contrast medium

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Radiocontrast agents are a type of medical contrast medium used to improve the visibility of internal bodily structures in an X-ray based imaging techniques such as Computed tomography (CT) or Radiography (commonly known as X-ray imaging). Radiocontrast agents are typically iodine or barium compounds.

Despite being part of radiology, Magnetic resonance imaging (MRI) functions through different principles and thus utilize different contrast agents. These compounds work by altering the magnetic properties of nearby hydrogen nuclei.

Contents 1 Types and uses 1.1 Gastro-intestinal 1.2 Intravascular 2 Adverse effects 2.1 Anaphylactoid reactions 2.1.1 Contribution of seafood and other allergies 2.2 Contrast-induced nephropathy 2.2.1 Choice of contrast agent 2.2.2 Hydration with or without bicarbonate 2.2.3 Methylxanthines 2.2.4 N-acetylcysteine 2.2.5 Prophylactic hemodialysis 2.2.6 Other interventions 3 References 3.1 General references 3.2 Specific references 4 See also

Types and uses

Radiocontrast agents used in X-ray examinations can be grouped based on its use.

Gastro-intestinal

Barium sulfate, an insoluble white powder is typically used for enhancing contrast in the GI tract. Depending on how it is to be administered the compound is mixed with water, thickeners, de-clumping agents, and flavourings 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.

Intravascular

Modern intravenous contrast agents are typically 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 requirements but may result in additional complications. Organic agents which covalently bind the iodine 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.

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

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 (as in diskography of the spine) and intraabdominally - just about any body cavity or potential space.

Commonly used iodinated contrast agents

Compound	Name	Type	Iodine Content	Osmolality	Level
Ionic	Diatrizoate (Hypaque 50)	Ionic Monomer	300	1550	High Osmolar
Ionic	Metrizoate (Isopaque Coronar 370)	Ionic	370	2100	High Osmolar
Ionic	Ioxaglate (Hexabrix)	Ionic dimer	320	580	Low Osmolar
Non-Ionic	Iopamidol (Isovue 370)	Non-ionic monomer	370	796	Low Osmolar
Non-Ionic	Iohexol (Omnipaque 350)	Non-ionic	350	884	Low Osmolar
Non-Ionic	Ioxilan (Oxilan)	Non-ionic			Low Osmolar
Non-Ionic	Iopromide	Non-ionic			Low Osmolar
Non-Ionic	Iodixanol (Visipaque 320)	Non-ionic dimer	320	290	Iso Osmolar

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.^[1] 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.^[2] In other words, over 85% of patients with seafood allergies will not have an adverse reaction to iodinated contrast.^[1] 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.^[1][3]

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.^[4]

A new definition of contrast nephropathy in patients undergoing percutaneous coronary intervention was recently proposed by Harjai, et al. This tripartite definition classifies contrast nephropathy as grade 0 (serum creatinine increase <25% above baseline and <0.5 mg/dL above baseline), grade 1 (serum creatinine increase >/=25% above baseline and <0.5 mg/dL above baseline), or grade 2 (serum creatinine increase >/=0.5 mg/dL above baseline). This classification is prognostic of long-term outcomes of patients after percutaneous coronary intervention. Patients with grade 2 nephropathy had the worst outcome while those with grade 0 nephropathy had the best outcome on long-term follow-up. ^[5]

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.^[6] A separate meta-analysis addresses interventions in for emergent patients with baseline renal insufficiency.^[7]

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.^[8][9]

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)^[10]:

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

• Risk of CIN - 7.5
• Risk of Dialysis - 0.04%

6–10 points

• Risk of CIN - 14.0
• Risk of Dialysis - 0.12%

11–16 points

• Risk of CIN - 26.1*
• Risk of Dialysis - 1.09%

>16 points

• Risk of CIN - 57.3
• Risk of Dialysis - 12.8%

Choice of contrast agent

The osmolality of the contrast agent was previously believed to be of paramount importance in contrast-induced nephropathy. Today it has become increasingly clear that other physicochemical properties play a greater role, such as viscosity. Attention should be paid to use contrast agents of low viscosity. Moreover, sufficient fluids should be supplied to limit fluid viscosity of urine. Modern iodinated contrast agents are non-ionic, the older ionic types caused more adverse effects and are not used much anymore.

A former study suggested that iso-osmolar, nonionic contrast media may be superior to others. randomized controlled trial.^[11] However, several subsequent studies failed to confirm this. A large scale study strongly suggested that an iso-osmolar contrast media more often cause clinically relevant kidney failure than a low-osmolar contrast agent. ^[12]

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) .^[13] 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^[14]. However, additional confirmatory trials with sodium bicarbonate are needed because the largest trial to date showed no benefit of sodium bicarbonate over normal saline .^[15]. 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.^[16].

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.^[17]

Methylxanthines

Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help^[7] although studies have conflicting results.^[18] The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.^[19][20]

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.^[21]. 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^[22].

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC^[23] and one of 600 mg give four times around coronary angiography^[24], found statistically insignificant trends towards benefit.

Some authors believe the benefit is not overwhelming.^[25] The strongest results were from an unblinded randomized controlled trial that used NAC intravenously.^[26] A systematic review by Clinical Evidence concluded that NAC is "likely to be beneficial" but did not recommend a specific dose.^[27] One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself.^[28] 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.^[26]

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^[29]

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.^[17][30] Of course, limiting the total contrast volume also aids greatly in reducing the incidence of contrast nephropathy.

References

General references

• Greenberger PA, Patterson R, Tapio CM (1985). "Prophylaxis against repeated radiocontrast media reactions in 857 cases. Adverse experience with cimetidine and safety of beta-adrenergic antagonists". Arch Intern Med 145 (12): 2197–200. doi:10.1001/archinte.145.12.2197. PMID 2866755. 
• Greenberger PA, Patterson R (1988). "Adverse reactions to radiocontrast media". Prog Cardiovasc Dis 31 (3): 239–48. doi:10.1016/0033-0620(88)90017-5. PMID 3055068. 
• Karnegis JN, Heinz J (1979). "The risk of diagnostic cardiovascular catheterization". Am Heart J 97 (3): 291–7. doi:10.1016/0002-8703(79)90427-7. PMID 420067. 
• Lang DM, Alpern MB, Visintainer PF, Smith ST (1993). "Elevated risk of anaphylactoid reaction from radiographic contrast media is associated with both beta-blocker exposure and cardiovascular disorders". Arch Intern Med 153 (17): 2033–40. doi:10.1001/archinte.153.17.2033. PMID 8102844. 
• Lasser EC, Berry CC, Talner LB, Santini LC, Lang EK, Gerber FH, Stolberg HO (1987). "Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material". N Engl J Med 317 (14): 845–9. PMID 3627208. 
• Lasser EC, Berry CC, Talner LB, Santini LC, Lang EK, Gerber FH, Stolberg HO (1988). "Protective effects of corticosteroids in contrast material anaphylaxis". Invest Radiol 23 Suppl 1: S193–4. PMID 3058630. 
• Wittbrodt ET, Spinler SA (1994). "Prevention of anaphylactoid reactions in high-risk patients receiving radiographic contrast media". Ann Pharmacother 28 (2): 236–41. PMID 8173143. 

Specific references

See also

• Contrast medium

v • d • e Contrast media (V08) X-ray, iodinated Water-soluble Nephrotropic, high osmolar: Diatrizoic acid · Metrizoic acid · Iodamide · Iotalamic acid · Ioxitalamic acid · Ioglicic acid · Acetrizoic acid · Iocarmic acid · Methiodal · Diodone Nephrotropic, low osmolar: Metrizamide · Iohexol # · Ioxaglic acid · Iopamidol · Iopromide · Iotrolan · Ioversol · Iopentol · Iodixanol · Iomeprol · Iobitridol · Ioxilan Hepatotropic: Iodoxamic acid · Iotroxic acid · Ioglycamic acid · Adipiodone · Iobenzamic acid · Iopanoic acid · Iocetamic acid · Sodium iopodate · Tyropanoic acid · Calcium iopodate Non-watersoluble Ethyl esters of iodised fatty acids · Iopydol · Propyliodone · Iofendylate X-ray, non-iodinated Barium sulfate MRI Paramagnetic Gadopentetic acid · Gadoteric acid · Gadodiamide · Gadoteridol · Mangafodipir · Gadoversetamide · Ferric ammonium citrate · Gadobenic acid · Gadobutrol · Gadoxetic acid Superparamagnetic Ferumoxsil · Ferristene · Iron oxide, nanoparticles Other Perflubron Ultrasound Microspheres of human albumin · Microparticles of galactose · Perflenapent · Microspheres of phospholipids · Sulfur hexafluoride # = WHO-EM