ANZCTR - Registration

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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]

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

heart disease

cardiothoracic surgery

Condition category

Condition code

Renal and Urogenital

Kidney disease

Cardiovascular

Coronary heart disease

Surgery

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]

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]

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]

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]

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]

End of cardiopulmonary bypass.

Secondary outcome [2]

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]

End of cardiopulmonary bypass.

Secondary outcome [3]

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]

Duration of the surgical procedure.

Secondary outcome [4]

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]

Duration of cardiopulmonary bypass.

Secondary outcome [5]

Post-operative change in urinary concentration of neutrophil gelatinase associated lipocalin (NGAL), indexed for urinary concentration of creatinine.

Timepoint [5]

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]

Post-operative change in urinary concentration of insulin-like growth factor-binding protein 7 (IGFBP7), indexed for urinary concentration of creatinine.

Timepoint [6]

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]

Post-operative change in urinary concentration of liver fatty acid binding protein (L-FABP), indexed for urinary concentration of creatinine.

Timepoint [7]

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]

Post-operative change in urinary concentration of tissue inhibitor of metalloproteinase 2 (TIMP-2), indexed for urinary concentration of creatinine.

Timepoint [8]

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]

Survival to discharge:

We will assess acute (in-hospital) death from electronic hospital records.

Timepoint [9]

Discharge from hospital or mortality during the admission for cardiac surgery.

Secondary outcome [10]

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]

(i) Discharge from hospital and (ii) 90 days after the surgical procedure.

Secondary outcome [11]

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]

Prior to the surgical procedure and again ninety days after the surgical procedure.

Secondary outcome [12]

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]

Ninety days after the surgical procedure.

Secondary outcome [13]

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]

(i) Discharge from hospital and (ii) 90 days after the surgical procedure.

Secondary outcome [14]

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]

Termination of the surgical procedure.

Secondary outcome [15]

Survival to 90 days after surgery

Timepoint [15]

Ninety days after the day of surgery.

Secondary outcome [16]

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]

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?

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

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

3168 - Clayton

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

National Heart Foundation of Australia

Address [1]

2/850 Collins Street
Melbourne
Victoria 3008

Country [1]

Australia

Primary sponsor type

Hospital

Name

Monash Health

Address

246 Clayton Road
Clayton, Victoria 3168

Country

Australia

Secondary sponsor category [1]

University

Name [1]

Monash University

Address [1]

Monash Research Office
Monash University
Wellington Road
Clayton
Victoria 3800

Country [1]

Australia

Other collaborator category [1]

Individual

Name [1]

Associate Professor Andrew Cochrane

Address [1]

Department of Cardiothoracic Surgery
Monash Health
246 Clayton Road
Clayton, Victoria 3168

Country [1]

Australia

Other collaborator category [2]

Individual

Name [2]

Professor Roger Evans

Address [2]

Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800

Country [2]

Australia

Other collaborator category [3]

Individual

Name [3]

Professor Julian Smith

Address [3]

Department of Surgery, Monash University
Monash Health
246 Clayton Road
Clayton, Victoria 3068

Country [3]

Australia

Other collaborator category [4]

Individual

Name [4]

Professor Amanda Thrift

Address [4]

Department of Medicine, Monash University
Monash Health
246 Clayton Road
Clayton, Victoria 3068

Country [4]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health Human Research Ethics Committee

Ethics committee address [1]

Monash Health
246 Clayton Road
Clayton, Victoria 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/02/2019

Approval date [1]

20/06/2019

Ethics approval number [1]

HREC/46510/MonH-2019-164093(v1)

Summary

Brief summary

Open heart surgery saves thousands of lives each year in Australia, but often injures the kidney. Kidney oxygen deficiency is a major cause of kidney injury. We propose a new way to prevent acute kidney injury by increasing kidney oxygen levels during heart surgery. The aim of this trial is to determine whether this new approach to prevention of kidney injury is safe, feasible and effective.

Trial website

None

Trial related presentations / publications

Public notes

Presentations and publications regarding data in support of the  rationale of the trial

Presentations

2016 Kidney oxygenation in acute kidney injury. FASEB Summer Conference on Renal Hemodynamics and Cardiovascular Function in Health and Disease, June 19-23 Big Sky, Montana, USA. (http://faseb.org/src/micro/Site/Renal/home.aspx)
2016 Why does the kidney fail in cardiac surgery? It’s medullary hypoxia. Renal Support in the Critically Ill Conference, October 7, Melbourne. (http://www.cvent.com/events/3rd-renal-support-in-the-critically-ill-conference/event-summary-9d53549997534279b97d9dafdcd87c92.aspx)
2017 Renal oxygenation during cardiac surgery on cardiopulmonary bypass: Lessons from clinical, experimental and computational studies. Plenary Speaker, Uppsala Kidney Oxygen Conference, August 17-20, Uppsala, Sweden. (http://www.mcb.uu.se/kidney2017) [Plenary]
2017 Renal Physiology: regulation of intrarenal oxygenation. 2nd International Symposium on Functional Renal Imaging: Where Physiology, Nephrology, Radiology and Physics Meet, October 11-13, Berlin, Germany. (https://www.mdc-berlin.de/renal) [Also Session Chair]
2017	Early identification of renal hypoxia as a predictor of acute kidney injury Invited Speaker, Joint meeting of the Association of Thoracic and Cardiovascular Surgeons of Asia and the Australian and New Zealand Society of Cardiothoracic Surgeons, November 16-19, 2017, Melbourne, Australia (http://www.atcsa2017.com/).
2018	Kidney oxygenation during cardiopulmonary bypass and post-operative acute kidney injury. Invited Speaker, International Society of Nephrology Frontiers Meeting: Kidney Disease & Cardiovascular Disease, February 22-25, Tokyo, Japan. [Keynote] (http://www.isnfrontiers.org/tokyo/).



Publications

Evans RG, Smith JA, Wright C, Gardiner BS, Smith DW, Cochrane AD. (2014) Urinary oxygen tension: a clinical window on the health of the renal medulla? American Journal of Physiology - Regulatory Integrative and Comparative Physiology 306, R45-R50.
Sgouralis I, Evans RG, Gardiner BS, Smith JA, Fry BC, Layton AT. (2015) Renal hemodynamics, function and oxygenation during cardiac surgery performed on cardiopulmonary bypass: A modeling study. Physiology Reports 3 (1) e12260, doi: 10.14814/phy2.12260.
Calzavacca P, Evans RG, Bailey M, Bellomo R, May CN. (2015) Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury. Critical Care Medicine 43, e431-e439. 
Evans RG, Smith JA, Gardiner BS, Smith DW, Thrift AG, Lankadeva YR, May CN, Cochrane AD. (2016) Hypoxia as a biomarker of kidney disease. Biomarkers in Kidney Disease, Eds Preedy VR & Patel VB. Series: Biomarkers of Disease: Methods, Discoveries and Applications (series editor VR Preedy), Springer-Verlag, Berlin, pp 83-105. http://link.springer.com/referenceworkentry/10.1007%2F978-94-007-7743-9_7-1.
Lankadeva YR, Kosaka J, Evans RG, Bailey SR, Bellomo R, May CN. (2016) Intra-renal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury. Kidney International, 90, 100-108. 
Sgouralis I, Kett MM, Ow CPC, Abdelkader A, Layton AT, Gardiner BS, Smith DW, Lankadeva YR, Evans RG. (2016) Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: Experimental and modelling studies. American Journal of Physiology - Regulatory Integrative and Comparative Physiology 311, R532-R544.
Sgouralis I, Evans RG, Layton AT. (2017) Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat. Mathematical Medicine and Biology 34, 313-333.
Lankadeva YR, Kosaka J, Evans RG, Bellomo R, May CN. (2018) Urinary oxygenation as a surrogate measure of medullary oxygenation during angiotensin II therapy in septic acute kidney injury. Critical Care Medicine 46, e41-e48.
Evans RG, Lankadeva YR, Cochrane AD, Marino B, Iguchi N, Zhu MZL, Hood SG, Smith JA, Bellomo R, Gardiner BS, Lee C-J, Smith DW, May CN. (2018) Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass. Acta Physiologica 222: e12995.
Ow CPC, Ngo JP. Ullah M, Hilliard LM, Evans RG. (2018) Renal hypoxia in kidney disease: Cause or consequence? Acta Physiologica 222, e12999.
Zhu MZ, Martin A, Cochrane AD, Smith JA, Thrift AG, Harrop GK, Ngo JP, Evans RG. (2018) Urinary hypoxia: An intra-operative marker of risk of cardiac surgery-associated acute kidney injury. Nephrology Dialysis Transplantation doi: 10.1093/ndt/gfy047

Contacts

Principal investigator

Name

A/Prof Andrew Cochrane

Address

Department of Cardiothoracic Surgery
Monash Health
246 Clayton Road
Clayton, Victoria 3168

Country

Australia

Phone

+61 3 9594 4515

Fax

Andrew.Cochrane@monashhealth.org

Contact person for public queries

Name

Roger Evans

Address

Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800

Country

Australia

Phone

+61 3 99051466

Fax

roger.evans@monash.edu

Contact person for scientific queries

Name

Roger Evans

Address

Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology
26 Innovation Walk
Monash University
Victoria 3800

Country

Australia

Phone

+61 3 99051466

Fax

roger.evans@monash.edu

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.	Type	Citation	Link	Email	Other Details	Attachment
1117	Informed consent form			roger.evans@monash.edu		375704-(Uploaded-21-01-2019-17-05-48)-Study-related document.docx
4501	Study protocol			roger.evans@monash.edu

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Intraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.	2023	https://dx.doi.org/10.1111/1440-1681.13812

N.B. These documents automatically identified may not have been verified by the study sponsor.

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