Radiocontrast

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In diagnostic imaging, radiocontrast agents (also simply contrast agents or contrast materials) are contrast media given to a patient and used to improve the visibility of internal bodily structures in an X-ray image, including computed tomography (CT).

This article does not include other contrast media not based on the transmission of X-rays through the body, such as gadolinium for magnetic resonance imaging, and preparations that circulate microbubbles through the blood for contrast with ultrasonography. Not contrast agents per se, other forms of medical imaging, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), generate images from substances also introduced into the patient's body, but are sources of radiation rather than radiopaque materials to external radiation.

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.

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

Acute kidney injury from radiocontrast is called contrast-induced nephropathy. It 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]

To minimize the risk for contrast-induced nephropathy, various actions can be taken if the patient has predisposing conditions. These have been reviewed in meta-analyses[5][6], although none of the meta-analyses include the more recent randomized controlled trial[7]. A separate meta-analysis addresses interventions in for emergent patients with baseline renal insufficiency.[8]

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.[9][10]

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)[11]:

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
  • 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 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.[12]

Hypo-osmolar, non-ionic contrast agents are beneficial if iso-osmolar, nonionic contrast media is not available due to costs.[13]

Hydration with or without bicarbonate

Randomized controlled trials of sodium bicarbonate[14][15][16][7]
Study name or
first author		 Patients Intervention Primary outcomes Conclusion
Definition Rate in control group Rate in intervention group
Merten (2004)[14] 119 patients with kidney disease (serum creatinine at least 1.1 mg/dL). Mean GFR was 41 mL/min per 1.73 m2 • 3 mL/kg per hour for 1 hour before contrast
• 1 mL/kg per hour for 6 hours during and after contrast		 > 25% rise in serum creatinine within 2 days 13.6% 1.7% Bicarb is beneficial
REMEDIAL (2007)[15] 219 patients with kidney disease (serum creatinine at least 2.0 mg/dL or GFR 40 mL/min per 1.73 m2 or less) undergoing coronary and/or peripheral procedures.
All patients received NAC		 • 3 mL/kg per hour for 1 hour before contrast
• 1 mL/kg per hour for 6 hours during and after contrast
Controls received isotonic saline:
• 3 mL/kg per hour for 1 hour before contrast
• 1 mL/kg per hour for 6 hours during and after contrast		 > 25% rise in serum creatinine within 2 days 9.9% 1.9% Bicarb is beneficial
Maioli (2008)[16] 502 patients with kidney disease (creatinine clearance 60 mL/min per 1.73 m2 or less; mean GFR was 48 mL/min per 1.73 m2) undergoing coronary angiography
All patients received NAC		 • 3 mL/kg per hour for 1 hour before contrast
• 1 mL/kg per hour for 6 hours after contrast
Controls received:
• isotonic saline 1 ml/kg/hr for 12 hours pre/post contrast		 0.5 mg/dl rise in creatinine within 5 days 11.5% 10% Bicarb is not beneficial
Brar (2008)[7] 353 patients with kidney disease (GFR 60 mL/min per 1.73 m2 or less; mean creatinine clearance was 36 - 39 mL/min) undergoing coronary angiography or intervention • 3 mL/kg per hour for 1 hour before contrast
• 1.5 mL/kg per hour for 4 hours during and after contrast
Controls received isotonic saline:
• 3 mL/kg per hour for 1 hour before contrast
• 1.5 mL/kg per hour for 4 hours during and after contrast		 > > 25% fall in GFR within 4 days 14.6% 13.3% Bicarb is not beneficial

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) .[14] 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[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.[17].

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.[18]

Methylxanthines

Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help[8] although studies have conflicting results.[19] The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.[20][21]

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.[22]. 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[23].

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC[24] and one of 600 mg give four times around coronary angiography[25], found statistically insignificant trends towards benefit.

Some authors believe the benefit is not overwhelming.[26] The strongest results were from an unblinded randomized controlled trial that used NAC intravenously.[27] A systematic review by Clinical Evidence concluded that NAC is "likely to beneficial" but did not recommend a specific dose.[28] One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself.[29] 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.[27]

Prophylactic hemodialysis

Randomized controlled trials found benefit from prophylactic hemodialysis for patients with chronic kidney disease and a creatinine over 309.4 µmol/L (3.5 mg.dl) who have elective coronary catheterization, .[30][31]

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.[18][32]

References

  1. ↑ 1.0 1.1 1.2 Coakley F, Panicek D (1997). "Iodine allergy: an oyster without a pearl?". AJR Am J Roentgenol 169 (4): 951-2. PMID 9308442.
  2. ↑ Shehadi W (1975). "Adverse reactions to intravascularly administered contrast media. A comprehensive study based on a prospective survey". Am J Roentgenol Radium Ther Nucl Med 124 (1): 145-52. PMID 1170768.
  3. ↑ van Ketel W, van den Berg W (1990). "Sensitization to povidone-iodine". Dermatol Clin 8 (1): 107-9. PMID 2302848.
  4. ↑ Barrett BJ, Parfrey PS (2006). "Clinical practice. Preventing nephropathy induced by contrast medium". N. Engl. J. Med. 354 (4): 379–86. DOI:10.1056/NEJMcp050801. PMID 16436769. Research Blogging.
  5. ↑ Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC (February 2008). "Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy". Annals of internal medicine 148 (4): 284–94. PMID 18283206. [e]
  6. ↑ Pannu N, Wiebe N, Tonelli M (2006). "Prophylaxis strategies for contrast-induced nephropathy". JAMA 295 (23): 2765-79. DOI:10.1001/jama.295.23.2765. PMID 16788132. Research Blogging.
  7. ↑ 7.0 7.1 7.2 Brar SS, Shen AY, Jorgensen MB, et al (September 2008). "Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial". JAMA : the journal of the American Medical Association 300 (9): 1038–46. DOI:10.1001/jama.300.9.1038. PMID 18768415. Research Blogging.
  8. ↑ 8.0 8.1 Sinert R, Doty CI (2007). "Evidence-based emergency medicine review. Prevention of contrast-induced nephropathy in the emergency department". Annals of emergency medicine 50 (3): 335-45, 345.e1-2. DOI:10.1016/j.annemergmed.2007.01.023. PMID 17512638. Research Blogging.
  9. ↑ McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW (1997). "Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality". Am J Med 103 (5): 368-75. PMID 9375704.
  10. ↑ Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, Legako RD, Leon DF, Murray JA, Nissen SE, Pepine CJ, Watson RM, Ritchie JL, Gibbons RJ, Cheitlin MD, Gardner TJ, Garson A Jr, Russell RO Jr, Ryan TJ, Smith SC Jr (1999). "ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions". J Am Coll Cardiol 33 (6): 1756-824. PMID 10334456.
  11. ↑ Mehran R, Aymong ED, Nikolsky E, et al (2004). "A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation". J. Am. Coll. Cardiol. 44 (7): 1393–9. DOI:10.1016/j.jacc.2004.06.068. PMID 15464318. Research Blogging.
  12. ↑ Aspelin P, Aubry P, Fransson S, Strasser R, Willenbrock R, Berg K (2003). "Nephrotoxic effects in high-risk patients undergoing angiography". N Engl J Med 348 (6): 491-9. PMID 12571256.
  13. ↑ Schwab S, Hlatky M, Pieper K, Davidson C, Morris K, Skelton T, Bashore T (1989). "Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographic contrast agent". N Engl J Med 320 (3): 149-53. PMID 2643042.
  14. ↑ 14.0 14.1 14.2 Merten G, Burgess W, Gray L, Holleman J, Roush T, Kowalchuk G, Bersin R, Van Moore A, Simonton C, Rittase R, Norton H, Kennedy T (2004). "Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial". JAMA 291 (19): 2328-34. PMID 15150204.
  15. ↑ 15.0 15.1 15.2 Briguori C, Airoldi F, D'Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A (2007). "Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies". Circulation 115 (10): 1211-7. PMID 17309916.
  16. ↑ 16.0 16.1 Maioli M, Toso A, Leoncini M, et al (August 2008). "Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention". Journal of the American College of Cardiology 52 (8): 599–604. DOI:10.1016/j.jacc.2008.05.026. PMID 18702961. Research Blogging.
  17. ↑ Mueller C, Buerkle G, Buettner H, Petersen J, Perruchoud A, Eriksson U, Marsch S, Roskamm H (2002). "Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty". Arch Intern Med 162 (3): 329-36. PMID 11822926.
  18. ↑ 18.0 18.1 Solomon R, Werner C, Mann D, D'Elia J, Silva P (1994). "Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents". N. Engl. J. Med. 331 (21): 1416–20. PMID 7969280. [e]
  19. ↑ Bagshaw SM, Ghali WA (2005). "Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis". Arch. Intern. Med. 165 (10): 1087-93. DOI:10.1001/archinte.165.10.1087. PMID 15911721. Research Blogging.
  20. ↑ Huber W, Schipek C, Ilgmann K, et al (2003). "Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency". Am. J. Cardiol. 91 (10): 1157–62. DOI:10.1016/S0002-9149(03)00259-5. PMID 12745095. Research Blogging.
  21. ↑ Huber W, Ilgmann K, Page M, et al (2002). "Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study". Radiology 223 (3): 772–9. PMID 12034949. [e]
  22. ↑ Kay J, Chow W, Chan T, Lo S, Kwok O, Yip A, Fan K, Lee C, Lam W (2003). "Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial". JAMA 289 (5): 553-8. PMID 12578487.
  23. ↑ Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli A (2006). "N-acetylcysteine and contrast-induced nephropathy in primary angioplasty". N Engl J Med 354 (26): 2773-82. PMID 16807414.
  24. ↑ Haase M, Haase-Fielitz A, Bagshaw SM, et al (2007). "Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients". Crit. Care Med. 35 (5): 1324–31. DOI:10.1097/01.CCM.0000261887.69976.12. PMID 17414730. Research Blogging.
  25. ↑ Seyon RA, Jensen LA, Ferguson IA, Williams RG (2007). "Efficacy of N-acetylcysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention". Heart & lung : the journal of critical care 36 (3): 195–204. DOI:10.1016/j.hrtlng.2006.08.004. PMID 17509426. Research Blogging.
  26. ↑ Gleeson TG, Bulugahapitiya S (2004). "Contrast-induced nephropathy". AJR Am J Roentgenol 183 (6): 1673-89. PMID 15547209.
  27. ↑ 27.0 27.1 Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ (2003). "A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study". J. Am. Coll. Cardiol. 41 (12): 2114–8. PMID 12821233. [e]
  28. ↑ Kellum J, Leblanc M, Venkataraman R (2006). "Renal failure (acute)". Clinical evidence (15): 1191–212. PMID 16973048. [e]
  29. ↑ Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK (2004). "The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable". J Am Soc Nephrol 15 (2): 407-10. PMID 14747387.
  30. ↑ Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW (1999). "Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators". Stroke 30 (6): 1223–9. PMID 10356104. [e]
  31. ↑ Lee PT, Chou KJ, Liu CP, et al (2007). "Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial". J. Am. Coll. Cardiol. 50 (11): 1015–20. DOI:10.1016/j.jacc.2007.05.033. PMID 17825709. Research Blogging.
  32. ↑ Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M, Kent KM, Leon MB (1999). "Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency". Am J Cardiol 83 (2): 260-3, A5. PMID 10073832.
  • 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. PMID 2866755.
  • Greenberger PA, Patterson R (1988). "Adverse reactions to radiocontrast media". Prog Cardiovasc Dis 31 (3): 239-48. PMID 3055068.
  • Karnegis JN, Heinz J (1979). "The risk of diagnostic cardiovascular catheterization". Am Heart J 97 (3): 291-7. 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. 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.
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