Intravenous Radiocontrast Media: A Review of Allergic Reactions

US Pharm. 2012;37(5):HS-14-HS-16.

Intravenous radiocontrast, or IV dye, is used for many different diagnostic procedures to enhance the images in various radiologic studies. Examples of studies include computed tomography (CT) scans, angiograms, and pyelograms. These diagnostic procedures are done on a daily basis in hospital interventional radiology and cardiology departments around the world. In general, they are used to enhance the visibility of blood vessels.¹

There are two basic types of contrast media that are used for most radiologic studies: ionic high-osmolality contrast media and nonionic low-osmolality contrast media. The latter has become the preferred form of IV dye in recent years, given its better safety record, especially for women who are breastfeeding. However, it is far more expensive than high-osmolality contrast media. Allergy reactions to IV dye are common, can range from mild to moderate, and can sometimes be life-threatening.¹

It is believed that people who have an allergy to seafood (shellfish) may show an allergy to contrast media as well, due to the presence of iodine in both. We will briefly review the types, applications, and allergy profile of these products in this article.

Types of Radiocontrast Media

Both high-osmolar contrast media (ionic) and low-osmolar contrast media (nonionic or organic) agents contain iodine and are administered intravenously. Most intravascular contrast media are derivatives of tri-iodobenzoic acid. The iodine molecule is an effective x-ray absorber in the energy range where most clinical systems operate. Iodinated contrast media are the most efficient products to enhance the visibility of vascular structures and organs during radiographic procedures. The ionic type creates more charged particles and causes a high osmolality in blood, which may cause a potentially life-threatening contrast media reaction in some individuals with medical conditions. The nonionic agents generate less dissociation and particles and decrease this risk, but are much more expensive. The nonionic contrast media are much more widely used today. The iodine concentration of contrast media is determined by the number of iodine molecules in milligrams present in a milliliter of a solution (mg/mL).²

Concentration of any contrast media agent determines how radiopaque the agent will be. The higher the iodine concentration, the better the chance that more x-ray photons will be absorbed. Therefore, that particular contrast agent may be more radiopaque than a comparable low-iodine concentrated agent.

The osmolality of a solution is the measurement of the number of molecules and particles in a solution per kilogram of water. In other words, osmolality can be described as a measurement of the number of molecules that can crowd out or displace water molecules in a kilogram of water. The radiographic significance of the osmolality value of contrast media is that it is higher than the osmolality value of blood plasma. Any solution that has an osmolality value greater than blood plasma is said to be a hyperosmolar solution. Therefore, ionic and nonionic contrast media are hyperosmolar solutions when compared to blood plasma.

Since certain radiographic procedures, such as myelography, cannot use ionic contrast media, the discovery of nonionic contrast media in 1974 (e.g., metrizamide) revolutionized these procedures.²

Contrast Media Applications

Examples of currently used ionic and nonionic contrast media are perflutren-protein type-A microspheres injection (Optison), iohexol injection (Omnipaque), and nonionic iodixanol injection (Visipaque).

Optison is used in patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders.

Omnipaque is used for angiocardiography; aortography including studies of the aortic root, aortic arch, ascending aorta, and abdominal aorta and its branches; contrast enhancement for CT scan of head and body imaging; IV digital subtraction angiography (DSA) of the head, neck, abdominal, renal, and peripheral vessels; peripheral arteriography; and excretory urography.

Nonionic or organically bound iodine contrast media such as Visipaque (270 mgI/mL) are used for DSA. Visipaque Injection (320 mgI/mL) is used for angiocardiography, peripheral arteriography, visceral arteriography, and cerebral arteriography. Visipaque Injection (270 mgI/mL and 320 mgI/mL) is indicated for CT of the head and body (excretory urography). Visipaque Injection (270 mgI/mL) is also indicated for peripheral venography. Another example of the nonionics is Isovue-300 (iopamidol), which is used to help diagnose certain disorders of the heart, brain, blood vessels, and nervous system.^1,3

Dosing and Administration

It is reported that the calculation of contrast media dose and injection rate on the basis of lean body weight leads to increased patient-to-patient uniformity of hepatic parenchymal and vascular enhancement. This is likely related to the greater perfusion of contrast media to solid organs, muscles, and vessels compared with the highly variable but poorly perfused adipose tissue. As an example, the volume and injection rate of contrast material administration based proportionately on a 70-kg man with 25% body fat or a 70-kg woman with 30% body fat is about 45 g iodine IV at 0.9 g/sec.⁴

The rate or speed of contrast media injections may increase the risk of an adverse reaction. Also, the viscosity or thickness of the contrast media can cause resistance to its flow. The viscosity is related to the concentration, the size of the molecules in a specific contrast agent, and the temperature of the contrast agent. Contrast media with higher viscosity values should be injected at a slower rate. Heating the contrast media, usually to body temperature, reduces viscosity. Iodine concentration, viscosity, temperature of the contrast media, catheter inner diameter, catheter length, and the number of catheter holes are all factors that influence contrast media flow.¹

Allergies

In most cases, shortly after infusion, iodinated contrast media cause a warming sensation throughout the body. In certain areas of the body this feeling is more pronounced. Patients receiving contrast media via IV typically experience a hot feeling around the throat, and this hot sensation gradually moves down to the pelvic area.

Reactions to IV dye are observed in 5% to 8% of patients who receive them. Mild reactions include a feeling of warmth, nausea, and vomiting. Generally, these symptoms occur only for a short period of time and do not require treatment. Moderate reactions, including severe vomiting, hives, and swelling, occur in 1% of patients receiving contrast media and frequently require treatment. Severe, life-threatening reactions, including anaphylaxis, occur in 0.1% of people receiving contrast media, with an expected death rate of one person in every 75,000. The most severe reactions, including death, have been reported to occur at similar rates with both types of contrast media.⁵

Reactions to contrast media are not a true allergy, but rather a pseudoallergy in nature, meaning that there is no allergic antibody present that causes the reaction. Rather, contrast media act to directly release histamine and other chemicals from mast cells. The iodine concentration has an effect on the severity of an adverse reaction. The higher the iodine concentration, the greater the risk of an adverse reaction.⁹

Iodinated contrast media are toxic to the kidneys and kidney functions. The serum creatinine of the patient receiving a dose should be monitored before the procedure. In addition, the estimated glomerular filtration rate (eGFR) should be no lower than 30 mL/min in patients receiving iodinated contrast, and discretion should be used in patients with eGFR less than 45 mL/min. Following injections with extra fluids is highly recommended.¹

Numerous studies have shown that although iodine is common in contrast media, iodine is not the cause of allergic reactions. Certain proteins in seafood, rather, are the cause of allergy in patients with seafood allergies. It is noted that true allergic effects are by definition immunoglobulin E–related, and studies have shown that contrast media cause no such reaction in vivo. Therefore, contrast media or the iodine is not likely to act as an allergen.⁵

Radiocontrast Media Allergy Diagnosis

Skin testing and RAST (radioallergosorbent test) have not been helpful in the diagnosis of contrast media allergy. Small “test” doses are also not helpful, with reports of severe, life-threatening reactions occurring even at such amounts. Severe reactions to larger doses of contrast media have been observed after a person tolerated a small dose of IV dye. Therefore, the diagnosis of contrast media allergy is made only after symptoms have occurred. Otherwise, it is only possible to determine that a person is at increased risk of a reaction to contrast media based on the risk factors outlined below.⁶

Allergy Prevention and Treatment

As mentioned above, the purpose of using these contrast agents is for diagnosis, but like any medical procedure in any radiological study, the right dose or volume of contrast media needs to be determined prior to a procedure. The total volume or dose is dependent upon several factors: iodine concentration of the contrast media; type of injectable contrast media (ionic or nonionic); patient’s body weight, anatomical structures or regions; speed of the injection; and age or disease process that could increase the risk of an adverse reaction. The treatment of an acute reaction to contrast media is no different from any other anaphylactic reaction. Treatment may include injectable epinephrine and antihistamines, as well as the use of IV fluids for low blood pressure and shock.⁷

Contrast media reactions can be prevented by a test dose for the intended contrast or the use of an alternative; the use of nonionic versus ionic media if applicable; and the use of certain medicines prior to the administration of contrast media such as prednisone 50 mg orally taken at 13, 7, and 1 hour prior to procedure, or diphenhydramine (Benadryl) 50 mg orally, IV or intramuscularly, 1 hour prior to receiving radiocontrast media.⁷

Risk Factors

As mentioned above, people who have seafood allergy are not at risk if they need to use contrast media. In addition, people with an allergy to topical iodine cleaners or iodides are also not at increased risk for reactions to contrast media. Patients who are at higher risk include those with past reactions to contrast media (up to 44%); those with asthma; those who have a history of heart and kidney and thyroid (both hypo- and hyperthyroidism) diseases; those taking beta-blockers or metformin; and females and the elderly (appear to be at higher risk for severe reactions).^8,11

Note: Timely follow-up of serum creatinine levels in patients with diabetes who are receiving metformin therapy is highly important, and monitoring is required by pharmacists. Nearly 4% of patients with diabetes mellitus and normal renal function may develop contrast material–associated neuropathy with nonionic contrast media. Roughly 8% of patients with diabetes receiving metformin, whose baseline serum creatinine levels are below 1.5 mg/dL, develop an increased risk of lactic acidosis requiring metformin therapy to be withheld for at least 48 hours after administration of IV contrast material. The FDA currently recommends metformin monitoring in patients who are undergoing radiologic procedures involving administration of IV contrast media.¹¹

REFERENCES

1. American College of Radiology (ACR) Manual on Contrast Media. 2010. Version 7.
2. Meth MJ, Maibach HI. Current understanding of contrast media reactions and implications for clinical management. Drug Saf. 2006;29:133-141.
3. Thomson K, Varma D. Safe use of radiographic contrast media. Australian Prescriber. 2010;33:19-22. www.australianprescriber.com/magazine/33/1/19/22/.
4. Ho LM, Rendon C. Nelson RC, DeLong DM.Determining contrast medium dose and rate on basis of lean body weight: does this strategy improve patient-to-patient uniformity of hepatic enhancement during multi–detector row CT? Radiology. 2007;243,431-437.
5. Boehm I. Seafood allergy and radiocontrast media: are physicians propagating a myth? Am J Med. 2008;121(8):e19.
6. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006;354:379-385.
7. Tramer MR, von Elm E, Loubeyre P, Hauser C. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review. BMJ. 2006;333:675.
8. Canter LM. Anaphylactoid reactions to radiocontrast media. Allergy Asthma Proc. 2005;26:199-203.
9. Brockow K. Contrast media hypersensitivity: scope of the problem. Toxicology. 2005;209:189-192.
10. www.medscape.com/viewarticle/489319_5.
11. Keller DM, Iodinated contrast media raises risk for thyroid dysfunction. Arch Intern Med. 2012;172:153-159.

To comment on this article, contact rdavidson@uspharamcist.com.