REVIEW

Propofol for ECT Anesthesia a Review of the Literature Keith G. Rasmussen, MD Abstract: Propofol is a commonly used anesthetic drug for electroconvulsive therapy (ECT), as evidenced by the frequency with which its use is reported in ECT literature. Concerns have been raised over its propensity to be associated with shortened seizure duration vis-à-vis other anesthetic drugs, thus limiting its use in some settings. However, in the surgical anesthesia literature, propofol has shown distinct advantages such as improved hemodynamics and postanesthesia recovery. Given the capricious availability of standard barbiturate anesthetics in some countries, propofol use has probably increased. Thus, a review of its profile for a number of outcome measures in ECT is appropriate. Herein, the author reviews the extensive literature for propofol in ECT, focusing on 5 outcome measures: seizure duration, hemodynamics, postanesthesia recovery, cognitive adverse effects, and therapeutic efficacy. Results indicate that propofol is indeed robustly associated with shorter seizures than other anesthetics but that antidepressant efficacy does not seem to be compromised. Heart rate and blood pressure changes are not as high with propofol, and postanesthesia recovery may be quicker with propofol as well. Not enough data are available regarding cognitive adverse effects to make definitive conclusions, but so far, there does not seem to be a worsened cognitive profile when it is used in ECT. Propofol seems to be an acceptable anesthetic for ECT with advantages for some situations. Using the lowest effective anesthetic dosage minimizes its effect on seizure elicitation and duration. Key Words: electroconvulsive therapy, propofol, anesthesia (J ECT 2014;30: 210–215)

T

raditionally, the barbiturates methohexital and thiopental have been the most commonly used anesthetic agents for ECT. However, there have been occasional shortages of these medications, making it necessary to use alternatives. Among these, propofol has received much research attention. When introduced into surgical anesthesia in the 1980s, propofol was considered advantageous in being associated with a favorable hemodynamic profile and quicker recovery times. Its use in ECT anesthesia has been reported since shortly thereafter and, as reviewed later in this paper, was quickly assessed to cause reductions in ECT seizure duration. This led to concerns about possible disadvantageous effects on therapeutic efficacy. However, in some settings, methohexital and thiopental have limited availability, and other ECT anesthetics such as etomidate and ketamine are associated with disadvantages, so that propofol use has been common. Review of the ECT literature on propofol reveals, somewhat surprisingly to this author, several dozen well-controlled randomized trials comparing various outcome measures pertinent to ECT practice between propofol and the other ECT anesthetics. Thus, it was felt that a review at this time would be helpful and informative to ECT practitioners. Herein, we focus on 5 sets of outcome measures: seizure duration,

From the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN. Received for publication August 23, 2013; accepted October 30, 2013. Reprints: Keith G. Rasmussen, MD, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905 (e‐mail: [email protected]). The author has no conflict of interest or financial disclosures to report. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/YCT.0000000000000093

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hemodynamics, postictal recovery, intertreatment cognition, and antidepressant efficacy. Of note, the anesthetic agent methohexital is also known as “methohexitone,” and thiopental is also known as “thiopentone,” in the literature. In this report, only the terms methohexital and thiopental will be used.

Propofol and Seizure Duration Table 1 presents results of studies, mostly randomized trials, in which seizure duration was compared between propofol and at least one other anesthetic drug.1–38 The trials are either randomized crossover designs, in which each patient received at least one treatment with each of the study anesthetics, or randomized noncrossover trials, in which each patient was randomized to receive only one of the study anesthetics throughout their course of treatment. The former methodology allows assessment of outcome variables that depend on a single treatment, such as seizure duration, hemodynamics, and postictal recovery, whereas the latter methodology allows concurrent assessment of therapeutic and cognitive outcomes associated with an anesthetic drug as discussed later in this paper. Two of the studies involved nonrandomized data collections,30,37 but the results were considered meaningful enough to include in Table 1. As summarized in Table 1, seizure durations were shorter with propofol than with all other anesthetics in most studies. This is a very robust, consistent finding. It would be difficult, however, to enter all these trials into a single meta-analysis, as designs and comparator drugs vary as well as the treatments in the course of ECT, which are assessed for duration. For example, if one study assesses just the first and second treatments of a series, whereas another assesses all treatments in a series, the 2 outcome data sets probably should not be combined into one data set, as the durations tend to be longer earlier in the course of treatments. Additionally, methods for determining motor and EEG duration were almost never described in the individual studies, making the task of combining results even less certain. Finally, the doses of the different anesthetics varied from study to study. The differences would seem to be greatest between propofol and etomidate and least between propofol and thiopental, with methohexital being intermediate. A metaanalysis comparing methohexital with propofol did conclude that on average motor durations are 8.4 seconds greater with methohexital.39 Numerous studies comparing these 2 drugs have been published since that time and are included in Table 1. In addition to the prospective randomized studies presented in Table 1, a few retrospective data sets are worth mentioning. Mitchell et al40–42 reviewed their experience treating patients undergoing ECT with either propofol or thiopental. Mean motor seizure duration in their full sample41,42 with propofol was 18.1 seconds, whereas that with thiopental was 24.7 seconds (P < 0.01 in comparison with thiopental). Swaim et al43 retrospectively reviewed their experience with propofol, thiopental, and methohexital, doses unspecified, and found in 95 total patients mean EEG durations of 42.8, 47.5, and 51.3 seconds, respectively. The difference between methohexital and the two others was significant (P < 0.01) but not that between thiopental and propofol (P = 0.07). Eser et al44 studied 455 total patients retrospectively receiving either propofol, thiopental, methohexital, or etomidate, Journal of ECT • Volume 30, Number 3, September 2014

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TABLE 1. Propofol and Seizure Duration Comparator Drug Etomidate* Ketamine

Sevoflurane Thiopental§ Methohexital

No. Patients‡

Designs† 22–25,33,34

Four RC Two RC27,28 One RNC29 One NR30 Three RC 35,36,38 One NR37 Five RC1,2,5,26,32 Three RNC3,4,31 Ten RC6,7,10–12,18–21,24 Six RNC8,9,13–17

Summary of Results

94 185

All 4 studies showed robustly higher seizure duration with etomidate. Ketamine alone resulted in higher seizure duration than propofol alone. Combination propofol/ketamine was approximately equal overall to propofol alone.

143

Three of 4 studies showed higher seizure duration with sevoflurane; one showed higher duration with propofol.

281

In 7 studies, thiopental had higher seizure durations. In one study, there was no difference.

486

Methohexital resulted in higher seizure durations in all studies, although in two, it was not significant19,20 and in two, no statistics were provided.13,21

*Four separate studies22,23,33,34; 22–23 and 33–34 are one study each. †RC indicates randomized crossover; RNC, randomized noncrossover; NR, nonrandomized data collection. ‡Refers to total N of all studies. §One study5 involves thiamylal, a barbiturate of similar potency to thiopental.

and found quite small differences, probably owing to the inordinately large barbiturate doses: 5.0 mg/kg for thiopental and 1.9 mg/kg for methohexital. Regarding dose-response relationships for propofol and seizure duration, some findings from the studies listed in Table 1 are noteworthy. First, there were 2 studies in which multiple doses of propofol were used.5,24 In both of these, lower doses of propofol (0.75 or 1.0 mg/kg) were associated with higher seizure durations. Also, in all the studies in which low doses of propofol were used (defined here as ≤ 1.0 mg/kg),5,10,22–24,27,30,33,34 the mean motor duration was approximately 34.9 seconds, whereas that for EEG was approximately 48.1 seconds, both of which would be considered more or less “normal” durations for ECT practice. Whereas the relationship between seizure duration and clinical response is complex and has not been completely clarified in the ECT literature, for situations in which propofol use in higher doses is associated with what seem to be unacceptably short seizures or even lack of seizure elicitation, the lower dose range of 0.75 to 1.0 mg/kg, which is lower than most of the propofol reports in Table 1, presents a clinically tested strategy that might be of help.

Propofol and Hemodynamics As mentioned earlier, one of the advantages of propofol for surgical anesthesia is improved hemodynamics (blood pressure

and heart rate). The studies of propofol relevant to ECT hemodynamics are presented in Table 2.2,5–7,10,11,14,19–21,24–30,32–38,45–47 As can be appreciated, there are numerous randomized studies, either with or without crossover, comparing propofol with at least one other anesthetic in which blood pressure, heart rate, or some other measures of cardiovascular function such as echocardiography, are assessed. The studies vary with regard to the time points in which these measures were obtained, making it impossible to provide a quantified summary of how much higher blood pressure and heart rate rise is with other anesthetics than propofol. However, in each of the studies listed in Table 2, the hemodynamic metric studied, which was most often blood pressure and heart rate, showed more intense increase with the comparator than with propofol. In many studies, the blood pressures did not rise appreciably in the postictal time period with propofol. This aspect of propofol use is a very robust finding in comparison with other anesthetics. Of course, the incidence of cardiovascular complications with ECT, such as myocardial infarction, stroke, or malignant dysrhythmia requiring transfer to an intensive care unit, is very small. Thus, a legitimate question is whether the blunted rise in myocardial workload with propofol is of clinical significance, especially considering that it lasts on average only a few minutes or so. However, for patients in delicate cardiac status, such as low ejection fraction, propofol may offer an advantage.

TABLE 2. Propofol and ECT Hemodynamics Comparator Drug Etomidate Ketamine

Sevoflurane Thiopental Methohexital

Designs 24,25,33,34,47

Four RC Two RC27,28 One RNC29 One NR30 Three RC35,36,38 One NR37 Four RC2,5,26,32 Two RNC45,46 Eight RC6,7,10,11,19–21,24 One RNC14

No. Patients

Summary of Results

78 185

Higher postictal BP or HR with etomidate Higher postictal BP or HR with ketamine

143

Higher postictal HR or BP with sevoflurane

146

Higher postictal BP, HR, or left ventricular hemodynamic changes with thiopental

249

Higher postictal BP or HR with methohexital

BP indicates blood pressure; HR, heart rate.

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TABLE 3. Propofol and ECT Recovery Comparator Drug

Designs

No. Patients

24

Etomidate

One RC One RNC49 Two RC27,28 One RNC29 One NR30 Two RC36,38 One NR37 Five RC1,2,5,26,32 Two RNC4,49 Six RC10,11,19–21,24 Two RNC16,17 One NR48

Ketamine

Sevoflurane Thiopental Methohexital

Summary of Results

40

Recovery quicker with propofol than etomidate

185

Possible shorter time to recovery with propofol. More fear upon awakening with ketamine

113

Mixed results—overall, the 2 drugs seem similar in recovery speed

219

Speed of recovery similar or slightly faster with propofol

217

Overall, approximately equal recovery speed between propofol and methohexital. Maybe less posttreatment nausea with propofol

Propofol and Postanesthesia Recovery There are several dimensions to post-ECT recovery, including time to breathing, eye opening, following commands, orientation, and discharge from the postanesthesia care unit. Most of the studies in Table 3 focus on these variables.1,2,4,5,10,11,16,17, 19–21,24,26–30,32,36–38,48,49 Additionally, qualitative aspects of recovery include nausea/vomiting, headache, muscle soreness, and behavioral agitation. As summarized in Table 3, there are numerous data sets in which one or more of these aspects of recovery are compared between propofol and at least one other anesthetic drug. For the most part, recovery speed seems comparable between propofol and the other agents with most differences favoring quicker recovery with propofol. Bailine et al,48 in a retrospective chart review study, indicate that postECT nausea may be reduced with propofol versus methohexital. Regarding the cognitive aspects of postictal recovery, Butterfield et al1 performed neuropsychological testing 45 minutes after ECT treatments and found consistent benefits with propofol versus thiopental. Additionally, several studies found that orientation scores were equal in recovery between propofol and other drugs,5,16,24 although one study found quicker time to orientation with propofol than methohexital.10 Thus, in summary, there is no signal indicating worsened recovery with propofol and even a few data sets indicating some possible advantages of this drug.

Propofol and Cognitive Adverse Effects There are 5 data sets in which some type of neurocognitive testing was performed during the intertreatment interval (as

opposed to the immediate posttreatment recovery period, which is reviewed in the preceding section) comparing propofol to another anesthetic drug. Geretsegger et al14 compared propofol with methohexital in 50 patients. This was a randomized, noncrossover trial allowing comparison of anesthetic effects on cognition over a course of treatments. Testing was performed at baseline (ie, before the first treatment), after the third to fifth treatments, after the last treatment, and 2 weeks and 2 months later. Unfortunately, outcome results are not presented to allow for comparisons between propofol and methohexital at each of these time points separately, but rather just global results. There were no differences in anterograde memory function but better performance in the propofol group on processing speed and category sorting. Martensson et al16 also compared, over a course of treatments, cognitive performance in patients undergoing ECT anesthetized with propofol versus methohexital. The sample size was 47 total patients. Testing was performed at baseline, after treatment 5, after last treatment, and 3 days later. Testing included the Mini Mental State Examination (MMSE) and tests of verbal learning and delayed recall. There were no differences on these tests at any time point for the 2 anesthetics. Vaidya et al,50 in a retrospective chart review in patients anesthetized either with propofol or methohexital, found no post-ECT differences in MMSE performance. Bauer et al,3 comparing propofol with thiopental in a randomized, noncrossover trial in 62 total patients, found that MMSE scores were 2 points lower for the propofol group 5 days after the last treatment. Finally, Ingram et al31 also compared propofol to thiopental and

TABLE 4. Propofol and ECT Antidepressant Efficacy Comparator Drug

Designs* 29

Ketamine

One RT One NRT30 Three RT3,4,31 One CR41,42

Thiopental

Methohexital

Five RT8,9,13–16 One CR50

No. Patients

Summary of Results

71

Early greater reductions in depression ratings with ketamine Similar ratings after a few days29 or at end of treatment30 Two trials showed no difference.3,41,42 One trial showed higher final depression ratings for thiopental.4 One showed more responders at treatment 6 with thiopental.31 All 6 studies showed no difference in depression outcomes.

204

255

*RT indicates randomized trial; NRT, nonrandomized trial; CR, chart review.

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found slightly better anterograde verbal and visual memory after the last treatment for thiopental but no differences 1 month later. The authors speculated that the older age of the propofol group may have confounded these results.

Propofol and Therapeutic Efficacy Table 4 provides data on the outcome studies, which used depression ratings.3,4,8,9,13–16,29–31,41,42,50 This consists of 9 randomized trials, one nonrandomized trial, and one chart review as can be seen from that table. Table 5 presents the actual rating scale scores for the studies providing such data.3,4,8,9,13–16,29–31 Overall, it has been a rather robust finding that antidepressant efficacy has not been compromised by the use of propofol, although it is associated with shorter seizure durations. A weakness of many of these studies is relatively small sample sizes with lack of a power analysis. Confounding an attempt to combine them all into a meta-analysis is the lack of a single comparator drug, different time points of outcome assessment, different electrode placements used, different doses of propofol used, and lack of blinding in at least four of the reports. The one potentially disconcerting study regarding propofol and antidepressant efficacy of ECT is that of Ingram et al,31 in which scores on the Hamilton Depression Rating Scale are several points higher in the propofol group after treatment 6, last treatment, and at 1-month follow-up. None of these differences was statistically significant, perhaps owing to lack of statistical power. The

proportion of responders after treatment 6 was statistically significantly higher in the thiopental group. However, in the study by Purtuloglu et al,4 also comparing propofol to thiopental, end-oftreatment scores were significantly lower in the propofol group by approximately 3 points. None of the other studies comparing propofol with thiopental show a signal of lesser response in the propofol group. Two data collections involving chart review are noteworthy. Eser et al44 did publish a very large review of their experience treating 455 patients naturalistically in their institution with ECT using thiopental, etomidate, methohexital, or propofol for anesthesia. Unfortunately, outcome assessment consisted of abstracting physicians’ impressions from chart notes, which is a very crude method of quantifying outcome (and thus this study is not included in Table 4 or 5). Nonetheless, improvement seemed to be a bit better for the group given propofol than all other groups (P < 0.05 in the statistical analysis). In the Mitchell et al series,40–42 a group of patients who had been naturalistically treated with ECT with either thiopental or propofol were described. Only 6 patients had been given only propofol during their courses of treatments and had baseline and 1- to 2-week posttreatment Hamilton Depression Rating Scale scores, whereas that number for thiopental was 10. The differences in reductions in scores were not statistically different although numerically, the propofol group had a higher proportional reduction in scores (approximately 68% vs 48%).

TABLE 5. Depression Ratings in Prospective Trials of Propofol Versus Another Anesthetic Study Fear

8,9

Malsch13 Martensson16 Kirkby15 Geretsegger14 Ingram31 Bauer3 Purtuloglu4 Okamoto30║

Wang29║

Baseline Scores*

Intermittent Scores

End-of-Tx Scores

P = 20.9 M = 24.7 P = 27.5 M = 30.7 P = 34.7 M = 32.8 P = 19.63 M = 22.69 P = 26.5 M = 31.3 P = 25.39 T = 27.58 P = 27 T = 25 P = 37.3 T = 36.7 P = 30.3 K = 31.9

P = 8.4† M = 14.6

P = 7.9 M = 11.5 P = 4.4 M = 6.9 P = 12.6 M = 15.7

P = 30.1 K = 28.9 PK = 29.2

Follow-Up Scores

Statistical Results ns ns ns

P = 8.56‡ M = 7.31

P = 14.10§ T = 10.85

After Tx 2, 4, 6: P = 25,18,10 K = 19,10,8 One day after Tx: P = 22 K = 14 PK = 15

P = 9.8 M = 13.7 P = 12.69 T = 9.33 P = 11 T=9 P = 10.7 T = 13.4 P=7 K=6 Two/Three days after Tx: P = 20/19 K = 11/10 PK = 11/10

ns ns

P = 18.90‡ T = 13.01

ns ns P < 0.05

7 days after Tx: P = 13 K=7 PK = 7

After Tx 2: P < 0.001 After Tx 4: P < 0.001 After Tx 8: P = 0.360 PK vs K: ns P vs [K or PK]: ns at 7 d; P < 0.01 at 1, 2, and 3 days

*All are Hamilton Depression Rating Scale scores except Martensson, which is MADRS. †After treatment 3 ‡One-month follow-up §After treatment 6 ║All values except baseline are estimates abstracted from a figure. P indicates propofol; M, methohexital; T, thiopental; K, ketamine; PK, propofol/ketamine combination; Tx, treatment.

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Summary Propofol seems to be associated with some advantages in ECT practice, including less rise in blood pressure and heart rate as well as faster postictal recovery on some measures. Data on cognitive functioning, although limited, generally indicate no decrement in cognition related to propofol. Seizure duration on average is shorter with this drug than with the others in ECT anesthesia, but the relevance for this to clinical efficacy can be questioned. Furthermore, in situations where seizures do seem either unacceptably short or even impossible to elicit, lower doses than what are usually reported with propofol seem associated with longer seizures. Such doses of propofol as 0.75 to 1.0 mg/kg are associated with more typical ECT seizure durations. Other strategies to prolong seizures under propofol anesthesia include hyperventilation for a few minutes, thus allowing lowered carbon dioxide levels and some redistribution of the propofol away from the brain, as well as the use of much smaller doses of propofol, say 0.5 mg/kg, with supplementation with a high-potency opiate like remifentanil or alfentanil. Occasionally, in ECT practice, seizures cannot be elicited when propofol is used for anesthesia, or the initial seizure threshold may be considered unacceptably high, especially in unilateral ECT, in which case an alternative is needed. If a barbiturate is not available, then etomidate or ketamine may prove helpful. Finally, several prospective randomized and retrospective chart review studies support the lack of detrimental effect of propofol on antidepressant efficacy of ECT. For ECT practices in which barbiturates are unavailable, propofol presents an acceptable alternative. It also may be indicated in situations where particular concern regards the rise in myocardial workload (eg, congestive heart failure) and in minimizing postictal nausea and vomiting.

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Propofol for ECT anesthesia a review of the literature.

Propofol is a commonly used anesthetic drug for electroconvulsive therapy (ECT), as evidenced by the frequency with which its use is reported in ECT l...
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