Which type of iodine based contrast media is less likely to cause adverse reactions when injected into a patients bloodstream?

This peer reviewed course is applicable for the following professions:

Advanced Practice Registered Nurse (APRN), Certified Nurse Midwife, Certified Nurse Practitioner, Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Nursing Student, Registered Nurse (RN), Registered Nurse Practitioner

This course will be updated or discontinued on or before Saturday, July 22, 2023

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CEUFast, Inc. is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. ANCC Provider number #P0274.

≥ 92% of participants will know the purpose of different contrast agents and the challenges encountered with the administration of contrast media, specifically related to adverse or allergic reactions.

By the end of this activity, the participant will be able to:

1. Identify three types of contrast agents.
2. Compare the two main categories of iodinated contrast agents.
3. Describe the risk factors associated with adverse reactions to contrast agents.
4. Compare and contrast the two types of allergic reactions to contrast agents.
5. Analyze the effect of contrast agent use in breastfeeding women.

CEUFast Inc. and the course planners for this educational activity do not have any relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Last Updated: 12/15/2021

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   (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)

Historical Overview of Early Imaging and Contrast Agents

Radiography and Iodine-Based Contrast Agents

According to Zamora and Castillo (2017), X-rays were first discovered in November 1875 when Wilhelm Conrad Roentgen obtained the first images of the human body. One of the most famous initial images was a human hand with a ring in place belonging to Roentgen's wife (Zamora & Castillo, 2017). Zamora and Castillo (2017) note that X-rays could effectively distinguish between soft tissues and bones. However, it became very clear that there was very little contrast between soft tissues on standard x-rays, necessitating a product to provide adequate contrast (Zamora & Castillo, 2017). Initially, Roentgen focused on using high atomic number elements, given that they cast dark shadows on imaging. Specifically, he used elements such as Iodine, Bismuth, and Barium. Note that, Iodine and barium are still being used today as contrast agents.

The first accounts of an external contrast medium used in radiology were in Vienna by Lindenthal and Haschek. They injected an amputated hand with a mixture of petroleum, lime, and cinnabar. Meanwhile, at Johns Hopkins Hospital, Hemmeter asked patients to ingest rubber bags filled with lead or mercury acetate into their gastrointestinal system as a form of contrast media. He subsequently used bismuth sulfate and eventually stopped using the bags, given that bismuth subnitrate was a commonly used salt to treat peptic ulcers and other disorders. Bismuth subnitrate was subsequently replaced by barium sulfate partially due to the toxic effects of bismuth salts and the lack of bismuth during the First World War. From that point forward, barium has remained the agent of choice for gastrointestinal studies with a limited role in bronchography for a few decades.

By 1917, Cameron began using iodides, including sodium and potassium iodides, as contrast media. Iodine had become popular for use as an antibacterial before penicillin was ever even discovered in 1928. Iodine was first injected intravenously as a contrast agent at the Mayo Clinic in 1923 by Osborne and his colleagues. It was used in a patient undergoing intravenous excretory urography since it was officially recognized that urine containing Iodine was radiopaque. The initial iodinated contrast media were not water-soluble, making them relatively toxic in patients. In the 1920’s, the first water-soluble agents were developed, setting the stage for developing new contrast agents. Today, water-soluble contrast agents are used for intravenous urography, angiography, and myelography. Note that hyperosmolar agents can cause excruciating pain for patients when injected. As such, it became a focus for scientists to develop agents with decreased osmolality.

Computed Tomography (CT)-based contrast agents are similar to radiography iodine-based contrast agents given that the physics is similar, relying on the attenuation of different materials (Zamora & Castillo, 2017).

Magnetic Resonance Imaging (MRI) and Gadolinium-Based Contrast Agents

Magnetic resonance imaging (MRI) is a much more recent imaging modality developed when chemistry and physics were far more advanced than radiography development. MRI has inherent soft-tissue contrast in soft tissues, far superior to other imaging modalities even without contrast media administration. However, MRI still relies on the use of contrast agents to enhance morphologic or functional aspects of the body part being imaged. The mechanism of action of MRI contrast agents is radically different from radiography and CT-based contrast agents, which focus mostly on substance attenuation.

Nuclear magnetic resonance (MR) was discovered in 1938 by an Austrian physicist named Isidor Rabi, who won the Nobel Peace Prize in Physics in 1944 for his work. He sent a beam of lithium chloride molecules through a magnetic field and manipulated the magnetic field using varying radio frequencies to emit radio waves. The first whole-body MR machine became available in 1980. Further research into the MR imaging modality techniques and contrast agents has drastically improved contrast and spatial resolution in MRI.

Despite the extensive research over the years, gadolinium remains largely the only contrast agent for MRI. Gadolinium essentially provided an opportunity for the visualization of structures that are magnetically similar in contrast to conventional MR imaging. Initially, several paramagnetic ions were used in imaging research. However, gadolinium has demonstrated the strongest influence on the relaxation times out of the elements tested.

Gadolinium is a rare earth metal that Jean-Charles de Marignac discovered in Geneva, Switzerland. Gadolinium got its name from gadolinite, which is a mineral. Gadolinium is toxic in its free form and has to be chelated to ligands before being injected into any living organisms.

The first commercially available MR imaging contrast agent was gadopentetate dimeglumine. The concept of macrocyclic gadolinium agents was proposed in 1985 by Bonnemain and Meyer. Macrocyclic agents are more stable than linear agents and they create a rigid cage around the gadolinium, thereby making it resistant to dechelation. The first macrocyclic agent developed was gadoteric acid which the Food and Drug Administration (FDA) approved in 2013. Gadoteridol was the first non-ionic macrocyclic agent on the market, while gadodiamide was the first non-ionic linear contrast agent. Gadodiamide has less than half the osmolarity of godopentetate dimeglumine, its predecessor with an osmolarity approximately 7 times higher than that of plasma.

The Purpose of Contrast Agents

Today, contrast agents are used for all imaging modalities, including Ultrasonography (US) and Fluoroscopy (Fluoro) and Computed Tomography (CT), and Magnetic Resonance Imaging (MRI). Contrast media are used primarily to enhance soft-tissue contrast obtaining more diagnostic information. However, administering contrast agents is not a benign endeavor. The administration of contrast agents comes with inherent risks which need to be mitigated, and when contrast reactions occur, they need to be appropriately managed. Therefore, providers must understand and consider the potential risks associated with each respective contrast agent.

There is a plethora of information regarding adverse reactions to contrast agents. However, the etiology of these contrast reactions is not completely understood and is likely multifactorial. As such, it is important to understand each contrast agent's pharmacology and the associated adverse reactions. This course will discuss in detail the contrast agents used for radiography and fluoroscopy, CT, and MRI. We will then discuss risk factors for adverse reactions to contrast reactions, each type of reaction, and how to manage them.

Ultrasonography Contrast Media

The use of contrast agents with US is not yet ubiquitous but continues to gain considerable ground for certain applications, particularly cardiac imaging. Microbubble compounds contrast ultrasound imaging by altering the acoustic impedance between the blood and the injected gas. The first ultrasonic agent was introduced in the late 1960s by Charles Joyner. Following that, agitated saline was used as a contrast agent. However, its effects were short-lived. The first available contrast agent for ultrasound came to the market in 1984 and was named SHU-454. SHU-454 consisted of galactose microcrystals containing air bubbles that were released after injection. SHU-454 was mostly used in salpingography since it did not cross the lung capillaries and could not be used for cardiac imaging.

The challenge with ultrasonic contrast agents is developing particles that are echogenic enough and small enough in size. Microbubbles can range in size from 1 to 7 um in diameter. Research to develop submicrometer ultrasound contrast agents remains in progress.

Specific Types of Contrast Agents

Iodinated Contrast Agents Used for Radiography, Fluoroscopy, and Computed Tomography

The risk of adverse reactions from iodinated contrast agents used in imaging is well-established (American College of Radiology [ACR], 2021). The exact etiology of contrast reactions after administration of intravascular iodinated contrast agents, however, is not well known (ACR, 2021). The average incidence of allergic reactions for nonionic formulations is approximately 3% or less. The assumption is that the incidence for ionic contrast agents is higher than nonionic contrast agents.

Types of Iodinated Contrast Agents

Contrast agents can be administered by mouth, intravenously, per rectum, intrathecally (into the epidural space), intravesical (bladder), or into joint spaces (arthrograms). Being able to administer these contrast agents in so many ways and via so many routes including ostomies allows radiologists and other clinicians to enhance the differences between tissues that would normally be very close in attenuation. In the world of imaging today, the use of contrast is ubiquitous for most imaging modalities especially CT imaging.

The primary routes of delivery for CT contrast are intravenous and enteric (oral and rectal). Intravascularly-administered agents are iodinated material that moves quickly into the extracellular fluid. No significant metabolism or transformation occurs. Excretion is primarily through the kidneys. In patients with compromised renal function, there is greater excretion through the biliary system and gastrointestinal tract.

Intravascular Contrast Agents

Usually, water-soluble contrast agents are used intravenously in CT imaging for better visualization of vascular structures and hypervascular tissues. First generation contrast agents are high osmolar compounds with an osmolality up to 5 to 8 times the osmolality of blood. When used intravenously, these agents are associated with intravascular volume overload due to their high osmolality which proved problematic for patients with heart failure. They are also associated with more reports of pain when administered intravenously. Currently, the only use for high osmolality agents is for gastrointestinal or retrograde urological procedures such as cystography. They are, in fact, advantageous because of their low cost. An example is Isopaque.

Low osmolality nonionic compounds are associated with fewer adverse reactions when administered intravenously. Examples include Omnipaque and Isovue.

Nonionic iso-osmolar agents such as Visipaque are hydrophilic. These hydrophilic agents are better to be used in patients at increased risk for Contrast-Induced Nephrotoxicity.

Gastrointestinal Agents

Barium Sulfate mixtures are used to opacify the bowel loops. The contrast agent is administered orally about 1.5 to 2 hours prior to imaging to allow for appropriate transit within the bowel. If bowel perforation is suspected, water-soluble iodinated agents are recommended instead. High-osmolality iodinated contrast agents should be avoided in patients who are at risk for aspiration. Aspirated high-osmolality contrast agents can cause chemical pneumonitis with associated pulmonary edema. Aspiration of large volumes of both barium-based and iodinated oral contrast agents have rarely been reported as fatal.

Volumen is an ultra-low concentration barium sulfate agent which contains sorbitol-a sugar alcohol known to promote gastrointestinal distention. Volumen proves particularly useful for CT enterography. Volumen is useful in that it provides negative enteric contrast filling the bowel with a low attenuation fluid. This allows for better evaluation of bowel wall thickening or abnormal enhancement when used in conjunction intravenous agents.

Gadolinium-Based Contrast Agents

Mild reactions from gadolinium-based agents typically occur in about 1% of all patients (ACR, 2021). Severe and anaphylactic reactions to gadolinium-based contrast are extremely rare. All gadolinium-based contrast agents are chelated with the intention of making the agents less toxic or non-toxic while also allowing for renal excretion.

Risk Factors for Adverse Reactions to Intravenous Contrast Agents

Providers and other clinical team members are encouraged to review each patient’s risk factors as it pertains to contrast reactions prior to the administration of these contrast agents (ACR, 2021). Nurses and radiology technicians play a critical role in identifying that the patient’s risk factors have been reviewed comprehensively. Although, it is the ordering provider’s responsibility to ensure that the patient’s history is thoroughly reviewed, each member of the clinical team should be aware of these factors and must be encouraged to speak up if they feel something is being overlooked by other team members.

As is the case with any diagnostic exam or procedure, the ordering provider and the radiologist must carefully consider the risk to the patient versus the benefits of the diagnostic exam. For example, a patient who reports an “allergic” reaction of nausea and vomiting with the administration of iodinated contrast presents with symptoms concerning for acute pulmonary embolism. The ordering provider must first understand that while contrast agents may elicit nonideal physiologic responses in a patient, the risk of this possible reaction may outweigh the risk of delaying the diagnosis of a potentially life-threatening condition.

In addition to evaluating the risk/benefit ratio for each diagnostic or therapeutic test prior to administering the contrast agent, alternatives to the test currently ordered must also be considered and the radiologists will provide insight into whether these alternatives will be able to answer the clinical question. For example, an indication for chest pain would not warrant ordering transvaginal ultrasound or MRI of the pelvis.

The need for a signed consent for the administration of contrast agents depends on the state law, department policy, and institutional policy. Most facilities do not require a signed consent for the administration of contrast materials. However, special circumstances may warrant a consent.

History of Prior Allergic Reactions

It is common knowledge that any history of allergic reactions predisposes individuals to future allergic reactions to other substances. A history of allergic reactions is sometimes challenging to evaluate in clinical practice because the definition of allergy reactions is not as clear to a patient reporting them as it is to providers, nurses, and other healthcare team members. For example, seasonal rhinitis is a very common allergy, but this would not be a symptom that would be documented as an allergic reaction.

A prior allergy-like reaction to contrast media increases the risk of a subsequent reaction by up to 5-fold. If the patient reports a history of allergies, the providers and other clinical staff should focus specifically on the type of reaction, the specific contrast agent involved in the reaction (not just the agent class), the type of symptoms experienced, and the duration of the symptoms. The goal here is to establish the severity of the “allergy reaction” in order to clearly identify patients who may be atopic.

Atopy is defined as a genetically determined propensity to produce specific immunoglobulin E (IgE) following exposure to an allergen. Once this occurs, the patient is sensitized, but it is important to note that sensitization does not imply that the host exposed is allergic to that specific allergen. Individuals sometimes produce IgE to allergens in a given substance but never go on to develop symptoms upon subsequent exposure to that substance. It is not fully understood why certain individuals develop active allergic disease while others are only sensitized. The main concern is that patients who are atopic could experience more severe reactions with each exposure potentially leading to a future anaphylactic reaction.

Asthma

A history of asthma may confer an increased risk of developing an allergic reaction to contrast agents because these patients typically also have a history of other atopy-related conditions such as eczema.

Cardiovascular Disease

Patients with cardiovascular disease issues such as angina, congestive heart failure, severe aortic stenosis, primary pulmonary hypertension, or cardiomyopathy are at risk for adverse reactions to contrast agents. In this group of patients, the volume of contrast and the osmolality of the contrast agents administered are critical because these two factors affect the cardiovascular status significantly.

Anxiety

There are a few studies which have shown that the patient’s emotional state can affect the occurrence of adverse effects to contrast agents. In a patient with a known history of anxiety, pre-medication with anti-anxiety medications or reassurance of the patient prior to the test can be helpful.

Age

Infants and neonates are at increased risk for adverse effects of contrast agents. Contrast volume is an important consideration because of the low blood volume of patients in this age group. Low blood volume makes them at increased risk for hyperosmolality with its associated cardiotoxic effects.

Risk Factors Pertaining to Renal Insufficiency

Renal insufficiency prior to the administration of iodinated contrast increases the risk of Contrast-Induced Nephrotoxicity (CIN) and Nephrogenic Systemic Fibrosis (NSF) which will be discussed later in this course. Patients with Acute Renal Failure, as well as End Stage Renal Disease (ESRD) are at increased risk.

Beta-Blockers

Some reports have suggested that the use of beta-blockers lowers the systemic threshold for contrast reactions and could potentially limit the effectiveness of epinephrine. However, the evidence for this is not significant enough to warrant pre-medication based solely on the use of beta-blockers. In fact, patients on beta-blockers do not need to discontinue their medications prior to the administration of contrast agents (ACR, 2021).

Types of Contrast Reactions

Allergic-Type Reactions

These reactions can either occur acutely or can be delayed for up to 1 week after the administration of contrast agents. Allergic-type reactions are of unclear etiology and occur above an unknown threshold. They are not dose nor concentration related. Allergic-type contrast reactions are likely independent of dose and concentration above a certain unknown threshold.

Physiologic Reactions

These are typically related to chemical attributes related to the specific molecules within contrast agents such as hyperosmolality or chemotoxicity. Physiologic reactions tend to be dose and concentration dependent. Examples include cardiac arrhythmias and seizures.

Acute Adverse Reactions

In general, acute adverse reactions can be considered either allergic or physiologic which can then be graded as mild, moderate, or severe. Note that this classification is used for both reactions to iodinated contrast media as well as gadolinium-based contrast agents.

Mild Reactions

Mild symptoms tend to be self-limited and require no further treatment. They tend to resolve without progressing to a more severe reaction. Mild reactions can further be characterized as allergic-type or physiologic.

Mild Allergic-Type Reactions

These include:

• Sneezing
• Conjunctivitis
• Rhinorrhea
• Cutaneous edema
• Itchy or scratchy throat
• Pruritis
• Limited urticaria
• Nasal congestion

Mild Physiologic Reactions

These include:

• Nausea and vomiting (self-limited)
• Transient flushing
• Warmth
• Chills
• Headache
• Dizziness
• Mild hypertension
• Vasovagal reactions that resolve spontaneously

Moderate Reactions

These reactions typically require medical treatment and can become severe if not well treated. As such, clinical team members must remain vigilant when these reactions occur.

Moderate Allergic-Type Reactions

These include:

• Wheezing
• Bronchospasm (typically associated with mild or absent hypoxia)
• Diffuse urticaria
• Diffuse pruritis
• Facial edema with shortness of breath
• Diffuse erythema with hemodynamic stability and hoarseness with shortness of breath

Moderate Physiologic Reactions

These include:

• Vasovagal reactions (require treatment and are responsive to treatment)
• Isolated chest pain
• Protracted nausea and vomiting
• Hypertensive urgency
  • Hypertensive urgency is defined as a blood pressure greater than 180/120 without any evidence of end organ damage which differentiates it from a hypertensive emergency

Severe Reactions

Symptoms associated with severe reactions can be life-threatening and carry a significant risk for morbidity or death if they are not addressed promptly and appropriately. Unfortunately, both allergic-like and physiologic reactions can result in cardiopulmonary arrest. Sometimes it is unclear what type of reaction caused the cardiopulmonary arrest.

Pulmonary edema is a rare severe reaction which can occur regardless of cardiac reserves. Patients with low cardiac reserves get cardiogenic pulmonary edema while patients with normal cardiac reserves get noncardiogenic pulmonary edema.

Severe Allergic-Type Reactions

These include:

• Diffuse edema with shortness of breath
• Laryngeal edema with stridor
• Wheezing
• Bronchospasm with significant hypoxia
• Diffuse erythema with hypotension
• Anaphylactic shock (characterized by hypotension and tachycardia)

Severe Physiologic Reactions

These include:

• Vasovagal reactions (which are resistant to treatment)
• Arrhythmias
• Seizures
• Convulsions
• Hypertensive emergency
  • Which is defined as a blood pressure greater than 180/120 with evidence of end organ damage

Delayed Reactions

Delayed adverse reactions typically occur 30 minutes to 1 week or more after the administration of the contrast agent. Delayed reactions are more likely following the administration of an ionic contrast agent than a nonionic contrast agent. The typical symptoms of delayed reactions involve urticaria or pruritus and are treated with antihistamines or topical steroids.

Non-Allergic Reactions

Contrast-Induced Nephropathy

Contrast-Induced Nephropathy (CIN) is defined as an Acute Kidney Injury (AKI) which occurs within 24-48 hours after the administration of contrast agents. It is important to note that other causes of AKI must be excluded prior to diagnosing CIN. AKI is defined as an absolute increase in the serum creatinine of 0.5 mg/dl or relative increase by 25% from the baseline. The risk of CIN is very low in a patient with normal renal function (that is, a glomerular filtration rate (GFR) greater than 60 ml/min). In general, CIN is self-limiting and the renal function should return to baseline within 7 -10 days without progressing on to chronic renal failure.

On the other hand, if a patient has an abnormal renal function at baseline, that is a GFR less than 60, then the risk of CIN is much higher. This is especially true in elderly patients with diabetes. In these patient groups, traditionally what has been done is appropriate screening with subsequent hydration before and after contrast administration.

Nephrogenic Systemic Fibrosis

History

Gadolinium was first discovered in 1880 and named after Johan Golin (ACR, 2021; Zamora & Castillo, 2017). Gadolinium has seven unpaired electrons making it one of the strongest paramagnetic atoms on the periodic table. Consequently, even when gadolinium is bound to a chelator, the unpaired electrons are still available for interaction with other protons and nuclei to facilitate the longitudinal relaxation times (T1 property) and also influencing the transverse relaxation time (T2 property).

The first known case of Nephrogenic Systemic Fibrosis (NSF) occurred in 1997 after the administration of high doses in patients with renal failure had become the standard of practice. At the time of the initial diagnosis, NSF was previously called Nephrogenic Fibrosing Dermopathy. It was named based on the primary dermatologic manifestations which were initially noticed. Once the involvement of internal organs was noted, the name was changed to Nephrogenic Systemic Fibrosis.

The cause of NSF was discovered in 2006 by a Danish Nephrologist, Thomas Grobner, who noted that 5 out of the 9 patients with renal failure who had gadolinium-enhanced MR imaging were subsequently diagnosed with NSF.

In cases where the patient gets exposed to the non-chelated component of gadolinium contrast agent, there has been an association with NSF. In the past, gadolinium contrast agents were administered in high doses for MR imaging including in patients with acute renal failure or patients on dialysis. In the early 2000’s, the association between contrast administration and NSF was established thereby prompting clinicians to start administering low doses of contrast agents especially in patients undergoing dialysis or patients with a GFR < 30 ml/min. High doses are very rare nowadays with most applications being adjusted to a standard dose of 0.1mmol/kg.

Possible Physiologic Effects

Regulatory authorities both in the United States and Europe have issued a black-box warning for all gadolinium-based contrast agents. They have also issued a cautionary warning to patients with acute or chronic renal dysfunction, patients with a GFR < 30 ml/min, patients with acute renal failure secondary to hepatorenal syndrome, and patients who are in the perioperative period for liver transplantation.

NSF is a condition in which patients on dialysis or patients with profound renal failure are affected by the administration of gadolinium-based contrast. It is a rare, fibrosing condition whose clinical manifestations include:

• Skin thickening
• Thickened underlying connective tissue leading to contractures (decreased range of motion)
  • Occasionally, the process of fibrosis can extend to involve the heart, muscles, and the lungs with debilitating consequences.

An overwhelming majority of NSF cases are mild and remain limited to dermatologic conditions. However, up to 5% of cases progress to severe manifestations of the condition, and some cases take a fulminant course leading to death.

Protocols

There are very limited treatment options for NSF. Therefore, prevention is important. As such exposure of gadolinium-based contrast agents is limited in patient groups who are at increased risk for developing NSF including diabetics, patients on dialysis, and patients with severe renal failure (GFR < 30 ml/min).

In patients already on dialysis, the current recommendation is prompt dialysis following the performance of a contrast enhanced MR study using gadolinium-based contrast agents. When gadolinium-based contrast agents are administered in patients undergoing dialysis, the recommendation is that the administration of these agents should be scheduled just before the next dialysis treatment to facilitate quick clearance from the patient’s system.

In patients who are at risk for NSF, alternating diagnostic procedures using different modalities should be considered, or MR imaging without the use of gadolinium-based contrast agents should be performed.

Specific Risk Factors

1. Renal Failure:
   1. Note that NSF is usually diagnosed in patients with severe renal dysfunction especially patients undergoing dialysis or approaching the stage of needing dialysis, hence the use of the term “nephrogenic” in NSF.
   2. The GFR is usually calculated based on the age, gender, ethnicity, and the serum creatinine.
   3. It is not recommended to perform MR imaging with gadolinium-based contrast agents in patients with Acute Renal Failure with rising creatinine levels.
   4. These individuals should be scheduled for gadolinium-based contrast agents enhanced MR once the creatinine levels start to decrease.
2. Dialysis:
   1. Originally, it was believed that dialysis was a risk factor for NSF that up to 80% of the patients diagnosed were on dialysis at the time of diagnosis.
   2. However, it seems that some of these patients received gadolinium-based contrast agents prior to the time dialysis was initiated.
   3. However, at the time of dialysis, the renal failure was so severe that the patients necessitated dialysis and therefore an erroneous connection was made between the two.
   4. The fact that dialysis therapy was necessary at the time of dialysis only underscores the severe renal dysfunction associated with NSF.
   5. As previously mentioned, the current recommendations are that dialysis should be performed within 24 hours of gadolinium-based contrast agent administration in patients with End-Stage Renal Disease (ESRD).
3. Gadolinium-Based Contrast Agent Dose:
   1. It has been reported that the use of high doses of gadolinium-based contrast agents and possibly the use of linear nonionic gadolinium-based contrast agents both increase the risk of NSF.
   2. Multiple studies have implicated the use of high doses of gadolinium-based contrast agents as an independent risk factor for NSF.
4. Gadolinium-Based Contrast Agent Type:
   1. There are significant differences between macrocyclic and linear agents as well as between ionic and nonionic linear agents.
   2. Linear agents are simpler and generally less expensive to synthesize compared to macrocyclic agents.
   3. Macrocyclic agents are different from linear agents in that they have greater kinetic stability due to the complete encircling of the gadolinium (Gd) ion with covalent bonds.
   4. This covalent bond makes it very difficult for Gd ions to be released into the tissue, even when there is delayed excretion.
   5. This supports the idea that macrocyclic agents are almost completely safe and practically free of risk of NSF.
   6. Although nonionic agents have a far lower incidence of allergic reactions compared to ionic agents, they are less stable once injected compared to ionic agents. This makes the nonionic linear more likely to be associated with NSF.
5. Pro-inflammatory Events:
   1. All the patients diagnosed with NSF had underlying pro-inflammatory conditions such as recent major surgery or infection.
   2. The theory is that pro-inflammatory states are marked by high levels of circulating fibrocytes which are attracted to gadolinium deposited in tissues.
   3. Additionally, pro-inflammatory conditions are associated with edema, which increases the fluid in the interstitial compartment, thereby increasing the chances of NSF.
6. Hyperphosphatemia:
   1. When phosphates bind to a gadolinium ion, the bond is irreversible with preventing the gadolinium ion from rapidly reassociating with the chelator.
   2. Once the Gd irreversibly binds to phosphates and precipitates out of solution into tissues, the unidirectional reaction releasing gadolinium from the chelator continues to be propagated.

Clinical Manifestations

Radiologists rarely encounter NSF because, unlike other contrast reactions, it does not occur at the time of the imaging study. Rather it occurs several weeks to months later. The lesions of NSF usually involve the dermis in the extremities, symmetrically, and less frequently, it will affect the trunk.

The course of NSF is usually more indolent with several weeks to months of symptoms before the diagnosis is made. Less often the disease adopts a fulminant course leading to rapid death on occasion. The primary lesions of NSF are firm to hard skin-colored or erythematous papules which may coalesce to involve large areas of the trunk or the extremities. Occasionally they have been described as thickened, brawny indurations which look like the Peau D’Orange lesion or have a cobblestoned appearance.

As the disease progresses, the skin will progressively harden and become tethered. Joint contractures may develop when the fibrosis crosses through the joint thus severely impairing physical function and movement.

Patients afflicted with NSF usually complain of severe extremity pain, pruritus, skin tightness, or sometimes a burning sensation.

Management of Contrast Reactions

Allergic-Type Reactions

Pre-testing patients for potential major adverse reactions has been shown to be of no value in determining who will have an adverse reaction (ACR, 2021). Nonionic contrast media has mostly replaced ionic contrast media for most clinical practices in order to minimize the chance of allergic and other adverse contrast reactions.

Patients reporting allergic reactions to contrast media should be pre-medicated with prednisone and diphenhydramine. The prednisone is usually administered orally the night before. The morning of administration, prednisone is again given, as well as oral diphenhydramine.

Pre-treatment with corticosteroids is noted to be useful in reducing all types of contrast reactions except those predominantly characterized by hives. However, it is important to note that premedication may not prevent the occurrence of adverse reactions completely.

Treatment with H2-receptor blockers has not been shown to be valuable in preventing allergic reactions to contrast. However, the pre-treatment of patients with known prior anaphylactic reactions to contrast with H1-receptors has been shown to be effective.

Contrast-Induced Nephropathy

Interventions to prevent Contrast-Induced Nephropathy (CIN) include pre and post-hydration and the maintenance of increased urine output or flow which is usually greater than 200 mL/hr. Some studies have shown N-acetylcysteine administration prior to intravenous contrast administration has been shown to CIN.

Patients at increased risk for CIN include those patients with pre-existing kidney impairment (serum creatinine ≥ 1.3 mg/dL or a GFR < 60 mL/min).

Other factors included are hypertension, hemodynamic instability, dehydration, older age (age > 75 years), Congestive Heart Failure (CHF) and higher doses of contrast media.

Regarding pre-procedural hydration, the fluids are administered orally or intravenously. However, the recommendation is to not use oral fluids alone in patients at increased risk for CIN.

Contrast Extravasation

Extravasated contrast material could potentially lead to compartment syndrome if enough contrast material leaks into surrounding tissue. Typical rates of contrast injections are 4 to 6 ml/second for vascular examinations.

Treatment for contrast extravasation includes elevation of the extremity and cold compresses. A thorough physical assessment should be performed including evaluation of capillary refill and distal pulses. A thorough neurological exam should also be performed. Plastic surgery should be consulted, if necessary, and this consultation is often initiated by the radiologist.

Patients Taking Metformin

Patients who take Metformin or Metformin-containing medications and are scheduled for imaging studies are challenging to manage. Given that Metformin is excreted unchanged by the kidney, patients with renal dysfunction will have higher than expected serum levels and are at risk of developing lactic acidosis. Lactic acidosis has been reported to be fatal in some cases. In addition, individuals with very poor cardiac function or acute hepatic compromise have increased lactate production or impaired lactate breakdown and also are at risk of developing lactic acidosis. For all such patients, the use of Metformin is contraindicated.

The Metformin package insert which was approved by the United States Food and Drug Administration (FDA) states that Metformin use should be stopped at the time an iodinated contrast agent is administered and that the patient should wait 48 hours before resuming use of Metformin (Metformin, 2021). There is no mandate to measure serum creatinine levels at that time. Instead, the patient should be re-evaluated clinically, and a creatinine value should be obtained if there are any other reasons that the patient’s renal function may have been compromised, such as major surgery or cardiogenic shock.

The important point to remember is that Metformin is contraindicated in patients with any compromise in renal function. It is surprising how often patients who take Metformin and who have elevated serum creatinine levels are referred for a contrast agent study. In these patients, the imaging study should be delayed and the referring physician should be notified.

Special Topics

Shellfish Allergy and Allergy to Iodinated Contrast Agents: Truth or Myth?

Clinical providers including some radiologists have commonly believed that there is a link between an allergic reaction to shellfish and increased risk of allergic reaction to iodinated contrast agents (ACR, 2021). This connection between an allergy to shellfish and iodinated contrast agents was first reported in the 1970’s. The assumption is based on the fact that both shellfish and iodinated contrast contain significant amounts of iodine. This idea has led some providers to encourage pre-medication of patients who self-report a shellfish allergy prior to the administration of iodinated contrast agents. Premedication is usually done with corticosteroids or antihistamines to block the allergic response. Providers have even gone as far as recommending that iodinated contrast media not be administered at all.

Shellfish allergy remains one of the most common food allergies among adults and also remains a common cause of anaphylactic reactions related to food consumption. Shellfish are separated into two groups:

1. The crustaceans also known as arthropods and the molluscs.
   1. Examples of arthropods include:
      1. Crab
      2. Lobster
      3. Prawn
      4. Shrimp
   2. Examples of molluscs include:
      1. Clams
      2. Mussels
      3. Oysters

Like most other allergic reactions, the treatment for shellfish allergies is antihistamines, corticosteroids, and epinephrine, if needed (ACR, 2021).

Allergies to shellfish are mainly due to tropomyosins and iodine has been shown to have no contributory effects to the allergic reactions. Additionally, iodine plays a significant role in the human survival because it is used by the thyroid gland for functions essential to human life.

Reactions to iodinated contrast are not true allergic reactions in that they are not mediated by IgE but rather they occur by direct stimulation of mast cells and basophils. The stimulation of these cell types yields a pseudo-allergy-like reaction also known as anaphylactoid reactions whereas a true allergic reaction would produce allergy-specific immunoglobulin E (IgE) following exposure, making the patient sensitized to the allergen. Finally, the anaphylactoid reaction that occurs with iodinated contrast media does not occur due to iodine, but rather occurs due to the hyperosmolality of the contrast media compared to blood (ACR, 2021).

Even though a large number of providers continue to specifically inquire about shellfish allergy as a way to screen for allergies to iodinated contrast, there is no evidence to support the practice, and it is recommended that the practice is discontinued (ACR, 2021).

Contrast Agent Use in Breastfeeding Women

The half-life of intravenously-administered iodinated contrast agents is around two hours by which time almost 100% of the agent is cleared from the bloodstream in patients with normal baseline renal function (provided it was last measured in the previous 24-hour period) (ACR, 2021).

Given that iodinated contrast agents have low lipid solubility, less than 1% of the agents administered are excreted into breast milk. Of the amount of contrast agents ingested by breastfeeding babies, less than 1% is absorbed from the infant’s gastrointestinal tract. In effect, the dose presumably absorbed by a breastfeeding infant via their mother’s milk is less than 0.01% of the dose administered intravascular to the mother.

In comparison, this dose is less than 1% of the standard dose which would be prescribed to a similar infant for the performance of an iodinated contrast enhanced imaging study. The standard dose is usually 1.5 to 2 mL/kg for infants (ACR, 2021).

The risks to the infant are direct toxicity and allergic sensitization or potentially an allergic reaction. It is important to note that these risks remain theoretical and have not been reported in literature. There is also a risk that if the contrast agent is secreted in the mother’s milk, it may alter the taste of the milk.

The American College of Radiology recognizes that an informed decision to temporarily stop breastfeeding is one which is made by the mother (ACR, 2021). However, their recommendation is that it is safe for the mother and the infant to continue breastfeeding during the administration of iodinated contrast agents given that the available data supports this position. If the mother still has concerns after reviewing the available data, she could defer breastfeeding for 24 to 48 hours after the administration of the iodinated contrast agent (ACR, 2021).

Gadolinium Deposition in Brain Tissues

Gadolinium-based contrast agents have been considered relatively safe since they first appeared on the market and were approved by the FDA. Life-threatening adverse reactions to gadolinium-based contrast agents typically appear within a few minutes after the administration of the contrast agent. The current rate of adverse contrast reactions to gadolinium-based contrast agents is between 0.001 to 0.01%.

Potentially lethal NSF was first documented as a reaction to gadolinium-based contrast agents in patients with renal failure. The incidental deposition of gadolinium-based contrast agents in the brain was reported in 2014 (Kanda et al., 2014). Since then, several other studies have confirmed these findings. The underlying mechanism of action remains unclear, and currently, there is no clear evidence that the deposition of gadolinium accumulation in the brain is detrimental. As of today, the FDA has decided not to restrict the use of gadolinium-based contrast agents for this reason (Samson, 2015).

However, some European countries have decided to restrict the marketing of some gadolinium-based agents. For example, marketing authorizations for some linear agents have been suspended based on recommendations by the European Medicines Agency's Pharmacovigilance and Risk Assessment Committee (Choi & Moon, 2019). The linear agents involved include Multihance, gadodiamide, gadopentetate dimeglumine, and gadoversetamide. In Japan, specific changes in the labeling inform patients about the retention of gadolinium in the brain.

Dechelation of free gadolinium is the first step in the mechanism of gadolinium deposition in the brain (Choi & Moon, 2019). Endogenous ions in the body such as iron (Fe3+), magnesium (Mg2+), or copper (Cu2+) also increase the risk of dechelation by attracting the ligands from the gadolinium ion in a process known as transmetallation.

There is increased concern that the deposition of gadolinium in brain tissues may be linked to disease (Choi and Moon, 2018). As a consequence, there is increased research interest in this field over the past few years. It is important that patients get their questions answered truthfully and their concerns about gadolinium validated without provoking unwarranted fear and concern.

Case Scenario

You are a nurse working on a medical/surgical floor when you get an order for a CT of the abdomen and pelvis with IV and oral contrast in a patient with suspected diverticulitis.

The patient has a shellfish allergy with the documented allergic response being anaphylaxis.

In addition, the patient has a documented allergy to “Iodine” with no specific reaction listed.

As the nurse on the floor, the patient raises concerns about receiving iodinated contrast given that they have a severe allergy to contrast.

How should you address this dilemma?

Discussion for Case

The first step is to clarify the patient’s allergy list, especially when you have certain allergies with undocumented allergic responses. In this case, the patient has an allergy to Iodine with an undocumented response. The first thing to realize an Iodine allergy is incompatible with life because the thyroid gland uses Iodine to make thyroid hormone, which, again, is necessary for life. The body needing Iodine is true even for patients with congenital hypothyroidism. So, an allergy to Iodine is just like saying you are allergic to calcium which is an essential element for life. Because of this, the allergy to Iodine should be deleted from the patient's record.

The patient may have an allergy to some Iodine-containing substance and that should be clarified and documented accordingly. For example, a patient could be allergic to betadine due to sensitization and this should be documented properly in the record, but an allergy to betadine does not necessarily imply an allergy to iodinated intravenous contrast agents. Most of the time, the allergy is to other substances in the Iodine-rich materials and not to the Iodine itself.

Finally, an allergy to shellfish does not confer a related allergy to iodinated contrast agents. This belief has been erroneously promulgated in medical literature and among the healthcare community, especially among the nursing community. Allergies to shellfish are true IgE-mediated allergic reactions due to tropomyosins whereas the anaphylactoid reaction to iodinated contrast agents is secondary to the hyperosmolality of the contrast media compared to blood and are mediated by mast cells and basophils.

These issues should be discussed with this patient and any additional questions that come up should be answered. These aforementioned issues are not contraindications to receiving the IV contrast for this CT.

Summary

Adverse reactions to contrast agents are an understandable cause for concern for both patients and clinical providers. A thorough understanding of true allergies to contrast agents and how to manage these reactions is necessary for clinicians in today’s practice. With the increasing ubiquitous use of electronic medical records, a history of an allergy to contrast agents, either real or perceived, could easily get propagated in the medical record. It is important for all clinicians to fully understand the typical adverse reactions to contrast agents, especially nurses who are often responsible for documenting allergies in the medical record. When documenting allergies in the medical record, it is imperative to clarify what the exact allergy is. The patient should be educated about side effects of each contrast agent being administered, given that inaccurately documented allergies to contrast agents may limit the ability for providers to get appropriate diagnostic tests in the future.

Finally, it is imperative for clinical providers to understand that an allergy to a certain contrast agent does not imply automatic contraindication to that class of agents or the specific agent. Clinical decisions should be made on each patient’s case, based on the risk-benefit ratio of the ordered test. For example, if a patient needs a lifesaving cardiac catheterization procedure, a mild adverse reaction to intravenous iodinated contrast agents becomes negligible.

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References

• American College of Radiology. (2021). ACR Committee on Drugs and Contrast Media: ACR manual on contrast media. American College of Radiology (ACR). Retrieved March 9, 2021.Visit Source.
• Choi, J. W., & Moon, W. J. (2019). Gadolinium deposition in the brain: Current updates. Korean Journal of Radiology, 20(1), 134. Visit Source.
• Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2014). High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology, 270(3), 834–841. Visit Source.
• Metformin—FDA prescribing information, side effects and uses. (2021). Drugs.com. Retrieved June 30, 2021.Visit Source.
• Samson, K. (2015). FDA Investigating risk of brain deposits of gadolinium MRI contrast agents. Neurology Today, 15(17), 25–26. Visit Source.
• Zaer, N. F., Amini, B., & Elsayes, K. M. (2015). Overview of diagnostic modalities and contrast agents. In K. M. Elsayes & S. A. Oldham (Authors), Introduction to Diagnostic Radiology. New York, NY: McGraw-Hill.
• Zamora, C. A., & Castillo, M. (2017). Historical perspective of imaging contrast agents. Magnetic Resonance Imaging Clinics of North America, 25(4), 685–696. Retrieved March 8, 2021.Visit Source.

Additional Resources

(References used for course but not specifically cited in-text)

• Di Carli, M. F., Solomon, S. D., & Kwong, R. Y. (2018). Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging. In D. Kasper, J. Loscalzo, J. Jameson, A. Fauci, S. Hauser, & D. Longo (Authors), Harrison's Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill. Retrieved March 9, 2021. Visit Source.
• Mukundan, S. L., Jacobson, F., Sodickson, A., Ross, J. J., Dressler, D. D., & Scheurer, D. B. (2017). Patient Safety Issues in Radiology. In S. C. McKean (Author), Principles and Practice of Hospital Medicine, (2nd ed.). New York, NY: McGraw-Hill.
• Umakoshi, H., Nihashi, T., Shimamoto, H., Yamada, T., Ishiguchi, H., Takada, A., Hirasawa, N., Ishihara, S., Takehara, Y., Naganawa, S., Davenport, M., & Terasawa, T. (2020). Pharmacologic and non-pharmacologic interventions to prevent hypersensitivity reactions of non-ionic iodinated contrast media: A systematic review protocol. BMJ open. Visit Source.

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