Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00334191 |
| Other study ID # |
H2005/02249 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
June 5, 2006 |
| Last updated |
July 6, 2009 |
| Start date |
June 2006 |
| Est. completion date |
June 2006 |
Study information
| Verified date |
July 2009 |
| Source |
Austin Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Australia: Department of Health and Ageing Therapeutic Goods Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Many patients develop kidney failure after cardiac surgery. Although this kidney failure can
usually be treated effectively, a longer stay in intensive care is often required. While
many patients suffer no long term ill effects after developing post-operative kidney
failure, some require long term kidney dialysis. We also know that patients who develop
post-operative kidney failure are much more likely to die before they leave hospital.
Why some people develop kidney failure after cardiac surgery is not known. However, doctors
suspect that the process of cardiopulmonary bypass (where the functions of the heart and
lungs are taken over by a machine during the operation, to allow the surgeon to operate)
overactivates some of the same mechanisms the body uses to defend itself against severe
infection.
Many of the cell changes by which severe infection causes kidney failure also occur after
cardiopulmonary bypass. One of the main overactive defence mechanisms is the release of
highly toxic compounds derived from oxygen - a process called 'oxidative stress'.
The investigators believe that sodium bicarbonate might reduce the oxidative stress, which
occurs during cardiac surgery, and so prevent or decrease the kidney failure, which occurs
in many patients.
The investigators hope to give sodium bicarbonate (in similar doses to those used safely for
treatment of acidosis) to patients during, and for 24 hours after cardiac surgery, and to
compare the effects with patients who have not had sodium bicarbonate. The drug, or a
placebo, will be given through the drip, which is present in all cardiac surgery patients.
Whether a particular patient receives the drug or placebo will be decided at random, and
neither the patient nor the investigators will know which has been given. We will measure
kidney function before and after the operation using the standard blood tests.
The investigators will also take four 20ml samples of blood, spaced before, during, and
after the operation, from the arterial catheter routinely inserted in every patient. This
blood would be used to measure oxidative stress, and also some of the proteins inside the
blood cells, which are responsible for creating the toxic oxygen compounds. In this way we
will discover not only the effect of sodium bicarbonate, but also the mechanism of that
effect.
Sodium bicarbonate is commonly used to treat metabolic acidosis in severe renal disease,
circulatory insufficiency due to shock or severe dehydration and has been shown to be an
effective drug in preventing contrast-induced nephropathy.
Sodium bicarbonate is considered to be safe in the setting of intensive care treatment and
is often used in the treatment of patients with metabolic acidosis without any discernible
adverse clinical effects.
This is a pilot study. If the drug proves effective in this context, further studies on a
larger scale would be required to justify its general use.
There will be no extra risk to a patient who participates in the study, and no discomfort
other than that normally associated with cardiac surgery.
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.
Description:
Renal impairment following cardiopulmonary bypass is common. 11.4% to 42% of patients with
previously normal renal function show a postoperative rise in serum creatinine. 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 dysfunction1.
Cardiopulmonary bypass activates components of the non-specific immune system, which leads
to the generation of compounds containing oxygen free radicals. A study of 14 patients
undergoing cardiac surgery found increased levels of serum lipid peroxidation products
(thiobarbituric acid reactive substances) within 15 minutes of the commencement of
cardiopulmonary bypass, which returned to preoperative levels by the following morning. The
total serum antioxidative capacity was correspondingly decreased intraoperatively, and
remained decreased at 24 hours postoperatively. A similar study of total plasma antioxidant
status showed decreased levels up to 72 hours postoperatively. It is clear that
cardiopulmonary bypass causes oxidative stress and depletion of antioxidant capacity.
N-Nitrosation of oxygenated nitric oxide (NO.) solutions was previously shown to be
significantly inhibited by the strong scavenging ability of NaBic presumably by anion
scavenging of nitrosating agents. At physiologic concentrations, NaBic scavenges
peroxynitrite and reactive oxygen species generated from nitric oxide. This may contribute
to a reduction in the deleterious effects of NO generating agents. NaBic is therefore a
potential regulator of NO-induced toxicity. NaBic is considered to be safe in the setting of
intensive care treatment and is often used in the treatment of patients with metabolic
acidosis without any discernible adverse clinical effects. NaBic increases the pH-level by
buffering of hydrogen ions, which can cause electrolyte balance shifts, e.g. Potassium will
be shifted increasingly intracellular. Frequent control of pH and potassium levels is
required to prevent alkalosis and hypokalemia. These adverse effects are uncommon or
typically only biochemical in nature.
Oxidative stress can be produced experimentally using hypertonic glycerol. Intramuscular
injection of hypertonic glycerol in rats precipitates acute renal failure associated with a
marked decrease in renal reduced levels of antioxidative agents. Pre-treatment with NaBic is
more protective than sodium chloride in animal models of acute renal failure secondary to
ischaemia or doxorubicin.
Radio-contrast dye commonly causes renal dysfunction, in part through oxidative stress in
the kidney. While not an approved indication, intravenous sodium bicarbonate has been used
successfully to attenuate radiocontrast-induced nephropathy, and was more effective than
standard intravenous fluid prophylaxis. Hydration with NaBic before contrast exposure is
more effective than hydration with sodium chloride for prophylaxis of contrast-induced renal
failure. By increasing medullary pH in the kidneys, NaBic might protect from oxygen injury
by slowing pH-dependent radical production.
While never investigated for its effects on renal function after cardiac surgery, the effect
of perioperative sodium bicarbonate on other systems has been studied.
In a clinical trial with 15 infants who were mechanically ventilated during the immediate
postoperative period after corrective cardiac surgery sodium bicarbonate increased the
arterial pH, lowered the mean pulmonary arterial pressure and increased the cardiac index
resulting in a decrease in pulmonary vascular resistance. Infusion of sodium bicarbonate
resulted in a significant improvement in skin microcirculatory perfusion in an observation
study with 15 patients undergoing cardiopulmonary bypass.
The negative effects of peroxynitrite causing oxidative stress after tyrosine nitration in
neurodegenerative disorders were strongly reduced in the presence of sodium bicarbonate in
in-vitro experiments.
There is thus evidence that sodium bicarbonate affects the cardiovascular, respiratory and
immune systems and may be of benefit to patients undergoing cardiac surgery.
Hypotheses Sodium bicarbonate administered from the time of induction of anaesthesia prior
to cardiac surgery and for 24 hours postoperatively results in a decreased change in renal
function measured as serum creatinine change greater than 25% from baseline to peak level
within first five postoperative days.
Secondary outcomes which will be measured include:
- change in serum creatinine greater than 50% from baseline to peak level
. creatinine clearance over the first postoperative day;
- length of ventilation;
- ICU stay;
- hospital stay;
- serum creatinine levels on day 2 post-op;
- plasma antioxidant activity;
- NF-kB activation in the cellular components of blood;
- pro-inflammatory cytokine response
- Activation of the nitric oxide synthase pathway
Study Design - overview and rationale
Patients will be randomised to receive sodium bicarbonate in 5% dextrose from the induction
of anaesthesia until 24 hours postoperatively, or a placebo (vehicle) (154mEq/L saline in 5%
dextrose solution).
Serum creatinine is the most commonly used clinical indicator of renal function along with
urine output. Both will be measured for 48 hours postoperatively - the time period during
which renal impairment is most likely to develop. A more sensitive indicator of renal
dysfunction is creatinine clearance. This will be measured over the first 24 hours
postoperatively.
The efficacy of sodium bicarbonate in preventing oxidative stress will be assessed using a
measure of total plasma antioxidant activity (the bathocuproine assay) and by quantification
of the 8-isoprostane levels.
Any renal effect of sodium bicarbonate will be correlated with levels of plasma
pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha), which are known to be associated with
oxidative-stress induced renal failure. Activation of inducible nitric oxide production is
also associated with renal failure, and the effect of sodium bicarbonate on nitric oxide
synthase mRNA expression in the cellular components of blood will be assayed by real-time
PCR. Nitric oxide production will be assessed by measurement of plasma nitrotyrosine
concentration. Assay of nitrotyrosine is superior to the traditional Greiss reaction (which
measures nitrate and nitrite derivatives of nitric oxide), as nitrate and nitrite undergo
renal excretion, and many of these patients will have altered renal function.
At a molecular level, many of the genes responsible for stimulating oxidative stress are
regulated by the promoter NF-kB. The cellular components of blood will be assayed for NF-kB
using an established ELISA technique. NF-kB in the cellular components of blood will also be
assayed using real-time PCR.
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
infusion bags. This will be delivered to the anaesthetic staff looking after the patient in
theatre, and the ICU nurse caring for the patient postoperatively.
Detailed protocol
Immediately following the induction of anaesthesia, prior to the first surgical incision,
Sodium Bicarbonate will be administered in a dose of 154mEq/L in 5% dextrose over 60 mins
(3mL/kg/h) followed by continuous IV infusion of 154mEq/L in 5% dextrose over 23 hours
(1mL/kg/h) or placebo (154mEq/L saline in 5% dextrose). Patients randomised to receive
placebo will receive an equivalent volume of dextrose. The appearance of the dextrose
solution and sodium bicarbonate solutions is similar, and there will be no marking on the
infusion bag other than an identifying study number.
A 24 hour urine collection will begin immediately on arrival in ICU, to allow determination
of creatinine clearance. This will be measured in the hospital clinical pathology
laboratory.
Clinical data will be recorded as detailed below by the investigators or the ICU research
nurse.
20 ml samples of heparinized blood will be taken from the arterial line for cytokine and
molecular analysis. Samples will be taken immediately after the induction of anaesthesia, on
arrival in the intensive care unit, and 6, 12 and 24 and 72 hours postoperatively.
Immediately following collection, the blood will be centrifuged at low speed to separate the
plasma from the cellular components, both of which will be stored in aliquots at -70 degrees
prior to batch analysis.
Analysis of plasma total antioxidant activity and 8-isoprostane, IL-1, IL-6, TNF-alpha and
nitrotyrosine concentrations will be performed using commercially available ELISA reagent
kits (Oxford Biomedical Research, Oxis Research, BioCore). The cellular components of blood
will be assayed for NF-kB concentration using a commercially available ELISA kit (Oxford
Biomedical Research), also for iNOS and NF-kB mRNAs using a real-time PCR machine and
Applied Biosystems pre-developed assay reagents with 18S as the endogenous control. The
principal investigator has experience of these or similar techniques.
Statistics and power calculation Using data available from our cardiac surgery database of
over 2500 patients in the last 5 years, we expect 50% of patients developing an increase in
serum creatinine greater than 25% from baseline to peak in the control group.
Given a minimal clinically important reduction of this proportion to 30% in the Sodium
Bicarbonate group, 100 patients are needed to have a 90% power of detecting a difference
between the control and the intervention group at an alpha of 0.05.
Data collection Data collection will be performed by the principal investigator, ICU
research nurse and ICU nursing staff.
The following variables will be obtained:
Code for patient, gender and age. Date of admission to ICU Operative procedure and time on
cardiopulmonary bypass Preoperative assessment of left ventricular function Serum creatinine
and urea preoperatively, immediately postoperatively, 12 and every 24 hours thereafter (as
measured for clinical purposes). Doses of frusemide administered (or rate of frusemide
infusion) Use of inotropes Cardiac output whenever measured for clinical purposes in the
first 24 hours postoperatively Urine output in each 6 hour period for the 24 hours
postoperatively Date of discharge from ICU and hospital or 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, the investigators
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.
