Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001270808
Ethics application status
Approved
Date submitted
11/08/2021
Date registered
20/09/2021
Date last updated
20/09/2021
Date data sharing statement initially provided
20/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Heparin Pharmacokinetics in Response to Temperature Variation during Cardiopulmonary Bypass
Scientific title
A prospective, observational study of the effects of therapeutic variable hypothermia on heparin metabolism in adult patients undergoing cardiac surgery on cardiopulmonary bypass
Secondary ID [1] 305007 0
None
Universal Trial Number (UTN)
U1111-1268-5624
Trial acronym
HepTemp
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anticoagulant use 323180 0
Surgery requiring cardiopulmonary bypass 323181 0
Therapeutic intra-operative hypothermia 323676 0
Condition category
Condition code
Blood 320762 320762 0 0
Clotting disorders
Cardiovascular 320972 320972 0 0
Other cardiovascular diseases
Anaesthesiology 320973 320973 0 0
Other anaesthesiology
Surgery 320974 320974 0 0
Other surgery

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Most patients undergoing cardiac surgery will require a heart-lung machine, or cardiopulmonary bypass (CPB). This is to allow the heart to be temporarily stopped during surgery to allow the surgeon to operate on a still, bloodless field. The heart-lung machine allows blood to circulate in the body during this time, keep the body supplied with oxygen and for carbon dioxide to be removed.

During CPB, patients are often cooled to protect the organs. The 'target temperature' for cooling ranges between 28 and 34°C depending on the type of surgery and the surgeon preference. The duration of cooling and the duration of CPB are determined by the operation, not the study protocol. Patients will spend the same amount of time on CPB and cooled during their surgery regardless of whether they participate in the study.

All patients receive a dose of heparin to stop blood clotting in the heart-lung machine during surgery. For this study, patients will receive 400 IU/kg based on ideal body weight. They will then be cooled to the target temperature during CPB. Once the target temperature is reached as measured by a catheter in the bladder, a further dose of 100 IU/kg based on ideal body weight will be administered, and a series of blood samples (2 mL every 6 minutes for 30 minutes) will be taken to measure heparin levels. The dose of heparin will not be altered by changes in clearance, although if the measured activated clotting time (ACT) falls below 450 seconds, a further dose of 100 IU/kg of heparin can be administered.
Intervention code [1] 321405 0
Not applicable
Comparator / control treatment
Each patient shall act as their own control, and will undergo intervention (hypothermia) and control (normothermia) sampling.

At a time determined by the surgeon, the patient will be warmed up from the target temperature. The duration this takes place over varies, but is normally between 10 and 30 minutes (depending on the starting temperature). Once the patient has a temperature of more than 36°C as measured by bladder catheter, a further dose of 100 IU/kg of heparin will be administered based on ideal body weight, and a series of blood samples will be taken (2 mL every 3 minutes for 15 minutes) will be taken to measure heparin levels. Again, if the ACT falls below 450 seconds, a further dose of 100 IU/kg of heparin can be administered.

After the 15-minute period of sampling, the function of the heart will be assessed, and the patient will be weaned off the heart-lung machine.
Control group
Active

Outcomes
Primary outcome [1] 328571 0
Relative change in the rate of heparin clearance on cardiopulmonary bypass determined by anti-Xa level at 28°C relative to 36°C as measured by bladder temperature catheter.
Timepoint [1] 328571 0
Hypothermic sampling will be started at the time the participant reaches the predefined target temperature on cardiopulmonary bypass measured by indwelling bladder temperature catheter. Hypothermic sampling will involve one 2mL sample every 6 minutes for 30 minutes, and will measure heparin concentration using anti-Xa levels.

Normothermic sampling will start at the point the patient reaches 36°C measured by indwelling bladder temperature catheter. Normothermic sampling will involved one 2 mL sample every 3 minutes for 15 minutes and will measure heparin concentration using anti-Xa levels.
Primary outcome [2] 328750 0
Relative change in the rate of heparin clearance on cardiopulmonary bypass determined by anti-Xa level at 30°C relative to 36°C as measured by bladder temperature catheter.
Timepoint [2] 328750 0
Hypothermic sampling will be started at the time the participant reaches the predefined target temperature on cardiopulmonary bypass measured by indwelling bladder temperature catheter. Hypothermic sampling will involve one 2mL sample every 6 minutes for 30 minutes and will measure heparin concentration using anti-Xa levels.

Normothermic sampling will start at the point the patient reaches 36°C measured by indwelling bladder temperature catheter. Normothermic sampling will involved one 2 mL sample every 3 minutes for 15 minutes and will measure heparin concentration using anti-Xa levels.
Primary outcome [3] 328751 0
Relative change in the rate of heparin clearance on cardiopulmonary bypass determined by anti-Xa level at 32°C relative to 36°C as measured by bladder temperature catheter.
Timepoint [3] 328751 0
Hypothermic sampling will be started at the time the participant reaches the predefined target temperature on cardiopulmonary bypass measured by indwelling bladder temperature catheter. Hypothermic sampling will involve one 2mL sample every 6 minutes for 30 minutes and will measure heparin concentration using anti-Xa levels.

Normothermic sampling will start at the point the patient reaches 36°C measured by indwelling bladder temperature catheter. Normothermic sampling will involved one 2 mL sample every 3 minutes for 15 minutes and will measure heparin concentration using anti-Xa levels.
Secondary outcome [1] 399490 0
Relative change in the rate of heparin clearance on cardiopulmonary bypass determined by anti-Xa level at 34°C relative to 36°C as measured by bladder temperature catheter (actually additional primary outcome).
Timepoint [1] 399490 0
Hypothermic sampling will be started at the time the participant reaches the predefined target temperature on cardiopulmonary bypass measured by indwelling bladder temperature catheter. Hypothermic sampling will involve one 2mL sample every 6 minutes for 30 minutes and will measure heparin concentration using anti-Xa levels.

Normothermic sampling will start at the point the patient reaches 36°C measured by indwelling bladder temperature catheter. Normothermic sampling will involved one 2 mL sample every 3 minutes for 15 minutes and will measure heparin concentration using anti-Xa levels.

Eligibility
Key inclusion criteria
Patient undergoing cardiac surgery requiring cardiopulmonary bypass
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Administration of therapeutic low molecular weight heparin or unfractionated heparin infusion < 24 hours prior to planned cardiac surgery
End-stage renal failure or anticipated requirement for haemofiltration on cardiopulmonary bypass
Anticipated duration of cardiopulmonary bypass < 60 minutes
Plan for intra-operative cooling below 25°C
BMI > 30 kg/m²
Patients unable to give informed consent

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Demographic and clinical characteristics of the study patients will be described by mean (SD) and frequency (%) for continuous and categorical variables respectively.

A two-stage analysis of the heparin concentration data will be performed. In the first stage, compartmental pharmacokinetic modelling will be performed to estimate the clearance of heparin concentrations for each patient at different cooling temperatures. In the second stage, the (estimated) values of clearance will be compared within-patient to provide mean differences (95% CI) in clearance for the different cooling temperatures using linear mixed-effects modelling.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2021
Actual
Date of last participant enrolment
Anticipated
1/03/2022
Actual
Date of last data collection
Anticipated
1/03/2022
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20211 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 34941 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 309385 0
Charities/Societies/Foundations
Name [1] 309385 0
Austin Medical Research Foundation
Country [1] 309385 0
Australia
Primary sponsor type
Hospital
Name
Department of Anaesthesia, Austin Health
Address
145 Studley Road
HEIDELBERG VIC 3084
Country
Australia
Secondary sponsor category [1] 310365 0
None
Name [1] 310365 0
Address [1] 310365 0
Country [1] 310365 0
Other collaborator category [1] 281938 0
University
Name [1] 281938 0
School of Population and Global Health, The University of Melbourne
Address [1] 281938 0
The University of Melbourne
207 Bouverie St
CARLTON VIC 3053
Country [1] 281938 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309200 0
Austin Health Human Ethics Committee
Ethics committee address [1] 309200 0
145 Studley Road, Heidelberg VIC 3084
Ethics committee country [1] 309200 0
Australia
Date submitted for ethics approval [1] 309200 0
08/06/2021
Approval date [1] 309200 0
11/08/2021
Ethics approval number [1] 309200 0
HREC/72696/Austin-2021

Summary
Brief summary
HepTemp is a prospective observational study of heparin pharmacokinetics whereby the effect of therapeutic hypothermia on heparin clearance will be observed at different temperatures in individual patients and compared with the equivalent rate of clearance when the same patient is returned to normothermia at the end of cardiopulmonary bypass, prior to separation. Mathematical modelling to demonstrate the changes in elimination time constant with differing temperatures will be derived to allow correction of existing mathematical models of heparin elimination.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113326 0
A/Prof Lachlan Miles
Address 113326 0
Department of Anaesthesia
Austin Health
145 Studley Road
HEIDELBERG VIC 3084
Country 113326 0
Australia
Phone 113326 0
+61394965704
Fax 113326 0
Email 113326 0
[email protected]
Contact person for public queries
Name 113327 0
A/Prof Lachlan Miles
Address 113327 0
Department of Anaesthesia
Austin Health
145 Studley Road
HEIDELBERG VIC 3084
Country 113327 0
Australia
Phone 113327 0
+61 394965704
Fax 113327 0
Email 113327 0
[email protected]
Contact person for scientific queries
Name 113328 0
A/Prof Lachlan Miles
Address 113328 0
Department of Anaesthesia
Austin Health
145 Studley Road
HEIDELBERG VIC 3084
Country 113328 0
Australia
Phone 113328 0
+61 394965704
Fax 113328 0
Email 113328 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data regarding participant characteristics and primary outcome(s)
When will data be available (start and end dates)?
After publication of the trial manuscript, anticipated late 2022. Data will be available for 7 years thereafter.
Available to whom?
All interested parties with a clinical or academic affiliation
Available for what types of analyses?
Systematic review and meta-analysis (including individual patient meta-analysis)
How or where can data be obtained?
Contact the coordinating principal investigator at [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



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.