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Iodinated Contrast Media: Adverse Effects, Contraindications, and Dosing

Classification of Iodinated Contrast Media

Iodinated contrast media (ICM) enhance the visualization of anatomic structures and physiologic functions during radiologic imaging procedures, see also intravenous urography, cystography, retrograde urethrography, retrograde pyelography, and computed tomography.

High-Osmolality Iodinated Contrast Media:

High-osmolality contrast media represent the first generation of iodinated contrast agents and are, in most high-resource settings, no longer used for routine intravascular administration. Their monomeric ionic structure, with dissociation of sodium and methylglucamine, results in an osmolality approximately five- to sevenfold higher than serum osmolality (high-osmolality contrast media, HOCM). When administered orally, these agents act as osmotic laxatives. Examples include amidotrizoate (diatrizoate) in various concentrations (Gastrografin, Urografin) for imaging of the gastrointestinal tract, retrograde pyelography, or cystography.

Low-Osmolality Iodinated Contrast Media:

Low-osmolality iodinated contrast media are modern nonionic agents with an osmolality of approximately 300 to 800 mOsm/kg H₂O (low-osmolality contrast media, LOCM). They are further classified by molecular structure (monomeric versus dimeric compounds).

Monomeric Nonionic Contrast Media:

Iohexol (Omnipaque), Iopamidol (Isovue), Ioversol (Optiray), and Iopromide (Ultravist) are examples of widely used nonionic, low-osmolality monomeric contrast media.

Dimeric Nonionic Contrast Media:

Dimeric iodinated contrast agents contain two tri-iodinated, substituted benzene rings. Iodixanol (Visipaque) is most commonly used and exhibits iso-osmolar properties.

Mechanism of Action

Because of iodine's high atomic number, iodinated contrast media attenuate X-rays substantially more than blood, soft tissue, or urine. Following intravascular administration, they opacify the blood vessels. Within minutes, they increase the contrast between parenchymal organs and surrounding tissues, thereby improving the visibility on radiography and computed tomography (CT). During the excretory phase, the contrast medium is filtered by the glomeruli, providing high-contrast visualization of the kidneys and the urinary tract.

Pharmacokinetics

Iodinated contrast media are usually administered intravenously or intraarterially with complete bioavailability. They distribute rapidly within the extracellular fluid compartment, exhibit low plasma protein binding, and undergo virtually no metabolic transformation. Elimination predominantly occurs in the unchanged form via glomerular filtration in the kidneys, with a plasma half-life of approximately 1 to 2 hours in individuals with normal renal function. In patients with impaired renal function, the half-life increases significantly, and a smaller fraction may be excreted via the biliary or intestinal route.

Adverse Effects of Iodinated Contrast Media

Allergic-Like Reactions to Iodinated Contrast Media:

Patients may experience either pseudoallergic (anaphylactoid) reactions without prior sensitization (idiosyncratic reactions) or true type I IgE-mediated allergic reactions after previous sensitization.

Mild Reactions:

Mild reactions include a metallic taste, a sensation of warmth, sneezing, coughing, and limited urticaria; they occur in approximately 1% of patients receiving LOCM.

Moderate Reactions:

Moderate reactions (approximately 1% to 0.1%) include vomiting, generalized urticaria, facial edema, headache, and palpitations or tachycardia.

Severe, Potentially Life-Threatening Reactions:

Severe reactions (approximately 0.1% to 0.01%) include hypotension, tachycardia, shock, bronchospasm, laryngeal edema, pulmonary edema, and loss of consciousness. The overall mortality attributable to intravascular administration of modern iodinated contrast media is very low, on the order of approximately 1 in 1,000,000 examinations.

Risk Factors for an Allergic-Like Reaction:

Risk factors for allergic-like reactions include atopy, asthma, a history of a previous moderate or severe contrast media reaction, and other significant allergic diseases.

Thyroid Dysfunction Induced by Iodinated Contrast Media:

Iodine exposure from contrast media can precipitate hyperthyroidism, and, in severe cases, a thyrotoxic crisis. Risk factors for contrast-induced hyperthyroidism include overt or subclinical hyperthyroidism, iodine deficiency goiter, and autonomously functioning thyroid nodules. In rare cases, particularly in patients with autoimmune thyroid disease, a transient hypothyroidism may occur.

Renal Adverse Effects of Iodinated Contrast:

Osmotically induced diuresis can contribute to intravascular volume depletion, subsequent renal vasoconstriction, and a usually reversible reduction in glomerular filtration rate (GFR). In addition, iodinated contrast media may promote oxidative stress and the generation of reactive oxygen species, which can directly cause tubular injury. With modern low-osmolality and iso-osmolar agents, the causal contribution of contrast media to acute kidney injury is considered more limited than previously thought; the condition is frequently referred to as post-contrast acute kidney injury (PC-AKI), reflecting its often multifactorial pathogenesis.

Acute Kidney Injury (AKI):

Typical contrast-associated acute kidney injury presents with oliguria and a rise in serum creatinine, usually peaking 3 to 5 days after contrast administration. The incidence with high-osmolality agents has been reported at approximately 1:1,000 to 1:5,000; with modern low-osmolality and iso-osmolar agents (LOCM/IOCM), the incidence is considerably lower.

Risk Factors for AKI:

Risk factors for contrast-associated AKI include preexisting chronic kidney disease, diabetic nephropathy, dehydration, heart failure, hyperuricemia, proteinuria, repeated contrast administration within 24 hours, age over 70 years, multiple myeloma (especially in the presence of dehydration or hypercalcemia), and concomitant nephrotoxic medication (e.g., NSAIDs and gentamicin).

Lactic Acidosis:

In patients with renal impairment who are treated with metformin, the development of acute kidney injury can lead to lactic acidosis with a high case fatality rate. According to current recommendations, metformin does not need to be discontinued routinely before intravenous contrast administration in patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min and no evidence of acute kidney injury. In patients with an eGFR less than 30 mL/min, with acute kidney injury, or in those receiving intraarterial contrast media with first-pass exposure of the kidneys, metformin should be withheld from the time of contrast administration. The eGFR should be reassessed within 48 hours, and metformin can be resumed if renal function remains stable.

Cardiovascular Adverse Effects of Iodinated Contrast Media:

The intravascular volume load and osmotic effects of iodinated contrast media can exacerbate preexisting heart failure and may precipitate pulmonary edema; rarely, cardiac arrhythmias or ischemic events may occur.

Central Nervous System (CNS) Adverse Effects:

CNS complications occur primarily in patients with a disrupted blood–brain barrier, cerebral ischemia, trauma, epilepsy, or intracranial tumors, particularly in the setting of intraarterial contrast administration.

Rare Adverse Effects:

Rare severe adverse effects include toxic epidermal necrolysis (Lyell syndrome), iodide-induced sialadenitis (“iodide mumps”), and other very uncommon but serious cutaneous or systemic reactions.

Contraindications to Iodinated Contrast Media

Severe, untreated renal insufficiency, a history of severe contrast media reactions, overt hyperthyroidism, and pronounced dehydration represent important risk constellations or relative contraindications. In situations of vital or compelling diagnostic indication, administration of contrast media may still be justified after careful risk–benefit assessment and, if appropriate, the implementation of preventive measures (e.g., optimization of thyroid function, adequate volume replacement).

Drug Interactions

• Metformin: There is a risk of lactic acidosis in the setting of contrast-associated acute kidney injury; management is described in the section on adverse effects.
• Nephrotoxic medications: Concomitant use of nephrotoxic drugs, such as NSAIDs, aminoglycosides, high-dose diuretics, or certain oncologic agents (e.g., cisplatin), increases the risk of acute kidney injury.
• Iodine saturation of the thyroid gland can persist for several weeks and may interfere with laboratory thyroid testing, thyroid scintigraphy, and radioiodine therapy (e.g., radioiodine ablation may need to be postponed).
• β-Blockers: may worsen or mask anaphylactic reactions and make them more difficult to treat.

Prevention of Adverse Effects of Iodinated Contrast Media

Prevention of Nephrotoxicity:

In patients with preexisting renal insufficiency or dehydration, adequate intravenous volume expansion before and after contrast administration is crucial and can significantly reduce the risk of post-contrast acute kidney injury. Current recommendations favor isotonic crystalloid solutions (e.g., 0.9% sodium chloride or balanced electrolyte solutions) at approximately 1 to 3 mL/kg body weight per hour, starting about 6–12 hours before the examination and continuing for up to 6–12 hours afterward. For outpatients, oral hydration before and after the examination is sufficient. Before the contrast agent is administered, 500 ml of 0.9% NaCl is administered as a bolus infusion.

Prevention of Hyperthyroidism:

In patients with normal thyroid-stimulating hormone (TSH) levels and normal thyroid hormone concentrations, iodinated contrast media can usually be administered safely without specific prophylaxis.

The risk of iodine-induced hyperthyroidism is increased in patients with subclinical hyperthyroidism (suppressed TSH with normal thyroid hormone levels) and in those with suspected autonomous thyroid function (multinodular goiter or autonomous adenoma). Hyperthyroidism can be prevented by blocking iodine uptake by the thyroid gland with perchlorate (Irenat) orally before KM administration. Thyroid hormone levels must be monitored afterwards.

In patients with manifest hyperthyroidism, elective administration of iodinated contrast media is contraindicated. In emergencies with vital indications, contrast administration may be considered after consultation with an endocrinologist and appropriate premedication.

Premedication in Patients with an Allergic Risk Profile:

Premedication may be indicated in patients with a history of previous contrast media reactions, particularly after moderate or severe reactions; it may also be considered in individuals with pronounced atopy or poorly controlled asthma. The evidence for premedication is limited, and severe reactions can still occur despite prophylaxis.

Oral Premedication:

Oral premedication typically begins 12 hours before contrast administration and may consist of prednisolone 30 mg given 12 hours, 6 hours, and 1 hour before contrast exposure, dimetindene 1 mg orally 12 hours and 1 hour before contrast administration, and cimetidine 200 mg orally 12 hours and 1 hour before contrast administration.

Dosage of Iodinated Contrast Media

The dosing of iodinated contrast media is primarily based on the total iodine load. Iodine concentration is usually expressed as milligrams of iodine per milliliter (mg I/mL). For an intravenous urography, 1 to 1.5 mL/kg body weight of a contrast medium with a concentration of 300 mg I/mL is typically administered.

Modern CT protocols adjust the dose and concentration of the contrast agent specifically for each examination. In CT angiography, for example, high vascular contrast is desired. To achieve this, higher-concentration preparations (e.g., 350–400 mg I/ml) are administered quickly and precisely with a lower injection volume using a modern contrast agent injector.

References

Bettmann 2004 BETTMANN, Michael A.: Frequently asked questions: iodinated contrast agents.
In: Radiographics
24 Suppl 1 (2004), Oct, S. S3–10

European Society of Urogenital Radiology (ESUR): Guidelines on Contrast Agents.

  Deutsche Version: Nebenwirkungen und Kontraindikationen von jodhaltigen Kontrastmitteln

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