Sodium Bicarbonate in Cardiac Surgery Study

NCT00672334 | Terminated Phase 2 DMC

• 1 other identifier: EudraCT 2007-002223-32
• Study Type: interventional
• Target: 350
• Locations: 4 countries
• Sites: 4

Brief Summary

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.

Conditions

Cardiac Surgery; Cardiopulmonary Bypass

Keywords

Cardiac surgery; Cardiopulmonary bypass; Oxidative stress; Acute renal dysfunction; Sodium bicarbonate

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• 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

Study Arms (2)

2

PLACEBO COMPARATOR

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

1

EXPERIMENTAL

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

Interventions

Sodium Bicarbonate DRUG

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).

Also known as: Hypertonic bicarbonate

1

Sodium Chloride DRUG

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).

Also known as: hyeprtonic sodium chloride

2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Austin Health: lead

Study Sites (4)

Austin Health

Melbourne, Victoria, 3084, Australia

Location

University of Alberta

Edmonton, Alberta, T6G 2B7, Canada

Location

Charité University Medicine

Berlin, State of Berlin, 13353, Germany

Location

University Clinic Dublin, School of Medicine and Medical Science

Dublin, Dublin, Ireland

Location

Related Publications (5)

• 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.

  PMID: 34543256 DERIVED

• 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.

  PMID: 34028701 DERIVED

• 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.

  PMID: 23610561 DERIVED

• 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.

  PMID: 23062413 DERIVED

• 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.

  PMID: 21816077 DERIVED

MeSH Terms

Interventions

Sodium Bicarbonate; Sodium Chloride

Intervention Hierarchy (Ancestors)

Bicarbonates; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Inorganic Chemicals; Sodium Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds

Study Officials

• Rinaldo Bellomo, MD, FRACP

  Austin Health, Melbourne, Australia

  STUDY CHAIR

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of ICU research

Study Record Dates

• First Submitted: May 1, 2008
• First Posted: May 6, 2008
• Study Start: May 1, 2008
• Primary Completion: June 1, 2011
• Study Completion: January 1, 2012
• Last Updated: August 1, 2012

Record last verified: 2012-07

Locations

IE (1); DE (1); CA (1); AU (1)