Adverse reactions to contrast material: recognition, prevention, and treatment - Radiologic Decision

Author: Thomas G. Maddox
Date: Oct 1, 2002

The osmolality of a particular contrast agent is determined by the number of osmotically active particles formed when it is dissolved in solution. Ionic agents dissociate into ions when dissolved in water and contain an iodinated benzene ring. As a result, ionic agents have a higher osmolality than blood. Nonionic agents do not dissociate into separate particles when dissolved in water; their osmolality is therefore one half that of ionic agents. Contrast agents are categorized according to their chemical structure and relative osmolality. Table 1 lists types of contrast agents.

Contrast agents with higher osmolality are more likely to cause adverse reactions of all kinds. Renal toxicity has long been associated with exposure to high-osmolality agents. (1) Low-osmolality agents are associated with less discomfort, and fewer cardiovascular and anaphylactic-type reactions. However, these agents have a significantly higher cost, which prevents them from being used exclusively.

Types of Adverse Reactions

ANAPHYLACTIC

Anaphylactic reactions are serious, potentially life-threatening reactions associated with the administration of contrast material. Acute bronchospasm, profound hypotension, and severe urticaria may occur within minutes of administration of as little as 1 mL of contrast material. These reactions are not "true" allergic reactions, because they can occur in patients who have not been exposed to contrast material previously. IgE antibodies, which are associated with allergic reactions, have not been demonstrated in most patients with anaphylactoid reactions. (2) The etiology of these anaphylactic reactions is unclear.

DOSE DEPENDENT

Dose-dependent, systemic adverse reactions to contrast material include nausea and vomiting, a metallic taste in the mouth, and generalized warmth or flushing. These reactions are usually nonlife-threatening, self-limited problems.

Renal failure is another form of adverse reaction that is dependent on the dose of contrast material used. Intravenous administration of contrast material is responsible for 12 percent of cases of hospital-acquired renal failure. (3) Renal failure following administration of contrast material occurs in 0.1 to 13 percent of patients who receive contrast material. (4) This range results from the lack of a set definition for contrast-induced nephrotoxicity. A generally accepted definition is the elevation of serum creatinine to greater than 25 percent of baseline within three days of receiving contrast material. Proteinuria is often found on routine urinalysis but is not required for the diagnosis of contrast-induced nephropathy.

Patients with preexisting renal insufficiency and diabetes are at greatest risk of developing permanent renal failure following administration of contrast material. Patients with multiple myeloma are also at increased risk of developing renal failure, especially if they are dehydrated. The risk of renal failure in patients with myeloma is caused by an interaction of light chains and contrast material. How contrast materials cause renal failure is unclear, but direct cellular toxicity and intrarenal vasoconstriction are believed to be the primary causes of renal function changes. (4,5)

DELAYED REACTIONS

Adverse reactions that occur 30 minutes or more after the administration of contrast material are considered delayed reactions. Delayed reactions are more common with the use of ionic agents. (6) Up to 30 percent of patients receiving ionic contrast materials develop delayed reactions. Administration of nonionic agents is associated with delayed reactions in only 10 percent of patients. The symptoms of delayed reactions resemble a flulike syndrome and include fever, chills, nausea, vomiting, abdominal pain, fatigue, and congestion.

EXTRAVASATION OF CONTRAST MATERIAL

Tissue damage from extravasation of contrast material is caused by the direct toxic effect of the agent. Compartment syndrome may occur if enough contrast material leaks into surrounding tissue.

Patients at Risk

A patient who has renal insufficiency before the administration of contrast material is five to 10 times more likely to develop contrast-induced renal failure than patients in the general population. (6,7) Patients with a history of anaphylactic reaction to contrast material are more likely to have a similar reaction if they are again exposed to contrast material, but even these patients may not experience repeat reactions on reexposure.

Patients with a history of asthma have double the risk of developing adverse reactions compared to the general population, even if the patient's asthma is under control. (6) Patients with multiple food or medication allergies and those with multiple medical problems (e.g., cardiac disease, preexisting azotemia) are more likely to develop complications when exposed to contrast agents. (8)

No substantive data support the myth that patients with seafood allergy are at higher risk of developing allergic reactions to contrast media. Patients treated with nephrotoxic medications (e.g., aminoglycosides and nonsteroidal anti-inflammatory agents) are at greater risk of developing renal failure. Advanced age is also considered a risk factor for developing renal insufficiency. Metformin (Glucophage), an oral agent used in the treatment of diabetes, has been associated with the development of severe lactic acidosis following administration of intravenous contrast media. (9) Many experts recommend stopping metformin therapy at the time of the procedure, or before, and for at least 48 hours following the administration of contrast material. The medication should be resumed only after the patient's renal function has returned to baseline (as determined by the serum creatinine level).

Contrast material should not be administered to pregnant women. Alternative forms of visualization are recommended for these patients.

The extent to which mutagenesis of fetal tissue is associated with the use of contrast material is not known. Inhibition of fetal thyroid tissue has occurred after the use of contrast material before delivery. (6) Table 2 lists conditions associated with adverse reactions to contrast material.

Avoiding Problems

GENERAL PRINCIPLES

Adverse reactions can be reduced if general principles are applied to all patients. The smallest amount of contrast agent possible should be used for each procedure. Allowing at least 48 hours to elapse between procedures in which contrast material is used enables the kidneys to recover. (6) Table 3 outlines methods of preventing contrast-induced renal insufficiency.

HYDRATION

It has been well documented that hydration minimizes, or decreases, the incidence of renal failure induced by contrast material. Unless contraindicated, infusion of 0.45 or 0.9 percent saline at a rate of 100 mL per hour beginning four hours before the procedure and continuing for 24 hours after the procedure, is recommended. (10,11)

In patients able to take oral fluids, hydration can be achieved through ingestion of 500 mL of fluid before the procedure followed by 2,500 mL over the 24 hours after the procedure. There have been no prospective studies comparing different fluids for hydration.

CORTICOSTEROIDS

Nonrenal reactions to contrast material can be reduced by premedicating the patient with corticosteroids. (12,13) [Reference 12--Evidence level A, randomized controlled trial (RCT); Reference 13--Evidence level B, uncontrolled study] This protective effect functions for ionic and nonionic contrast materials. Many physicians give corticosteroids only to patients known to have a previous history of idiosyncratic adverse reactions. (6)

Combining corticosteroid use with a histamine [H.sub.1]- receptor blocker further reduces the chance that adverse reactions will develop. Adverse reactions decreased from a range of 17 to 35 percent to a range of 5 to 10 percent when corticosteroids were combined with an [H.sub.1] blocker (diphenhydramine). (14,15) [References 14 and 15--Evidence level B, uncontrolled study]

The following premedication protocol has been recommended for use in patients with a history of idiosyncratic reactions: methylprednisolone (one 32-mg tablet at 12 hours and two hours before the study) or prednisone (one 50-mg tablet at 13 hours, seven hours, and one hour before the study). (6) If the previous reaction was moderate or severe or included a respiratory component, the physician can add the following: an H1 blocker such as diphenhydramine (one 50-mg tablet one hour before the study) and an [H.sub.2] blocker (optional) such as cimetidine (Tagamet), one 300-mg tablet one hour before the study, or ranitidine (Zantac), one 50-mg tablet one hour before the study. Using an [H.sub.2] blocker without also using an [H.sub.1] blocker is not recommended.

OTHER DRUGS

(11.) Brown R, Ransil B, Clark B. Prehydration protects against contrast nephropathy in high-risk patients undergoing cardiac catheterization [Abstract]. J Am Soc Nephrol 1990;1:330A.

(12.) Lasser EC, Berry CC, Talner LB, Santini LC, Lang EK, Gerber FH, et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. N Engl J Med 1987:317:845-9.

(13.) Greenberger P, Patterson R, Kelly J, Stevenson DD, Simon D, Lieberman P. Administration of radiographic contrast media in high-risk patients. Invest Radiol 1980:15;S40-3.

(14.) Greenberger PA, Patterson R, Tapio CM. Prophylaxis against repeated radiocontrast media reactions in 857 cases. Adverse experience with cimetidine and safety of beta-adrenergic antagonists. Arch Intern Med 1985:145;2197-200.

(15.) Kelly JF, Patterson R, Lieberman P, Mathison DA, Stevenson DD. Radiographic contrast media studies in high-risk patients. J Allergy Clin Immunol 1978:62;181-4.

(16.) Weinstein JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 1992:62;413-5.

(17.) Neumayer HH, Junge W, Kufner A, Wenning A. Prevention of radiocontrast-media-induced nephrotoxicity by the calcium channel blocker nitrendipine: a prospective randomised clinical trial. Nephrol Dial Transplant 1989:4;1030-6.

(18.) Jensen N, Dorph S. Adverse reactions to urographic contrast medium. Rapid versus slow injection rate. Br J Radiol 1980:53;659-61.

(19.) Manual on contrast media. Ed 4.1, 1998. Reston, Va.: American College of Radiology, 2001.

The editors of AFP welcome the submission of manuscripts for the Radiologic Decision-Making series. Send submissions to Jay Siwek, M.D., following the guidelines provided in "Information for Authors."

Coordinators of this series are Mark Meyer, M.D., University of Kansas School of Medicine, Kansas City, Kan., and Walter Forred, M.D., University of Missouri-Kansas City School of Medicine, Kansas City, Mo.

THOMAS G. MADDOX, M.D., F.A.A.F.P., is associate director of the University of Missouri, Kansas City, Family Practice Residency Program and associate professor at the University of Missouri School of Medicine in Kansas City. He is also a clinical instructor for the University of Kansas Medical Center, director of Saint Luke's Family Care, and chair of the Department of Family Practice at Saint Luke's Hospital in Kansas City, Mo. A graduate of the University of Nebraska College of Medicine, Omaha, he completed residency training at St. Mary's Hospital, Kansas City, Mo.

Address correspondence to Thomas G. Maddox, M.D., Saint Luke's Family Care, 4400 Broadway, Suite 409, Kansas City, MO 64111 (tmaddox@saint-lukes.org). Reprints are not available from the author.

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