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Trial registered on ANZCTR


Registration number
ACTRN12618000144213
Ethics application status
Approved
Date submitted
10/01/2018
Date registered
31/01/2018
Date last updated
8/01/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the feasibility of microdialysis to monitor vascular endothelial function in paediatric cardiac patients.
Scientific title
A prospective study assessing the feasibility of monitoring vascular endothelial integrity and activation in post-operative paediatric cardiac surgical patients
Secondary ID [1] 293753 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
systemic inflammation 306135 0
vascular endothelial capillary leak 306136 0
congenital cardiac disease 306203 0
Condition category
Condition code
Inflammatory and Immune System 305250 305250 0 0
Other inflammatory or immune system disorders
Cardiovascular 305311 305311 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Experimental patients will undergo the insertion of a microdialysis catheter to monitor interstitial protein levels and serial blood tests for biomarkers of inflammation (cytokines) and endothelial activation.

A 66 Linear Microdialysis Catheter (AshMed Medical Pty Ltd) will be inserted under the skin of the forearm in anaesthetised children by the research personnel under the supervision of the anaesthetist. The microdialysis catheter will be perfused with sterile saline (0.9% NaCl) solution. The microdialysis pump will run at 1 microliter per minute.

Dialysate samples will be collected every 2 ± 2 hours in 0.5 mL Eppendorf tubes. The tubes will be placed on ice and transferred to the laboratory. The microdialysate will be analysed for protein and inflammatory markers.

Second hourly urine samples from the indwelling urinary catheter will be collected throughout the procedure and for the first 48 post-operative hours.
As per the paediatric intensive care unit (PICU) protocol, all patients will have routine post-operative blood taken for blood gas analysis (including lactate and central venous oxygen saturations), full blood count, plasma electrolytes, renal and liver functions tests and coagulation profiles. At this time researchers will organise the collection of an additional 1.0-2.0mL of blood. In this sample 200 µL of plasma will be used to measure levels of EphA2 (Human Magnetic Luminex® Screening Assay kit, R&D Systems, Inc.), EphA4, EphB4, ephrin-A1 and ephrin-B2 (ELISA, R&D Systems Inc.). We will also measure inflammatory markers (CRP, procalcitonin), complement (C5a), endothelial markers (endocans, VEGF, Ang-1, Ang-2) and cytokines (TNF-a, IL-1ß, IL-6, IL-8, IL-10 and IFN-gamma) using standard Bio-RAD ELISA kits as per the manufacturers’ instructions.

The catheter will remain in situ for the duration of the study - experimental patients 72 hours, control patients until discharge from the recovery ward.

If the catheter is accidentally dislodged the researchers will decide if the catheter should be replaced.
Intervention code [1] 300006 0
Diagnosis / Prognosis
Comparator / control treatment
The control patients will undergo an elective cardiac catheterisation procedure under general anaesthesia with the insertion of a microdialysis catheter to monitor interstitial protein levels and serial blood tests for biomarkers of inflammation (cytokines) and endothelial activation.
Control group
Active

Outcomes
Primary outcome [1] 304404 0
Monitoring interstitial protein levels (vascular leak) by quantitating microdialysate protein levels and plasma biomarkers of inflammation and endothelial activation. (composite primary outcome)

From the routine blood samples, 200 µL of plasma will be used to measure levels of EphA2 (Human Magnetic Luminex® Screening Assay kit, R&D Systems, Inc.), EphA4, EphB4, ephrin-A1 and ephrin-B2 (ELISA, R&D Systems Inc.). We will also measure plasma inflammatory markers (CRP, procalcitonin), complement (C5a), endothelial markers (endocans, VEGF, Ang-1, Ang-2) and cytokines (TNF-a, IL-1ß, IL-6, IL-8, IL-10 and IFN-gamma) using standard Bio-RAD ELISA kits as per the manufacturers’ instructions.
Timepoint [1] 304404 0
0h (induction of anaesthesia), 1h, 2h, 4h, 12h, 24h, 48h, 72h - the primary time point is induction of anaesthesia and sample collection (microdialysate, plasma, urine) continues during the PICU admission until PICU discharge - which is usually 48-72h.
Secondary outcome [1] 341844 0
Urine from the indwelling catheter will be collected and urinary proteins measured (microalbuminuria) by standard laboratory techniques (Pierce protein assay).
Timepoint [1] 341844 0
0h (induction of anaesthesia), 1h, 2h, 4h, 12h, 24h, 48h, 72h

Eligibility
Key inclusion criteria
1. control - children undergoing cardiac catheterisation under general anaesthesia for diagnosis of congenital cardiac disease prior to elective surgical correction.
2. experimental - undergoing surgical correction of congenital cardiac disease either cardiopulmonary bypass and non bypass cases.
Minimum age
No limit
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
No exclusion criteria

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



Intervention assignment
Parallel
Other design features
N/A
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
We will enrol 20 control and 20 experimental patients = 40 total.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/03/2019
Actual
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
31/01/2020
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 18500 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 298365 0
Charities/Societies/Foundations
Name [1] 298365 0
Financial Markets Foundation for Children
Country [1] 298365 0
Australia
Funding source category [2] 298366 0
Government body
Name [2] 298366 0
National Health and Medical Research Council - Project Grant
Country [2] 298366 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Naomi Epstein
Administrative Officer
Health and Biomedical Initiatives
Office of Sponsored Research
The University of Queensland
Brisbane Queensland 4072
Australia
Country
Australia
Secondary sponsor category [1] 297493 0
Hospital
Name [1] 297493 0
Children's Health Queensland Hospital and Health Service
Address [1] 297493 0
501 Stanley Street
South Brisbane
Queensland 4101

Postal address
PO Box 3474
South Brisbane
Queensland 4101
Country [1] 297493 0
Australia
Other collaborator category [1] 279883 0
Individual
Name [1] 279883 0
Associate Professor Trent M Woodruff
Address [1] 279883 0
NHMRC Career Development Fellow
School of Biomedical Sciences
Faculty of Medicine
The University of Queensland
St Lucia Q 4072
Country [1] 279883 0
Australia
Other collaborator category [2] 279884 0
Individual
Name [2] 279884 0
Dr Debbie A Long
Address [2] 279884 0
Nurse Researcher
Paediatric Intensive Care Unit
Division of Critical Care
Lady Cilento Children’s Hospital
Children's Health Queensland Hospital and Health Service
501 Stanley St, South Brisbane
PO Box 3474 South Brisbane QLD 4101


Country [2] 279884 0
Australia
Other collaborator category [3] 279885 0
Individual
Name [3] 279885 0
Dr Benjamin Anderson
Address [3] 279885 0
Department of Cardiology
Level 7
Lady Cilento Children's Hospital
501 Stanley Street
South Brisbane Q4101
Country [3] 279885 0
Australia
Other collaborator category [4] 279886 0
Individual
Name [4] 279886 0
Dr Nelson Alphonso
Address [4] 279886 0
Director of Cardiac Surgery
Level 7
Lady Cilento Children's Hospital
501 Stanley Street
South Brisbane Q4101
Country [4] 279886 0
Australia
Other collaborator category [5] 279887 0
Individual
Name [5] 279887 0
Dr Prem Venugopal
Address [5] 279887 0
Department of Cardiac Surgery
Level 7
Lady Cilento Children's Hospital
South Brisbane Q4101
Country [5] 279887 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299361 0
Children's Health Queensland Hospital and Health Service
Ethics committee address [1] 299361 0
Human Research Ethics Committee
Centre for Children’s Health Research
Lady Cilento Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101
Ethics committee country [1] 299361 0
Australia
Date submitted for ethics approval [1] 299361 0
27/11/2017
Approval date [1] 299361 0
19/12/2017
Ethics approval number [1] 299361 0
HREC/17/QRCH/274

Summary
Brief summary
The systemic inflammatory response syndrome (SIRS) characterises up to 80% of critical illness in children. The fundamental pathophysiological features underpinning SIRS are changes to the vascular endothelium, which include: 1) increased permeability to fluid and protein ("leaky") and, 2) increased activation ("sticky").

We recently published data which confirms a direct role for Eph/ephrin signalling in endothelial leakage both in a mouse gut ischaemia/reperfusion injury model of systemic inflammation and in vitro in TNF-a induced vascular leakage in human umbilical venous endothelial cells.

Based on this data we hypothesise that vascular endothelial function can be monitored in the intensive care unit by: (a) quantifying interstitial protein levels by microdialysis; measuring urinary albumin; and (c) measuring plasma levels of Eph/ephrins a s endothelial activation markers. Positive fluid balance is a poor prognostic sign, but without clear science, opinion on fluid management in the critically-ill patient remains divided.

The aim of this project is to determine whether it is feasible to monitor the integrity of the vascular endothelium in critically-ill children by:
a) using microdialysis to quantify interstitial protein levels;
(b) measuring plasma levels of Eph/ephrin proteins as endothelial activation biomarkers and (c) monitoring urinary albumin (microalbuminuria).

This preliminary feasibility study will be undertaken in post-operative paediatric cardiac surgical patients who are routinely admitted to a paediatric intensive care unit for cardiorespiratory support and monitoring. (The control patients undergo an elective cardiac catheterisation without the inflammatory stimulus of cardiopulmonary bypass.)

Monitoring the permeability of the vascular endothelium may inform clinicians about the stage and severity of SIRS and assist in clinical decision-making regards fluid resuscitation and fluid balance management. This may improve supportive care in the ICU and result in reduced ventilator days, hospital length of stay and mortality in critically-ill children.
Trial website
Not applicable.
Trial related presentations / publications
Not applicable
Public notes
Attachments [1] 2322 2322 0 0
/AnzctrAttachments/374280-RESEARCH PROTOCOL - MICRODIALYSIS CARDIAC PATIENTS V2 17.11.17.doc (Protocol)
Attachments [2] 2323 2323 0 0
/AnzctrAttachments/374280-HREC17QRCH274 ethics approval 191217.pdf (Ethics approval)
Attachments [3] 2324 2324 0 0
/AnzctrAttachments/374280-Parent-Guardian Consent Form V2 17.11.17.doc (Participant information/consent)
Attachments [4] 2326 2326 0 0
/AnzctrAttachments/374280-Parent-Guardian Information Sheet_Cardiac_V3 12.12.17.doc (Participant information/consent)

Contacts
Principal investigator
Name 80178 0
A/Prof Mark G Coulthard
Address 80178 0
UQ Faculty, Level 7 Queensland Children's Hospital, 501 Stanley Street, South Brisbane Q4101
Country 80178 0
Australia
Phone 80178 0
+61730684676
Fax 80178 0
+61730684673
Email 80178 0
Mark.Coulthard@health.qld.gov.au
Contact person for public queries
Name 80179 0
Mark G Coulthard
Address 80179 0
UQ Faculty, Level 7 Queensland Children's Hospital, 501 Stanley Street, South Brisbane Q4101
Country 80179 0
Australia
Phone 80179 0
+61730684676
Fax 80179 0
+61730684673
Email 80179 0
Mark.Coulthard@health.qld.gov.au
Contact person for scientific queries
Name 80180 0
Mark G Coulthard
Address 80180 0
UQ Faculty, Level 7 Queensland Children's Hospital, 501 Stanley Street, South Brisbane Q4101
Country 80180 0
Australia
Phone 80180 0
+61730684676
Fax 80180 0
+61730684673
Email 80180 0
Mark.Coulthard@health.qld.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
This is an observational study.


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.