Since their introduction in the 1950s, organic radiographic iodinated contrast media (ICM) have been among the most commonly prescribed drugs in the history of modern medicine. The phenomenon of present-day radiologic imaging would be lacking without these agents. ICM generally have a good safety record. Adverse effects from the intravascular administration of ICM are generally mild and self-limited; reactions that occur from the extravascular use of ICM are rare.
Nonetheless, severe or life-threatening reactions can occur with either route of administration.
All currently used ICM are chemical modifications of a 2,4,6-tri-iodinated benzene ring.
They are classified on the basis of their physical and chemical characteristics, including their chemical structure, osmolality, iodine content, and ionization in solution. In clinical practice, categorization based on osmolality is widely used. Osmotic effects of contrast media that are specific for the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Secondary effects include osmotically induced diuresis with a dehydrating effect.
Radiologists and other physicians must be aware of the risk factors for reactions to contrast media, use strategies to minimize adverse events, and be prepared to promptly recognize and manage any reactions to the contrast media.
For ICM classifications, see the image below.
Classification of iodinated contrast agents by their molecular structures.
High-osmolality contrast media
High-osmolality contrast media consist of a tri-iodinated benzene ring with 2 organic side chains and a carboxyl group. The iodinated anion, diatrizoate or iothalamate, is conjugated with a cation, sodium or meglumine; the result is an ionic monomer (see the image below). The ionization at the carboxyl-cation bond makes the agent water soluble. Thus, for every 3 iodine atoms, 2 particles are present in solution (ie, a ratio of 3:2).
Classification of iodinated contrast agents by their molecular structures.
The osmolality in solution ranges from 600 to 2100 mOsm/kg, versus 290 mOsm/kg for human plasma. The osmolality is related to some of the adverse events of these contrast media.
Ionic monomers are subclassified by the percentage weight of the contrast agent molecule in solution (eg, 30% or 76%).
In the United States, commonly used high-osmolality ICM are Renografin (diatrizoate anion; Bracco Diagnostics Inc, Princeton, NJ ) or Hypaque (diatrizoate anion; GE Healthcare, Inc, Princeton, NJ) and Conray (iothalamate anion; tyco Healthcare and Mallinckrodt Inc, St. Louis, Mo).
Low-osmolality contrast media
There are 3 types of low-osmolality ICM: (1) nonionic monomers, (2) ionic dimers, and (3) nonionic dimers.
In nonionic monomers, the tri-iodinated benzene ring is made water soluble by the addition of hydrophilic hydroxyl groups to organic side chains that are placed at the 1, 3, and 5 positions. Lacking a carboxyl group, nonionic monomers do not ionize in solution. Thus, for every 3 iodine atoms, only 1 particle is present in solution (ie, a ratio of 3:1). Therefore, at a given iodine concentration, nonionic monomers have approximately one half the osmolality of ionic monomers in solution. At normally used concentrations, 25-76%, nonionic monomers have 290-860 mOsm/kg.
Nonionic monomers are subclassified according to the number of milligrams of iodine in 1 mL of solution (eg, 240, 300, or 370 mg I/mL).
The larger side chains increase the viscosity of nonionic monomers compared with ionic monomers. The increased viscosity makes nonionic monomers harder to inject, but it does not appear to be related to the frequency of adverse events.
Common nonionic monomers are iohexol (Omnipaque; GE Healthcare, Inc), iopamidol (Isovue; Bracco Diagnostics Inc), ioversol (Optiray; tyco Healthcare and Mallinckrodt Inc), and iopromide (Ultravist; Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ).
The nonionic monomers are the contrast agents of choice. In addition to their nonionic nature and lower osmolalities, they are potentially less chemotoxic than the ionic monomers.
Ionic dimers are formed by joining 2 ionic monomers and eliminating 1 carboxyl group. These agents contain 6 iodine atoms for every 2 particles in solution (ie, a ratio of 6:2). The only commercially available ionic dimer is ioxaglate (Hexabrix; tyco Healthcare and Mallinckrodt Inc). Ioxaglate has a concentration of 59%, or 320 mg I/mL, and an osmolality of 600 mOsm/kg. Because of its high viscosity, ioxaglate is not manufactured at higher concentrations. Ioxaglate is used primarily for peripheral arteriography.
Nonionic dimers consist of 2 joined nonionic monomers. These substances contain 6 iodine atoms for every 1 particle in solution (ie, ratio of 6:1). For a given iodine concentration, the nonionic dimers have the lowest osmolality of all the contrast agents. At approximately 60% concentration by weight, these agents are iso-osmolar with plasma. They are also highly viscous and, thus, have limited clinical usefulness. Examples of nonionic dimers are iotrol and iodixanol (Visipaque; Amersham Health Inc, Princeton, NJ).
The incidence of any adverse reaction to ICM is about 15%. Most of these reactions are mild and require no treatment.
Ionic ICM versus nonionic ICM
In a large Japanese case series (337,647 cases), the overall risk of any adverse reaction was 12.66% with ionic ICM and 3.13% with nonionic ICM; the risk of a severe adverse drug reaction was 0.2% for ionic ICM and 0.04% for nonionic ICM; and the risk of a very severe adverse drug reaction was 0.04% for ionic ICM and 0.004% for nonionic ICM.
In another large study, in which 6000 patients received ionic ICM, the incidence of mild adverse drug reactions was 2.5%; moderate reactions, 1.2%; and severe reactions, 0.4%.
However, in 7170 patients who received nonionic ICM, the incidences were only 0.58% for mild reactions, 0.11% for moderate reactions, and 0% for severe reactions.
Dillman et al performed a retrospective review of 11,306 children (age 24 </ref>Overall, the authors found that 0.18% of the children had acute allergic-like reactions to the contrast agent; of the affected patients, 80% of the reactions were categorized as mild, 5% as moderate, and 15% as severe.
High-osmolality ICM versus low-osmolality ICM
A meta-analysis of the published data from 1980-1989 by Caro et al revealed that the risk of severe adverse reaction was 0.157% for high-osmolality ICM and 0.031% for nonionic ICM.
The investigators found that the risk of death was 1 death in 100,000 patients with either type of agent.
Other reports indicate that low-osmolality agents are somewhat less nephrotoxic in patients with azotemia than in other patients.
Nonionic ICM are less likely than conventional ionic ICM to cause tissue damage when they are extravasated.
Nonetheless, compartment syndromes and skin blistering are reported after the extravasation of nonionic agents.
Some toxic effects of ICM, such as nausea and vomiting, are more common with ionic dimers than with nonionic monomers.
Most authorities believe that the preponderance of evidence that supports the lower rate of adverse reactions with low-osmolality ICM compared with high-osmolality ICM is conclusive.
The reason that low-osmolality ICM have not completely replaced the older high-osmolality ICM is the higher cost of the low-osmolality agents. Professional organizations have formulated guidelines regarding the selective use of low-osmolality ICM for certain high-risk patients. However, with the selective use of nonionic ICM, severe adverse contrast reactions are 3 times as likely in low-risk patients who receive conventional ionic agents (0.09%) than in high-risk patients who receive nonionic agents (0.03%). Thus, the single most important risk factor for an adverse reaction is the type of contrast agent that is chosen for injection.