A 68-year-old diabetic woman hospitalized for non-ST-segment elevation myocardial infarction develops increasing chest pain despite maximal appropriate medical therapy and is referred for urgent coronary angiography. She is normotensive, weighs 60 kg, and is without signs of congestive heart failure on examination. The serum creatinine is 1.6 mg/dL (her baseline). What is her risk for contrast media-induced nephropathy (CIN)? What measures can be undertaken to reduce her risk?
Radiocontrast agents are well-recognized nephrotoxins that can cause a usually reversible, non-oliguric form of renal failure within 24 hours and up to five days following administration. Contrast nephropathy is associated with longer hospital stays and higher mortality. The incidence varies widely according to patient characteristics and the type and quantity of contrast agent used.
The pathogenesis of CIN is not completely understood, but likely represents a combination of contrast-mediated renal vasoconstriction, oxidative damage, and direct cytotoxic effects. Newer low-osmolar or iso-osmolar contrast agents are associated with lower rates of CIN than high-osmolar contrast agents. Multiple pharmacologic strategies for CIN prevention have been investigated, with several important trials published in the past two years. This review summarizes the risk assessment and prophylactic strategies required for optimal protection of patients from CIN.
Assesment of Patient Risk
Contrast-induced nephropathy is defined variably in clinical trials, most commonly as a 25% increase in serum creatinine above baseline at 48 hours after contrast administration. The most important risk factor for CIN is pre-existing kidney disease—more specifically, a diminished glomerular filtration rate (GFR) below 60 mL/minute/1.73 m2 body surface area.1 The serum creatinine concentration can be misleading. Advancing age, female gender, low lean body mass, or unstable rising creatinine all can lead to overestimation of the GFR. The Modification of Diet in Renal Disease (MDRD) estimate of GFR and the Cockcroft-Gault estimate of creatinine clearance are calculated in a basic formula. (see Table 1, left)
Several other factors have been linked to increased risk for CIN. Table 2 (left) summarizes these risk factors and assigns them various point scores. In general, patients with chronic kidney disease or any of these risk factors should have a serum creatinine drawn before the contrast study to clarify their CIN risk and facilitate decisions regarding prophylaxis. Patients with a score of six or more are at substantial risk for CIN.1
Strategy for Prophylaxis
Low-osmolar and iso-osmolar contrast agents have been associated with lower rates of CIN compared to high-osmolar contrast. However, the referring hospitalist rarely determines the type and volume of contrast used. Fortunately, high-osmolar contrast is used infrequently today. The primary strategy for CIN prophylaxis is to:
1) Determine CIN risk using a validated tool (see Table 2).
2) If “at risk,” consider alternate diagnostic modalities that do not involve the intravenous administration of iodinated contrast. Consider delaying testing with contrast agents until potentially reversible conditions affecting GFR are addressed, such as volume depletion, recent contrast use, or concomitant use of nonsteroidal anti-inflammatory drugs or angiotensin-converting enzyme inhibitors.
3) Provide pharmacologic and intravenous fluid prophylaxis as described below.
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.
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
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).
The sodium bicarbonate regimen was the same as that reported by Merten in 2004—namely, 154 mEq/L of sodium bicarbonate in 5% dextrose solution, given at 3 mL/kg/hr for one hour before contrast administration and 1 mL/kg/hr for six hours afterward. The saline regimen (154 mEq/L) was the same as that reported by Mueller in 2002—1 mL/kg/hr for 12 hours before contrast administration and 12 hours afterward. All patients received NAC at a dose of 1,200 mg twice daily the day before and the day of contrast administration. It is not possible to conclude from this trial whether sodium bicarbonate without NAC would have been as effective as the regimen studied. Ascorbic acid was included in this trial as another antioxidant to compare with NAC. The three other RCTs published in 2007 are summarized in Table 3 (see p. 21).11,12,13
Recently, two large RCTs of saline versus bicarbonate concluded there was no difference between the two.14,15 These trials were the largest to date, each of them single center and unblinded, and using slightly different methods than the REMEDIAL trial. CIN also was defined more broadly as a 0.5mg/dL or 25% change in creatinine within five days after contrast. Follow-up was only 88% in one trial. Nevertheless, these two new trials reach quite different conclusions than those before. Table 3 (see p. 21) summarizes seven RCTs of saline versus bicarbonate in the prevention of CIN. Differences in design and methods, definitions of CIN, completeness of follow-up, and severity of renal dysfunction among patients studied, make direct comparisons among these trials difficult. But as five of the seven RCTs of saline versus bicarbonate have concluded that bicarbonate is superior, and none have concluded saline is superior, this author recommends that at the present time intravenous sodium bicarbonate be used according to the Merten protocol when providing IVF for the prevention of CIN.
Back to the Case
The patient in the vignette has an estimated GFR of about 32 mL/min by the MDRD equation. With this level of renal dysfunction, the presence of diabetes mellitus, mellitus and assuming at least a 100 cc contrast bolus with the angiography, her risk for CIN is about 14% (eight points on the Mehran scale illustrated in Table 21). Alternatives to coronary angiography are limited in this example, and pharmacologic and IVF measures to prevent CIN are indicated. Borrowing from the regimen used in the REMEDIAL trial, she should ideally receive NAC 1200 mg orally BID for two days, starting one day prior to the procedure (in this case, would begin as soon as the risk for CIN is appreciated and continue for four doses). More importantly, she should receive sodium bicarbonate 154mEq/L at a rate of 3 mL/kg/hr one hour prior to contrast and 1 mL/kg/hr during and for six hours following the contrast procedure.
Contrast nephropathy risk varies inversely with GFR and can be estimated according to a validated tool. Patients at risk for CIN should be identified early and offered NAC and sodium bicarbonate, if there are no alternatives to administering intravenous contrast. Intravenous saline also is effective, but may not be as effective as bicarbonate. TH
Dr. Anderson is an assistant professor of medicine at the University of Colorado Denver and the associate chief, Medical Service, at the Denver VA Medical Center.
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