General introduction

Reason for making this guideline

The Radiological Society of The Netherlands (RSTN - NVvR) deemed a set of new guidelines on the Safe Use of Contrast Media (CM) highly necessary and relevant, due to recent publications on many topics concerning contrast safety. Because of recent scientific developments, the recommendations of the most recent CM guideline (CBO, 2007) were in conflict with what should be considered best clinical practice. In order to update and elaborate on this 2007 CBO Guideline, which only covered selected topics on the use of iodine-containing CM, a plan has been developed to make a set of 3 new guidelines covering the safe use of all types of CM in adults.

 

The patient population for which these guidelines are meant consists of adult patients (18 years and older) who receive intravascular, oral or intracavitary (intra-articular, intra-vesical, intra-cholangiographic) contrast media both in the clinical setting, as well as for outpatients. The guidelines do not cover radioactive contrast tracer use in nuclear medicine.

 

The three parts of the Safe Use of Contrast Media guidelines were planned to be produced and will cover following topics regarding CM safety (part 3 is still in the planning phase, topics to be finalized):

 

Safe Use of Contrast Media - Part 1 (finalized in 2017):

 

Safe Use of Contrast Media - Part 2 (2016-2019):

 

Safe Use of Contrast Media - Part 3 (2020-2022):

 

The nephrotoxicity of gadolinium-based contrast media and/or microbubble contrast media and the recommendations for measurement of eGFR will be integrated with the guidelines for prevention of Nephrogenic Systemic Fibrosis. These recommendations are published in this guideline Safe Use of Contrast Media, part 2.

 

Focus of the guideline

This part 2 of the Safe Use of Contrast Media guideline focuses on all adult (18 years and older) patients that receive CM during radiologic or cardiologic studies or interventions.

 

Terminology and definitions

The terminology and definitions will be discussed in the introductory chapters of each of the 4 subtopics of this guideline.

 

Guideline Disclaimers

General

The aim of clinical guidelines is to help clinicians to make informed decisions for their patients. However, adherence to a guideline does not guarantee a successful outcome. Ultimately, healthcare professionals must make their own treatment decisions about care on a case-by-case basis, after consultation with their patients, using their clinical judgement, knowledge and expertise. A guideline cannot replace a physician’s judgment in diagnosing and treatment of particular patients.

 

Guidelines may not be complete or accurate. The Working Group of this guideline and members of their boards, officers and employees disclaim all liability for the accuracy or completeness of a guideline, and disclaim all warranties, express or implied to their incorrect use.

 

Guidelines users always are urged to seek out newer information that might impact the diagnostic and treatment recommendations contained within a guideline.

 

Individualisation

In specific high-risk patient groups clinicians may have to regress from these general guidelines and decide on individualisation to best fit the needs of their patients.

 

Life-threatening situations or conditions

In acute life-threatening situations or conditions clinicians may have to regress from these general guidelines and decide on individualisation to best fit the needs of their patients in these situations or conditions.

 

Abbreviations Used in this Guideline

ACR American College of Radiology

ADR Adverse Drug Reaction

AGEP Acute Generalized Exanthematous Pustulosis

AGREE Appraisal of Guidelines for Research & Evaluation

BAT Basophil Activation Test

CA Contrast Agent

CI Confidence Interval

CM Contrast Medium/Media

CT Computed Tomography

CVC Central Venous Catheter

DRESS Drug Reaction with Eosinophilia and Systemic Symptoms

DSA Digital Subtraction Angiography

DX Digital Radiography

EAACI European Association of Allergy and Clinical Immunology

EEM Erythema Exsudativa Multiforme

EMA European Medicines Agency

ENDA European Network for Drug Allergies

ESUR European Society of Urogenital Radiology

FDE Fixed Drug Eruption

GBCA Gadolinium-Based Contrast Agent/Agents

Gd Gadolinium

GRADE Grades of Recommendation, Assessment, Development, and Evaluation

HC Haemodialysis Catheter

HSR Hypersensitivity Reaction/Reactions

ICM Iodine-based Contrast Medium/Media

IDT Intradermal Test

IgE Immunoglobulin E

IM Intramuscular

IV Intravenous

LAREB Landelijke Registratie en Evaluatie Bijwerkingen

MRI Magnetic Resonance Imaging

NPV Negative Predictive Value

NSF Nephrogenic Systemic Fibrosis

NVvR Nederlandse Vereniging voor Radiologie

OBS Observational Study

OR Odds Ratio

PC-AKI Post-Contrast Acute Kidney Injury

PICC Peripherally Inserted Central Catheter

PO Peroral

PPV Positive Predictive Value

PSI Pounds per Square Inch

RCT Randomized Clinical Trial

RF Fluoroscopy

RSTN Radiological Society of The Netherlands

SD Standard Deviation

SJS Stevens-Johnson Syndrome

SPT Skin Prick Test

SR Systematic Review

TEN Toxic Epidermal Necrolysis

TIVAD Totally Implantable Venous Access Device

US Ultrasound

WAO World Allergy Organisation

 

Introduction to hypersensitivity reactions to contrast media.

The increased use of contrast media (CM) may give rise to an increased occurrence of both mild and severe hypersensitivity reactions.

 

Terminology and Definitions

The following definitions and terminology are based on the standard terminology recommended by the World Allergy Organisation (Johansson, 2003; Johansson, 2004; Simons, 2011).

 

Hypersensitivity: Objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus that is tolerated by normal subjects.

 

Allergy: Hypersensitivity reactions initiated by specific immunological mechanisms.

 

Acute hypersensitivity reaction: an adverse reaction that occurs within 1 hour of contrast agent injection. Acute reactions can either be allergy-like (IgE-mediated or not) hypersensitivity reactions or chemotoxic responses.

 

Late hypersensitivity reaction: an adverse reaction that occurs between 1 hour and 1 week after contrast agent injection.

 

Anaphylaxis: A severe life threatening generalized systemic hypersensitivity reaction that is characterized by being rapid in onset with life-threatening airway breathing or circulatory problems and usually associated with skin and mucosal changes.

 

Adverse drug reaction (ADR): a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man (WHO definition).

 

The WAO has defined anaphylaxis as a serious allergic reaction that is rapid in onset and that can be fatal. For diagnosis, there are three possible clinical scenarios:

  1. Sudden onset of an illness (minutes to hours) with involvement of the skin, mucosal tissue (or both), and at least one of the following: a) respiratory compromise and b) reduced blood pressure or symptoms of end-organ dysfunction.
  2. Two or more of the following that occur after exposure to a likely allergen or other triggers (minutes to several hours): skin/mucosal symptoms and signs, respiratory compromise, reduced blood pressure or associated symptoms, and/or gastrointestinal symptoms (crampy abdominal pain or vomiting).
  3. Reduced blood pressure after exposure to a known allergen (minutes to hours).

 

Acute hypersensitivity reactions to contrast media

Pathophysiology

Hypersensitivity reactions to CM are poorly understood. Recent research suggests that hypersensitivity reactions to nonionic CM are a heterogeneous disease. It can develop from multiple mechanisms such as IgE-dependent, complement dependent, direct membrane effects of CM, and possibly other mechanisms that have not been identified yet (Zhai, 2017). When an immunologic mechanism is excluded, unlikely or cannot be proven, hypersensitivity is the preferred term (Johansson, 2003; Johansson, 2004).

 

Allergy-like hypersensitivity reactions may or may not be true IgE-mediated. In general, allergy can be either antibody- or cell-mediated. Cell-mediated reactions occur usually after one or several days, while antibody mediated reactions tend to be more immediate. A well-known reason for immediate reactions is the presence of antigen-specific IgE antibodies fixed to the surface of mast cells and basophil granulocytes. After cross-linking of IgE antibodies on the surface of these cells a degranulation process follows, resulting in production of histamine and many other mediator substances. Other stimuli can also cause degranulation such as degree of ionization, osmolality, temperature of the injected solution. Some drugs such as opiates are known to cause histamine production without the presence of specific IgE.

 

Compared to reactions to iodine-based CM, reactions to gadolinium-based CA are more frequently IgE-mediated, and thus true allergic reactions.

 

Note: Not all symptoms experienced by patients in the hour after contrast agent injections are adverse reactions to the contrast agent. Patient anxiety may cause symptoms after contrast agent administration, known as the Lalli effect (Lalli, 1974).

 

Clinical features and risk factors

The same acute adverse reactions are seen after intravascular administration of iodine-based contrast media and after gadolinium-based contrast agents or ultrasound contrast agents.

 

The term adverse drug reaction (ADR) is wider than hypersensitivity reactions, and includes a number of chemotoxic effects of CM injection, such as a feeling of warmth, dry mouth, or mild pain during injection, etc. Therefore, incidence figures between studies on hypersensitivity reactions and studies on ADR (for example post-marketing surveillance studies) can vary.

 

Mild reactions include allergy-like reactions such as limited urticaria/pruritus, limited cutaneous oedema, itchy/scratchy throat, nasal congestion, and sneezing/conjunctivitis/rhinorrhoea. In this category are included also physiologic/chemotoxic reactions such as limited nausea/vomitus, transient flushing/warmth/chills, headache/dizziness/anxiety, altered taste, mild hypertension or spontaneously resolving vasovagal reactions (ACR Manual on contrast media; ESUR guidelines on contrast safety; Wang 2008).

 

Moderate reactions include allergy-like reactions such as diffuse urticaria/pruritus, diffuse erythema with stable vital signs, facial oedema without dyspnoea, throat tightness/hoarseness without dyspnoea, mild wheezing/bronchospasm. Physiologic reactions are protracted nausea/vomitus, hypertensive urgency, isolated chest pain, and vasovagal reactions responsive to treatment (ACR Manual on contrast media; ESUR guidelines on contrast safety; Wang 2008).

 

Severe reactions include allergy-like reactions such as diffuse erythema with hypotension, diffuse/facial oedema with dyspnoea, laryngeal oedema with stridor, and severe wheezing/bronchospasm with hypoxia, and generalized anaphylactic reaction/shock. Physiologic reactions are treatment-resistant vasovagal reactions, arrhythmia, hypertensive emergencies, and convulsions/seizures. Also to this category belong pulmonary oedema and cardiopulmonary arrest (ACR Manual on contrast media; ESUR guidelines on contrast safety; Wang 2008).

 

Risk factors

Risk factor analysis is often done by retrospective observational studies without control groups.

 

The most common risk factors for hypersensitivity reactions to CM are (ACR Manual on contrast media; Lalli, 1980):

  1. A prior hypersensitivity reaction to contrast media.
  2. A history of allergy, particularly multiple severe allergies.
  3. A history of asthma requiring treatment.

 

Female gender could not be substantiated as an independent risk factor for hypersensitivity reactions.

 

Incidence of acute hypersensitivity reactions

Incidence after iodine-based contrast media

The incidence is highest after iodine-based contrast media and lowest after ultrasound contrast agents. The incidence of acute adverse reactions has declined considerably after the introduction of low-osmolar and iso-osmolar iodine-based contrast media (ACR Manual on contrast media; ESUR guidelines on contrast safety).

 

In the early days of low-osmolar media, the classic Japanese study by Katayama (1990) reported relatively high adverse drug reactions after nonionic CM in up to 3,1%, with severe and very severe reactions occurring in 0,44%. In contrast, more recent studies with large patient cohorts focusing more specifically on hypersensitivity (allergic-like) reactions have shown considerably lower incidence rates of 0,15 to 0,69% with severe reactions occurring in 0,005 to 0,013% (Hunt, 2009; Mortele, 2005; Wang, 2008).

 

Hypersensitivity reactions after non-vascular CM administration (either oral, rectal, intraductal, intravesical or intra-articular) are rare. Such reactions occur slower and the incidence is much lower than after intravascular administration and will be influenced by the integrity and condition of the wall of the cavity into which the contrast agent is administered (for example inflamed mucosa may lead to leakage into the intravascular compartment). Nevertheless, severe reactions can occur, even with non-vascular CM administration (Davis, 2015).

 

Incidence using specific iodinated contrast media

Large post-marketing surveillance studies of iobitridol and iodixanol have shown acute adverse events of 0,58-0,59% with severe events in 0,004 to 0,010% (Maurer, 2011; Zhang, 2014). A third study using iopromide is more difficult to compare due to different definitions, and had higher rates of 2,49% and 0,034%, respectively (Palkowitch, 2014). It must be noted that chemotoxic reactions (feeling of warmth, metallic taste) make up a considerable part of these events.

 

In addition, a number of retrospective, observational studies have looked at differences in acute hypersensitivity rates among iodine-based CM. Although imperfect, these studies indicate a somewhat higher rate for iopromide and iomeprol compared to other CM (Gomi, 2010; Kim; 2017; Seong, 2014). It remains controversial whether iobitridol has a lower percentage, as indicated in one study (Kim, 2017).

 

Incidence after gadolinium-based contrast agents

Recent studies with large adult patient cohorts focusing on hypersensitivity (allergic-like) reactions have shown low incidence rates of 0,06-0,17% with severe reactions occurring in 0,003 to 0,006% (Aran 2015; Behzadi, 2018; Dillman, 2007; Prince, 2011). In a recent large meta-analysis, the overall rate was 92 per 100,000 gadolinium-based contrast agent (GBCA) injections (0,09%) with severe reactions occurring in 5,2 per 100,000 injections (0,005%) (Behzadi, 2018).

 

In that meta-analysis it was shown that the type of GBCA is of influence on the number of reactions. Linear nonionic GBCA had an incidence of 15 per 100,000 and linear ionic GBCA of 52 per 100,000. However, these GBCA are no longer available in Europe. The macrocyclic GBCA had slightly higher rates, macrocyclic ionic 90 per 100,000 and macrocyclic nonionic 160 per 100,000.

 

The highest rate was for linear ionic with protein-binding, 170 per 100,000 injections (Behzadi, 2018).

 

A new, large, retrospective study analysed 281,945 GBCA injections. The overall rate of hypersensitivity reactions was 156 per 100,000 GBCA injections. Severe reactions occurred in only 2,1 per 100,000 injections. Relatively more hypersensitivity reactions occurred after gadobenate and gadobutrol compared with gadodiamide or gadoterate injection (McDonald, 2019).

 

Breakthrough, Protracted and Biphasic Hypersensitivity Reactions

So-called “breakthrough” hypersensitivity reactions are recurring reactions despite premedication with corticosteroids and H1-antihistamines. The occurrence in published series is 2 to 17%. These reactions are most often of similar severity as the original (culprit) reaction for which premedication was prescribed. Breakthrough reactions can be severe in incidental cases (Davenport, 2009; Mervak, 2015).

 

While the majority of hypersensitivity reactions to CM are uniphasic, other patterns may also occur. A protracted reaction is defined as a reaction lasting > 5h in which symptoms incompletely resolve. This pattern is rare following CM, occurring in only 4% of anaphylactic (severe) reactions and may be predicted by a low responsiveness to initial adrenaline therapy (Kim, 2018).

 

A biphasic reaction is defined as a reaction recurring 0 to 72h after an initial hypersensitivity reaction. The median time for start of the second reaction is 8 to 12h after the first reaction. This pattern is also rare, occurring in 10% of anaphylactic (severe) reactions. Usually, the second reaction is of similar severity or milder than the initial reaction. Predictors for biphasic anaphylaxis are severe initial symptoms requiring adrenaline redosing or a long (> 40 min) duration of the initial reaction. An observation time of 6-12h after the initial anaphylactic reaction has resolved is practical (Lee, 2016; Kim, 2018; Kim, 2019). Corticosteroids may have some benefit in the prevention of a biphasic anaphylactic reaction with relatively few side effects, but this remains controversial (Simons, 2015; Lee, 2016).

 

For ultrasound contrast agents the risk is low, but no large series have been published to date. Most adverse reactions are cardiovascular, and the incidence of hypersensitivity reactions is 0,009% with severe reactions occurring in 0,004% (Khawaja, 2010).

 

Classification

Historically, hypersensitivity reactions to CM have been graded as mild, moderate or severe. This radiological classification shows overlap with other used classifications, such as the World Allergy Organisation (WAO) classification (Johansson, 2003; Johansson, 2004) and modifications of the Ring - Messmer classification of allergic reactions (Ring, 1977).

 

Table 1 Severity grading of anaphylactic reactions (modi­fied Ring and Messmer):

Grade

Skin

Abdomen

Airways

Cardiovascular

I

Itch

Flush

Urticaria

Angioedema

-

-

-

II

Itch

Flush

Urticaria

Angioedema

Nausea

Cramps

Rhinorrhoea

Hoarseness

Dyspnoea

Tachycardia (> 20 bpm)

Hypertension (>20 mm Hg)

Arrhythmia

III

Itch

Flush

Urticaria

Angioedema

Vomitus

Defecation

Laryngeal oedema

Bronchospasm

Cyanosis

Shock

IV

Itch

Flush

Urticaria

Angioedema

Vomitus

Defecation

Respiratory arrest

Cardiac arrest

Classification according to the most severe symptom, no symptom is mandatory

 

A practical classification of acute hypersensitivity reactions to contrast media for radiological practices may be (free after ACR Manual on contrast media; ESUR guidelines on contrast safety):

 

Mild: Itching, sneezing, flushing, conjunctivitis, rhinorrhoea, epiphora, nausea, short-duration or incidental vomiting, altered taste, limited scattered urticaria (10 or less).

Moderate: Generalized or extensive urticaria, diffuse erythema without hypotension, facial or angioedema without dyspnoea, mild wheezing/bronchospasm, protracted vomiting, mild isolated hypotension.

Severe: Severe wheezing/bronchospasm, profound hypotension, pulmonary oedema, generalized anaphylactic reaction, seizures/convulsions, respiratory arrest, and cardiac arrest.

 

Late Hypersensitivity Reactions to Contrast Media

Pathophysiology

There is evidence that drug-specific T-cells play an important role in late hypersensitivity reactions. In skin reactions an infiltrate in the dermis consisting of activated CD4+ or CD8+ T-cells and eosinophilic leucocytes is usually found (Christiansen, 2000; Christiansen, 2003).

 

In vitro studies have shown two different pathways of CM recognition which both require major histocompatibility complex (MHC) molecules for stimulation: a) direct binding of CM to the T-cell receptor (p-i concept), and b) after uptake and processing by antigen-presenting cells and presented to T-cells via MHC-II molecules ((pro)hapten concept (Keller, 2009)).

 

The hapten-independent pathway could explain results of cross-reactivity analyses that revealed that CM-specific activated T-cell clones reacted to CM with shared structural elements.

 

It has been postulated that CM do not induce a primary immune response, but instead interact with receptors on activated memory T-cells raised against other foreign substances. For this reason, patients with late hypersensitivity should not be at risk for an immediate or late anaphylactic reaction (mediated by IgE or other mechanisms) upon re-exposure to CM.

 

Clinical features and risk factors

Many patients show a variety of nonspecific symptoms, which include headache, nausea, dizziness, gastro-intestinal upset, mild fever, and arm pain (Bellin, 2011; Christiansen, 2000). When compared to control populations (Loh, 2010), skin rashes with erythema and swelling are the most frequent true late hypersensitivity reactions. Most patients present with cutaneous symptoms similar to other drug-induced skin eruptions, usually in the form of a macular or maculopapular exanthema. The exanthema usually occurs 2 to 10 days after first exposure to ICM and 1 to 2 days after re-exposure to the same ICM. Most reactions are mild to moderate in severity, are usually self-limiting and resolve within 1 week (Bellin, 2011).

 

Other skin reactions include fixed drug eruptions (FDE), erythema exudativa multiforme (EEM) and scaling skin eruptions. In rare cases severe reactions have been described, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis (TEN), acute generalized exanthemic pustulosis (AGEP), and Stevens-Johnson syndrome (SJS).

 

Established risk factors for late hypersensitivity reactions to iodine-based CM include a previous hypersensitivity reaction and IL-2 immunotherapy (ACR Manual on contrast media; Bellin (2011); ESUR guidelines on contrast safety).

 

Patients with a history of late hypersensitivity reactions to ICM are not at increased risk for acute reactions to ICM as these reactions are mechanistically unrelated (Christiansen, 2003; Mazori, 2018).

 

Incidence of late hypersensitivity reactions

The frequency of late hypersensitivity reactions to CM varies greatly between studies and is believed to be between 1 to 3% of patients after iodine-based CM administration and only very rarely after gadolinium-based CA administration (Bellin, 2011; Christiansen, 2000).

 

Incidence using specific iodine-based CM

Late skin reactions tend to be more common after iodixanol (Benin, 2011; Sutton, 2003). The incidence of late hypersensitivity reactions is not significantly different for the other iodine-based low-osmolar CM (Bellin, 2011).

 

Cross-reactivity between contrast media

Cross-reactivity between iodine-based CM

Most of the current cross-reactivity data come from skin testing. Cross-reactivity in late hypersensitivity reactions is probably caused by the presence of CM-specific T-cells, some of which may show a broad cross-reactivity pattern. There may be a link between the chemical structure of iodine-based CM and the pattern of cross-reactivity, but results are not consistent.

 

Several studies have shown considerable cross-reactivity between different iodine-based CM, but specific data on acute versus late hypersensitivity reactions are lacking until now. In the larger studies, most cross-reactivity has been seen between the nonionic dimer iodixanol and its monomer iohexol, with relatively fewer positive skin reactions with iobitridol (Hasdenteufel, 2011; Lerondeau, 2016).

 

Based on cross-reactivity patterns Lerondeau, et al divided iodine-based CM in three groups, with relatively high intra-group cross-reactivity but less intergroup cross-reactivity (Lerondeau, 2016). Based on additional data, it seems reasonable to add iopromide to group A as well (Schrijvers, 2018). Table 2 may be helpful for selecting an alternative agent for imaging studies.

 

Table 2 Cross-reactivity grouping of iodine-based CM

Group A

Group B

Group C

Ioxithalamate (Telebrix)

Iobitridol (Xenetix)

Amidotrizoate (Gastrografin)

Iopamidol (Iopamiro)

Ioxaglate (Hexabrix)

 

Iodixanol (Visipaque)

 

 

Iohexol (Omnipaque)

 

 

Ioversol (Optiray)

 

 

Iomeprol (Iomeron)

 

 

Iopromide (Ultravist)

 

 

 

Cross-reactivity between gadolinium-based CM

Information on cross-reactivity between GBCA is limited to case reports. Skin testing and provocation tests in such cases have shown that cross-reactivity among macrocyclic GBCA does exist.

 

Cross-reactivity between iodine-based and gadolinium-based CM

A recent study examined the risk of reactions to both iodine-based CM and gadolinium-based CA in the same patient in a large patient cohort. The incidence of primary hypersensitivity reactions was 0,047% and the incidence of secondary reactions 0,024%. Nearly all reactions were mild, requiring no treatment. Therefore, cross-reactivity between iodine-based and gadolinium-based CM is an extremely rare event (Sodagari, 2018).

 

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