Contrast agents, also called contrast media, are substances used to enhance the radiodensity of a targeted tissue by altering the way that electromagnetic radiation or ultrasound waves pass through the body. These substances can be administered to the patient orally, rectally, or intravenously. The type of contrast agent used depends on the modality and purpose of the imaging the patient will receive.
For patients undergoing radiographic imaging like x-rays or computed tomography (CT) scans, contrast agents are either iodine or barium based. Iodinated contrast agents are classified based on their osmolality, ranging from approximately 300 to 1200 osmol/kg HO. Because iodine is the radiopaque substance in all iodinated contrast agents, the radiopacity produced by administration of these contrast agents depends on their concentration of iodine. Iodinated contrast agents are most frequently administered via intravascular injection, but the substance quickly redistributes to the extravascular space due to the capillary permeability of the contrast molecules.
Sometimes, iodinated agents are also employed as oral or rectal contrasts to enhance images of the stomach and bowels. However, barium sulfate is the predominant contrast agent in use for gastrointestinal imaging. Barium-based contrast agents are typically given as a solution of finely pulverized barium powder mixed into a slurry with approximately 236.5 to 473.2 mm of liquid. The patient orally ingests this solution or administers an enema into the rectum.
In the setting of magnetic resonance imaging (MRI), most contrast agents are based on chelated gadolinium. Unlike iodinated or barium contrast agents that attenuate x-rays to improve imaging, gadolinium contrast agents enhance the signal intensity of biologic tissues by decreasing the time it takes water protons to align with the magnetic field created by the imaging machine. The chelating agents in gadolinium contrast agents also allow the substance to remain circulatory vessels longer than radiographic contrast agents before extravasating.
For ultrasound (US) imaging, use of contrast agents is significantly less common compared to other imaging modalities. However, microbubble contrast agents consisting mainly of a gas core and a stabilized biological shell are sometimes used to enhance US images. These bubbles range between 1 to 10 uM in size, approximately the dimensions of a red blood cell, and are administered to the patient intravenously.
The use of contrast agents has become ubiquitous in recent clinical practice. With the proliferation of contrast usage, concerns about toxicities of the different agents have proliferated as well.
Contrast toxicity occurs when the substances used as contrast agents - iodine, barium, gadolinium, or microbubbles as mentioned above - cause harmful effects to organic tissues. Toxicity may occur when the health history of a patient is not fully understood, especially regarding allergy, cardiac conditions, or renal disease. Special populations including pregnant women, breastfeeding women, and patients taking metformin also merit further consideration of possible injury from contrast use. Radiologists performing contrast-enhanced imaging frequently do not know the patient well and must rely on a referring physician's judgment or a time-limited informed consent process to assess the appropriateness of the requested study.
Further risk of contrast toxicity is incurred by off-label use of contrast agents. Current regulations from the Food and Drug Administration (FDA) in the United States have a limited number of approved contrast agents for specific uses in specific body areas. Because the FDA has not yet been able to comprehensively test all contrast agents in all populations for all purposes, the actual clinical use of contrast agents by necessity must encompass off-label use not yet assessed by the FDA. Diagnostic needs in MR angiography, cardiac, and pediatric populations are among those least addressed by the FDA that remain frequently required in clinical practice.
Finally, even if a patient is without health history of any kind and their imaging type of their body type has been approved by FDA guidelines, contrast toxicity may still occur simply due to the interaction of a foreign substance with organic tissue. In short, contrast toxicity can be caused by any contrast agent in any patient who is exposed.
The most common toxicity discussed in contrast agent usage is contrast-induced nephropathy (CIN). CIN is an iatrogenic acute kidney injury characterized by a sudden compromise in renal function within 24 to 48 hours of exposure to a contrast agent. Although there are no quantitative diagnostic criteria for CIN currently, the diagnosis is strongly suggested if a patient demonstrates one of the following within 48 hours of exposure to an iodinated contrast agent:
Rates of CIN have been estimated to be as high as 10% of all hospital-acquired renal failure and contrast is accepted to be the third most common cause of new acute kidney failure in hospitalized patients. However, a recent meta-analysis of 54,000 matched patients found no difference in the prevalence of acute kidney injury between patients who received imaging with or without contrast. This finding is supported by a large retrospective cohort study of 17,000 patients that found no difference in the rate of acute kidney injury between patients imaged with or without contrast. These studies suggest that the frequency of CIN is far less than was previously believed.
Interestingly, all cases of CIN have been detected following administration of radiography contrast agents. Gadolinium-based contrast agents for MRI have been extensively studied and found to cause no such impairment in renal function, even in patients with baseline renal insufficiency. Instead, gadolinium agents have been loosely associated with nephrogenic systemic fibrosis (NSF), a chronic disease characterized by severe skin induration. There are currently no mechanisms proposed for NSF, but exposure to gadolinium in a patient with advanced renal disease has become an accepted risk factor for NSF development.
Many studies group together adverse reactions other than CIN as allergic-like reactions and physiologic reactions. In the past, the use of high osmolar agents resulted in an adverse reaction in up to 15% of patients. The use of newer low osmolar agents has significantly decreased the number of adverse reactions to a range of 0.2% to 0.7%.
Gadolinium contrast material has even lower adverse effects compared to low osmolar agents used for CT. One study showed an adverse effect for 0.04% of the doses. Of these effects, approximately 90% were nausea, vomiting, and a mild rash that were managed with observation and diphenhydramine alone. A recent literature review also showed the conflation of shellfish allergies with iodine allergies to be a medical myth, noting that there was no increase in contrast allergic-like reactions in patients with known seafood allergies. The American College of Radiology specifically states that there is no evidence to support the practice of inquiring about a patient’s history of allergy to seafood before giving the contrast.
Contrast toxicity presents in a myriad of ways, with each manifestation often having several underlying mechanisms of action.
Much like its epidemiology, the pathophysiology of CIN remains incompletely understood. Many mechanisms of kidney injury have been postulated to be the source of acute tubular necrosis (ATN) following contrast exposure. Among these, the most well-accepted explanation is a combination of direct cytotoxicity on kidney tubule cells and induced renal vasoconstriction. Contrast media has also been shown to diminish glomerular filtration rate by altering the viscosity of the tubular fluid, inhibit tubuloglomerular feedback by causing diuresis, and damage nephron membranes via increased production of reactive oxygen species. 
The mechanism by which high-osmolar iodinated agents compromise cardiac function and hemodynamic status is thought to be more singular than the effects of CIN. Specifically, the high-osmolar content of contrast results in water being pulled from the interstitium and expanding the blood volume, leading to right heart overload and diminished cardiac functions.
The reaction to contrast is an anaphylactoid reaction, not an anaphylactic reaction. Allergic-like reactions to contrast agents are assumed to be mediated through direct release of histamine and other mediators from basophils and eosinophils. The reaction is not associated with the involvement of IgE.  Patients will have a response after primary exposure to the contrast without prior sensitization. The newer low osmolality nonionic agents tend to produce lower levels of histamine release resulting in less adverse events.
The histories and physicals of patients presenting with contrast related toxicity share only one feature – exposure to a contrast agent within the past 72 hours. Otherwise, patient presentations can be dizzyingly diverse.
CIN may present as a transient elevation in serum creatinine with or without oliguria. The diagnosis cannot be officially made until a follow-up measurement showing decreasing creatinine is obtained within 2 to 3 days. However, there are several acknowledged risk factors in a patient history for CIN including chronic kidney disease, diabetes mellitus, dehydration, diuretic use, advanced age, and concomitant exposure to other drugs or diseases that affect renal hemodynamics. The Roxana Mehran score predictor for CIN calculates patient risk based on the following elements in their history:
The minimal risk score using the Roxana Mehran calculator is 7.5% for less than 6 points on the scale. The maximum risk is indicated by greater than 16 points, calculated to be 57% risk of CIN.   However, this score is not widely used in clinical practice.
Acute adverse reactions can be grouped into either allergic-like or physiologic. Allergic-like reactions include nausea, vomiting, hives, bronchospasm, angioedema, and other anaphylactoid responses. Physiologic reactions include cardiac arrhythmias, depressed myocardial contractility, cardiogenic pulmonary edema, and seizures.
Preexisting conditions may increase the risk of certain adverse events. Patients with a history of chronic obstructive pulmonary disease (COPD) or asthma have more bronchospasm than patients without these conditions. Hemodynamic changes are more common in patients with a prior history of cardiovascular disease. Patients with a prior history of myasthenia gravis have a significant increase in disease-related symptoms exacerbation within 24 hours of contract. The greatest risk factor for adverse events seems to be a prior history of an adverse event.
Laboratory measurements of BUN and creatinine are commonly performed before use of contrast agents to provide an adequate baseline measurement for future kidney function assessments. Evaluation of a patient's vitals preceding and during use of contrast agents can be another helpful test to monitor for toxicity. Significant changes in blood pressure, either elevation or depression, may occur due to cardiac or allergic reactions to the contrast agent.
However, there is currently no standardized set of tests required to evaluate for contrast toxicity. Due to the varied presentations of toxicity, evaluation principally relies on a thorough history and physical exam to assess for adverse events in the setting of a recent contrast agent exposure.
All patients showing an acute, allergic-like reaction to contrast should immediately have contrast administration stopped if possible, and receive hydration as well as antihistamine treatment. Although literature review demonstrates an absence of specific medication regimens, treatment for allergic-like reactions to contrast agents is typically comprised of intravenous fluids, diphenhydramine, hydrocortisone, or adrenaline in severe anaphylactoid presentations. Prophylactic medication regimens including prednisone, methylprednisone, hydrocortisone, and diphenhydramine have also been used in patients with allergic risk factors. A systematic found a small reduction in respiratory symptoms and hemodynamic compromise with pretreatment with an estimated NNT of 100 to 150. However, premedication does not seem to reduce the risk of moderate or severe reactions. The American college of radiology recommends premedication for patients with prior allergic like or unknown type contract reactions.
The treatment of patients with CIN is even less defined. Administration of acetylcysteine, fenoldopam, and hydration with normal intravenous saline or sodium bicarbonate have all been used in clinical trials as methods to prevent the development of CIN with statistically insignificant effects. Management of CIN is typically supportive, with intravenous hydration and close observation of serum creatinine serving as the cornerstones of treatment.
The presentation of contrast toxicity may be concurrent with or confused for many other medical disorders. These may include:
The prognosis of contrast toxicity is benign, with severe adverse events occurring less than 1% of the time. CIN has been documented to occur much more frequently in the range of 10%, but recent meta-analyses have brought this into question. Overall, the benefits of contrast agent administration for diagnostic purposes are considered to outweigh the infrequent complication of toxicity substantially.
Complications of contrast toxicity are postulated to vary from minor physiological symptoms to extremely rare but life-threateningly severe reactions. However, there is extremely limited data on these complications, and more research is still needed to elucidate all possible complications of contrast toxicity.
Some of these possible complications include:
Prevention of contrast toxicity is highly individualized since the risk of adverse reactions are relatively small, and the benefits of an expedited, more accurate diagnosis is tremendous. A complete discussion of the risks, benefits, and alternatives to using contrast agents may be conducted before the use of contrast agents in a patient. Informed consent is not presently required for contrast administration, but increasing patient education may help prevent against and prepare for adverse events related to contrast use.
A diverse, interprofessional team of care providers is required to prevent and manage contrast toxicity. Both the physician ordering the imaging and the radiologist performing the imaging have critical responsibilities in assessing the patient's appropriateness for the receipt of contrast. The American College of Radiation Manual on Contrast Media provides evidence-based, standardized guidelines for safe practices in the use of contrast agents. The nursing staff ensures patient safety by monitoring their vital signs and presentation before, during, and after contrast administration. Pharmacists may be involved to protect against drug interactions and coordinate appropriate dosing of contrast agents. An interprofessional team approach will provide the best outcomes. [Level 5]
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