Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000128190
Ethics application status
Approved
Date submitted
9/10/2018
Date registered
29/01/2019
Date last updated
16/12/2022
Date data sharing statement initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Renal protection during open heart surgery
Scientific title
A prospective single centre randomised controlled trial of increased pump flow and arterial pressure during cardiopulmonary bypass to prevent post-operative acute kidney injury.
Secondary ID [1] 295700 0
Nil known
Universal Trial Number (UTN)
U1111-1218-3518
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
acute kidney injury 309086 0
heart disease 309087 0
cardiothoracic surgery 309088 0
Condition category
Condition code
Renal and Urogenital 307961 307961 0 0
Kidney disease
Cardiovascular 307962 307962 0 0
Coronary heart disease
Surgery 308875 308875 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients undergoing cardiac surgery requiring cardiopulmonary bypass will be randomised to either usual care or a 20-25% greater pump flow (up to a maximum of 3.0 L/min per square metre of body surface area) at a target mean arterial pressure of at least 80 mmHg. The pump flow employed during surgery is controlled by the attending clinical perfusionist. The duration of cardiopulmonary bypass for each patient will depend on the nature of their surgical procedure but will usually range from 60 min to 120 min. Fidelity of the intervention will be assessed by the researcher in the operating theatre who will record pump flow and arterial pressure at 5 min intervals, and/or by analysis of the electronic records generated by the heart lung machine.
Intervention code [1] 302021 0
Prevention
Comparator / control treatment
Standard care: The perfusion conditions employed as standard care are determined by the perfusionist in collaboration with the head surgeon, These are not based on specific guidelines but are determined by institutional protocols. At Monash Health most patients undergoing coronary artery bypass graft operations or valve procedures receive a pump flow of 2.4 L/min per square metre of calculated body surface area and a target arterial pressure of 70 mmHg.
Control group
Active

Outcomes
Primary outcome [1] 306943 0
The incidence of stage 1 post-operative acute kidney injury. We will use modified Kidney Disease Improving Global Outcomes (KDIGO) criteria for diagnosis of mild acute kidney injury. That is, an increase in serum creatinine of 0.3 mg/dL (26.5 µM) or more at any time within the first 48 h after surgery or an increase of serum creatinine to 1.5-1.9 times its baseline level within the first 5 days after surgery (Kidney Int. 2012;Suppl. 2:1-138.). We will not use the urine output criterion because it can result in false diagnosis of acute kidney injury (Koeze et al. BMC Nephrol. 2017;18:70).
Timepoint [1] 306943 0
Within 5 days of completion of surgery. Serum creatinine will be measured as part of patient care at least daily during this 5 day period.
Secondary outcome [1] 350168 0
Feasibility of randomisation of patients to an intervention or usual care treatment arm during their surgery.

We will document recruitment rate and whether perfusionists follow the correct protocol for each patient. Data from the ‘pump sheets’, used to record perfusion conditions, will be analysed to determine the fidelity of the intervention.
Timepoint [1] 350168 0
End of cardiopulmonary bypass.
Secondary outcome [2] 350169 0
Change in usual care over the course of the trial.

Data from the ‘pump sheets’, used to record perfusion conditions, will be analysed to assess whether standard perfusion conditions vary systematically during the course of the trial, both across all perfusionists and for individual perfusionists involved in the trial.
Timepoint [2] 350169 0
End of cardiopulmonary bypass.
Secondary outcome [3] 350170 0
Differences in urinary (and by inference medullary) PO2.

Urinary oxygen tension (PO2) will be measured continuously during surgery, using a sterilised fibre optic luminescence optode (NX-LAS-1/O/E-5m, Oxford Optronix, Abingdon, UK) advanced through the lumen of the bladder catheter, to the catheter tip, so that the sensing tip of the probe is in direct contact with bladder urine. The fibre optic probe will be connected to a luminescence lifetime oximeter (Oxylite Pro, Oxford Optronix, UK) interfaced with a laptop computer running LabChart software (Version 8, ADInstruments, Bella Vista, NSW, Australia). We will assess differences in urinary PO2 between the intervention and control arm on an intention-to-treat basis. Assessed outcomes will include mean and nadir urinary PO2 during and after bypass as well as the durations and areas under the curve for cut-offs of urinary PO2 of 15, 10 and 5 mmHg.
Timepoint [3] 350170 0
Duration of the surgical procedure.
Secondary outcome [4] 350171 0
Differences in cerebral oxygenation, measured using an INVOS 5100C Monitor System (near infrared spectroscopy; Medtronic Australasia, Macquarie Park, NSW). The outcome variable will be mean cerebral oxygen saturation (SO2) during cardiopulmonary bypass.
Timepoint [4] 350171 0
Duration of cardiopulmonary bypass.
Secondary outcome [5] 350172 0
Post-operative change in urinary concentration of neutrophil gelatinase associated lipocalin (NGAL), indexed for urinary concentration of creatinine.
Timepoint [5] 350172 0
Entry into the intensive care unit, and 3, 6, 12, 24 and 48 h later, compared to levels soon after induction of anaesthesia.
Secondary outcome [6] 350176 0
Post-operative change in urinary concentration of insulin-like growth factor-binding protein 7 (IGFBP7), indexed for urinary concentration of creatinine.
Timepoint [6] 350176 0
Entry into the intensive care unit, and 3, 6, 12, 24 and 48 h later, compared to levels soon after induction of anaesthesia.
Secondary outcome [7] 350179 0
Post-operative change in urinary concentration of liver fatty acid binding protein (L-FABP), indexed for urinary concentration of creatinine.
Timepoint [7] 350179 0
Entry into the intensive care unit, and 3, 6, 12, 24 and 48 h later, compared to levels soon after induction of anaesthesia.
Secondary outcome [8] 350181 0
Post-operative change in urinary concentration of tissue inhibitor of metalloproteinase 2 (TIMP-2), indexed for urinary concentration of creatinine.
Timepoint [8] 350181 0
Entry into the intensive care unit, and 3, 6, 12, 24 and 48 h later, compared to levels soon after induction of anaesthesia.
Secondary outcome [9] 350903 0
Survival to discharge:

We will assess acute (in-hospital) death from electronic hospital records.
Timepoint [9] 350903 0
Discharge from hospital or mortality during the admission for cardiac surgery.
Secondary outcome [10] 350904 0
Adverse events.

We will assess multiple outcomes related to morbidity and post-operative care. These will include ventilation time, ICU length of stay and hospital length of stay, need for return to theatre, as well as all therapeutic interventions in the intensive care unit and cardiac ward. We will also assess differences in standard post-operative assessments such as liver function tests, and serum urea and electrolytes. These data will be obtained from the patient's electronic health records. These will be combined as a composite end-point of 'adverse event'.
Timepoint [10] 350904 0
(i) Discharge from hospital and (ii) 90 days after the surgical procedure.
Secondary outcome [11] 350905 0
Change in quality of life: A quality of life questionnaire (AQoL-8D) will be administered to patients before their operation and again 90 days after surgery.
Timepoint [11] 350905 0
Prior to the surgical procedure and again ninety days after the surgical procedure.
Secondary outcome [12] 350913 0
Renal function.

All patients enrolled in the study will be visited by a research nurse 90 days after surgery for collection of a blood sample for measurement of serum creatinine.
Timepoint [12] 350913 0
Ninety days after the surgical procedure.
Secondary outcome [13] 350914 0
Cost-effectiveness of the intervention will be assessed by determining costs of post-operative care in the ICU and cardiac ward, costs of return to theatre if required, for each patient, and by data linkage to the Health Insurance Commission and the Department of Human Services, costs of access to healthcare outside the hospital system.
Timepoint [13] 350914 0
(i) Discharge from hospital and (ii) 90 days after the surgical procedure.
Secondary outcome [14] 350915 0
Feasibility of passive blinding of staff in the operating theatre other than the perfusionist.

We will ask the lead surgeon, anaesthetist and nurse whether they knew which arm of the study the patient was assigned to and ask them to give their best guess. These data will also permit sensitivity analyses to determine the impact of blinding on other outcomes.
Timepoint [14] 350915 0
Termination of the surgical procedure.
Secondary outcome [15] 353123 0
Survival to 90 days after surgery
Timepoint [15] 353123 0
Ninety days after the day of surgery.
Secondary outcome [16] 353124 0
Urinary albumin excretion at follow up.

All patients enrolled in the study will be visited by a research nurse 90 days after surgery for collection of a spot urine sample for measurement of urinary albumin to creatinine ratio.
Timepoint [16] 353124 0
Ninety days after the day of surgery.

Eligibility
Key inclusion criteria
Key inclusion criteria: (1) Non-emergency cardiac surgery on CPB (coronary artery bypass graft and/or valve surgery) at Monash Health, (2) An expected duration of CPB of 90 minutes or more.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) An expected duration of CPB of less than 90 minutes, (2) An expected nadir core body temperature during CPB of <32 °C (rare for this type of surgery), (3) Pre-existing AKI as defined by the KDIGO criteria, (4) Severe chronic kidney disease (serum creatinine >265 µmol/L), (5) Need for haemodialysis, (6) Prior renal transplantation, (7) A pre-operative state that precludes informed consent.

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)
Central randomisation by phone or computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation will be concealed using permuted blocks. Secure computer-generated randomisation will be used. Randomisation will be stratified according to site and blocked (sizes of 4, 6 or 8) according to a Mehta score of = or < 0.7% predicted risk of post-operative requirement of dialysis (the median risk in our recently published observational study). This will ensure that equal numbers of higher and lower risk patients are randomised to the intervention and control arms.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Primary outcome: The recently completed GIFT trial (J Thorac Cardiovasc Surg 2018;156:1918-1927) deployed inclusion and exclusion criteria similar to those we propose for this trial. The only relevant exception was that they excluded patients with pre-operative anaemia. We will not exclude these patients because we predict they might benefit from an intervention to improve renal oxygenation. In the GIFT trial the incidence of Stage 1 AKI in the usual care arm was 22.4% while in the goal directed perfusion arm it was 11.5%. With 200 patients per arm we have 83% power to detect this difference (two-tailed a=0.05, Chi Squared).). If we factor in a 4% loss of outcome data due to intraoperative mortality (i.e. a sample size of 192 per arm) we still have 80% power.
Secondary outcomes: Differences in proportions will be assessed using Chi Squared tests. For observations made at multiple time points we will employ repeated measures analysis of variance. P values for within-subject factors will be adjusted using the method of Greenhouse and Geisser. Missing data will be imputed using the 'last observation carried forward' (LOCF) method.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Other reasons/comments
Other reasons
Because of disruption to elective surgery during the COVID-19 pandemic, recruitment was slowed.
Date of first participant enrolment
Anticipated
5/09/2019
Actual
3/09/2019
Date of last participant enrolment
Anticipated
30/06/2023
Actual
2/09/2021
Date of last data collection
Anticipated
30/09/2023
Actual
3/09/2021
Sample size
Target
400
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11553 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 23581 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 300286 0
Charities/Societies/Foundations
Name [1] 300286 0
National Heart Foundation of Australia
Country [1] 300286 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
246 Clayton Road
Clayton, Victoria 3168
Country
Australia
Secondary sponsor category [1] 299715 0
University
Name [1] 299715 0
Monash University
Address [1] 299715 0
Monash Research Office
Monash University
Wellington Road
Clayton
Victoria 3800
Country [1] 299715 0
Australia
Other collaborator category [1] 280274 0
Individual
Name [1] 280274 0
Associate Professor Andrew Cochrane
Address [1] 280274 0
Department of Cardiothoracic Surgery
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country [1] 280274 0
Australia
Other collaborator category [2] 280305 0
Individual
Name [2] 280305 0
Professor Roger Evans
Address [2] 280305 0
Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800
Country [2] 280305 0
Australia
Other collaborator category [3] 280306 0
Individual
Name [3] 280306 0
Professor Julian Smith
Address [3] 280306 0
Department of Surgery, Monash University
Monash Health
246 Clayton Road
Clayton, Victoria 3068
Country [3] 280306 0
Australia
Other collaborator category [4] 280307 0
Individual
Name [4] 280307 0
Professor Amanda Thrift
Address [4] 280307 0
Department of Medicine, Monash University
Monash Health
246 Clayton Road
Clayton, Victoria 3068
Country [4] 280307 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301097 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 301097 0
Ethics committee country [1] 301097 0
Australia
Date submitted for ethics approval [1] 301097 0
04/02/2019
Approval date [1] 301097 0
20/06/2019
Ethics approval number [1] 301097 0
HREC/46510/MonH-2019-164093(v1)

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

Contacts
Principal investigator
Name 85874 0
A/Prof Andrew Cochrane
Address 85874 0
Department of Cardiothoracic Surgery
Monash Health
246 Clayton Road
Clayton, Victoria 3168
Country 85874 0
Australia
Phone 85874 0
+61 3 9594 4515
Fax 85874 0
Email 85874 0
[email protected]
Contact person for public queries
Name 85875 0
Roger Evans
Address 85875 0
Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800
Country 85875 0
Australia
Phone 85875 0
+61 3 99051466
Fax 85875 0
Email 85875 0
[email protected]
Contact person for scientific queries
Name 85876 0
Roger Evans
Address 85876 0
Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800
Country 85876 0
Australia
Phone 85876 0
+61 3 99051466
Fax 85876 0
Email 85876 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?
Individual participant data underlying published results only.
When will data be available (start and end dates)?
Beginning 3 months following main results publication; no end date determined
Available to whom?
Only researchers who provide a methodologically sound proposal, on a case-by-case basis at the discretion of the Principal Investigator (Andrew Cochrane) and Data Custodian (Roger Evans).
Available for what types of analyses?
For meta-analyses and data pooling studies.
How or where can data be obtained?
Subject to ethics approval, and approval by the Principal Investigator and Data Custodian, those requesting data will be asked to sign a data access agreement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1117Informed consent form  [email protected] 375704-(Uploaded-21-01-2019-17-05-48)-Study-related document.docx
4501Study protocol  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIntraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.2023https://dx.doi.org/10.1111/1440-1681.13812
N.B. These documents automatically identified may not have been verified by the study sponsor.