The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000128190
Ethics application status
Approved
Date submitted
9/10/2018
Date registered
29/01/2019
Date last updated
6/09/2019
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
Gender
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