Context Contrast-induced nephropathy remains a common complication of radiographic
procedures. Pretreatment with sodium bicarbonate is more protective than sodium
chloride in animal models of acute ischemic renal failure. Acute renal failure
from both ischemia and contrast are postulated to occur from free-radical
injury. However, no studies in humans or animals have evaluated the efficacy
of sodium bicarbonate for prophylaxis against contrast-induced nephropathy.
Objective To examine the efficacy of sodium bicarbonate compared with sodium chloride
for preventive hydration before and after radiographic contrast.
Design, Setting, and Patients A prospective, single-center, randomized trial conducted from September
16, 2002, to June 17, 2003, of 119 patients with stable serum creatinine levels
of at least 1.1 mg/dL (≥97.2 µmol/L) who were randomized to receive
a 154-mEq/L infusion of either sodium chloride (n = 59) or sodium bicarbonate
(n = 60) before and after iopamidol administration (370 mg iodine/mL). Serum
creatinine levels were measured at baseline and 1 and 2 days after contrast.
Interventions Patients received 154 mEq/L of either sodium chloride or sodium bicarbonate,
as a bolus of 3 mL/kg per hour for 1 hour before iopamidol contrast, followed
by an infusion of 1 mL/kg per hour for 6 hours after the procedure.
Main Outcome Measure Contrast-induced nephropathy, defined as an increase of 25% or more
in serum creatinine within 2 days of contrast.
Results There were no significant group differences in age, sex, incidence of
diabetes mellitus, ethnicity, or contrast volume. Baseline serum creatinine
was slightly higher but not statistically different in patients receiving
sodium bicarbonate treatment (mean [SD], 1.71 [0.42] mg/dL [151.2 {37.1} µmol/L]
for sodium chloride and 1.89 [0.69] mg/dL [167.1 {61.0} µmol/L] for
sodium bicarbonate; P = .09). The primary end point
of contrast-induced nephropathy occurred in 8 patients (13.6%) infused with
sodium chloride but in only 1 (1.7%) of those receiving sodium bicarbonate(mean
difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; P = .02). A follow-up registry of 191 consecutive patients receiving
prophylactic sodium bicarbonate and meeting the same inclusion criteria as
the study resulted in 3 cases of contrast-induced nephropathy (1.6%; 95% CI,
0%-3.4%).
Conclusion Hydration with sodium bicarbonate before contrast exposure is more effective
than hydration with sodium chloride for prophylaxis of contrast-induced renal
failure.
The increasing number of diagnostic procedures requiring radiographic
contrast has triggered a parallel increase in the incidence of contrast-induced
nephropathy, which accounts for more than 10% of hospital-acquired renal failure
and is a leading cause of acute renal failure.1,2 Compromise
of renal function increases morbidity, mortality, length of hospitalization,
and acceleration toward end-stage renal disease.2
Previous strategies to prevent contrast-induced renal failure have been
largely unsuccessful.3-6 Reported
benefit of the free radical scavenger N-acetylcysteine7-12 supports
the hypothesis that contrast-induced renal failure is caused by free-radical
generation.13-15 Use
of the iso-osmolar contrast agent iodixanol16 and
hemofiltration before and after contrast injection17 have
been recently described to reduce renal failure following contrast but are
expensive strategies that tax the financial resources of health care systems.
All protocols to prevent contrast-induced nephropathy include the infusion
of sodium chloride.1-11,16-18 However,
in prophylactic hydration, it is possible that the most efficacious anion
for sodium is not chloride but bicarbonate. Free-radical formation is promoted
by an acidic environment typical of tubular urine19 but
is inhibited by the higher pH of normal extracellular fluid.20,21 Because
free radicals are postulated to mediate contrast-induced nephropathy,13-15 alkalinizing renal
tubular fluid with bicarbonate22 may reduce
injury. Pretreatment with sodium bicarbonate is more protective than sodium
chloride in animal models of acute renal failure from ischemia23,24 or
doxorubicin.25 However, to our knowledge no
studies in humans have evaluated the efficacy of sodium bicarbonate vs sodium
chloride for prophylaxis against contrast-induced nephropathy. We examined
the hypothesis that the bicarbonate anion results in better outcomes than
the chloride anion in hydration fluids administered before and after exposure
to radiographic contrast.
This single-center, randomized controlled trial compared infusion of
sodium chloride vs sodium bicarbonate as the hydration fluid to prevent renal
failure in patients with stable renal insufficiency undergoing diagnostic
or interventional procedures requiring radiographic contrast. A subsequent
registry was established to additionally test the hypothesis that patients
receiving sodium bicarbonate treatment experience a low incidence of contrast-induced
renal failure. 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) were considered for enrollment. Eligible patients included
individuals aged 18 years or older with stable serum creatinine levels of
at least 1.1 mg/dL (≥97.2 µmol/L) who were scheduled to undergo cardiac
catheterization, computed tomography, diagnostic or therapeutic arteriography,
or transjugular intrahepatic portal systemic shunt placement. Exclusion criteria
included serum creatinine levels of more than 8 mg/dL (>707 µmol/L),
change in serum creatinine levels of at least 0.5 mg/dL (≥44.2 µmol/L)
during the previous 24 hours, preexisting dialysis, multiple myeloma, pulmonary
edema, uncontrolled hypertension (treated systolic blood pressure >160 mm
Hg or diastolic blood pressure >100 mm Hg), emergency catheterization, recent
exposure to radiographic contrast within 2 days of the study, allergy to radiographic
contrast, pregnancy, and administration of dopamine, mannitol, fenoldopam,
or N-acetylcysteine during the intended time of the
study.
The study was reviewed and approved by the institutional review board
of the Carolinas Health Care System. All patients gave written informed consent
for participation in the randomization trial or the subsequent registry phase.
Patients were identified as study candidates based on preliminary laboratory
test results and referral from the physician scheduled to perform the contrast
study. Qualified patients who agreed to enter the study were sequentially
assigned to 1 of 2 treatment groups by the pharmacy based on a computer-generated
randomization schedule. Patients allocated to the sodium chloride group received
154 mEq/L of sodium chloride in 5% dextrose and H2O. Patients allocated
to the sodium bicarbonate group received 154 mEq/L of sodium bicarbonate in
dextrose and H2O, mixed in the hospital pharmacy 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 precontrast fluid was administered. The initial intravenous
bolus was 3 mL/kg per hour for 1 hour immediately before radiocontrast injection.
Following this, patients received 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 were
limited to those doses administered to a patient weighing 110 kg. Diuretics
were routinely held on the day of contrast injection. A basic metabolic panel
of serum chemistries was obtained on the morning of the procedure and on postprocedure
days 1 and 2, and until any increase of serum creatinine resolved. Urinary
pH was measured after infusion of the bolus when the patient next spontaneously
voided. No diuretics were administered after a patient received contrast.
This study was partially but not completely blinded. The primary end
point, serum creatinine level, was determined in a fully blinded fashion by
laboratory personnel who measured serum creatinine by autoanalyzer without
knowledge of patient study groups. Patients were not told to which group they
were randomized. Although the investigators theoretically could have determined
the results of randomization by inspection of solutions infused, their direct
contact with patients consisted solely of obtaining informed consent before
randomization.
Data Collection and Management
Clinical data were prospectively collected by 3 investigators (G.J.M,
W.P.B, L.V.G.), coded, and entered into a computerized database. An independent
physician data and safety monitoring board periodically assessed safety throughout
the study. The clinical management of the patient was the responsibility of
the attending physician.
Study End Points and Statistical Analysis
The primary outcome measure was development of contrast-induced nephropathy,
defined by an increase in serum creatinine of 25% or more within 2 days after
administration of the radiographic contrast. This definition is identical
to that used in a recent large meta-analysis in contrast-induced nephropathy.12 Postcontrast creatinine was assessed the mornings
of days 1 and 2. The highest serum creatinine on postcontrast days 1 or 2
was used to calculate the change in serum creatinine (the primary end point),
the estimated glomerular filtration rate (a secondary end point) by using
the Modification of Diet in Renal Disease Study group formula,26 and
incidence of contrast-induced nephropathy.
Before beginning the study, the institution's biostatistician (H.J.N.)
estimated the sample size needed for the primary end point of contrast-induced
nephropathy, assuming development of contrast-induced renal failure in 15%
of the sodium chloride group and 5% of the sodium bicarbonate group. χ2 Analysis indicated that a sample size of 260 patients would be required
to detect a statistically significant difference with a power of 80% (α
= .05).
Tests for significance were conducted using the t test for continuous variables and χ2 test or Fisher
exact test for categorical variables. All analyses were conducted using SAS
software version 8.2 (SAS Institute Inc, Cary, NC). Data are expressed as
mean (SD). All tests are 2-tailed, with differences reported as significant
if P<.05. The study analysis was modified intention
to treat and did not include protocol violators. Ten patients (5 per group)
who did not return for follow-up laboratory tests were excluded. Inclusion
of their baseline data in the analysis as last-observation-carried-forward
was not informative and did not affect the results.
Midway through accumulation of the planned number of study patients,
the safety monitor, who was not a study investigator and was blinded to the
intervention groups, asked for an interim analysis to ensure that the sodium
bicarbonatetreatment group was experiencing an incidence of contrast-induced
nephropathy no worse than that of the control group hydrated with sodium chloride.
Although there were no prospectively established stopping rules, the study
was halted after a review of the data because of ethical concern about continuing
to expose the control group to the substantially higher risk of contrast nephropathy
associated with sodium chloride hydration. Subsequent eligible patients were
treated with the sodium bicarbonate prophylaxis and asked to enroll in a registry.
The registry comprised all patients who met the same inclusion criteria
as the study. Outcomes were collected in the same way as the randomized trial.
To simplify the sodium bicarbonate preparation for registry patients, the
sodium bicarbonate solution was prepared by adding 3 ampules (150 mEq) of
sodium bicarbonate to 1 L of 5% dextrose in H2O, yielding a 130-mEq/L
concentration of sodium bicarbonate and 4.35% dextrose. To obtain the same
sodium bicarbonate load as those patients in the randomized phase, these registry
patients received a 3.5-mL/kg initial bolus for 1 hour immediately before
contrast injection, followed by an infusion of 1.18 mL/kg per hour thereafter
for 6 hours.
Between September 16, 2002, and June 17, 2003, 137 patients were randomized
to receive sodium bicarbonate (n = 69) or sodium chloride (n = 68), with 119
patients completing the study (Figure 1).
A total of 18 patients did not complete the study. Five outpatient study patients
in each group neglected to follow instructions to return for follow-up laboratory
studies but had good urine output at discharge. Although measurements of serum
creatinine are not available for these individuals, none are known to have
developed clinical renal failure following contrast exposure. Eight patients
were protocol violations: 5 were not candidates because serum creatinine values
were too low (≤1.0 mg/dL [≤88.4 µmol/L]) on the morning of the
procedure, 2 had received another prophylactic agent (dopamine or N-acetylcysteine), and 1 was identified before contrast injection as
having an increasing serum creatinine level from bladder outlet obstruction.
One patient's prophylaxis regimen was arbitrarily changed by the attending
physician from sodium chloride to sodium bicarbonate but this patient was
included in the sodium chloride group analysis based on the intention-to-treat
principle.
Characteristics of the 119 patients completing the study are shown in Table 1. There were no statistically significant
differences between the groups in age, sex, ethnicity, incidence of diabetes
mellitus, or weight. Cardiac catherization was the most frequent radiocontrast
procedure in this study (Figure 1).
Treatment groups did not differ significantly by mean volume of contrast administered
or in volumes of contrast received by individuals in either treatment group
undergoing cardiac catheterization, computed tomography, or other miscellaneous
procedures (Table 2). The mean
baseline serum creatinine was slightly but not statistically higher (P = .09) and the glomerular filtration rate lower in patients
receiving sodium bicarbonate treatment compared with those patients receiving
sodium chloride. More patients with severe renal insufficiency (serum creatinine,
≥2.5 mg/dL [≥221 µmol/L]) were randomized to receive sodium bicarbonate
(n = 8) than sodium chloride (n = 2) (Figure
2). Because elevated serum creatinine is an important risk factor
for development of contrast-induced nephropathy,1,2 our
nonstratified randomization procedure could have biased the study outcome
against patients receiving sodium bicarbonate.
Postcontrast data for serum creatinine levels increased for those patients
receiving sodium chloride but decreased slightly for patients receiving sodium
bicarbonate. Despite a higher mean baseline serum creatinine and a higher
number of individuals with a baseline creatinine level of at least 2.5 mg/dL
(≥221 µmol/L), the group receiving sodium bicarbonate treatment incurred
only a 1.7% (1 of 60) incidence of contrast-induced nephropathy compared with
13.6% (8 of 59) in patients who received sodium chloride (mean difference,
11.9%; 95% confidence interval [CI], 2.6%-21.2%; P =
.02) (Table 2). Post hoc analysis
revealed that the percentage change in glomerular filtration rate after contrast
(Figure 3) was significantly improved
in patients receiving sodium bicarbonate treatment (+8.5%) compared with those
receiving sodium chloride (–0.1%) (mean difference, –8.6%; 95%
CI, −17.0% to −0.2%; P = .02). When results
were analyzed by another common definition of contrast nephropathy, at least
0.5 mg/dL (≥44.2 µmol/L) change in serum creatinine, 7 (11.9%) of
59 patients who were treated with sodium chloride developed contrast nephropathy
vs only 1 (1.7%) of 60 who received sodium bicarbonate (mean difference, 10.2%;
95% CI, 1.3%-19.1%; P = .03). The absolute risk reduction
of contrast-induced nephropathy (defined as ≥25% change in serum creatinine),
using sodium bicarbonate compared with sodium chloride was 11.9%, resulting
in a number needed to treat of 8.4 patients to prevent 1 case of renal failure.
All cases of contrast-induced nephropathy occurred in patients undergoing
cardiac catheterization (8 [17%] of 48 patients who were treated with sodium
chloride and 1 [2%] of 49 patients who were treated with sodium bicarbonate).
When patients undergoing cardiac catheterization were analyzed independently,
the benefit of sodium bicarbonate treatment was even larger (incidence of
contrast-induced nephropathy, 16.7% for sodium chloride vs 2.0% for sodium
bicarbonate; mean difference, 14.7%; 95% CI, 3.4%-25.9%; P = .02). All individuals with contrast-induced nephropathy experienced
prolonged hospitalization as a consequence of this complication but none required
dialysis. Of the 9 randomized patients who experienced contrast-induced nephropathy,
the mean (SD) baseline serum creatinine was 1.66 (0.56) mg/dL (146.7 [49.5]
µmol/L) among the 8 patients receiving sodium chloride and 2.1 mg/dL
(185.6 µmol/L) in the single patient treated with sodium bicarbonate.
In the cases of contrast-induced nephropathy, the 8 patients who received
sodium chloride had a mean (SD) contrast volume of 151 (50) mL (range, 100-250),
not statistically different from the overall sodium chloride cohort. The only
patient in the sodium bicarbonate treatment group who developed contrast-induced
nephropathy received only 65 mL of contrast but experienced 24 hours of profound
hypotension associated with an acute myocardial infarction. After restoration
of this patient's hemodynamic stability, the serum creatinine level returned
to the baseline of 2.1 mg/dL (185.6 µmol/L) 4 days after contrast.
In each group, bolus administration of hydration fluid caused a moderate
increase in both systolic and diastolic blood pressures that was not significantly
different between groups (Table 2).
The medical records of all patients who had a serum creatinine level increase
of 25% or more were reviewed in detail. Other than the single patient in the
sodium bicarbonate treatment group who developed contrast-induced nephropathy,
no other patient was found to have an alternative explanation for deterioration
of serum creatinine. No patient developed clinical heart failure or respiratory
distress. One patient in the sodium bicarbonate treatment group had a blood
pressure increase of more than 30 mm Hg with the administration of the bolus.
The fluid bolus administration was discontinued and diuretic therapy was administered
before proceeding with contrast injection. Following diuretics and contrast,
the infusion was continued and the patient did not develop contrast-induced
nephropathy.
Urine pH measurements after the initial bolus of fluid confirmed that
patients receiving sodium bicarbonate experienced urinary alkalinization (Table 2). A small but significant increase
in serum bicarbonate occurred in patients receiving sodium bicarbonate. There
was a small nonsignificant decrease in serum potassium in the sodium bicarbonate
group, indicating that the alkaline load from sodium bicarbonate did not induce
a decrease in serum potassium sufficient to create a risk for disturbances
of cardiac rhythm.
When randomization was discontinued, all subsequent patients meeting
the original inclusion criteria were treated with sodium bicarbonate and asked
to enroll in the registry until February 8, 2004. The demographic data of
these 191 patients were not statistically different from either of the randomized
groups. The mean (SD) serum creatinine level of registry patients was 1.79
(0.62) mg/dL (158.2 [54.8] µmol/L). The mean (SD) percentage change
in serum creatinine was 0% (13.5%) and the mean (SD) percentage change in
estimated glomerular filtration rate was + 2.5% (16.9%). Contrast-induced
nephropathy occurred in 3 (1.6%) of 191 patients (95% CI, 0%-3.4%).
In this study, we showed that replacing chloride ion with bicarbonate
as the anion in sodium-containing hydration fluids significantly reduced nephropathy
following radiographic contrast injection. In a recent meta-analysis, the
incidence of contrast-induced nephropathy ranged from 2% to 26% in patients
receiving N-acetylcysteine plus sodium chloride and
11% to 45% in those patients administered sodium chloride hydration alone.12 The cumulative incidence of contrast-induced nephropathy
in our patients in the sodium bicarbonate treatment group (1.7% in randomized
patients and 1.6% in the subsequent registry) is equal to or less than the
lowest rate of injury reported with N-acetylcysteine12 and is far less than the published experience in
patients hydrated with sodium chloride.1-11,16-18These
studies were performed with so-called nonionic low osmotic contrast agents
of approximately 600 to 900 mOsm/L, similar to that of the iopamidol used
in our study (796 mOsm/L). The subsequent data registry further confirms that
preprocedure intravenous administration of sodium bicarbonate reduces renal
injury from radiographic contrast. We envision that sodium bicarbonate could
also be combined with other agents such as N-acetylcysteine,
which alone does not always prevent contrast nephropathy.27-30
The apparent success of sodium bicarbonate in reducing contrast-induced
nephropathy is not likely the result of better volume expansion from sodium
bicarbonate31,32 but is consistent
with the hypothesis that contrast injury is from free radicals13-15 generated
within the acid environment of the renal medulla. Contrast-induced nephropathy
appears to be caused by the hyperosmolar nature of most contrast agents.1,3,16 Hyperosmolar stress
triggers prompt cellular generation of reactive oxygen species.33,34 Effects
from hyperosmolar stress might be compounded in the renal medulla, which is
normally deficient in oxygen, with a PaO2 of 10 to 20 mm Hg.35 Radiocontrast causes vasoconstriction,13,14,36 a
decrease in renal blood flow, and a further increase in medullary hypoxia37 that is exacerbated by the already compromised renal
circulation in diabetes mellitus or preexisting kidney damage,35 or
by nonsteroidal anti-inflammatory agents, which block normal prostaglandin
enhancement of medullary blood flow.37,38 Paradoxically,
decreased tissue oxygen tension promotes mitochondrial generation of reactive
oxygen species.39,40 Oxidant stress
could also be magnified by the enhanced neutrophil adherence and emigration
that is stimulated by local hypoxia.41 Thus,
local conditions in the renal medulla after contrast favor oxidant injury,
a hypothesis supported by the abrupt increase of malondialdehyde in renal
venous plasma immediately following contrast-induced vasoconstriction and
the reduction in experimental contrast-induced nephropathy by superoxide dismutase
or allopurinol.13-15 The
superoxide (O2-)–driven Haber-Weiss reaction,
Fe3+ + O2−→ Fe2+ +
O2
Fe2+ + H2O2→ Fe3+ + ⋅OH + OH−
accounts for free-radical production in many oxidant-mediated human
diseases.20 The reaction is catalyzed by minute
amounts of iron in the biologic environment and is most active at acid pH
(pKa = 4.9). However, at neutral pH, uncomplexed ferric ions precipitate as
insoluble ferric hydroxides,21 reducing the
production of injurious hydroxyl (.OH) radicals.20 By
increasing medullary pH, bicarbonate might protect from oxidant injury by
slowing Haber-Weiss radical production. Also, superoxide generated by ischemia
might react with medullary nitric oxide to form the potent oxidant peroxynitrite.42 At physiologic concentrations, bicarbonate scavenges
peroxynitrite and other reactive species generated from nitric oxide.43 Thus, several oxidant mechanisms of renal injury
might be disrupted by sodium bicarbonate.
The potential effect of sodium bicarbonate on these events is not surprising
in light of pH conditions within the nephron. Near the end of the proximal
tubule in the medulla, as a consequence of active reabsorption, the tubular
bicarbonate concentration has declined to about 6 mEq/L, and the tubular fluid
pH is approximately 6.5.19 In the descending
Loop of Henle, water and chloride are passively reabsorbed,19 and
urine pH increases to about 7.4 at the tip of the papilla, which is spared
from contrast nephropathy,35 suggesting that
higher pH is protective. In fact, patients with enhanced urinary acid excretion
from high aldosterone (eg, dehydration, congestive heart failure, nephrotic
syndrome, and cirrhosis) have increased risk of contrast-induced nephropathy.3 The beneficial effect of higher proximal tubular pH
is supported by a report that acetazolamide, which blocks proximal tubular
bicarbonate reabsorption, is protective in a rat model of contrast-induced
renal failure.44
A recent study advocated hemofiltration before and after contrast to
prevent contrast-induced renal failure from coronary angiography.17 All dialysis procedures are alkalinizing and as reported,
this study left open the question of whether its major benefit was from the
increased clearance conferred by this invasive and expensive procedure or
by the infusion of alkalinizing replacement solution.
Our study has several limitations. The results are from a single institution,
sample sizes are small although adequately powered, and dropouts occurred
in both study groups from outpatient participants who failed to return for
postcontrast measurement of serum creatinine. Also, the study was terminated
early when significant differences were found between groups, because of ethical
concern about continuing to expose control patients to the substantially higher
risk of contrast nephropathy associated with sodium chloride hydration alone.
Nevertheless, the results suggest that hydration with sodium bicarbonateis
efficacious and practical, requiring pretreatment only an hour before contrast
injection. Although confirmation in a larger multi-institution study would
be appropriate, infusion of sodium bicarbonatemay provide an inexpensive,
safe, practical, and simple method for preventing contrast-induced renal failure.
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