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Emergency Medicine News:
In Focus: Part 2 in a Series

Complications of Radiographic Contrast Material: Acute Anaphylactoid Reactions

Roberts, James R. MD

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A compendium of Dr. James Roberts' InFocus columns is available in book form. The 302-page volume, InFocus: Roberts' Practical Guide to Common Medical Emergencies, is available from Lippincott Williams & Wilkins for $59.95 by calling (800)638–3030.

Author Credentials and Financial Disclosure: James R. Roberts, MD, is the Chairman of the Department of Emergency Medicine and the Director of the Division of Toxicology at Mercy Health Systems, and a Professor of Emergency Medicine and Toxicology at the Drexel University College of Medicine, both in Philadelphia, PA. Dr. Roberts has disclosed that he has no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

Release Date: July 2004

Learning Objectives: After reading this article, the physician should be able to:

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1. Discuss the incidence of anaphylactoid reactions to IV contrast material.

2. Describe the pathophysiology and characteristics of anaphylactoid reactions to IV contrast material.

3. Summarize the treatment of anaphylactiod reactions to IV contrast material.

Emergency physicians often order numerous studies that use iodenated intravenous contrast material. We are all aware of the occasional anaphylactoid reaction that occurs, a nightmare for the radiology department, the patient, and the ordering physician. There are, however, other clinical considerations surrounding the use of contrast material, including the effect on renal function and the inadvertent extravasation of dye into the soft tissues.

It is not uncommon to get a call from radiology saying they are sending over a patient (always a bad way to start a conversation) who is having an allergic reaction, or an individual who had IV infiltrate during a dye injection. The worst scenario is a code called in radiology, occasionally a disaster with regard to logistics and outcome. Radiologists are the true the experts in this field, and they often totally handle minor reactions or extravasations. Most minor reactions never make it to the ED. The majority of EPs probably think that IV dyes are totally safe, and don't give a second thought to the process of an intravenous injection. The burden of evaluating and treating an aliquot of such patients often ends up in the ED's mix of the sick and injured.

Fortunately, the advent and now routine use of newer and less toxic contrast agents has markedly reduced the incidence of serious reactions, including anaphylactoid reactions. Local tissue reactions, once a formidable problem, have all but disappeared. Although the newer contrast agents are more expensive than their predecessors, most radiology departments have changed their protocols to use the newer and less toxic agents exclusively.

Last month's column discussed the problems of extravasation of IV dye. Fortunately, most extravasations, even large ones, are minimally problematic, and one should avoid over-treatment or unnecessary anxiety-producing remarks, conclusions, or interventions.

Adverse Reactions to Contrast Material: Recognition, Prevention, and Treatment, Maddox T, Am Fam Physician, 2002;66:1229

This recent review article discusses a variety of reactions to IV contrast material. The discussion begins with a now dated discussion of the pros and cons of ionic versus nonionic contrast agents. It's my conclusion that almost all hospitals now universally use the low osmolality nonionic dyes, eschewing the ionic agents that once dominated the market.

The ionic v. nonionic nature of a dye is most relevant in the osmolality of a particular contrast agent. The osmolality is determined by the number of osmotically active particles in a dissolved solution, such as blood. The older ionic agents dissociate into ions that contain an iodinated benzene ring. The result is the production of an agent that has osmolality higher than blood. Because the newer nonionic agents do not dissolve into separate particles, their osmolality is half that of ionic agents. Contrast agents that have a high osmolality are much more likely to cause an adverse reaction, and all types of adverse reactions are more common with these agents. Low osmolality agents have fewer side effects, produce fewer systemic reactions, and are associated with less serious cardiovascular and anaphylactoid reactions. Although they have a significantly higher cost, the ability to reduce adverse events has led to the routine use of the less toxic dyes.

Anaphylactic Reactions: Anaphylactic reactions are potentially life-threatening conditions associated with the IV administration of contrast material. Clinically, such reactions include acute bronchospasm, hypotension, severe urticaria, and rarely cardiorespiratory arrest. The majority of reactions occur within minutes of administration of as little as 1 ml of contrast material. These are not true allergic reactions. Patients can develop acute allergic-like reactions without ever having been previously exposed to any contrast material. IgE antibodies, which are associated with true allergic reactions, are not present in dye-related reactions. Such reactions are more properly called anaphylactoid reactions. The etiology of these reactions is unknown.

Less serious systemic reactions include nausea, vomiting, metallic taste, and generalized warmth or flushed feeling. These reactions are relatively common, usually self-limited, and generally dose-dependent. They are not life-threatening. Anaphylactoid reactions may be life-threatening, and can occur with only a few mls of contrast agent.

Although most adverse reactions occur within a few minutes of the administration of contrast dye, some patients experience delayed reactions. Delayed reactions can occur with both the ionic and nonionic dyes, but they are more common in patients receiving ionic contrast material. Up to 10 percent of patients administered the less toxic nonionic agents will have some sort of delayed reaction. These reactions are less severe and less specific, and include such manifestations as flu-like symptoms, fever, chills, nausea, abdominal pain, fatigue, and congestion. Patients who have had a history of a prior anaphylactic-type reaction to contrast material are statistically more likely to have a similar reaction if they are re-exposed. Even patients who have had a serious anaphylactoid reaction may not experience a similar reaction with repeat exposure to the exact same dye.

Table. Suggested Pre...
Table. Suggested Pre...
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Patients with asthma have almost twice the overall risk of developing adverse reactions compared with the general population, even if the asthma is under control. Individuals with food or medication allergies or those with multiple medical problems also are more likely to develop complications when exposed to contrast material.

Although it is commonly believed that patients with seafood allergies are at higher risk for developing acute allergic reactions, this is essentially a myth with no substantial data to support it. Nonetheless, this concept probably will remain forever in the medical literature. Many EPs are not familiar with some of the more esoteric conditions that are associated with an increased incidence of dye reactions (see table). There are specific high-risk situations, such as multiple myeloma and pheochromocytoma, and uncontrolled hyperthryroidism. Nonetheless, scans of all types are still performed, even in light of theoretical concerns. The vast majority of patients who have relative contraindications or other cautions do well. (Most clinicians have to think long and hard to remember a significant contrast material complication in an ED patient. It would be prudent, however, to consider the possible risks, and identify those patients at higher risk the next time you order a CT scan for a questionable indication.)

Not all reactions can be prevented, but a few general principles may aid in decreasing the number and seriousness of dye reactions. The smallest amount of contrast material should be used for each procedure, a decision that is not usually under the control of the ordering physician. Allowing 48 hours to elapse between different contrast material infusions may allow the kidneys to recover. It is generally agreed that non-renal reactions to contrast dye can be reduced by premedication, especially with the use of corticosteroids. This precaution is extant for both ionic and nonionic dyes, and the protective nature of steroids is well accepted.

Most physicians do not routinely premedicate even high-risk individuals who have not had a prior reaction, but it is prudent to pretreat with corticosteroids if the patient has had a previous idiosyncratic or anaphylactoid reaction. To be most protective, corticosteroids should be given at least 12 hours prior to the administration of dye. Combining corticosteroids with an antihistamine may further reduce the chance of an adverse reaction. The histamine H1 receptor blockers are the drugs that are most studied and most effective. Diphenhydramine is the one usually chosen. Some physicians also include the use of an H2 blocker, such as Zantac (ranitidine) for patients who have had a prior severe reaction, but this tactic has less support. Other minor dose-dependent reactions, such as warmth, flushing, and nausea can be mitigated by a slower injection, usually not a practical intervention for most ED studies.

Anaphylactoid reactions are treated similarly to classic acute anaphylactic reactions. The mainstay of treatment is epinephrine, but cortisone and antihistamines also are routinely administered. There is no known specific treatment for delayed reactions. Delayed reactions may not be recognized, and usually resolve spontaneously.

Nonionic agents cost up to 10 times more than the high osmolality ionic agents. Guidelines, as of 2002, promulgated by the American College of Radiology, call for the use of low osmolality nonionic agents in patients who are at increased risk for adverse reactions. This includes patients who have had previous contrast reactions and those who have asthma, multiple allergies, or diseases that would be aggravated by the higher osmolality ionic agents.

Acute Pulmonary Edema After the Intravenous Administration of Contrast Media, Greganti M, Flowers W, Radiology, 1979;132(3):583

This worrisome article is a report of acute pulmonary edema developing in two previous healthy young women who had received IV contrast material. The reaction appeared to be limited to acute pulmonary edema, and it was not explained by anaphylaxis, contrast media overdose, fluid overload, or acute myocardial infarction. The authors termed the acute pulmonary reaction an idiosyncratic reaction, and seem to differentiate it from the well known anaphylactoid reaction that also may include the lungs.

In the first case, a healthy 22-year-old woman was undergoing an IVP, and developed tachypnea, diaphoresis, peripheral cyanosis, and severe shortness of breath within minutes of receiving a high osmolality contrast agent (Conray 400). Her blood pressure was unobtainable, and rales were heard bilaterally. There were no wheezes. She was treated with IV fluids, Benadryl, epinephrine, methylprednisolone, and a dopamine infusion. There were no changes on the EKG, and a chest x-ray revealed a classic pulmonary edema pattern. She recovered with the use of CPAP. She did not require tracheal intubation.

In the second case, a 17-year-old woman obtained a CT scan for the evaluation of headaches. Shortly after the infusion, the patient experienced anxiety and generalized urticaria. The initial symptoms appeared to dissipate with Benadryl and a single dose of epinephrine. She was discharged from the hospital after two hours of observation. She then experienced diaphoresis, nausea, and became dizzy. Shortness of breath and syncope quickly developed, and she was brought back to the ED in a cyanotic state, exhibiting acute pulmonary edema. She was expectorating frothy bloody sputum, had systolic hypotension, rales without wheezes, and a normal EKG. A chest x-ray demonstrated classic non-cardiogenic pulmonary edema. Treatment included additional doses of Benadryl, epinephrine, Lasix, and methylprednisolone. A dopamine infusion was required to maintain blood pressure. She slowly improved over 48 hours without the need for ventilator support.

The authors note that both patients developed a reaction that was not classic for previously described anaphylactoid reactions. The main target organ was the lung, and they postulate possibly a separate mechanism for the development of the pulmonary reaction. No additional data were obtained, and both patients recovered, but each had a serious life-threatening pulmonary insult related to the IV contrast material. Of particular note was that one case developed hours after the dye was given.

Table. Selected Reac...
Table. Selected Reac...
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Comment: A number of years ago, most hospitals realized that they were fighting a losing battle trying to save money on contrast material. Despite recommendations on selected use, most have now switched entirely to the nonionic low osmolality dyes. The price of such dyes has been reduced significantly. As an example, Optiray, the dye most commonly used in our hospital, is now less than $20 per dose, down from a few hundred dollars 10 years ago. There is no question that systemic reactions to these agents are much less common when compared with the high osmolality ionic agents, but serious reactions to these safer dyes do still occur.

Table. Reactions to ...
Table. Reactions to ...
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Antibodies to contrast agents have never been demonstrated, and although the reactions clinically look exactly like those produced by bee stings, food allergies, and medication reactions, they have never been proven to be IgE mediated type 1 hypersensitivity reactions. Such reactions have been termed anaphylactoid rather than anaphylactic, although from a clinical standpoint, the nomenclature is inconsequential. These patients look like they are having acute anaphylaxis (although itching and urticaria are not always present), and the treatment is the same as if one were treating anaphylaxis from a hymenoptera sting.

The low osmolality agents reduce, but do not eliminate such reactions. It is rare to see a cardiac arrest from IV dye these days, but most older clinicians can remember STAT calls to the radiology suite to treat some unfortunate young patient who suffered a cardiac arrest or near cardiac arrest within seconds of receiving just a few mls of dye. These are always stressful situations. The radiology suite is not an ideal place to run a code, and deaths do occur despite textbook treatment. In their early stages, even minor reactions seem to be a harbinger of an impending disaster, so any reaction should be taken very seriously.

Cochran et al (AJR 2001;176:1385) noted trends in adverse reactions to contrast material from 1985 to 2000. In 1985, only ionic contrast material was used at their institution, and there was a period where both agents were administered. By 1995 all IV ionated contrast material was nonionic. Numerous reactions were noted, including allergic-like reactions such as sneezing, nasal congestion, hives, itching, rash, and swelling. Some patients experienced pharyngeal edema, bronchospasm, and classic anaphylaxis. Other patients reported shaking, chills, fever, numbness, malaise, aches, shortness of breath, and chest pain. Hypertension and pulmonary edema also were occasionally noticed.

Over the study period, more than 90,000 patients received IV contrast. When only ionic contrast material was used, the reaction rate was 10 percent to 12 percent. This included minor reactions such as nausea and injection site pain. If these minor reactions were excluded, six percent to eight percent of patients experienced a reaction to the ionic contrast media, most of them being allergic-like. After nonionic contrast material was routinely used in every case, the reaction rate dropped to 0.2 percent. Again, most of the reactions were allergic-like. Like prior authors, these investigators found a few rare cases of pulmonary edema progressing through respiratory arrest. Overall, there were two deaths in 90,473 doses of iodinated contrast media. One occurred with ionic dye and one with nonionic dye. This study clearly demonstrates that reactions to nonionic low osmolality contrast agents are generally mild, less serious, and less frequent when compared with ionic contrast dyes (overall 8% v. 0.2 % respectively).

The overall mortality rate generally quoted for the use of nonionic dyes is about one in 100,000. The package insert for Optiray (loversol), a common nonionic dye, quotes a very low mortality rate (0.00066–0.01%). This rate is extremely low, and most physicians will never see a fatal reaction. but if your institution does enough CT scans, a fatal reaction is statistically possible. Patients can still die from an IV contrast reaction, and one has to respect this potential.

Table. Toxicity of I...
Table. Toxicity of I...
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Regardless of the pathophysiology involved, the general clinical approach to contrast material reactions is similar: Treat them like true allergic reactions. No single mechanism has been identified to account for all dye reactions. Histamine release, complement activation, and the elaboration of other vasoactive agents are likely involved. Some disruption of vascular endothelium is likely present. However, there is no evidence that these reactions are immunologically induced, thereby short-circuiting the definition of a true allergic reaction.

The new dyes have become so safe, and reactions are so few, that patients are routinely sent to the radiology suite unaccompanied by a nurse or doctor. Many studies are performed in freestanding radiology centers. Cardiac monitors and pulse oximetry are not routinely used in the otherwise healthy patient. Dye injections are usually accomplished via a mechanical pump with the x-ray tech outside the room and the radiologist off reading other studies. The days when a physician administered the dye are long gone, although I can remember many such requests of emergency physicians during the night. Vagal reactions and anxiety can produce reactions similar to allergies. Many patients are just plain scared of the dye and hyperventilate.

Of particular note is the ARDS/pulmonary edema that has been associated with contrast material. I have not seen this in 32 years of practice. Pulmonary edema was not part of the few serious anaphylactoid reactions I have treated. Of great concern are those sporadic reports that identify this reaction hours after dye has been given, even after the patient has been discharged. After a contrast study is complete, patients are not routinely observed in the outpatient setting. Once ED patients return from the radiology suite, physicians give little thought to a delayed contrast reaction. Most EPs have never even heard of delayed reactions. I personally have not noticed the chills, malaise, abdominal, pain, etc. that have been described as occurring hours after contrast administration, but all review articles mention them. I don't believe they are as common as these articles propose.

Table. Reaction Rate...
Table. Reaction Rate...
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Pretreatment with steroids and the use of nonionic dyes have clearly reduced overall reactions (5% to about 1.7%). Reactions in high-risk patients can be reduced three- to fivefold with pretreatment (New Engl J Med 1987;317:845, Invest Radiol 1980;15:540).

Pretreatment in patients at high risk usually requires a 12-hour prep, always with steroids and usually also with antihistamines. I have seen no data on pretreatment of ED patients at risk for allergic-like reactions who must undergo an emergency CT scan. If I just had to have the study, I would pretreat with IV steroids/antihistamines, and send a physician to radiology with epinephrine in hand. Surprisingly, this issue rarely comes up, and I could not find the subject addressed in the emergency medicine literature.

Some clinicians are so cautious that they totally avoid the use of contrast material if there is a history of a serious reaction in the past. The presence of asthma or multiple medication allergies do not seem to be contraindications, and in the past I have not paid much attention to these particular cautions. One could opt for an MRI, VQ scan, or ultrasound study instead.

Many radiologists will not perform a dye injection in the presence of a seafood allergy, and this myth has clearly pervaded the general population and the medical community. There are just no data to support the seafood allergy concept, although it is universally believed by nurses, technicians, and most physicians. People who are allergic to seafood are more likely to be allergic to other things, so that's probably where the myth got started and why it is promulgated. Most think that the iodine in fish is the issue, but that's also probably mostly myth. Patients with asthma are frequently sent for CT scans to rule out PE, and other medical conditions without a second thought being given to their increased propensity for allergic reactions. In my experience, asthmatics do not have reactions anywhere near the incidence in these reports. Our ED orders scores of contrast studies a day, and I can't remember the last reaction that was reported to the ED from radiology. Certainly delayed reactions have escaped my radar for 30 some years; I had never even heard of them before researching this topic.

Although serious reactions are very uncommon these days, I am still quite respectful of IV contrast material's potential to wreak havoc. If I am called to the radiology suite to see a patient who is experiencing any suspicious reaction, even if its just a few hives or itching, I will routinely prescribe Benadryl and IV cortisone, and quickly get them off the radiology table. You just cannot predict the next few minutes, so it's best to be paranoid and expect the worst. These patients should be brought to the ED for cardiac monitoring, with a watchful eye on the dreaded pulmonary edema scenario.

Epinephrine is a wonderful agent for hives and hypotension, and it can be given in 0.3 mg aliquots, subcutaneously or MI. One could use 0.1 mg, or up to 0.5 mg, titrating the dose based purely on clinical judgment. My threshold for giving epinephrine in allergic reactions is low, and I do not always given the higher doses right away in questionable cases. In all but the most serious cases, the IV route can be avoided. I can't remember the last time I had to administer IV epinephrine for a dye reaction, but I can recall using it IV for serious bee sting anaphylaxis and medication allergies on a few occasions. One must be very careful with the use of IV epinephrine in patients with an intact circulation because severe hypertension and tachycardia can result with even miniscule amounts.

Anaphylaxis in pregnant patients is a special issue. Although anaphylaxis in pregnancy is generally treated the same, it may be more physiologic to treat with ephedrine (20–50 mg IV) as opposed to epinephrine to lessen uterine artery vasoconstriction. There are not enough data to formalize this issue, but the EP should keep ephedrine as an option. In life-threatening cases, it would seem prudent to use standard epinephrine.

Next month's column will discuss other reactions to IV dyes, including renal toxicity and reactions in patients on beta blockers.

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Delayed Reactions to IV Contrast Material

▪ The majority of reactions that occur following administration of IV contrast material are seen within a few minutes of intravenous injection. Reactions that occur more than 30 to 60 minutes after administration are termed delayed reactions. Delayed reactions are more common with the older high osmolality ionic agents. Reaction rates with the newer nonionic agents are less common (overall about 10% compared with 30% with the ionic materials).

▪ The majority of delayed reactions are a minor annoyance consisting of flu-like symptoms, headache, fever, chills, nausea, vomiting, abdominal pain, nonspecific fatigue, and congestion. Most escape medical detection. Many clinicians do not even know about this entity.

▪ Serious delayed reactions are extremely rare, but may be life-threatening. Acute pulmonary edema or ARDS may occur a number of hours after IV contrast administration, but these are extremely unusual and are relegated to case reports. It is not standard to provide prolonged observation to patients receiving IV dyes, but any patient who develops symptomatology in the first 24 hours of IV contrast administration should be considered to have a delayed reaction.

▪ There is no specific way to prove that a certain symptom is a delayed dye reaction or simply related to the underlying medical condition. Those affected should seek medical care or at least make contact with a clinician to discuss their symptoms. It is prospectively impossible to determine which patients will have a delayed reaction.

▪ Unfortunately, the majority of adverse reactions from the intravascular administration of IV contrast dyes occur at random and are totally unpredictable. Most reactions are mild and self-limited, but life-threatening reactions can occur. Fatalities, although rare, have been documented with both ionic and nonionic contrast media. Fortunately, most reactions occur within 20 minutes of injection, and patients having problems will be identified while still in the radiology department or ED.

Sources: Chest 1982;81:6; Radiology 1979;132:583.

© 2004 Lippincott Williams & Wilkins, Inc.

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