Contrast Medium Reactions Clinical Presentation

Updated: Jan 25, 2023
  • Author: Nasir H Siddiqi, MD; Chief Editor: Eugene C Lin, MD  more...
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Adverse reactions to ICM are classified as idiosyncratic and nonidiosyncratic. [1, 19, 31, 32, 33, 34, 35] The pathogenesis of such adverse reactions probably involves direct cellular effects; enzyme induction; and activation of the complement, fibrinolytic, kinin, and other systems. Regarding the risk for ICM-related reactions, patients can generally be assigned to 3 categories, as follows: (1) those with an increased risk for idiosyncratic reactions, (2) those with an increased risk for nonidiosyncratic reactions, and (3) those with an increased risk for contrast agent–induced nephropathy.

Idiosyncratic reactions

Idiosyncratic reactions typically begin within 20 minutes of the ICM injection, independent of the dose that is administered. A severe idiosyncratic reaction can occur after an injection of less than 1 mL of a contrast agent.

Although reactions to ICM have the same manifestations as anaphylactic reactions, these are not true hypersensitivity reactions. [36, 37] Immunoglobulin E (IgE) antibodies are not involved. In addition, previous sensitization is not required, nor do these reactions consistently recur in a given patient. For these reasons, idiosyncratic reactions to ICM are called anaphylactic reactions. The symptoms of anaphylactic reaction can be classified as mild, moderate, and severe.

Idiosyncratic reactions may occur in people with a previous reaction to ionic or nonionic ICM, asthma, and/or food or medication allergies.

Previous reactions to ionic or nonionic ICM increase the relative risk of a repeat reaction 3.3- to 6.9-fold compared to the risk in the general population. Approximately 60% of patients who had hives after ICM administration in the past have hives with a repeat exposure. Similarly, facial edema has a recurrence rate in 68% of patients; difficulty breathing, 59%; and bronchospasm, 38%.

Idiosyncratic reactions do not recur in all patients. Patients with a history of a reaction to ICM may report having undergone a recent contrast-enhanced study without adverse manifestations. Nevertheless, these patients still have a higher risk than that of the general population.

People with asthma have 1.2-2.5 times the risk of such reactions than the general population. In addition, when the reactions occur, they are more likely to be severe. Severe reactions are 5-9 times more common in people with asthma than in others.

Patients with allergies, including hay fever, are 1.5-3 times more likely to have an adverse reaction to ICM than other people. However, no consistent data warrant the use of any unique precautions in patients who have seafood or shellfish allergies.

Mild symptoms include the following: scattered urticaria, which is the most commonly reported adverse reaction; pruritus; rhinorrhea; nausea, brief retching, and/or vomiting; diaphoresis; coughing; and dizziness. Patients with mild symptoms should be observed for the progression or evolution of a more severe reaction, which requires treatment. Moderate symptoms include the following: persistent vomiting; diffuse urticaria; headache; facial edema; laryngeal edema; mild bronchospasm or dyspnea; palpitations, tachycardia, or bradycardia; hypertension; and abdominal cramps. Severe symptoms include the following: life-threatening arrhythmias (ie, ventricular tachycardia), hypotension, overt bronchospasm, laryngeal edema, pulmonary edema, seizures, syncope, and death.

A meta-analysis to determine differences in rates of immediate allergic events between classes of gadolinium-based contrast agents (GBCAs) found the overall and severe rates of GBCA allergic-like adverse events were 9.2 and 0.52 per 10 000 administrations, respectively: 81% (539 of 662) were mild, 13% (86 of 662) were moderate, and 6% (37 of 662) were severe reactions. The lowest rate of immediate allergic events was with use of the nonionic linear GBCA gadodiamide (1.5 per 10,000 administrations) in comparison to those of ionic linear GBCAs (8.3 per 10,000 administrations) or nonionic macrocyclic GBCAs (16 per 10,000 administrations). A higher rate of immediate allergic adverse events was associated with ionicity, protein binding, and macrocyclic structure. [38]

Nonidiosyncratic reactions

Nonidiosyncratic reactions include the following: bradycardia, hypotension, and vasovagal reactions; neuropathy; cardiovascular reactions; extravasation; and delayed reactions. Other nonidiosyncratic reactions include sensations of warmth, a metallic taste in the mouth, and nausea and vomiting.

ICM administration can aggravate diseases such as cardiac arrhythmias, angina, and pheochromocytoma.

In patients who have received interleukin-2 immunotherapy for cancer, ICM administration increases the incidence and severity of delayed reactions. These reactions primarily include fevers, chills, rigors, flushing, dizziness, and, occasionally, hypotension. These reactions can occur even if immunotherapy is administered as long as 2 years before ICM administration.

Metformin, an oral antihyperglycemic medication that is excreted predominantly by the kidneys, is not nephrotoxic per se, and it does not cause hypoglycemia in and of itself. If patients who receive metformin become azotemic, increased tissue levels of metformin may rarely induce life-threatening lactic acidosis. The drug should be discontinued in all patients at the time of or before any intravascular contrast-enhanced study is performed. Moreover, metformin administration should be withheld for at least 48 hours after the contrast-enhanced study, and its administration should be resumed only after the absence of renal dysfunction has been documented.

Through their pharmacodynamic effects, beta-blockers can aggravate ICM-induced bradycardia, other cardiac arrhythmias, hypotension, and bronchospasm; these conditions can interfere with the treatment of ICM-related adverse events.

When possible, the intravenous administration of contrast material should be avoided in pregnant women. Results of in vitro experiments have shown that contrast material is mutagenic to human cells; however, a few studies have failed to reveal a teratogenic effect in animals. Intravascular ICM crosses the placenta and can potentially produce transient fetal hypothyroidism. Lasting adverse effects on the fetus or neonates have not been identified. Nonetheless, nonionic agents are preferred to conventional ionic agents in pregnant women.

By inducing heightened systemic parasympathetic activity, ICM can precipitate bradycardia (eg, decreased discharge rate of the sinoatrial node, delayed atrioventricular nodal conduction) and peripheral vasodilatation. The end result is systemic hypotension with bradycardia. This may be accompanied by other autonomic manifestations, including nausea, vomiting, diaphoresis, sphincter dysfunction, and mental status changes. If left untreated, these effects can lead to cardiovascular collapse and death. Some vasovagal reactions may be a result of coexisting circumstances such as emotion, apprehension, pain, and abdominal compression, rather than ICM administration.

Cardiovascular reactions

ICM can cause hypotension and bradycardia. Vasovagal reactions, a direct negative inotropic effect on the myocardium, and peripheral vasodilatation probably contribute to these effects. The latter 2 effects may represent the actions of cardioactive and vasoactive substances that are released after the anaphylactic reaction to the ICM. This effect is generally self-limiting, but it can also be an indicator of a more severe, evolving reaction.

ICM can lower the ventricular arrhythmia threshold and precipitate cardiac arrhythmias and cardiac arrest. Fluid shifts due to an infusion of hyperosmolar intravascular fluid can produce an intravascular hypervolemic state, systemic hypertension, and pulmonary edema. Also, ICM can precipitate angina.

The similarity of the cardiovascular and anaphylactic reactions to ICM can create confusion in identifying the true nature of the type and severity of an adverse reaction; this confusion can lead to the overtreatment or undertreatment of symptoms.

Other nonidiosyncratic reactions include syncope; seizures; and the aggravation of underlying diseases, including pheochromocytomas, sickle cell anemia, hyperthyroidism, and myasthenia gravis.


Extravasation of ICM into soft tissues during an injection can lead to tissue damage as a result of direct toxicity of the contrast agent or pressure effects, such as compartment syndrome.

A systematic review of 17 papers reporting 2191 extravasations in 1,104,872 patients (0.2%) undergoing computed tomography (CT) or magnetic resonance imaging (MRI) reported that extravasation rates were 0.045% for gadolinium-based contrast agents (GBCA) for MRI and were nearly 6-fold higher (0.26%) for iodinated contrast agents used in CT. Factors associated with increased contrast media extravasations included older age, female gender, using an existing IV line instead of placing a new IV in radiology, inpatient status, use of automated power injection, high injection rates, catheter location, and failing to warm up the more viscous contrast media to body temperature. [39]

Delayed reactions

In a study by Egbert et al, delayed reactions become apparent at least 30 minutes after, but within 7 days after, the ICM injection. These reactions were identified in as many as 14-30% of patients after the injection of ionic monomers and in 8-10% of patients after the injection of nonionic monomers. [40]

Common delayed reactions include the development of flulike symptoms, such as fatigue, weakness, upper respiratory tract congestion, fevers, chills, nausea, vomiting, diarrhea, abdominal pain, pain in the injected extremity, rash, dizziness, and headache. Less frequently reported manifestations are pruritus, parotitis, polyarthropathy, constipation, and depression. These signs and symptoms almost always resolve spontaneously; usually, little or no treatment is required. Some delayed reactions may be coincidental.

Barr et al found that pediatric patients (< 18 yr) who were exposed to iodinated contrast media (ICM) were at higher risk for iodine-induced thyroid dysfunction. The risk of incident hypothyroidism was found to be significantly higher following ICM exposure. The median interval between exposure and onset of hypothyroidism was 10.8 months, and in hypothyroid cases, the median serum thyroid-stimulating hormone concentration was 6.5 mIU/L (interquartile range, 5.8-9.6). The authors noted that children receiving ICM should be monitored for iodine-induced thyroid dysfunction, particularly during the first year after exposure. [41]

Contrast agent–induced nephropathy

Contrast agent–related nephropathy is an elevation of the serum creatinine level that is more than 0.5 mg% or more than 50% of the baseline level at 1-3 days after the ICM injection. The elevation peaks by 3-7 days, and the creatinine level usually returns to baseline in 10-14 days. The incidence of contrast agent–related nephropathy in the general population is estimated to be 2-7%. [42]

As many as 25% of patients with this nephropathy have a sustained reduction in renal function, most commonly when the nephropathy is oliguric. [43, 44]  The mechanism of this type of nephropathy is thought to be a combination of preexisting hemodynamic alterations; renal vasoconstriction, possibly through mediators such endothelin and adenosine; and direct ICM cellular toxicity.

Patients with preexisting renal insufficiency have 5-10 times the risk of ICM-related nephropathy. Patients whose renal failure is the result of diabetic nephropathy are at the greatest risk. Azotemic diabetic patients also have the highest incidence of irreversible renal deterioration. In general, the higher the preexisting serum creatinine level, the greater the likelihood of contrast agent–induced nephrotoxicity.

Other factors that are implicated in increasing the risk of renal failure after ICM administration include American Heart Association class IV congestive heart failure, dehydration, hyperuricemia, concomitant use of nephrotoxic drugs such as aminoglycoside antibiotics and nonsteroidal anti-inflammatory agents (NSAIDs), advanced age, and large doses of ICM for a single study or multiple contrast-enhanced studies that are performed within a short period.

Diseases that affect renal hemodynamics, such as cirrhosis and nephrotic syndrome, are also suspected of increasing a patient's susceptibility to renal damage from ICM. Diabetes mellitus alone is a controversial risk factor. Many authorities do not regard the presence of diabetes mellitus in the absence of renal failure as a risk factor for contrast agent–induced nephropathy.

The risk of nephropathy is magnified when multiple risk factors are present in the same patient. Results of one study identified heart failure, low BMI, and repeated contrast material administration as risk factors for contrast material–induced nephropathy (CIN). [45] Well-hydrated patients with myeloma who receive contrast material have a low incidence of subsequent renal failure (0.6-1.25%). There is evidence to support hydration as a preventive measure in patients at high risk for CIN. [45]