Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000558820
Ethics application status
Approved
Date submitted
2/03/2021
Date registered
12/05/2021
Date last updated
12/05/2021
Date data sharing statement initially provided
12/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Measuring and investigating causes of fluid accumulation in tissues and in critically unwell children in intensive care
Scientific title
A prospective study of the aetiology and detection of fluid overload and oedema in critically ill children
Secondary ID [1] 303576 0
nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fluid overload
 320947 0
Oedema 321342 0
Condition category
Condition code
Cardiovascular 318754 318754 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
A prospective study in 100 mechanically ventilated critically ill children measuring the prevalence and evolution of fluid overload and oedema over 48 hours, standardise the way they are quantified, investigate their relationship and investigating aetiological factors such as fluid administration, endothelial dysfunction and inflammation.
The study will collect patient data for 48 hours and intensive outcome data at intensive care discharge.
Fluid overload will be quantified by measuring change in weight between baseline and subsequent time points and will be used in the primary analysis.
In addition change in fluid balance will be measured from net change in intake and output using fluid balance charts.
Facial oedema will be quantified using 3D imaging. We have developed the process for performing such images and aligning interval images to quantify change from baseline.
We have also devised a clinical oedema score and validated it in a pilot study. We will also measure change in mid-arm and mid-leg circumference. These will be performed at all 3 time point.
Standard methods for measuring fluid overload exist and we will use this as part of this study. Oedema has not been previously quantified in the context of critical illness. We aim to validate clinical and objective measures (3D imaging) of change in tissue oedema.
Intervention code [1] 319864 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326698 0
Fluid overload as measured by change in patient weight using built in Atom infant warmer cot scales. These scales are electronic. We have tested the accuracy of these scales and found them to be accurate to 0.8gms (SD 1.4).
Timepoint [1] 326698 0
Baseline, 24 hours and 48 hours from enrollment
Primary outcome [2] 327008 0
Eye oedema measured by 3D imaging
Timepoint [2] 327008 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [1] 392403 0
Proteomics - serum biomarkers of endothelial dysfunction / glycocalyx degradation (Soluble Vascular Cell Adhesion Molecule (sVCAM), Soluble Intracellular Adhesion Molecule (sICAM), sE-Selectin, and sFlt-1) (heparan sulphate, syndecan-1, hyaluronan, and angiopoietin 2)

The investigation of biomarkers and oedema and fluid overload are exploratory secondary outcomes
Timepoint [1] 392403 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [2] 393438 0
Proteomics -serum biomarkers of Inflammation (IL-6, IL-8, Cytokine TNF, Complement c3a c4a c5a, Bradykinin)

The investigation of biomarkers and oedema and fluid overload are exploratory secondary outcomes
Timepoint [2] 393438 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [3] 393440 0
Lung ultrasound measurements of lung oedema determined by B lines in the midclavicular line, anterior axillary line and posterior axillary line bilaterally
Timepoint [3] 393440 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [4] 394667 0
Mid arm and mid leg circumference measured using a tape measure and guided by a standard operating procedure. Measurements will be performed by the PI
Timepoint [4] 394667 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [5] 394668 0
Duration of mechanical ventilation as recorded from the intensive care unit database




Timepoint [5] 394668 0
Baseline, 24 hours and 48 hours from enrollment and PICU discharge
Secondary outcome [6] 394946 0
Proportion requiring and duration of vasoactive therapies as recorded in the electronic medical record
Timepoint [6] 394946 0
Duration of paediatric intensive care admission
Secondary outcome [7] 394947 0
Organ dysfunction measured by PELOD-2 score calculated from variables in the electronic medical record
Timepoint [7] 394947 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [8] 394948 0
vasoactive support measured by the vasoactive inotrope score calculated from the electronic medical record
Timepoint [8] 394948 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [9] 394949 0
Intensive care length of stay from enrollment to PICU discharge as recorded from the electronic medical record and intensive care unit database
Timepoint [9] 394949 0
intensive care discharge
Secondary outcome [10] 394950 0
Intensive care mortality as recorded from the electronic medical record and intensive care unit database
Timepoint [10] 394950 0
Intensive care discharge
Secondary outcome [11] 394953 0
Clinical Oedema Score - 6 region clinical score. each region 0-3 therefore total score of 18.
Measured by the PI
The eye measurement will be performed by the PI, second intensive care doctor and the bedside nurse
Timepoint [11] 394953 0
Baseline, 24 hours and 48 hours from enrolment
Secondary outcome [12] 395285 0
Lower limb pitting oedema as measured with 3D imaging
Timepoint [12] 395285 0
Baseline, 24 hours and 48 hours from enrollment
Secondary outcome [13] 395286 0
Frusemide administration as recorded per 24 hour period from the electronic medical record
Timepoint [13] 395286 0
Baseline, 24 hours and 48 hours from enrollment

Eligibility
Key inclusion criteria
1. Mechanically ventilated at enrolment or expected to be intubated upon elective PICU admission
2. Admitted to the PICU within previous 72 hours
3. Expected to be mechanically ventilated until the day after tomorrow
4. Expected to have arterial or venous access for 48 hours after enrolment
5. Can be safely and accurately weighed
Minimum age
1 Days
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to be weighed safely (haemodynamic instability, traumatic brain injury and unstable intracranial pressure, unsecured spinal injury, severe orthopaedic injuries, insecure endotracheal tube)
2. Children expected to stay in PICU less than 48 hours
3. Cerebral venous obstruction/proximal upper limb, upper leg venous obstruction or thrombosis/ cavo- pulmonary shunt
4. Ocular/facial injury/Surgery
5. Inability to lie supine in a fixed position
6. Prone positioning in the 6 hours prior to enrolment
7. Known protein losing states – e.g. Nephrotic syndrome, protein losing enteropathy, lymphangiectasia
8. Prior enrolment in the same study
9. Expected weight > 65 kg
10. COVID-19 positive or clinical suspicion of COVID-19

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Statistical methods / analysis
Descriptive analysis of demographic and clinical variables
Demographic and clinical variables of enrolled participants, such as age, weight, sex, PIM3, proportion and duration of intensive care supports and outcomes, will be described using frequency and proportions. Non-symmetrically distributed data will be described using median and interquartile ranges and symmetrical data, mean and standard deviation. Distribution of symmetry of data will be assessed using Shapiro Wilks test and visual inspection of data. Non-symmetrically distributed data will be described using median and interquartile ranges. Inferential statistics will be used to compare groups based on presence and degree of fluid overload and oedema. Chi squared test and t-test or Mann-Whitney-U tests will be used to test significance of proportions and variable mean/medians respectively. Descriptive analyses over time will include 3 time points of enrollment (baseline), 24 hours and 48 hours.
In order to adjust for the analysis of outcomes for baseline variables, the following data will be recorded:
• Serum albumin and serum creatinine at enrollment, 24 hours and 48 hours
• Frusemide administration
• Volume of fluid bolus administration per kilogram per 24 hours
Descriptive analysis of demographic and clinical characteristics based on the presence of fluid overload and oedema
We will describe the demographic and clinical characteristics of participants based on the presence of
1. fluid overload only,
2. fluid overload and oedema and
3. neither fluid overload nor oedema.
Fluid overload will be determined by peak weight gain compared to baseline within the first 48 hours. Oedema will be determined by the peak increase in tissue volume measured by 3D photography within 48 hours.
We will then further describe the first 2 groups based on the degree of fluid overload being <5% increase from baseline, 5-10% increase from baseline and >10% from baseline
Descriptive analysis of anthropometry, clinical oedema score and 3D measurements
Anthropometric data (including weight), clinical oedema score and eyelid and lower limb oedema will be described using mean and standard deviation for symmetrically distributed data or median and interquartile range for asymmetrically distributed data at each time point.
Mid-arm and mid-leg circumferences will be measured as absolute values and percentage change as percentage from baseline will be calculated at 24-hour and 48-hour time points.
Lower limb oedema will be measured as the depression depth between the surface level skin and the mid-cuff level of the skin detected by 3D photographs.
3D measurement of eyelid oedema will be measured in volume and peak distance in mm from baseline and change at each time point.
There is no prior experience with measuring eyelid oedema as a continuous variable in critically ill children. After 20 patients an analysis of oedema as a continuous variable will be performed to investigate for equal distribution within categories of mild moderate and severe. In the event that categories of mild, moderate or severe degrees of oedema are determined analyses may be based on these.
Analysis of clinical measurement of oedema
We will investigate the relationship between clinical measures of oedema and 3D photographic changes in skin volume.
Linear regression analyses will be performed to measure the relationship between oedema and anthropometry in 2 ways. Firstly, peak change in value within 48 hours from baseline controlling for baseline value and secondly, at 48 hours. We will use linear regression analyses to assess the relationship between:
• 3D measures of oedema and clinical oedema score to investigate whether a clinical oedema scoring system correlates with objective changes in tissue oedema. Both will be measured on a continuous scale.
• 3D measures of oedema and mid-forearm and mid-leg circumference to investigate if simple bedside measures correlate with objective changes in tissue oedema
• 3D measure of eyelid oedema and clinical score of eyelid oedema
Analyses will be controlled for age and PIM3 score.
Analysis of relationship between fluid overload and oedema
Linear regression analyses will be performed to measure the relationship between fluid overload and oedema in 2 ways. Firstly, peak change in value within 48 hours from baseline controlling for baseline value and secondly, at 48 hours. Fluid overload will be measured as a continuous variable determined by percentage weight change from baseline.
• Weight(current) – weight(baseline)/weight baseline x 100
• Eyelid oedema will be recorded as a volume change from baseline and mm increase from baseline
We will use linear regression analyses to assess the relationship between:
• Weight change and change in eyelid oedema to investigate the relationship between fluid overload and oedema
• Weight change and change in lower limb oedema to investigate the relationship between fluid overload and oedema
• Weight change and fluid balance to investigate if fluid balance is an accurate reflection of fluid overload
Each analysis will be controlled for age and PIM3.
Analysis of relationship of fluid overload and oedema on clinical outcomes
We will investigate the relationship between both peak fluid overload and peak oedema within 48 hours as continuous variables and:
• Daily organ dysfunction in the first 48 hours – PELOD 2 score
• Duration of mechanical ventilation
• Proportion receiving and duration of vasoactive medications during PICU admission
• PICU LOS in hours
We will describe PICU Mortality (mortality is expected to be less than 5% of the sample).

Analysis of biomarkers as predictors of oedema and fluid overload as well as clinical outcomes.
The relationship between biomarker values and outcomes of oedema and fluid overload will be investigated. Primary biomarkers of interest will include those reflecting endothelial dysfunction, glycocalyx degradation and inflammation as described above to investigate whether these are independently associated with the degree of fluid overload and oedema. In the first instance, we will describe the biomarker values at baseline, 24 and 48 hours using mean and standard deviation or median and interquartile range as appropriate. We will then investigate the relationship between biomarker expression and peak oedema, peak fluid overload and the following clinical outcomes:
• Peak organ dysfunction in the first 48 hours – PELOD 2 score
• Duration of mechanical ventilation during the ICU admission
• Proportion receiving and duration of vasoactive medications during PICU admission
• Peak daily VIS in the first 48 hours from PICU admission
• PICU LOS in hours
Analysis will be performed using baseline biomarker value and peak value within 48 hours and controlled for age and PIM3.
Protein expression analyses will be completed using the Fluorescence Intensity readout for the multiplex assays and protein concentrations or relative quantities for ELISA and SWATH-MS data (85) respectively. All biomarker data will be analysed using paired, non-parametric analyses to accommodate the sample size, as well as non-normal distributions.
The relationship between fluid overload, oedema and biomarker expression and clinical outcomes
Multivariate regression analyses will be performed to identify predictors of peak fluid overload and oedema within 48 hours. In addition, we will also analyse whether fluid overload and/or oedema within 48 hours predict clinical outcomes. We will perform similar analyses to estimate whether baseline biomarkers or peak biomarker within 48 hours predicts clinical outcomes. Logistic regression analyses will be performed for binary outcomes.

Predictor variables such as age, Paediatric Index of Mortality will be considered as potential covariates. An entry criterion for inclusion into each model will be univariate analyses for the outcome with a p value <0.15.
If sufficiently sized subgroup analyses will be performed for children post congenital heart disease surgery and children less than 1 year old.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
12/05/2021
Actual
Date of last participant enrolment
Anticipated
1/07/2022
Actual
Date of last data collection
Anticipated
1/09/2022
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18835 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 33331 0
3052 - Parkville
Recruitment postcode(s) [2] 33332 0
3052 - Melbourne University

Funding & Sponsors
Funding source category [1] 307997 0
Hospital
Name [1] 307997 0
The Royal Children's Hospital
Country [1] 307997 0
Australia
Primary sponsor type
Hospital
Name
The Royal Children's Hospital
Address
Paediatric Intensive Care Unit
Royal Children's Hospital
3West Clinical Offices
50 Flemington Rd
Parkville 3052
Victoria
Country
Australia
Secondary sponsor category [1] 308719 0
None
Name [1] 308719 0
Address [1] 308719 0
Country [1] 308719 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307991 0
Royal Children's Hospital HREC
Ethics committee address [1] 307991 0
Ethics committee country [1] 307991 0
Australia
Date submitted for ethics approval [1] 307991 0
03/08/2020
Approval date [1] 307991 0
30/08/2020
Ethics approval number [1] 307991 0
65005

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

Contacts
Principal investigator
Name 109154 0
Dr Ben Gelbart
Address 109154 0
Royal Children's Hospital
Paediatric Intensive Care Unit
3 West clinical offices
50 Flemington Rd
Parkville 3052
Victoria
Country 109154 0
Australia
Phone 109154 0
+61 03 93455211
Fax 109154 0
none
Email 109154 0
[email protected]
Contact person for public queries
Name 109155 0
Ben Gelbart
Address 109155 0
Royal Children's Hospital
Paediatric Intensive Care Unit
3 West clinical offices
50 Flemington Rd
Parkville 3052
Victoria
Country 109155 0
Australia
Phone 109155 0
+61 03 93455211
Fax 109155 0
none
Email 109155 0
[email protected]
Contact person for scientific queries
Name 109156 0
Ben Gelbart
Address 109156 0
Royal Children's Hospital
Paediatric Intensive Care Unit
3 West clinical offices
50 Flemington Rd
Parkville 3052
Victoria
Country 109156 0
Australia
Phone 109156 0
+61 03 93455211
Fax 109156 0
none
Email 109156 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?
Summary data or individual data may be available at the discretion of the primary investigator
When will data be available (start and end dates)?
Data will be available from 12 months after publication of the manuscript for 5 years after the date of publication
Available to whom?
Data will be provide at the discretion of the primary investigator as a proxy for the study investigators, to investigators who provide a detailed study protocol that has been approved by a human research ethics committee and registered on a clinical trial registry
Available for what types of analyses?
Systematic review or meta-analyses
How or where can data be obtained?
Contacting the PI [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.