Acute Kidney Injury Clinical Trial
Official title:
A Phase IIb Multiple Blind Randomized Controlled Trial of Sodium Bicarbonate in Cardiac Surgery at High-risk of Acute Kidney Injury
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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