1. Introduction

Etomidate is an anaesthetic agent primarily used for inducing general anaesthesia and sedation. In 1965, Janssen Pharmaceuticals designed a compound to combat fungal infections, which also revealed its surprising ability to induce deep sleep and emerged as a safer alternative to traditional barbiturates.Etomidate is administered as a purified R(+) enantiomer formulation which is hydrophobic in nature and requires specialized formulations to enhance its solubility. It isprepared as a 0.2% solution in propylene glycol, lipid emulsion, or in cyclodextrins. Clinical trials have established intravenous bolus doses of 0.2-0.4 mg/kg for short-term hypnosis and continuous infusions of 30-100 µg/kg/min for maintenance of general anaesthesia and can also be administered via oral, trans mucosal and rectal routes [1].

Electroconvulsive therapy (ECT) is a treatment in psychiatry, with a history spanning over many decades. It has proven to be safe, well-tolerated and highly effective treatment for various conditions including mood disorders, schizophrenia, catatonia, Parkinson’s disease, delirium, neuroleptic malignant syndrome, autism as well as agitation in patients with dementia. There are no absolute contraindications, but caution is advised for patients with increased intracranial pressure, recent cardiovascular events [2]. The introduction of general anaesthesia and muscle relaxation in ECT has been added to patient acceptance and when it comes to selecting an anaesthetic agent, the main criteria are a swift induction and recovery, minimal impact on seizure quality and having no adverse effects on hemodynamics or patient safety [4]. Advances have minimized side effects making modified ECT a viable option for vulnerable populations, including geriatric, adolescent and even pregnant patients. Common adverse effects include headache, nausea and myalgias, transient amnesia while cardiovascular complications can also be seen [2]. As described by Addersley and Hamilton in 1953,an adequate seizure duration is when there is a seizure for at least 25 seconds characterized by generalized tonic-clonic motor activity. In cases where motor activity was ambiguous, an alternative criterion of 30 seconds of abnormal left frontal electroencephalogram (EEG) activity, as previously established by Warmflash et al. in 1986 would be considered. General anaesthesia is now a standard component of ECT and its absence can lead to increased risks of musculoskeletal injuries and post-traumatic stress disorder [4,5]. Various anaesthetic agents, such as propofol, methohexital, ketamine and etomidate are commonly employed for ECTeach with its unique benefits and drawbacks. Despite this, the efficacy of a suitable anaesthetic agent for ECT remains a topic of discussion with no consensus yet reached [4].

A retrospective analysis comparing various anaesthetic agents in depression revealed etomidate's advantages. Although propofol resulted in shorter seizure durations, it required significantly higher stimulus charges and led to a higher rate of failed seizures. Etomidate demonstrateda more stable treatment profile with no significant increase in stimulus charge requirements [6]. A study comparing the effects of etomidate and S-ketamine on ECT in patients with major depression revealed etomidate demonstrating a consistent safety profile and effective seizure management. Although S-ketamine showed a lower initial seizure threshold etomidate's advantages included a lower risk of cardiovascular side effects. Etomidate did not significantly impact the clinical global impression scores, number of ECT sessions or incidence of adverse events [7]. A comparative study on schizophrenia revealed that etomidate demonstrated longer seizure durations both in EEG- and EMG-registered measurements compared to propofol. Propofol reduced seizure duration to a greater extent, whereas etomidate showed comparable efficacy in electrophysiological parameters correlated with clinical outcomes. Etomidate's hemodynamic effects were more evident, with a greater increase in mean arterial pressure (MAP) compared to propofol but with no impact on the number of necessary restimulations or postictal suppression [8] Etomidate also demonstrated comparable efficacy to propofol in managing seizure activity duringECT in patients with schizophrenia as it induced longer seizure durationsas measured by EEG and EMG without significant differences in minimum seizure eliciting stimulation energy or restimulation frequency. It also maintained seizure durations above the minimal threshold ensuring effective treatment [9]. An RCT investigated the efficacy of ECT in treating unipolar (UP) and bipolar (BP) depressive illnesses. With the four anaesthetic agents methohexital, thiopental, etomidate and propofolshowed equivalent remission and response rates as well as similar numbers of ECT sessions, for both UP and BP depression groups [10]. In a comparative study of patients undergoing ECT etomidate demonstrated a similar seizure duration profile to thiopental. Etomidate achieved this without requiring a lower electrical dose unlike thiopental, whereas propofol resulted in shorter seizure durations. Etomidate's balanced performance makes it a suitable choice for ECT offering a reliable and effective treatment option [11]. A study comparing the effects of propofol, thiopental and etomidate; etomidate demonstrated a comparable safety and efficacy profile to propofol and thiopental with no significant differences in cardiovascular effects, seizure variables, cognitive functions, or treatment response [12]. A retrospective analysis highlighted etomidate's superiority in ECT for affective and psychotic disorders. Notably, etomidate maintained consistent electroencephalographic seizure durations throughout treatment and was associated with fewer side effects during and after ECT making it a safer choice [13]. Etomidate emerges as a superior alternative to traditional induction agents for ECT with shorter ECT courses, lower seizure thresholds, and reduced electrical charges. Hence our study aims to review the efficacy of etomidate by looking into various parameters as the literatures are sparce conveying the same. By opting for etomidate, clinicians can potentially reduce the length and cost of inpatient stays, improving overall patient outcomes [14].

2. Methodology: Search Strategy

This systematic review was done in a tertiary care centre. Studies on etomidate as an anaesthetic agent in modified ECT were searched in scientific search engines like Pubmed, Google scholar and Cochrane from 1965 to 2024. The terms used for searching data were “Etomidate”, “Electroconvulsive therapy”, “Seizure duration”, “anaesthetic agents”, “Side effects”, “Recovery”, “Depression”, “Schizophrenia” and “Catatonia” using MeSH terms “and” and “or”. Initially, the search yielded 5439 articles with the search keywords ‘electroconvulsive therapy and etomidate’. We excluded 1429 case reports and further refined with the addition of the key words and only including studies mentioning key words such as seizure duration, hemodynamic profile, clinical response, side effects and recovery, which are the parameters to assess the efficacy of etomidate. We analysed the abstracts of all these studies and whenever necessary, read the complete articles. Finally, we included the37articles that contained important recommendations which are the efficacy parameters for the preparation of this systematic review. Publications dealing with ECT in special situations are scarce and most of the literature is based on clinical cases, usually short series and reviews based on expert opinions. All research articles excluding case reports and case series mentioning the above parameters are included for the study. The search was limited to studies done in humans, published in English without regard to the level of evidence.

3. Results

ECT relies on general anaesthesia to create a controlled environment for seizures while mitigating its risks. The anaesthetic strategy aims to induce amnesia, brief immobility and protect patients and staff from injury, while ensuring adequate oxygenation, hemodynamic stability, and timely recovery.We have compared etomidate with studies using common agents like thiopental, propofol, methohexital, ketamine and midazolam. Many studies have found propofol, etomidate and thiopental have similar safety and efficacy with etomidate giving better seizure duration and less side effects. Some of the anaesthetic agents are found to be better in particular mental disorders compared to other whereas some studies failed to reveal any. Etomidate’s ability to produce adequate seizure duration and theophylline’s ability to be used as an adjunct to prolong seizures where also noted. Selecting an anaesthetic agent considering its safety on hemodynamic were analysed and found many studies revealing inconclusive results. Recovery from anaesthesia was also taken as a parameter and found studies comparing the various commonly used anaesthetic agents in its efficacy on cardiac and other hemodynamic parameters. Clinical responses following sessions of modified ECT on the mental disorders found few studies revealing similar clinical efficacy profiles at discharge with some benefit of etomidate in some mental disorders.

Table 1: various anaesthetic agents used in Electroconvulsive therapy

3.1 Seizure duration

Etomidate stands out as a superior induction agent for electroconvulsive therapy (ECT) due to its ability to prolong seizure duration, a critical factor in ECT efficacy. A comprehensive meta-analysis of revealed that etomidate significantly outperformed propofol and thiopental in terms of both EEG and motor seizure duration [15]. In a study comparing the impact of thiopental and etomidate anaesthesia on seizure duration. The results revealed that etomidate sessions resulted in significantly longer mean seizure durations compared to thiopental sessions potentially leading to improved treatment outcomes [16]. A study conducted investigated etomidate's efficacy in improving seizure duration compared to thiopental showed a significant reduction in electric stimulation dose and a substantial increase in seizure duration and electroencephalograph-recorded duration. Noted particularly in patients with high seizure thresholds, and should be considered as the primary anaesthetic for augmenting seizures [17]. A retrospective analysis investigated the potential dose-dependent relationship between etomidate and seizure duration in ECT found a weak negative correlation between etomidate dose and seizure duration, indicating no clinically relevant dose-dependent relationship between etomidate and seizure duration in ECT [18]. Theophylline may be a valuable adjunct for patients with inadequate seizure duration as per a retrospective study to examine the relationship between anaesthetic management and seizure duration in ECT. It showed that theophylline administration was the sole factor significantly associated with prolonged seizure duration, whereas other variables, including S-ketamine, remifentanil, thiopental, age, sex, session number, and energy level, had no significant impact [19]. Althesin significantly shortened seizure duration in comparison with methohexitone and Etomidate as per a comparative study on etomidate and althesin. Seizure duration was the same when either etomidate or methohexitone were used, whereas local pain on injection andsuperficial thrombophlebitis occurred frequently with methohexitone and did not occur with etomidate or Althesin [20]. Premedication with low-dose midazolam before etomidate anaesthesia induction significantly reduced the incidence and intensity of myoclonus compared to low-dose etomidate as per a comparative study. Compared to etomidate alone, it showed significant differences in myoclonic movement frequency between the groups, with the midazolam group experiencing fewer myoclonic movements than the placebo and etomidate groups [21]

3.2 Hemodynamic profile

The evolution of ECT has seen a shift from its initial use without anaesthesia to the introduction of general anaesthesia in the 1950s, aimed at mitigating complications such as fractures, dental damage, and muscle injuries. [22]. The administration of anaesthesia for ECT requires specialized training emphasizing the need to possess an in-depth knowledge of hemodynamics and the effects of ECT. The electrical current stimulate the autonomic nervous system, inducing unique hemodynamic changes in both systemic and cerebral circulation. To ensure safe and effective treatment, medications with anticholinergic and antihypertensive properties along with adequate ventilation should be used to mitigate excessive changes in heart rate, blood pressure, and cardiac function. Even when serious complications are rare, patients with pre-existing ischemic heart disease or cerebrovascular disease require careful management to prevent adverse cardiac or neurological events [23]. It is associated with significant cardiovascular changes, prompting concerns about the optimal anaesthetic choice. Despite numerous studies, the debate still persists due to inconsistent findings. An RCT revealed that etomidate, propofol, and thiopental exhibited comparable cardiovascular profiles, providing valuable insights for ECT anaesthetic selection [24]. Comparing two widely used anaesthetic agents propofol and etomidate, etomidate revealed a significant increase in mean heart rate (HR) from baseline, during and after seizure activity,also a significant increase in mean blood pressure (MBP), Propofol did not exhibit any significant changes throughout the monitoring period. This can be attributed towards propofol's cardiovascular depressant effect, which outweighs the sympathetic stimulation caused by seizure activity during ECT [25]. Dexmedetomidine may be a useful adjunct in ECT, reducing hemodynamic stress without interfering with seizure duration or recovery timeuse of dexmedetomidine with reduced-dose propofol did not prolong recovery time [26]. Etomidate caused a significant increase in QTc after seizure cessation, whereas propofol did not have an impact. This was a study conducted on patients with major depression. Etomidate was associated with increased HR and MAP at all measurement times, whereas propofol demonstrated better hemodynamic control [27]. Alfentanil significantly decreased heart rate, diastolic arterial pressure, and mean arterial pressure without affecting the increase in these variables during seizures. Alfentanil did not influence seizure duration but had prolonged apnea duration as found by a prospective study. It may be beneficial in reducing tachycardia and hypertension during ECT in high-risk patients without impacting seizure duration, and it does not have a proconvulsive effect when combined with etomidate [28]. In a prospective study conducted by Tejaswini et al on 50 adults, it was found that Etomidate has better hemodynamic profile with few changes in Blood pressure, Heart rate and mean arterial blood pressure compared to propofol [29]. Whereas Erdil et al [30] & Gazdag et al [31] have observed that propofol has a better hemodynamic response compared to propofol. However, there are reviews which provide findings which are inconclusive regarding the effects of intravenous anaesthetics on ECT treatment quality and respiratory and cardiovascular side effects [22].

3.3 Clinical response

Etomidate was associated with significantly longer motor and electroencephalogram seizure durations compared to propofol as per a retrospective study conducted to investigate the impact of general anesthetic agents on the efficacy of ECT. The study compared the clinical effects and seizure variables of etomidate and propofol in patients undergoing ECT. However, both agents demonstrated similar clinical efficacy profiles at discharge, with no significant differences in Clinical Global Impression scale scores, mood at discharge, or adverse effects [32]. Etomidate led to a greater reduction in depression scores compared to sodium thiopental in an RCT comparing the efficacy of etomidate and sodium thiopental in alleviating depression symptoms in patients undergoing ECT. Additionally, the etomidate group also exhibited significantly longer seizure durations across all sessions indicating that etomidate may be more effective than sodium thiopental in improving major depressive disorder symptoms in patients undergoing ECT [33]. Patients who received etomidate for ECT required significantly fewer sessions compared to the propofol and that patients receiving propofol may need additional treatment sessions to achieve similar clinical outcomes as those receiving etomidate. But there weren’t any significant differences in mood during the time of discharge, remission, and length of hospital stay between the two groups [32].

3.4 Side effects and recovery

The effects of etomidate and propofol on adrenocortical function and hemodynamics during electroconvulsive therapy (ECT) were assessed by Wang et al showed that etomidate caused a temporary decrease in serum cortisol levels, remaining within normal ranges, while propofol had no significant effect. Adrenocorticotropic hormone levels remained unchanged in both groups. Both anaesthetics were deemed safe for ECT, with no significant impact on adrenocortical function [37]. A study compared methohexital and etomidate anaesthesia for ECT showed comparable hemodynamics to methohexital but had significant drawbacks, including a 24% longer mean wakeup time and a higher incidence of pain on injection. However, these disadvantages may outweigh etomidate's advantages, particularly in patients where rapid recovery is crucial [34]. It also has adverse effects including etomidate-induced myoclonus [21] and painful injection [15] resulting in unpleasant experiences for patients. A study conducted by Moacir a rosa et al by comparing propofol etomidate and thiopental showed that Propofol needed higher charge but had shorter recovery when compared to etomidate and thiopental [35].

Table2: Efficacy of Etomidate using various parameters

4. Discussion

Historically, methohexital a short-acting barbiturate has been the preferred anaesthetic for modified ECT due to its ability to induce prolonged seizure duration. However, etomidate has emerged as a popular alternative, offering advantages such as a rapid onset, brief duration, and stable hemodynamics. Notably, etomidate has been linked to extended EEG and motor seizure durations, potentially due to its lack of anticonvulsant properties. As a result, etomidate may be the optimal induction agent for patients who experience insufficient seizure activity, making it a valuable option for modified ECT procedures [36].

Our review compared etomidate with common agents like thiopental, propofol, methohexital, ketamine, and midazolam. Numerous studies found that propofol, etomidate, and thiopental have similar safety and efficacy profiles, with etomidate offering better seizure duration and fewer side effects. However, some agents are more suitable for specific mental disorders, while others show no difference. Notably, etomidate's ability to produce adequate seizure duration and theophylline's potential as an adjunct to prolong seizures were observed. The selection of an anaesthetic agent considering its impact on hemodynamics was analyzed, revealing inconclusive results in many studies. Recovery from anaesthesia was also evaluated, with studies comparing the efficacy of various agents on cardiac and hemodynamic parameters. Clinical responses following modified ECT sessions on mental disorders showed similar efficacy profiles at discharge, with some benefits of etomidate in specific disorders. The efficacy of etomidate was analysed using various parameters such as seizure duration, hemodynamic profile, clinical profile, side effects and recovery. Etomidate's efficacy in various mental disorders was analysed, revealing its potential in enhancing seizure duration during modified ECT. Etomidate demonstrated a longer seizure duration compared to thiopental and methohexital, with no significant differences in hemodynamic profile, although few studies mentioned propofol to be a better agent. It also has a distinct advantage over thiopental in producing seizures of adequate duration during modified ECT and can be used as the first-line measure in augmenting seizures in patients with very high seizure thresholds. Our study also found that theophylline can be a useful adjunct for patients with inadequate seizure duration. Sub threshold seizure was seen with the Propofol group more than Etomidate. Clinically, etomidate showed a good response in patients undergoing modified ECT, with equivalent remission and response rates in unipolar and bipolar depression groups had lesser number of modified ECTs without triggering manic episodes. However, etomidate had a longer wake-up time and was found to cause pain on injection. In terms of side effects, etomidate had a lower incidence of myoclonic movements compared to midazolam and methohexital. On the contrary, there were also studies mentioning that QTc interval was shorter in Propofol group compared to etomidate group and controlled the hemodynamic response better than etomidate during modified ECT. Recovery-wise, etomidate had a stable hemodynamic profile, although propofol had a faster and smoother recovery. Notably, etomidate decreased depression scores more than sodium thiopental, and its use did not trigger manic episodes in depressed patients. Overall, etomidate appears to be a better induction agent than propofol in modified ECT, with a distinct advantage in producing seizures of adequate duration

5. Conclusion

In our systematic review it is found that etomidate stands out as a superior choice in modified ECT particularly in patients with schizophrenia where it has demonstrated better evidence. Its advantages are evident in seizure duration surpassing thiopental methohexital and propofol. While propofol offers asmoother and faster recovery, etomidate and propofol share similar clinical efficacy profiles at discharge. Notably, etomidate may have a more significant impact on improving major depressive disorder compared to sodium thiopental in modified ECT patients. Although propofol has a better recovery profile, etomidate's benefits in seizure duration and clinical efficacy make it a preferred choice in certain cases.

Funding:

None

Conflict of interest:

Nil

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