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Clinical Editor's Corner
Contrast Anaphylactoid Reaction: Is There a Preventative Treatment?
Several weeks ago, Dr. Chris White from the Ochsner Clinic commented, “I need some 
help. I have a vasculopathic patient who was admitted with resting moderately severe angina. He had CABG [coronary artery bypass graft] surgery several years ago, and has had multiple coronary procedures over the following years. Although the first cath procedure he ever had was uneventful, every procedure since then has been complicated by honest-to-goodness, airway-obstructing, hypotensive, life-threatening contrast reactions. He has been premedicated for multiple days before the procedure, with dexamethsone, H-2 blockers, and H-1 blockers. Nothing has diminished the intensity of his anaphylactoid reaction. The last time he had a procedure, an anesthesiologist was present for deep sedation, and intubated him when he crashed. He spent a week in ICU recovering. Anybody have any tricks for this type of refractory response to contrast?”
Contrast reactions can be life-threatening, and patients who give a history of a reaction are a cause of great concern. When we get such a history, we should ask for more detail. Was the reaction just a rash, did it occur with or without hives, with or without laryngeal stridor, with or without hypotension? Each question tells us how severe and how genuine the contrast reaction was and what may occur on another contrast exposure. Vomiting alone is not truly a contrast reaction, but is often considered as such by the patient. A history of allergy to foods, fish, or other drugs indicates a potential for reaction to contrast but is not an automatic need for premedication before the next contrast study. A recurrent and severe hypotensive shock-like episode as described by Dr. White is truly a major concern. At this time, maximal premedication over several days is the only potential protection, but it is known that even this may not work in some patients. With this problem in mind, I asked my cath lab director colleagues about what they would do with the worst contrast reaction they have ever seen.
Question: Can you desensitize the patient to contrast media?
From Chicago: I am certainly not an allergist, but my understanding is that since contrast reactions are not IgE mediated (true anaphylaxis), but rather due to direct mast cell degranulation (anaphylactoid) from contrast media contact, desensitization is not possible.
From Florida: I know of no positive data about desensitization or premedication for the prophylactic treatment of these types of patients. Use of low-osmolality contrast may decrease, but not eliminate, the risk. Gadolinium (an MRI imaging agent) has been used in this situation for non-coronary imaging. An MRI could help in the assessment of graft patency. I like the idea of alternative imaging methods (e.g. IVUS [intravascular ultrasound]) in the cath lab. For stent placement, you could use the prior angiograms. The stents might serve as landmarks for IVUS-guided assessment and possible intervention.
From New Orleans: You could perform fractional flow reserve (FFR) on all vessels and attempt blind angioplasty of the abnormal segment using anatomy and sizing from last films. If patient crashes this time, then consider another etiology of the crash.
Question: Can you skin test for contrast reaction?
From Winston-Salem: I came across a series of articles addressing the issue of severe contrast reaction despite pre-medication. There is a suggestion that skin testing may be useful to identify a contrast agent that might be used without reaction prior to considering your next move. The IgE-mediated reaction will likely be problematic unless you start a low-dose epinephrine drip (e.g. bee-sting therapy). One article I found was from https://www.ajronline.org/cgi/content/full/190/3/666, which says that since anaphylactoid contrast material reactions are not true allergic reactions, they can occur in patients who have not been previously exposed to contrast material and who are without IgE antibodies. Further investigations by an allergologist to identify IgE-mediated allergy are not mentioned. Treatment for patients at high risk for severe contrast material-induced anaphylaxis, despite premedication, still remains speculative.
The IgE mechanism could explain the high risk of reaction recurrence and the ineffectiveness of premedication in some patients. Skin tests are performed with intradermal injection of 10% dilution of the contrast material. Only a very small number of patients with anaphylaxis have a positive skin test to contrast material. Because the contrast skin and basophil activation tests have been constantly negative in most patients and in control subjects, the positive predictive value is likely to be high, whereas the negative predictive value is uncertain. Careful, controlled, challenge testing may be attempted to verify negative in vivo and in vitro test results. However, experience tells us that the majority of patients refuse challenge tests. The reasons are fear of anaphylaxis and uncertain need for contrast media re-exposure.
Question: Is there contrast media cross-reactivity?
After diagnosis of an IgE-mediated allergy to one or more contrast material, the question of possible cross-reactivity among other contrast material arises. Comparison of the chemical structures of contrast material does not give a clue of potential cross-reactivity in individual patients. For example, one patient had an iopromide-iomeprol allergy and tolerated iopamidol, whereas another patient had an iomeprol allergy and tolerated iopromide. For patients with undiagnosed previous anaphylaxis to contrast material (i.e., allergologic testing not performed yet), imaging procedures that do not require the administration of iodinated contrast material should be considered or a contrast material of another class should preferentially be used.
Question: Does premedication prevent contrast reactions?
Data supporting the usefulness of premedication in patients with a history of allergic anaphylaxis are lacking and physicians who are dealing with these patients should therefore not rely on the efficacy of premedication. Other causes for the reaction symptoms should always be considered. For example, the patient may have a contact reaction to natural rubber latex. Nonsteroidal anti-inflammatory drugs, β-blockers, or angiotensin-converting enzyme inhibitors can trigger symptoms of anaphylaxis. Finally, contrast material injections are capable of precipitating symptoms of occult mastocytosis with an anaphylactoid-like presentation. Besides a careful clinical history, certain laboratory tests (i.e., tryptase measurement, IgE-specific for natural latex or penicillins), skin tests, and drug challenge tests help to clarify the precise diagnosis. Contrast material reactions are frequently falsely considered as an allergy to iodine because contrast materials are iodine-based. However, neither contrast material-induced anaphylaxis correlated to IgE-mediated iodine allergy nor allergic contact dermatitis due to iodine-containing antibacterial preparations should be considered evidence of IgE-mediated contrast material allergy.
From Boston: If faced with this patient and the absolute need for iodinated contrast, I would consider putting the patient in the CCU and seeing if the allergists would help with a desensitization protocol with progressive micro-micro-doses of IV contrast with progressive increases; then cath once desensititziation is complete.
From Boston, elsewhere: Chris, do something called BYPASS SURGERY, even without a cath, since you have the previous films. What is the point of putting the guy through a cath that will carry more risk than a CABG?
From New Haven: If you have a sense of the anatomy from prior angiograms, you could consider IVUS-guided intervention without contrast. [This approach] would require a high level of comfort with IVUS, of course, and good lesion selection.
Question: Can I use CO2 or gadolinium?
From Worchester, Mass.: It is true that some people just don’t belong in the cath lab, but if you feel absolutely compelled, you could use CO2 as the contrast agent. [This would] not [be] the highest quality study, but it might get you what you need.
From Ocala, Fl.: My partner has used gadolinium, but visualization is suboptimal, so he usually mixes it with a little iohexol. Our radiologists have used CO2, but again, visualization is terrible and they usually supplement the studies with traditional contrast angiography. I have treated a stenosed dialysis fistula patient with the same recurrent life-threatening contrast reactions. I used ultrasound and pressure gradients to dilate recurrent stenoses. If you are assessing whether restenosis of previously treated lesion(s) has occurred, you could use fluoroscopy and IVUS or FFR without contrast.
Question: Which contrast agent(s) should you use?
From Pennsylvania: I agree that desensitization has no role, as the reaction is not IGE-mediated. If you have not used iodixanol, this might be a time to try it. Given that 3.0 ratio agents have a reduced reaction rate compared to historical 1.5 ratio agents, it would seem plausible to try going to an iso-osmotic 6.0 ratio agent.
help. I have a vasculopathic patient who was admitted with resting moderately severe angina. He had CABG [coronary artery bypass graft] surgery several years ago, and has had multiple coronary procedures over the following years. Although the first cath procedure he ever had was uneventful, every procedure since then has been complicated by honest-to-goodness, airway-obstructing, hypotensive, life-threatening contrast reactions. He has been premedicated for multiple days before the procedure, with dexamethsone, H-2 blockers, and H-1 blockers. Nothing has diminished the intensity of his anaphylactoid reaction. The last time he had a procedure, an anesthesiologist was present for deep sedation, and intubated him when he crashed. He spent a week in ICU recovering. Anybody have any tricks for this type of refractory response to contrast?”
Contrast reactions can be life-threatening, and patients who give a history of a reaction are a cause of great concern. When we get such a history, we should ask for more detail. Was the reaction just a rash, did it occur with or without hives, with or without laryngeal stridor, with or without hypotension? Each question tells us how severe and how genuine the contrast reaction was and what may occur on another contrast exposure. Vomiting alone is not truly a contrast reaction, but is often considered as such by the patient. A history of allergy to foods, fish, or other drugs indicates a potential for reaction to contrast but is not an automatic need for premedication before the next contrast study. A recurrent and severe hypotensive shock-like episode as described by Dr. White is truly a major concern. At this time, maximal premedication over several days is the only potential protection, but it is known that even this may not work in some patients. With this problem in mind, I asked my cath lab director colleagues about what they would do with the worst contrast reaction they have ever seen.
Question: Can you desensitize the patient to contrast media?
From Chicago: I am certainly not an allergist, but my understanding is that since contrast reactions are not IgE mediated (true anaphylaxis), but rather due to direct mast cell degranulation (anaphylactoid) from contrast media contact, desensitization is not possible.
From Florida: I know of no positive data about desensitization or premedication for the prophylactic treatment of these types of patients. Use of low-osmolality contrast may decrease, but not eliminate, the risk. Gadolinium (an MRI imaging agent) has been used in this situation for non-coronary imaging. An MRI could help in the assessment of graft patency. I like the idea of alternative imaging methods (e.g. IVUS [intravascular ultrasound]) in the cath lab. For stent placement, you could use the prior angiograms. The stents might serve as landmarks for IVUS-guided assessment and possible intervention.
From New Orleans: You could perform fractional flow reserve (FFR) on all vessels and attempt blind angioplasty of the abnormal segment using anatomy and sizing from last films. If patient crashes this time, then consider another etiology of the crash.
Question: Can you skin test for contrast reaction?
From Winston-Salem: I came across a series of articles addressing the issue of severe contrast reaction despite pre-medication. There is a suggestion that skin testing may be useful to identify a contrast agent that might be used without reaction prior to considering your next move. The IgE-mediated reaction will likely be problematic unless you start a low-dose epinephrine drip (e.g. bee-sting therapy). One article I found was from https://www.ajronline.org/cgi/content/full/190/3/666, which says that since anaphylactoid contrast material reactions are not true allergic reactions, they can occur in patients who have not been previously exposed to contrast material and who are without IgE antibodies. Further investigations by an allergologist to identify IgE-mediated allergy are not mentioned. Treatment for patients at high risk for severe contrast material-induced anaphylaxis, despite premedication, still remains speculative.
The IgE mechanism could explain the high risk of reaction recurrence and the ineffectiveness of premedication in some patients. Skin tests are performed with intradermal injection of 10% dilution of the contrast material. Only a very small number of patients with anaphylaxis have a positive skin test to contrast material. Because the contrast skin and basophil activation tests have been constantly negative in most patients and in control subjects, the positive predictive value is likely to be high, whereas the negative predictive value is uncertain. Careful, controlled, challenge testing may be attempted to verify negative in vivo and in vitro test results. However, experience tells us that the majority of patients refuse challenge tests. The reasons are fear of anaphylaxis and uncertain need for contrast media re-exposure.
Question: Is there contrast media cross-reactivity?
After diagnosis of an IgE-mediated allergy to one or more contrast material, the question of possible cross-reactivity among other contrast material arises. Comparison of the chemical structures of contrast material does not give a clue of potential cross-reactivity in individual patients. For example, one patient had an iopromide-iomeprol allergy and tolerated iopamidol, whereas another patient had an iomeprol allergy and tolerated iopromide. For patients with undiagnosed previous anaphylaxis to contrast material (i.e., allergologic testing not performed yet), imaging procedures that do not require the administration of iodinated contrast material should be considered or a contrast material of another class should preferentially be used.
Question: Does premedication prevent contrast reactions?
Data supporting the usefulness of premedication in patients with a history of allergic anaphylaxis are lacking and physicians who are dealing with these patients should therefore not rely on the efficacy of premedication. Other causes for the reaction symptoms should always be considered. For example, the patient may have a contact reaction to natural rubber latex. Nonsteroidal anti-inflammatory drugs, β-blockers, or angiotensin-converting enzyme inhibitors can trigger symptoms of anaphylaxis. Finally, contrast material injections are capable of precipitating symptoms of occult mastocytosis with an anaphylactoid-like presentation. Besides a careful clinical history, certain laboratory tests (i.e., tryptase measurement, IgE-specific for natural latex or penicillins), skin tests, and drug challenge tests help to clarify the precise diagnosis. Contrast material reactions are frequently falsely considered as an allergy to iodine because contrast materials are iodine-based. However, neither contrast material-induced anaphylaxis correlated to IgE-mediated iodine allergy nor allergic contact dermatitis due to iodine-containing antibacterial preparations should be considered evidence of IgE-mediated contrast material allergy.
From Boston: If faced with this patient and the absolute need for iodinated contrast, I would consider putting the patient in the CCU and seeing if the allergists would help with a desensitization protocol with progressive micro-micro-doses of IV contrast with progressive increases; then cath once desensititziation is complete.
From Boston, elsewhere: Chris, do something called BYPASS SURGERY, even without a cath, since you have the previous films. What is the point of putting the guy through a cath that will carry more risk than a CABG?
From New Haven: If you have a sense of the anatomy from prior angiograms, you could consider IVUS-guided intervention without contrast. [This approach] would require a high level of comfort with IVUS, of course, and good lesion selection.
Question: Can I use CO2 or gadolinium?
From Worchester, Mass.: It is true that some people just don’t belong in the cath lab, but if you feel absolutely compelled, you could use CO2 as the contrast agent. [This would] not [be] the highest quality study, but it might get you what you need.
From Ocala, Fl.: My partner has used gadolinium, but visualization is suboptimal, so he usually mixes it with a little iohexol. Our radiologists have used CO2, but again, visualization is terrible and they usually supplement the studies with traditional contrast angiography. I have treated a stenosed dialysis fistula patient with the same recurrent life-threatening contrast reactions. I used ultrasound and pressure gradients to dilate recurrent stenoses. If you are assessing whether restenosis of previously treated lesion(s) has occurred, you could use fluoroscopy and IVUS or FFR without contrast.
Question: Which contrast agent(s) should you use?
From Pennsylvania: I agree that desensitization has no role, as the reaction is not IGE-mediated. If you have not used iodixanol, this might be a time to try it. Given that 3.0 ratio agents have a reduced reaction rate compared to historical 1.5 ratio agents, it would seem plausible to try going to an iso-osmotic 6.0 ratio agent.
The bottom line
Contrast-media reactions are divided into two categories: anaphylactoid and chemotoxic.1 The anaphylactoid reaction is not IgE-mediated and caused by mast cell degranulation, but is otherwise similar to anaphylactic reactions in their clinical manifestations and treatment. The chemotoxic reactions are related to osmolarity, viscosity, and calcium binding, which cause hypotension, bradyarrhythmias and discomfort. Since premedications are of marginal value, all patients with a history of severe anaphylaxis symptoms should have an allergologic workup, including skin testing (and basophil activation testing, if available) with a panel of different contrast materials to determine the presence of an IgE-mediated reaction and to identify alternative contrast material that can be used safely. Although widely practiced, there is little evidence that steroid pretreatment (or for that matter, desensitization) would prevent recurrence of an anaphylactoid reaction. When confronted with the severe, recurrent, contrast-mediated anaphylactoid reaction, carefully review all the options as discussed above before proceeding with another exposure to contrast media.Reference
- Goss JE, Chambers CE, Heupler FA Jr. Systemic anaphylactoid reactions to iodinated contrast media during cardiac catheterization procedures: guidelines for prevention, diagnosis, and treatment. Laboratory Performance Standards Committee of the Society for Cardiac Angiography and Interventions. Cathet Cardiovasc Diagn 1995 Feb;34(2):99-104; discussion 105.
