Contrast Medium Reactions

Updated: Feb 12, 2024
  • Author: Agatha Stanek, MD, FRCPC; Chief Editor: Eugene C Lin, MD  more...
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Overview

Practice Essentials

Adverse effects from the intravascular administration of iodinated contrast media (ICM), gadolinium-based contrast agents (GBCA), and ultrasound contrast agents (UCA) are generally mild and self-limited; reactions from extravascular administration are rare. [1] Nonetheless, life-threatening reactions can occur with the use of these agents by either route. [2, 3, 4, 5, 6, 7, 8, 9, 10, 11] This article discusses the risk factors, adverse reactions to ICM and GBCA, appropriate treatment, and prophylaxis.

Clinical practice guidelines and consensus statements are available regarding safe and effective use of ICM and GBCA. See Guidelines. [1, 12, 13, 14] A consensus statement is also available regarding ICM in patients with kidney disease. [15]

The pathophysiology of contrast reactions has been studied extensively but remains incompletely understood. [1, 16, 17, 14, 18, 19, 20] Generally, these reactions can be considered as allergy-like or physiologic in nature; the latter are thought to involve direct toxic effects of the agent. Reactions can also be defined by their time of onset: immediate, when occurring within the first 20-30 minutes after injection; or delayed, if occurring beyond 30 minutes. There are rare reports of biphasic and delayed reactions, in the case of anaphylaxis secondary to ICM injections. [21, 13]

Many risk factors for contrast reactions have been identified. The most significant one is a previous reaction to the same class of contrast medium, which in the case of ICM is estimated to pose a fivefold risk for subsequent reactions. [1, 19] With GBCA, the frequency is 8 times higher in patients with prior reaction. [1] If the reaction was moderate or severe, premedication strategies are strongly encouraged for subsequent use of that class of contrast. Cross-reactivity between different classes of contrast media does not occur: A contrast reaction with an ICM is not associated with an increased inherent risk of reaction to GBCA, or vice versa. [1]

Various medical disorders may also be risk factors for contrast reactions, as may certain medications. (See Overview/Risk Factors for Adverse Reactions to Contrast Agents and Presentation/History.)

When acute kidney injury (AKI) is diagnosed within 48 hours after contrast exposure, the terms contrast-associated AKI (previously termed post-contrast AKI) and contrast-induced AKI (previously termed contrast-induced nephropathy) have been used in the literature. The American College of Radiology (ACR) and the National Kidney Foundation suggest differentiating contrast-associated AKI (ie, AKI coincident with contrast administration) from contrast-induced AKI (ie, AKI caused by contrast administration), with the latter being far less common. [1, 22] The estimated glomerular filtration rate (eGFR) is currently the favored tool for predicting the risk of contrast-induced AKI. [1, 15]

Although in general, reactions occur much less frequently with GBCA than with other contrast classes, nephrogenic systemic fibrosis (NSF) is an important complication of GBCA use, especially in patients with severe chronic kidney disease. Residual gadolinium has been found in the brain tissue of patients who received multiple doses of GBCA, but as yet no adverse health effects of this deposition have been noted. The ACR and the European Society of Urogenital Radiology (ESUR) have issued recommendations on NSF. [1, 13]

For pregnant patients, contrast may be considered in exceptional circumstances. ESUR guidelines recommend that when a woman has received ICM during pregnancy, her newborn should undergo thyroid function testing within a week after delivery. [13] The risks to the developing fetus in GBCA exposure are not clearly known and as such, the ACR recommends against routine use of GBCAs in pregnant patients. [1] No neonatal follow-up is currently recommended by the ESUR for GCBA injections during pregnancy.

In lactating patients who undergo ICM injections, a trace amount can be excreted into the breast milk. However, current data demonstrate no adverse effects, so it is deemed safe to continue breastfeeding. This also applies to GBCA. Alternatively, breastfeeding patients may consider expressing and discarding milk for 12-24 hours post injection. [1] ESUR guidelines are more conservative and do not encourage GBCA use in lactating patients at all. [1, 13]

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Background

Contrast media play a vital role in patient care, and they are used with various imaging modalities. Use of intravenous iodinated contrast media (ICM) with computed tomography (CT) was introduced in the 1950s. ICM contain approximately 270-370 mg of iodine per mL and diffuse from the plasma approximately 2-5 minutes after intravenous injection. [19] Excretion occurs primarily via glomerular filtration, with the majority excreted in the urine within a day. [13]

Use of gadolinium-based contrast agents (GBCAs) in MRI began in 1988, following approval of the first of these agents. [1] GBCA rely on the paramagnetic properties of the heavy metal gadolinium for contrast in MRI examinations. All GBCA have a gadolinium ion (Gd3+) complexed with a chelating ligand; this prevents its deposition in the patient's tissues. Typical GBCA doses are low and thus not directly damaging to the nephrons. [1]

Oral contrast such as barium sulfate media is commonly employed with fluoroscopy in the assessment of the gastrointestinal tract, including the pharynx, esophagus, stomach, and small bowel, as well as the colon and rectum. [1]  This facilitates detailed visualization of the mucosa.

Opacification of the biliary and pancreatic duct with direct injection of contrast is also commonly performed for the assessment of anatomy, stones, and lesions, as well as during endoscopic retrograde cholangiopancreatography (ERCP). Water-soluble ICM is typically used for ERCP. Iopanoic acid tablets can be employed for assessment of the biliary tree and gallbladder. In some areas outside of North America, intravenous iodipamide is also offered, but its use continues to dwindle due to its higher rate of reactions and the trend toward performing cholangiopancreatography with MRI, which does not require contrast injection.

Contrast-enhanced ultrasound was first employed for cardiac chamber assessment in the 1990s. It was primarily used in Europe and Asia at first, with gradual adoption in North America. [23] Ultrasound contrast agents involve microbubbles of gas or microspheres for assessment of vessels and blood flow and in the evaluation of solid hepatic and renal lesions, as well as assessment of post therapy changes in focal tumors, trauma, and endoleak in the aorta. [1]

A myriad of reactions to contrast media have been reported, ranging from mild to severe to fatal. Multiple studies in the last few decades have assessed appropriate and effective prophylactic measures for patients at risk of a moderate or severe reaction, with the caveat that these reactions are not truly an allergic response (see Pathophysiology).

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Pathophysiology

Although reactions to ICM have the same clinical manifestations as allergic reactions, these are not true hypersensitivity reactions. [16, 17] Immunoglobulin E (IgE) antibodies are not always involved, although this is somewhat controversial, as some small-scale studies document their presence. [1, 11, 14, 19, 24] In addition, previous sensitization is not required, nor do these reactions consistently recur in each patient. For those reasons, idiosyncratic reactions to ICM are called allergy-like or allergic-like reactions. These reactions are dose independent.

The precise pathogenesis at the cellular level is still not completely understood. [1, 18] What is known is that the release of histamine is involved in both allergic-like and physiologic reactions, and that reactions occur more frequently with higher-osmolarity agents. [1, 18] More specifically, there is postulated release of histamine from mast cells and basophils, activation of complement systems, and the production of bradykinin.

Basophil function can be assessed with the histamine release test, although this has limitations. The test can utilize light microscopy or flow cytometry. The former detects the disappearance of metachromatic granules with basophil degranulation while the latter detects CD63 molecules on activated basophils. Normally, this molecule is not present on resting basophils, but with an appropriate stimulus that induces degranulation these markers appear on the cell surface. A study of the ability of various nonionic ICMs to induce CD63 expression on human basophils suggested that this could be used as a tool for understanding and identifying ICM hypersensitivity reactions. [18]

Other postulated mechanisms of allergic-like reactions include direct membrane effects from media osmolality, with activation of the complement system; and direct bradykinin formation. [1, 11]

Delayed reactions have been postulated to be T-cell mediated. Some data have shown perivascular infiltrates of CD4+ and CD8+ T cells with expression of CD25, HLA-DR, cutaneous lymphocyte-associated antigen (CLA), and CD69. [25] Consequently, testing for type IV allergic response has been suggested. [1, 11] Severe or fatal reactions have been associated with increased tryptase levels. [11]

Physiologic reactions are related to direct chemotoxicity, osmolarity, and other molecular factors. [1]

The mechanism of nephropathy from contrast media is thought to be a combination of preexisting hemodynamic alterations; renal vasoconstriction, possibly through mediators such endothelin and adenosine; and direct ICM cellular toxicity. [26, 27] Studies of ICM-related nephropathy in animal models have demonstrated hemodynamic alterations involving nephron arterioles and subsequent perfusion changes, direct injury from free radicals, pro-apoptosis, inflammation. and hypoxia. [22]

When hypotension and bradycardia occur in reactions, these reflect parasympathetic overactivity and/or direct negative inotropic effects on the myocardium, with a decreased discharge rate of the sinoatrial node, delayed atrioventricular nodal conduction, and peripheral vasodilation. 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 involve coexisting circumstances such as emotion, apprehension, and pain.

ICM can also lower the threshold for ventricular arrhythmia 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.

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Epidemiology

Most contrast reactions are allergic-like and are mild and self-limited. Of the 40-70 million imaging studies with contrast that are performed annually worldwide, ICM allergic-like reactions occur in about 0.6%, and reactions to GBCA in about 0.01-0.22%. [1, 19] Rates of severe reactions to ICM and GBCA are estimated at 0.04% and 0.008%, respectively. [1] This is an improvement from the 1980s, in which the incidence of mild immediate reactions was reported to be 3.8-12.7%, but those reactions involved high-osmolality agents. With both ICM and GBCA, the mortality rate is 1 in 100,000 cases. [11]

Determining the frequency of delayed allergic-like reactions is inherently challenging, due to the difficulty in confirming causality. The reported range is 0.5-23%. [19] A study by Egbert et al of delayed reactions after ICM injection — defined as reactions that become apparent from 30 minutes to 7 days after the injection — identified these reactions in 14-30% of patients who received ionic monomers and in 8-10% of patients who received nonionic monomers. [28]

In contrast, a review of delayed reactions to ICM by Bellin et al reported an incidence of 2-4% with nonionic monomers, with reactions occurring 3-4 times more often following nonionic dimer injection. This review found that most delayed reactions involve the skin and most are mild in nature. [29]

No large-scale studies have assessed biphasic and protracted allergic-like reactions, given their infrequency. In a retrospective study of 145 patients with ICM anaphylaxis, 15 patients had a biphasic reaction and six had protracted reactions. [21]

A meta-analysis found that the overall rate of GBCA-related allergic-like adverse events was 9.2 per 10,000 administrations: 81% (539 of 662) were mild, 13% (86 of 662) were moderate, and 6% (37 of 662) were severe; severe reactions occurred at a rate of 0.52 events per 10,000 administrations. The lowest rate of immediate allergic-like events was with use of the nonionic linear agent gadodiamide (1.5 events per 10,000 administrations); in comparison, reactions to ionic linear GBCA occurred at a rate of 8.3 events per 10,000 administrations, and reactions to nonionic macrocyclic GBCA occurred at a rate of 16 events per 10,000 administrations. A higher rate of immediate allergic adverse events was associated with ionicity, protein binding, and macrocyclic structure. [30]

A study of 456,930 contrast doses — 298,491 of ICM and 158,439 of GCBA — found 522 adverse events. The most common manifestations were hives (274 cases; 52.5%) and nausea (92 cases, 17.6%). Nine cases required the use of epinephrine. [31]   

In a study by Nucera and colleagues of mild to moderate hypersensitivity reactions to contrast media in 350 patients, 79% involved an ICM and 19% involved a GBCA. Iomeprol, iopamidol, and gadobenic acid were the agents most often involved. [32] In a 2021 study, iodixanol was the agent causing the most frequent adverse events. [33]

Most reactions to GBCA are mild and physiologic; allergic-like reactions are rare, occurring at rates of 0.004-0.7%. [1] Severe reactions are also rare, and fatal reactions even more so, reported at 0.0019%. [34]

In oral contrast use with barium sulfate, the estimated frequency of adverse reactions is 1 per 750,000 ingestions. Most reactions are mild; 1 in 2.5 million are moderate or severe. [1]

With ultrasound contrast media, the rate of serious reactions in two extensive studies with over 100,000 cases was 1 in 10,000. No deaths were reported. The majority of adverse events are mild and likely physiologic in etiology, occurring within 30 minutes of injection. [1, 13, 23]

When premedication is used for prophylaxis, the majority of patients will not have a breakthrough reaction. When reactions do occur, most are similar in severity to the original reaction. [1, 35] In a retrospective study of 252 examinations in which oral steroid premedication was used (in most cases because of prior acute adverse reactions to contrast media), nine (4.5%) breakthrough reactions occurred with ICM and only one (1.9%) with GBCA. [36]

Extravasation is a rare complication, with reported rates ranging from 0.1-1.2%. [1] A systematic review of 17 studies reported 2191 extravasations in 1,104,872 patients (0.2%); extravasation rates were 0.045% for GBCA and nearly 6-fold higher (0.26%) for ICM.

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Types of Iodinated Contrast Media

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, based on the number of benzene rings (monomer with one ring; and dimer with two rings), osmolality (hyper-, iso-, hypo); and ionization in solution (ionic or non-ionic). In solution, ionic contrast media dissociate into two particles: an anion with the tri-iodinated benzene ring and a cation with sodium or methylglucamine. Nonionic contrast agents do not dissociate in solution.

Ionic monomeric ICM have the highest recorded osmolality and are otherwise known as high-osmolality agents. 

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. [37, 38]  Radiologists and other physicians must be aware of possible reactions to contrast media, use strategies to minimize adverse events, and be prepared to promptly recognize and manage any reactions to the contrast media. [39, 40, 41, 42, 43]

High-osmolality contrast media

High-osmolality contrast media consist of a tri-iodinated benzene ring with two 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. The ionization at the carboxyl-cation bond makes the agent water soluble. Thus, for every three iodine atoms, two particles are present in solution (ie, a ratio of 3:2).

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 with these contrast media.

In the United States, a high-osmolality ICM that is commonly used for opacification of the small bowel is diatrizoate meglumin/diatrizoate sodium (Gastrografin, Renocal 76, Renografin, MD-Gastroview). Along with inactive ingredients, these products contain 660 mg/mL diatrizoate meglumine and 100 mg/mL diatrizoate sodium, creating a solution of 367 mg of iodine/mL. These products are also useful for assessing postoperative leak after various gastric procedures.

High-osmolality contrast media are not presently employed for intravascular purposes. [1]

Low-osmolality contrast media

There are 3 types of low-osmolality ICM:

  • Nonionic monomers
  • Ionic dimers
  • 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 half the osmolality of ionic monomers in solution. At normally used concentrations (25-76%), nonionic monomers have 290-860 mOsm/kg, which is roughly twice that of serum.

Nonionic monomers are subclassified according to the number of milligrams of iodine in 1 mL of solution (eg, 240, 300, or 370 mg/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 iohexoliopamidolioversol, and iopromide. Ioxehol has been approved in the US for use per mouth and rectum. [1]

Currently, the nonionic monomers are the contrast agents most often used in CT imaging. In addition to their nonionic nature and lower osmolality, 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. Ioxaglate has a concentration of 59%, or 320 mg/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. It is not currently used in the US. 

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. A clinical example of a nonionic dimer is iodixanol.

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 reaction was 0.2% for ionic ICM and 0.04% for nonionic ICM; and the risk of a very severe adverse reaction was 0.04% for ionic ICM and 0.004% for nonionic ICM. [44]

In another large study, in which 6000 patients received ionic ICM, the incidence of mild adverse reactions was 2.5%; moderate reactions, 1.2%; and severe reactions, 0.4%. [45] In contrast, 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. [46]

Dillman et al performed a retrospective review of contrast reactions in 11,306 pediatric patients (age < 19 yr) who received intravenous low-osmolality nonionic ICM over a 6.5-year period at their institution. [47]  Overall, 0.18% of the patients had acute allergic-like reactions to the contrast agent; 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 by Caro et al concluded that the risk of severe adverse reaction was 0.157% for high-osmolality ICM and 0.031% for nonionic ICM. [48]  The investigators found that the mortality rate was one 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. [49]  Nonionic ICM are less likely than conventional ionic ICM to cause tissue damage in cases of extravasation. [50]  Nonetheless, compartment syndromes and skin blistering have been 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. [51]  Most authorities believe that the preponderance of evidence supports a lower rate of adverse reactions with low-osmolality ICM than with high-osmolality ICM.

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, severe adverse contrast reactions are three times more likely in low-risk patients who receive conventional ionic agents (0.09%) than in high-risk patients who receive nonionic agents (0.03%). 

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Types of Gadolinium Contrast Agents

Used in MRI studies for a variety of pathologies, GBCA contain gadolinium, which is a paramagnetic substance, meaning it contains unpaired electrons and will tend to move in the magnetic field's direction—unlike human tissue, which is considered diamagnetic. The strength of paramagnetic substances increases with more unpaired electrons, and gadolinium ions have seven free electrons. [52]

Gadolinium ions are considered unstable; on their own they can form hydroxide crystals and deposit in tissue. For that reason, GBCA contain a chelating agent, which can be linear or cyclic in morphology, to limit toxic deposition in tissues. [1, 34] GBCA can also be subdivided as ionic or nonionic. [32]

Gadopentetic acid was the first gadolinium-based agent approved, in 1988, with multiple agents developed subsequently. First-generation agents are given at a dose of 0.1 mmol/kg body weight in the form of an aqueous solution of 0.5 M gadolinium. [52] These agents diffuse into the extracellular space of the body and are excreted by the kidneys. 

Second-generation agents (eg, gadobenate dimeglumine, gadoxetic acid) are hepatobiliary; in addtion to diffusing extracellularly, they are also actively transported into functioning hepatocytes and are then excreted into bile. Thus, these agents can provide characterization of hepatic lesions and functional imaging of the biliary tract. [52]

Linear agents

Linear agents have an unbent molecule that surrounds the gadolinium ion. They can be ionic or nonionic

Ionic linear agents include the following:

  • Gadopentetate dimeglumine
  • Gadobenate dimeglumine
  • Gadoxetate disodium
  • Gadofosveset trisodium

Nonionic linear agents include the following:

  • Gadodiamide
  • Gadoversetamide

Macrocyclic agents

Macrocyclic agents contain a ligand essentially shaped like a fence or cage that surrounds the gadolinium ion. Gadoterate meglumine is an ionic macrocyclic agent; nonionic macrocyclic agents include gadobutrol and gadoteridol. 

Categorization based on risk of nephrogenic systemic fibrosis

The American College of Radiology (ACR) also organizes GBCA on the basis of their risk for nephrogenic systemic fibrosis (NSF), as follows [1] :

  • Group I (highest risk of NSF): Gadodiamide, gadopentetate dimeglumine, and gadoversetamide are responsible for nearly all documented cases of NSF
  • Group II (few if any unconfounded cases of NSF): Gadebenate dimeglumine, gadobutrol, dotarem, gadoteridol, and gadopiclenol
  • Group III (few if any unconfounded cases of NSF but data are limited due to few published reports of use in high-risk patients): Gadoxetate disodium (gadoxetic acid)

A review by Schieda and colleagues of 71 studies found that gadoxetic acid was associated with a 0.3% incidence of immediate hypersensitivity, with no deaths. In four studies that reported 106 injections of this agent in patients with stage 4-5 kidney disease or on dialysis, the incidence of NSF was 2.8%. The authors argue that given these findings, the safety of gadoxetic acid is similar to that of group II agents in the ACR, despite its classification in group 3. The review found few data regarding the retention of this agent in human tissue. [53]

With respect to group I agents, gadodiamide, gadopentetate dimeglumine, and gadoversetamide are no longer advertised in the United States and have been withdrawn from the market in other countries. The European Medicines Agency (EMA) has suspended intravenous use of gadodiamide and gadopentetate dimeglumine, and gadoversetamide has been withdrawn from the European market; however, the EMA suggests that gadopentetate dimeglumine may be used for arthrography. [13]

Gadoxetate disodium is supported for its use in hepatobiliary imaging. For low-risk agents, the European Society of Urogenital Radiology (ESUR) advises caution in patients with a GFR < 30 mL/min1.73 m2. A consensus statement from the ACR and the National Kidney Foundation recommends balancing the potential benefit and risk of using GBCA for MRI in patients with kidney disease and advises that, depending on the clinical indication, the potential harms of delaying or withholding group II or group III GBCA for an MRI in a patient with acute kidney injury or eGFR less than 30 mL/min/1.73 m2 may outweigh the risk of NSF. [54]

Investigational agents

In the past decade, researchers have studied the use of superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents in MRI scans. SPIONs have even higher magnetic properties than paramagnetic materials. [52] These materials are usually coated with a synthetic polymer or ionic molecule to facilitate a stable suspension, and have been studied in hepatic, lymphatic, and vascular MRI. [52, 55, 56]

Once injected intravenously, SPIONs are engulfed by macrophages, so these agents can be used for assessment of inflammation or infection. One SPION, ferumoxytol, has been approved for treatment of iron deficiency anemia. Neuwelt and colleagues have reviewed the potential future uses of ferumoxytol, such as identifying and monitoring treatment response in septic arthritis and osteomyelitis, as well as assessment of atherosclerosis and multiple sclerosis. [55] A review by Hope and colleagues describes the application of this agent in a variety of imaging applications, which is beyond the scope of this article. [56] This is an evolving topic. 

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Oral Contrast Agents

The most commonly employed oral contrast agent is barium sulfate, a micropulverized white powder, which typically requires mixing with water; prepackaged barium-containing preparations with a number of additional ingredients are also available. A typical suspension of barium is 60% weight/volume (w/v). [1] For upper GI studies of the esophagus, stomach, and duodenum, high-density barium (up to 250% w/v) is used, with separate ingestion of air bubbles for double-contrast studies. [1]

An appropriate volume of use when assessing the small bowel is approximately 500 mL of 40% w/v barium suspension. [1] For the colon, high-density (85-100%) w/v suspension is typically recommended, with a volume of 1000-2000 mL. 

The principal safety concern with barium is that if it leaks from the GI lumen it can cause adverse effects, including mediastinitis and peritonitis. [1, 13] Consequently, if the integrity of the gut wall is known or suspected to be compromised, an iodine-based water soluble contrast media agent is preferred. Allergic-like reactions to barium are rare (1 in 750,000 examinations) and mostly mild, but if the patient has a history of an allergic-like reaction history, CT evaluation with ICM agents is suggested. [1, 13]

For bowel strictures, careful use of small amounts of contrast is encouraged, as increased luminal pressure from over-injection poses the theoretical possibility of a bowel perforation. For extensive colitis, barium enemas are to be completely avoided.

Aspiration of barium may cause symptoms, especially in patients with lung disease. Removal of aspirated material with bronchoscopy can be considered if a large amount is present. Chest physiotherapy and antibiotics are also suggested. [13]

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Ultrasound Contrast Agents

Ultrasound contrast agents (UCA) are a relatively new category of media that are widely used in Europe and Asia and have gained popularity in the US. These agents rely on ultrasound's use of sound waves and reflection between various interfaces when the probe is placed on a patient, and the conversion of those waves to electrical signals and subsequent images. [23]

These contrast agents are composed of tiny gas bubbles with a supporting shell, usually consisting of phospholipids or proteins, which are smaller in size than human red blood cells. [23] The microbubbles oscillate when exposed to ultrasonic sound waves, which results in reflection of particular sound waves with marked echogenicity, or increased imaging of a white color on the screen. [1] The microbubbles eventually burst and the gas is dissolved in the blood. The gas is then removed from the body via expiration, within 10 minutes from time of initial injection.

UCA are injected intravenously and then flushed with saline and generally will remain in the patient's blood vessels, given their increased particle size, as compared with ICM and GBCA. [1, 23]

In the US, the following three UCA are currently approved for use in echocardiography [1, 13, 23, 57, 58] :

  • Perflutren lipid microspheres (Definity)
  • Sulfur hexafluoride lipid–type A microspheres (SonoVue, Lumason)
  • Perflutren protein–type A (Optison)

Perflutren lipid microspheres come in a suspension in a 2-mL glass vial containing a solution of three phospholipids and separate octafluorpropane (C3F8) gas. The microspheres are injected following emulsification with a specific device. This product was approved in the US in 2001 and is also approved in Canada and Australia for assessment of liver and kidney lesions. [57, 58]

The sulfur hexafluoride lipid–type A microsphere kit contains lyophilized phospholipid powder sealed under a headspace of sulfur hexafluoride gas, a transfer system, and sodium chloride solution for reconstitution. Following reconstitution, it can be stored for up to  six hours. The dosage varies according to the procedure. This agent was approved in Europe and China in the early 2000s for left ventricular chamber assessment, as well as for hepatic and breast lesions. It was approved in the US in 2014 for echocardiography. In the US, Europe, and China, it is also approved for assessment of urinary bladder function in pediatric patients. [23, 57, 58]

Perflutren protein-type A is essentially a gas core (the perflutren) surrounded by a capsule of human serum albumin. Preparation requires resuspending the microspheres by inverting and gently rotating the vial. The product must be injected into a peripheral vein within one minute of resuspension. It is given at a maximum rate of 1 mL/sec. After injection, the line must be flushed with saline to improve image acquisition. The recommended dose is 0.5 mL; additional doses in increments of 0.5 mL may be given for further contrast enhancement, as needed, but the maximum total dose in any 10-minute period should not exceed 5 mL, and the maximum total dose in any one study should not exceed 8.7 mL. [57]

Sonazoid microspheres are used in Japan, South Korea, Norway, Taiwan, and China. This agent is a lyophilized powder for injection, with perflurobutaine microspheres surrounded by a membrane made of hydrogenated egg yolk phophatidyl serine. After mixing with sterile water, the product can be injected as a suspension. It is used in hepatic imaging. [57]

General guidelines encourage the lowest level of acoustic output and shortest scanning time that still permits a diagnosis. Specifically, using a mechanical index of less than 0.8 is preferred, to avoid cavitation or rupture. Images are collected at one point in time and can assess both arteries and veins. [23, 57, 58] The half-life of UCA is approximately 5 minutes. [23]

The main advantages of this form of media are its applicability to patients with renal or hepatic disease, since the contrast is not excreted through the kidneys. There is also no radiation exposure, as is the case with CT. [1, 13, 23, 57, 58]

There is little reported evidence of significant events in critically ill patients and in those with known acute cardiac disease, although this may be related to the current indications of use, which do not typically involve these specific patient populations. The only contraindication to these agents is to avoid use within 24 hours of extracorporeal shock wave therapy. [13]

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Risk Factors for Adverse Reactions to Contrast Agents

The most important risk factor for an adverse reaction to contrast media is a history of a prior reaction. However, other medical conditions and medications can affect the risk of an adverse reaction.

Medical conditions

Note the following [1] :

  • Allergy: A history of allergy increases the risk of a contrast reaction by 2- to 3-fold, but is not itself an indication for pre-medication. Patients with shellfish and other food allergies do not require prophylaxis. 
  • Asthma: Patients with asthma are at increased risk for an allergic-like reaction, but asthma itself is not an indication for premedication.
  • Sickle cell disease or trait: Although strong magnetic fields may affect the alignment of deoxygenated sickled red blood cells, both the ACR and ESUR found no evidence that any GBCA pose increased risk of vaso-occlusive or hemolytic complications in patients with sickle cell disease. [13, 1] The ESUR states that patients with sickle cell disease may be at risk of a sickle cell crisis but also notes that with low and iso-osmolar ICM, the rate of adverse events is no greater in patients with sickle cell disease than in the general population. [13]
  • Pheochromocytoma: No premedication is required for patients with pheochromocytoma, but ESUR guidelines suggest using a non-ionic agent for ICM injections. Any GBCA can be used. [13]
  • Myasthenia gravis: Data on the risk of disease exacerbation in patients with myasthenia gravis remain controversial and unclear. [1] .
  • Multiple myeloma: Provided that their kidney function is normal, patients with multiple myeloma do not require special precautions such as hydration. However, those patients with reduced kidney function are at increased risk of acute kidney injury, so correction of hypercalcemia is often encouraged, as well as discussion with the treating hematology team. [13]
  • Thyroid disorders: Use of contrast should be avoided in patients who are experiencing thyroid storm, receiving iodine therapy, or undergoing radioactive imaging of the thyroid gland. In patients who have received ICM, ACR guidelines suggest a washout period before initiation of radioactive iodine therapy or radioactive iodine imaging of the thyroid gland: 3-4 weeks for hyperthyroidism and 6 weeks for hypothyroidism. Patients with untreated Graves disease or a multinodular goiter may be at theoretical risk of thyrotoxicosis with contrast administration. Thus, only patients with normal thyroid function are encouraged to receive ICM. [13]
  • Kidney insufficiency: Existing kidney disease or acute kidney injury are of concern, given that excretion of contrast occurs principally via the kidneys. Decreased kidney function has been associated with contrast-associated acute kidney injury and contrast-induced kidney injury. [1, 13, 15] However, the current literature suggests that this risk has been overstated. [22] In GBCA injections, the main concern in patients with severely decreased kidney function is nephrogenic systemic fibrosis (see Presentation/Complications and Treatment/Prevention of Nephrogenic Systemic Fibrosis).

Medications

Note the following:

  • Beta-blockers: ACR guidelines state that current literature does not support medication discontinuation or premedication in patients taking beta-blocking agents. [1]

  • Metformin, an oral antihyperglycemic drug that is excreted predominantly by the kidneys, is not nephrotoxic per se, and it does not cause hypoglycemia in and of itself. However, if patients who are taking metformin develop acute kidney injury and become azotemic, increased tissue levels of metformin may rarely induce life-threatening lactic acidosis. [1] In patients who have acute kidney injury or severe chronic kidney disease, or are undergoing arterial catheter studies that might result in emboli to the renal arteries, metformin should be discontinued before any intravascular ICM-enhanced study is performed and should be withheld for at least 48 hours after the study, and its administration should be resumed only after the absence of kidney dysfunction has been documented. For GBCA administration, holding metformin is not required.

  • Interleukin-2 immunotherapy: In patients who have received interleukin-2 immunotherapy for cancer, the incidence and severity of delayed reactions after ICM administration are increased. [1, 13, 19] Thus, it is important to monitor patients post procedure and educate patients on symptoms to watch out for and reasons to seek urgent care.

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Timing Between Contrast Examinations in the Same Patient

The belief that risk of kidney injury from contrast is increased in patients undergoing more than one contrast-enhanced study in a short time frame is based on limited studies. There are no large-scale studies available on this topic. [22] Since 75% of ICM is excreted by 4 hours post initial injection, a patient with normal kidney function or mild kidney impairment (GFR > 30 mL/min/1.73 m2) can be considered for an additional enhanced CT examination on the same day. ESUR guidelines do suggest waiting at least 4 hours before the second ICM injection. [13] This also applies if a patient receives ICM for CT and GBCA for an MRI examination on the same day.

For patients with severely reduced kidney function (ie, those who have eGFR < 30 mL/min/1.73 m2 or are on dialysis and have remnant kidney function) ESUR guidelines recommend a 48-hour window between two injections of ICM and a 7-day window between two injections of GBCA, or between injections of ICM and GBCA. [13]

Of note, no large-scale study has identified a threshold dose of contrast that is associated with definite toxicity with ICM. [22] Given the low volume of contrast use in GBCA, this is even less of a concern. [1, 15]

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Pregnancy

When possible, the intravenous administration of contrast agents should be avoided in pregnant women. Granted, studies have failed to reveal a teratogenic effect in animals with low-osmolality contrast agents, and there are no high-caliber studies documenting teratogenesis in pregnant patients. Intravascular ICM crosses the placenta and may rarely produce transient fetal hypothyroidism. However, this complication was reported with outdated procedures using fat-soluble ICM; there are no large-scale studies involving the water-soluble ICM that are currently employed. [1] Lasting adverse effects on the fetus or neonates have not been identified. [1] Nevertheless, nonionic agents are preferred to conventional ionic agents in pregnant women.

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