Clinical trial NCT00878956: Bicarbonate in Cardiac Surgery
Official title: A Phase IIb Multiple Blind Randomized Controlled Trial of Sodium Bicarbonate in Cardiac Surgery at High-risk of Acute Kidney Injury
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Kidney Injury
Keywords: Cardiac surgery
Cardiopulmonary bypass
Oxidative stress
Acute renal dysfunction
Sodium bicarbonate
Lead sponsor: Austin Health
Sponsor class: OTHER_GOV
First posted: 2009-04-09
Enrollment: 427
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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). 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.

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 will be stored in aliquots 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 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.

Eligibility criteria: Inclusion Criteria:

* Age above 70 years
* Pre-existing renal impairment (preoperative plasma creatinine concentration \> 1.4 mg/dL
* New York Heart Association class III/IV or impaired left ventricular function (left ventricular ejection fraction \< 50%)
* Valvular surgery or concomitant valvular and coronary artery bypass graft surgery
* Redo cardiac surgery
* Insulin-dependent diabetes mellitus

Exclusion Criteria:

* End stage renal disease (plasma creatinine concentration \> 3.4 mg/dL)
* Emergency cardiac surgery
* Planned off-pump cardiac surgery
* Known blood-borne infectious disease
* Chronic inflammatory disease on immunosuppression
* Chronic moderate to high dose corticosteroid therapy (\> 10 mg/d prednisone or equivalent)
* Enrolled in conflicting research study
* Age \< 18 years

Primary outcomes:
measure: Proportion of patients developing an increase in serum creatinine greater than 25% or 44 mmol/L (0.5 mg/dL) postoperative increase in serum creatinine after adjustment for relevant baseline variables
timeFrame: within first five postoperative days
Secondary outcomes:
measure: Mean changes in serum creatinine after adjustment for relevant baseline variables
timeFrame: within first five postoperative days
measure: mean changes in serum cystatin C after adjustment for relevant baseline variables
timeFrame: within first five postoperative days
measure: mean changes in urinary neutrophil gelatinase-associated lipocalin (NGAL)after adjustment for relevant baseline variables
timeFrame: within first five postoperative days
measure: Duration of ventilation
timeFrame: Until time of extubation from mechanical ventilation
measure: Proportion of patients developing any of the RIFLE criteria: R, I or F
timeFrame: within first five postoperative days
measure: Incidence of post-operative atrial fibrillation
timeFrame: within first five postoperative days
measure: Duration of stay in the intensive care unit (ICU)
timeFrame: from admission to the ICU
measure: Duration of stay in hospital
timeFrame: from admission to discharge from hospital
measure: 90-day mortality
timeFrame: during 90 days postoperatively
measure: Change in electrolyte status from baseline to peak
timeFrame: within first 24-48hrs postoperatively
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Warringal Private Hospital
state: Victoria
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
Study officials:
affiliation: Austin Hospital, Melbourne Australia
name: Rinaldo Bellomo, MD, FRACP
role: PRINCIPAL_INVESTIGATOR
affiliation: Waikato Hospital, Hamilton, New Zealand
name: Frank van Haren, MD
role: STUDY_CHAIR
affiliation: Auckland City Hospital
name: Shay McGuinness, MB ChB, FRCA, FANZCA
role: STUDY_CHAIR
References: