Bi-Spectral Index-Guided Comparison of Propofol versus Etomidate for Induction in Electroconvulsive Therapy.

BACKGROUND: Previous studies have compared varying doses of propofol and etomidate for electroconvulsive therapy (ECT) without monitoring the depth of anesthesia. Seizure duration may vary with the depth of anesthesia. AIM: This study aimed to compare the effects of bi-spectral index (BIS)-guided induction with propofol and etomidate on various parameters of ECT. SETTINGS AND
DESIGN: This was a prospective, randomized, double-blind study.
MATERIALS AND METHODS: Sixty patients undergoing ECT were randomly allocated to two groups. Group P received intravenous propofol 1-2 mg.kg -1 and Group E received etomidate 0.1-0.3 mg.kg -1 to attain a BIS of 40-60. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and BIS were recorded at various time points intraoperatively till 30 min following ECT. Seizure duration, recovery time, and adverse effects were also recorded. STATISTICAL ANALYSIS: Quantitative data were compared using unpaired t-test. Chi-square test or Fisher's exact test was used to compare categorical data. P < 0.05 was considered statistically significant.
RESULTS: The mean induction time and seizure duration were shorter (P < 0.001), and recovery time to obey commands was longer in Group P as compared to that of Group E (P = 0.031). HR, SBP, and DBP for 10 min after ECT had elevated more in Group E than that in Group P (P < 0.05). The incidence of myoclonus was higher in Group P compared to that of Group E (P = 0.012).
CONCLUSION: During ECT, BIS-guided induction with propofol provides more stable hemodynamics than etomidate, but reduces induction time, seizure duration, and recovery time more as compared to that of etomidate. Copyright:

INTRODUCTION

Electroconvulsive therapy (ECT) is a well-established effective treatment for various psychiatric disorders such as severe major depressive disorders, mania, schizophrenia, and catatonia.[1] Initially, ECT was done without anesthesia and was associated with complications such as bone fractures, joint dislocation, tongue biting, tearing of muscle fibers, and hemodynamic changes including elevation in the systolic blood pressure (SBP) and heart rate (HR), and sometimes arrhythmia.[23] The use of anesthesia for ECT has made its use safe and comfortable, with reduced adverse effects and increased efficacy. For effective ECT, a balance needs to be maintained between adequate anesthetic state and the optimal duration of motor seizure activity (>15 s). The ideal anesthetic agent for ECT would be the one with rapid onset and shorter duration of action, enabling rapid recovery with minimal effects on the threshold and duration of seizures, while attenuating the hemodynamic response to electrical stimulus.[4] Commonly used anesthetic drugs for ECT are methohexital, thiopentone, etomidate, propofol, and ketamine, each with its advantages and disadvantages.[567]

Bi-spectral index (BIS) is a continuous, processed electroencephalogram (EEG) measurement that provides a consistent and reliable index of depth of anesthesia. BIS scores of 95 or greater indicate full consciousness, 60–80 indicate sedation, and 40–60 indicate a state of general anesthesia.[8] Previous studies have reported a significant correlation between the depth of anesthesia and seizure duration (higher BIS value prolongs seizure duration).[910] A literature search revealed that most of the studies have compared the effects of varying doses of propofol and etomidate on induction time, motor seizure duration, and recovery time for ECT, without monitoring the depth of anesthesia for dose titration. Most of the studies have found a shorter induction time and longer motor seizure duration with etomidate than propofol.[11] Recovery time after ECT was found to be statistically significantly shorter with propofol than etomidate in some studies (P < 0.05),[1112] whereas no significant difference was found by another study (P = 0.322).[13] BIS-guided comparison of etomidate and propofol for ECT has not been done before. BIS-guided induction will alleviate the effects of varying depths of anesthesia on measured parameters of ECT, as expected with the different doses of propofol and etomidate used in various studies. Hence, the present study aimed to compare the effects of BIS-guided induction with propofol to etomidate on ECT variables. The primary outcome measures of our study were induction time, motor and EEG seizure duration, hemodynamic parameters, and recovery time. The secondary outcome measures were any adverse effects during induction (pain on injection, cough, gag reflex, and myoclonus) or after ECT (nausea, vomiting, and hypotension).

MATERIALS AND METHODS

This prospective, randomized, double-blind study was conducted between July 2018 and June 2019 at a tertiary care hospital after approval from the institutional ethical committee/review board (vide no. 18/6919). Written informed consent was obtained from all the patients and/or their relatives for participation in the study and the use of patient data for research and educational purposes. The authors assert that all the work related to this study was in concordance with the ethical standards of the institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Patients aged 18–60 years, weighing 45–65 kg, belonging to American Society of Anesthesiologists (ASA) physical status Classes I or II, of either sex, and scheduled to undergo ECT for neurological illness were included in the study. Exclusion criteria were body mass index ≥30 kg/m2, moderate-to-severe heart or lung disease (ASA Class ≥III), history of seizures, pregnant patients, history of chronic alcoholism, drug addictions, and history of drug allergy. A total of sixty patients were randomized to two groups of thirty each by using computer-generated randomization and the allotment was done using coded sealed opaque envelopes. Group P patients received intravenous (i.v.) propofol (1%) 1–2 mg.kg −1 and Group E patients received i.v. etomidate 0.1–0.3 mg.kg −1 to attain a BIS score of 40–60.

All patients underwent preoperative anesthetic evaluation 1 day before the procedure. Antipsychotic treatment was continued till the day of the procedure, and all patients were kept fasting for 6 h before ECT. After shifting to the procedure room, baseline monitors were attached which included electrocardiogram (ECG), noninvasive blood pressure, and oxygen saturation (SpO2). Single-use, BIS (BIS VISTATM, Aspect Medical Systems, MA, USA) sensor electrodes were applied on the forehead of the patient. An i.v. line was established, and all the patients were premedicated with i.v. glycopyrrolate 0.2 mg. After preoxygenation with 100% for 3 min, anesthesia was induced with an i.v. anesthetic agent as per the group allocation. After induction, a sphygmomanometer cuff applied on the arm was inflated to a value above the SBP before the administration of i.v. succinylcholine 0.5 mg.kg−1. When fasciculation stopped and adequate neuromuscular relaxation was obtained, a bite block of adequate size was inserted to prevent tongue bite. After induction of anesthesia, a psychiatrist delivered a brief pulse stimulus for about 1–3 s, frequency of 60–90 Hz, and pulse width of 1 with bi-temporal electrodes using Brief Pulse Constant Current ECT machine (MEDISYS, RMS PC ECTON, Chandigarh, India) to all the study patients to produce seizures. Subsequently, the patient was ventilated with 100% O2 using Bain's circuit at a rate of 12–15 breaths/min to keep end-tidal carbon dioxide at 30–35 mmHg and SpO2 of 98% to 100% until the return of spontaneous breathing.

Motor seizure duration was monitored by isolated limb technique and calculated as the time interval from ECT stimulus until the cessation of tonic-clonic motor activity in the isolated arm, and the duration of electrical seizure activity was calculated as the time interval from ECT stimulus until the cessation of raw EEG seizure activity on the BIS monitor. HR, SBP, diastolic blood pressure (DBP), SpO2, and BIS were recorded at the following time periods: baseline (T0); just after induction (T1); just before ECT (T2); and 1 min (T3), 2 min (T4), 3 min (T5), 5 min (T6), 10 min (T7), and 15 min (T8) following ECT; and at recovery (T9). Recovery time was calculated from the injection of anesthetic agent to the first response to verbal command. Time to return of spontaneous respiration was also recorded. Any adverse effects during induction (such as pain on injection, cough, gag reflex, and myoclonus) or after ECT (such as nausea, vomiting, and hypotension) were also noted.

Statistical analysis

The sample size was calculated based on a pilot study conducted by us on 14 patients (7 in each group), considering motor seizure duration as the primary objective, with the power of study as 90% and α error of 0.05. Statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA, version 15.0 for Windows). Normally distributed data were presented as mean and standard deviation. Quantitative data were compared using the unpaired t-test. Chi-square or Fisher's exact test was used to compare the categorical variables. All tests were evaluated at a 95% confidence interval. P < 0.05 was considered statistically significant.

RESULTS

Patient characteristics

The demographic profile was comparable between the two groups [Table 1].

Table 1

Demographic characteristics of the patients

	Group P (n=30)	Group E (n=30)	P
Age (years)	46.71±5.4	45.56±6.7	0.467
Weight (kg)	58.18±5.7	55.65±5.6	0.088
Gender
Male	16	15	0.796
Female	14	15
ASA Class
I	24	22	0.541
II	6	8

All variables except ASA status and gender are expressed as mean±SD. Group P received propofol and Group E received etomidate for induction. ASA=American Society of Anesthesiologists, SD=Standard deviation

Induction time

The mean induction time in the propofol group was 35 ± 5.15 s, whereas that in the etomidate group was 47.77 ± 4.72 s. The difference in the induction time between the two groups was found to be statistically significant (P < 0.001) [Table 2].

Table 2

Induction time, seizure duration, and recovery time compared in the two groups

Variables	Group P	Group E	P
Induction time (s)	35±5.15	47.77±4.72	<0.001*
Motor seizure duration (s)	28.63±5.46	45.23±12.0	<0.001*
EEG/electrical seizure duration (s)	42.07±8.64	63.60±13.60	<0.001*
Time to spontaneous respiration (min)	4.27±1.23	4.57±1.36	0.374
Time to obeying commands (min)	8.65±2.54	10.2±2.91	0.031*

All variables are expressed as mean±SD. Group P received propofol and Group E received etomidate for induction. *P<0.05 is considered statistically significant. SD=Standard deviation, EEG=Electroencephalogram

Seizure duration

Patients’ average motor seizure duration was 28.63 ± 5.46 s with propofol and 45.23 ± 12.0 s with etomidate. Whereas, EEG-recorded seizure duration was 42.07 ± 8.64 s and 63.60 ± 13.60 s with propofol and etomidate respectively. Both motor and EEG seizure duration were statistically significantly shorter (P < 0.001) in the propofol group as compared to that of the etomidate group [Table 2].

Recovery time

The time to return of spontaneous respiration was 4.27 ± 1.23 min in the propofol group and 4.57 ± 1.36 min in the etomidate group (P = 0.374). However, time to obey commands after anesthesia was statistically significantly longer in the etomidate group as compared to that of the propofol group (P = 0.031) [Table 2].

Hemodynamic parameters

Baseline hemodynamic parameters (HR, SBP, and DBP) were comparable among the two groups [Table 3]. However, there was a significant difference in HR between the two groups from 1 to 10 min after ECT, with HR being relatively higher in the group receiving etomidate. However, there was no significant difference in HR after induction, just before ECT, and after 15 min from ECT. Just after induction, there was a drop in SBP and DBP in both the groups. However, the difference between the groups was not statistically significant. After initiation of ECT, a gradual increase in SBP and DBP was observed reaching peak levels at approximately 2 min after ECT in both the groups. Following this, there was a gradual decline in SBP and DBP, before stabilizing. Both SBP and DBP were significantly higher in the etomidate group for the first 15 min after ECT as compared to that of the propofol group (P < 0.05). However, in either of the groups, a drop in blood pressure itself was not significant to be classified as hypotension (<20% of baseline).

Table 3

Trend of heart rate, systolic blood pressure, and diastolic blood pressure in the two groups

Time interval	Heart rate (beats/min)			SBP (mmHg)			DBP (mmHg)
	Group P	Group E	P	Group P	Group E	P	Group P	Group E	P
Baseline (T0)	86.27±14.12	86.37±13.43	0.978	128.40±24.77	130.40±24.99	0.757	74.60±11.75	77.07±9.99	0.385
Just after induction (T1)	79.40±12.88	79.37±11.69	0.992	105.73±18.32	108.27±20.41	0.615	68.13±10.50	71.53±8.94	0.182
Just before ECT (T2)	78.67±12.44	80.33±12.14	0.601	101.33±17.02	109.27±21.01	0.114	67.90±10.06	71.40±9.40	0.169
1 min after ECT (T3)	94.57±12.25	107.7±13.79	<0.001*	131.20±22.32	145.73±20.37	0.011*	83.37±11.87	93.23±11.70	0.002*
2 min after ECT (T4)	97.53±12.49	111.9±14.10	<0.001*	135.00±23.35	148.80±21.66	0.021*	85.93±11.96	96.40±11.86	<0.001*
3 min after ECT (T5)	93.47±12.23	106.4±13.28	<0.001*	128.60±21.94	144.20±20.65	0.006*	79.80±10.78	90.90±10.41	<0.001*
5 min after ECT (T6)	88.77±11.57	99.10±12.63	<0.001*	124.27±21.44	136.93±19.89	0.021*	75.33±10.98	84.50±10.29	<0.001*
10 min after ECT (T7)	85.93±11.49	91.90±11.41	0.048*	119.78±21.14	132.20±19.70	0.022*	73.07±10.91	80.27±9.77	0.009*
15 min after ECT (T8)	84.37±11.85	87.70±11.59	0.275	119.13±21.40	133.53±23.04	0.015*	73.00±11.58	78.73±9.32	0.039*
30 min after ECT (T9)	85.27±12.16	88.93±12.09	0.246	125.20±22.88	135.87±23.96	0.083	73.57±11.54	80.17±9.91	0.021*

All variables are expressed as mean±SD. Group P received propofol and Group E received etomidate for induction. *P<0.05 is considered statistically significant. SBP=Systolic blood pressure, DBP=Diastolic blood pressure, SD=Standard deviation, ECT=Electroconvulsive therapy

Bi-spectral index

The mean total dose of propofol and etomidate used to achieve a BIS score of 40–60 for induction was 90 ± 12 mg and 18 ± 6 mg, respectively. During the course of observation, after the electrical stimulus, there was a rise from preictal BIS scores followed by a fall at 3 min after ECT and then a constant rise till 30 min in both the groups. The difference in BIS score was not significant in the two groups except at 30 min after ECT, where BIS scores were statistically significantly lower (P = 0.015) in the etomidate group (82.67 ± 8.24) as compared to that in the propofol group (88.00 ± 8.26) [Table 4].

Table 4

Bi-spectral index score compared in the two groups

Time interval	Bi-spectral index		P
	Group P	Group E
Baseline (T0)	88.10±7.88	86.47±8.41	0.441
Just after induction (T1)	51.43±5.6	50.67±5.03	0.831
Just before ECT (T2)	39.77±5.66	39.7±6.63	0.984
1 min after ECT (T3)	42.53±5.20	46.30±5.30	0.293
2 min after ECT (T4)	59.40±7.43	62.03±7.24	0.312
3 min after ECT (T5)	50.93±7.76	54.40±7.53	0.393
5 min after ECT (T6)	69.67±6.08	69.93±7.70	0.928
10 min after ECT (T7)	77.17±8.99	76.17±8.39	0.718
15 min after ECT (T8)	83.77±8.00	82.47±8.17	0.582
30 min after ECT (T9)	88.00±8.26	81.67±8.24	0.039*

All variables are expressed as mean±SD. Group P received propofol and Group E received etomidate for induction. *P<0.05 is considered statistically significant. SD=Standard deviation, ECT=Electroconvulsive therapy

Adverse effects

The incidence of pain on injection in the propofol group was 23%, whereas in the etomidate group, it was 3% (P = 0.052). The incidence of myoclonus found in the etomidate group was 30% as compared to 1% in the propofol group (P = 0.012). However, other adverse effects such as cough or gag reflex on induction, nausea, vomiting, and hypotension were not observed in any of the groups.

DISCUSSION

A lot of development has taken place in the technique of ECT since its first use. These advancements have enabled us to provide the therapy in a more controlled manner to get anticipated results and maximize the efficacy while making the procedure safe and more comfortable for the patients. Anesthesiologists should be well aware of the electrophysiological disturbances caused by ECT and the effects of various anesthetic drugs on seizure activity, hemodynamics, and recovery profile. Few studies have found a positive correlation between the duration of seizure and efficacy of ECT.[141516] However, many anesthetic drugs have anti-epileptic properties and cause a variable reduction in the duration of seizure activity.[17] Many studies have compared varying doses of propofol with etomidate for ECT without monitoring the depth of anesthesia. Propofol is known to cause a dose-dependent decrease in seizure duration, whereas the effect of etomidate on seizure duration is dose independent.[18] The effects of BIS-guided dose titration of propofol on seizure duration have been studied before.[9] However, standardization of the depth of anesthesia (targeted BIS of 40–60), to compare the effects of propofol and etomidate on ECT parameters, has not been studied before. In the present study, we compared the effects of BIS-guided induction with propofol and etomidate, in patients undergoing ECT for induction time, seizure duration, recovery, depth of anesthesia monitored by BIS, hemodynamic parameters, and associated side effects. We found a significantly reduced motor and EEG-recorded seizure duration in the propofol group as compared to that of the etomidate (P < 0.001), with no reported seizure of <15 s in duration in either of the groups. This was in concordance with the study conducted by Avramov et al. who compared varying doses of methohexital, propofol (0.75, 1.0, or 1.5 mg.kg −1, respectively), and etomidate (0.15, 0.2, or 0.3 mg.kg −1, respectively) in ten patients with depression undergoing ECT and reported the longest and shortest seizure duration with etomidate and propofol, respectively.[18] Gazdag et al. also observed a reduced motor and EEG seizure duration with propofol (1 mg.kg −1) than etomidate (0.2 mg.kg −1) (P = 0.006 and 0.014, respectively), but also inferred that it did not result in seizures shorter than 20 s, which would have necessitated more frequent re-stimulations.[19] According to our study, BIS-guided induction dose (targeted BIS of 40–60) of propofol and etomidate does not alter the fact that propofol reduces seizure duration more than etomidate, as also observed by other studies.

In the present study, induction time with a targeted BIS of 40–60 was shorter with propofol (35 ± 5.15 s) than etomidate (47.77 ± 4.72 s). Our findings were similar to those of another study conducted by Mir et al. where a fixed dose of propofol (1.5 mg.kg −1) and etomidate (0.2 mg.kg −1) was used for ECT.[11] However, Zheng et al. found that the time to loss of consciousness was significantly less with the use of etomidate than that with propofol.[20] This confliction may be attributed either to the different doses of propofol (1.64 mg.kg − 1 vs. 1–2 mg.kg −1) and etomidate (0.23 mg.kg −1 vs. 0.1–0.3 mg.kg − 1) used by Zheng et al. and our study or, to the different clinical profile of patients included in the studies.

There was no statistically significant difference (P = 0.374) in the time to return of spontaneous respiration among the two groups. However, the time to obeying commands was statistically significantly longer in the etomidate group as compared to that of the propofol group (P = 0.031). Similar results have been reported by Mir et al. and Rosa et al., who also concluded that propofol offered a better recovery profile than etomidate.[1112] However, Jindal et al. found no difference in recovery time with propofol and etomidate (P = 0.322).[13] This may be attributed to the varying depths of anesthesia caused by different doses of propofol and etomidate used for induction in these studies. In our study, lower BIS scores at 30 min in Group E also correlated with the longer recovery time found in the same group, further emphasizing the need to monitor the depth of anesthesia while comparing propofol with etomidate.

Many studies have confirmed the association of ECT with a significant increase in blood pressure and HR, which might be caused by myotonic reflexes, direct stimulation of the sympathetic nervous system, and norepinephrine release from the adrenal medulla.[21] In our study, for 10 min after ECT, the rise in HR and blood pressure was more statistically significant in the etomidate group as compared to that of the propofol group (P < 0.05). Propofol causes blunting of sympathetic response which attenuates the hemodynamic changes induced by ECT, whereas etomidate having minimal effect on the cardiovascular profile is unable to compensate for the rise in HR and BP caused by ECT. Similar findings have been reported by Mir et al. who compared thiopentone, propofol (1.5 mg.kg −1), and etomidate (0.2 mg.kg − 1) for ECT and found that propofol results in less rise in SBP, DBP, and HR after the electrical stimulus and offers more stable hemodynamics as compared to that of etomidate.[11] Gazdag et al. also found more stable hemodynamics with propofol (1 mg.kg −1) than etomidate (0.2 mg.kg −1) in patients undergoing ECT for schizophrenia.[19] However, in a study conducted by Zahavi et al., who compared propofol (0.6 mg.kg −1), etomidate (0.1 mg.kg −1), and thiopentone induction for ECT, contradictory results were found. They found a statistically significant increase in DBP with propofol, whereas etomidate offered more stable hemodynamics (P = 0.016).[22] Zahavi et al. used a much lesser dose of propofol as compared to that of the other studies, without monitoring the depth of anesthesia, which may have affected their results. According to our study, with targeted BIS of 40–60, propofol offers a more stable hemodynamic profile than etomidate in patients undergoing ECT.

In our study, the incidence of myoclonus was more in the etomidate group as compared to that of the propofol group (P = 0.012). Similarly, Mir et al. also found a higher incidence of myoclonus with etomidate than propofol (P < 0.0001),[11] although the exact cause of myoclonus by etomidate is unclear. The most proposed mechanism is the disinhibition of subcortical activity which leads to involuntary movements.[23] Myoclonus per se does not have any significant detrimental effect on patients undergoing ECT, however as it can resemble generalized seizure both clinically and in EEG, there may be a difficulty in evaluation of the depth of anesthesia.[2425]

The limitation of our study was that we included patients with various psychiatric disorders. The effect of various psychiatric disorders and their treatment regimens on BIS scores and induction doses of propofol and etomidate were not evaluated. Another limitation was that we used a wide range of BIS scores of 40–60 and we also did not compare the effects of BIS-guided doses of propofol and etomidate on subsequent ECT treatments separately. We also did not use multi-parametric recovery scores to assess recovery in our patients. We believe that future research is required to study the effects of a targeted BIS score of 40–60 on the degree of reduction in seizure duration and efficacy of ECT. In addition, a study of point-to-point BIS score is required for propofol and etomidate to unleash its effects on the efficacy of ECT and find out the best possible BIS score, which would avoid awareness during anesthesia without altering the efficacy of ECT.

CONCLUSION

We conclude that for a targeted BIS of 40–60, propofol reduces induction time and seizure duration more than that compared to etomidate, which is also in concordance with the other studies performed using non-BIS monitored doses of propofol and etomidate. However, recovery time and hemodynamic profile could vary with BIS and non-BIS-guided doses of propofol and etomidate, with propofol resulting in faster recovery and more stable hemodynamics as compared to that of etomidate.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.