Hyperventilation Combined With Etomidate or Ketamine Anesthesia in ECT Treatment of Major Depression

Hyperventilation and ECT Seizure Duration: Effects on Cerebral Oxygen Saturation, and Therapeutic Outcome With Comparisons Between Etomidate and Ketamine in Patients With Major Depressive Disorder

This is a randomized controlled study assessing the effect of pre-emptive hyperventilation on ECT seizure duration, cerebral desaturation and remission of depressive symptoms in patients with Major Depressive Disorder. Comparison of etomidate and ketamine on remission of depressive symptoms with and without pre-emptive hyperventilation will also be studied.

Study Overview

• Status: Unknown
• Conditions: Depression
• Intervention / Treatment: Drug: Etomidate; Procedure: Electroconvulsive therapy (ECT); Drug: Ketamine; Procedure: Hyperventilation

Detailed Description

Electroconvulsive therapy (ECT) is an effective treatment for medication-resistant forms of depression, including major depressive disorder and mania. Therapeutic success of ECT is related to the duration and quality of Electroencephalogram (EEG) and motor seizures. Previous studies have demonstrated that deliberate hyperventilation augments seizure duration in anesthetized subjects. It has also been shown that seizure activity significantly increases cerebral metabolic rate, predisposing the patient to potentially severe cerebral desaturation events. These desaturation events are predicted to be exacerbated by pre-emptive hyperventilation which has a potent cerebral vasoconstrictive effect. Despite the widespread use of ECT, little is known about the effect of hyperventilation on cerebral metabolism in this setting. Ketamine has recently been demonstrated to have anti-depressant properties in patients with major depressive disorder, suggesting that patients treated with ketamine anesthesia and then ECT, may benefit clinically from the additive effects of both treatment modalities, compared to ECT alone.

The investigators hypothesize that hyperventilation will facilitate prolonged seizure duration and faster remission of depressive symptoms. As well there may be significant cerebral desaturation and cardiovascular side effects of ECT therapy following hyperventilation. Lastly, the effect of hyperventilation on the efficacy of ECT therapy may be improved when ketamine anesthesia is used simultaneously. To test this hypothesis this study will compare ketamine anesthesia to etomidate anesthesia. Etomidate is a short acting anesthetic that is commonly used in these procedures.

The study objectives (primary and secondary) are as follows:

1. To quantify the effect of hyperventilation and type of anesthetic agent on ECT-induced seizure duration
2. To assess the effect of hyperventilation immediately prior to ECT on cerebral metabolism as measured by cerebral oximetry
3. To determine the effect of hyperventilation and anesthetic agent on the remission of symptoms in Major Depressive Disorder
4. To assess the side effect profile of hyperventilation during ECT on hemodynamics

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ian McIntyre, MD, MSc; Phone Number: 204 787-1414; Email: ian.mcintyre@umanitoba.ca

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Recruiting
      • Health Sciences Centre
      • Contact: Ian McIntyre, MD, MSc; Phone Number: 204 787-2560; Email: ian.mcintyre@umanitoba.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults patients aged 18 to 85 years
• Diagnosed with Major Depressive Disorder, unipolar or bipolar depression
• Undergoing ECT for treatment of their symptoms
• Currently residing in Manitoba

Exclusion Criteria:

• Relative contraindications to ECT therapy (recent MI or CVA, increased intracranial pressure, intracranial mass lesion, intracranial aneurysm, epilepsy, known cardiac arrhythmia, pheochromocytoma, pregnancy)
• Contraindications to etomidate (sepsis, primary or secondary adrenal insufficiency, porphyria)
• DSM-V diagnosis of a lifetime history of psychotic spectrum disorder
• Drug or alcohol dependence, or abuse within the past 3 months, soy-bean oil allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ECT with Etomidate; Immediately prior to ECT study patients will be administered intravenous etomidate for anesthesia at a dose of 0.3 mg/kg given as a bolus dose.	Drug: Etomidate; Etomidate will be administered as a bolus intravenously to induce an adequate depth of anesthesia just prior to ECT at a dose of 0.3 mg/kg; Other Names: Amidate; Procedure: Electroconvulsive therapy (ECT); Bilateral, bitemporal electrode placement will be utilized to elicit a seizure via a SpECTrun 5000Q (MECTA Inc.). The electrical dose required will be determined in advance by the patient's attending psychiatrist.
Active Comparator: ECT with Ketamine; Immediately prior to ECT study patients will be administered intravenous ketamine for anesthesia at a dose of 0.5 -1.0 mg/kg given as a bolus dose.	Procedure: Electroconvulsive therapy (ECT); Bilateral, bitemporal electrode placement will be utilized to elicit a seizure via a SpECTrun 5000Q (MECTA Inc.). The electrical dose required will be determined in advance by the patient's attending psychiatrist.; Drug: Ketamine; Ketamine will be administered as a bolus intravenously to induce an adequate depth of anesthesia just prior to ECT at a dose of 0.5 to 1.0 mg/kg.; Other Names: Ketalar
Active Comparator: ECT with Etomidate and Hyperventilation; Immediately prior to ECT study patients will be administered intravenous etomidate for anesthesia at a dose of 0.3 mg/kg given as a bolus dose. Hyperventilation will be administered (20 breaths in 30 seconds) by face mask immediately prior to ECT.	Drug: Etomidate; Etomidate will be administered as a bolus intravenously to induce an adequate depth of anesthesia just prior to ECT at a dose of 0.3 mg/kg; Other Names: Amidate; Procedure: Electroconvulsive therapy (ECT); Bilateral, bitemporal electrode placement will be utilized to elicit a seizure via a SpECTrun 5000Q (MECTA Inc.). The electrical dose required will be determined in advance by the patient's attending psychiatrist.; Procedure: Hyperventilation; Hyperventilation will be performed in patients after full pre-oxygenation and induction of anesthesia, by administering 20 breaths in 30 seconds using a well-fitting face mask immediately before application of the ECT electrical stimulus.
Active Comparator: ECT with Ketamine and Hyperventilation; Immediately prior to ECT study patients will be administered intravenous ketamine for anesthesia at a dose of 0.5 -1.0 mg/kg given as a bolus dose. Hyperventilation will be administered (20 breaths in 30 seconds) by face mask immediately prior to ECT.	Procedure: Electroconvulsive therapy (ECT); Bilateral, bitemporal electrode placement will be utilized to elicit a seizure via a SpECTrun 5000Q (MECTA Inc.). The electrical dose required will be determined in advance by the patient's attending psychiatrist.; Drug: Ketamine; Ketamine will be administered as a bolus intravenously to induce an adequate depth of anesthesia just prior to ECT at a dose of 0.5 to 1.0 mg/kg.; Other Names: Ketalar; Procedure: Hyperventilation; Hyperventilation will be performed in patients after full pre-oxygenation and induction of anesthesia, by administering 20 breaths in 30 seconds using a well-fitting face mask immediately before application of the ECT electrical stimulus.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG seizure duration (seconds)	Duration of seizure spike wave morphology will be assessed by the attending psychiatrist and independently by a second psychiatrist.	Up to 3 minutes post ECT
ECT-induced seizure duration (seconds)	Duration of motor seizures will be assessed by timing the onset and offset of appropriate motor twitches in the intrinsic foot muscles and extra-ocular muscles by the attending psychiatrist.	Up to 3 minutes post ECT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cerebral metabolism assessed by cerebral saturation (%)	Cerebral metabolism will be assessed by continuous cerebral oximetry measurements using the ForeSight Cerebral Oximeter, from immediately prior to ECT to 5 minutes post ECT	Up to 5 minutes post ECT
Remission of depressive symptoms assessed by HAM-D	Patients will be assessed using a clinician-administered Hamilton Depression Rating Scale (HAM-D) both prior to, and at intervals of 2, 4 and 8 weeks after completion of the study. The HAM-D is a validated healthcare professional-administered assessments of clinical depressive symptoms including: hopelessness, guilt or depressed mood and physical symptoms such as agitation, restlessness and fatigue.	Approximately one week prior to, and at 2, 4 and 8 weeks post ECT
Remission of depressive symptoms assessed by MADRS	Patients will be assessed using a clinician-administered Montgomery-Asberg Depression Scale (MADRS) both prior to, and at intervals of 2, 4 and 8 weeks after completion of the study. The MADRS is a validated healthcare professional-administered assessments of clinical depressive symptoms including: hopelessness, guilt or depressed mood and physical symptoms such as agitation, restlessness and fatigue.	Approximately one week prior to, and at 2, 4 and 8 weeks post ECT
Effect on blood pressure	Systolic, diastolic and mean blood pressure will be recorded every minute from immediately prior to 7 minutes post ECT.	Up to 7 minutes post ECT
Effect on heart rate	Heart rate (bpm) will be continuously recorded from immediately prior to 7 minutes post ECT.	Up to 7 minutes post ECT
Duration of stay in post-anesthesia care unit (hours)		Up to 2 hours post arrival in post-anesthesia care unit (PACU).
Incidence of nausea in post-anesthesia care unit (%)	The number of instances of nausea while in PACU will be recorded.	Up to 2 hours post arrival in PACU.
Incidence of vomiting in post-anesthesia care unit (%)	The number of instances of vomiting while in PACU will be recorded.	Up to 2 hours post arrival in PACU.

Collaborators and Investigators

• Sponsor: University of Manitoba
• Investigators: Principal Investigator: Ian McIntyre, MD, MSc, University of Manitoba; Principal Investigator: Michael Harrington, MD, University of Manitoba

Publications and helpful links

General Publications

• Ghasemi M, Kazemi MH, Yoosefi A, Ghasemi A, Paragomi P, Amini H, Afzali MH. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res. 2014 Feb 28;215(2):355-61. doi: 10.1016/j.psychres.2013.12.008. Epub 2013 Dec 13.
• Loo C, Simpson B, MacPherson R. Augmentation strategies in electroconvulsive therapy. J ECT. 2010 Sep;26(3):202-7. doi: 10.1097/YCT.0b013e3181e48143.
• Aksay SS, Bumb JM, Janke C, Hoyer C, Kranaster L, Sartorius A. New evidence for seizure quality improvement by hyperoxia and mild hypocapnia. J ECT. 2014 Dec;30(4):287-91. doi: 10.1097/YCT.0000000000000109.
• Fabbri F, Henry ME, Renshaw PF, Nadgir S, Ehrenberg BL, Franceschini MA, Fantini S. Bilateral near-infrared monitoring of the cerebral concentration and oxygen-saturation of hemoglobin during right unilateral electro-convulsive therapy. Brain Res. 2003 Dec 5;992(2):193-204. doi: 10.1016/j.brainres.2003.08.034.

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: September 30, 2016
• First Submitted That Met QC Criteria: October 3, 2016
• First Posted (Estimate): October 5, 2016

Study Record Updates

• Last Update Posted (Estimate): October 21, 2016
• Last Update Submitted That Met QC Criteria: October 20, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Depression; Ketamine; Nervous System Diseases; Anesthesia; Mental Disorders; Electroencephalography; Major depressive disorder; Electroconvulsive therapy; Etomidate; Hyperventilation; Cerebral Metabolism
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Respiratory Tract Diseases; Mood Disorders; Respiration Disorders; Signs and Symptoms, Respiratory; Depression; Depressive Disorder; Hyperventilation; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Hypnotics and Sedatives; Ketamine; Etomidate
• Other Study ID Numbers: B2015050

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No