Clinical trial NCT04828226: Clonidine to Prevent Delirium After Electroconvulsive Therapy.
Official title: Clonidine to Prevent Postictal Delirium After ElectroConvulsive Therapy: a Randomised, Placebo-controlled, Triple-blind, Single-centre Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Major Depressive Disorder
Catatonia
Bipolar Disorder
Delirium Postseizure
Keywords: Electroconvulsive Therapy
ECT
Clonidine
Postictal Delirium
Postseizure Delirium
Postictal Agitation
Postseizure Agitation
CAM-ICU
RASS
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: University of Bern
First posted: 2021-04-01
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective, randomised, placebo-controlled, triple blind, single-centre, two-arm parallel groups superiority trial assessing incidence and severity of postictal delirium.
Primary purpose: PREVENTION

Brief summary: Electroconvulsive therapy (ECT) is a highly effective treatment for some psychiatric disorders like major depressive or bipolar disorder, but may lead to agitation and delirium after the procedure in up to 65% of patients. This can have negative side effects and be dangerous for patient and attending staff. Clonidine, a central-acting alpha2-receptor agonist, is an approved antihypertensive medication with known sedative side effects. Clonidine's newer but more expensive successor, dexmedetomidine, has recently shown its potential to reduce this kind of delirium. The investigators therefore hypothesise that pre-treatment with 2 mcg/kg clonidine prior to electroconvulsive therapy will significantly reduce the incidence of postictal delirium. This potentially makes a highly efficient treatment for patients with otherwise refractory psychiatric illness safer and more accessible.

Detailed description: Electroconvulsive therapy (ECT) is a highly efficacious therapy for psychiatric disorders, especially major depressive disorder, bipolar disorder and catatonia resistant to psychopharmacology or drug-psychotherapy combination therapy. At therapy induction, usually a series of 10-12 ECT sessions is planned with two to three days in between sessions. Thereafter, maintenance therapy can be continued with longer session intervals thereafter to avoid relapses and to support further drug and psychotherapy treatment. Without maintenance therapy, relapses can happen in up to 80% of all patients within one year.

Nowadays conducted under general anaesthesia (etomidate in the investigator's centre) and muscle relaxation (suxamethonium) to prevent adverse events, ECT can be challenging for the anaesthesiologist, as it usually leads to rapid cardiovascular changes such as sudden bradycardia due to vagal discharge, followed by sympathetic counter regulation associated with tachycardia and hypertension. For the patient, known immediate side effects are headache in about 30% and postictal confusion and delirium in up to 65%. This confusional state can lead to involuntary movements and agitation and therefore be harmful for patients and attending staff. It usually resolves within 45 minutes but nevertheless seems to be linked with adverse side effects like persistent retrograde amnesia. Identified risk factors are long seizure time and pre-existing catatonic features. Postictal delirium has been classified by Kikuchi et. al. into four categories from no delirium, mild, moderate or severe delirium. Moderate to severe delirium needing restraints or sedative medication like benzodiazepines or Propofol was present 36% of patients, which is in line with older data. The more severe forms of delirium are easily recognised in clinical practice because of the need for intervention. When including mild forms, delirium was present in 52% of all patients in the study of Kikuchi et al. In newer studies using a more sensitive tool (CAM-ICU, Confusion Assessment Method - Intensive Care Unit) to assess the presence of delirium, the rates are up to 65% at 10 minutes after ECT stimulation respectively 10 minutes after arrival in the post-anaesthesia care unit. CAM-ICU is a brief but sensitive test, which has been extensively validated in the intensive care setting. Therefore, it seems that postictal delirium is frequently underdiagnosed in clinical practice. As we know from the intensive care literature, even hypoactive forms of delirium are associated with higher complication rates and higher mortality and therefore cannot be neglected.

In previous small studies, premedication with promethazine, midazolam and dexmedetomidine successfully reduced incidence of postictal delirium. Dexmedetomidine, a highly selective, relatively short acting alpha2-agonist, has been more extensively studied in the setting of ECT and has recently been able to show his potency to reduce postictal delirium by a third when given as a bolus pre-induction in a randomised controlled trial.

In this prospective, randomised, placebo-controlled, triple-blind, single-centre, two-arm parallel groups superiority trial, the investigators aim to lower incidence and severity of postictal delirium and agitation using a pre-induction dose of 2 mcg/kg clonidine intravenously compared to placebo (sodium chloride). The investigators also hypothesise, that a pre-induction dose of clonidine will reduce incidence of postictal agitation, the need for sedative rescue medication and the need for short-acting antihypertensive medication. It therefore might increase patient safety and cost effectiveness without prolonging post-anaesthesia care unit stay or negatively affecting treatment efficacy.

Eligibility criteria: Inclusion Criteria:

* Aged 18 and more;
* Scheduled for an elective series of ambulatory ECT sessions at the University Hospital Bern;
* Informed Consent as documented by signature (Appendix Informed Consent Form).

Exclusion Criteria:

* Contraindications to the study drug, e. g. known allergy or hypersensitivity, hypotension, bradycardia, higher grade atrioventricular block;
* On regular Clonidine for another indication (e.g. arterial hypertension)
* Patients undergoing emergency ECT;
* Unable to consent (incapable of judgment, next-of-kin consent necessary or under tutelage);
* Inability to follow the procedures of the study, e. g. due to language barrier;
* Previous enrolment into the current study;
* Participation in another study with investigational drug within the 30 days preceding and during the present study;
* Enrolment of the investigator, his/her family members, employees and other dependent persons.
* Women who are pregnant or breast feeding;
* Intention to become pregnant during the course of the study;
* Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration (and 4 weeks thereafter), such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.

Primary outcomes:
measure: Incidence of delirium after electroconvulsive therapy over all (twelve) ECT sessions
timeFrame: 20 minutes after muscle relaxation
Secondary outcomes:
measure: Incidence of mild agitation
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Incidence of severe agitation
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Use of rescue medication
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Duration of seizure activity
timeFrame: during procedure (estimated to be on average 10-15 minutes)
measure: Quality of seizure activity
timeFrame: during procedure (estimated to be on average 10-15 minutes)
measure: Seizure Quality Index
timeFrame: during procedure (estimated to be on average 10-15 minutes)
measure: Need for seizure terminating medication
timeFrame: during procedure (estimated to be on average 10-15 minutes)
measure: Total number of electroconvulsive therapy sessions
timeFrame: whole treatment course (12 ECT sessions, about 4 weeks)
measure: Reason for terminating or continuing the electroconvulsive series
timeFrame: whole treatment course (12 ECT sessions, about 4 weeks)
measure: Length of post-anaesthesia care unit stay
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Incidence of desaturation
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Incidence of hypotension
timeFrame: during procedure (estimated to be on average 10-15 minutes)
measure: Incidence of bradycardia
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Cardiovascular changes needing intervention
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Use of cardiovascular medication
timeFrame: post-anaesthesia care unit stay (up to 2 hours)
measure: Adverse events potentially attributable to ECT
timeFrame: whole treatment course (12 ECT sessions, about 4 weeks)
measure: Adverse events potentially attributable to Study Drug
timeFrame: whole treatment course (12 ECT sessions, about 4 weeks)
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Department of Anaesthesiology and Pain Medicine, Bern University Hospital, University of Bern
Study officials:
affiliation: Department of Anaesthesiology and Pain Medicine, Bern University Hospital, University of Bern
name: Patrick Y Wüthrich, Prof, MD
role: PRINCIPAL_INVESTIGATOR
References: