Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00353340 |
| Other study ID # |
70202 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
July 17, 2006 |
| Last updated |
February 24, 2010 |
| Start date |
January 2005 |
| Est. completion date |
May 2009 |
Study information
| Verified date |
February 2010 |
| Source |
Shaare Zedek Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel: Israeli Health Ministry Pharmaceutical Administration |
| Study type |
Interventional
|
Clinical Trial Summary
The objective of this study is to assess the efficacy of sodium bicarbonate compared with
sodium chloride and oral N-acetylcysteine (NAC ) pretreatment for prevention of contrast
nephropathy in patients with advanced renal disease undergoing cardiac catheterisation.
Description:
PROTOCOL
Prevention of Contrast Nephropathy by Sodium Bicarbonate Versus Sodium Chloride and
N-Acetylcysteine
Nephrology and Cardiology Services, Shaare Zedek Medical Center, Jerusalem
1. Background and rationale
The development of acute renal failure following cardiac catheterization has been
recognized since the 1970's. The syndrome of acute renal failure following cardiac
catheterization is presently felt to be due either to atheroembolic disease or what is
now referred to as contrast induced nephropathy. Since the clinical course of each is
different, it is now usually not difficult to diagnose acute contrast induced
nephropathy.
All protocols to prevent contrast nephropathy include the infusion of sodium chloride
with or without oral N-acetylcysteine (NAC) pretreatment, although several recent
meta-analyses raise some doubt about the efficacy of.
Review of Shaare Zedek Medical Center experience from 2000 thru 2003 demonstrated a
significant decrease in the incidence of acute contrast induced nephropathy after
cardiac catheterization following the introduction of routine NAC usage. This effect
was detected in a patients with mild renal insufficiency only (creatinine less than
1.5mg/dl). Patients with higher plasma creatinines did not appear to benefit from NAC
prophylaxis.
A recent study demonstrated that preventive hydration with sodium bicarbonate was more
effective than sodium chloride in patients undergoing radiographic procedures. However,
in that study, there was no subdivision of the patients by severity of their kidney
disease and it is not clear if sodium bicarbonate was as effective in patients with
more severe kidney disease as in those with milder renal impairment. In addition the
rate, duration and kind of fluids that were used for preventive hydration differed from
that currently recommended.
Because free radicals are postulated to mediate contrast induced nephropathy and their
formation is promoted by an acidic environment, alkalinizing renal tubular fluid with
bicarbonate may reduce renal injury by reducing free radial formation. NAC is also
known to be a free radical scavenger but since this compound was relatively ineffective
in preventing contrast nephropathy in our patients with moderate to severe renal
impairment (plasma creatinine > 1.5 mg%), we postulate that sodium bicarbonate may be
more effective in the prevention of contrast nephropathy in these high risk patients.
The proposed study is designed to test the efficacy of preventive hydration with sodium
bicarbonate versus sodium chloride and oral NAC pretreatment in patients with stable
advanced renal insufficiency (CKD stage 3 and 4-GFR 15-60ml/min/1.73m2 calculated by
MDRD formula) undergoing cardiac catheterization.
2. Study objectives
The objective of this study is to assess the efficacy of sodium bicarbonate compared
with sodium chloride and NACpretreatment for prevention of contrast nephropathy in
patients with advanced renal disease.
3. Outcome measure
The incidence of contrast induced nephropathy, defined as 25% or more increase in serum
creatinine within 2 days of contrast administration, will be assessed.
4. Study design
This is a prospective, randomized, single center trial. Patients due to undergo cardiac
catheterization either electively or following acute coronary syndromes will be
eligible for inclusion. Elective patients will be admitted the day before the
procedure. After baseline assessment and laboratory tests, they will be randomly
assigned to one of two groups. One group will receive 12 hours infusion of 154 meq/l
(0.9%) sodium chloride at a rate of 1ml/kg per hour before cardiac catheterization and
NAC 600mg x 2/d PO the day before and the day of the procedure.
The second group will receive 154meq/l sodium bicarbonate in 5% dextrose in water mixed
by the nursing staff by adding 154 ml of 1000 meq/l sodium bicarbonate to 846 ml of 5%
dextrose in water, slightly diluting the dextrose concentration to 4.23%.The initial IV
bolus will be 3 ml/kg for one hour before cardiac catheterization. Following this
bolus, patients will receive the same fluid at a rate of 1 ml/kg per hour during the
contrast exposure and for 6 hours after the procedure.
A basic panel of blood chemistries (Na, K, Cl, Ca, P, BUN, creatinine, total protein,
albumin, complete blood count, pH, HCO3, pCO2 and O2 sat) will be obtained before the
procedure and post-procedure day 1 and 2 and until any increase of serum creatinine is
resolved. GFR will be calculated by MDRD formula in all patients before cardiac
catheterization.
5. Patient selection
Patients will be identified as study candidates based on preliminary laboratory tests
results. They will referred from the clinics of Shaare Zedek, Kupot Cholim and the
inpatient services of Shaare Zedek Medical Center. Eligible patients include
individuals aged 18 year or older with GFR 15-60ml/min calculated by MDRD formula, who
were scheduled to undergo cardiac catheterization. During the randomized study,
consecutive eligible patients scheduled for exposure to the nonionic radiographic
contrast agent iopamidol (796 mOsm/kg H2O, 755 mg of iopamidol per milliliter, and 370
mg iodine per milliliter) will be considered for enrollment.
6. Exclusion criteria
i. Serum creatinine levels more than 8mg/dl or GFR less than 15ml/min
ii. Change in serum creatinine levels of ³0.5mg/dl during the previous 24 hours.
iii. Preexisting dialysis
iv. Multiple myeloma.
v. Pulmonary edema.
vi. Uncontrolled hypertension (treated systolic blood pressure more than 160 mmHg, or
diastolic blood pressure more than 100mmHg.)
vii. Emergency catheterization.
viii. Recent exposure to radiographic contrast (within two days of the study).
ix. Allergy to radiocontrast.
x. Pregnancy.
xi. Administration of dopamine, mannitol or NAC before the study.
7. Blinding
The study will be completely blinded. The serum creatinine level will be determined in
a fully blinded fashion by laboratory personnel. The investigators from the Nephrology
service will analyze the laboratory data without knowledge of patient study groups. The
patients will not know to which group they will be randomized. The investigators from
the Cardiology service will know the patient study groups, but will not analyze the
patients laboratory tests results.
8. Study Methods
Qualified patients who agree to enter the study will be assigned to 1 of 2 treatment
groups based on a computer-generated randomization schedule. Patients allocated to the
sodium chloride-NAC group will receive 154mEq/L of sodium chloride at a rate of 1ml/kg
per hour for 12 hours before cardiac catheterization and NAC 600mgx2/d PO the day
before and the day of the procedure. Patients allocated to the sodium bicarbonate group
will receive 154 mEq/L of sodium bicarbonate in dextrose and H2O, mixed by the Nursing
Service by adding 154 mL of 1000 mEq/L sodium bicarbonate to 846 mL of 5% dextrose in
H2O, slightly diluting the dextrose concentration to 4.23%.
After appropriate nursing evaluation and initial measurement of blood pressure and
weight, the pre-contrast fluid will be administered. Patients allocated to the sodium
chloride-NACgroup will receive 154 mEq/L of sodium chloride at a rate of 1ml/kg per
hour for 12 hours before cardiac catheterization and NAC 600mgx2/d PO the day before
and the day of the procedure The initial intravenous bolus in the NaHCO3 group will be
3 mL/kg per hour for 1 hour immediately before radiocontrast injection. Following this,
patients will receive the same fluid at a rate of 1 mL/kg per hour during the contrast
exposure and for 6 hours after the procedure. For patients weighing more than 110 kg,
the initial fluid bolus and drip will be limited to those doses administered to a
patient weighing 110 kg. Diuretics will be routinely withheld on the day of contrast
injection. A basic panel of blood chemistries (Na, K, Cl, Ca, P, BUN, creatinine, total
protein, albumin, complete blood count, serum pH, HCO3, pCO2 and O2 sat)) will be
obtained before the procedure and post-procedure days 1 and 2 and until any increase of
serum creatinine is resolved. GFR will be calculated by MDRD formula before the
procedure.
9. Study End Points and Statistical Analysis
The primary outcome measure is development of contrast-induced nephropathy, defined by
an increase in serum creatinine of 25% or more within 2 days after cardiac
catheterization. This definition is identical to that used in a recent large
meta-analysis in contrast-induced nephropathy. Post-contrast creatinine will be
assessed the mornings of days 1 and 2. The highest serum creatinine on post-contrast
days 1 or 2 will be used to calculate the change in serum creatinine (the primary end
point).
Before beginning the study, we estimated the sample size needed for the primary end
point of contrast-induced nephropathy. Based on our own and other previous data, we
assumed the development of contrast-induced renal failure in 15% of the sodium
chloride-NAC group and 5 % of the sodium bicarbonate group. Analysis indicated that a
sample size of 281 patients would be required to detect a statistically significant
difference with a power of 80% (two tailed p = 0.05).
Tests for significance will be conducted using the t test for continuous variables and
c2 or Fisher exact test for categorical variables. All analyses will be conducted using
SAS software version 8.2 (SAS Institute Inc, Cary, NC). Data will be expressed as mean
(SD). All tests will be 2-tailed, with differences reported as significant if p <0.05.
10. Feasibility of the study
The average number of cardiac catheterizations performed in Shaare Zedek Medical Center
is 25-30 procedures per week. A recent review of 30 consecutive cardiac catheterization
patients showed that 8 would be eligible for enrollment in this protocol. Thus, it
should take about 10-12 months to enroll the required number of patients.
11. Safety
The infusion of sodium bicarbonate and sodium chloride is safe. In the published sodium
bicarbonate study bolus administration of hydration fluids caused a moderate increase
in both systolic and diastolic blood pressure (mean 11mm Hg in the sodium chloride
group and 14 mmHg in the sodium bicarbonate group.) No patients developed clinical
heart failure or respiratory distress. Since the patients enrolled in our study should
have controlled hypertension (patients with blood pressure more than 160/100 will be
excluded) this mild elevation in blood pressure should not be problematic.
12. Study significance
Contrast induced nephropathy is a common complication of cardiac catheterizations.
Prophylactic hydration with sodium chloride and NAC which is currently in use is less
effective in patients with advanced renal disease and the observed incidence of acute
contrast induced nephropathy is approximately 15%. In addition the use of this regimen
requires preventive hospitalization and may be especially problematic in patients with
chronic kidney disease when they require urgent cardiac catheterization. If preventive
hydration with sodium bicarbonate is as effective or better than the currently used
saline-NAC regimen, the pretreatment time for cardiac catheterization could be significantly
shortened, hence permitting its usage before emergent procedure. Since emergent procedures
preclude the use of current relatively long pretreatment regimens, bicarbonate could reduce
the incidence of acute contrast induced nephropathy in this highly vulnerable group.
