Immediate and Nonimmediate Reactions to Contrast Media

Since their development in the 1950s tri-iodinated benzene derivates have been used for opacification of the urinary tract. The radiopacity of such compounds is produced by molecular iodine, which is attached to the benzene ring. The agents are further characterized by their ionic and nonionic side chains as well as their monomeric or dimeric ring structure.

Contrast media are used in many diagnostic and in-terventional procedures, including intravenous ur-ography, CT scan, angiography, intraoperative antegrade or retrograde pyelography, urethrogram, and cy-stogram.

Adverse effects of contrast media are generally classified into two large groups: chemotoxic effects and idiopathic or anaphylactoid reactions. Chemotoxic effects are thought to be dose-related and have a direct toxic effect on the target organ, such as the nephrotoxicity of contrast media.

Anaphylactoid reactions simulate a true allergic reaction, but are not mediated by immunoglobulins. No antibodies to contrast material have ever been demonstrated. The diagnosis of contrast media-associated nonallergic anaphylaxis is based on clinical history alone.

Serious reactions to CM are comparable to type 1 hypersensitivity reactions (anaphylaxis), which begin within minutes after antigen exposure and are mediated by a variety of chemotactic, vasoactive, and spasmogenic compounds. Histamine seems to be the primary mediator of anaphylaxis/anaphylactoid reaction and is responsible for the intense immediate manifestations. Preformed histamine is present in basophils and mast cells and is released rapidly by degranulation of these cells in a response to a variety of stimuli. There are several other biological mediators produced by mast cells and basophils, including leukotrienes, prostaglandins, enzymes, and a variety of cytokines. These substances act in an autocrine, paracrine, and endocrine fashion, triggering a cascade of inflammatory mediators. They induce vasodilatation, an increase in vascular permeability leading to edema, contraction of smooth muscle cells precipitating bronchospasm, and an increase in airway mucous secretion. The cytokines and chemo-tactic factors recruit leukocytes, eosinophils, baso-

phils, monocytes, and T cells, which release additional waves of mediators and cytokines (Morcos 2005).

The mechanisms by which CM activate basophils and mast cells to release histamine and other mediators are not completely understood. They may include direct effects of CM particles on these cells or activation of immunological mechanisms involving IgE antibodies, thymus-derived lymphocytes (T cells) or the complement system (Morcos 2005).

Hypersensitivity reactions to all classes of contrast media (CM) occur either immediately within the first hour after CM administration, or nonimmediately, more than 1 h after CM exposure.

Mild immediate reactions occur in 0.7%-3.1% of patients receiving lower-osmolar/nonionic CM (Brok-kow et al. 2005a). Pruritus and mild urticaria are the most common immediate manifestations. More severe reactions involve the respiratory and cardiovascular systems.

The frequency of nonimmediate hypersensitivity reactions appears to range from 1 % to 3 %, and skin reactions of the maculopapular exanthematous and urti-carial/angioedematous types account for the majority of them. At present, the exact pathogenesis of these delayed reactions is still unclear. There is, however, increasing evidence that a significant proportion of the reactions is T cell-mediated (Christiansen et al. 2000).

In a large study of over 330,000 patients, Katayama et al. evaluated the incidence of severe and very severe reactions following intravascular administration of CM. He found an incidence of 0.22% and 0.04%, respectively, after administration of high-osmolar contrast media (HOCM), but only 0.04% and 0.004%, respectively, after low-osmolar contrast media (LOCM) (Katayama et al. 1990; Table 4.6). The study concluded that the use of LOCM has resulted in reducing the incidence of severe and very severe reactions by a factor 10 in comparison to HOCM. However, no difference was observed in the incidence of fatal reactions to both types of CM, which were exceedingly rare (1: 170,000). Nevertheless, iodin-ated CMs are one of the top ten drugs responsible for anaphylaxis/anaphylactoid reactions (Wang et al. 1998), with a mortality rate of 0.9 per 100,000 examinations (Pumphrey 2000; Caro 2001).

Table 4.6. Frequency of adverse reactions to contrast media (338,000 patients)

Adverse reactions

High-osmolar/ ionic contrast media

Low-osmolar/ nonionic contrast media

Total

12.66%

3.13%

Severe

0.22%

0.04%

Very severe

0.04%

0.0004%

Fatal

0.0006%

0.0006%

After Katayama et al. 1990

After Katayama et al. 1990

Diagnostics

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions to CM are at least in part associated with histamine and tryptase release from basophils and mast cells (Laroche et al. 1998). The role of skin prick tests and intradermal tests (IDT) in diagnostic procedures has been evaluated for many years, but positive tests have only been reported in patients with a history of severe reactions (Brockow 2005a). Determination of plasma histamine and tryp-tase immediately after reactions to CM may confirm basophil or mast cell mediator release (Laroche et al. 1998). However, recent results indicate that these tests maybe oflimitedvalue (Laroche 2004). Onlytwo out of 20 patients with immediate reactions had increased levels of these mediators after CM exposure. Both patients had experienced a life-threatening reaction. Whereas tryptase levels remain relatively stable within at least 2 h, histamine is rapidly degraded, and levels have to be determined as soon as possible after the reaction.

Some investigators have reported the presence of CM-specific IgE antibodies in the serum of patients with an immediate reaction, but the frequency of positive test results varies widely between 2 % and 47 %. No commercial assay is available for routine measurement, and the relative merit of the test in diagnosing severe immediate reactions has yet to be established (Brockow 2005a).

Additionally, the role of a histamine release test and other in vitro basophil activation tests in the diagnosis of allergic reactions to CM has not yet been defined.

Skin Reactions

Skin reactions of the maculopapular exanthematous and urticarial/angioedematous types account for the majority of nonimmediate hypersensitivity reactions to CM. There is increasing evidence that a significant proportion of the reactions are T cell-mediated (Christiansen et al. 2000). Skin tests have been widely used to confirm such delayed hypersensitivity. CM have consistently tested positively as an allergen in patch tests and/ or delayed intradermal tests (IDT) in reactors but not in controls (Brockow et al. 2005a). These tests may be useful in allergy diagnosis of nonimmediate skin reactions to CM, but further evaluation is needed with regard to the sensitivity and specificity as well as of the positive and negative predictive value of such tests.

More data from larger studies are needed to assess the usefulness of the skin tests and other diagnostic tests as routine tools in the follow-up of patients with either immediate or nonimmediate hypersensitivity reactions after CM exposure. At present such tests cannot yet be recommended for routine clinical practice (Brok-kow 2005b).

Risk Factors

Although the majority of anaphylactoid reactions occur unpredictably, certain risk factors have been well documented. Even though these reactions are not true allergic reactions, patients with a history of a previous adverse response to contrast material have a risk of subsequent reaction that is three- to fourfold greater than the general population (Katayama et al. 1990; Morcos and Thomsen 2001). Other important risk factors include asthma and a history of atopy, including hay fever and food allergies (Morcos and Thomsen 2001; Shehadi 1982). In addition, patients treated with -adrenergic blockers and interleukin-2 are at increased risk of acute adverse reactions to CM (Thom-sen and Morcos 2004; Morcos 2005).

Prevention

The European Society of Urogenital Radiology (ESUR) has produced guidelines on prevention of generalized reactions to CM (Morcos et al. 2001; Table 4.7). They recommend the use ofnonionic CM to decrease the risk of generalized CM reactions; they also recommend pre-medicating high-risk patients with prednisolone (30 mg orally) or methylprednisolone (32 mg orally) 12 and 2 h before CM exposure. However, the value of such premedication in the prevention of severe reactions to lower-osmolar CM has not been conclusively demonstrated. It has yet to be definitively decided whether antihistamines H1 and H2 are of additional benefit in premedication (Morcos et al. 2001; Morcos 2005).

In case of emergency administration of CM in patients with a high risk of severe reactions to CM, particularly those with a history of previous serious reaction to CM, pretreatment is recommended with hydrocortisone (200 mg intravenously) immediately and every 4 h until the procedure is completed, as well as with diphenhydramine (50 mg intravenously) before the procedure and the use of low-osmolar nonionic CM (Greenberger et al. 1986).

However, the best prevention of acute reactions to iodinated contrast media is to avoid its administration (Morcos 2005). Therefore in high-risk patients, imaging procedures that use other contrast media should be considered. Anaphylaxis to gadolinium-based contrast media used in magnetic resonance imaging is very rare and is a safe alternative.

Table 4.7. Prevention of generalized reactions to contrast media

A. Risk factors for reactions

• Previous generalized reaction to a contrast medium, either moderate (e.g., urticaria, bronchospasm, moderate hypotension) or severe (e.g., convulsions, severe bronchospasm, pulmonary edema, cardiovascular collapse)

• Allergy requiring medical treatment

B. To reduce the risk of generalized contrast medium reactions

• Use nonionic agents

C. Premedication is recommended in high-risk patients (defined in A)

• When ionic agents are used

• Opinion is divided about the value of premedication when nonionic agents are used

D. Recommended premedication

• Corticosteroids

Prednisolone (30 mg orally) or methylprednisolone (32 mg orally) 12 and 2 h before contrast Medium is administered. Corticosteroids are not effective if given less than 6 h before contrast medium

• Antihistamines H1 and H2 maybe used in addition to corticosteroids, but opinion is divided about the merits of this approach

Remember for all patients

• Have a trolley with resuscitation drugs in the examination room

• Observe patients for 20-30 min after contrast-medium injection

F. Extravascular administration

• When absorption or leakage into the circulation is possible, take the same precautions as for intravascular administration

After Morcos et al. (2001b); www.esur.org 4.7.4

Treatment

Severe, even life-threatening reactions may still occur in patients who receive both corticoid premedication and low-osmolar contrast media. Prompt recognition and treatment of adverse side effects to CM can be invaluable in diminishing the response and may prevent a reaction from becoming severe or even life-threatening (Morcos and Thomsen 2001). For at least 20 min after a CM injection, the patient should never be left alone, because 94 % -100 % of severe and fatal reactions occur in that interval. Knowledge, training, and preparation are very important for effective treatment of an adverse contrast-related reaction. Therefore, all personnel involved in intravascular application of CM should be adequately trained in cardiopulmonary resuscitation, and all equipment for resuscitation (crash cart, defibrillator, necessary drugs) should be checked regularly.

Mild reactions are usually self-limiting and do not require active treatment. However, the application of the agents must be stopped immediately, and the patient should be observed until full recovery.

Table 4.8. Simple guidelines for first-line treatment of acute reactions to CM

Nausea or vomiting

• Transient: supportive treatment

• Severe, protracted: appropriate antiemetic drugs should be considered

Urticaria

Scattered, transient: supportive treatment including observation

Scattered, protracted: appropriate H1-antihistamine intramuscularly or intravenously should be considered; drowsiness and/or hypotension may occur

• Profound: consider adrenaline 1:1,000, 0.1 -0.3 ml

(0.1 -0.3 mg) intramuscularly up to 0.3 maximum in children. Repeat as needed

Bronchospasm

(3-2-agonist metered dose inhaler (two to three deep inhalations) Adrenaline Normal blood pressure

Intramuscular: 1:1,000,0.1-0.3 ml (0.1-0.3 mg) (use smaller dose in a patient with coronary artery disease or elderly patient)

In pediatric patients: 0.01 mg/kg up to 0.3 mg maximum Decreased blood pressure

Intramuscular: 1:1,000,0.5 ml (0.5 mg), (in pediatric patients: 0.01 mg/kg intramuscularly)

Laryngeal edema

• Intramuscular adrenaline (1:1,000), 0.5 ml (0.5 mg) for adults, repeat as needed

Hypotension

Isolated hypotension

• Elevate patient's legs

Intravenous fluid: rapidly, normal saline or lactated Ringer's solution

• If unresponsive: adrenaline: 1:1,000,0.5 ml (0.5 mg) intramuscularly, repeat as needed

Vagal reaction (hypotension and bradycardia) Elevate patient's legs

• Atropine 0.6-1.0 mg intravenously, repeat if necessary after 3-5 min, to 3 mg total (0.04 mg/kg) in adults. In pediatric patients, give 0.02 mg/kg intravenously (max.

0.6 mg per dose) repeat if necessary to 2 mg total Intravenous fluid: rapidly, normal saline or lactated Ringer's solution

Generalized anaphylactoid reaction

Call for resuscitation team

• Suction airway as needed

• Elevate patient's legs if hypotensive

• Intramuscular adrenaline (1:1,000), 0.5 ml (0.5 mg) in adults. Repeat as needed. In pediatric patients, 0.01 mg/ kg to 0.3 mg (maximum dose)

• Intravenous fluids (e.g., normal saline, lactated Ringer's)

• H1-blocker, e.g., diphenhydramine 25-50 mg i.v.

-2-agonist metered dose inhaler for persistent broncho-spasm: two or three inhalations

After Thomsen et al. (2004); www.esur.org

The management of acute adverse reactions to contrast media is well defined and all other anaphylactic reactions, for example to latex and drugs, are managed in the same way This includes establishment of an adequate airway, oxygen supplementation, administration of intravascular physiological fluids, and measurement of the blood pressure and heart rate. Talking to the patient while checking the pulse rate provides useful initial information: breathing is assessed, the possibility of a vagal reaction (bradycardia) is determined, and a rough estimation of systolic pressure is obtained. H1-antihistamine and adrenaline are administered in correlation with the severity of the reaction.

Wherever an anaphylactic reaction may occur (e.g., the ward, the operating room, the examination room of the radiology department), the following basic medical equipment should be available:

• Adrenalin 1: 1,000 (suitable for injection)

• Antihistamine H1 (suitable for injection)

Atropine

|32-agonist metered-dose inhaler

• i.v. fluids: normal saline or Ringers solution

• Anticonvulsive drugs (diazepam)

• Sphygmomanometer

One-way mouth breather apparatus

Guidelines on first-line treatment have been published by the European Society of Urogenital Radiology (ESUR) (Thomsen and Morcos 2004; Table 4.8, www.esur.org). The subsequent management of severe adverse reactions (including the administration of second-line drugs) should be handled by the resuscitation team.

H2 antihistamines and H2 receptor blockers have a limited role in treating contrast media reactions. They are used primarily to reduce symptoms from skin reactions. High-dose intravenous corticoids do not play a role in the first-line treatment of acute adverse reactions. Standard doses can be effective in reducing delayed recurrent symptoms, occurring up to 48 h after the initial reaction (intravenous prednisolone 250 mg or methylprednisolone 50 mg). However, very high doses may have an immediate stabilizing effect on the mast cell membrane and can be used in the second-line treatment (intravenous prednisolone 500 -1,000 mg or methylprednisolone 100-200 mg). It can take 6 h before corticoids are fully active (Thomsen and Morcos 2004).

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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