Sodium Bicarbonate in Cardiac Surgery Study (Bic-MC)

A Multicenter, Randomized, Double Blind, Placebo Controlled Study of the Effect of Sodium Bicarbonate on Postoperative Renal Function in Patients Undergoing Elective Cardiopulmonary Bypass

With over one million operations a year, cardiac surgery with cardiopulmonary bypass is one of the most common major surgical procedures worldwide (1). Acute kidney injury is a common and serious postoperative complication of cardiopulmonary bypass and may affect 25% to 50% of patients (2-4). Acute kidney injury carries significant costs (4) and is independently associated with increased morbidity and mortality (2,3). Even minimal increments in plasma creatinine are associated with an increase in mortality (5,6).

Multiple causes of cardiopulmonary bypass-associated acute kidney injury have been proposed, including ischemia-reperfusion, generation of reactive oxygen species, hemolysis and activation of inflammatory pathways (7-10). COMT LL genotype appears to increase the risk of vasodilatory shock and AKI after cardiac surgery. To date, no simple, safe and effective intervention to prevent cardiopulmonary bypass-associated acute kidney injury in a broad patient population has been found (11-14).

Urinary acidity may enhance the generation and toxicity of reactive oxygen species induced by cardiopulmonary bypass (10,15). Activation of complement during cardiac surgery (16) may also participate in kidney injury. Urinary alkalinization may protect from kidney injury induced by oxidant substances, iron-mediated free radical pathways, complement activation and tubular hemoglobin cast formation (9,17,18). Of note, increasing urinary pH - in combination with N-acetylcysteine (19,20) or without (21) - has recently been reported to attenuate acute kidney injury in patients undergoing contrast-media infusion.

In a pilot double-blind, randomized controlled trial the investigators found sodium bicarbonate to be efficacious, safe, inexpensive and easy to administer. These findings now need to be confirmed or refuted by further clinical investigations in other geographic and institutional settings.

Accordingly, the investigators hypothesized that urinary alkalinization might protect kidney function in patients at increased risk of acute kidney injury undergoing cardiopulmonary bypass needs to be confirmed in an international multicenter, double-blind, randomized controlled trial of intravenous sodium bicarbonate.

Study Overview

• Status: Terminated
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass
• Intervention / Treatment: Drug: Sodium Chloride; Drug: Sodium Bicarbonate

Detailed Description

Renal impairment following cardiopulmonary bypass is common. While most of these patients do not require either short or long term renal replacement, the mortality of patients with acute renal failure is substantially greater than those who do not develop renal dysfunction.

In a pilot double-blind, randomized controlled trial we found sodium bicarbonate to be efficacious, safe, inexpensive and easy to administer. These findings now need to be confirmed or refuted by further clinical investigations in other geographic and institutional settings.

There is evidence that sodium bicarbonate affects the cardiovascular, respiratory and immune systems and may be of benefit to patients undergoing cardiac surgery.

Study Design - overview and rationale Patients will be randomised to receive sodium bicarbonate from the induction of anaesthesia until 24 hours postoperatively, or a placebo (sodium chloride).

Serum creatinine is the most commonly used clinical indicator of renal function along with urine output. Both will be measured for several days postoperatively - the time period during which renal impairment is most likely to develop.

Randomisation The randomisation will be based on random numbers generated by computer. Once consent is obtained, the allocation of either treatment with sodium bicarbonate or placebo will be organised by an independent person (clinical trials pharmacist) who will dispense the coded and blinded infusion bags (shrink-wrapped in extra black plastic bags). This will be delivered to the anaesthetic staff looking after the patient in theatre, and the ICU nurse caring for the patient postoperatively.

20 ml samples of heparinised blood and urine will be taken from the arterial line or urine catheter. Samples will be taken immediately after the preoperative insertion of the arterial/urine catheter, at 6, 24, 48, 72, 96 and 120 hours after commencement of cardiopulmonary bypass. Immediately following collection, the preoperative, 6 and 24 hour blood and urine will be centrifuged at low speed to separate the plasma from the cellular components. Urine and plasma and full-blood (for COMT polymorphism) will be stored in aliquots (where necessary) at -70 degrees prior to batch analysis.

The following variables will be obtained:

Code for patient, gender and age. Date and time of admission to ICU Operative procedure and date and time on and off cardiopulmonary bypass Preoperative assessment of left ventricular function, Comorbidities, Pre-, intra- and post-operative medication, Markers of renal function and COMT polymorphism as described above, Doses of frusemide administered (or rate of frusemide infusion) Use of inotropes or vasopressors Cardiac output whenever measured for clinical purposes in the first 24 hours postoperatively Requirement of renal replacement therapy Urine output in each 6 hour period during the presence of urine catheter Acid base status and electrolytes at baseline, 6 and 24 hours after commencement of cardiopulmonary bypass, Time of intubation and extubation, Date and time of arrival on and discharge from ICU and hospital, death Resources required The principle of the study has been discussed with the involved cardiac anaesthetists, cardiac surgeons, intensivists and intensive care nurses, who have offered their co-operation. ICU research nurse to allocate patients and collect clinical data. Pharmacy will be required to prepare drug and placebo infusion bags. Clinical pathology will be required to perform 24 hour creatinine clearance estimation (in addition to those tests clinically indicated) Protocol violations All protocol violations will be recorded. It will then be decided whether the nature of such violation had been such that the patient should be excluded from primary data analysis. Such evaluation will be blinded to treatment.

Withdrawal The treating clinician will have the right to withdraw the patient from the study if he or she believes that continued participation is jeopardising the patient's well being.

Ethical Issues sodium bicarbonate used in this study is considered to be very safe as has been demonstrated by its widespread clinical use in the management of critically ill patients with metabolic acidosis. We consider the potential benefit of this treatment theoretically significant. Given the balance of benefits and risks, we consider it ethical to proceed and seek informed consent.

Indemnity This is an investigator-initiated study and, accordingly, no commercial sponsor's indemnity has been provided.

Informed consent will be obtained from the patient prior to the operation by one of the investigators or the ICU research nurse. The clinical care of a patient who does not consent for any reason will not be affected.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3084
      • Austin Health
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
• Germany
  • Berlin, Germany, 13353
    • Charité University Medicine
• Ireland
  • Dublin, Ireland
    • University Clinic Dublin, School of Medicine and Medical Science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cardiac surgical patients in whom the use of cardiopulmonary bypass was planned and:
• Written informed consent of patient
• Age >18 years

• And having at least one ore more of the following risk factors for postoperative AKI:

  • Age =/>70 years
  • Preoperative plasma creatinine >120 µmol/L New York Heart Association class III / IV or LVEF <35%
  • Insulin dependent diabetes mellitus
  • Valve surgery (with or without coronary artery bypass graft)
  • Redo cardiac surgery

Exclusion Criteria:

• Cardiac surgical patients will not be considered eligible if:
• An emergency operation is indicated (within 24 hours after hospital admission or on intra-aortic balloon pump) or
• Pregnancy is confirmed or breastfeeding is present or
• A renal allograft is present or
• Preoperative acute renal failure within 6 weeks (acute rise in serum creatinine >50% from baseline) is present or
• Pre-operative end stage renal disease (serum creatinine >300 µmol/L) is present or
• Chronic moderate to high dose corticosteroid therapy (>10 mg/d prednisone or equivalent) is present

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; sodium chloride at 0.5 mmol/kg loading pre-induction and then at 0.2 mmol/kg/hr over 24 hours after induction until the next day	Drug: Sodium Chloride; In all patients body weight adjusted dose of study medication will be achieved by infusion of sodium chloride at a dose of 0.5 mmol/kg body weight (=bolus) diluted in 250 mL over 1 hour immediately after the induction of anesthesia, prior to the first surgical incision followed by continuous intravenous infusion of 0.2 mmol/kg/hr (=maintenance) diluted in 1000 mL 23 hours (total dose of 5 mmol/kg over 24 hours).; Other Names: hyeprtonic sodium chloride
Experimental: 1; The active intervention is loading (05. mmol/kg) pre-surgery and continuous infusion of bicarbonate at 0.2 mmol/kg/hr for 24 hours after induction	Drug: Sodium Bicarbonate; In all patients body weight adjusted dose of study medication will be achieved by infusion of sodium bicarbonate at a dose of 0.5 mmol/kg body weight (=bolus) diluted in 250 mL over 1 hour immediately after the induction of anesthesia, prior to the first surgical incision followed by continuous intravenous infusion of 0.2 mmol/kg/hr (=maintenance) diluted in 1000 mL 23 hours (total dose of 5 mmol/kg over 24 hours).; Other Names: Hypertonic bicarbonate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients developing an increase in serum creatinine > 25% or >44µmicromol/L from baseline to peak level after adjustment for relevant baseline characteristics	within first two-five postoperative days.

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients developing an increase in serum creatinine greater than 50% from baseline to peak level after adjustment for relevant baseline characteristics	within first two-five postoperative days
Proportion of patients developing an increase in serum creatinine greater than 100% from baseline to peak level after adjustment for relevant baseline characteristics	within first two-five postoperative days
Change in serum creatinine from baseline to peak level after adjustment for relevant baseline characteristics	within first two-five postoperative days
Proportion of patients developing any of the RIFLE criteria: R, I or F after adjustment for relevant baseline characteristics	within first five postoperative days
Proportion of patients developing any of the AKI stages: 1, 2 or 3 (using network definition)after adjustment for relevant baseline characteristics	within 48 hours postoperatively
Change in serum urea from baseline to peak	within first two-five postoperative days
Change in NGAL from baseline to peak	within first 24 postoperatively
Change in electrolyte status from baseline to peak	within first 24-48hrs postoperatively
Requirement of renal replacement therapy	within first postoperative days
Length of ventilation	from commencement to end of intubation
Length of stay in Intensive care	from admission to discharge from Intensive care
Length of stay in hospital	from admission to discharge from hospital
Hospital-Mortality	during hospital stay
90-day mortality	during 90 days postoperatively
COMT polymorphism	sampling at induction of anesthesia

Collaborators and Investigators

• Sponsor: Austin Health
• Investigators: Study Chair: Rinaldo Bellomo, MD, FRACP, Austin Health, Melbourne, Australia; Principal Investigator: Michael Haase, MD, Charité-University Medicine (Berlin, Germany); Principal Investigator: Sean M Bagshaw, MD, University of Alberta, Edmonton, Canada; Principal Investigator: Patrick Murray, MD, University Clinic Dublin, Dublin, Ireland

Publications and helpful links

General Publications

• Elitok S, Kuppe H, Devarajan P, Bellomo R, Isermann B, Westphal S, Kube J, Albert C, Ernst M, Kropf S, Haase-Fielitz A, Haase M. Urinary Neutrophil Gelatinase-Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial. Anesth Analg. 2021 Dec 1;133(6):1510-1519. doi: 10.1213/ANE.0000000000005741.
• Elitok S, Devarajan P, Bellomo R, Isermann B, Haase M, Haase-Fielitz A. NGAL/hepcidin-25 ratio and AKI subtypes in patients following cardiac surgery: a prospective observational study. J Nephrol. 2022 Mar;35(2):597-605. doi: 10.1007/s40620-021-01063-5. Epub 2021 May 24.
• Haase M, Haase-Fielitz A, Plass M, Kuppe H, Hetzer R, Hannon C, Murray PT, Bailey MJ, Bellomo R, Bagshaw SM. Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial. PLoS Med. 2013;10(4):e1001426. doi: 10.1371/journal.pmed.1001426. Epub 2013 Apr 16.
• Haase-Fielitz A, Plass M, Kuppe H, Hetzer R, Ostland V, Westphal S, Hoffmann J, Prowle J, Mertens PR, Westerman M, Bellomo R, Haase M. Low preoperative hepcidin concentration as a risk factor for mortality after cardiac surgery: a pilot study. J Thorac Cardiovasc Surg. 2013 May;145(5):1380-6. doi: 10.1016/j.jtcvs.2012.09.003. Epub 2012 Oct 9.
• Haase-Fielitz A, Mertens PR, Plass M, Kuppe H, Hetzer R, Westerman M, Ostland V, Prowle JR, Bellomo R, Haase M. Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study. Crit Care. 2011 Aug 4;15(4):R186. doi: 10.1186/cc10339.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: May 1, 2008
• First Submitted That Met QC Criteria: May 1, 2008
• First Posted (Estimate): May 6, 2008

Study Record Updates

• Last Update Posted (Estimate): August 1, 2012
• Last Update Submitted That Met QC Criteria: July 31, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Oxidative stress; Cardiac surgery; Cardiopulmonary bypass; Sodium bicarbonate; Acute renal dysfunction
• Other Study ID Numbers: EudraCT 2007-002223-32