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Trial registered on ANZCTR


Registration number
ACTRN12623000240640
Ethics application status
Approved
Date submitted
15/02/2023
Date registered
6/03/2023
Date last updated
23/05/2023
Date data sharing statement initially provided
6/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Lidocaine Infusion Population Pharmacokinetics Study (LIPPS): determining pharmacokinetics of lidocaine in those undergoing breast reconstructive surgery
Scientific title
A trial to develop a population pharmacokinetics model for the administration of intravenous lidocaine to adult female patients undergoing breast reconstructive surgery
Secondary ID [1] 308950 0
Nil Known
Universal Trial Number (UTN)
Nil Known
Trial acronym
LIPPS
Linked study record
Not Applicable

Health condition
Health condition(s) or problem(s) studied:
Pain Management 328960 0
Condition category
Condition code
Anaesthesiology 325946 325946 0 0
Pain management
Anaesthesiology 326093 326093 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intraoperative intravenous bolus and infusion of lidocaine during breast reconstructive surgery.

Drug: Lidocaine 2%

Suitable candidates will be given an intravenous bolus dose of Lidocaine followed by an infusion for the duration of their surgery according to the following dosing parameters:

1) Intravenous bolus of (2.5mg/kg/LBW)/2 [2% lidocaine]
2) Intraoperative infusion of (3.33mg/kg/hr/LBW)/2 [2% lidocaine]
Lean body weight= (9270 x weight)/ (8780 + (244 x BMI))8
where BMI = total body weight/ (height in metres) = W / H2

W = total body weight in kg
H = height in metres.

Ideal body weight is capped at 68Kg.

The values entered into the Alaris PK pump program MUST be double checked against the printout from the drug dosing module by the research coordinator with the attending anaesthetist.

The bolus and infusion will be commenced at induction of anaesthesia and the infusion will be ceased at the completion of surgery. The exact duration of infusion is therefore dependent on operative considerations.

The dose of the intervention is determined by each individual patient's lean body weight.

The attending Anaesthetist will be responsible for the administration of the intravenous lidocaine. Patients will be under the constant supervision of an Anaesthetist throughout the duration of the infusion.
Samples to determine serum lidocaine concentrations will be taken at hourly intervals for the duration of the infusion, once in the Postoperative Anaesthetic Care Unit (PACU) and twice more between 8 and 26 hours post cessation of the infusion.

Intervention code [1] 325397 0
Treatment: Drugs
Comparator / control treatment
No Control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333798 0
To establish the pharmacokinetics of lidocaine administered by intravenous infusion, as assessed by serial blood sample concentration determination. Parameters assessed will include the central and peripheral volume of distribution (VD), interdepartmental clearances, hourly clearance and elimination half-life (t½elim) of lidocaine when administered by intravenous infusion
Timepoint [1] 333798 0
Serial serum lidocaine samples will be taken in study participants at specified time intervals to plot serum concentrations according to dosage and time. Samples will be taken hourly for the duration of the infusion, once postoperative in PACU and twice more (to examine elimination pharmacokinetics) between 8 and 26 hours post cessation of the infusion
Secondary outcome [1] 418851 0
Incidence of treated bradycardia intraoperatively
Timepoint [1] 418851 0
This outcome will be assessed continuously for the duration of surgery.
Information available from patient's recorded observations on the intraoperative monitor and Anaesthesia record. A record of treatment given will be taken from the patient's written Anaesthesia record. The patient's HR will be monitored by continuous ECG for the duration of surgery.
Secondary outcome [2] 418852 0
Incidence of treated hypotension intraoperatively
Timepoint [2] 418852 0
This outcome will be assessed continuously for the duration of surgery.
Hypotension will be recorded from the patient's monitor and/or the Anaesthesia record. Treatment given will be documented form the patient's Anaesthesia record. The patient will have a combination of non-invasive and invasive arterial blood pressure monitoring during the case
Secondary outcome [3] 418853 0
Incidence of treated bradycardia in PACU
Timepoint [3] 418853 0
This outcome will be assessed continuously for the duration of PACU admission.
Information will be obtained from the patient's recorded PACU observations where patients will have continuous ECG monitoring. Treatment given will be recorded from the patient's drug administration records
Secondary outcome [4] 418854 0
Incidence of treated hypotension in PACU
Timepoint [4] 418854 0
This outcome will be assessed continuously for the duration of PACU admission.
Information will be obtained from the patient's recorded PACU observations where patients will have intermittent non-invasive and/or continuous invasive blood press monitoring. Treatment given will be recorded from the patient's drug administration records
Secondary outcome [5] 418855 0
Incidence of intraoperative infusion stopping events
Timepoint [5] 418855 0
This outcome will be assessed continuously for the duration of surgery.
Information will be obtained from the intraoperative anaesthesia record. Where events has occurred, further information will be sought from the treating Anaesthetist where appropriate
Secondary outcome [6] 418856 0
Incidence of suspected lidocaine toxicity events
Timepoint [6] 418856 0
This outcome relates to the duration of the patient's hospital stay from the time of surgery to discharge. It will be assessed at the time of discharge.
Information will be obtained from the patient's medical records. Where an incident has occurred, the circumstances will be documented (presentation, treatment given, outcome etc). Further information may be sought from the treating team directly where appropriate
Secondary outcome [7] 418857 0
Incidence of suspected SEVERE local anaesthetic toxicity events (generalised seizure, sudden unexplained loss of consciousness, life-threatening arrhythmia, cardiac arrest)
Timepoint [7] 418857 0
This outcome relates to the duration of the patient's hospital stay from the time of surgery to discharge. It will be assessed at the time of discharge.
Information will be obtained from the patient's medical records. Where an incident has occurred, the circumstances will be documented (presentation, treatment given, outcome etc). Further information may be sought from the treating team directly where appropriate
Secondary outcome [8] 418858 0
Incidence of Medical Emergency Team (MET) activation
Timepoint [8] 418858 0
This outcome relates to the duration of the patient's hospital stay from the time of surgery to discharge. It will be assessed at the time of discharge.
Information will be obtained from the patient's medical records. Where the a MET review was required, the details will be recorded (reason for review and treatment given/outcomes if applicable). If required, further information may be sought from the treating team.
Secondary outcome [9] 418861 0
Incidence of unplanned ICU, HDU or CCU admission
Timepoint [9] 418861 0
This outcome relates to the duration of the patient's hospital stay from the time of surgery to discharge. It will be assessed at the time of discharge.
The reason form ICU admission, ( including relevant treatment and outcomes) will be recorded from the patient's medical records (both electronic and physical)
Secondary outcome [10] 419201 0
Likely episodes of potential or actual lidocaine toxicity and safety endpoints set out above (and listed below for clarity) will also be assessed together as a composite secondary outcome.

1. Incidence of treated bradycardia intraoperatively, Information will be collected from the patient's recorded observations on the intraoperative monitor and/or the Anaesthesia record.

2. Incidence of treated hypotension intraoperatively, Information will be recorded from the patient's monitor and/or the Anaesthesia record.

3. Incidence of treated bradycardia in PACU, Information will be obtained from the patient's recorded PACU observations where patients will have continuous ECG monitoring.

4. Incidence of treated hypotension in PACU, Information will be obtained from the patient's recorded PACU observations where patients will have intermittent non-invasive and/or continuous invasive blood pressure monitoring.

5. Incidence of intraoperative infusion stopping events, Information will be obtained from the intraoperative anaesthesia record.

6. Incidence of suspected lidocaine toxicity events, Information will be obtained from the patient's medical records

7. Incidence of suspected SEVERE local anaesthetic toxicity events (generalised seizure, sudden unexplained loss of consciousness, life-threatening arrhythmia, cardiac arrest), Information will be obtained from the patient's medical records.

8. Incidence of Medical Emergency Team (MET) activation, Information will be obtained from the patient's medical records.

9. Incidence of unplanned ICU, HDU or CCU admission, Information will be obtained from the patient's medical records.
Timepoint [10] 419201 0
Safety outcomes 1, 2 & 5 will be assessed continuously for the duration of surgery.
Safety outcomes 3 & 4 will be assessed for the duration of PACU admission.
Safety outcomes 6-9 will be assessed at the time of discharge

Composite data will be measured during data analysis, based on the data obtained individually, as listed above.

Eligibility
Key inclusion criteria
• Adult biological female patient aged >=18 and <80 years old
• Undergoing remote breast reconstructive surgery with a unilateral or bilateral DIEP (or other myocutaneous) flap
• ASA physical status 1-3
Minimum age
18 Years
Maximum age
79 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Inability to provide informed consent – impaired cognition. Where consent cannot be obtained in English, an interpreter should be used to obtain informed consent
• Pregnancy
• History of epilepsy
• History of anaphylaxis, sensitivity or known contraindication to lidocaine or other amide local anaesthetics, including patients with porphyria and methaemaglobinaemia
• Baseline HR <50bpm or SBP <100mmHg
• Acute coronary event within the last 3 months
• Cardiac Conduction abnormalities including: Heart block (all degrees), Bundle Branch Block or Fascicular Block, Prolonged QT interval, Wolf Parkinson White Syndrome, channellopathy (e.g. Brugada Syndrome). A preoperative ECG is not mandatory.
• Abnormal serum sodium and/or potassium concentrations
• Active liver disease or abnormal liver function tests
• Medications within the last 7 days which affect lidocaine metabolism (amiodarone, beta blockers, cimetidine, fluoroquinolones, fluvoxamine, imidazoles, macrolides, verapamil, HIV drugs
• Cardiac Failure
• Severe renal disease (CrCl <30ml/min or dialysis dependent)
• Recruitment into LOLIPOP or any other Trial
• Planned regional anaesthesia/analgesia technique
• Co-administration of lidocaine within 24 hours of surgery (e.g. lidocaine patch)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not Applicable - this is an uncontrolled, non-randomised trial
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Data will be analysed using the first-order conditional estimation method with interaction. The pharmacokinetics of lidocaine will be described by a compartmental model parameterized in terms of clearance from the central compartment, apparent central and peripheral volumes of distribution (Vd) and intercompartmental clearances. It will include the assessment of parent-metabolite (MEGX, GX) models. Covariates such as patient demographics, body composition, plasma binding, phenotype and other covariates will be evaluated and included in the models. Model selection will be based on visual inspection of diagnostic scatter plots, the objective function value (OBJ) computed by NONMEM and biological plausibility of parameter estimates. All final models will be evaluated by performing a visual predictive check (VPC). Covariates will be evaluated for statistical significance using a stepwise forward addition and backward elimination process. The statistical criteria for retaining a covariate in the model will be p < 0.05 during forward addition and p < 0.01 for backward elimination. Five-hundred bootstrap runs will be conducted in order to assess the precision of final models’ parameter estimates. The final model will be evaluated by constructing prediction-corrected visual predictive checks (pcVPC), whereby the median, 5th and 95th percentile of the observed data will be compared against the median, 5th and 95th percentile of 1000 simulated versions of the original index dataset. Investigator Somogyi has published a similar type of modelling approach for ketamine and metabolites in treatment resistant depression.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2023
Actual
Date of last participant enrolment
Anticipated
1/06/2024
Actual
Date of last data collection
Anticipated
1/07/2024
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23975 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 39463 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 313162 0
Hospital
Name [1] 313162 0
Royal Perth Hospital
Country [1] 313162 0
Australia
Primary sponsor type
Hospital
Name
Royal Perth Hospital
Address
Royal Perth Hospital
Victoria Square
Perth
WA 6000
Country
Australia
Secondary sponsor category [1] 314870 0
None
Name [1] 314870 0
Address [1] 314870 0
Country [1] 314870 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312449 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [1] 312449 0
Ethics committee country [1] 312449 0
Australia
Date submitted for ethics approval [1] 312449 0
20/02/2023
Approval date [1] 312449 0
20/04/2023
Ethics approval number [1] 312449 0
RGS0000005943

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124542 0
Dr Peter Mc Cauley
Address 124542 0
Research Department
Department of Anaesthesia and Pain Medicine
Level 4 Block R
Royal Perth Hospital
Victoria Square
Perth
WA 6000
Country 124542 0
Australia
Phone 124542 0
+61 0892241036
Fax 124542 0
Email 124542 0
peter.mccauley@health.wa.gov.au
Contact person for public queries
Name 124543 0
Peter Mc Cauley
Address 124543 0
Research Department
Department of Anaesthesia and Pain Medicine
Level 4 Block R
Royal Perth Hospital
Victoria Square
Perth
WA 6000
Country 124543 0
Australia
Phone 124543 0
+61 0892241036
Fax 124543 0
Email 124543 0
peter.mccauley@health.wa.gov.au
Contact person for scientific queries
Name 124544 0
Tomas Corcoran
Address 124544 0
Research Department
Department of Anaesthesia and Pain Medicine
Level 4 Block R
Royal Perth Hospital
Victoria Square
Perth
WA 6000
Country 124544 0
Australia
Phone 124544 0
+61 0892241036
Fax 124544 0
Email 124544 0
Tomas.Corcoran@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Maintenance of patient confidentiality


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.