Adverse Reactions to Contrast Agents: Dispelling the Myths (FL Autonomous Practice INITIAL Pharmacology)

According to Zamora and Castillo (2017), X-rays were first discovered in November 1875 when Wilhelm Conrad Roentgen obtained the first human body images. 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 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 1920s, 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).

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 of ionic contrast agents is higher than nonionic 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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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 in 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. On 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.

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.

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 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.

Clinical providers including some radiologists have commonly believed that there is a link between an allergic reaction to shellfish and an 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 are also known as arthropods and mollusks.
   1. Examples of arthropods include:
      1. Crab
      2. Lobster
      3. Prawn
      4. Shrimp
   2. Examples of mollusks 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 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 an anaphylactoid reaction 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).

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 the 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 that 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-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 has been 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.

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.