Radiocontrast

Overview
Radiocontrast agents (also simply contrast agents or contrast materials) are compounds used to improve the visibility of internal bodily structures in an X-ray image.

Contrast agents are also used in MRI (Magnetic Resonance Imaging). Although MRI is usually considered a branch of radiology, it is not based on X-rays. MRI contrast agents are usually gadolinium-based, and work not by being radioopaque, but rather by altering the magnetic properties of nearby hydrogen nuclei.

Types and uses
There are two basic types of contrast agents used in X-ray examinations.

One type of contrast agent is based on barium sulfate, an insoluble white powder. This is mixed with water and some additional ingredients to make the contrast agent. As the barium sulfate doesn't dissolve, this type of contrast agent is an opaque white mixture. It is only used in the digestive tract; it is usually swallowed or administered as an enema. After the examination, it leaves the body with the feces.

The other type of contrast agent is based on iodine. This may be bound either in an organic (non-ionic) compound or an ionic compound. Ionic agents were developed first and are still in widespread use depending on the examination they are required for. Ionic agents have a poorer side effect profile. Organic compounds have fewer side effects as they do not dissociate into component molecules. Many of the side effects are due to the hyperosmolar solution being injected. i.e. they deliver more iodine atoms per molecule. The more iodine, the more "dense" the x-ray effect. There are many different molecules. Some examples of organic iodine molecules are iohexol, iodixanol, ioversol. Iodine based contrast media are water soluble and harmless to the body. These contrast agents are sold as clear colorless water solutions, the concentration is usually expressed as mg I/ml. Modern iodinated contrast agents can be used almost anywhere in the body. Most often they are used intravenously, but for various purposes they can also be used intraarterially, intrathecally (the spine) and intraabdominally - just about any body cavity or potential space.

An older type of contrast agent, Thorotrast was based on thorium dioxide, but this was abandoned since it turned out to be carcinogenic.

Adverse effects
Modern iodinated contrast agents are safe drugs; adverse reactions exist but they are uncommon. The major side effects of radiocontrast are anaphylactoid reactions and contrast-induced nephropathy.

Anaphylactoid reactions
Anaphylactoid reactions occur rarely (Karnegis and Heinz, 1979; Lasser et al, 1987; Greenberger and Patterson, 1988), but can occur in response to injected as well as oral and rectal contrast and even retrograde pyelography. They are similar in presentation to anaphylactic reactions, but are not caused by an IgE-mediated immune response. Patients with a history of contrast reactions, however, are at increased risk of anaphylactoid reactions (Greenberger and Patterson, 1988; Lang et al, 1993). Pretreatment with corticosteroids has been shown to decrease the incidence of adverse reactions (Lasser et al, 1988; Greenberger et al, 1985; Wittbrodt and Spinler, 1994).

Anaphylactoid reactions range from urticaria and itching, to bronchospasm and facial and laryngeal edema. For simple cases of urticaria and itching, Benadryl (diphenhydramine) oral or IV is appropriate. For more severe reactions, including bronchospasm and facial or neck edema, albuterol inhaler, or subcutaneous or IV epinephrine, plus diphenhydramine may be needed. If respiration is compromised, an airway must be established prior to medical management.

Contribution of seafood and other allergies
It must be noted that suspicion of seafood "allergy", often based more on medical myth than fact, is not a sufficient contraindication to the use of iodinated contrast material. A relationship between iodine levels in seafood and seafood allergy is part of medical lore. While iodine levels in seafood are higher than in non-seafood items, the consumption of the latter exceeds that of the former by far and there is no evidence that the iodine content of seafood is related to reactions to seafood. Available data suggests that seafood allergy increases the risk of a contrast-mediated reaction by approximately the same amount as allergies to fruits or those with asthma. In other words, over 85% of patients with seafood allergies will not have an adverse reaction to iodinated contrast. Finally, there is no evidence that adverse skin reactions to iodine-containing topical antiseptics (e.g., Betadine, Povidine) are of any specific relevance to administration of I.V. contrast material.

Contrast-induced nephropathy
Contrast-induced nephropathy is defined as either a greater than 25% increase of serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL.

To minimize the risk for contrast-induced nephropathy, various actions can be taken if the patient has predisposing conditions. These have been reviewed in a meta-analysis. A separate meta-analysis addresses interventions in for emergent patients with baseline renal insufficiency.

Three factors have been associated with an increased risk of contrast-induced nephropathy: preexisting renal insufficiency (such as Creatinine clearance < 60 mL/min [1.00 mL/s] - online calculator), preexisting diabetes, and reduced intravascular volume.

A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h) :

Risk Factors:
 * Systolic blood pressure <80 mm Hg - 5 points
 * Intraarterial balloon pump - 5 points
 * Congestive heart failure (Class III-IV or history of pulmonary edema) - 5 points
 * Age >75 y - 4 points
 * Hematocrit level <39% for men and <35% for women - 3 points
 * Diabetes - 3 points
 * Contrast media volume - 1 point for each 100 mL
 * Renal insufficiency:
 * Serum creatinine level >1.5 g/dL - 4 points
 * or
 * Estimated Glomerular filtration rate (online calculator)
 * 2 for 40–60 mL/min/1.73 m2
 * 4 for 20–40 mL/min/1.73 m2
 * 6 for < 20 mL/min/1.73 m2

Scoring: 5 or less points 6–10 points 11–16 points >16 points
 * Risk of CIN - 7.5
 * Risk of Dialysis - 0.04%
 * Risk of CIN - 14.0
 * Risk of Dialysis - 0.12%
 * Risk of CIN - 26.1*
 * Risk of Dialysis - 1.09%
 * Risk of CIN - 57.3
 * Risk of Dialysis - 12.8%

Choice of contrast agent
The osmolality of the contrast agent is believed to be of great importance in contrast-induced nephropathy. Ideally, the contrast agent should be iso-osmolar to blood. Modern iodinated contrast agents are non-ionic, the older ionic types caused more adverse effects and are not used much anymore.

Iso-osmolar, nonionic contrast media may be the best according to a randomized controlled trial.

Hypo-osmolar, non-ionic contrast agents are beneficial if iso-osmolar, nonionic contrast media is not available due to costs.

Hydration with or without bicarbonate
Administration of sodium bicarbonate 3 mL/kg per hour for 1 hour before, followed by 1 mL/kg per hour for 6 hours after contrast was found superior to plain saline on one randomized controlled trial of patients with a creatinne of at least 1.1 mg/dL (97.2 µmol/L). To make the solution, the study used 154 mL of 1000 mEq/L sodium bicarbonate to 846 mL of 5% dextrose. This is approximately three 50 ml ampules of bicarbonate in 850 ml of water with 5% dextrose. This was subsequently corroborated by a multi-center randomized controlled trial, which also demonstrated that IV hydration with sodium bicarbonate was superior to 0.9% normal saline. The renoprotective effects of bicarbonate are thought to be due to urinary alkalinization, which creates an environment less amenable to the formation of harmful free radicals. .

Alternatively, one randomized controlled trial of patients with a creatinine over 1.6 mg per deciliter (140 µmol per liter) or creatinine clearance below 60 ml per minute used 1 ml/kg of 0.45 percent saline per per hour for 6-12 hours before and after the contrast.

Methylxanthines
Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help although studies have conflicting results. The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.

N-acetylcysteine
N-acetylcysteine (NAC) 600 mg orally twice a day, on the day before and of the procedure if creatinine clearance is estimated to be less than 60 mL/min [1.00 mL/s]) may reduce nephropathy. . A randomized controlled trial found higher doses of NAC (1200-mg IV bolus and 1200 mg orally twice daily for 2 days) benefited (relative risk reduction of 74%) patients receiving coronary angioplasty with higher volumes of contrast.

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC and one of 600 mg give four times around coronary angiography, found statistically insignificant trends towards benefit.

Some authors believe the benefit is not overwhelming. The strongest results were from an unblinded randomized controlled trial that used NAC intravenously. A systematic review by Clinical Evidence concluded that NAC is "likely to beneficial" but did not recommend a specific dose. One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself. This is supported by a lack of correlation between creatinine levels and cystatin C levels.

In one study 15% of patients receiving NAC intravenously had allergic reactions.

Prophylactic hemodialysis
Patients with chronic renal insufficiency and a creatinine over 309.4 µmol/L (3.5 mg.dl) who have elective coronary catheterization, a randomized controlled trial found benefit from prophylactic hemodialysis

Other interventions
Other pharmacological agents, such as furosemide, mannitol, dopamine, and atrial natriuretic peptide have been tried, but have either not had beneficial effects, or had detrimental effects.