Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000150842
Ethics application status
Approved
Date submitted
9/12/2020
Date registered
15/02/2021
Date last updated
7/09/2022
Date data sharing statement initially provided
15/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the impact of body composition on the activity of propofol in babies, infants and children undergoing anaesthesia.
Scientific title
The impact of body composition on the pharmacokinetics and pharmacodynamics of propofol infusions in neonates infants and children
Secondary ID [1] 302982 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaesthesia 320034 0
Obesity 320035 0
Condition category
Condition code
Anaesthesiology 317957 317957 0 0
Anaesthetics
Diet and Nutrition 318207 318207 0 0
Obesity

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The aim of this study is to investigate the influence of body composition on propofol pharmacokinetics and pharmacodynamics in neonates infants and children (0-15 years).
This will be a prospective population based PKPD study to examine the influence of body composition on propofol pharmacokinetics in neonates infants and children.
Participants will include 50 neonates infants and children aged 0-15 years undergoing surgical procedures at Starship Children’s Hospital. Children undergoing cardiac or liver transplant surgery will not be included. This study will include both obese and non-obese children.
A case report form (CRF) will be used to collect details for each case. These will include patient demographics, details of the surgical procedure and the timing of drug and surgical events. Details such as dose and timing of dose will be recorded for other drugs including inhalational anaesthetics and opioids. This information will be used to assess the effects of these drugs given in combination. The time at which each blood sample is taken will be recorded. A copy of the final anaesthetic record will be obtained for the study records, but all identifying information will be removed. The patients recruited into this study will be a sample of convenience which will depend on the theatre schedule and the availability of the researcher on any given day. Informed consent will be obtained from the children’s parents or legal guardian before being enrolled into the study.
Body composition will be measured in all participants using skin fold thickness and bioimpedance analysis with the ImpediMed Imp-DF50 instrument. These measures will be taken at the bedside before or after surgery, or in the operating room while the participant is anaesthetised before their surgery begins. These methods are both rapid (they will take approximately 10 minutes) and non-invasive. The skinfold thickness calliper measures a pinch of skin at a precise location to determine the subcutaneous fat layer. Body composition can be estimated from this information using predictive equations. The biceps, triceps, subscapular and suprailiac skinfolds will be measured. These will be located using standard anatomical landmarks to ensure consistency between participants. The triceps skin fold will be located midway between the acromion and olecranon process on the posterior surface of the right arm. The biceps skin fold will be located at the same level on the anterior surface, in line with the cubital fossa. The subscapular skin fold will be measured approximately 2 cm below the inferior angle of the scapula at a 45-degree angle. The suprailiac skinfold will be located approximately 2 cm above the iliac crest at the anterior of the axillary line. We intend to supplement these measures with dual X-ray absorptiometry (DXA) or air displacement plethysmography (ADP) wherever possible. The DXA scan requires the participant to remain still for approximately 5 minutes. The entire clinic visit in which a DXA scan could be obtained should take no longer than 20 minutes. DXA scanning will be an optional extra measure of body composition. It will be at the parents’ discretion as to whether they think their child would remain still for the duration of the scan. DXA provides both whole-body and regional estimates of body composition and has the ability to separate muscle from FFM and calculate bone mineral density. The Pea Pod (Cosmed, Rome, Italy) is a commercially available device which has shown to be useful for determining body composition in neonates and infants < 8 kg using air displacement plethysmography. It is a is a three-compartment measure that determines fat mass, total body water and non-aqueous solids. Measurement of body composition using the PeaPod will be offered at the parents’ discretion. All body composition measurements will be obtained by a study researcher who is completing this study as part of a PhD. Study measurements can be taken at a time prior or following surgery, whenever is convenient for participants and their families.
Anaesthetic treatment will be in accordance with the Australian and New Zealand College of Anaesthetists (ANZCA) standards. Doses and time of doses will be recorded in these cases on the study CRF for inclusion in analysis. Anaesthesia will be induced by inhalation of sevoflurane or an intravenous bolus dose of propofol. Anaesthesia will be maintained with a propofol infusion using an Alaris® PK syringe pump (Cardinal Health, Alaris Products, Basingstoke, UK). BIS and infusion data will be recorded during the anaesthetic through the routine automated monitoring system SaferSLEEP® (Auckland, New Zealand) and from the Alaris PK syringe pump. The maintenance dose rate of propofol administered will be at the discretion of the consulting anaesthetist. This may be either through automatic infusions based on existing PK models, or a manual infusion regimen. The delivery of propofol is in accordance with routine clinical care.
Real time infusion and BIS data will be recorded and transferred from the SaferSLEEP® monitor to a study computer. Infusion data could include time, target concentration, dose and dose rate. BIS data will include time, minimum and maximum BIS values, and the average signal quality index (SQI). Inspired and end tidal sevoflurane concentration may also be recorded.
A maximum of 5 mL arterial or venous blood will be taken from participants. This will be obtained from the existing indwelling arterial or venous catheter. An optimal design study will guide the times samples are obtained in order to provide the most accurate estimates of the PK parameter CL and the parameter Ffat. The duration of blood sampling is dependent on the duration of the surgical procedure. Samples are unlikely to be obtained more than one hour after cessation of propofol due to logistics (i.e. patients transferred into recovery and onto the ward).
Patients will be observed from the time they are brought into theatre (this is to collect baseline information prior to propofol administration) until the last sample is obtained after the infusion is stopped.
This study will record bispectral index (BIS), a modified form of electroencephalography (EEG) used to assess depth of sedation. This is routinely collected during surgical procedures to minimise accidental anaesthetic awareness and the risks associated with deep anaesthesia.

Blood samples will be analysed by high performance liquid chromatography (HPLC) to determine plasma concentrations of propofol. Selective and sensitive methods for the analysis of propofol concentrations in blood have been developed and validated in terms of recovery, linearity, lower limit of quantification and precision and accuracy. The total concentration of propofol will be measured. Propofol samples will be analysed by the Burns Trauma & Critical Care Research Centre, University of Queensland, Brisbane, Australia.


Intervention code [1] 319269 0
Not applicable
Comparator / control treatment
Healthy children (non-obese) will also be included in the study population. Obesity will be determined based on a BMI > 95% for age and sex, determined by the Children’s BMI calculator and assigned to one of 3 categories as defined as the % above the 95th centile, as follows:
• Obesity Grade I: > 95%-120% of 95th percentile (adult BMI >30 -35 equivalent)
• Obesity Grade II: 120-140% of 95th percentile (adult BMI 35- 40 equivalent)
• Obesity Grade III: > 140% of 95th percentile (adult BMI > 40 equivalent)
Control group
Active

Outcomes
Primary outcome [1] 325972 0
Identify the influence of fat mass on propofol pharmacokinetics (assessed using clearance, volume of distribution and equilibration half-time) in neonates infants and children.
Timepoint [1] 325972 0
Blood samples will be collected at non-critical time points during the surgical procedure. Non-linear mixed effects models allow for flexible sampling times. We will try to obtain samples around 3, 6, 12 and 30 minutes after the propofol infusion commences. Additional samples will be taken at 15-30 minute intervals during the maintenance of anaesthesia. We will try to obtain our final sample 15-60 minutes after the propofol infusion is stopped.
Primary outcome [2] 326197 0
Fat mass assessed by dual X-ray absorptiometry
Timepoint [2] 326197 0
Modelling of these data will take place one the samples are collected and the plasma propofol concentrations have been measured. This will depend on the time taken by the analytical laboratory.
Secondary outcome [1] 389716 0
Body composition determined by a composite of bioimpedance analysis and skin fold calliper measurements of the biceps, triceps, subscapular and suprailiac areas
Timepoint [1] 389716 0
This outcome will be assessed following completion of data collection.

Eligibility
Key inclusion criteria
Participants will include 50 neonates infants and children aged 0-15 years undergoing surgical procedures at Starship Children’s Hospital. This study will include both obese and non-obese children. Obesity will be determined based on a BMI > 95% for age and sex, determined by the Children’s BMI calculator and assigned to one of 3 categories as defined as the % above the 95th centile, as follows:
• Obesity Grade I: > 95%-120% of 95th percentile (adult BMI >30 -35 equivalent)
• Obesity Grade II: 120-140% of 95th percentile (adult BMI 35- 40 equivalent)
• Obesity Grade III: > 140% of 95th percentile (adult BMI > 40 equivalent)
Minimum age
0 Years
Maximum age
15 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Children undergoing cardiac or liver transplant surgery will not be included.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Pharmacokinetic analysis will involve nonlinear mixed effects modelling using NONMEM (NONMEM 7.3, Icon Development Solutions, Ellicott City, MD, USA) and incorporate covariates relating to body size such as TBM and FFM. Influential covariates will be retained in the model using a stepwise model building process, with a forward inclusion criteria (p < 0.05) based on the Chi-squared distribution for inclusion of significant covariates. Allometric scaling and a maturation function (MF) for children under 2 years to describe the increase in CL over the first few years of life.

Pharmacodynamic analyses will involve relating propofol concentrations to BIS. We will endeavour to include other co-medications such as midazolam in our analysis where they are likely to impact on the BIS readings.
The delay in drug response can be described using an effect compartment (Ce) which accounts for the equilibration of the theoretical effect compartment with plasma concentration. This delay can be quantified using the effect compartment equilibration half-time T1/2ke0. The relationship between propofol concentration in the effect compartment and BIS score will be described using the sigmoid EMAX equation.

The quality of the model will be evaluated using objective functions, residual diagnostics and resampling techniques. Prospective validation could involve programming the model into current infusion pumps and assessing its performance. Data processing and visualisation will be performed using RStudio (RStudio, Integrated Development for R, Boston, MA). The final model could be used to perform Monte Carlo simulations with the intention of designing an improved dosing regimen.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2021
Actual
15/03/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
10
Final
Recruitment outside Australia
Country [1] 23286 0
New Zealand
State/province [1] 23286 0
Auckland

Funding & Sponsors
Funding source category [1] 307394 0
Hospital
Name [1] 307394 0
Auckland DHB Charitable Trust
Country [1] 307394 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
University of Auckland
85 Park Road Grafton
1023
Auckland
Country
New Zealand
Secondary sponsor category [1] 308053 0
Hospital
Name [1] 308053 0
Auckland City Hospital
Address [1] 308053 0
2 Park Road Grafton
1023
Auckland
Country [1] 308053 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307481 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 307481 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 307481 0
New Zealand
Date submitted for ethics approval [1] 307481 0
Approval date [1] 307481 0
01/09/2020
Ethics approval number [1] 307481 0

Summary
Brief summary
There are a lack of dosing guidelines surrounding propofol infusions in neonates and obese children, with current
infusion regimens unsuitably based from non-obese children aged 3-11 years. The correct size metric to guide
doses of propofol in the in these groups that achieves desired anaesthetic targets is unclear. The impact of obesity
on propofol pharmacokinetics in children has not been assessed with a direct measure of body composition,
instead it is often estimated from sex weight and height. The results of a robust PKPD model could improve the
accuracy of propofol infusions in a broad population from neonates to obese children.
Trial website
Trial related presentations / publications

Public notes

Contacts
Principal investigator
Name 107382 0
Prof Brian Anderson
Address 107382 0
Department of Anaesthesia
Auckland Children's Hospital
2 Park Road Grafton 1023
Auckland
Country 107382 0
New Zealand
Phone 107382 0
+64 21535825
Fax 107382 0
Email 107382 0
[email protected]
Contact person for public queries
Name 107383 0
Prof Brian Anderson
Address 107383 0
Department of Anaesthesia
Auckland Children's Hospital
2 Park Road Grafton 1023
Auckland
Country 107383 0
New Zealand
Phone 107383 0
+64 21535825
Fax 107383 0
Email 107383 0
[email protected]
Contact person for scientific queries
Name 107384 0
Prof Brian Anderson
Address 107384 0
Department of Anaesthesia
Auckland Children's Hospital
2 Park Road Grafton 1023
Auckland
Country 107384 0
New Zealand
Phone 107384 0
+64 21535825
Fax 107384 0
Email 107384 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?
We might make the raw data (drug levels over time, age, weight and height) available to other researchers in this area via an open online database. These data will be presented as numbers only with no identifying information.
When will data be available (start and end dates)?
Upon publication with no end date.
Available to whom?
Freely available to researchers via an open access website
Available for what types of analyses?
PKPD analyses
How or where can data be obtained?
www.opentci.org


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.