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Trial registered on ANZCTR


Registration number
ACTRN12622000920796
Ethics application status
Approved
Date submitted
10/06/2022
Date registered
28/06/2022
Date last updated
19/09/2022
Date data sharing statement initially provided
28/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Ketamine for analgesia in mechanically ventilated adults
Scientific title
A prospective randomised, double-blind, placebo-controlled pilot study of the effect of ketamine for adjunct analgesia therapy on opioid requirements in adult mechanically ventilated patients
Secondary ID [1] 306984 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain 326099 0
Mechanical ventilation 326739 0
Condition category
Condition code
Anaesthesiology 323413 323413 0 0
Other anaesthesiology
Anaesthesiology 324001 324001 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ketamine HCl (200mg/2ml) will be mixed with 98ml 0.9% NaCl for a final concentration of 2mg/ml of active ketamine in 100ml infusion flask.

Patients will receive approximately 0.15 mg/kg/hr (0.075 ml/kg/hr) actual body weight (to a maximum equivalence of 100kg or 15 mg/hr) via continuous intravenous infusion while they are receiving an opioid infusion and are mechanically ventilated in the intensive care unit.

Trial medication will be infused while the patient is receiving an opioid infusion.
If opioid infusion is stopped:
- weaning or ceasing of study drug is a clinical decision
- study drug can continue while patient is intubated + post extubation
- study drug must be weaned within 12hrs following extubation

Adherence will be monitored via audit of medication charts, electronic medical records or observation charts.
Intervention code [1] 323423 0
Treatment: Drugs
Comparator / control treatment
100ml 0.9% NaCl.

Patients will receive approximately 0.15 mg/kg/hr (0.075 ml/kg/hr) actual body weight (to a maximum equivalence of 100kg or 15 mg/hr) via continuous intravenous infusion while they are receiving an opioid infusion and are mechanically ventilated in the intensive care unit.

Trial medication will be infused while the patient is receiving an opioid infusion.
If opioid infusion is stopped:
- weaning or ceasing of study drug is a clinical decision
- study drug can continue while patient is intubated + post extubation
- study drug must be weaned within 12hrs following extubation

Adherence will be monitored via audit of medication charts, electronic medical records or observation charts.
Control group
Placebo

Outcomes
Primary outcome [1] 331159 0
Total administered opioid dose
Timepoint [1] 331159 0
From the date of first index intensive care unit admission through to intensive care unit discharge as measured as fentanyl or fentanyl equivalents using ratio of fentanyl: morphine of 10 micrograms:550micrograms, as recorded in the medication charts, electronic medical records or observation charts.
Secondary outcome [1] 409462 0
Ventilation duration, in days, while in the intensive care unit
Timepoint [1] 409462 0
Duration in days from intensive care unit admission until intensive care unit discharge as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [2] 410656 0
Duration of intensive care unit admission in days
Timepoint [2] 410656 0
Duration in days from intensive care unit admission until intensive care unit discharge as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [3] 410657 0
Duration of hospital admission in days
Timepoint [3] 410657 0
Duration in days from hospital admission until hospital discharge as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [4] 410658 0
Invasive mechanical ventilation-free days
Timepoint [4] 410658 0
From the date of intensive care unit admission and censored at day 28 post-intensive care unit admission as determined via medical record audit or the Adult Patient Database of the Australian New Zealand Intensive Care Society, as appropriate.
Secondary outcome [5] 410659 0
Intensive care unit free days from intensive care admission to day-28
Timepoint [5] 410659 0
From the date of intensive care unit admission and censored at day 28 post-intensive care unit admission as determined via medical record audit or the Adult Patient Database of the Australian New Zealand Intensive Care Society, as appropriate.
Secondary outcome [6] 410660 0
Hospital free days from hospital admission to day-28
Timepoint [6] 410660 0
From the date of hospital admission until hospital discharge and censored at day 28 post-hospital admission as determined via medical record audit or the Adult Patient Database of the Australian New Zealand Intensive Care Society, as appropriate.
Secondary outcome [7] 410661 0
Mortality at intensive care unit discharge
Timepoint [7] 410661 0
Mortality status at the time of intensive care unit discharge as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [8] 410662 0
Mortality at hospital discharge
Timepoint [8] 410662 0
Mortality status at the time of hospital as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [9] 410663 0
New requirement for tracheostomy insertion during intensive care unit admission
Timepoint [9] 410663 0
Documentation of the insertion and use of a percutaneous or surgical tracheostomy from admission to the intensive care unit discharge from the intensive care unit as recorded in the Adult Patient Database of the Australian New Zealand Intensive Care Society.
Secondary outcome [10] 410666 0
Propofol medicine used during intensive care unit admission
Timepoint [10] 410666 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [11] 410667 0
Midazolam medicine used during intensive care unit admission
Timepoint [11] 410667 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [12] 410668 0
Dexmedetomidine medicine used during intensive care unit admission
Timepoint [12] 410668 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [13] 410669 0
Paracetamol medicine used during intensive care unit admission
Timepoint [13] 410669 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [14] 410670 0
Non-steroidal anti-inflammatory medicine used during intensive care unit admission
Timepoint [14] 410670 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record
Secondary outcome [15] 410671 0
Quetiapine medicine used during intensive care unit and hospital admission
Timepoint [15] 410671 0
From the date of first index intensive care unit admission through to intensive care unit discharge and hospital admission to hospital discharge as recorded in the patient's electronic medical record or scanned medical record
Secondary outcome [16] 410672 0
Olanzapine medicine used during intensive care unit and hospital admission
Timepoint [16] 410672 0
From the date of first index intensive care unit admission through to intensive care unit discharge and hospital admission to hospital discharge as recorded in the patient's electronic medical record or scanned medical record
Secondary outcome [17] 410675 0
Haloperidol medicine used during intensive care unit and hospital admission
Timepoint [17] 410675 0
From the date of first index intensive care unit admission through to intensive care unit discharge and hospital admission to hospital discharge as recorded in the patient's electronic medical record or scanned medical record
Secondary outcome [18] 410677 0
Adverse events identified by the patient's treating intensive care unit doctors that are requiring the cessation of trial drug. Such events may include tachyarrhythmia, hypertension, agitation or severe delirium.
Timepoint [18] 410677 0
Reported cessation of the prescribed trial drug as reported in the patient's medical record and in the study-specific log, in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0) during the study period as reported by the trial site treating doctors to the investigating team members.
Secondary outcome [19] 410678 0
Hospital discharge use of opioid medication
Timepoint [19] 410678 0
As recorded in the patient's electronic medical record or scanned medical record at the time of the patient's discharge from hospital
Secondary outcome [20] 410679 0
Use of opioid medication 3 and 6 months after hospital discharge
Timepoint [20] 410679 0
To determine opioid use at 3 and 6 months post-hospital discharge, an audit of Safescript, a centralised database of Victorian government, that records real-time prescription of certain medications that includes opioids, will be performed after the 6-month time-frame has elapsed..
Secondary outcome [21] 410681 0
Assessment of pain as a composite measure will be determined based on the levels as reported by intensive care unit clinicians using numerical rating scale, visual analogue scale, faces pain scale or a critical care pain observation tool, depending on which is appropriate.
Timepoint [21] 410681 0
As assessed 4-hourly during mechanical ventilation while intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [22] 410683 0
Sedation scores as assessed using the Richmond Agitation-Sedation Scale (RASS) method during intensive care unit admission
Timepoint [22] 410683 0
As assessed 4-hourly during mechanical ventilation while intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record.
Secondary outcome [23] 410684 0
Delirium assessment as assessed using the Confusion Assessment Method - Intensive Care Unit (CAM-ICU) method during intensive care unit admission
Timepoint [23] 410684 0
As assessed 8-hourly from the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record
Secondary outcome [24] 410685 0
Feasibility outcome for the enrolment rate.
Timepoint [24] 410685 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record or as reported by site investigators from the time the screening is commenced until final participant has been discharged from the intensive care unit.
Secondary outcome [25] 411084 0
Feasibility outcome for protocol compliance
Timepoint [25] 411084 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record or as reported by site investigators from the time the screening is commenced until final participant has been discharged from the intensive care unit.
Secondary outcome [26] 411085 0
Feasibility outcome for protocol violations
Timepoint [26] 411085 0
From the date of first index intensive care unit admission through to intensive care unit discharge as recorded in the patient's electronic medical record or scanned medical record or as reported by site investigators from the time the screening is commenced until final participant has been discharged from the intensive care unit.

Eligibility
Key inclusion criteria
Equal to or greater than 18 years of age
Mechanically ventilated at the time of assessment for eligibility
Opioid medication infusion prescribed by treating intensive care unit physician
Enrolment to occur within the first 12 hours of intensive care unit admission
Minimum age
18 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Cardiac surgical patients
Previous adverse reaction to ketamine
Equal to or older than 80 years of age
Pregnancy or lactation
Uncontrolled hypertension defined as systolic blood pressure of greater than 180 millimeters of mercury
Uncontrolled heart failure
Patients admitted to intensive care for end-of-life care or to facilitate organ donation
Previous enrolment in the KALME trial
No legal surrogate identified or able to provide informed consent to continue for patient

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation via computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be computer generated stratified permuted block randomisation, stratified according to hospital, age (less than 65 years and equal to or greater than 65 years) and medical/surgical status. Randomisation will be achieved via a password-protected encrypted web-based interface.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
This is a pilot study to determine feasibility of this type of trial for ketamine in mechanically ventilated ICU patients. Data from a previous study in mechanically ventilated patients described mean (plus/minus SD) hourly fentanyl dose of 67 plus/minus 39 µg/hr. An enrolment of 114 patients would have 80% power to detect a 25% reduction in fentanyl use to 51 plus/minus 29 µg/hr (at a two-sided alpha level of 0.05) in the ketamine group. Allowing for missing data and withdrawal of consent, we aim to enrol 120 patients in total.

A detailed statistical analysis plan will be published before the end of recruitment. All analyses will be conducted on an intention-to-treat basis. The primary outcome will be assessed considering unadjusted generalized linear models with a Gaussian distribution. As a sensitivity analysis for the primary outcome, a mixed-effect model adjusting for age, hepatic and renal impairment, and considering the centre as random effect will be performed. Secondary outcomes will be assessed with generalized linear models with binomial (for binary outcomes) or Gaussian (for continuous outcomes) distribution. If the primary outcome is missing for more than 5% of the patients, a sensitivity analysis considering multiple imputation will be considered. All analyses will be performed using R v.4.0.3

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2022
Actual
7/09/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 22333 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 22334 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 37494 0
3076 - Epping
Recruitment postcode(s) [2] 37493 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 311295 0
Hospital
Name [1] 311295 0
Austin Health
Country [1] 311295 0
Australia
Funding source category [2] 312259 0
Charities/Societies/Foundations
Name [2] 312259 0
Avant Foundation for quality, safety and professionalism
Country [2] 312259 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 313046 0
None
Name [1] 313046 0
Address [1] 313046 0
Country [1] 313046 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310798 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 310798 0
145 Studley Road
Heidelberg VIC 3084
Ethics committee country [1] 310798 0
Australia
Date submitted for ethics approval [1] 310798 0
24/01/2022
Approval date [1] 310798 0
23/05/2022
Ethics approval number [1] 310798 0
HREC/83652/Austin-2022

Summary
Brief summary
Most ICU patients who need a breathing machine (ventilator) to help them breathe require sedation and pain relief with one or more sedative (calming) and analgesic (pain reliever) drugs given as continuous drip into a vein. Combinations of sedative and analgesic drugs are usually used in the ICU to make patients on ventilators comfortable. The focus of this study is on the analgesic component of this management. Analgesic drugs will treat a patient’s pain, but may also provide some sedation. The type and the manner in which analgesic agents are used will vary. The type of analgesic drug and the way they are given may determine whether or not a patient is deeply or lightly sedated (more or less responsive to voice or physical stimulation).

Currently, there is no agreement amongst doctors around the world about the best choice of analgesic drug or the best way to manage pain in patients receiving mechanical ventilation. Many of the commonly used analgesic drugs have side effects and may be associated with longer time on the ventilator, longer stay in the ICU, leading to delirium (a confused state often including hallucinations) and decreased mental awareness after recovery from critical illness.

Clinical guidelines recommend a multi-modal approach to pain relief in patients who are being treated with a breathing machine (mechanical ventilation). This approach is to try and minimise the amount of pure analgesic agents used and theoretically minimise side effects of these agents.

The purpose of this study is to evaluate a drug which has both analgesic and sedative properties, ketamine (Ketalar®), that might decrease the need for other analgesic agents and improve survival and recovery (reduce delirium, time on a ventilator and time in ICU) for patients who are receiving mechanical ventilation in the ICU.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118906 0
Dr Andrew Casamento
Address 118906 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country 118906 0
Australia
Phone 118906 0
+61394964835
Fax 118906 0
+61394963932
Email 118906 0
andrew.casamento@austin.org.au
Contact person for public queries
Name 118907 0
Dr Andrew Casamento
Address 118907 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country 118907 0
Australia
Phone 118907 0
+61394964835
Fax 118907 0
+61394963932
Email 118907 0
andrew.casamento@austin.org.au
Contact person for scientific queries
Name 118908 0
Dr Andrew Casamento
Address 118908 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country 118908 0
Australia
Phone 118908 0
+61394964835
Fax 118908 0
+61394963932
Email 118908 0
andrew.casamento@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a small sample size, feasibility trial in which we do not plan on making individual participant data available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15973Study protocol  andrew.casamento@austin.org.au



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.