Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000428965
Ethics application status
Approved
Date submitted
20/04/2011
Date registered
27/04/2011
Date last updated
24/02/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Using a pharmacokinetic-pharmacodynamic response surface interaction model to control propofol – remifentanil infusion for bispectral index (BIS) targeted anaesthesia
Scientific title
Using a PK-PD interaction model to control propofol – remifentanil infusion for bispectral index (BIS) targeted anaesthesia in patients: a proof of concept study
Secondary ID [1] 260048 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Evaluating pharmacokinetic pharmacodymic interaction models for infusion of anaesthetic drugs 265727 0
Condition category
Condition code
Anaesthesiology 265850 265850 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Current automated methods to infuse anaesthetic drugs are reliant on pharmacokinetic models. These models target plasma concentrations and do not account for interactions between drugs. We will conduct a proof of concept study to evaluate the use of linked pharmacokinetic - pharmacodynamic models for infusion of anaesthetic drugs. The study model will target effect (as Bispectral Index, or BIS monitoring) and will account for interactions between anaesthetic drugs. Propofol and remifentanil will be given as study drugs. Only patients who were to receive these agents as part of their standard anaesthetic care will be recruited. Doses of propofol and remifentanil will be within the normal range of standard care - the dose given during total intravenous anaesthesia (TIVA) for both drug varies with patient requirements during normal practice and this will also be the case in this study. For the purposes of the study, we will be interested in the ratio of propofol dose to remifentanil dose. Standard procedure for administration of TIVA using propofol and remifentanil is via pharmacokinetic based infusion pump. In this situation anaesthetists select a target plasma or effect site concentration. Although the same pumps will be used, the pumps themselves will be driven by external software from a study designated laptop and drug infused as per a pharmacodynamic response surface model. Anaesthetists will instead select a target BIS level. All patients will receive BIS monitoring as part of the study protocol. This is already considered standard monitoring in our hospital.All aspects of patient care will remain with the attending anaesthetist as is routine care. Patients will be studied only once, during their surgery.
Intervention code [1] 264466 0
Other interventions
Comparator / control treatment
There is no comparator group for this study as it is a proof-of-concept project at this stage. Future research may compare infusion accuracy between pharmacodynamic response surface models and pharmacokinetic models. The results of this project will be interpreted in the context of the variability associated with currently established pharmacokinetic models and with other published response surface models.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 266610 0
The difference between model predicted BIS values and observed BIS values will be used to calculate the percentage performance error as a measure of model performance.
Timepoint [1] 266610 0
Continuous (values assessed as per recordings during anaesthetic)
Secondary outcome [1] 276091 0
Divergence, bias and wobble will be assessed as secondary measures of model performance. These are measures of accuracy of model predicted BIS values as compared with observed BIS values; as for the primary variable these will be calculated at each timepoint where a predicted and observed BIS are available (likely one per 5 minute epoch during anaesthetic maintenance, and one per 30 second epoch during anaesthetic induction).
Timepoint [1] 276091 0
Continuous (values assessed as per recordings during anaesthetic)

Eligibility
Key inclusion criteria
Patients will be eligible if they are
1. American Society of Anesthesiologists physical status I and II,
2. aged 18-45 years,
3. scheduled for a general anaesthetic with endotrachael intubation and the use of muscle relaxants,
4. scheduled for elective surgery on Levels 4 and 8 of Auckland City Hospital.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they
1. have a history of chronic opioid consumption,
2. use psychoactive medication (including high alcohol intake),
3. have neurological dysfunction,
4. require premedication before surgery

Study design
Purpose of the study
Educational / counselling / training
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Twenty suitable patients will be recruited from the waiting list for elective surgery at Auckland City Hospital on Levels 4 and Levels 8. Potential participants will be approached either on the hospital ward (wherever possible) or during preoperative check-in. As this is an uncontrolled, proof of study participants do not require allocation to one or other treatments - all participants will recieve their total intravenous anaesthetic (TIVA) as infused by the study model and under the study conditions.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
n/a
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2011
Actual
1/11/2011
Date of last participant enrolment
Anticipated
1/05/2012
Actual
24/07/2012
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment outside Australia
Country [1] 3419 0
New Zealand
State/province [1] 3419 0
Auckland City Hospital, Auckland, New Zealand

Funding & Sponsors
Funding source category [1] 264942 0
Hospital
Name [1] 264942 0
Green Lane Research and Educational Board (Phd stipend)
Country [1] 264942 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Deptartment of Anaesthesiology
L12 Support Building
Auckland City Hospital
2 Park Road
Auckland
1023
Country
New Zealand
Secondary sponsor category [1] 264051 0
None
Name [1] 264051 0
Address [1] 264051 0
Country [1] 264051 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 266899 0
Upper South B Regional Ethics Committee
Ethics committee address [1] 266899 0
Ministry of Health
6 Hazeldean Road
Lvl 1 Montgomery Watson Building
Addington
Christchurch
Ethics committee country [1] 266899 0
New Zealand
Date submitted for ethics approval [1] 266899 0
25/04/2011
Approval date [1] 266899 0
04/07/2011
Ethics approval number [1] 266899 0
URB/11/06/014

Summary
Brief summary
Response surface models are becoming increasingly prevalent in the anaesthetic literature. They have been shown to be useful in indentifying optimal drug dose combinations designed to achieve specific clinical outcomes. An example is the optimal combination of propofol and remifentanil required to tolerate esophageal instrumentation while maintaining spontaneous breathing. Additionally, these models can be used to predict patient wake up times at the end of anaesthesia, and have been implemented in novel anaesthetic display monitors. The latter is likely to improve drug titration for individual patients by promoting the active use of pharmacokinetic and pharmacodynamic knowledge in theatre.
We believe that response surface models are potentially useful when combinations of drugs that are known to display synergistic interactions are given as infusions. Knowledge about drug interactions is commonly employed in anaesthesia, but rarely is it directly applied using pharmacodynamic models. Software is available that allows us to drive infusions based on interaction models using standard ADHB alaris infusion pumps. These models are extendable to three drug interactions. We wish to conduct a ‘proof of concept’ study to validate our hypothesis that pharmacodynamic response surface models can be directly applied to administration of anaesthesia, and to assess the clinical feasibility of using these models in this context. We hypothesise that response surface model driven infusions will allow anaesthetists to target a level of drug effect (in this study Bispectral Index, or BIS, as a measure of depth of anaesthesia) while varying the ratio of propofol:remifentanil. This would be a useful tool in anaesthesia where the ratio of hypnotic:opioid is often varied depending on the particular needs of individual patients, but manual targeting of effect levels such as BIS is often difficult.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32526 0
A/Prof Timothy Short
Address 32526 0
Dept of Anesthesia
Auckland City Hospital
Park Road
Grafton
Auckland 1023
Country 32526 0
New Zealand
Phone 32526 0
+64274542464
Fax 32526 0
Email 32526 0
[email protected]
Contact person for public queries
Name 15773 0
Miss Jacqueline Hannam
Address 15773 0
Department of Anaesthesiology
University of Auckland
L12 Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland
1023
Country 15773 0
New Zealand
Phone 15773 0
+64 3737 599 ext 89300
Fax 15773 0
Email 15773 0
[email protected]
Contact person for scientific queries
Name 6701 0
Miss Jacqueline Hannam
Address 6701 0
Department of Anaesthesiology
University of Auckland
L12 Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland
1023
Country 6701 0
New Zealand
Phone 6701 0
+64 3737 599 ext 89300
Fax 6701 0
Email 6701 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseRefining Target-Controlled Infusion: An Assessment of Pharmacodynamic Target-Controlled Infusion of Propofol and Remifentanil Using a Response Surface Model of Their Combined Effects on Bispectral Index.2016https://dx.doi.org/10.1213/ANE.0000000000000386
N.B. These documents automatically identified may not have been verified by the study sponsor.