A systematic review of modified electroconvulsive therapy (ECT) to treat delirium

Delirium is costly for patients, carers, and healthcare systems. In addition, non‐pharmacological and pharmacological management of delirium is challenging. Electroconvulsive therapy (ECT) has been proposed and used as an anecdotal treatment of delirium in clinical practice. However, the efficacy and safety of this approach are not well understood.

who were treated with ECT were identified. In 33/40 cases, the aetiology of delirium was substance withdrawal. The number of ECT treatments administered ranged from 1 to 13. ECT was reported to positively contribute towards treatment of delirium in all cases, although objective measures of improvement were reported in only 6/13 patient cases from case reports and case series (46%). The singular quasi-experimental study reported a statistically significant decrease in duration of delirium, time spent in physical restraint, and in benzodiazepine requirement when ECT was used as an adjunct in benzodiazepine withdrawal delirium. When adverse events were described these included mild confusion and memory deficits; all were reported as time limited and reversible. Considerable limitations in the quality of the evidence base were identified, including the risk of selection, publication and reporting bias. Much data reporting on safety and efficacy of ECT in delirium was missing. Conclusion: There is insufficient literature to support modified ECT as a clinical treatment for delirium. The few studies identified were generally of weak evidence lacking important data on safety and objective outcome measures, and not including populations with broad delirium aetiologies. Further research using more robust methodologies and broader populations (age, aetiology) of people with delirium treated with ECT is needed.

| INTRODUCTION
Delirium is a common complication of hospital-based care that incurs substantial costs for the healthcare system and causes considerable distress to patients and carers. 1 Contemporary literature emphasises taking assertive efforts to prevent the emergence of delirium and address underlying causes, 2 and acknowledges the potential role of symptomatic management using non-pharmacological treatments such as environmental optimisation as first line treatment. 3 Often these interventions are unsuccessful, and/or there is severe patient distress or safety concerns, and in these instances other approaches such as pharmacological management or even electro-convulsive therapy (ECT) are considered. 4 ECT involves the therapeutic induction of a seizure using a pulsed electrical stimulus and is an efficacious treatment for a broad range of acute psychiatric and neuropsychiatric conditions. [5][6][7][8] When used for the right patient at the right time, ECT can have lifesaving effects, attenuating psychiatric symptoms and distress. 9 Significant advances in ECT practice have improved the procedure's safety, tolerability, and effectiveness. 6 These include the use of anaesthetic agents and muscle relaxants (modified ECT), new approaches to electrode placement, electroencephalogram (EEG) monitoring, dosing based on seizure threshold determination, and changes to the stimulus parameters in the use of brief and ultra-brief pulse widths. Known adverse effects of ECT treatment include delirium itself, agitation, and the potential for longer-term impacts on cognition. [10][11][12][13] As such, its use in treating delirium may seem counter intuitive. However, it has been theorised that ECT may have specific antidelirium properties 10 and there is some evidence in the literature that it has been implemented to address severe and treatment-resistant delirium in hospital settings; a range of case reports and observational studies report the use of ECT as a treatment of delirium. 12,[14][15][16][17][18][19][20][21][22][23][24][25] To date, there have been no focussed systematic reviews attempting to synthesise the evidence-base relating to the use of ECT as a treatment for delirium.

Summations
• There is insufficient evidence supporting ECT as a treatment for delirium. • The most common aetiology of delirium treated with ECT in the literature was substanceinduced withdrawal delirium, thus limiting the generalisability of results. • Future research exploring the effectiveness of ECT for delirium must include robust methodologies, outcome measures and broader populations of people with delirium.

Limitations
• Few studies identified and of a low-quality evidence base; as such, subject to selection, publication and reporting bias. • Much data reporting on safety and efficacy of ECT in delirium was missing. • Published cases are largely limited to younger patients with relatively few comorbidities and narrow delirium aetiologies.
The topic was previously considered as part of a broad systematic review considering ECT as a treatment for neurological and somatic disease completed in 1994. 26 This review included several studies focused on the use of ECT in a wide range of organic aetiologies and concluded that ECT may be used with caution as a treatment for delirium. Since this publication, several new studies have been published highlighting the need for a contemporary review.

| AIMS OF THE STUDY
To appraise and synthesise the current literature to understand better the use of ECT in treating organic delirium. The review examines approaches to ECT delivery, treatment efficacy, and the frequency and severity of adverse effects.

| METHOD
A systematic review was completed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance and was prospectively registered on PROSPERO (https://www.crd.york.ac.uk/prospero/ display_record.php?RecordID=241741). Databases including PubMed, CINAHL, Cochrane Library, and PsycINFO were searched with a search period from 1980 to June 2021 independently by two authors (KL, SS) (see Supplementary data). Additional records were identified from a review of the reference lists of any records considered at the full-text level during the data extraction. Any discrepancies were resolved by discussion with the senior author (SP). Studies were included if there was a diagnosis of delirium and ECT was utilised at any stage for the treatment for delirium symptoms. All study types and languages were included. Cases with confusional states known to arise directly due to the acute phase of a primary mental health condition (e.g., delirious mania, Leonard's psychosis, and confusional psychosis) were excluded. Also excluded were delirium with an underlying diagnosis of catatonia or neuroleptic malignant syndrome, given ECT is an established evidenced based treatment in these conditions. 27 Age was restricted to 18 years and above. The date specifier of 1980 onwards was set with the view that from this time modified ECT was widely established in clinical practice.
Data was extracted by two authors independently (KL, SS), with any discrepancies being resolved by a third author (SP). Pre-specified variables included demographics, past medical and psychiatric history, indication for ECT, psychotropic and other treatments, ECT timing (both in relation to delirium onset as well as the interval between treatments), prescription, and adverse effects. Treatment response and outcome were categorised as improvement, no improvement, or deterioration. Missing data were noted.
All included records were first ranked using the hierarchy of evidence-based medicine 28 ; quality was then assessed using the Joanna Briggs critical appraisal checklists. 29,30 Pooled data across the cases identified were analysed using descriptive statistics.

| Study and case characteristics
Of 1226 records were identified ( Figure 1). Ten studies met the inclusion criteria: six case reports, three case series, and one quasi-experimental study. Within these studies, only 40 individual patient cases were described (27 from the quasi-experimental study, 13 from case reports and series) reporting on the use of ECT for the treatment of delirium. Of the cases included in case reports and series, the mean age was 49.6 ± 15.8 years, and the male to female ratio was 11:2. The cases from the quasi-experimental study had a mean age of 42.2 ± 11.7 years and a male-to-female ratio of 11:16.
The literature base was of mixed quality. Ratings based on the Joanna Briggs critical appraisal checklists considered the quasi-experimental study to be of 'fair' quality, three of the case reports to be of 'poor' quality (and three of 'fair' quality), and two of the three case series to be of 'poor' quality, with the other rated as 'fair' (see Supplementary data for additional detail).
Geographical origin of the studies varied throughout, with three originating from the United States, two from Denmark, and other source countries including Iran, Germany, France, India, and Japan.

| ECT indications
Most of the literature described the use of ECT in the treatment of delirium arising due to substance withdrawal (33/40 cases identified, including all cases in the only empirical study). The single quasi-experimental study focused on delirium occurring in severe benzodiazepine withdrawal states. 31 The case reports/series considered prescribed medications ('tranquillisers/sedatives', unspecified), and drugs of abuse (methamphetamine, and alcohol). Other aetiologies of delirium states treated with ECT were encephalitis (Japanese B encephalitis, herpes simplex virus limbic encephalitis), motor neurone disease, traumatic brain injury, and pneumonia (Table 1).

| ECT characteristics
Within the single quasi-experimental study, 31 ECT was modified and delivered three times per week until resolution of symptoms. The specific number of ECT treatments required to achieve this outcome was not described. No information was provided regarding ECT lead placement or pulse width. Of the 13 cases identified through case reports, most described the use of bilateral or bitemporal ECT (9/13), one case described bifrontal ECT, another described unilateral ECT, and two cases not specifying the electrode placement ( Table 2). All cases specifying the pulse width of ECT stimulus reported 'brief pulse' administration (6/13). Half of the case report/series studies described ECT administration at least daily. Based on the available case data the number of ECT administrations ranged from 1 to 13 (mean 7.08 ± 3.27), with the total duration of the ECT course ranging 1-35 (mean 15.42 ± 12.34) days, although this data was only available in 7/13 of the case reports. Limitations in the adequacy of the description of the ECT were present in most case reports (7/13).

| Outcomes
The only empirical study was a quasi-experimental study by Kurokawa et al. 31 that examined the impact of ECT on delirium relating to benzodiazepine (BZD) withdrawal. In this study, inpatients who presented with BZD withdrawal delirium were divided into two groups, one receiving modified ECT (m-ECT) (n = 14) + BZD tapering therapy, and one which received BZD tapering therapy alone (non-m-ECT) (n = 13). The specific BZD tapering therapy regime is not described in the study. Patients were allocated to each treatment arm based on explanation of ECT and discussion with the family and/or patient; allocation was not randomised. ECT was administered three times per week, until symptoms of delirium resolved, although no quantifiable measure of this was provided in the study. Total number of treatments required to achieve resolution of symptoms was not reported, nor were the specific characteristics of ECT (electrode placement, pulse width, general anaesthetic/ muscle relaxant used, number of treatments administered). Specific detail regarding the type of benzodiazepine utilised in this study was not provided but the study states a diazepam conversion was used in order to compare results between treatment groups. The group receiving m-ECT + BZD tapering therapy experienced significantly shorter durations of delirium (4.4 ± 1.5 days vs. 7.2 ± 2.2 days, p < 0.01), reduced time spent in physical restraint (4.6 ± 1.8 days vs. 7.0 ± 1.8 days, p < 0.01), and a reduced benzodiazepine dose requirement (BZD dose prior to admission in m-ECT group was 27.9 ± 16.7 mg vs. 23.4 ± 11.5 mg in the non m-ECT group). On discharge, the BZD dosage in the m-ECT group was 3.9 ± 3.5 mg vs. 15.1 ± 12.8 mg in the non-m-ECT group, p < 0.01. Notably, the authors state there was no cooccurring disease present within either group at the time of the study. Neither adverse outcomes nor adverse effects of ECT treatments were discussed. All case reports and series described ECT as being efficacious in the treatment of delirium (Table 3). From the cases, where relevant data was presented, the number of ECT administrations needed to observe improvement in symptoms ranged from one-to-five (5/13 cases), and in 12/13 cases total resolution of symptoms was achieved after one-to-nine treatments. Pre-and post-ECT quantitative measures were presented in support of the improvements in delirium symptoms following ECT for 6/13 cases. Nielsen et al. 12 described five cases where ECT was used to treat organic delirium in an intensive care unit (ICU) setting. Prior to commencement of ECT all these patients tested positive on the Confusion Assessment Measures-ICU (an objective test designed for the ICU setting, which assesses the domains of altered/fluctuating mental status, inattention, altered level of consciousness, and disorganised thinking 32 ). All patients then received bitemporal, brief pulse en bloc (daily ECT for 3 days) treatment followed by a maintenance dose of 3Â ECT treatments per week until resolution of symptoms (Table 2). After this treatment four of the five patients were CAM-ICU negative, and the patient remaining positive was thought to be related to post-traumatic amnesia rather than delirium.
In another case, Kant et al. 18 described a 34-year old man who received six bilateral brief-pulse ECT for a prolonged delirium after a traumatic brain injury. Prior to ECT, he presented with a Mini-Mental State Examination (MMSE) of 8/30, and a Galveston Orientation and Amnesia Test (GOAT) of 5/100. After six ECT administrations his MMSE score had improved to 18/30 and his GOAT increased to 67.5/100. The GOAT is a highly specific and sensitive assessment of orientation, as well as anterograde and retrograde amnesia. 33

| Adverse events
Kurokawa et al.'s 31 quasi-experimental study did not discuss the emergence (or absence) of adverse events associated with ECT treatment (Table 4). Only 6/13 of the cases identified in the case reports/series provided information about adverse effects associated with ECT as a treatment for delirium. For two cases no adverse events were noted. In the other four cases adverse events were 'mild confusion' with worsening language deficits which improved completely following the ECT course completion, 18 reversible memory deficits, 17 retrograde amnesia with full recovery within 3 months, 23 and ongoing amnesia following the conclusion of ECT attributed to post-traumatic amnesia rather than ECT. 12

| DISCUSSION
We found insufficient evidence to recommend modified ECT as a treatment for delirium in clinical practice. A total of only 40 patients have been reported in the literature. A single 'fair' quality quasi-experimental study found efficacy of ECT when used as an adjunct in the treatment of benzodiazepine withdrawal delirium in 27 patients. Additionally, 13 individual cases described within case reports/ series (low-level evidence) were identified; all reported a positive response to delirium from ECT but had significant methodological limitations. ECT as a treatment for delirium may be deemed counter-intuitive secondary to its potential adverse effect profile; ECT is known to induce delirium, and this bi-directional relationship adds where adverse effects of ECT as a treatment of delirium occurred, these were time-limited, reversible, and consistent with the known adverse effects of ECT. 13 Patients receiving ECT as a treatment for delirium were relatively young and generally had few medical comorbidities. Such patients are unlikely to represent most people experiencing delirium in medical settings, given that known risk factors include increasing age, cognitive impairment, and comorbidity. 34 When delirium is secondary to presentations such as sepsis, organ failure, or even in older adults with vulnerable brain architecture, this may limit the appropriateness of ECT due to anaesthetic safety concerns and pre-existing cognitive impairment being a risk factor for memory problems following ECT. Further, delirium secondary to substance withdrawal constituted most reported cases (82.5%). Given the myriad different causes of delirium, there are likely distinct neurobiological pathways involved in its development. 35 Possibly delirium secondary to substance withdrawal (especially GABAergic drugs such as benzodiazepines and alcohol, which were the majority of cases) may be more responsive to ECT than delirium from other aetiologies, accounting for the apparent positive outcomes in this cohort. Furthermore, ECT treatments such as 'multiple monitored ECT' (two seizures administered during one anaesthetic) as employed in the included study by Ahmadi et al. 19 is not in line with current evidence-based treatment recommendations and, as such, less relevant to current clinical practice. 27 ECT was generally used as a last resort treatment for delirium after failed non-pharmacological and pharmacological treatments. This is unsurprising as delirium is not a recognised indication for ECT. A further challenge in the use of ECT as a treatment of delirium is consent. In some jurisdictions, the use of ECT as treatment for a psychiatric diagnosis is covered by mental health legislation. The same legislation cannot be used when ECT is used as a treatment for an organic illness, although Guardianship legislation may be relevant. Furthermore, most cases of delirium will be treated in a medical rather than a psychiatric setting, where familiarity and access to ECT may be limited. Significant input from a Consultation-Liaison Psychiatry service may facilitate ECT treatment in the general hospital.
Kurokawa et al. 31 propose various potential mechanisms of action for the use of ECT in delirium including Fair the impact of ECT on brain blood flow. Positron emission tomography (PET) scan imaging has previously demonstrated an increase in blood flow to numerous anatomical structures in the brain as an ECT-induced seizure occurs. They also discuss the use of Statistical Parametric Mapping (SMP) to demonstrate blood flow changes during a course of ECT, noting blood flow initially decreases secondary to propofol administration, increases during ECT, and decreases in the post-ECT period. Kranaster et al. 17 suggest ECT's beneficial effect in alcohol withdrawal delirium may be due to a positive effect on the associated 'GABA-ergic deficit'. Charlton 10 further proposes that delirium is an underpinning of most psychiatric presentations, precipitated by disruption to the sleep-wake cycle. ECT, by inducing a generalised seizure, may work to encourage 'deep restorative sleep', thus normalise this disruption and as such exert its therapeutic effect. 10 These hypotheses are just that; to date the understanding of the underlying mechanism of action ECT in delirium is limited, 36 which introduces another consideration for future research. Significant limitations impact the generalisability of the findings to routine clinical practice. The number of reported cases is small, and only a single empirical study was identified. Except for a single record, delirium was not defined using a structured assessment tool. Very few of the case reports described consistent measures being completed pre-and post-ECT to quantify (and substantiate) the reported improvements. In terms of the quality of the evidence base, the single empirical study, which did not have random allocation or control for potential confounders, was assessed to be of 'fair' quality. 31 All other evidence was in the form of case reports and case series, the lowest levels of evidence, 37 which were assessed as 'fair' to 'poor' quality. 29 It is difficult to comment on clinical utility with such a wide range of confounding factors; the origin of delirium itself varied greatly, as did the patient demographics, treatments trialled prior to commencement of ECT treatment, the type of ECT utilised and number of ECT treatments administered. Within many of these cases key information was missing, particularly regarding safety. The ongoing use of the term 'confusion' when reporting an adverse effect of ECT is problematic in a cohort who already experiencing delirium-an acute confusional state. It is unclear how the confusion occurring in association with ECT may be objectively measured and distinguished from the underlying delirium itself. Another issue, especially with uncontrolled trials and case reports, is that delirium can resolve with time, good quality care/brain optimisation and treatment of the underlying cause. 35 Thus, some of the positive outcomes attributed to ECT may have been due to delirium resolution that may have occurred without ECT. Furthermore, much of the data was obtained from case reports and case series, thus introducing selection, publication, and reporting bias. These limitations suggest a high risk of overestimating treatment effectiveness; the reported beneficial outcomes must be considered with caution.
Studies focusing on psychiatric causes of delirium were excluded in this systematic review. However, the overlap between delirium and the neuropsychiatric syndrome of catatonia has been emphasised in the literature. Oldham and Lee 38 have speculated that catatonia is often under-diagnosed due to delirium's higher position in the diagnostic hierarchy, current DSM5 criteria and that catatonia may masquerade as a delirium. Similarly, Denysenko 39 argued that delirium and catatonia should not be regarded as 'mutually exclusive' in settings given their similar symptomatology. In essence, diagnostic clarity is often lacking. This diagnostic conundrum between catatonia and delirium introduces an important topic for future research. Additionally, the literature identified provides no guidance regarding the use of ECT in patients experiencing delirium superimposed on dementia as no studies were identified considering using ECT in that context. Furthermore, the decision to exclude data pre-1980 on the assumption that modified ECT was a widely accepted phenomenon following this date limits this reviews comprehensiveness. However, unmodified ECT is associated with specific additional adverse effects and complications and is largely no longer used in clinical practice, so the relevance of these early papers is questionable. 40 Considerations for future research include assessment of efficacy and safety within a wider cohort of age, recognising the increased risk of delirium in the elderly population and those with underlying comorbidities. 34 Most of the available literature focuses on ECT as a treatment for benzodiazepine withdrawal delirium; focusing on using ECT in alternative aetiologies of delirium is relevant. Ethical, practical and legal issues may present barriers to high-quality research in this area. On a practical level, access to ECT is inconsistent, considering that most patients presenting with delirium are managed on medical wards rather than a psychiatric unit. Ethical and legal concerns exist around the consent process in patients presenting with delirium and the safety of ECT in medically compromised patients. Barriers to the further consideration of ECT as a treatment for delirium include legislative restrictions and negative public perceptions of ECT generally. 41 However, such barriers could be overcome with clarification of legislation, close working relationships with hospital physicians and psychiatrists, and education of patients and healthcare professionals.
The limitations of the available literature highlight the need for further study examining the utility and safety of ECT as an approach to treating delirium. The positive outcomes reported in the single quasi-experimental study 31 suggest there may be a limited role for ECT in delirium for young adult patients with severe benzodiazepine withdrawal. While the available case reports were consistently positive in their description of the contribution of ECT to resolving delirium, they have major methodological problems. In many of these cases the delirium had not responded to multiple alternative treatments and was associated with considerable risk. Extreme caution is needed in considering the relevance of these findings in guiding clinical practice, given the limited empirical data, poor methodological quality and low-level evidence. Therefore, based on our review we cannot conclude that ECT is an evidence-based or safe practice for treating delirium.

SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.