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Contrast Medium Reactions

  • Author: Nasir H Siddiqi, MD; Chief Editor: Eugene C Lin, MD  more...
 
Updated: Jun 02, 2016
 

Overview

Since their introduction in the 1950s, organic radiographic iodinated contrast media (ICM) have been among the most commonly prescribed drugs in the history of modern medicine. The phenomenon of present-day radiologic imaging would be lacking without these agents. ICM generally have a good safety record. Adverse effects from the intravascular administration of ICM are generally mild and self-limited; reactions that occur from the extravascular use of ICM are rare.[1] Nonetheless, severe or life-threatening reactions can occur with either route of administration.[2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]

For ICM classifications, see the image below.

Classification of iodinated contrast agents by the Classification of iodinated contrast agents by their molecular structures.

Radiologists and other physicians must be aware of the risk factors for reactions to contrast media, use strategies to minimize adverse events, and be prepared to promptly recognize and manage any reactions to the contrast media.[14, 15, 16, 17, 18]

Skin testing

Brockow et al performed a prospective study to determine the specificity and sensitivity of skin tests in patients who have experienced contrast-related reactions and found that skin test specificity was 96-100%. Skin prick, intradermal, and patch tests were conducted in 220 patients with either immediate or nonimmediate reaction. For immediate reactors, the intradermal tests were the most sensitive, whereas delayed intradermal tests in combination with patch tests were needed for optimal sensitivity in nonimmediate reactors. Contrast medium cross-reactivity was more common in the nonimmediate than in the immediate group. The data suggested that at least 50% of hypersensitivity reactions to contrast media are caused by an immunologic mechanism. Skin testing appears to be a useful tool for diagnosis of contrast medium allergy and may play an important role in selection of a safe product in previous reactors.[13]

In a retrospective study of 37 patients with suspected immediate hypersensitivity reaction to iodinated contrast media (ICM), the negative predictive value for skin tests and intravenous provocation test (IPT) with low dose ICM was 80% (95% CI 44-97%).[19]

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Types of Iodinated Contrast Media

Approach considerations

All currently used ICM are chemical modifications of a 2,4,6-tri-iodinated benzene ring.[1] They are classified on the basis of their physical and chemical characteristics, including their chemical structure, osmolality, iodine content, and ionization in solution. In clinical practice, categorization based on osmolality is widely used.

Osmotic effects of contrast media that are specific for the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Secondary effects include osmotically induced diuresis with a dehydrating effect.[20, 21]

High-osmolality contrast media

High-osmolality contrast media consist of a tri-iodinated benzene ring with 2 organic side chains and a carboxyl group. The iodinated anion, diatrizoate or iothalamate, is conjugated with a cation, sodium or meglumine; the result is an ionic monomer (see the image below). The ionization at the carboxyl-cation bond makes the agent water soluble. Thus, for every 3 iodine atoms, 2 particles are present in solution (ie, a ratio of 3:2).

Classification of iodinated contrast agents by the Classification of iodinated contrast agents by their molecular structures.

The osmolality in solution ranges from 600 to 2100 mOsm/kg, versus 290 mOsm/kg for human plasma. The osmolality is related to some of the adverse events of these contrast media.

Ionic monomers are subclassified by the percentage weight of the contrast agent molecule in solution (eg, 30% or 76%).

In the United States, commonly used high-osmolality ICM are Renografin (diatrizoate anion; Bracco Diagnostics Inc, Princeton, NJ ) or Hypaque (diatrizoate anion; GE Healthcare, Inc, Princeton, NJ) and Conray (iothalamate anion; tyco Healthcare and Mallinckrodt Inc, St. Louis, Mo).

Low-osmolality contrast media

There are 3 types of low-osmolality ICM: (1) nonionic monomers, (2) ionic dimers, and (3) nonionic dimers.

Nonionic monomers

In nonionic monomers, the tri-iodinated benzene ring is made water soluble by the addition of hydrophilic hydroxyl groups to organic side chains that are placed at the 1, 3, and 5 positions. Lacking a carboxyl group, nonionic monomers do not ionize in solution. Thus, for every 3 iodine atoms, only 1 particle is present in solution (ie, a ratio of 3:1). Therefore, at a given iodine concentration, nonionic monomers have approximately one half the osmolality of ionic monomers in solution. At normally used concentrations, 25-76%, nonionic monomers have 290-860 mOsm/kg.

Nonionic monomers are subclassified according to the number of milligrams of iodine in 1 mL of solution (eg, 240, 300, or 370 mg I/mL).

The larger side chains increase the viscosity of nonionic monomers compared with ionic monomers. The increased viscosity makes nonionic monomers harder to inject, but it does not appear to be related to the frequency of adverse events.

Common nonionic monomers are iohexol (Omnipaque; GE Healthcare, Inc), iopamidol (Isovue; Bracco Diagnostics Inc), ioversol (Optiray; tyco Healthcare and Mallinckrodt Inc), and iopromide (Ultravist; Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ).

The nonionic monomers are the contrast agents of choice. In addition to their nonionic nature and lower osmolalities, they are potentially less chemotoxic than the ionic monomers.

Ionic dimers

Ionic dimers are formed by joining 2 ionic monomers and eliminating 1 carboxyl group. These agents contain 6 iodine atoms for every 2 particles in solution (ie, a ratio of 6:2). The only commercially available ionic dimer is ioxaglate (Hexabrix; tyco Healthcare and Mallinckrodt Inc). Ioxaglate has a concentration of 59%, or 320 mg I/mL, and an osmolality of 600 mOsm/kg. Because of its high viscosity, ioxaglate is not manufactured at higher concentrations. Ioxaglate is used primarily for peripheral arteriography.

Nonionic dimers

Nonionic dimers consist of 2 joined nonionic monomers. These substances contain 6 iodine atoms for every 1 particle in solution (ie, ratio of 6:1). For a given iodine concentration, the nonionic dimers have the lowest osmolality of all the contrast agents. At approximately 60% concentration by weight, these agents are iso-osmolar with plasma. They are also highly viscous and, thus, have limited clinical usefulness. Examples of nonionic dimers are iotrol and iodixanol (Visipaque; Amersham Health Inc, Princeton, NJ).

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Adverse Reactions to ICM

Overview

Adverse reactions to ICM are classified as idiosyncratic and nonidiosyncratic.[1, 15, 22, 23, 24, 25, 26] The pathogenesis of such adverse reactions probably involves direct cellular effects; enzyme induction; and activation of the complement, fibrinolytic, kinin, and other systems.

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.[27, 28] 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.

Mild symptoms

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

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

Severe symptoms include the following: life-threatening arrhythmias (ie, ventricular tachycardia), hypotension, overt bronchospasm, laryngeal edema, pulmonary edema, seizures, syncope, and death.

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.

Bradycardia, hypotension, and vasovagal reactions

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. 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.

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%. As many as 25% of patients with this nephropathy have a sustained reduction in renal function, most commonly when the nephropathy is oliguric.[29, 30]

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.

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

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.

Delayed reactions

Delayed reactions become apparent at least 30 minutes after but within 7 days of the ICM injection. These reactions are 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.[31]

Common delayed reactions include the development of flulike symptoms, such as the following: 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.

Pediatric patients (<18 yr) who were exposed to iodinated contrast media (ICM) were found to be at higher risk for iodine-induced thyroid dysfunction. The risk of incident hypothyroidism was found to be significantly higher following ICM exposure (OR 2.60, 95% CI 1.43 - 4.72, p<0.01). 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 following exposure.[32]

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Incidence of Adverse Reactions to ICM

The incidence of any adverse reaction to ICM is about 15%. Most of these reactions are mild and require no treatment.

Ionic ICM versus nonionic ICM

In a large Japanese case series (337,647 cases), the overall risk of any adverse reaction was 12.66% with ionic ICM and 3.13% with nonionic ICM; the risk of a severe adverse drug reaction was 0.2% for ionic ICM and 0.04% for nonionic ICM; and the risk of a very severe adverse drug reaction was 0.04% for ionic ICM and 0.004% for nonionic ICM.[33]

In another large study, in which 6000 patients received ionic ICM, the incidence of mild adverse drug reactions was 2.5%; moderate reactions, 1.2%; and severe reactions, 0.4%.[34] However, in 7170 patients who received nonionic ICM, the incidences were only 0.58% for mild reactions, 0.11% for moderate reactions, and 0% for severe reactions.[35]

Dillman et al performed a retrospective review of 11,306 children (age <19 yr) who received intravenous administration of low-osmolality nonionic ICM over a 6.5-year period (January 1999 to June 2006) at their institution.[36] Overall, the authors found that 0.18% of the children had acute allergic-like reactions to the contrast agent; of the affected patients, 80% of the reactions were categorized as mild, 5% as moderate, and 15% as severe.

High-osmolality ICM versus low-osmolality ICM

A meta-analysis of the published data from 1980-1989 by Caro et al revealed that the risk of severe adverse reaction was 0.157% for high-osmolality ICM and 0.031% for nonionic ICM.[37] The investigators found that the risk of death was 1 death in 100,000 patients with either type of agent.

Other reports indicate that low-osmolality agents are somewhat less nephrotoxic in patients with azotemia than in other patients.[38] Nonionic ICM are less likely than conventional ionic ICM to cause tissue damage when they are extravasated.[39] Nonetheless, compartment syndromes and skin blistering are reported after the extravasation of nonionic agents.

Some toxic effects of ICM, such as nausea and vomiting, are more common with ionic dimers than with nonionic monomers.[40] Most authorities believe that the preponderance of evidence that supports the lower rate of adverse reactions with low-osmolality ICM compared with high-osmolality ICM is conclusive.

The reason that low-osmolality ICM have not completely replaced the older high-osmolality ICM is the higher cost of the low-osmolality agents. Professional organizations have formulated guidelines regarding the selective use of low-osmolality ICM for certain high-risk patients. However, with the selective use of nonionic ICM, severe adverse contrast reactions are 3 times as likely in low-risk patients who receive conventional ionic agents (0.09%) than in high-risk patients who receive nonionic agents (0.03%). Thus, the single most important risk factor for an adverse reaction is the type of contrast agent that is chosen for injection.

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Risk Factors for Adverse Reactions to ICM

Regarding the risk for ICM-related reactions, patients can be assigned to 3 categories, as follows: (1) those with an increased risk for idiosyncratic reactions, (2) those with an increased risk for contrast agent–induced nephropathy, and (3) those with an increased risk for nonidiosyncratic reactions.

Risk factors related to idiosyncratic reactions

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 with 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.

Risk factors related to contrast agent–induced nephropathy

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 the following: 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).[41] 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.[41]

Risk factors related to nonidiosyncratic reactions

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 (Glucophage; Bristol-Myers Squibb Co, Princeton, NJ), 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.

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Prophylaxis for Adverse Reactions to ICM

Prophylactic medications

Corticosteroid prophylaxis is the standard of care in the United States[1]  for the prevention of allergic contrast reactions. However, corticosteroid prophylaxis is more controversial in Europe. For example, corticosteroid prophylaxis is only suggested by European guidelines[42] , and not recommended by United Kingdom guidelines.[43] Prophylaxis is controversial because there is no level I evidence supporting its use for the prevention of severe reactions to low osmolar contrast media (level I evidence only exists for high osmolar media). In addition, despite premedication, severe breakthrough reactions can occur.[44, 45]

Corticosteroid premedication before IV administration of iodinated contrast material has been found to reduce the overall risk of a contrast reaction, although its efficacy in the prevention of moderate and severe reactions is more controversial.[44] As severe contrast reactions—even in at-risk patients—are rare, a large number of patients would need to be premedicated to acheive any effect. In a study by Mervak et al,[45] it was estimated that 69 patients would need to be premedicated to prevent a reaction of any severity, and 569 patients would need to be premedicated to prevent a severe reaction.

In the same Mervak study,[45] patients premedicated for a previous allergic-like contrast reaction had a breakthrough rate 3 to 4 times the ordinary reaction rate when undergoing CT with iodinated low-osmolality contrast material. For comparison, in patients who have had a previous allergic-like reaction to the same class of contrast material, the risk of reaction to IV low osmolar contrast media in the absence of corticosteroid prophylaxis has been estimated to be 5 to 6 times that of the general population.

In a study of 190 breakthough allergic-like reactions to intravenous low osmolar contrast media, Davenport et al found that most premedicated patients will not experience breakthrough reactions, although premedication does not eliminate the risk.[46] The severity of breakthrough reactions is usually similar to the index reaction. For example, patients who experience a mild index reaction have a very low risk of a severe breakthrough reaction. Patients with moderate or severe index reactions are at high risk of experiencing another moderate or severe reaction if another breakthrough event occurs.

Kolbe et al suggest that premedication in patients with only an index reaction of urticaria is not necessary.[47] In these patients, premedication did not decrease the risk of repeat reactions, and most patients who were not premedicated did not have a subsequent reaction. When patients did experience a reaction, it was similar to the index event.

In a study by Lasser et al, methylprednisolone, 2 oral doses of 32 mg each administered at 12 and 2 hours before ICM administration, reduced the incidence of all adverse reactions to ionic ICM from 9% to 6.4%.[34] The frequency of severe reactions that required treatment was also reduced, from 2% to 1.2%. However, a single dose of 32 mg of methylprednisolone that was given 2 hours before ICM administration had virtually no effect. In the same study, oral corticosteroid premedication in 2 doses, one 6-24 hours before and the other 2 hours before ICM injection, significantly reduced the incidence of the total number of ICM-related adverse reactions from 5% to 2%.[34]

Greenberger et al showed that a premedication regimen of 50 mg of oral prednisolone at 13 hours, 7 hours, and 1 hour before injection of the contrast material and 50 mg of oral diphenhydramine at 1 hour before ICM injection substantially reduced the rate of adverse reactions from 9% to 7% in those with previous reactions, compared with historical control subjects.[48]

In another study, premedication with a single 100-mg tablet of hydroxyzine 12 hours before the intravenous injection of the ionic dimer ioxaglate reduced the incidence of adverse reactions compared with placebo (2 reactions in the treatment group vs 25 reactions in placebo group, all mild).

Studies of the potential role of H2 blockers, such as cimetidine, have shown a beneficial effect, no effect, or even adverse effects with the addition of H2 blockers to the premedication regimen.

Some investigators have incorporated ephedrine into their premedication regimens. Because of concern about the sympathomimetic cardiac effects of ephedrine, its use has not gained wide acceptance.

In a study by Dillman et al of allergic-like breakthrough reactions to IV gadolinium-containing contrast following premedication with corticosteroids and antihistamines, there were 9 breakthrough reactions (8 of which occurred in adults), with 6 being mild and 3 being moderate. All of the patients who had reactions had a previous history of reactions to either gadolinium- or iodine-containing contrast media. There were no severe or fatal breakthrough reactions.[2]

On September 9, 2010, the FDA announced the requirement that gadolinium-based contrast agents (GBCAs) carry new warnings on their labels about the risk for nephrogenic systemic fibrosis (NSF) and its association when administered to certain patients with kidney disease. The FDA’s review of the safety of the most widely used GBCAs determined that Magnevist, Omniscan, and Optimark were associated with a greater risk than other GBCAs for NSF and would be described as inappropriate for use in certain patients with kidney disease.[49]

Recommended prophylactic regimens

Methylprednisolone, one 32-mg tablet, may be orally administered at 12 and 2 hours before the study, or prednisone, one 50-mg tablet, may be orally administered 13 hours, 7 hours, and 1 hour before the contrast-enhanced study.

If the patient had a previous moderate or severe reaction to ICM or one that included a respiratory component, an alternative study, such as ultrasonography or magnetic resonance imaging (MRI), should be considered. Otherwise, the following may be used: H1 antihistamines; diphenhydramine, one 50-mg tablet orally administered 1 hour before the study; H2-histamine receptor blockers, which is optional; cimetidine, 300 mg orally administered 1 hour before the study; and/or ranitidine 50 mg orally administered 1 hour before the study.

Most authorities restrict corticosteroid pretreatment to patients in whom previous idiosyncratic adverse reactions to ICM were moderate or severe. Usually, corticosteroids are well tolerated and cause no adverse effects when only a few doses are administered.

Although the utility of H2-receptor blockers is questionable, these agents are well tolerated and might be of benefit, particularly because they are effective in the treatment of at least some allergic cutaneous reactions to agents other than ICM. However, H2 blockers should not be used without H1 blockers.

The treatment of the nonidiosyncratic adverse reactions of nausea and vomiting is not considered a routine indication for corticosteroid premedication or the use of nonionic ICM.

Reducing the incidence of ICM nephropathy

Other nephrotoxic drugs should be discontinued whenever possible, and the minimal amount of contrast material that is needed to perform a diagnostic study should be used. Nonionic agents are the ICM of choice. If multiple studies are required, time (as long as 5 days) should be allotted between the studies to allow the kidneys to recover fully from the ICM injection. Patients can be well hydrated until 12 hours before a contrast-enhanced study, and hydration should be continued for at least 2 hours after a contrast-enhanced procedure is performed.[22]

Other measures

Use of mannitol or furosemide is not recommended, at least in patients with diabetic nephropathy. In several studies, these medications were not effective in reducing the incidence of ICM nephropathy. In other studies, the incidence of nephropathy was higher in patients who were given mannitol or furosemide. The use of mannitol or dopamine at renal vasodilatory doses or atrial natriuretic peptide reduced the incidence of ICM nephropathy in nondiabetic azotemic patients, compared with azotemic patients who received only hydration with sodium chloride solution.

Several investigators have suggested that ICM nephrotoxicity can be reduced with the use of oral or intravenous theophylline, acetylcysteine, fenoldopam, or bosentan (an endothelin antagonist). Research with these agents is promising, but results are preliminary.[50] Some prospective studies have suggested that prophylactic administration of 600 mg acetylcysteine twice daily in combination with hydration reduces the incidence of ICM nephrotoxicity.[51]

Prophylaxis in nonvascular studies

Although rare, systemic reactions are reported after extravascular instillation of ICM (eg, during retrograde pyelography).[39]

When patients have had previous severe idiosyncratic or anaphylactic reactions to intravenous ICM, premedication with corticosteroids should be considered, even in nonvascular studies.

Rate and temperature of ICM injection

The perception that adverse reactions to ICM, particularly nausea and vomiting, are more common with a rapid rate of injection than with a slow injection has been refuted by findings from 2 studies.[52, 53]

Warming ICM to body temperature reduces their viscosity and may make the injection more comfortable for the patient.

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Evaluating the Patient Before ICM Administration

A pertinent patient medical history should be obtained, and the following elements should be stressed: history of allergies, asthma, diabetes mellitus, renal insufficiency, and/or cardiac diseases; currently or recently used medicines; possibility of pregnancy; and previous contrast agent administration. If the patient had a reaction in the past, the nature of the reaction must be determined. Also, serum creatinine levels should be determined.[50, 54]

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Treatment of Adverse Reactions

Overview

Most acute severe adverse reactions to ICM occur within 20 minutes of injection. For this reason, the patient should be monitored for a minimum of 20 minutes after an ICM injection. Furthermore, any physician who is responsible for an imaging study that requires the use of ICM must be able to recognize and treat acute adverse reactions.

Rooms in which contrast material is administered should be stocked with appropriate basic and advanced life support monitoring equipment and drugs. The equipment should be regularly checked.

In the examination of a patient with an adverse reaction, a brief history should be obtained, including a summary of the current symptoms, any medical conditions (eg, heart disease), and the patient's medications. Vital signs should be assessed, and any patient with an adverse reaction should be closely monitored until the symptoms have stabilized or resolved. Assessment of the patient's airway, breathing, and circulation (ABCs) remain the cornerstone of the management of moderate or severe adverse reactions to ICM.

In the treatment of adverse reactions, immediately discontinue ICM administration. Monitor the patient's cardiac rhythm, blood pressure, and oxygen saturation. Mild reactions are self-limiting and do not require treatment. However, the patient should be closely monitored until the symptoms resolve.

Treatment of anaphylactic reactions

The treatment of most anaphylactic reactions, once they are recognized and differentiated from other types of reactions, is often straightforward.[27] These are summarized below.

A respiratory component to an adverse reaction requires more aggressive therapy. Oxygen administration, 10-12 L/min via a partial nonrebreathing mask, should be considered in any patient with respiratory difficulty. If bronchospasm is accelerating or severe, if it does not respond to inhalers, or if an upper airway edema (including laryngospasm) is present, epinephrine should be injected promptly. Intravenous use of epinephrine is optional in normotensive patients, but it is necessary in hypotensive patients with respiratory reactions.

Epinephrine must be administered with care to patients who have cardiac disease or those who are taking beta-blockers such as atenolol, propranolol, metoprolol, and nadolol, because the unopposed alpha effects of epinephrine in these patients may cause severe hypertension or angina.

H1 antihistamines, such as diphenhydramine, and H2-receptor blockers, such as cimetidine, do not have a major role in the treatment of respiratory reactions, but they may be administered after epinephrine.

Monitoring the vital signs can be helpful in determining the cause of the hypotension. Tachycardia (ie, heart rate more than 100 bpm) indicates that an anaphylactic reaction is more likely than other types of reactions. If the patient is bradycardic (ie, heart rate less than 60 bpm), a vasovagal reaction is probable, provided that the patient is not receiving beta-blockers.

Hypotension resulting from an anaphylactic reaction is treated with an intravenous iso-osmolar fluid (ie, normal saline, Ringer lactate solution) in large volumes. Several liters of fluid may be required. If fluid and oxygen are unsuccessful in reversing the patient's hypotension, the use of vasopressors should be considered. The most specifically effective vasopressor is dopamine; at infusion rates of 2-10 mcg/kg/min, the cerebral, renal, and splanchnic vessels remain dilated, whereas the peripheral vessels constrict. Epinephrine is less useful, its results are less predictable, and it has more adverse effects.

Urticaria

In asymptomatic patients, no treatment is needed.

In patient with symptomatic urticaria that is mild or moderate, diphenhydramine 50 mg may be administered orally, intramuscularly, or intravenously.

In severe cases, treatment is as above; consider adding cimetidine 300 mg by slow intravenous injection or ranitidine 50 mg by slow intravenous injection.

Bronchospasm

For mild bronchospasm, treatment includes oxygen 10-12 L by face mask, close observation, and/or 2 puffs of an albuterol or metaproterenol inhaler.

For moderate cases without hypotension, treatment is as above, with epinephrine 1:1000, 0.1-0.3 mL given subcutaneously, repeated every 10-15 minutes as needed until 1 mL is administered.

In patients with severe bronchospasm, administer epinephrine 1:10,000 1 mL slow intravenous injection over approximately 5 minutes, repeated every 5-10 minutes as needed.

Laryngeal edema

For mild to moderate laryngeal edema, treatment includes oxygen 10-12 L by face mask and epinephrine 1:1000 0.1-0.3 mL given subcutaneously, repeated every 10-15 minutes as needed until 1 mL is administered.

In moderate to severe cases, consider calling a code or intubating the patient. Consider adding diphenhydramine 50 mg slow intravenous injection and cimetidine 300 mg slow intravenous injection or ranitidine 50 mg slow intravenous injection.

Isolated hypotension

Raise the patient's legs as much as possible while preparing to administer intravenous fluids. The Trendelenburg position can also be effective, but many radiographic tables do not tilt. Oxygen should be administered in high doses.

Hypotension with tachycardia

In mild to moderate cases, elevate the patient's legs. Administer oxygen 10-12 L by face mask, and intravenous isotonic fluid (eg, 0.9% isotonic sodium chloride solution, Ringer lactate solution).

For patients with severe hypotension with tachycardia or patients who are unresponsive, treatment is as above, with dopamine 2-20 mcg/kg/min. Call a code if no response occurs.

Vasovagal reaction

In cases of mild to moderate vasovagal reactions, elevate the patient's legs. Administer oxygen 10-12 L by face mask, and intravenous isotonic fluid (eg, 0.9% isotonic sodium chloride solution, Ringer lactate solution).

For severe reactions or unresponsive patients, administer intravenous atropine 0.6-1 mg, repeated every 3-5 minutes as needed until a total of 3 mg is administered.

Unresponsive patient

In cases of unresponsive patients, do the following:

Treatment of nonidiosyncratic reactions

Treatments for nonidiosyncratic reactions depend on the type of reaction.

Vasovagal reaction

Hypotension resulting from a vasovagal reaction is also treated with iso-osmolar fluid; however, if the patient remains symptomatic, bradycardia can be reversed with intravenous atropine 0.6-1 mg, repeated every 3-5 minutes to a total dose of 3 mg, if needed. Low doses of atropine, those less than 0.5 mg, are contraindicated because they may have the paradoxical effect of accentuating bradycardia or causing sudden respiratory or cardiac arrest.

In these instances, as well as in other circumstances in which preliminary treatment of a moderate or severe reaction does not seem to be effective, call a code. Administer basic life support and, if necessary, advanced cardiac life support techniques should be initiated.

Cardiac arrhythmias

A defibrillator should be obtained immediately, and cardioversion or defibrillation should be performed. The response of ventricular fibrillation to defibrillation decreases dramatically in the first few minutes, and with the likelihood of a successful response diminishes by approximately 10% with each minute. For this reason, physicians who administer contrast material should be capable of using defibrillators.

Hypertensive reactions

Hypertensive reactions can be initially treated with oxygen and appropriate antihypertensive medications. In the past, nifedipine, a 10-mg tablet that was punctured with a needle tip and allowed to drip sublingually, was commonly used; however, nifedipine is no longer the favored drug because of the unpredictability of its response, its hemodynamic profile, and the risk of reflex sympathetic hyperactivity.

Additional doses of the patient's usual antihypertensive medications may be helpful. Intravenous fenoldopam, labetalol, and nitroglycerin, as well as oral clonidine or captopril, are reasonable choices, depending on the particular clinical situation. Intravenous furosemide 40 mg can also be used.

Seizure

Seizure can occur as a result of hypoxia due to respiratory insufficiency or an intrinsic central nervous system (CNS) response to the ICM. Patients should be turned on their side to prevent aspiration, and high-dose oxygen should be administered. When hypoxia is the cause of the seizure activity, intubation may be required for adequate oxygenation. In the case of primary CNS seizure activity, intravenous diazepam 5 mg may be injected and repeated if necessary. An emergency medical specialist should be consulted.

Pulmonary edema

Pulmonary edema is initially treated by elevating the patient's head, administering oxygen, and intravenous injection of furosemide and morphine 1-3 mg every 5-10 minutes as needed.

Angina

Patients with angina should be given sublingual nitroglycerin and oxygen. An electrocardiogram (ECG) may be obtained to assess ischemic changes. If the patient's symptoms persist or are new (ie, if the patient has no previous history of cardiac disease), a cardiologist should be consulted, or the patient should be transferred to an emergency department.

Contrast agent–induced nephropathy

In most cases, only watchful waiting, adequate hydration, and follow-up of serum chemical findings are required. In a few patients, temporary or permanent hemodialysis may be needed.

Delayed reactions

Delayed reactions are treated in a supportive manner, and analgesics are administered to treat headaches; antipyretics to treat high temperatures; meperidine to treat rigors; and isotonic fluid to treat hypotension.[31]

Extravasation injuries

Extravasation injuries are treated by elevating the affected extremity and applying cold compresses. A plastic surgeon should be consulted if the patient's pain gradually increases over 2-4 hours, if skin blistering or ulceration develops, or if the circulation or sensation changes at or distal to the level of the extravasation. No specific treatment is unequivocally effective; therefore, most extravasation injuries are conservatively treated with supportive measures.

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Summary

A basic understanding of iodinated contrast media (ICM), the risks of their administration, the choice of the available agents, and premedication regimens for high-risk patients is beneficial in preparing patients for their contrast-enhanced imaging examinations. Radiologists are the primary physicians who administer contrast material. Because reactions to ICM may occur unexpectedly, radiologists should be able to recognize and treat the various types of possible adverse reactions, and they should seek clinical assistance as needed.

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Contributor Information and Disclosures
Author

Nasir H Siddiqi, MD Consultant Interventional Radiologist, King Faisal Specialist Hospital and Research Center; Associate Professor (Adj), Department of Radiology, Alfaisal University College of Medicine, Saudia Arabia

Nasir H Siddiqi, MD is a member of the following medical societies: American College of Radiology, American Medical Association, American Roentgen Ray Society, Radiological Society of North America

Disclosure: Nothing to disclose.

Specialty Editor Board

Bernard D Coombs, MB, ChB, PhD Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand

Disclosure: Nothing to disclose.

Douglas M Coldwell, MD, PhD Professor of Radiology, Director, Division of Vascular and Interventional Radiology, University of Louisville School of Medicine

Douglas M Coldwell, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Heart Association, SWOG, Special Operations Medical Association, Society of Interventional Radiology, American Physical Society, American College of Radiology, American Roentgen Ray Society

Disclosure: Received consulting fee from Sirtex, Inc. for speaking and teaching; Received honoraria from DFINE, Inc. for consulting.

Chief Editor

Eugene C Lin, MD Attending Radiologist, Teaching Coordinator for Cardiac Imaging, Radiology Residency Program, Virginia Mason Medical Center; Clinical Assistant Professor of Radiology, University of Washington School of Medicine

Eugene C Lin, MD is a member of the following medical societies: American College of Nuclear Medicine, American College of Radiology, Radiological Society of North America, Society of Nuclear Medicine and Molecular Imaging

Disclosure: Nothing to disclose.

Additional Contributors

Gary P Siskin, MD Professor and Chairman, Department of Radiology, Albany Medical College

Gary P Siskin, MD is a member of the following medical societies: American College of Radiology, Society of Interventional Radiology, Cardiovascular and Interventional Radiological Society of Europe, Radiological Society of North America

Disclosure: Nothing to disclose.

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Classification of iodinated contrast agents by their molecular structures.
 
 
 
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