3) Provide pharmacologic and intravenous fluid prophylaxis as described below.
Pharmacologic Prophylaxis
Multiple agents have been investigated in the prevention of CIN: mannitol, furosemide, theophylline, fenoldopam, dopamine, N-acetylcysteine, and others. The most effective noteworthy of these is N-acetylcysteine (NAC). The first major trial of NAC for CIN prevention was published in 2000.2 Since then, more than two dozen studies, mostly randomized controlled trials (RCTs), and nearly a dozen meta-analyses have been published, with inconsistent results.
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Of particular note, systematic reviews and meta-analyses have reached differing conclusions on the overall efficacy of NAC in the prevention of CIN. One recent study including NAC trials published before June 2006 concluded there has been “significant publication bias throughout the life cycle of this clinical question … further amplified by meta-analyses.”3 It has been estimated a single trial enrolling 1,800 patients (about 10 times larger than most completed trials) would be needed to definitively answer this question.4 The latest meta-analysis includes at least one large RCT of NAC not included in prior meta-analyses and concludes that NAC is effective in the prevention of CIN.5 The pooled relative risk for CIN was 0.62 (95% C.I. 0.44-0.88). These investigators concluded there was no significant publication bias.
Taken together, the primary literature and secondary meta-analyses suggest that NAC is probably effective in the prevention of CIN, although there may be some publication bias. Practically speaking, NAC is essentially without side effects, and the likelihood that it affords some degree of protection suggests it should be used routinely, unless or until larger studies demonstrate otherwise. A NAC dose of 1,200 mg twice daily beginning the day prior and continuing through the day of contrast administration was part of the successful protocol published by Brigouri, et al., in 2007.
Intravenous Crystalloids Trials
A landmark trial published in 1994 showed half-normal saline in 5% dextrose given 12 hours before and 12 hours after administering a radiocontrast agent was superior to half-normal saline plus mannitol or half-normal saline plus furosemide in preventing CIN.6 This regimen remained the standard of care until 2002, when a large RCT compared half- normal saline in 5% dextrose to isotonic normal saline in 1,620 patients undergoing coronary angioplasty.7 About 20% of the patients had underlying renal dysfunction and about 15% were diabetic. The rate of CIN decreased from 2% (14/698) to 0.7% (5/685), a modest-but-statistically-significant difference. After this study, practice generally shifted to using normal saline at 1 mL/kg/hr 12 hours before and 12 hours after contrast procedures. One notable review article published in 2006 concluded that isotonic saline was the best-proven strategy for the prevention of CIN.8
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How does intravenous sodium chloride reduce the rate of CIN? The mechanism is unclear, but it may work simply by treating subclinical states of volume depletion. But as free radical oxidation has been implicated in the pathophysiology of CIN, investigators hypothesized that alkalinizing the urine (reducing free radical formation) with isotonic sodium bicarbonate might better protect patients from CIN than saline. In 2004, the first trial demonstrating the efficacy of bicarbonate was stopped early after the rate of CIN had decreased from 13.6% (8/59) in the saline arm to 1.7% (1/60) in the bicarbonate arm.9 The editorial accompanying this small trial cautioned “prospective confirmation should be required before accepting new therapies into routine clinical practice.”
In 2007, four prospective trials comparing various hydration regimens were published; each concluding that bicarbonate is superior to saline. The largest of these studies was the REMEDIAL trial.10 Patients were referred for coronary angiography and had a baseline serum creatinine of 2.0 mg/dl or higher or an estimated GFR below 40 mL/minute/1.73 m2 (or both). In double-blind fashion, patients were randomized to one of three preventative strategies: normal saline plus NAC (n=111), sodium bicarbonate plus NAC (n=108), or normal saline plus NAC plus ascorbic acid (n=107). The primary endpoint was defined as a 25% or higher increase in serum creatinine at 48 hours. This occurred in 9.9% (11/111) of the normal saline plus NAC group, 1.9% (2/108) of the sodium bicarbonate plus NAC group, and 10.3% (11/107) of the normal saline plus NAC plus ascorbic acid group (p=0.019 for sodium bicarbonate plus NAC versus normal saline plus NAC).