Cardiac Surgery and Cardiopulmonary Bypass Clinical Trial
Official title:
High-Dose N-Acetylcysteine in Cardiac Surgery Patients at High-Risk of Postoperative Renal Dysfunction.
At least 14% of 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. The investigators
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'.
Another well-known cause of oxidative stress is paracetamol (Panadol) overdose. In large
doses the oxidative stress caused by paracetamol damages cells in the liver, where it is
digested, and the kidney. N-acetylcysteine is a drug in common use for the treatment of
paracetamol overdose. Patients who would otherwise die of liver failure are routinely saved
by N-acetylcysteine, which acts as a strong anti-oxidant.
The investigators believe that N-acetylcysteine might similarly 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 N-acetylcysteine (in similar doses
to those used safely for paracetamol poisoning) to patients during, and for a day after
cardiac surgery, and compare the effects with patients who have not had N-acetylcysteine.
The drug, or a 5% glucose 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. The investigators will measure kidney function before and after the operation using
the standard tests which are performed for the purposes of clinical care of every patient.
Also, the investigators will do an extra test involving the collection of urine (from the
urinary catheter every patient has after cardiac surgery), which provides an even better
measure of kidney function. This is a potential benefit to the patient, as while this test
is not routinely performed, the results will be available to the doctors in the intensive
care unit. 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 is an insignificant amount of blood compared to that taken for other tests,
and would have no adverse effects. 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 the investigators will discover not only the effect of
N-acetylcysteine, but the mechanism of that effect.
N-acetylcysteine is routinely used to treat paracetamol overdose with few side effects. An
itchy skin rash is the only common side effect. Sometimes patients develop nausea and
vomiting, but the treatment for this is usually very effective, and the drug will be stopped
if it occurs. Rarely, as with all drugs, allergic reactions have been reported, but there
are no other reported adverse effects.
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. The itchy rash which occasionally
develops with N-acetylcysteine would occur under anaesthetic, and would almost certainly be
gone by the time the patient wakes up.
Informed consent will be obtained from the patient prior to the operation by one of the
investigators or the ICU research nurse.
Background
Renal impairment following cardiopulmonary bypass is common. 11.4% (1) to 42% (2) 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 (3). A similar study of total plasma
antioxidant status showed decreased levels up to 72 hours postoperatively(4). It is clear
that cardiopulmonary bypass causes oxidative stress and depletion of antioxidant capacity.
N-acetylcysteine is routinely used in the treatment of paracetamol overdose. Paracetamol is
metabolised by the liver by cytochrome p450 to form a toxic reactive oxygen compound. This
metabolite is normally detoxified by conjugation with hepatic reduced glutathione (GSH). In
overdose, the GSH stores are depleted, leading to liver cell necrosis through oxidative
damage. N-acetylcysteine is a sulfydryl group donor, which allows regeneration of GSH, thus
augmenting the antioxidant defence of the liver. Treatment of paracetamol overdose is
currently the only approved indication for N-acetylcysteine. Possible adverse reactions
include an urticarial rash, nausea and vomiting, and an anaphylactoid reaction (involving
hypotension, tachycardia, bronchospasm, and facial oedema). These reactions occur most
commonly either during, or at the end of, the period of the loading dose infusion, and may
be concentration related (5).
Oxidative stress can be produced experimentally using hypertonic glycerol. Intramuscular
injection of hypertonic glycerol in rats precipitated acute renal failure associated with a
marked decrease in renal reduced glutathione (GSH) levels. Pretreatment with
N-acetylcysteine largely prevented these changes (6). During reperfusion after renal
ischaemia in rats, renal blood flow was reduced compared to pre-ischaemic values. GFR was
also reduced, and plasma peroxynitrite (a marker of nitric oxide synthesis, a component of
oxidative stress) was increased. Pretreatment with N-acetylcysteine partially prevented
these changes (7). N-acetylcysteine (combined with a nitric oxide donor and an endothelin
converting enzyme inhibitor) also decreased the effect of renal ischaemia/reperfusion injury
in dogs, in terms of improved renal function as well as reduced interstitial
pro-inflammatory cytokines and inducible nitric oxide synthase (8).
Radiocontrast commonly causes renal dysfunction, in part through oxidative stress in the
kidney. While not an approved indication, intravenous N-acetylcysteine has been used
successfully to attenuate radiocontrast induced nephropathy, and was more effective than
standard intravenous fluid prophylaxis (relative risk 0.28) (9). While not an approved
product indication, N-acetylcysteine is currently used in our hospital for this purpose.
Infrarenal abdominal aortic aneurysm repair commonly causes ischaemia/reperfusion injury to
the kidney, producing a similar oxidative stress to that of radiocontrast. A mixture of
antioxidants including N-acetylcysteine given to patients undergoing infrarenal abdominal
aortic aneurysm repair produced a significantly better creatinine clearance (compared to
placebo controls) 48 hours postoperatively (10).
While never investigated for its effects on renal function after cardiac surgery, the effect
of perioperative N-acetylcysteine on other systems has been studied. The oxidative burst
response of neutrophils from patients undergoing cardiopulmonary bypass was significantly
attenuated by infusion of N-acetylcysteine into the bypass circuit (11).
A study of dogs undergoing cardiopulmonary bypass found preload-recruitable stroke work was
maintained at pre-bypass levels in those animals given N-acetylcysteine, whereas it fell in
control animals. N-acetylcysteine significantly enhanced myocardial oedema resolution, and
prevented the rise in plasma 8-isoprostane (a marker of oxidative stress) seen in control
animals (12). Similar results were found in a study of 40 patients undergoing cardiac
surgery: left ventricular biopsy specimens showed less 8-isoprostane content and less
nitrotyrosine (a marker of nitric oxide production; nitric oxide can act as an oxygen free
radical). There were no differences in haemodynamics or clinical outcomes noted, but
unfortunately indices of renal function were not examined in this study (13).
Ascorbate is an antioxidant which might be expected to have a similar action to
N-acetylcysteine. Supplemental ascorbate was given to 43 patients before, and for 5 days
after, coronary artery bypass surgery. Patients receiving ascorbate had a 16.3% incidence of
postoperative AF, compared to 34.9% in control subjects, perhaps by reducing oxidative
damage to the myocardium (14).
Pulmonary endothelium-dependent vasodilation is usually impaired after cardiopulmonary
bypass, a process thought to be related to reactive oxygen species. Pulmonary vasodilation
induced by acetylcholine following cardiopulmonary bypass was better maintained in 12
patients given a cocktail of antioxidants (including N-acetylcysteine) compared to that in
10 control patients (15).
There is thus evidence that in the immune, cardiovascular and respiratory systems,
N-acetylcysteine may be of benefit to patients undergoing cardiac surgery.
Clinical sepsis or experimental exposure to lipopolysaccharide stimulate cells of the
inflammatory system to form oxygen free radicals. N-acetylcysteine decreases cytokine and
adhesion molecule gene expression and NF-kB activation in vitro. In animal models of sepsis
N-acetylcysteine reduces inflammatory cell chemotaxis and improves survival (as reviewed by
ref. 16). In patients suffering oxidative stress due to sepsis, N-acetylcysteine results in
decreased NF-kB activation and decreased IL-8 production (16).
Hypotheses N-acetylcysteine administered from the time of induction of anaesthesia prior to
cardiac surgery and for 24 hours postoperatively results in decreased change in serum
creatinine from baseline to peak level within first 5 postoperative days.
Other secondary outcomes which will be measured include:
- better creatinine clearance over the first postoperative day;
- shorter ICU stay;
- shorter hospital stay;
- lower serum creatinine levels on day 2 post-op;
- greater plasma antioxidant activity;
- less oxidative stress;
- less NF-kB activation in the cellular components of blood;
- less pro-inflammatory cytokine response; and
- less activation of the nitric oxide synthase pathway.
Study Design - overview and rationale
Patients will be randomised to receive N-acetylcysteine from the induction of anaesthesia
until 24 hours postoperatively, or a placebo (5% glucose).
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, and will form the primary end point of the study. As patients in our
intensive care unit are routinely given frusemide to maintain a postoperative urine output
of >0.5ml/kg/hr (once fluid volume, inotropy and vascular tone have been manipulated into
what is judged to be acceptable ranges), the dose of frusemide required is also an indicator
of renal function. Rarely are other diuretics given, though where this is the case it will
also be noted.
The efficacy of N-acetylcysteine in preventing oxidative stress will be assessed using a
measure of total plasma antioxidant activity (the bathocuproine assay) (17) and by
quantification of the 8-isoprostane levels (18). Total antioxidant activity and
8-isoprostane have previously been shown to be affected by cardiac surgery and
N-acetylcysteine.
Any renal effect of N-acetylcysteine 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 (19, 20). Activation of inducible nitric oxide
production is also associated with renal failure (21), and the effect of N-acetylcysteine 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 by 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 (22) thought to be more sensitive than the
electrophoretic mobility shift assay used to demonstrate an effect of N-acetylcysteine in
human sepsis (16). 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 N-acetylcysteine 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, N-acetylcysteine will be administered in a dose of 150 mg/kg IV in 200 mL
5% glucose over 15 minutes followed by continuous IV infusion of 50 mg/kg in 500 mL 5%
glucose over 4 hours, then 100 mg/kg in 1 L 5% glucose over 20 hours (total dose 300 mg/kg
in 24 hours). This is the standard dose of N-acetylcysteine used clinically in paracetamol
overdose (5.) Patients randomised to receive placebo will receive an equivalent volume of 5%
glucose. The appearance of the 5% glucose and N-acetylcysteine 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. Creatinine clearance will be the primary endpoint of the study.
Clinical data will be recorded as detailed below by the investigators or the ICU research
nurse.
Four 20 ml samples of heparinised 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 and 24 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), and 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 a mean increase in serum creatinine from
baseline to a peak value of 50 micromol/L in the control group, with a standard deviation of
30 micromol/L. Given these changes, 60 patients are needed to have a 90% power of detecting
a 30 micromol/L 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:
Name gender, age, and medical record number 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, 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
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Prevention
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00334191 -
Sodium Bicarbonate in Cardiac Surgery
|
Phase 2 |