Anaesthesia for electroconvulsive therapy: An overview with an update on its role in potentiating electroconvulsive therapy.

Despite advances in pharmacotherapy, electroconvulsive therapy (ECT) remains a mainstay treatment option in psychiatry since its introduction in 1930s. It can be used primarily in severe illnesses when there is an urgent need for treatment or secondarily after failure or intolerance to pharmacotherapy. The 'unmodified' technique of ECT was practised initially, with a high incidence of musculoskeletal complications. Several modifications including general anaesthesia and muscle relaxation are used to increase the safety and patient acceptability of ECT. Various anaesthetic techniques including medications are considered to provide adequate therapeutic seizure, simultaneously controlling seizure-induced haemodynamic changes and side effects. A brief review of literature on choice of these anaesthetic techniques is discussed. This article is intended to reinforce the knowledge of clinicians, who may have limited exposure to ECT procedure. Importance is given to the recent updates on the role of induction agents in potentiating therapeutic response to ECT in psychiatric disorders.

INTRODUCTION

Electroconvulsive therapy (ECT), introduced by Cerlitti and Bini in 1937, is the induction of a generalised seizure by electrical stimulation of one or both cerebral hemispheres. It has become a highly sophisticated and precise procedure with passage of time. Initially, 'unmodified' technique was practised in which patients were conscious and without muscle relaxation. This resulted in musculoskeletal complications in as many as 40% patients. Beginning in the 1950s and 1960s, however, several refinements including anaesthetic medications and muscle relaxants were introduced to increase the safety and patient acceptability.[123]

Initially, ECT was used to treat several types of psychiatric disorders and to calm disruptive inpatients in psychiatric wards, regardless of their diagnosis. In recent years, its use is restricted primarily to severe mental illnesses when there is an urgent need for treatment or secondarily after failure or intolerance to pharmacotherapy. Although there are no absolute contraindications to ECT, some medical conditions are known to increase the risk due to the significant cardiovascular and cerebrovascular changes associated with ECT. The cardiovascular effects result from autonomic nervous system (ANS) activation during ECT procedure. This leads to an initial 10–15 s of parasympathetic discharge resulting in bradycardia and occasional asystole (the tonic phase). This is followed by a pronounced sympathetic response of hypertension, tachycardia and other arrhythmias peaking 1 min after ECT stimulation and generally resolving within 5–10 min thereafter (the clonic phase). There is increased cerebral metabolic rate (CMR) which results in a marked increase in cerebral blood flow (CBF) and intracranial pressure (ICP). Furthermore, there is increased intraocular and intragastric pressure. Short-term memory loss is also common.[123]

The anaesthetic requirements for ECT include control of these haemodynamic changes and related complications, together with the primary requirements of amnesia and muscle relaxation. Although these are essential, the level of anaesthesia should not be so deep as to overly suppress the seizure activity which is the goal of the treatment. The clinician must be well versed on the anaesthetic management of patients undergoing ECT. This article is a narrative overview of existing literature intended to reinforce the knowledge of clinicians, who may have limited exposure to ECT procedure. Relevant information was extracted from searches of computerised databases, hand searches and authoritative texts from inception through 18th February 2017, and the search was limited to the English language. Recent updates on the role of induction agents in potentiating therapeutic response to ECT in the treatment of psychiatric disorders are discussed in detail.

ADMINISTRATION OF ANAESTHESIA

Pre-medication

Anticholinergic agents such as glycopyrrolate and atropine are often given to antagonize the initial parasympathetic discharge. Glycopyrrolate (0.01 mg/kg) is preferred and administered either intramuscularly at least 3 min prior the scheduled procedure or intravenously just before injecting the induction agent. It may decrease the likelihood and severity of bradycardia or asystole and the risk of aspiration due to vagal effects of ECT. Routine use of anticholinergics, however, has been criticised as unnecessary. They may be particularly useful in patients who are receiving sympathetic blocking agents, such as beta-blockers or to whom a seizure threshold has not yet been established (i.e., for those undergoing their first ECT session). Beta blockers such as esmolol (1 mg/kg) and labetalol (0.3 mg/kg) can be used to attenuate the sympathetic response of surge in systolic pressure and heart rate. However, they should be considered after a detailed evaluation of each patient's cardiovascular risk. Esmolol has a lesser effect on seizure duration than labetalol. Calcium channel blockers and alpha 2 agonists can also be used. Clonidine and dexmedetomidine (1 mcg/kg over 10 min before induction of anaesthesia) control blood pressure without affecting seizure duration. Medications that increase the morbidity (lithium) or decrease the efficacy (benzodiazepines, anticonvulsants) of ECT should be appraised.[12345]

Oxygenation

Many patients became hypoxic and cyanotic with loss of sphincter control with the practice of unmodified ECT. The introduction of modified ECT with muscle relaxation results in reduced oxygen requirement. Despite this, however, cerebral oxygen consumption increases almost 200% during the seizure. It is, therefore, a standard recommendation that the lungs should be ventilated with 100% oxygen at a rate of 15–20 breaths/min, beginning approximately 1 min before the induction, continued until the resumption of spontaneous breathing. Hyperventilation may prolong the seizure.[26]

INDUCTION AGENTS

Induction agents provide amnesia for the brief period of electrical stimulation and the action of the muscle-relaxing agent. A variety of induction agents may be used depending on clinical characteristics of the patient. An ideal induction agent should have a short half-life with rapid onset and recovery, maintain haemodynamic stability and have no interference with seizure duration or seizure threshold.[124]

Availability and preference of induction agent

Sodium pentothal (2–4 mg/kg) was the first induction agent used because of its availability at that time. Methohexital (0.5–1.0 mg/kg), a newer barbiturate, became more popular after its development. It remained the most widely used general anaesthetic for ECT for many decades and is considered the 'gold standard'. However, it's unlicensed status in the United Kingdom and problems with its supply present practical difficulties to those who wish to use it.[127] Ketamine (1.5–2 mg/kg) and etomidate (0.15–0.6 mg/kg) might seem preferable to other agents in the light of their lack of anticonvulsant properties, however, other aspects such as drug's safety require consideration.[8] Ketamine-propofol mixture (“ketofol”) and ketofol-dexmedetomidine combination (ketofol-dex mixture) can be used as alternative induction agents, which overcome disadvantages of individual agents.[910]

Sevoflurane (5%–8% for induction, followed by 1–2 minimal alveolar concentration [MAC] is the only inhalational agent in widespread use for induction in ECT, with comparable effects to intravenous (IV) agents. It is preferred in patients not cooperative for IV access. It has the advantage of attenuating uterine contractions following ECT and is used in the third trimester of pregnancy.[111] Opioids, such as remifentanil in higher doses, can be used as a sole agent in patients refractory to seizure induction. However, they are not usually recommended as sole agents and are combined with other anaesthetic agents. They offer an advantage of attenuating haemodynamic responses to ECT and also increase the seizure duration by an induction agent dose-sparing effect.[712]

In the current health-care environment, use of general anaesthetic techniques with a rapid onset and recovery is essential to facilitate the discharge of the patients within 1–2 hours after the ECT. Since the half-life of propofol is shorter than that of anaesthetic barbiturates and, with the advantage of minor haemodynamic effects, it is universally becoming the induction agent of choice, in spite of higher cost. It is also considered as reference agent due to its wider use and advantages over others.[489] Because of 'smoother' anaesthesia experience and relatively greater anticonvulsant action than other induction agents, it may be the agent of choice for ECT in children and adolescents, many of whom may have prolonged seizures early in their treatment course.[12]

There is no robust evidence to recommend a particular induction agent for ECT and all currently available induction agents are suitable for ECT. They should be chosen on the basis of their effect on seizure quality, adverse effect profile and emergence time.[13] A careful balance will need to be struck between the clinical condition of the patient and the induction agent utilised. Whichever drug is used, it is preferable to utilise the same one throughout a course of ECT and rarely may need to be changed during the course of treatment.[4]

ACTION ON SEIZURE: DURATION OF SEIZURE

ECT seizure duration provides, at best, a moderate predictor of the efficacy of treatment. It is monitored by both motor and electroencephalogram (EEG) activity as each has its own limitations. The goal is to induce a motor and a central EEG seizure of at least 25 and 40 s respectively.[11]

Induction agents in the descending order of seizure duration after their use are:[1471415]

Etomidate > ketamine > methohexital > sevoflurane > thiopental > propofol.

The durations of EEG and motor seizures are longest after etomidate and shortest after propofol. Thus, etomidate and also ketamine are effective in patients in whom it has been found to be difficult to produce any seizure activity. Although the seizure duration of propofol is shortest, this does not alter seizure quality indicators and does not affect efficacy. Therefore, it may be useful in the presence of prolonged seizures. Methohexital produce dose-dependent decreases in seizure duration and can be minimised by giving divided doses. Alternatively, induction agents such as methohexital, propofol and etomidate are combined with a short acting, highly potent opioids, such as alfentanil (10–25 mcg/kg) or remifentanil (1 mcg/kg) but not fentanyl, to increase seizure duration.[171416] Another useful adjunct to augment seizure duration is moderate hyperventilation (approximately twenty breaths) with an end-tidal carbon dioxide of around 30 mmHg. It is given immediately after the succinylcholine (SCh) is injected and continued (with a break for stimulus delivery) until the desired seizure duration is achieved. It is generally considered safe with an advantage of more rapid orientation following the treatment. However, there is increased chance of prolonged seizures (>120 s) and diminished drive to breathe postictally, particularly for patients with chronic obstructive pulmonary disease.[241112]

SEIZURE THRESHOLD

Initiation of ECT routinely involves the estimation of the seizure threshold as it varies in different individuals. Stimulus should be suprathreshold to ensure therapeutic seizure. Most of the patients have seizure threshold below specified stimulation levels. However, older patients or those on anticonvulsants, have higher threshold levels. In addition, the cognitive side-effects of ECT are proportional to how much the stimulus dose is above threshold. To reduce the threshold, the medication regime should be modified or hyperventilation may be considered.[11]

Induction agents in descending order of seizure threshold reducing property are:[14812171819]

Etomidate > ketamine > methohexital > thiopental > propofol.

Many anaesthetics exhibit dose-dependent anticonvulsant and/or proconvulsant properties. All agents have been reported to produce EEG excitatory activity on induction of anaesthesia. The highest incidence appears to be with etomidate, followed by methohexital, thiopental and propofol.[117] A systematic review by Hooten and Rasmussen on all currently available induction agents (except ketamine) reported etomidate as the only induction agent that may reduce the seizure threshold.[14] At higher doses, all agents act as anticonvulsants. At these doses, the barbiturates (thiopental and methohexital), ketamine and propofol are well established as agents for the treatment of refractory status epilepticus.[17] To reduce the anticonvulsant effects on seizure expression, the anaesthetic-ECT time interval should be extended to as long as practically possible to facilitate the production of better quality seizures.[15] Combining opioids such as remifentanil or alfentanil with these agents reduce seizure threshold by an induction agent dose-sparing effect. Remifentanil, for instance, is the medication recommended in patients who when treated with methohexital remain refractory despite maximum stimulus.[1] Sevoflurane, similarly, has both proconvulsant and anticonvulsant properties at different doses. High concentration of sevoflurane has seizure-provoking activity, particularly in children and when used in conjunction with hypocapnea.[417]

EFFECTS ON CARDIOVASCULAR FUNCTION

All induction agents used in ECT, except etomidate and ketamine, blunt the acute haemodynamic response of ECT procedure.[1] Etomidate maintains cardiovascular stability compared to others and produces minimal changes in heart rate and cardiac output. Because of its reduced cardiovascular depressant properties, the acute haemodynamic response to ECT become more prominent, when compared to barbiturates and propofol.[20] Ketamine, through its sympathomimetic action, produces tachycardia and hypertension. However, they are manageable and does not impede its use.[19] Thus, all induction agents used in ECT can be used safely in patients with normal cardiovascular function.

The anaesthetic barbiturates produce dose-dependent decreases in mean arterial pressure (MAP), and an elevation in heart rate, provided that the baroreceptor reflex is active. Propofol also produces a dose-dependent decrease in blood pressure. This decrease is significantly greater than thiopental. It simultaneously blunts the baroreceptor reflex or is directly vagotonic; in some patients, this may result in significant bradycardia and even asystole. Therefore, thiopental and propofol should be used with caution in patients at risk for or intolerant of decreases in blood pressure. However, propofol should be considered in patients who have problematic pre-existing hypertension during ECT.[2021] Unlike other anaesthetics, ketamine typically increases blood pressure, heart rate, cardiac output and myocardial oxygen consumption. Thus, it can be used in patients at risk for hypotension during anaesthesia; however, it is not an ideal drug for patients at risk for myocardial ischaemia. Sevoflurane produces a concentration-dependent decrease in arterial blood pressure, without reflex tachycardia. Thus, it may be a preferable agent in patients prone to myocardial ischaemia. Etomidate, at induction doses, typically produces a small increase in heart rate and little or no decrease in blood pressure. It has little effect on coronary perfusion pressure and reduces myocardial oxygen consumption. Thus, of all induction agents, etomidate is best suited to maintain cardiovascular stability in patients with coronary artery disease, cardiomyopathy, valvular heart disease, cerebral vascular disease or hypovolemia.[2021] Opioids are known to blunt autonomic responses to noxious stimuli. Remifentanil and alfentanil can be combined with other agents to reduce haemodynamic response associated with ECT.[721]

Induction agents in the descending order of ability to increase heart rate:[2223]

Ketamine > methohexital > thiopental > etomidate (no effect) > propofol (decreased heart rate).

Induction agents in descending order of ability to decrease blood pressure (MAP):[2223]

Propofol > thiopental > methohexital > etomidate (no increase) > ketamine (increased MAP).

CARDIAC ARRHYTHMIAS: QT PROLONGATION

Major depression may alter ANS activity in a patient and may increase the risk of arrhythmias and sudden cardiac death. In addition, ECT may cause an acute rise in QT dispersion, which may predispose to arrhythmias. All induction agents used for ECT prolong the QT interval. Sevoflurane should be avoided in patients at risk of QT prolongation. Ketamine is not recommended because of its sympathomimetic properties. Propofol, etomidate and thiopental can be used safely.[1424]

CEREBRAL HAEMODYNAMICS

Barbiturates, propofol and etomidate reduce CBF, ICP and CMR, as measured by cerebral oxygen consumption (cerebral metabolic rate of oxygen [CMRO2]). Because they lower cerebral metabolism, they have been used for neuroprotection in patients at risk for cerebral ischaemia. Ketamine, however, increases CBF and ICP with minimal alteration of cerebral metabolism. It is relatively contraindicated for patients with increased ICP or those at risk for cerebral ischaemia as it may aggravate a “tight” brain. Total IV anaesthesia accomplished by propofol is often used for the “tight” brain, including moderate to severe brain oedema. Volatile anaesthetics like sevoflurane also reduce CMRO2 like IV agents. However, their effect on cerebral physiology is different from IV agents as they possess intrinsic cerebral vasodilatory activity, which is least with sevoflurane. At 1 MAC, CBF and ICP remain unchanged in patients with normal intracranial compliance. In patients with poor intracranial compliance and with MAC >1, sevoflurane dilates the cerebral vasculature, producing increased CBF and ICP. The increase in ICP may be prevented by hyperventilation as the response to hypocapnia is preserved during sevoflurane anaesthesia. Opioids have relatively little effect on CBF and CMR in the normal, unstimulated nervous system.[202526]

Induction agents in the descending order of CMRO2 reducing ability:[202526]

Propofol > sevoflurane > thiopental and methohexital > etomidate > ketamine.

Induction agents in the descending order of CBF and ICP reducing ability:[202526]

Propofol > thiopental and methohexital > etomidate > ketamine.

EMERGENCE TIME

Emergence time is the time from drug administration for general anaesthesia till eye opening or following commands. The differences in emergence time among induction agents suitable for ECT are small, and these small variations in emergence should not govern drug choice.[14]

Induction agents in the descending order of emergence time:[1427]

Ketamine > etomidate > barbiturates > propofol > sevoflurane.

OTHER EFFECTS

Etomidate, in a dose-dependent manner, inhibits the adrenal enzyme 11-β-hydroxylase, important for steroidogenesis. Single induction doses of etomidate may mildly and transiently reduce cortisol levels, but no significant differences in outcome after short-term administration have been found. In addition, it can cause nausea and vomiting resulting in delayed recovery. A unique and undesirable effect of ketamine is its association with psychomimetic emergence delirium. This can be particularly prominent after rapid awakening from induction doses. Patients can experience vivid dreams, illusions, hallucinations and delusions. The risk is lower in children and in those pre-medicated with benzodiazepines.[20]

MUSCLE RELAXATION

Muscle relaxation is used to eliminate musculoskeletal injury and aid in airway management. Succinylcholine (0.5–1.5 mg/kg) remains the relaxant of choice due to its rapid onset and short duration. Atracurium, mivacurium or rocuronium may be acceptable alternatives, although their relatively prolonged action will need continued anaesthesia and/or active reversal after treatment. Sevoflurane, the only inhalational induction agent used in ECT, has an advantage as it produces skeletal muscle relaxation and enhances the effects of neuromuscular blocking agents.[3720]

ROLE OF INDUCTION AGENTS IN POTENTIATING THERAPEUTIC EFFICACY OF ELECTROCONVULSIVE THERAPY

In the early days of modified ECT, barbiturates were the only choice for induction, and it did not occur to psychiatrists to be involved in decision making regarding anaesthetic agents. Over time, many anaesthetic agents have been developed. Furthermore, there has been increasing literature regarding the influence of induction agent on the therapeutic efficacy of ECT, which led psychiatrists to liaise with the anaesthesiologist in making the choice of the induction agent.[28]

Ketamine has intrinsic antidepressant properties as it is an N-methyl-D-aspartate antagonist.[12] Many studies assessed whether its antidepressant effect might be synergistic with ECT and showed mixed results.[192930] It may speed the onset of antidepressant response to ECT but does not result in greater efficacy at the end of the ECT course.[27] This could be due to the potential development of tolerance due to the repeated use. Administering other induction agent (like thiopental) in alternate treatment sessions with ketamine may prevent the development of tolerance.[31] The enhancement of efficacy early in the course by ketamine, may be particularly advantageous in two situations: (a) in right unilateral ultra-brief ECT where the onset of antidepressant effect is slower, (b) in cases of high suicide risk or high clinical severity (e.g., catatonia), when a very rapid response is required.[1527]

Propofol or barbiturates do not have any intrinsic antidepressant properties, however, they are quite comparable to ketamine in ultimate antidepressant efficacy of ECT, though ketamine produces a quicker response. Furthermore, combining propofol with ketamine (ketofol) retains the early antidepressant property of latter, while reducing the adverse effects. This suggests that propofol combined with ketamine anaesthesia might be the technique of first-choice in patients with depressive disorders undergoing ECT.[2832] Adding dexmedetomidine to this combination (ketofol-dex) has added anti-depressive effect following first ECT session, but not at the end. However, ketofol-dex combination has advantages in the form of increased seizure duration, lower incidence of agitation, more patient satisfaction and acceptable decrease in heart rate and blood pressure when compared to ketofol and without any significant side effects.[10]

Etomidate may improve major depressive disorder more than sodium thiopental.[28] However, depression is associated with stress-related hypothalamic pituitary adrenal axis dysregulation, and there is concern regarding the consequences of etomidate's unwanted suppression of adrenal function on depression, particularly on the course of illness.[8] However, the findings of Wang et al. in 2011, through measurements of serial cortisol levels at various time points during ECT, found no worrisome reductions with etomidate.[2833] There is no literature regarding the outcomes of depression with sevoflurane or with the combination of induction agents with opioids or hyperventilation.[28]

A recent meta-analysis on the role of IV induction agents in ECT for major depression showed that after excluding trials responsible for heterogeneity, the depression scores after the ECT course were lower with methohexital compared to propofol, and lower with propofol compared to thiopental. However, it concluded based on overall data, that it was not possible to highlight the superiority of any anaesthetic agent with regards to response rate at the end of treatment. These results also show that seizure duration, as a single factor, may not explain the superiority of one anaesthetic agent over other. Furthermore, it highlighted that ketamine administration cannot be recommended to date as an anaesthetic of choice for ECT for depression, alone or in combination. Anaesthetic agents should be chosen on the basis of adverse event profile and emergence, along with effect of these medications on seizure duration.[34]

There are no specific studies on the influence of induction agents on ECT when used for mania or psychosis. Switch from depression to mania can happen in bipolar patients with ketamine's use in ECT. However, as manic switches may also be a side-effect of ECT treatment, further studies are needed.[34] Ketamine can induce psychotic symptoms, however, practitioners have used it without encountering such problems.[12] Although barbiturates can be used for the treatment of catatonia, no studies compared them with other induction agents in ECT for catatonia. Transient cognitive deficits are common after ECT which are often a reason for terminating a course of ECT before remission is achieved. Ketamine was shown to be preferable to thiopental, methohexital and etomidate in this aspect.[8]

Neuroleptic malignant syndrome (NMS) is a serious side-effect produced by some antipsychotic drugs with some clinical similarities to malignant hyperthermia (MH). Although evidence is lacking to support NMS and MH having a similar pathophysiology, caution is advised when administering general anaesthesia to patients with NMS. Agents such as sevoflurane, suxamethonium (SCh) or their combination, known to trigger MH should be avoided, though the administration of SCh to patients receiving ECT for NMS is safe. Therefore, in patients with a history of NMS, a more promising method of muscle relaxation is to use rocuronium-sugammadex as an alternative to SCh.[16]

CONCLUSION

Anaesthesia not only enables the ECT procedure but may also have a significant influence on its clinical efficacy and tolerability through the impact on electrophysiological variables and seizure parameters. Psychiatrists used to be in charge of administration and recovery from ECT, many years ago. Nowadays, the procedure is performed in an ECT administration room where an anaesthesiologist is in charge of general anaesthesia and a psychiatrist administers ECT. Thus, anaesthesiologists and psychiatrists must be aware of not only the physiological responses to ECT and how to modify these but also understand the anaesthetic factors that may influence the efficacy of ECT.

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Conflicts of interest

There are no conflicts of interest.