ANZCTR - Registration

The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12622000920796

Ethics application status

Approved

Date submitted

10/06/2022

Date registered

28/06/2022

Date last updated

18/08/2024

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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Pain

Mechanical ventilation

Condition category

Condition code

Anaesthesiology

Other anaesthesiology

Anaesthesiology

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]

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]

Total administered opioid dose

Timepoint [1]

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]

Ventilation duration, in days, while in the intensive care unit

Timepoint [1]

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]

Duration of intensive care unit admission in days

Timepoint [2]

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]

Duration of hospital admission in days

Timepoint [3]

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]

Invasive mechanical ventilation-free days

Timepoint [4]

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]

Intensive care unit free days from intensive care admission to day-28

Timepoint [5]

Secondary outcome [6]

Hospital free days from hospital admission to day-28

Timepoint [6]

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]

Mortality at intensive care unit discharge

Timepoint [7]

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]

Mortality at hospital discharge

Timepoint [8]

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]

New requirement for tracheostomy insertion during intensive care unit admission

Timepoint [9]

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]

Propofol medicine used during intensive care unit admission

Timepoint [10]

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]

Midazolam medicine used during intensive care unit admission

Timepoint [11]

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]

Dexmedetomidine medicine used during intensive care unit admission

Timepoint [12]

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]

Paracetamol medicine used during intensive care unit admission

Timepoint [13]

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]

Non-steroidal anti-inflammatory medicine used during intensive care unit admission

Timepoint [14]

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]

Quetiapine medicine used during intensive care unit and hospital admission

Timepoint [15]

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]

Olanzapine medicine used during intensive care unit and hospital admission

Timepoint [16]

Secondary outcome [17]

Haloperidol medicine used during intensive care unit and hospital admission

Timepoint [17]

Secondary outcome [18]

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]

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]

Hospital discharge use of opioid medication

Timepoint [19]

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]

Use of opioid medication 3 and 6 months after hospital discharge

Timepoint [20]

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]

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]

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]

Sedation scores as assessed using the Richmond Agitation-Sedation Scale (RASS) method during intensive care unit admission

Timepoint [22]

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]

Delirium assessment as assessed using the Confusion Assessment Method - Intensive Care Unit (CAM-ICU) method during intensive care unit admission

Timepoint [23]

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]

Feasibility outcome for the enrolment rate.

Timepoint [24]

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]

Feasibility outcome for protocol compliance

Timepoint [25]

Secondary outcome [26]

Feasibility outcome for protocol violations

Timepoint [26]

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?

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.

The primary outcome will be analysed with Bayesian median regression model, which will calculate posterior probability distributions of median hourly dose of opioids used as an infusion, determined by fentanyl equivalents, and reported as µg/h (primary outcome) based on evidence accumulated in the trial and the prior probability distribution (the assumed previous knowledge). The median difference for the primary outcome will be modelled such that a value lower than 0 reflects a decrease in the median hourly dose of opioids in the ketamine group, implying benefit.
Other continuous outcomes will be analysed using the same model described for the primary outcome. Binary outcomes will be reported using a Bayesian logistic regression model reported as odds ratio with its 95% CrI. Time-to-event outcomes will be analysed using a Bayesian Cox proportional hazard model reported as hazard ratio with its 95% CrI. Free-days outcomes will be analysed using a Bayesian cumulative logistic model, reported as odds ratio with its 95% CrI, and with an odds ratio greater than 1 representing more free-days and implying benefit. There will be no planned adjustment for multiple comparisons of secondary outcomes, and results will be presented as the effect estimate with its 95% CrI, from which no conclusions can be drawn.

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

125

Accrual to date

108

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

The Northern Hospital - Epping

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3076 - Epping

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Avant Foundation for quality, safety and professionalism

Address [2]

Victoria State Office Avant
Level 36 Melbourne Central Tower
360 Elizabeth Street, Melbourne
Victoria 3000

Country [2]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road
Heidelberg VIC 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

145 Studley Road
Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/01/2022

Approval date [1]

23/05/2022

Ethics approval number [1]

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

Dr Andrew Casamento

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61394964835

Fax

+61394963932

[email protected]

Contact person for public queries

Name

Andrew Casamento

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61394964835

Fax

+61394963932

[email protected]

Contact person for scientific queries

Name

Andrew Casamento

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61394964835

Fax

+61394963932

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.	Type	Citation	Link	Email	Other Details	Attachment
15973	Study protocol			[email protected]

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.

Trial Review

Documents added manually

Documents added automatically