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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]

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

Condition category

Condition code

Anaesthesiology

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]

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]

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]

Continuous (values assessed as per recordings during anaesthetic)

Secondary outcome [1]

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]

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?

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland City Hospital, Auckland, New Zealand

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Green Lane Research and Educational Board (Phd stipend)

Address [1]

Green Lane Research and Educational Fund Board, PO Box 110042, Auckland Hospital, Auckland 1148

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Upper South B Regional Ethics Committee

Ethics committee address [1]

Ministry of Health
6 Hazeldean Road
Lvl 1 Montgomery Watson Building
Addington
Christchurch

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

25/04/2011

Approval date [1]

04/07/2011

Ethics approval number [1]

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

A/Prof Timothy Short

Address

Dept of Anesthesia
Auckland City Hospital
Park Road
Grafton
Auckland 1023

Country

New Zealand

Phone

+64274542464

Fax

[email protected]

Contact person for public queries

Name

Jacqueline Hannam

Address

Department of Anaesthesiology
University of Auckland
L12 Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland
1023

Country

New Zealand

Phone

+64 3737 599 ext 89300

Fax

[email protected]

Contact person for scientific queries

Name

Jacqueline Hannam

Address

Department of Anaesthesiology
University of Auckland
L12 Support Building
Auckland City Hospital
2 Park Road
Grafton
Auckland
1023

Country

New Zealand

Phone

+64 3737 599 ext 89300

Fax

[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

Source	Title	Year of Publication	DOI
Embase	Refining 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.	2016	https://dx.doi.org/10.1213/ANE.0000000000000386

N.B. These documents automatically identified may not have been verified by the study sponsor.

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