Following are case scenarios of patients who received radiographic contrast medium (RCM) for various investigations.

Case I. A 48 year old male, with a history of bronchial asthma since childhood, had an abnormal chest radiograph and required computed tomographic (CT) study with contrast to evaluate the suspected lung mass. After intravenous introduction of iodinated contrast medium, the patient complained of flushing, a sense of warmth, dizziness and nausea. His blood pressure and heart rate decreased and he subsequently collapsed.
Diagnosis :Vaso-Vagal attack / reaction
Case II. A 35 year old female with a history of allergic rhinitis and shellfish allergy had a suspected pulmonary embolism and required a CT scan. Five minutes after Contrast injection, she developed pruritus, hoarseness of voice and difficulty in breathing.
Diagnosis: Acute Anaphylactoid reaction (AR)
Case III. A 50 year old, smoker, with a history of previous mild RCM reaction, was admitted with acute myocardial infarction and scheduled for cardiac catheterization. He had an angiography with a non-ionic agent. However, 4 hours later, in the ward,a nurse called to report that the patient had developed pruritus, and limited urticaria.
Diagnosis: delayed Anaphylactoid reaction (AR)

Questions:
1. Identify RCM reactions in each case?
2. What are the predicted risks of RCM reaction in each of the above cases?
3. What are your options in the management of these cases?
4. What is the incidence of the RCM reaction?
5. Are RCM reactions always immediate?
6. Is there a relationship between sea food allergy and RCM reaction?
7. Is iodinated RCM the only agent that causes a reaction?
8. What are the guidelines in reducing the occurrence and prevention of reactions to radiographic contrast media?

Discussion:
RCM reaction:
Adverse reactions to RCM occur unexpectedly and may be life-threatening [1-5]. Manifestations of adverse reactions to contrast media are suggestive of, or compatible with, immunopathological mechanisms but are known to lack an immune basis and are, therefore, termed pseudoallergic reactions or anaphylactoid reaction (AR). The term AR refers to a syndrome clinically similar to anaphylaxis (immunologic [allergic] reaction), but these reactions are idiosyncratic, independent of immunoglobulin E antibody-mediated mast cell or basophil de-granulation .

RCM agents:
Although most radiographic contrast reactions are characteristic and involve traditional iodinated-type radiocontrast material (Figure 1), in rare circumstances, gadolinium agents can be responsible. Physicians should be aware of rare reactions from other agents that are not commonly thought to cause adverse or allergic-type reactions, such as blue dyes (e.g., sulfan blue) (which can be determined by a skin test); cholecystokinin (CCK); iodinated oral contrast agents (diatrizoate meglumine and diatrizoate sodium solutions [eg, Gastrografin]); Ethiodol (ethiodized oil); liver scanning with 99mTc (technetium 99m) albumin colloid; dipyridamole-thallium Cardiac imaging and thorotrast [1-2].

 

Figure 1. A scheme for classifying RCM

Types of reactions and symptoms to RCM:
• Vasovagal reaction
• Anaphylactoid reactions
• RCM-induced non-cardiogenic pulmonary edema [6],
• Aspiration of barium [7],
• Delayed hypersensitivity [8,9],
• Iodide mumps[10],
• Extravasation, and
• Cardiac arrest [11].


Vasovagal reactions result from vasomotor and vagal effects. The vasomotor effects includes self-limited warmth, nausea, and emesis. Vagal-type reactions include hypotension associated with bradycardia.

Anaphylactoid reactions, clinically indistinguishable from anaphylactic reactions but without a documented IgE-mediated mechanism, have been classified as minor, moderate, or severe. Minor reactions involve limited nausea, vomiting, limited urticaria, pruritus, and diaphoresis. Moderate anaphylactoid reactions may involve faintness, severe vomiting, profound urticaria, facial edema, laryngeal edema, and mild bronchospasm. Severe anaphylactoid reactions may include hypotensive shock, pulmonary edema, respiratory arrest, cardiac arrest, and convulsions.

Although the anaphylactoid RCM reactions usually occur within 30 minutes, delayed (late) adverse reactions may occur 1 hour to 1 week following the administration of intravascular iodinated contrast media which are milder in form [8,9].

Incidence:
Although the average historical risk of RCM reactions is 4.73% [12], Cochran and others recently reported an adverse reaction rate of 11% to 12% with ionic RCM and 0.2% with non-ionic RCM. However, the rate of severe reactions ranged from 0.01% to 0.02%. A Japanese study of 337,647 case administrations, showed an overall prevalence of adverse reactions of 12.66% (0.22% severe) in the ionic contrast group versus 3.13% (0.04% severe) in the non-ionic contrast group [5]. Another study reported that the rate of RCM reactions requiring hospital treatment was 0.69% (38 in 5,546). Life-threatening reactions occurred in approximately 0.03% of patients (1 in 3000) [14] in one study and in 0.02% (1 in 4,530) in another. The risk of death in Katayama’s study was 1 in 169,284 in the ionic contrast group and 1 in 168,363 in the nonionic contrast group, although a causal relationship between the death and contrast media was not proved [5]. The risk of extravasation into local tissues was 0.3% [15].

RISK FACTORS:
Significant risk factors are:
• A previous RCM reaction (by a factor of 5)
• History of asthma/bronchospasm (by a factor of 5- 10) [5]
The presence of asthma increases the risk of AR approximately five-fold [5]. Although, one study found that treated asthmatics were not at higher risk when compared to the general population. All patients with asthma should be considered at increased risk until more data is available on the impact of treatment [16].
• History of allergy or atopy (by a factor of 2 to 3) [5, 17].
Atopic individuals (i.e., those with asthma, allergic rhinitis, drug allergies, or food allergies) are three times more likely than non-atopic individuals to have a severe adverse reaction to intravenous iodinated contrast media [5]. However, much of this risk may be borne by the subgroup with asthma since few studies have evaluated those with atopic disease but without asthma.
• History of drug allergy in general. [5]
Other significant risk factors are:
• cardiac disease
• dehydration;
• hematological conditions such as sickle cell anemia and thrombotic tendencies (eg, polycythemia, multiple myeloma, pheochromocytoma)
• renal disease
• anxiety and apprehension
• Use of ionic as opposed to non-ionic contrast media.
Additional possible risk factors for RCM reactions include medications such as:
• Metformin [18]
• betablockers,
• interleukin-2,
• aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs), although there is no consensus regarding the deleterious effects of these medications [18].

What are the Guidelines for management of RCM reactions?
Recent consensus guidelines from the European Society of Urogenital Radiology (ESUR) suggest using steroid and antihistamine pre-treatment whenever absorption or leakage into the circulation is possible [19].
Several clinical trials have shown that anaphylactoid reactions to RCM can be reduced five to tenfold using a pre-medication regimen including, at least, corticosteroids and antihistamines [20-21] ( Table I ). In addition to the re-treatment of prior reactors, this pre-medication regimen should be considered for high-risk patients, especially strongly atopic individuals and those with extensive cardiovascular disease [22].
 

 Table I   Pre-medication for re-administration of RCM to Prior Anaphylactoid Reactors  

Strategies to decrease the incidence of RCM reaction:
Acute severe life threatening or fatal reactions to a contrast medium (CM) are often unpredictable and not
dose related. They are observed after intravenous or intra-arterial injection, but may also develop after alimentary or intra-cavitary administration (24). The risks of reaction should be assessed, and potential risks of the procedure should be explained to the patient. Appropriately trained staff should be present during contrast administration and adequate supplies for cardio-pulmonary resuscitation should be available. Consideration should be given to maintaining the intravenous access required for administration of the RCM agent. The need for contrast medium administration can be minimized by considering alternative diagnostic test like ultrasonography, magnetic resonance imaging or use of CO2, or Gadolinium compounds, for angiography. Analysis of our case scenarios are as follows;
Case I.
Non-contrast CT in a suspected mass lesion is less conclusive, therefore, a CT scan of the chest needs to be performed after pre-medicating the patient before the procedure. Plain CT examination will suffice if the patient is being assessed for emphysema, interstitial lung disease or bronchiectasis.

Case II.
Contrast medium administration is mandatory for assessment of pulmonary emboli. Since there is no history of severe reaction CT exam can be performed after a pre-medication regimen. Radionuclide perfusion study is an alternative in patients with earlier severe reaction.
Case III.
Essential procedures like cardiac angiogram need to be performed despite history of minor reaction. Fortunately, contrast reaction to intra-arterial injection is less common than for intravenous injection. However, if there is a history of severe reaction then consider other option such as carbon dioxide(CO2)-guided vascular studies, which have been suggested as an alternative to contrast medium in high-risk patients, to reduce, or eliminate, the need for iodinated contrast (26).
A recent prospective study demonstrated satisfactory angiographic quality in 44 out of 50 patients (88%) with CO2 alone. The other six patients required adjunctive radiocontrast or gadolinium. Complications of CO2-guided angiography include pain (1 out of 50 patients), malposition of the catheter (1out of 40 patients), and difficulty in visualizing select arterial segments owing to buoyancy of gas. Other alternatives to conventional iodinated contrast agents have included MR angiography, non-contrast CT, and intravascular ultrasound [27].
Pre-medication does not eliminate the possibility of a fatal reaction on re-administration of RCM, as a reaction may recur despite pre-treatment. Recurrence, despite pre-treatment, has been described in arterial as well as venous administrations of RCM [28–31]. In Greenberger’s 1985 report of 415 prednisone-diphenhydramine pre-treatments for essential studies, 45 reactions (10.8%) occurred, with transient hypotension in 3 (0.7%). Pre-medication with ephedrine, prednisone and diphenhydramine resulted in 9 reactions in 180 procedures (5%) [31]. The patient should be observed for 20 to30 minutes following the procedure [19].
Gadolinium-containing contrast media (e.g., gadopentetate dimeglumine [Gd- DTPA], gadobenate dimeglumine [Gd-BOPTA], gadoteridol, gadodiamide, and gadoversetamide) are used frequently as MR imaging contrast agents. Although significant reactions may occur with gadolinium-containing contrast media, the frequency of reactions is less than with the use of traditional RCM.
It is concluded that non-ionic contrast media significantly reduce the frequency of severe and potentially life-threatening adverse drug reactions to contrast media at all levels of risk, and that use of these media represents the most effective means of increasing the safety of contrast media examinations.
Seafood allergy and RCM reaction (A Medical Myth):
There is a very common misconception among the public that those who are allergic to seafood are actually reacting to the iodine in the seafood. It is known that those who are allergic to seafood are reacting to proteins in the fish or shellfish, not the iodine. This misconception may create a problem when these patients need a diagnostic x-ray requiring radiocontrast media (which may contain iodine). In this situation, patients assume that they are allergic to the radiocontrast media because it may contain iodine. This can cause great anxiety among patients scheduled for such tests, and has created problems for radiologists and allergists who receive calls from these worried patients [19]. Also, those individuals allergic to fish may suffer from atopy in general which would mean that they are at higher risk of reaction to the radiocontrast media (32).

Management of RCM reaction:
The risks of reaction should be assessed. Adequate supplies for cardio-pulmonary resuscitation and trained personnel should be available. Intravenous access required for administration of the RCM agent may be used for treatment of an immediate RCM reaction. (Table II)
Diagnosis of moderate and severe anaphylaxis reactions in adults is made clinically where themost common signs and symptoms are urticaria, angiodema, flushing, pruitus. However, the danger signs are rapid progression of the symptoms to include: stridor, respiratory distress (e.g. wheezing, increased effort to breathe, constant cough), hypertension, dysrhythmia and chest pain.
 

Table II. Management of RCM reaction per the type of reaction

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