Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000361202
Ethics application status
Approved
Date submitted
18/02/2018
Date registered
9/03/2018
Date last updated
7/08/2020
Date data sharing statement initially provided
1/08/2019
Date results information initially provided
7/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Preoperative Microvascular Protection in Patients Undergoing Major Abdominal Surgery
Scientific title
A Prospective Randomised Controlled Pilot Trial of Preoperative Microvascular Protection in Patients Undergoing Major Abdominal Surgery
Secondary ID [1] 294010 0
Nil
Universal Trial Number (UTN)
U1111-1207-2596
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glycocalyx degradation
 306522 0
Endothelial dysfunction 306523 0
Abdominal Surgery 306888 0
Condition category
Condition code
Cardiovascular 305634 305634 0 0
Diseases of the vasculature and circulation including the lymphatic system
Surgery 305986 305986 0 0
Other surgery
Anaesthesiology 305987 305987 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dexamethasone sodium phosphate 16mg, intravenous slow push, 30-60 minutes prior to skin incision
AND
20% Albumin 100ml (Albumex 20%) = 20g, intravenous infusion over 30mins, directly following dexamethasone dose

Further intraoperative bolus and maintenance fluid will be delivered as 4% albumin (made with 200ml of 20% albumin (40g) in 1000ml balanced crystalloid solution), titrated by the anaesthetist to meet patient fluid requirements utilising goal directed therapy
Intervention code [1] 300280 0
Prevention
Intervention code [2] 300281 0
Treatment: Drugs
Comparator / control treatment
These patients will receive a balanced crystalloid solution as their maintenance and resuscitation fluid for surgery.
Control group
Active

Outcomes
Primary outcome [1] 304743 0
Measurement of plasma syndican-1 (CD138) levels will be done using an Enzyme Linked Immunosorbent Assay (ELISA). A 100microml sample of patient plasma (or serum) will be used. This standardised quantitative assay has a sensitivity of <2.56ng/ml and a range of 8-256ng/ml. This method uses a multi-well plate pre-coated with human syndecan-1 monoclonal antibody. Syndecan 1 in the plasma binds to this. A detecting antibody is then added, which binds to syndecan 1 followed by a second enzyme-linked antibody, which is subsequently converted to a detectible form by the addition of another substrate.
Timepoint [1] 304743 0
24 hours post op
Secondary outcome [1] 342999 0
Measurement of plasma syndican-1 (CD138) levels will be done using an Enzyme Linked Immunosorbent Assay (ELISA). A 100microml sample of patient plasma (or serum) will be used. This standardised quantitative assay has a sensitivity of <2.56ng/ml and a range of 8-256ng/ml. This method uses a multi-well plate pre-coated with human syndecan-1 monoclonal antibody. Syndecan 1 in the plasma binds to this. A detecting antibody is then added, which binds to syndecan 1 followed by a second enzyme-linked antibody, which is subsequently converted to a detectible form by the addition of another substrate.
Timepoint [1] 342999 0
Completion of resection, Day 1 and Day 2 post op
Secondary outcome [2] 343000 0
Measurement of heparan sulphate levels will be done using an Enzyme Linked Immunosorbent Assay. A 50ml sample of patient plasma (or serum) will used be. This standardised quantitative assay has a sensitivity of <8ng/ml and a range of 20-8000ng/ml. This method uses a multi-well plate pre-coated with human heparan sulphate monoclonal antibody. Heparan sulphate in the plasma binds to this. A detecting antibody is then added, which binds to heparan sulphate followed by a second enzyme-linked antibody, which is subsequently converted to a detectible form by the addition of another substrate.
Timepoint [2] 343000 0
Completion of resection
Evening of surgery
Day 1 postop
Day 2 postop
Secondary outcome [3] 343001 0
Measurement of inflammatory and biomarker levels as an exploratory outcome measure will be performed using the Bio-rad Multiplex Immunoassay System. This standardised multiplex assay allows simultaneous detection and quantification of multiple biomarkers using a sandwich immunoassay format. The following markers are included in the assay: APRIL / TNFSF13, BAFF / TNFSF13B, sCD30 / TNFRSF8, sCD163, Chitinase-3-like 1, gp130 / sIL-6Rß, IFN-ß, IL-11, IL-19, IL-20, IL-26, IL-27 (p28), IL-28A / IFN-?2, IL-29 / IFN-?1, IL-32, IL-34, IL-35, LIGHT / TNFSF14, Osteocalcin, Pentraxin-3, sTNF-R1, sTNF-R2, TSLP, TWEAK / TNFSF12.
Timepoint [3] 343001 0
Completion of resection
Evening of surgery
Day 1 postop
Day 2 postop

Eligibility
Key inclusion criteria
• Adults aged > 18 years
• Undergoing elective open bowel resection, pancreatic resection or liver resection surgery
• Requiring a hospital stay of at least one postoperative night
• Routine use of arterial line for continuous blood pressure monitoring and intermittent positive pressure ventilation via an endotracheal tube as part of standard anaesthesia care
• American Society of Anesthesiologists (ASA) Physical status <5
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Poorly controlled diabetes (HbA1c > 9.0% or HbA1c >75 mmol/mol) if known
• Allergy to albumin or dexamethasone
• Surgery is being performed for treatment of an infective process (e.g. intra-abdominal sepsis)
• Planned postoperative intubation or ventilation
• Concurrent immunosuppressive therapies or immunosuppressed state
• Chronic steroid use (prednisolone 10mg/day or equivalent for greater for >1 week in preceding 3 months)
• Pregnant or lactating woman
• Surgical procedures within the preceding 2 months or expected within the subsequent 30 days

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Centralised allocation by central computer- based randomisation software (RedCAP Electronic Date Tools)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be block randomised. There will be 3 blocks of 24 patients (bowel, liver, pancreas resection). Within each block, 12 patients will be randomised to intervention and 12 to control using an automated random allocation algorithm (www.randomiser.org)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Block randomisation, with three parallel groups (Bowel, liver, pancreas resections)
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Randomisation will be undertaken by a central unit immediately prior to induction of anaesthesia as described above. Statistical analysis will be performed using commercial statistical software STATA (StataCorp, College Station, TX, USA). Figures will be constructed using Prism 7.0 GraphPad software (La Jolla, CA, USA).

The analysis will be conducted on intention-to-treat (ITT) basis using the full data set comprising all randomized participants. Subject to satisfiability of the missing-at-random assumption, missing data will be handled using ITT principles. Baseline characteristics will be reported using means (SD), medians (IQR) or frequencies (%) depending on the nature of the measurement scale, Primary analysis will be conducted using a one-way ANCOVA model with Plasma syndecan-1 levels at 24 hours after surgery as the dependent variable, treatment group as a factor with two levels (microvascular protection vs control), and type of surgery (liver vs pancreatic vs bowel resection) and baseline Plasma syndecan-1 level as co-variates.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/04/2018
Actual
18/07/2018
Date of last participant enrolment
Anticipated
Actual
14/01/2020
Date of last data collection
Anticipated
Actual
14/02/2020
Sample size
Target
72
Accrual to date
Final
72
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10054 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 10055 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 21572 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 9600 0
New Zealand
State/province [1] 9600 0
Grafton

Funding & Sponsors
Funding source category [1] 298635 0
Hospital
Name [1] 298635 0
Austin Health
Country [1] 298635 0
Australia
Funding source category [2] 306402 0
Charities/Societies/Foundations
Name [2] 306402 0
ANZCA Research Foundation - 2020 CSL Behring ANZCA Research Award
Country [2] 306402 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Rd
Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 297801 0
None
Name [1] 297801 0
-
Address [1] 297801 0
-
Country [1] 297801 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299595 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 299595 0
Austin Health
145 Studley Road
Heidelberg
Victoria
Australia, 3084
Ethics committee country [1] 299595 0
Australia
Date submitted for ethics approval [1] 299595 0
17/10/2017
Approval date [1] 299595 0
22/11/2017
Ethics approval number [1] 299595 0
HREC/17/Austin/397

Summary
Brief summary
Albumin and dexamethasone are often administered to patients undergoing major surgery. Despite these drugs being commonly used, it is not known how they impact on the stress response to surgery. Albumin is an intravenous fluid made up of a normal physiological protein (albumin) in a salt solution, that is routinely administered to patients having major surgery. It is TGA approved and readily available in Australia. Dexamethasone is a steroid medication, often used in many types of surgery to reduce the risk of nausea and vomiting. It also has anti-inflammatory and pain relieving effects. It is also TGA approved and readily available in Australia.

This pilot study aims to determine if giving albumin and dexamethasone immediately prior to surgery can reduce the stress response from surgery. Stress, or the inflammatory response during surgery can result in damage to the microvasculature (the smallest blood vessels in the body). By protecting these small vessels with dexamethasone and albumin, we hope to reduce the effects caused by the systemic inflammatory response that accompanies major surgery.

The study is a collaboration between 5 major hospitals that specialize in major abdominal surgery. These are Austin Health, Peter MacCallum Cancer Center, Warringal Private Hospital, Knox Private Hospital and Auckland City Hospital.

Importantly, for all patients in the study, standard of care will be maintained during anaesthesia, surgery, and the entire perioperative process and there will be NO deviation at any stage from acceptable routine care.

For this pilot study, patients undergoing 3 different types of major abdominal surgery will be randomized (allocated by chance) into two groups. The ‘Treatment Group’ will receive 16mg of dexamethasone and 100ml of 20% albumin solution 30-60minutes prior to the start of surgery, and a solution of 4% albumin to meet their ongoing fluid requirements during surgery. The ‘Control Group’ will receive no dexamethasone and 100ml of a standard balanced salt solution, with further balanced salt solution to meet their fluid requirements during surgery.

We will compare levels of Syndecan-1 (a marker of microvascular function) between the two groups at 5 different time points during and up to 48 hours after the operation to assess if microvascular function differs between the groups.

A total of 72 subjects will be included in the study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80962 0
Dr Shervin Tosif
Address 80962 0
Austin Health
145 Studley Rd
Heidelberg VIC 3184
Country 80962 0
Australia
Phone 80962 0
+61394965000
Fax 80962 0
Email 80962 0
[email protected]
Contact person for public queries
Name 80963 0
Dr Shervin Tosif
Address 80963 0
Austin Health
145 Studley Rd
Heidelberg VIC 3184
Country 80963 0
Australia
Phone 80963 0
+61394965000
Fax 80963 0
Email 80963 0
[email protected]
Contact person for scientific queries
Name 80964 0
Dr Shervin Tosif
Address 80964 0
Austin Health
145 Studley Rd
Heidelberg VIC 3184
Country 80964 0
Australia
Phone 80964 0
+61394965000
Fax 80964 0
Email 80964 0
[email protected]

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


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
SourceTitleYear of PublicationDOI
EmbaseTrajectory of plasma syndecan-1 and heparan sulphate during major surgery: A retrospective observational study.2023https://dx.doi.org/10.1111/aas.14150
EmbaseSerum Creatinine Levels and Nephrocheck Values With and Without Correction for Urine Dilution-A Multicenter Observational Study.2022https://dx.doi.org/10.3389/fmed.2022.847129
N.B. These documents automatically identified may not have been verified by the study sponsor.