ABSTRACT: The use of iodinated contrast agents for angiography dates back to the 1920s.1 The initial prototype has undergone modifications to reduce the toxicity and discomfort associated with the early contrast molecules. More importantly, these changes have dramatically decreased the rate and risk for severe adverse reactions such as hypersensitivity and anaphylaxis. With over 15 million contrast-requiring procedures performed annually in the United States,2 it is important to understand the risk factors, pathogenesis, diagnosis, prevention and treatment of contrast-induced anaphylactoid reactions. Reviews of adverse reactions are sparse in the cardiology literature, except for a landmark review in 1995 by Goss et al, which has served as the only practice guideline to date for cardiologists.3 In this report, we review the most recent literature to provide a guide for the general and interventional cardiologist in regards to the pretreatment and management of contrast-related reactions specifically in the cardiac catheterization laboratory.
J INVASIVE CARDIOL 2009;21:548–551
The number of diagnostic cardiac catheterization and revascularization procedures performed in the United States is rapidly increasing each year. The 2008 American Heart Association update on Heart Disease and Stroke Statistics reported a 350% increase in the number of cardiac catheterizations performed in the period between 1979 and 2005, with nearly 1.3 million percutaneous interventions in 2005 alone.4 Integral to these procedures is the use of iodinated contrast agents that allows for proper visualization of normal and diseased cardiovascular anatomy. Although the benefits of their use is obvious, the increasing use of contrast agents requires that the practitioner better understand and properly address the risk for and treatment of adverse reactions.
The radiocontrast molecule is an iodinated benzene ring. The new agents have been in use since the 1980s, and are of lower osmolality, which directly contributes to the decrease in pain encountered on injection and also drastically reduces the risk for adverse reactions. The low osmolality contrast agents include nonionic monomers: iohexol (Omnipaque, GE Healthcare, Wauwatosa, Wisconsin), iopamidol, iopromide (Ultravist, Bayer Healthcare, Wayne, New Jersey), ioversol (Optiray, Mallinckrodt, St. Louis, Missouri); and ionic dimer: ioxaglate (Hexabrix, Mallinckrodt). Iodixanol (Visipaque, GE Healthcare) is a nonionic dimer that is iso-osmolar to plasma.2 Today, iohexol (Omnipaque) and iodixanol (Visipaque) are the most commonly used contrast agents in the cardiac catheterization laboratory. Although these contrast agents are safe, adverse reactions ranging from a rash and a flushing sensation to fatal reactions such as angioedema, shock and death can occur.5 The overall risk for adverse reaction increases with higher osmolality and higher ionicity. In particular, the risk for all adverse reactions ranges from 4–12% with ionic agents compared to 1–3% with nonionic agents.5 These reactions include vasomotor reactions such as nausea, vomiting and a flushing sensation. The risk for severe reactions such as anaphylaxis and severe hemodynamic compromise is far lower, at 0.03%, for low-osmolality agents compared with 0.16% for high-osmolality agents.6 Goss et al reported the incidence of contrast-related complications in the cardiac catheterization laboratory to be 0.23%, with 1 mortality per 55,000 cases.3 The most severe contrast reactions are immediate hypersensitivity reactions. Because of the limited evidence of IgE specific to contrast agents, the severe reactions are commonly referred to as “anaphylactoid” due to their clinical resemblance to anaphylaxis. Anaphylactoid reactions can range from minor such as nausea, vomiting and localized urticaria with pruritus, to moderate, with laryngeal or facial edema and mild bronchospasm. Severe reactions consist of respiratory or cardiac arrest and anaphylactoid shock. Death from anyphylactoid reaction is most commonly due to respiratory arrest.7
Identifying patients at risk for contrast-mediated reactions has been extensively studied. The strongest risk factors predicting the likelihood of a reaction are a history of a previous contrast reaction and a history of atopic conditions such as asthma (Table 1). A history of a reaction to contrast portends a 17–35% risk of future reaction.8 Atopic conditions such as asthma and allergic rhinitis increase the overall risk as well. In particular, asthma increases the risk of a reaction by approximately 6 times compared to the general population.9 Other risk factors include the use of beta-blockers (cardiac drugs as well as ophthalmic preparations), interleukin-2 and female gender.10–13 Myasthenic crises have been reported with prolonged sequelae after intravenous contrast administration in patients with myasthenia.14
There has long been a specific concern regarding the purported risk of contrast reaction due to a patient’s history of shellfish allergy.15 As a result, it is common to routinely premedicate patients with a history of shellfish allergy before receiving contrast. However, there has never been a reported case of shellfish allergy where iodine was implicated, and the reactions to radiocontrast media have similarly never been proven to be related in any way to the iodine content in a particular preparation. Therefore, routine premedication for contrast reaction prior to contrast exposure cannot be supported by the available evidence for patients with a history of shellfish allergy.
Etiology and pathogenesis. Despite decades of use, current understanding of the etiology and pathogenesis of contrast-mediated reactions is limited. While the acute reaction that occurs from contrast administration has indistinguishable characteristics like that of immediate IgE-mediated hypersensitivity, the lack of specific IgE to contrast media has led to the use of the term “anaphylactoid” to describe these reactions.
Mast cells and basophils are likely the most important cells in the acute reaction to contrast. These cells immediately release histamine, which is a key mediator in anaphylactoid/anaphylaxis. Histamine and tryptase levels have been elevated in individuals with contrast media reactions.16 In vitro studies have demonstrated that direct administration of contrast media to human or animal cells can lead to histamine release from basophils and mast cells.17,18
Although several studies have reported specific IgE to various contrast media, some of these reports have only demonstrated skin-test reactivity, which implies but does not prove specific IgE.16 A recently published report used skin testing and basophil activation tests to study the occurrence of IgE-mediated reactions in contrast reactions.19 Their results concluded that only 4% may be IgE-mediated. This study demonstrates that if IgE-mediated responses to contrast occur, they are uncommon.
Approximately 2–5% of patients may develop delayed reactions characterized by the occurrence of a rash 1 hour to 1 week after contrast injection.20 Patients usually experience itching, maculopapular rash, urticaria, angioedema and fever.21 Recently, it has become extremely difficult to differentiate a contrast-induced rash from adverse reactions to newly prescribed drugs after stent implantation such as clopidogrel or penicillin antibiotics given at the conclusion of the interventional procedure. It is possible, for example, that a rash attributed to clopidogrel may in fact actually be a manifestation of a delayed reaction to contrast in some patients. The role of prophylactic antibiotics given in conjunction with radiocontrast media to prevent infectious complications associated specifically with arteriotomy closure devices also may be a complicating factor in identifying a delayed reaction to contrast.
Prevention. The key to preventing contrast reactions is to identify the patients at greatest risk and use prophylactic measures to reduce their risk. As mentioned earlier (Table 1), patients with previous reactions or a history of atopy or asthma are at increased risk. Indications for cardiac catheterization in these patients should be properly weighed against the risk of adverse reactions. Pretreatment for this subset of patients includes the use of steroids with or without antihistamines. The use of methylprednisolone pretreatment was shown in one study to reduce mild and moderate reactions.22 This study and others led the American College of Radiology to publish two commonly accepted pretreatment protocols (Table 2).23 Some studies have also advocated the preferential use of lower-osmolality contrast agents in high-risk patients.7 It is common to use iodixanol (Visipaque) in these patients for purported safety and efficacy. Many pretreatment protocols use the combination of corticosteroids, histamine-1 receptor antagonists and histamine-2 receptor antagonists. Although there is some evidence that cysteinyl leukotrienes may play a role in contrast media reactions, no studies exist to determine the role that leukotriene receptor antagonists may have in prevention.24 Nevertheless, the excellent side-effect profile and lack of drug interaction make pretreatment with montelukast a reasonable addition to a pretreatment protocol. Accordingly, at many institutions, all patients with a risk of contrast reaction are treated with panmediator blockade to include montelukast, diphenhydramine and cimetidine (Table 3). Additionally, prednisone 50 mg is given at 13, 7 and 1 hour(s) prior to the procedure. If steroids are not given ahead of the procedure, hydrocortisone sodium succinate (Solu-Cortef, Pfizer, New York) 100 mg is administered intravenously at the time of the procedure. Although pretreatment and use of lower-osmolality agents reduce the overall rate of adverse reactions, no protocol has completely eliminated the risk of severe or repeat reactions.25 Therefore, recognition and treatment of acute reactions remains essential for cardiologists in the cardiac catheterization laboratory.
Treatment of acute and delayed reactions. As previously described, acute contrast reactions can occur in a mild, moderate or severe form. Recognition of these events requires vigilant inspection and physical examination for signs and symptoms of contrast reactions, especially in the setting of unexplained hypotension. Examining exposed skin, as well as removing the sterile drapes to inspect for urticaria should be performed immediately. Laryngeal edema should be suspected when the patient’s voice becomes hoarse or inspiratory stridor occurs. In contrast, expiratory wheezing can denote the onset of bronchospasm. Mild reactions are usually self-limiting, as are delayed reactions, and do not need further intervention except for prompt recognition and careful monitoring for possible progression. Moderate reactions such as bronchospasm or profound hypotension require aggressive treatment with epinephrine to prevent progression. Epinephrine 0.1–0.3 ml should be administered intramuscularly (1:1,000 dilution) for moderate reactions26 (Table 4). In the event of a severe reaction, such as severe bronchospasm, laryngeal edema or cardiopulmonary arrest, intravenous epinephrine may be given in a diluted form (1:10,000) at a dose of 1–3 ml, recognizing that nearly all adverse outcomes caused by epinephrine result when given intravenously.27 One should perform careful monitoring for signs of toxicity due to epinephrine such as unexplained tachycardia, tremor, pallor and hypertensive emergency.28 The cardiac catheterization laboratory is perhaps the most ideal environment in which to treat anaphylaxis since patients undergo continuous hemodynamic and telemetry monitoring, and those most familiar with the cardiac toxicities associated with epinephrine are attending to the patient. Additionally, most patients with cardiac disease undergo beta blockade, which can increase the risk of adverse reaction and poor response to epinephrine therapy.29 Therefore, the use of intravenous epinephrine should be reserved for severe reactions refractory to intramuscularly administered epinephrine. The limited available data would also emphasize the use of an epinephrine drip titrated to effect rather than reliance on a single intravenous bolus dose in severe reactions.30,31 Supplemental oxygen and copious intravenous fluid can mitigate the effects of hypoxia and hypotension, respectively. Corticosteroids can also be given to prevent or decrease the severity of the reaction, but should not be expected to be of immediate benefit. After aggressive treatment in the cardiac catheterization laboratory, all patients with moderate-to-severe contrast reactions should be transferred to the intensive care unit for further close monitoring and tailored care.
Conclusions
Although anaphylactoid contrast reactions are rare, severe reactions can be life-threatening. Prompt recognition and treatment can reduce the severity and adverse clinical sequelae of this process. Patients at high risk for contrast reactions should be identified and given pretreatment and low-osmolar contrast agents. Since pretreatment does not completely eliminate the risk of contrast reactions, continued vigilance is necessary whenever contrast is administered to high-risk patients. All cardiac catheterization laboratory personnel should be familiar with the signs and symptoms of contrast reactions and be prepared to administer treatment including intravenous epinephrine. As the number of cardiac procedures performed increases annually, it is paramount that we be prepared to provide acute care for anaphylactoid contrast reactions in the cardiac catheterization laboratory.
From *Interventional Cardiology, Division of Cardiovascular Diseases, and §Allergy & Immunology, Division of Internal Medicine, Scripps Clinic, La Jolla and £Southern California Permanente Medical Group, San Diego, California.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted March 2, 2009, provisional acceptance given April 7, 2009, final version accepted April 13, 2009.
Address for correspondence: Keshav R. Nayak, MD, Scripps Clinic Torrey Pines, 10666 N. Torrey Pines Road, S1056, La Jolla, CA 92037. E-mail: Nayak.keshav@scrippshealth.org
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