Therapy Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial.
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Summary
Posted By:	Gordon S. Doig
E-Mail:	Gordon.Doig@EvidenceBased.net
Posted Date:	22 July 2005
Title:	Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial.
Authors:	Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Van Moore A, Simonton CA 3rd, Rittase RA, Norton HJ, Kennedy TP.
Reference:	JAMA. 2004 May 19;291(19):2328-34.
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	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 (> or =97.2 micromol/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] micromol/L] for sodium chloride and 1.89 [0.69] mg/dL [167.1 [61.0] micromol/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.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Allocation concealment was probably maintained. Patients were randomised 'by pharmacy' after ascertainment of eligibility.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	No. Follow-up was not complete and an intention to treat analysis was not presented. 137 patients were randomised into the trial. There was true loss to follow-up on 10 patients (5 from each group). These patients did not return for subsequent blood tests post contrast. This is an unavoidable form of true loss to follow-up. An additional 8 patients (4 from each group) were excluded from the primary analysis based on 'protocol violations'. These 8 patients should have been included in an intention to treat analysis.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes.
3. Were patients, health workers, and study personnel blind to treatment?
	Patients were not told which treatment they were receiving. It is unclear whether the healthcare team could determine treatment group by observing the study fluid.
4. Were the groups similar at the start of the trial?
	No. At baseline the bicarb group had a higher serum creatinine and lower GFR. Although it is implied that these two imbalances could have biased the results against bicarb, multivariate analysis was not provided. It may be possible that patients with a higher baseline creatinine are less likely to increase by 25% than patients with a lower creatinine. A lower absolute increase is required in the patients with lower creatinine in order to meet the critera of contrast induced nephropathy. Patients in the bicarb group (higher baseline creatinine) are reported as having an overall decrease in creatinine post contrast. It is possible that this is due to 'regression towards the mean'.
5. Aside from the experimental intervention, were the groups treated equally?
	Unsure. A table of other treatments received during the study period was not presented.
What are the Results?
1. How large was the treatment effect?
	This study was terminated early due to an interim analysis. The authors explicitly state that they did not contemplate formal stopping rules prior to this interim analysis. It is widely accepted that trials that are terminated early, without formal stopping rules, can over-estimate treatment effects Lancet. 2005 May 7-13;365(9471):1657-61. Given this caveat, the authors report a significant decrease in 'contrast induced nephropathy' from 13.6% in the saline group to 1.7% in the bicarb group (p=0.017, Fisher's Exact test).
2. How precise was the estimate of the treatment effect?
	The 95% confidence interval for the reduction ranges from 2.6% to 21.2%.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	Unsure. Because this trial was stopped early, without a priori stopping rules, it is highly likely that any treatment effect is over estimated. In addition, an intention to treat analysis was not conducted. 5.8% (8/137) of randomised patients were excluded from an ITT analysis due to 'protocol violations'. It is possible that these exclusions also result in a biased estimate of treatment effect.
2. Were all clinically important outcomes considered?
	No. In this paper, contrast induced nephropathy (CIN) was defined as a 25% increase in creatinine from baseline. Follow-up was limited to 2 days post contrast. We are unsure how often CIN leads to consequences that are meaningful to the patient (EX. need for dialysis, increased LoS, etc.). A longer term follow-up, recording clinically meaningful outcomes is needed.
3. Are the likely treatment benefits worth the potential harms and costs?
	This trial is too small to establish the true incidence of any potential harms. No downstream costs were established.
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