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Perspective |
1 Department of Diagnostic Radiology, Copenhagen University Hospital at Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Received April 24, 2003;
accepted after revision July 2, 2003.
Address correspondence to H. S. Thomsen
(heth{at}herlevhosp.kbhamt.dk).
Introduction
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Several measures have been recommended to reduce the incidence of contrast medium–induced nephropathy [6]. They include volume expansion; hydration with IV administration of normal saline solution (NaCl, 0.9%) or a half-strength saline solution (NaCl, 0.45%); infusion of mannitol; administration of atrial natriuretic peptide, loop diuretics, calcium antagonists, theophylline, dopamine, dopamine-1 receptor antagonist fenoldopam, and acetylcysteine; use of low-osmolar nonionic contrast media instead of high-osmolar ionic contrast media; use of isoosmolar contrast media instead of low-osmolar contrast media; use of gadolinium-based contrast media instead of iodine-based contrast media for radiography and CT; hemodialysis soon after contrast administration; injection of a small volume of contrast medium; and avoiding short intervals (< 48 hr) between procedures requiring intravascular administration of contrast media.
Of all these measures, extracellular volume expansion and the use of low-osmolar contrast media have been found to be most systematically effective [3, 7, 8]. Patients with preexisting renal impairment or multiple myeloma [9] should receive adequate hydration before contrast medium administration. This can be achieved with the IV injection of 100 mL/hr of 0.9% saline solution starting 4 hr before contrast administration and continuing for 24 hr afterward [6]. In a hot climate, more fluid should be given. This regime is suitable for patients who are not in congestive heart failure and who are not allowed to drink or eat before undergoing an interventional or surgical procedure. If there is no contraindication to oral administration, free fluid intake should be encouraged. At least 500 mL of water or soft drinks orally before and 2,500 mL for 24 hr after contrast administration should be recommended (Appendix 1). This fluid intake should secure diuresis of at least 1 mL/min in a nondehydrated patient. In addition, the concurrent administration of nephrotoxic drugs such as gentamicin and nonsteroidal antiinflammatory drugs should be avoided.
The main factors in the pathophysiology are considered to be a reduction in renal perfusion caused by a direct effect of contrast media on the kidney and toxic effects on the tubular cells, although the latter effect is controversial [10]. Experimental studies have indicated that the endogenous vasoactive peptide endothelin may play an important role in mediating these events. Therefore, it was expected that endothelin antagonists [11] would reduce the incidence of contrast medium–induced nephropathy in man, but a clinical study has shown the opposite effect [12]: a nonselective endothelin receptor antagonist and IV hydration exacerbated contrast medium–induced nephropathy compared with hydration alone. A similar discrepancy has been reported with regard to atrial natriuretic peptide [13]. Calcium-channel antagonists and adenosine antagonists are also not advantageous. Dopamine protected against contrast-induced decrease in renal function in patients with baseline serum creatinine greater than 1.9 mg/dL (170 µmol/L) in one study [14], whereas in another study it conferred no additional benefit compared with saline solution alone in preventing contrast medium–induced nephropathy [15]; dopamine had a deleterious effect on recovery. In another study, the administration of 200 mg of theophylline was shown to have a preventive effect [16], but theophylline has side effects. Administration of the antioxidant acetylcysteine has also been shown both to be effective in preventing contrast medium–induced nephropathy in some studies [17–19] and to be without any effect in others [8, 20]. The dopamine-1 receptor antagonist fenoldopam has been shown to reduce the incidence of contrast medium–induced nephropathy in patients with baseline serum creatinine greater than 2.0 mg/dL (180 µmol/L) with or without diabetes mellitus who are undergoing percutaneous coronary intervention [21], whereas in a randomized trial it had no effect [8]. It is appropriate to conclude that the efficacy of these drugs in the prevention of contrast medium–induced nephropathy remains debatable. Further studies are required. However, the administration of frusemide and mannitol should be avoided [1, 6, 7].
A recent multicenter study included 129 patients who underwent angiography with either an isoosmolar dimer or a nonionic monomer after randomization; those patients had serum creatinine levels between 1.5 mg/dL (132 µmol/L) and 3.5 mg/dL (308 µmol/L) due to diabetes mellitus [22]. Contrast medium–induced nephropathy was seen in only 3% of the patients after the dimer and in 26% after the monomer. Chalmers and Jackson [23] found, in patients with nephropathy of various causes, a 25% increase in 4% and 10% of patients after an isoosmolar nonionic dimer or a low-osmolar nonionic monomer, respectively. Taking the history of contrast medium–induced nephropathy into account, we must await further studies before a definitive conclusion can be reached. There is reason to believe that future studies of the dimer iodixanol will provide conflicting data [24].
Prophylactic Hemodialysis
Hemodialysis and peritoneal dialysis safely remove both iodinated and
gadolinium-based contrast media
[25]. The effectiveness of
hemodialysis depends on many factors, including blood and dialysate flow rate;
permeability of dialysis membrane; duration of hemodialysis; and molecular
size, protein binding, hydrophilicity, and electric charge of the contrast
medium. Generally, several hemodialysis sessions are needed for removal of all
contrast medium, and at least 3 weeks are required for continuous ambulatory
peritoneal dialysis to remove the agent completely. The role of hemodialysis
in preventing contrast medium–induced nephropathy is not well defined.
The cost of hemodialysis and the associated risks, including venous
cannulation and the possibility of heparin-induced bleeding, could be
justified only if hemodialysis prevented contrast medium–induced
nephropathy.
Thirty patients with moderately reduced renal function (mean serum creatinine level, 2.5 ± 0.15 mg/dL [212 ± 14 µmol/L]) were randomly assigned to receive either hemodialysis for 3 hr starting as soon as possible or no hemodialysis after administration of a nonionic monomeric contrast medium [26]. All patients were well hydrated before and after examination by means of the IV infusion of a normal saline solution. The incidence of contrast medium–induced nephropathy in the hemodialysis group was 53% and in the control group was 40%. The poor efficacy of hemodialysis in preventing contrast medium–induced nephropathy is related to the rapid onset of renal injury after the administration of contrast medium [27]. One hundred thirteen patients with chronic renal impairment (serum creatinine > 2.5 mg/dL [200 µmol/L]) were randomly assigned to either hemodialysis or no hemodialysis after the injection of nonionic monomeric contrast media [28]. All patients received saline infusion according to the same protocol as the previous study. The hemodialysis began 30–280 min after the radiographic procedure. The incidence of contrast medium–induced nephropathy in the hemodialysis group was 24% and in the no-hemodialysis group was 16%. No significant difference was seen between the two groups in relation to clinically important events (stroke, pulmonary edema, myocardial infarction, and death). Hemodialysis may cause deterioration of renal function through activation of inflammatory reactions and the release of vasoactive substances that may induce acute hypotension. Thus, the strategy of performing hemodialysis immediately after the administration of contrast media in patients with reduced renal function does not diminish the rate of complications. Relating the time of the contrast medium injection to the dialysis schedule is unnecessary (Appendix 2).
Gadolinium-Containing Contrast Media Instead of Iodinated Contrast
Media for Radiography of Patients with Increased Risk of Contrast
Medium–Induced Nephropathy
Gadolinium-based contrast agents are known be safe and not nephrotoxic in
the usual MRI doses of up to 0.3 mmol/kg body weight. Therefore, it has been
suggested that gadolinium-based contrast media could be used in place of
iodinated agents for radiologic examinations in patients with significant
renal impairment [29]. At the
kilovoltage used for digital angiography, the attenuation of X-ray beams by
gadolinium is approximately the same as for iodine. At the kilovoltage used
for CT, the attenuation by gadolinium is approximately double that of iodine.
Therefore, in theory gadolinium could replace iodine as a radiographic
contrast agent. However, the dose requirement for a satisfactory diagnostic
study differs between MRI and radiography because different properties of
gadolinium are being used in the two techniques. The commonly used dose for
body CT is 150 mL of a 300 mg I/mL (2.38 mmol I/mL) solution. The standard
dose for contrast-enhanced MRI is 0.2 mL/kg of body weight of a 0.5 mmol/mL
gadolinium-based contrast agent. For body CT, a patient weighing 70 kg would
receive 120 mmol of the iodinated agent molecule and 360 mmol of iodine. For
MRI, this same 70-kg patient would receive 7 mmol of the gadolinium-based
agent molecule and 7 mmol of gadolinium
[29]. Thus, the number of
iodinated contrast agent molecules administered would be almost 17 times that
of gadolinium-containing molecules, and the number of iodine atoms
administered is 51 times that of gadolinium.
In a study involving 64 patients who underwent MRI with a gadolinium-based agent and a radiographic examination with an iodinated agent, the authors concluded that gadolinium chelates are significantly less nephrotoxic than iodinated agents [30]. Eleven of the 64 patients had a significant increase in serum creatinine level after IV or intraarterial administration of iodine-based contrast media, whereas none had increased serum creatinine levels after IV administration of a gadolinium-based contrast agent. However, the molar doses and concentrations of the iodine and gadolinium atoms were not comparable. Albrecht and Dawson [31] studied 15 patients receiving 0.3 mmol/kg of body weight of gadopentetate dimeglumine; five underwent abdominal CT, five abdominal digital subtraction angiography, and five excretory urography. Generally, the image quality was inferior to that obtained subsequently with standard doses of an iodinated contrast medium (50–150 mL of a 300 or 350 mg I/mL solution).
During recent years, gadolinium-based contrast agents have been used for examinations such as CT, excretory urography, digital subtraction angiography of various parts of the body (e.g., hepatic, renal, and peripheral arteries), endoscopic retrograde cholangiography, cystography, urethrocystography, and retrograde pyelography, as well as during percutaneous nephrostomy and biliary tract drainage. Kaufmann et al. [32] examined 14 patients with abnormal serum creatinine levels who underwent digital subtraction vena cavography with a gadolinium-based contrast agent (a maximum of 0.4 mmol/kg of body weight) for filter placement, thrombolysis, or diagnosis. Three of the 14 patients had a significant increase in serum creatinine (> 0.5 mg/dL [44 µmol/mL]), but there were other potential concurrent causes that might account for the deterioration of renal function. Serum creatinine transiently increased from 4.0 to 9.3 mg/dL (350 to 820 µmol/L) after lower extremity arteriography with 80 mL of 0.5 mmol/mL (0.44 mmol/kg of body weight) of gadoteridol in a patient with diabetic nephropathy [33]. The deterioration was thought to most likely be due to the contrast agent. Thirty-one patients with azotemia or previous severe adverse reaction to iodinated contrast media have undergone digital subtraction angiography with between 20 and 60 mL of 0.5 mmol/mL of gadopentetate dimeglumine [34]. In nine cases, CO2 was also used, and in eight cases between 6 and 40 mL (mean, 17.8 mL) of iohexol 350 mg I/mL was used. In no case did a patient's serum creatinine level increase more than 0.5 mg/dL (44 µmol/L) within 48 hr. In another study [35], renal function deteriorated in one (6%) of 18 azotemic patients after undergoing CO2 angiography supplemented with 0.5 mmol/mL of gadodiamide (20–100 mL; mean volume, 55 mL; 0.13–0.40 mmol/kg). The affected patient received 70 mL of gadodiamide (0.3 mmol/kg of body weight).
After injections of 80–440 mL of gadodiamide during arteriography, the serum creatinine level increased 0.6 mg/dL (53 µmol/mL) or more in eight (40%) of 20 patients with a preprocedural serum creatinine of 1.3–6.3mg/dL (115–548 µmol/mL) [36]. In three of the eight patients, the creatinine values did not return to the baseline value. After peripheral gadolinium arteriography, angioplasty, and stent placement, a patient with renal insufficiency (serum creatinine level, 3.9 mg/dL [340 µmol/L]) developed acute renal failure and acute pancreatitis [37]. Acute pancreatitis has been seen both after intraarterial [33] and IV [38] injection of a gadolinium-based contrast agent.
According to experimental data from the study of animals, gadolinium-based contrast media have more nephrotoxic potential than iodinated contrast media in equivalent X-ray attenuating doses. For example, in an experimental model of renal ischemia in pigs, 0.5 mmol/mL of gadopentetate dimeglumine (3 mL/kg of body weight) caused severe impairment of renal function; the low-osmolar gadodiamide caused less deterioration in renal function, and the low-osmolar iohexol (3 mL of 190 mg I/mL per kg body weight) caused even less [39]. Three milliliters per kilogram of body weight of iohexol (70 mg I/mL), which for angiography is isoattenuating with 0.4 mmol/mL of gadopentetate dimeglumine, caused no change in renal function.
Nephrotoxicity of the gadolinium-based contrast agents has now been described in both man and animals when high doses (> 0.3 mmol/kg) are used. Use of such doses of the gadolinium agents in patients with impaired renal function is not recommended. Their use for radiography and CT is also not an approved indication anywhere in the world. A major drawback with using gadolinium-based contrast agents for CT or radiography is that commercially available contrast media have only one gadolinium atom per molecule and a low molar concentration. In comparison, iodinated monomers for radiographic examinations contain three iodine atoms per molecule and have molar concentration five times that of gadolinium in four of the five gadolinium-based contrast agents available on the market. Hence, image quality is generally inferior when gadolinium-based contrast media are used for radiography. A position statement on the use of gadolinium-based contrast media for radiography has been issued in Europe (Appendix 3).
Metformin-Induced Lactic Acidosis and the Intravascular
Administration of Contrast Media
Biguanide metformin (dimethylbiguanide) is used in patients with
non–insulin dependent diabetes mellitus and was introduced into clinical
practice in 1957. Approximately 90% of metformin is eliminated via the kidneys
in 24 hr. Renal insufficiency (glomerular filtration rate < 70 mL/min, or
serum creatinine > 1.6 mg/dL [140 µmol/L]) will lead to retention of
these biguanides in the tissues and to the potential development of fatal
lactic acidosis [40].
Contrast media should be used with care in patients receiving metformin. Contrast media can induce a reduction in renal function leading to retention of metformin that may induce lactic acidosis because the onset of renal injury after the administration of contrast medium is quite rapid [27]. However, no conclusive evidence exists indicating that the intravascular use of contrast media precipitates the development of metformin-induced lactic acidosis in patients with normal serum creatinine levels (< 1.5 mg/dL [130 µmol/L]). The complication was almost always observed in non–insulin dependent diabetic patients with abnormal renal function before the injection of contrast media. Serum creatinine levels should always be monitored to check that they are within normal range before the administration of metformin is resumed. The check should be done at least 48 hr after the administration of the contrast medium (Appendix 4).
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Acute reaction to contrast media can be divided into minor, intermediate, and severe life-threatening reactions. Minor reactions include flushing, nausea, arm pain, pruritus, vomiting, headache, and mild urticaria. Such reactions are usually mild in severity, of short duration, and self-limiting and generally require no specific treatment. Intermediate reactions are more serious degrees of the same symptoms, moderate degrees of hypotension, and bronchospasm. The reactions usually respond readily to appropriate therapy. Severe life-threatening reactions include severe manifestation of all the symptoms described as minor and intermediate reactions, plus convulsions, unconsciousness, laryngeal edema, severe bronchospasm, pulmonary edema, severe cardiac dysrhythmias and arrest, and cardiovascular and pulmonary collapse. The prevalence of adverse reactions with low-osmolar contrast media is less than with high-osmolar contrast media by a factor of 5–6 [41]. Lethal reactions rarely occur.
Several factors predispose a patient to adverse reactions to contrast
material. The incidence of severe adverse reactions increases in the presence
of these risk factors, particularly previous contrast medium reaction,
allergy, and bronchial asthma. Lasser et al.
[42], in a randomized study of
6,763 patients, found that corticosteroid prophylaxis reduces the incidence of
all reactions to ionic contrast medium. The data indicating a protective
effect of corticosteroid prophylaxis when nonionic agents are used are less
established. In a smaller randomized trial of 1,155 patients and control
subjects, Lasser et al. [43]
showed a significant decrease from 4.9% to 1.7% in all reactions when a
steroid was given rather than a placebo before nonionic contrast media. The
frequency of moderate and severe reactions after steroids was also less, but
the numbers were small and no statistically significant difference was found.
Katayama et al. [41] reported
no beneficial effect of steroid premedication in the nonionic contrast media
group. However, the patients received steroids IV only immediately before the
administration of contrast medium
[43], so the steroids did not
have time (
6 hr) to take effect. Wolf et al.
[44] found that the nonionic
agent iohexol provided better protection against reaction than did a
corticosteroid plus ionic contrast medium, but those authors did not evaluate
the effect of using corticosteroids with nonionic agents.
In view of the findings by Wolf et al., Dawson and Sidhu [45] suggested that corticosteroid prophylaxis should be abandoned. This suggestion was subsequently strongly contested [46–50]; and currently opinion is divided as to whether corticosteroid prophylaxis should be used with nonionic agents. This division was reflected in a survey from the United Kingdom that showed that 55% of responders used corticosteroid prophylaxis and 45% did not [51]. In a survey performed by the European Society of Urogenital Radiology [52], asthma was considered a significant risk factor; and only 48% of the responders give corticosteroid prophylaxis to these patients. Administration of a very short course of steroids is relatively safe and inexpensive but should be avoided in patients with diabetes mellitus, active tuberculosis, and peptic ulcer disease and in the presence of systemic infection [53, 54]. Both in the United States and Europe, a wide variety of regimes, with different doses, numbers of doses, and frequency, are used for corticosteroid prophylaxis, if it is given at all [52, 55]. On the basis of the results of a survey and review of literature, European guidelines for prevention of generalized reactions to contrast media have been proposed (Appendix 5). However, even in patients who receive both corticosteroid premedication and low-osmolar contrast media, severe adverse reactions may still occur [43].
Late Adverse Reactions
Late adverse reactions to intravascular iodinated contrast media are
defined as reactions occurring 1 hr to 1 week after injection. Such reactions
have received increasing interest during the past decade, but their prevalence
remains uncertain and their pathophysiology is not fully understood
[56]. The reactions include
symptoms such as nausea, vomiting, headache, itching, skin rash,
musculoskeletal pain, and fever. A significant proportion of these reactions
is unrelated to the contrast medium. However, allergylike skin reactions are
well-documented side effects of contrast media, with an incidence of
approximately 2%. Late reactions appear to be more common after nonionic
dimers. Most late skin reactions after contrast medium exposure are probably
T-cell-mediated allergic reactions. Patients at increased risk of late skin
reactions are those with a history of previous contrast medium reaction and
those undergoing interleukin-2 treatment. Most skin reactions are
self-limiting and resolve within a week. Treatment is symptomatic and similar
to the treatment of other drug-induced skin reactions (Appendix 6).
Extravasation
Extravasation of contrast material is a wellrecognized complication of
contrast-enhanced imaging. The introduction of automated power injection has
increased the incidence because power injection may result in extravasation of
large volumes in a short period of time
[57] and may lead to severe
tissue damage. Infants, young children, and unconscious and debilitated
patients are particularly at risk of extravasation during contrast media
injection. Fortunately, most extravasations result in minimal swelling or
erythema and have no long-term sequelae. However, severe skin necrosis and
ulceration may occur. Large volumes (> 50 mL) of high-osmolar contrast
media are known to induce significant tissue damage. Compartment syndrome may
be associated with the extravasation of large volumes. Conservative treatment
is often adequate, but in serious cases the advice of a plastic surgeon is
recommended (Appendix 7).
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