Use of adjunct continuous ketamine infusion in mechanically ventilated patients

ISRCTN	ISRCTN14730035
DOI	https://doi.org/10.1186/ISRCTN14730035
ClinicalTrials.gov (NCT)	NCT04075006
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	Research Advisory Council (RAC) number 2191 187
Sponsor	King Faisal Specialist Hospital & Research Centre
Funder	investigator initiated and funded

Submission date: 03/02/2020
Registration date: 05/02/2020
Last edited: 01/09/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Ketamine is used to produce sedation and relieve pain to minimize discomfort while a breathing tube placed in trachea (windpipe) and a machine (ventilator) used in the ICU. Several publications have shown that a low-dose ketamine in combination to opioids has been used to relieve acute pain after surgery. Ketamine has a favorable characteristics including bronchodilation, increase in blood pressure, does not cause constipation, maintain respiratory reflexes (respiratory spontaneous responses) make it an especially viable alternative for patients with unstable respiratory and hemodynamic function. However, the majority of these trials are conducted in a surgical ICU setting, retrospective in nature or randomized controlled clinical trials focusing on comparison of ketamine to placebo or two study drugs (e.g. ketamine versus opioid), despite the fact that most ICU patients are sedated with a combination of drugs.
The aim of this study is to assess weather ketamine can help to shorten the time of being in breathing tube and ventilator (duration of mechanical ventilation).

Who can participate?
ICU (Medical or surgical) patients (> 14 years old) who have been mechanically ventilated within the previous 24 hours and expected to remain intubated for more than 24 hours.

What does the study involve?
Participants will be randomly allocated to receive treatment as usual or a low dose of ketamine whilst under mechanical ventilation.

What are the possible benefits and risks of participating?
Benefit: increased medical attention irrespective of the group the patients are in and this study may help in improvement of knowledge and medical science progress
Risk: administration of sedative agents are standard of practice in the intensive care units to minimize discomfort and remain calm while a breathing tube placed on trachea (windpipe ) and a machine (ventilator). The expected adverse effects will not exceed what is encountered in daily practice (e.g. benzodiazepine associated delirium, opioid induced constipation, propofol and dexmedetomidine decrease blood pressure and heart rate, ketamine associated with increase in blood pressure and heart rate, possible delirium). The participants will be closely monitored to minimize any potential safety concerns

Where is the study run from?
King Faisal Specialist Hospital and Research Centre (Saudi Arabia)

When is the study starting and how long is it expected to run for?
September 2019 to December 2020

Who is funding the study?
Investigator initiated and funded

Who is the main contact?
Dr Marwa Amer
mamer@kfshrc.edu.sa
Dr Mohammed Bawazeer
mbawazeer@kfshrc.edu.sa

Contact information

Dr Marwa Amer
Scientific

Pharmaceutical Care Division , MBC # 11
King Faisal Specialist Hospital & Research Center
PO Box 3354
Riyadh
11211
Saudi Arabia

ORCID ID	0000-0002-9497-1451
Phone	+966 503412700
Email	mamer@kfshrc.edu.sa

Dr Mohammed Bawazeer
Scientific

Department of Critical Care Medicine (MBC 94)
King Faisal Specialist Hospital & Research Centre
P.O Box 3354
Riyadh
11211
Saudi Arabia

Phone	+966 11-216-2919 Ext: 24731
Email	mbawazeer@kfshrc.edu.sa

Study information

Primary study design	Interventional
Study design	Prospective randomized open-label active controlled parallel group pilot feasibility phase 3 study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Adjunct Low-Dose Ketamine Infusion versus Standard of Care in Mechanically Ventilated Critically Ill Patients at a Tertiary Saudi Hospital (ATTAINMENT Trial)
Study acronym	ATTAINMENT
Study objectives	Low-dose ketamine infusion will reduce the duration of MV with an acceptable safety profile compared to standard of care.
Ethics approval(s)	Approved 13/07/2019, Research Ethics Committee (REC) and Clinical Research Committee (CRC) at King Faisal Specialist Hospital and Research Center (MBC-03, PO Box 3354, Riyadh 11211, Saudi Arabia; +966114424528; aomar@kfshrc.edu.sa), ref: ACCM/462/40.
Health condition(s) or problem(s) studied	Mechanically ventilated adult critical illness
Intervention	Current interventions as of 19/03/2020: Experimental: Ketamine Group Adjunct low dose continuous infusion ketamine in addition to the standard of care. Ketamine will be given at a fixed infusion rate of 0.12 mg/kg/h (2 µg/kg/min) in the first 24 hours followed by 0.06 mg/kg/h (1 µg/kg/min) in the second 24 hours, then discontinued No Intervention: Control Group Standard of care in the ICU including propofol and/or fentanyl and/or midazolam according to KFSHRC sedation and analgesia protocol. Randomization: Patients will be randomly assigned to one of two study groups in a 1:1 ratio by a computer generated randomization list created by an independent biostatistician and no stratification will be performed. Our initial screening and eligibility assessment is done by bedside ICU nurses who are blinded to treatment assignment. To further ensure allocation concealment (masking), access to the randomization will be restricted to a Pharmacist (third party and not part of the study) to whom principal investigators refer at distance to know the assigned treatment (by telephone) The study investigators and study participants during recruitment and consenting process will be blinded to the treatment assignment. Once consenting process complete, principal investigators will contact the Pharmacist (third party) for patient allocation and initiation of the trial intervention. Group allocation will be concealed until after randomization. Previous interventions: Experimental: Ketamine Group Adjunct low dose continuous infusion ketamine in addition to the standard of care. Ketamine will be given at a fixed infusion rate of 0.12 mg/kg/hr (2 µg/kg/min) in the first 24 hours followed by 0.06 mg/kg/hr (1 µg/kg/min) in the second 24 hours, then discontinued No Intervention: Control Group Standard of care in the ICU including propofol and/or fentanyl and/or midazolam according to KFSHRC sedation and analgesia protocol. Randomization will involve reading from a computer-generated randomization list with blocks of size eight to ensure interim balance of treatment assignment. This randomization list is designed by KFSH&RC biostatistical and epidemiology section. The principal investigators will have access to the randomization list. Once a patient is recruited, the principal investigators will refer to the list and assign treatment accordingly.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Ketamine
Primary outcome measure(s)	Duration of Mechanical Ventilation [from Intubation to extubation date and off Mechanical Ventilation or until ICU discharge, death, or 28 days post randomization whichever occurs first]
Key secondary outcome measure(s)	Current secondary outcome measures as of 19/03/2020: Using patient records: 1. Cumulative Sedation Dosages within the first 48 h after randomization 2. Dexmedetomidine use within the first 48 h after randomization 3. Richmond Agitation Sedation Score (RASS) within the first 48 h after randomization 4. Pain score measured using the King Faisal Specialist Hospital & Research Centre (KFSHRC) pain scale within the first 48 h after randomization 5. Vasopressor Medication Dosages within the first 48 h after randomization 6. Changes in Mean Arterial Blood Pressure (MAP) and Heart Rate (HR) within the first 48 h after randomization 7. Hospital Length of Stay (LOS) throughout study completion measured at 1 year 8. ICU Length of stay (LOS) throughout study completion measured at 1 year 9. Tracheostomy rate at 28 days after randomization 10. Unplanned extubation at 28 days after randomization 11. Re-intubation rate at 28 days after randomization 12. Incidence of Delirium measured using Confusion Assessment Method in Intensive Care Unit (CAM-ICU) at 48 h after randomization 13. The use of anti-psychotics for confirmed ICU-acquired delirium within 48 h after randomization 14. Use of Physical restraints within 48 h after randomization 15. Frequency of endotracheal tube Suctioning: Proportion of patient with changes in requirements of suctioning frequency of 2 h or less within the first 48 h after randomization 16. Mortality at 28 days after randomization Previous secondary outcome measures: Using patient records: 1. Cumulative Sedation Dosages [first 48 hours after randomization] 2. Dexmedetomidine use [first 48 hours after randomization] 3. Richmond Agitation Sedation Score (RASS) [first 48 hours after randomization] 4. Pain score measured using the KFSHRC pain scale [first 48 hours after randomization] 5. Vasopressor Medication Dosages [first 48 hours after randomization] 6. Hospital Length of Stay (LOS) [throughout study completion (1 year)] 7. ICU Length of stay (LOS) [throughout study completion (1 year)] 8. Tracheostomy rate [28 days after randomization] 9. Unplanned extubation [28 days after randomization] 10. Re-intubation rate [28 days after randomization] 11. Incidence of Delirium measured using Confusion Assessment Method in Intensive Care Unit (CAM-ICU) [48 hours after randomization] 12. The use of anti-psychotics for confirmed ICU-acquired delirium [48 hours after randomization] 13. Use of Physical restraints [48 hours after randomization] 14. Mortality [28 days after randomization]
Completion date	31/12/2020

Eligibility

Participant type(s)	Patient
Age group	Mixed
Sex	All
Target sample size at registration	80
Total final enrolment	85
Key inclusion criteria	1. ICU (Medical or surgical) patients (> 14 years old) 2. Mechanically ventilated within the previous 24 hours and expected to remain intubated for more than 24 hours. 3. Patient requires ongoing sedative medication 4. No objection from the ICU attending MD for enrollment
Key exclusion criteria	Current participant exclusion criteria as of 19/03/2020: 1. Patients with a history of dementia or psychiatric disorders or on any anti-psychotics or anti-depressants medications at home 2. Pregnancy 3. Expected to need mechanical ventilation less than 24 hours 4. Known hypersensitivity to ketamine 5. Patient on dexmedetomidine as primary sedative agent prior to randomization 6. Patients with cardiogenic shock, heart failure, myocardial infarction 7. History of end-stage liver disease (Child Pugh score C) 8. Proven or suspected primary neurological injury (traumatic brain injury, ischemic stroke, intracranial hemorrhage, spinal cord injury, anoxic brain injury) 9. Patients with persistent heart rate (HR) > 150 bpm or systolic blood pressure (SBP) >180 mmHg 10. Patients who assigned as do-not-resuscitate order (DNR) or expected to die within 24 h 11. Patients on ECMO 12. Patients with status epilepticus patients who are receiving the ketamine infusion for refractory status epilepticus 13. Proven or suspected status asthmaticus 14. Patients with expected targeted RASS of -5 such as patients on continuous infusion neuromuscular blockade Previous participant exclusion criteria: 1. Patients with a history of dementia or psychiatric disorders or on any anti-psychotics or anti-depressants medications at home 2. Pregnancy 3. Expected to need mechanical ventilation less than 24 hours 4. Known hypersensitivity to ketamine 5. Patient on dexmedetomidine as primary sedative agent prior to randomization 6. Patients with cardiogenic shock, heart failure, myocardial infarction 7. History of end-stage liver disease. 8. Proven or suspected primary neurological injury (traumatic brain injury, ischemic stroke, intracranial hemorrhage, spinal cord injury, anoxic brain injury) 9. Patients with persistent heart rate (HR) > 150 bpm or systolic blood pressure (SBP) >180 mmHg 10. Patients who assigned as do-not-resuscitate order (DNR) or expected to die within 24 hours 11. Patients on ECMO 12. Patients with status epilepticus patients who are receiving the ketamine infusion for refractory status epilepticus 13. Proven or suspected status asthmaticus
Date of first enrolment	01/09/2019
Date of final enrolment	15/11/2020

Locations

Countries of recruitment

Saudi Arabia

Study participating centre

King Faisal Specialist Hospital and Research Centre

Zahrawi St
Al Maather
Riyadh
12713
Saudi Arabia

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in repository
IPD sharing plan	The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. Data will be collected in the KFSH&RC Research Electronic Data Capture (REDCap) platform, Riyadh, Saudi Arabia https://redcap.kfshrc.edu.sa/index.php?user_verify=M7cUjf6KwCb6qHkZLNTr. Each subject will be given a unique subject ID number (database numbers and all identifiers will be removed). A subject ID key will be used to match the subjects’ Medical Record Number and will be kept in a password-protected file that is accessible to the principal investigators. Access to REDCap requires authentication (username and password) for secure maintenance of the data. Access to the RedCap data will be limited to the principal investigators and co-investigators involved in data collection only. The database includes multiple logic checks for double entry and range checks for data values. All collected information will be stored in a secure manner and all patient data will be kept confidential. Data to be collected as follows: age, gender, weight, mode of MV at baseline, percentage of renal replacement therapy at baseline, lactate level at baseline, and severity of illness as estimated by Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score, with higher scores indicating higher severity of illness. Moreover, we will collect ICU type, baseline analgesics, sedatives, vasopressor requirements, and Pre-Deliric Delirium Risk Score, which is a delirium prediction model specifically designed for adult critical care patients 24 hours after ICU admission. It will be used to predict the factors that may influence delirium risk prior to randomization. We will also collect RASS, pain scores, and CAM-ICU scores at baseline, 24 and 48 hours post-randomization. The RASS is a scale used to assess the depth of sedation on a scale of -5 to +4, with a negative value indicating deeper sedation and positive values indicating increased agitation. The CAM-ICU is a valid and reliable delirium assessment tool. Patients with a RASS of -3 or lower will be excluded from CAM-ICU status assessment as they cannot participate in the exam. We will also record the proportion of eligible participants enrolled, rates of recruitment, protocol deviations and adverse events. To ensure consistency in data collection, training sessions will be held by the principal investigators for all research co-investigators involved in data collection prior to study commencement. Additionally, the principal investigators will conduct educational sessions for ICU physicians and ICU nurses, which will include the study protocol, and periodic follow-up educational sessions to provide feedback and ensure optimal compliance with the study protocol.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		30/08/2021	01/09/2021	Yes	No
Protocol article	protocol	20/03/2020	20/04/2020	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

01/09/2021: Publication reference added.
09/12/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2020 to 15/11/2020.
2. The total final enrolment number has been added.
3. The intention to publish date has been changed from 01/04/2021 to 28/02/2021.
13/07/2020: Recruitment has resumed.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
20/04/2020: Publication reference added.
19/03/2020: The following changes have been made:
1. The interventions have been updated.
2. The secondary outcome measures have been updated.
3. The participant exclusion criteria have been updated.
05/02/2020: Trial’s existence confirmed by King Faisal Specialist Hospital & Research Centre