 2007;27:4894e901. Riddle WJ, Scott AI, Bennie J, Carroll S, Fink G. Current intensity and oxytocin release after electroconvulsive therapy. Biological Psychiatry 1993;33:839e41. Robin A, De Tissera S. A double-blind controlled comparison of the therapeutic effects of low and high energy electroconvulsive therapies. The British Journal of Psychiatry 1982;141:357e66. Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nature Reviews Neuroscience 2004;5:709e20. Sackeim HA. The anticonvulsant hypothesis of the mechanisms of action of ECT: current status. The Journal of ECT 1999;15:5e26. Sackeim HA, Decina P, Prohovnik I, Malitz S, Resor SR. Anticonvulsant and antidepressant properties of electroconvulsive therapy: a proposed mechanism of action. Biological Psychiatry 1983;18:1301e10. Sackeim HA, Decina P, Prohovnik I, Malitz S, Resor SR. Studies of dosage, seizure threshold, and seizure duration in ECT. Biological Psychiatry 1987;22:249e68. Sackeim HA, Devanand DP, Prudic J. Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy. Psychiatric Clinics of North America 1991;14:803e43. Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Archives of General Psychiatry 2000;57:425e34. Saffer S, Berk M. Anesthetic induction for ECT with etomidate is associated with longer seizure duration than thiopentone. The Journal of ECT 1998;14:89e93. Shapira B, Lidsky D, Gorfine M, Lerer B. Electroconvulsive therapy and resistant depression: clinical implications of seizure threshold. The Journal of Clinical Psychiatry 1996;57:32e8. Stadtland C, Erfurth A, Ruta U, Michael N. A switch from propofol to etomidate during an ECT course increases EEG and motor seizure duration. The Journal of ECT 2002;18:22e5. Suppes T, Webb A, Carmody T, Gordon E, Gutierrez-Esteinou R, Hudson JI, et al. Is postictal electrical silence a predictor of response to electroconvulsive therapy? Journal of Affective Disorders 1996;41:55e8.
H. Janouschek et al. / Journal of Psychiatric Research 47 (2013) 686e693 Swartz CM. Stimulus dosing in electroconvulsive therapy and the threshold multiple method. The Journal of ECT 2001;17:87e90. Swartz CM, Nelson AI. Rational electroconvulsive therapy electrode placement. Psychiatry (Edgmont) 2005;2:37e43. Tew Jr JD, Mulsant BH, Haskett RF, Prudic J, Thase ME, Crowe RR, et al. Acute efficacy of ECT in the treatment of major depression in the old-old. The American Journal of Psychiatry 1999;156:1865e70. The UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003;361: 799e808.
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Weiner RD, Rogers HJ, Davidson JR, Squire LR. Effects of stimulus parameters on cognitive side effects. Annals of the New York Academy of Sciences 1986;462: 315e25. Wilkinson AM, Anderson DN, Peters S. Age and the effects of ECT. International Journal of Geriatric Psychiatry 1993;8:401e6. Zervas IM, Theleritis C, Soldatos CR. Using ECT in schizophrenia: a review from a clinical perspective. World Journal of Biological Psychiatry 2012;13:96e105. Zielinski RJ, Roose SP, Devanand DP, Woodring S, Sackeim HA. Cardiovascular complications of ECT in depressed patients with cardiac disease. The American Journal of Psychiatry 1993;150:904e9.
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Comparison of methohexital and etomidate as anesthetic agents for electroconvulsive therapy in affective and psychotic disorders H. Janouschek a, b, *, T. Nickl-Jockschat a, M. Haeck a, B. Gillmann c, M. Grözinger a a
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany Department of Neurology, RWTH Aachen University, Germany c Department of Anesthesiology, RWTH Aachen University, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 June 2012 Received in revised form 3 December 2012 Accepted 14 December 2012
Background: ECT is a well-established treatment for severe depression. The available data on psychosis are limited, but reliable. Its therapeutic potential relies on the induction of a generalized seizure. Besides other narcotics, methohexital and etomidate are used for general anesthesia in ECT. Since prolonged seizures have been reported following the use of etomidate, it can be deduced that the substances might differ in their anticonvulsant properties, resulting in a lower increase in stimulus intensity during the course of treatment under etomidate. Besides this hypothesis, we aimed to investigate the differential effects of etomidate and methohexital on clinical features, ECT parameters and side effects of the treatment. Methods: We performed a retrospective analysis of treatment data of patients with affective and psychotic diagnosis who received general anesthesia for ECT either with etomidate or with methohexital. Results: ECT with etomidate and methohexital was equally effective. During the course of therapies the administered electric charge increased significantly and equally in both treatment groups. In the methohexital group, but not in the etomidate group, electroencephalographic seizure duration had a declining trend during the course of therapies. We observed more side effects during and immediately after ECT in the methohexital group than in the etomidate group. Limitations: The limitations of this study are that the patients received various psychotropic comedications, which influence ictal parameters differently, and, secondly, the study is based on a retrospective analysis. Conclusion: The results of our analysis suggest that etomidate and methohexital affect ictal parameters to different extents. Longer seizure duration and fewer side effects are in favor of etomidate. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Electroconvulsive therapy Narcotics Etomidate Methohexital
1. Introduction Electroconvulsive therapy (ECT) is a well-established, highly effective treatment for severe depression. The available data on psychosis are limited, but reliable (The UK ECT Review Group, 2003; Zervas et al., 2012). Although the exact therapeutic mechanisms remain to be clarified, repeated induction of a generalized seizure is viewed as decisive for a therapeutic response (Sackeim et al., 1991). General anesthesia and muscular relaxation are performed in order to prevent injuries during the seizure.
* Corresponding author. Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. Tel.: þ49 241 8035986; fax: þ49 241 8082582. E-mail address: [email protected] (H. Janouschek). 0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2012.12.019
Cognitive-mnestic impairments are the most frequent severe side effects (The UK ECT Review Group, 2003). Although these impairments have been shown to be fully reversible (The UK ECT Review Group, 2003), they are usually perceived by patients as being very defacing, and sometimes to such an extent as to render a further administration of ECT impossible. Besides electrode placement, the electric charge needed for seizure induction has been shown to be a pivotal parameter influencing cognitive side effects (Weiner et al., 1986). Thus, all measures that lead to a reduction of the electric charge might also help reduce cognitive side effects. There is widespread consensus that a generalized seizure of sufficient duration is necessary for the therapeutic effect of the treatment (American Psychiatric Association, 2001), but this alone is likely not sufficient (Robin and De Tissera, 1982; Sackeim et al., 2000). While recent studies have sought to identify EEG measures that are able to predict ECT outcome (Perera et al., 2007),
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the notion that ictal parameters influence therapeutic properties of ECT continues to persist. Higher amplitudes of the ictal EEG, especially in the d-band, greater ictal coherence, stronger postictal suppression and a higher peak seizure heart rate are associated with greater success of the treatment (Perera et al., 2004; Folkerts, 1996). There is no relationship between seizure duration and ECTeffectiveness (Swartz, 2001). Since seizures are longer under the influence of etomidate than under the influence of methohexital (Eranti et al., 2009), it can be assumed that the anticonvulsant effect seen by the gain of electric charge necessary to elicit a sufficient seizure is smaller after etomidate than after methohexital. One of the aims of this study was to test this hypothesis. Besides this, we wanted to test if the choice of the narcotic had an effect on other ictal and treatment parameters. Since the choice of the narcotic might influence both the main effect and the side effects induced by ECT, a better characterization of the narcotics used in ECT is needed for further optimization of this treatment. Here we present a retrospective study with subjects who underwent ECT for clinical reasons in order to treat their affective disorder or their schizophrenia. One part of the patients received general anesthesia with methohexital, a short acting barbiturate, while the other part of the patients received etomidate, a non barbiturate. We sought to evaluate if these two patient groups differed in electric stimulation dose, main effect and the treatment’s side effects. Moreover, we examined whether the group that improved better during ECT differed from the one that improved less in any other aspect. 2. Methods 2.1. Study design This is a retrospective analysis of ECT treatments performed in our clinical institution from 2005 to 2007. All patients received general anesthesia. Originally, we performed ECT with methohexital as a narcotic. Then, with methohexital not being available in the market for some time, we resorted to using etomidate. None of the patients who received methohexital was included in the etomidate group. One reason for the choice of etomidate was that we thought the seizure parameters could be improved by this narcotic agent. In this analysis, 21 patients received methohexital and 47 patients received etomidate. Muscle relaxation was performed with the depolarizing muscle relaxant succinylcholine. Besides the use of two narcotic agents, all other treatment parameters stayed the same. The patients were suffering from major depression (n ¼ 51; ICD-10: F32.x, F33.x), schizoaffective disorder (n ¼ 6; F25.x) or treatment-resistant schizophrenia (n ¼ 11; F20.x). 2.2. ECT treatment Preoxygenation and post-seizure ventilation were performed by face mask until the patient’s own ventilation was sufficient again. Before and immediately after the ECT noninvasive arterial blood pressure was measured. Oxygen saturation, heart rate and electrocardiogram (ECG) were monitored. ECT treatment was performed using the Thymatron IV (SOMATICS, INC, Lake Bluff, IL) device. The treatment was started with right unilateral (RUL) stimulation as described by D’Elia et al. (1983). If a generalized EEG seizure of sufficient length could not be elicited even after raising the electric charge, or if no clinical response was seen, treatment was switched to left anterior right temporal (LART) stimulations (Swartz and Nelson, 2005). The seizures were monitored by two-channel EEG recording, with the EEG electrodes positioned bifrontally and over the mastoids. The energy administered during the first treatment was determined by the age
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method, which is frequently used in Germany (Loh et al., 2012). If the seizure quality was poor, the administered electric charge was raised by 10e30% for the following stimulation; in most cases the electric charge was raised by 20%. At very low stimulus doses, i.e. below 252 mC, the electric charge was raised only by 10%. At very high stimulus doses, i.e. above 756 mC, the charge was raised by 30% where applicable. A seizure of sufficient length was classified as of poor quality if the amplitudes of the ictal EEG were low due to visual classification of an experienced clinician, or if the postictal suppression was poor, as the latter finding suggests that the stimulus was not high enough supra-threshold (Nobler et al., 1993; Suppes et al., 1996; Krystal et al., 1995, 1998; Perera et al., 2004; Riddle et al., 1993). If the electroencephalographic seizure was below 20 s, or if no seizure could be elicited, a restimulation was performed. If the seizure as detected by the electroencephalogram was between 20 and 24 s, a restimulation was only performed if the ictal EEG had low amplitudes (Folkerts, 1996). No restimulation was performed above 25 s. In order to avoid restimulation during the refractory period of the brain, we performed restimulation 2 min after termination of the insufficient seizure. The energy administered is referred to in mC. Pulse duration was 0.5 ms for electric charges of 504 mC and below, while it was 1 ms for higher electric charges. ECT was performed twice a week. 2.3. Data acquisition We performed a retrospective analysis of treatment data of 68 patients who had been receiving ECT for clinical reasons. They were suffering from unipolar depression, bipolar depression, schizoaffective disorder or schizophrenia according to ICD-10. 21 patients received methohexital and 47 patients received etomidate as narcotic agent for ECT. For induction, 0.2e0.3 mg etomidate per kg body weight (20 4 mg) or 1e1.5 mg methohexital per kg body weight (117 28 mg) were administered. During and after each treatment session side effects were monitored. Pharmacological intervention was performed when necessary. The presence of cognitive side effects was assessed by the physician responsible for the patients’ treatment on the ward and by the supervisor. Cognitive deficits caused by ECT were labeled as mild, if they were observable, but not disabling in every-day life. They were labeled as intermediate, if they were disabling in every-day life, but a sufficient level of daily functioning was not impossible due to ECTinduced cognitive deficits. ECT-induced cognitive deficits were labeled as severe, if they were so disabling that they extensively impaired daily functioning. In these cases ECT was stopped. Information about the duration of the current episode, the duration of illness calculated from the first episode on, and history of hypertension or cardiac damage were gained from the patient’s medical records. GAF is a global parameter for daily functioning, which is applicable to severely ill patients not only with unipolar depression, but also schizoaffective disorder and schizophrenia. In order to compare the ECT-induced improvements of daily functioning of the etomidate and the methohexital group, GAF values were independently estimated before and after the course of ECT treatments by two psychiatrists responsible for the patients’ treatment on the ward. The mean of these GAF values was used for the analysis. The patients were treated with antidepressants, high-potency antipsychotics, low-potency antipsychotics, mood stabilizers and benzodiazepines. 2.4. Statistical analysis The following parameters of both treatment groups were compared by two-sided t-test: age, duration of illness, time from the first ECT treatment to discharge from hospital, GAF and alteration of
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GAF, number of ECT treatments, electric charge at the first treatment, number of LART stimulations and restimulations, and total number of side effects. Fisher’s exact-test (two-sided) was used for the following parameters: sex, prevalence of the respective psychiatric illness, cognitive deficits, ECG abnormalities at admission, history of cardiac damage or hypertension and frequency of prescription of certain psychiatric medications. Repeated measurement was used to determine if seizure duration, time to peak power or administered electric charge changed significantly during the course of therapies. Analysis of variance was used to determine if age or the given narcotic had a significant influence on the change of the GAF value. A subsample analysis was done for the patients suffering from unipolar depression. The subsample analysis was performed with respect to the following parameters: age, duration of illness, time from the first ECT treatment to discharge from hospital, GAF and alteration of GAF, number of ECT treatments, electric charge at the first and the 13th treatments, number of LART stimulations and restimulations, total number of side effects, sex, cognitive deficits, ECG abnormalities at admission, history of cardiac damage or hypertension and frequency of prescription of certain psychiatric medications, development of seizure duration and time to peak power during the course of therapies. A p-value below 0.05 was regarded as significant. 3. Results 3.1. Demographic and clinical features In each treatment group, most patients were suffering from unipolar depression (etomidate: n ¼ 31; methohexital n ¼ 12). 8 patients receiving etomidate were suffering from schizophrenia, 5 from bipolar disorder and 3 from schizoaffective disorder. In the methohexital group, 3 patients were suffering from schizophrenia, bipolar disorder and schizoaffective disorder respectively (Table 1). The groups didn’t differ significantly in the distribution of illnesses (Fisher’s exact-test unipolar depression: p ¼ 0.59; Fisher’s exacttest bipolar depression: p ¼ 0.70; Fisher’s exact-test schizophrenia: p ¼ 1.0; Fisher’s exact-test schizoaffective disorder: p ¼ 0.36), sexes (etomidate: 18 male, 29 female; methohexital: 10 male, 11 female; Fisher’s exact-test: p ¼ 0.60), age (etomidate: 56 12 years, methohexital 54 15 years, t-test: p ¼ 0.56) or duration of disease calculated from the first episode (etomidate: 15.8 13.3 years, methohexital 13.3 10.3 years, t-test: p ¼ 0.52). The period of time
from the first ECT until discharge from hospital was similar for patients receiving etomidate or methohexital (etomidate: 61.9 33.2 days, methohexital 63.9 35.2 days, t-test: p ¼ 0.83). From the subgroup of patients with unipolar depression, analogous results were obtained for sex, age, duration of disease calculated from the first episode and the period between the first ECT and discharge from hospital (see Table 1). The groups didn’t differ significantly in terms of the prevalence of ECG alterations at admission (etomidate: 12 patients, methohexital: 7 patients; Fisher’s exacttest: p ¼ 0.57), the number of patients having a history of hypertension (etomidate: 11 patients, methohexital: 2 patients; Fisher’s exact-test: p ¼ 0.32) or in the number of cases with a history of cardiac damage (etomidate: 5 patients, methohexital: no patient; Fisher’s exact-test: p ¼ 0.31). The subgroup of patients suffering from unipolar depression exhibited comparable results for the prevalence of ECG alterations at admission, the number of patients having a history of hypertension and the number of cases with a history of cardiac damage (see Table 1). Treatment effectiveness was measured by the alteration of GAF values before and after the course of ECT. Although the groups differed significantly in pretreatment GAF values (etomidate: 28.1 10.6 vs. methohexital: 21.4 8.3; t-test: p < 0.01), no difference could be seen in the improvement of GAF (etomidate: 31.2 18.1 vs. methohexital: 30.9 16.5; t-test: p ¼ 0.94). This is also true for the subgroup of patients with unipolar depression (see Table 1). Analysis of variance revealed a significant influence of age (p ¼ 0.03), but not the chosen narcotic (p ¼ 0.94) on the change of the GAF value. The older the people were, the better they responded to the treatment. In the etomidate group, low-potency neuroleptics were given significantly more often than in the methohexital group (etomidate: 20 patients vs. methohexital one patient; Fisher’s exact-test: p < 0.01). The subgroup of patients with unipolar depression showed a similar result (see Table 1). For the other psychotropic medications, no significant difference between the groups could be seen. Analogous results were obtained from the subgroup of unipolar depressed patients (see Table 1). Table 1 presents demographic and clinical features of each treatment group. 3.2. ECT and ictal parameters A total of 524 treatment sessions were performed with etomidate as a narcotic agent and 212 treatment sessions were
Table 1 Demographic and clinical features.
Agea Genderb ECG alterations at admissionb History of hypertensionb History of cardiac damageb Time since first episodea Unipolar depressionb Bipolar depressionb Schizophreniab Schizoaffective disorderb Antidepressantsb High-potency antipsychoticsb Low-potency antipsychoticsb Mood stabilizerb Benzodiazepinesb Time to discharge from hospitala GAF before ECTa Improvement of GAFa *Statistically significant. a Two-sided t-test. b Fisher’s exact test two-sided.
Etomidate all diagnoses
Methohexital all diagnoses
p value all diagnoses
p value unipolar depression
56 12 y. 38% male 12 (26%) 11 (23%) 5 (11%) 15.8 13.3 y. 31 (66%) 5 (11%) 8 (17%) 3 (6%) 41 (87%) 27 (57%) 20 (43%) 12 (26%) 10 (21%) 61.9 33.2 days 28.1 10.6 31.2 18.1
54 15 y. 48% male 7 (33%) 2 (10%) 0 (0%) 13.3 10.3 y. 12 (57%) 3 (14%) 3 (14%) 3 (14%) 16 (76%) 14 (67%) 1 (5%) 3 (14%) 6 (29%) 63.9 35.2 days 21.4 8.3 30.9 16.5
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. p < 0.01* n.s. n.s. n.s. p < 0.01* n.s.
n.s. n.s. n.s. n.s. n.s. n.s. e e e e e n.s. p ¼ 0.03* n.s. n.s. n.s. p < 0.01* n.s.
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performed with methohexital. The number of ECT sessions per patient didn’t differ significantly in either treatment group (etomidate: 11.1 4.2 vs. methohexital: 10.1 3.7; t-test: p ¼ 0.33). Similar results were derived from the subgroup of patients with unipolar depression (see Table 2). In the group of patients receiving etomidate, 423 treatment sessions were performed with right unilateral ECT as described by D’Elia et al. (1983), while 101 treatment sessions (19.3%) were performed with left anterior right temporal ECT. With etomidate, the average number of treatment sessions with LART stimulations was 2.15 3.37 per patient. In this group, a restimulation was necessary in 64 treatment sessions (15.6%) with an average number of 1.36 1.54 restimulations per patient. In the group of patients receiving methohexital, 179 treatment sessions were performed with RUL ECT, while 33 treatment sessions (15.6%) were performed with the LART technique. In this group the average number of treatment sessions with LART stimulations was 1.57 3.33 per patient. With methohexital, 28 restimulations (13.2%) were necessary with an average number of 1.33 2.18 restimulations per patient. There was no significant difference in the number of LART treatments and restimulations per patient between the treatment groups (t-test: p ¼ 0.95 for restimulations and p ¼ 0.52 for LART treatments). The subgroup of unipolar depressed patients showed equivalent results (see Table 2). Due to the use of the age method, the administered electric charge during the first treatment session didn’t differ significantly for patients receiving etomidate or methohexital (etomidate: 283.1 99.5 mC vs. methohexital: 309.6 112.2 mC; t-test: p ¼ 0.33). In both groups the applied energy rose significantly from the 1st to the 13th treatment session (etomidate: repeated measurement p < 0.01; methohexital: repeated measurement p < 0.01). During the 13th treatment session the groups didn’t differ significantly in the administered electric charge (etomidate: 639.5 241.9 mC vs. methohexital 655.2 274.2 mC; t-test: p ¼ 0.90). Fig. 1 illustrates the gain of electric charge during the course of therapies with all diagnoses included and with patients suffering from unipolar depression. Table 2 presents the dosages of the narcotic agents and treatment parameters. There was no significant difference in electroencephalographic seizure duration between the first and the 13th treatment sessions in the etomidate group (1st treatment: 55.8 24.7 s, 13th treatment 50.9 30.1 s; repeated measurement p ¼ 0.27). The unipolar depressed subgroup showed a similar result (see Table 2). With methohexital, however, a declining trend was observed in the electroencephalographic seizure duration during the course of electroconvulsive therapies (methohexital 1st treatment: 58.9 31.9 s, methohexital 13th treatment 32.7 10.1 s; repeated measurement p ¼ 0.10). For patients suffering from unipolar depression, the results were not significant (repeated measurement: p ¼ 0.21). Fig. 2 illustrates the development of the EEG seizure duration during the course of therapies. In both treatment groups, the TPP (time to peak power) in the ictal EEG was also declining during the course of ECT treatments.
689
However, the differences in TPP between the first and the 13th treatments did not reach statistical significance in either group. While peak power was reached after 21.0 18.0 s at the first treatment in the ictal EEG, it was reached in 13.4 10.8 s during treatment number 13 with etomidate (repeated measurement p ¼ 0.44). For patients suffering from unipolar depression, too, there was no significant decline in peak power from the first to the 13th treatment session (repeated measurement p ¼ 0.64). With methohexital, peak power in the ictal EEG was reached after 25.5 26.0 s at the first treatment and after 14.0 5.1 s at treatment number 13 (repeated measurement p ¼ 0.33). Here, too, the subgroup analysis with patients suffering from unipolar depression didn’t show any significant result (repeated measurement p ¼ 0.48). (Fig. 3 illustrates the decrease of time to peak power in the ictal EEG.) 3.3. Side effects Side effects observed during and immediately after each treatment session (peri-treatment side effects) were evaluated separately from accumulating cognitive side effects (which developed following several treatment sessions). Peri-treatment side effects occurred during 27 treatments out of the 524 treatments (5.2%) performed with etomidate and during 34 out of the 212 treatments (16%) performed with methohexital. During some treatment sessions different types of side effects occurred. The total number of peri-treatment side effects per patient was significantly lower in the etomidate group than in the methohexital group (etomidate: 0.57 0.95 vs. methohexital 1.62 1.86; t-test: p ¼ 0.02). An analogous result was derived from the unipolar depressed subgroup (see Table 3). With etomidate, peri-treatment side effects were detected in 4.7% of all treatments with restimulation. With methohexital, these side effects were detected in 10.7% of all treatments with restimulation. In 4% of all LART treatments under etomidate, peri-treatment side effects were seen while under methohexital; 30% of all LART treatments showed these side effects. The most frequent side effects of the electroconvulsive therapy were cognitive deficits which occurred in 11 patients of the etomidate group (23.4%) and in 5 patients of the methohexital group (23.8%). Here, statistical analysis revealed no difference between the treatment groups (Fisher’s exact-test: p ¼ 1.0). The same pvalue was achieved in the subgroup analysis involving patients suffering from unipolar depression. While the course of ECTs needed to be stopped due to severe cognitive deficits in 6 patients from the etomidate group, this wasn’t necessary in the methohexital group (Fisher’s exact-test: p ¼ 0.17). In the subgroup of patients suffering from unipolar depression, the treatment groups didn’t differ significantly in the prevalence of severe cognitive deficits (Fisher’s exact-test: p ¼ 0.56). Postictal restlessness and confusion were observed twelve times in each treatment group (5.7% of the treatments with methohexital, 2.3% of the treatments with etomidate). It was seen in 10 patients receiving etomidate (21.3% of all patients of this group) and in 6
Table 2 Treatment parameters. Etomidate all diagnoses Narcotic dosage Number of ECTs per patient Dosage of 1st stimulation Dosage of 13th stimulation Number of bilateral treatments per patient Number of restimulations per patient Two-sided t-test was used for statistics.
20 11.1 283.1 639.5 2.15 1.36
4 mg 4.2 99.5 mC 241.9 mC 3.37 1.54
Methohexital all diagnoses 117 10.1 309.6 655.2 1.57 1.33
28 mg 3.7 112.2 mC 274.2 mC 3.33 2.18
p value all diagnoses
p value unipolar depression
e n.s. n.s. n.s. n.s. n.s.
e n.s. n.s. n.s. n.s. n.s.
690
H. Janouschek et al. / Journal of Psychiatric Research 47 (2013) 686e693 60
1000
50
800
Etomidate all diagnoses
700 600
Methohexital all diagnoses
500 400
Etomidate + Methohexital unipolar depression
300 200 100
TPP in seconds
Electric charge in mC
900
40 Etomidate
30
Methohexital
20 10 0
0
1 1
2
3
4
5
6
7
8
9
2
3
Fig. 1. Increase of the electric charge during the course of the therapies.
EEG seizure duration in seconds
patients receiving methohexital (28.6% of all patients of this group). Statistical analysis showed no difference in the number of patients developing this side effect (Fisher’s exact-test: p ¼ 0.55). The unipolar depressed subgroup showed a similar result (see Table 3). One patient receiving etomidate developed delirium after ECT, while this side effect didn’t occur in the methohexital group. Bradycardia and cardiac arrhythmia were seen during 9 ECTs with etomidate (1.7%) and during 11 ECTs with methohexital (5.2%). These side effects were seen in 6 patients of the etomidate group (12.8%) and 8 patients of the methohexital group (38.1%). Statistical analysis revealed a higher rate of patients from the methohexital group with these side effects (Fisher’s exact-test: p ¼ 0.03). In the subgroup of patients suffering from unipolar depression, there was a trend toward a higher rate of bradycardia and cardiac arrhythmia in the methohexital group (Fisher’s exact-test: p ¼ 0.08). Severe events of hypertension, which required acute intervention, were seen during 3 treatments with etomidate, and in 9 treatments with methohexital. This side effect occurred in 3 patients (6.4%) receiving etomidate and in 4 patients (19%) receiving methohexital. This difference however didn’t reach statistical significance (Fisher’s exact-test: p ¼ 0.19). An analogous result was derived from the subgroup of patients with unipolar depression (see Table 3). The treatment groups didn’t differ significantly in average postictal systolic (etomidate: 166 13 mmHg vs. methohexital: 169 18 mmHg; t-test p ¼ 0.57) or diastolic (etomidate: 90 8 mmHg vs. methohexital: 91 10 mmHg; t-test p ¼ 0.53) blood pressure of each patient. No significant difference in the average systolic (t-test p ¼ 0.96) or diastolic (t-test p ¼ 0.70) blood pressure of each patient was observed in the group with unipolar depression. There was also no significant change in postictal systolic or diastolic blood pressure of the respective group during the course of therapies. With etomidate, systolic blood pressure was 162 24 mmHg during the first treatment session and 177 26 mmHg during the 13th treatment session (repeated
90 80 70 60 50
Etomidate
40
Methohexital
30 20 10 0 2
3
4
5
6
7
8
5
6
7
8
9
10
11
12
13
Number of ECT sessions
Number of ECTsessions
1
4
10 11 12 13
9
10
11
12
13
Number of ECT sessions
Fig. 2. Development of EEG seizure duration during the course of therapies.
Fig. 3. Decrease of time to peak power during the course of therapies.
measurement p ¼ 0.65). Diastolic blood pressure was 88 16 mmHg during the first treatment session and 89 15 mmHg during the 13th treatment session in this group (repeated measurement p ¼ 0.74). In the etomidate group, the unipolar depressed subgroup also did not reveal any significant alteration of systolic (repeated measurement p ¼ 0.66) or diastolic blood pressure (repeated measurement p ¼ 0.67) during the course of therapies. With methohexital, systolic blood pressure was 164 18 mmHg at the first treatment and 176 22 mmHg at the 13th treatment (repeated measurement p ¼ 0.51). Diastolic blood pressure was 90 13 mmHg during the first treatment session and 103 10 mmHg during the 13th session in this group (repeated measurement p ¼ 0.57). In the methohexital group, the unipolar depressed patients exhibited no significant alteration of systolic (repeated measurement p ¼ 0.95) or diastolic blood pressure (repeated measurement p ¼ 0.63). With etomidate, we saw hyperhidrosis and a prolonged wakeup time following ECT in one patient and prolonged tachycardia in another patient. Two patients of each group developed hypomania as a side effect of the ECT. One patient of the methohexital group complained about newly developed tinnitus during the course of treatments. Table 3 presents the most frequent side effects in absolute and relative frequencies. 4. Discussion Etomidate and methohexital didn’t differ in treatment effectiveness. However, with both narcotics older patients had a greater benefit. Due to the anticonvulsive effect, there was a significant increase in charge during the course of ECTs with no difference between the treatment groups. While the electroencephalographic seizure duration in the first and the 13th therapies was in the same range with etomidate, it declined with methohexital, although without reaching statistical significance. Another finding of this study was that the time to peak power of the ictal electroencephalogram declined in both groups during the treatment course. We observed significantly more peri-treatment side effects (hypertension, bradycardia, arrhythmia, restlessness and confusion) with methohexital than with etomidate. We also found significantly more patients with bradycardia and arrhythmia, and a tendency toward more patients with serious hypertension, in the methohexital group compared to the etomidate group. As an effect of diagnosis could not be excluded, a subsample analysis of the patients suffering from unipolar depression was performed. However, the results of the subsample analysis and the analysis of the whole group were comparable. Conforming to our results, Eranti et al. (2009) couldn’t find any significant difference in ECT treatment effectiveness between
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691
Table 3 Most common side effects in absolute and relative frequencies.
Peri-treatment side effects per patienta Cognitive deficits in totalb Severe cognitive deficitsb Intermediate cognitive deficitsb Mild cognitive deficitsb Postictal restlessness/confusionb Bradycardia/arrhythmiab Serious hypertensionb
Etomidate all diagnoses
Methohexital all diagnoses
p value all diagnoses
p value unipolar depression
0.57 0.95 11 (23%) patients 6 (13%) patients 1 (2%) patients 1 (2.1%) patients 10 (21%) patients 6 (13%) patients 3 (6%) patients
1.62 1.86 5 (24%) patients 0 (0%) patients 2 (10%) patients 2 (10%) patients 6 (29%) patients 8 (38%) patients 4 (19%) patients
p ¼ 0.02* n.s. n.s. n.s. n.s. n.s. p ¼ 0.03* n.s.
p ¼ 0.03* n.s. n.s. n.s. n.s. n.s. n.s. n.s.
*Statistically significant. a Two-sided t-test. b Fisher’s exact test two-sided.
etomidate and methohexital. Our findings support the notion that older age can be seen as a positive predictor of response. In agreement with this, Wilkinson et al. (1993) reported a superior response rate to ECT for elderly subjects. In a retrospective analysis by Black et al. (1993), the average age of responders to ECT was also slightly higher than the age of nonresponders. In line with these results, Tew et al. (1999) saw a lower rate of response to ECT in patients aged 59 years and younger compared to those aged 60e74 years. Moreover, younger age was a predictor of non remission under ECT in a study by Dombrovski et al. (2005). However, in some studies greater patient age wasn’t associated with better response. While in one study by Krystal et al. (1998) older subjects were more likely to be nonresponders to ECT, another study by the same authors didn’t find any significant relationship between age and response (Krystal et al., 2000). Based on the available data, we suggest that higher patient age should be regarded as an argument for, not against, the use of ECT. The significant gain in electric charge in both groups during the treatment course can be explained by the anticonvulsant effect of ECT (Sackeim et al., 1983; Sackeim, 1999), which has been shown to be mediated by GABAergic mechanisms, endogenous opioids (Coffey et al., 1995; Krystal et al., 1998; Krueger et al., 1993; Shapira et al., 1996; Sackeim et al., 1987; Sackeim, 1999) and the GABAagonistic properties of etomidate and methohexital (Kendall and Minchin, 1982; Rudolph and Antkowiak, 2004). Since the treatment groups didn’t differ in the electric charge administered during the 1st and the 13th treatment sessions, the anticonvulsant effect of the two narcotic agents isn’t different either. Based on these findings, the initial assumption that the anticonvulsive effect is smaller with etomidate than with methohexital has to be rejected. In our study, a non-significant reduction of seizure duration was observed in the methohexital group compared to the etomidate group. Supporting our data, Avramov et al. (1995) also found longer mean seizure durations with etomidate compared to methohexital. Going along with this, Eranti et al. (2009) reported a trend toward longer seizure durations under the influence of etomidate than under methohexital. Compared to other narcotics, like propofol (Stadtland et al., 2002; Gábor et al., 2007) or thiopentone (Christensen et al., 1986; Saffer and Berk, 1998; Conca et al., 2003), longer seizure durations have also been shown with etomidate. Since the study is a retrospective analysis of clinical data, both treatment groups received different kinds of psychotropic medications. The patients’ co-medications probably affected the seizure duration. Higher doses of lorazepam, for example, are associated with shorter EEG seizure duration (Krueger et al., 1993; Boylan et al., 2000). It was during the course of our evaluation that we realized exactly how high was the number of different psychotropic medications that patients had received during ECT. This, however, is a common practice, with most German medical centers
continuing to administer antidepressants and antipsychotics in the same dosage during the course of ECT (Loh et al., 2012), although it is unclear if psychotropic medication is necessary during ECT. Whether the administration of psychotropic agents should be continued during the course of ECTs is a question that needs to be addressed in future research. Neither the etomidate group nor the methohexital group showed any significant increase in postictal systolic or diastolic blood pressure during the course of therapies. The groups didn’t differ significantly in average systolic and diastolic blood pressure of each patient. Supporting our data, Kovac and Pardo (1992) reported no differences in blood pressure while comparing patients who received methohexital with those given etomidate for ECT. In our study, the treatment groups didn’t differ significantly in the prevalence of ECG alterations at admission to hospital or in history of hypertension or cardiac damage. In absolute numbers, however, more cases with ECG alterations at admission to hospital and a history of hypertension could be seen in the etomidate group. In light of this, the more than 3-fold higher rate of cardiac side effects, like hypertension, bradycardia and cardiac arrhythmia, under methohexital compared to etomidate is surprising. Significantly more patients receiving methohexital suffered from bradycardia and arrhythmia. Based on our data, it can be concluded that methohexital causes more cardiovascular side effects than etomidate. Contradicting our results, however, Kovac and Pardo (1992) reported no difference in the occurrence of cardiac arrhythmias in their crossover study involving 20 patients receiving 2 treatments with etomidate and 2 treatments with methohexital respectively. But in this study, only the frequency of arrhythmias is reported, without any reference to whether the number of patients developing this side effect differed between the two narcotics. Regarding the transient cardiovascular side effects, a retrospective study by Eser et al. (2010) couldn’t find significant differences between etomidate and methohexital. This study also didn’t test if the number of patients who developed this kind of side effect differed between the treatment groups. This question, however, might be of importance, because although ECT is regarded as a relatively safe treatment even for patients with severe cardiac diseases, a study examining the prevalence of cardiovascular complications with ECT proved that patients with cardiac diseases experienced significantly more cardiovascular complications than those without any cardiac disease. The type of such ECT complications was strongly associated with the nature of the preexisting cardiac disease (Zielinski et al., 1993). Postictal restlessness and confusion are often seen after ECT. We found a higher proportion of postictal restlessness and confusion with methohexital while Eranti et al. (2009) couldn’t find significant differences between etomidate and methohexital with respect to these side effects.
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5. Limitations This was a retrospective study without randomization of the patients to one anesthetic. Since the sample size of the methohexital group is much smaller than the one of the etomidate group, the capacity of the study to demonstrate differences between the two hypnotic agents might have been reduced. A serious limitation of this study is that the treatment groups differ significantly in pretreatment GAF values. 6. Conclusion Acknowledging the caveats listed above, our study was able to show that ECT with etomidate and methohexital is equally effective. However, there were significantly fewer side effects with etomidate than with methohexital. In particular, there were fewer cardiovascular side effects, like bradycardia, cardiac arrhythmia and hypertension, requiring acute intervention. This aspect is of clinical relevance, especially with regard to the treatment of the elderly, who suffer from cardiovascular comorbidities more frequently. For these patients, etomidate should be preferred as a narcotic. Funding No funding was received for this study. Contributors H. Janouschek, T. Nickl-Jockschat, M. Haeck and M. Grözinger conducted the ECT treatments. B. Gillmann provided Anesthesia for the ECT treatments. H. Janouschek and M. Grözinger undertook the statistical analysis. H. Janouschek wrote the first draft of the manuscript. T. Nickl-Jockschat and M. Grözinger looked over the first draft and made their comments. After consideration of these comments in a first revision the manuscript was given to B. Gillmann and M. Haeck for further contribution. All authors contributed to and have approved the final manuscript. Conflict of interest H. Janouschek, MD, T. Nickl-Jockschat, MD, M. Haeck, MD., B. Gillmann, MD and M. Grözinger MD do not have any financial disclosures. There is no conflict of interest. Acknowledgments None. References American Psychiatric Association. The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging: a task force report of the American Psychiatric Association. 2nd ed.; 2001. Washington, D.C. Avramov MN, Husain MH, White PF. The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy. Anesthesia & Analgesia 1995;81:596e602. Black DW, Winokur G, Nasrallah A. A multivariante analysis of the experience of 423 depressed inpatients treated with electroconvulsive therapy. Convulsive Therapy 1993;9:112e20. Boylan LS, Haskett RF, Mulsant BH, Greenberg RM, Prudic J, Spicknall K, et al. Determinants of seizure threshold in ECT: benzodiazepine use, anesthetic dosage, and other factors. The Journal of ECT 2000;16:3e18. Christensen P, Kragh-Sørensen P, Sørensen C, Thomsen HY, Iversen AD, Christensen KS, et al. EEG-monitored ECT: a comparison of seizure duration under anesthesia with etomidate and thiopentone. Convulsive Therapy 1986;2:145e50.
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A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Archives of General Psychiatry 2000;57:425e34. Saffer S, Berk M. Anesthetic induction for ECT with etomidate is associated with longer seizure duration than thiopentone. The Journal of ECT 1998;14:89e93. Shapira B, Lidsky D, Gorfine M, Lerer B. Electroconvulsive therapy and resistant depression: clinical implications of seizure threshold. The Journal of Clinical Psychiatry 1996;57:32e8. Stadtland C, Erfurth A, Ruta U, Michael N. A switch from propofol to etomidate during an ECT course increases EEG and motor seizure duration. The Journal of ECT 2002;18:22e5. Suppes T, Webb A, Carmody T, Gordon E, Gutierrez-Esteinou R, Hudson JI, et al. Is postictal electrical silence a predictor of response to electroconvulsive therapy? Journal of Affective Disorders 1996;41:55e8.
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Weiner RD, Rogers HJ, Davidson JR, Squire LR. Effects of stimulus parameters on cognitive side effects. Annals of the New York Academy of Sciences 1986;462: 315e25. Wilkinson AM, Anderson DN, Peters S. Age and the effects of ECT. International Journal of Geriatric Psychiatry 1993;8:401e6. Zervas IM, Theleritis C, Soldatos CR. Using ECT in schizophrenia: a review from a clinical perspective. World Journal of Biological Psychiatry 2012;13:96e105. Zielinski RJ, Roose SP, Devanand DP, Woodring S, Sackeim HA. Cardiovascular complications of ECT in depressed patients with cardiac disease. The American Journal of Psychiatry 1993;150:904e9.