Professor of Medicine
Department of Internal Medicine
Iodinated contrast media are among the most commonly prescribed medications in modern medicine with approximately 80 million doses administered in 2003 worldwide, corresponding to eight million litres.(1) The general indication for using iodinated contrast media is to create an X-ray attenuation differential in tissues in order to increase the visualisation of vessels or disease processes. Overall, the current generation of iodinated contrast media is very well tolerated. The major driving forces in the development of contrast media have been to eliminate systemic and central venous system toxicities.(1) Indeed, with the advent of nonionic, low-osmolarity contrast media in the 1980s, most adverse events are relatively mild and require no medical treatment.(1) Perhaps the most important remaining potential adverse effect is contrast-induced nephropathy (CIN).
Definition and pathophysiology
CIN is restricted to the intravenous or intra-arterial application of contrast media. In spite of the clinical importance of CIN, its pathophysiology is incompletely understood. Possible mechanisms underlying CIN include altered rheological properties, perturbation of renal haemodynamics, regional hypoxia and direct cytotoxic effects.(2) CIN is the third-leading cause of hospital- acquired acute renal failure, contributing not only to increased morbidity and mortality during hospitalisation, but also to higher overall costs of healthcare.(3-6) The risk factors for CIN are related to patient characteristics. These range from the severity of the underlying renal disease and cardiovascular performance to the characteristics of the procedure itself, and to the quantity of contrast agent administered. Most experts agree on the fact that there is currently insufficient evidence to conclude whether or not there is a difference among the various low-osmolar or iso-osmolar contrast media with regard to the development of CIN.(7)
CIN is most often defined as an increase in serum creatinine concentration of more than 0.5mg/dl (44mmol/l) or 25% above baseline within 48–72 hours after intravenous or intra-arterial contrast administration, when alternative explanations for renal impairment have been excluded.
Volume supplementation as a preventive measure
As CIN is caused by iatrogenic measures and no accepted therapy exists, effective prevention is of major importance. Volume supplementation remains the cornerstone for the prevention of CIN. It is safe, effective and inexpensive. Volume supplementation results in plasma volume expansion with concomitant suppression of the renin–angiotensin–aldosterone system, down-regulation of the tubuloglomerular feedback, dilution of the contrast media, prevention of renal cortical vasoconstriction and avoidance of tubular obstruction. The combination of intravenous and oral volume supplementation effectively prevents CIN in low- and moderate-risk patients. Recent evidence clearly demonstrates that normal saline (0.9%) should be used.(8,9) One study suggests that bicarbonate could even be of further value.(10)
Approximately 30 years ago it was documented that hypovolaemia accentuates the risk of CIN.(7) The incidence was higher in summer at a time when no special volume supplementation was performed and patients were not allowed to drink before excretory urograms in order to maximise the concentration of contrast media in the urinary tract. Observations comparing hydrated patients with historical controls provided the first evidence that a fluid load might prevent CIN. In 1994, these data were supported by a controlled study, primarily initiated to investigate the value of mannitol and furosemide administration.(11) In a randomised controlled trial including 78 patients with mild-to-moderate renal insufficiency, saline administration (0.45% saline over 24h starting 12h before administration of contrast media) alone was more effective than combinations of volume supplementation with mannitol or furosemide.(11)
Recently, three randomised studies specifically examined the effectiveness of volume supplementation. Trivedi and colleagues randomised 53 patients on the day before scheduled elective cardiac catherisation to one of two groups – group 1 (n=27) received normal saline for 24h (at a rate of 1ml/kg/h) beginning 12h prior to scheduled catheterisation, while group 2 (n=26) were allowed unrestricted oral fluids.(12)
Serum creatinine was measured at 24 and 48h, and postcardiac catheterisation was compared with the prerandomisation baseline value. The mean baseline calculated creatinine clearance was 80ml/min and the mean baseline creatinine was 106µmol/l. An increase in serum creatinine by at least 44.2µmol/l (0.5mg/dl), within 48h of contrast exposure, was considered to represent clinically significant acute renal failure. The incidence of acute renal failure was significantly lower in group 1 (one out of 27) as compared with group 2 (9 out of 26; p=0.005 for comparison between groups; relative risk 0.11, 95% confidence interval 0.02–0.79).
Bader and colleagues randomised 39 patients with normal renal function receiving at least 80ml of low-osmolarity contrast media during an angiographic procedure to one of the following volume supplementation regimens:(13)
- Group 1: volume expansion with 300ml saline during contrast media administration (n=20).
- Group 2: intravenous administration of at least 2,000ml saline within 12h before and after contrast media application (n=19).
Glomerular filtration rate (GFR) was measured by contrast media clearance (Renalyzer) at baseline and 48h after contrast media application. The primary endpoint was the mean change in GFR after 48h. Patients in group 1 showed a significantly higher decline in GFR (a difference in GFR of 35ml/min/1.73m(2)) compared with patients receiving the intravenous volume supplementation regimen (difference in GFR of 18ml/min/1.73m(2); p<0.05). A very similar observation was reported in a randomised trial performed to compare overnight (12h) volume expansion with half-normal saline with a 250ml bolus given on call to the catheter laboratory in patients with moderate renal insufficiency. Four of 37 patients (10.8%) in the bolus group versus none of 26 patients in the overnight group developed CIN.(14)
Therefore, the effectiveness of saline volume supplementation is now well documented by observational as well as randomised studies. Since saline is cheap and safe, these data suggest that volume supplementation with saline should be considered in all patients undergoing investigations involving the use of intravenous or intra-arterial contrast media. This is especially true for patients with pre-existing risk factors for the development of CIN.
Cardiac catheterisation and CIN
Until very recently, patients undergoing cardiac catheterisation were kept nil by mouth to avoid vomiting and nausea – which was common with high-osmolarity contrast agents – and to allow for tracheal intubation and emergency coronary artery bypass grafting in the case of coronary artery occlusion or rupture after percutaneous coronary intervention. Although the strategy to keep the patient in a fasting state was well founded, many patients and physicians erroneously considered a restriction in fluids parallel to the restriction in food. This misconception considerably impeded the widespread use of oral fluid replacement prior to the contrast procedure.
Given the advances in both contrast agents and percutaneous interventional techniques, most institutions currently allow a light meal several hours ahead of the cardiac catheterisation. This change in management should help the introduction of encouraged oral fluids prior to cardiac catheterisation and most indications for intravenous contrast application.
Patients undergoing percutaneous coronary intervention (PCI) are generally considered at high risk for CIN because they: have diffuse vascular disease; require catheter manipulation in the aorta as the guiding catheter needs to be advanced inside the arterial tree from the groin to the aorta; receive relatively high doses of contrast media. We therefore sought to estimate the incidence of CIN in patients receiving comprehensive intravenous and oral hydration for PCI during which iopromide (Ultravist 370, Schering) was used. We prospectively studied the development of CIN in 425 consecutive patients undergoing PCI applying comprehensive intravenous and oral hydration in all patients. Baseline renal function was assessed by calculating the GFR with the use of the abbreviated modification of diet in renal disease study equation. CIN was defined as an increase in serum creatinine of at least 0.5mg/dl (44µmol/l) within 48h. During PCI, 226±80ml of iopromide were used. With the comprehensive hydration strategy used, CIN developed in only six of 425 (1.4%; 95% confidence interval 0.5–3.1) patients. No patient required dialysis.(15) Therefore, applying the combination of appropriate volume supplementation and contemporary low-osmolar contrast agents results in a very low incidence of CIN following PCI.
- Katzberg RW, et al. Contrast-induced nephrotoxicity: clinical landscape. Kidney Int 2006;69:S3-S7.
- Persson PB, et al. Contrast medium-induced nephrotoxicity: the pathophysiology. Kidney Int 2006;69:S8-S10.
- Levy EM, et al. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-94.
- McCullough PA, et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997;103:368-5.
- Gruberg L, et al. The prognostic implications of further renal function deterioration within 48 hours of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000;36:1542-8.
- Rihal CS, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259-64.
- Solomon R, et al. Selection of contrast media. Kidney Int 2006;69:S39-S45.
- Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney Int 2006; 69:S16–S19.
- Mueller C, et al. Prevention of contrast media-associated nephropathy:randomized comparison of two hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:329-336.
- Merten GJ, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate. A randomized controlled trial. JAMA 2004;291:2328-34.
- Solomon R, et al. Effects of saline,mannitol, and furosemide on acute decrease in renal function induced by radiocontrast agents. N Engl J Med 1994;331:1416-20.
- Trivedi HS, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephropathy. Nephron Clin Pract 2003;93:c29-c34.
- Bader BD, et al. What is the best hydration regimen to prevent contrast media-induced nephrotoxicity? Clin Nephrol 2004;62:1-7.
- Holt S. Radiocontrast media-induced renal injury–saline is effective in prevention. Nephron Clin Pract 2003;93:c5-c6.
- Mueller C, et al. Incidence of contrast nephropathy in patients receiving comprehensive intravenous and oral hydration. Swiss Med Wkly 2005;135:286-90.