Safe use of contrast media - part 2

Initiatief: NVvR Aantal modules: 13

Laboratory tests in patients with hypersensitivity reaction to contrast media


What is the diagnostic value of serum and/or urine testing for contrast media induced hypersensitivity reactions?


Sub questions

  1. What is the diagnostic value of tryptase and/or urine (methyl-histamine, methyl-imidazolacetic acid) measurement at the time of the hypersensitivity reaction?
  2. What is the diagnostic value of follow-up examination of serum (tryptase) and/or urine (methyl-histamine, methyl-imidazolacetic acid) in order to estimate the risk for a hypersensitivity reaction in the future?
  3. What is the diagnostic value of the basophil activation test with contrast media?


Do not perform a Basophil Activation Test routinely in all patients with a history of hypersensitivity reactions receiving contrast medium.


Measure serum tryptase between 1 to 2 hours from the start of all moderately severe to severe acute hypersensitivity reactions to contrast media.


When tryptase is elevated, refer the patient to a drug allergy specialist.


Basophil Activation Test

Although no literature was found that answered the search question, a number of studies provide indirect evidence, which will be further discussed here.


Böhm (2011) described that plasma histamine and basophil degranulation using CD63 expression and flow cytometry in blood samples of patients receiving iotrolan (n=12) or iopromide (n=19) injections were analysed before and up to 24 hours after CM injection. In 5 of 12 and 5 of 19 resp. a significant activation of basophils could be measured. No relation with clinical parameters was reported.


Philipse (2012) described a case report where a 28-year old female patient experienced an anaphylactic shock immediately after administration of iomeprol. The reaction was documented by clinical parameters and by an elevation of serum tryptase. Iomeprol induced a dose-dependent CD63 elevation on blood basophils. No activation was shown after stimulation with iohexol and iopromide. CD63 expression on basophils incubated with iomeprol in five controls individuals remained unchanged.


Salas (2013) described a cohort study in which patients with symptoms suggestive of an immediate hypersensitivity reaction to radio contrast media were evaluated with skin tests and a drug provocation test. If skin tests or drug provocation tests were positive a BAT was carried out with the same test panel as used for skin tests. 62.5% of patients considered positive either from skin test or drug provocation test had a positive BAT. The authors suggested that the BAT test could contribute to diagnostic efficacy in patients with hypersensitivity reactions to contrast media. Chirumbolo (2013) responded to the above-mentioned publication (Salas, 2013) that the usefulness of a BAT test is limited due to technical problems in the laboratory and the possibility of delayed reactions to radio contrast media that are likely not to be detected in the BAT test.


Pinnobphun (2011) described a cohort study in which BAT tests were performed in 26 patients with immediate RCM (three different media) reactions and in 43 specimens from healthy volunteers. CD63 and CCR3 positive basophils were analysed by flow cytometry. The BAT test yielded a significantly higher percentage of activated basophils in patients than in normal controls. Both the percentage of activated basophils and the stimulation index had acceptable discrimination powers to diagnose RCM hypersensitivity according to the authors. The specificity of the test ranged from 88.4 to 100%, an ROC curve showed an area under the curve value of 0.79.


Trcka (2008) evaluated 96 patients with anaphylaxis symptoms after contrast media application. In 4 patients (anaphylaxis grade 2 or3) skin test and basophil activation tests suggested an IgE mediated allergy to contrast materials according to the authors. (iopromide, iomeprol, iopentol) Two patients were subsequently treated with an alternative compound that was well tolerated. CD63 and IgE double positive cells assessed the basophil activation. A positive response was dependant on an analysis of more than 5% activated basophils, provided a stimulation index equal or higher than 2.


Kolenda (2017) evaluated the value of BAT and skin test for the diagnosis of RCM hypersensitivity. Thirty-three patients had responded to an injection of GBCA during MRI. Skin test were performed according to EAACI–ENDA guidelines. BAT was performed using the Allergenicity kit (Beckman Coulter). Gadobenate, gadoteric acid and gadobutrol were analysed in three tenfold dilutions. Patients were considered as ‘non allergic’ when their skin tests were negative whereas they were considered ‘allergic’ when the skin tests were positive with an evocative clinical history. CD 203C expression induced in more than 6% of the basophil cells was considered as a positive response. In 13 of the 14 non-allergic patients the BAT was negative, corresponding to a specificity of 93%. When re-exposed five of 14 patients tolerated the culprit drug confirming the ‘non-allergic’ nature of the primary reaction. In the ‘allergic’ population BAT was positive in 13 of 19 for the pulled GBCA, sensitivity of 68%.


In conclusion:

To date four clinical studies, a case report and a mechanistic study have been published concerning application of the BAT in patients with hypersensitivity reactions to contrast media. Based on 3 studies two review articles concluded that: the literature demonstrated a sensitivity of 46 to 63% and specificity is of 89 to 100% (Mangodt, 2015; Steiner, 2016). This conclusion however bypasses heterogeneity in laboratory techniques, control groups and agents involved. It should be noted that these estimates of sensitivity and specificity were based on a low percentage of clinical reactors as were identified as hypersensitive by skin test or drug provocation tests. However, in the recent study of Kolenda almost half of the patients that had responded with symptoms within minutes after GBCA injections had positive skin tests (performed according the EAACI–ENDA guidelines). In these patients a high specificity and relatively high sensitivity was found.


Based on the earlier three studies, performing the BAT test in all patients with a history of hypersensitivity reactions to contrast media would probably only identify a very low percentage as ‘allergic’. However recent studies report a higher percentage of skin test positive patients. The diagnostic value of both skin testing and the BAT are dependent on studies with adequate power and an objective outcome parameter such as a graded dose challenge.


Serum Tryptase

Although no literature was found that answered the search question, a number of studies provide indirect evidence, which will be further discussed here.


Zhai (2017) described a cohort study in 27 adult patients presenting with at least a grade 2 immediate reaction after intravenous injection of ICM during CT. Blood samples were evaluated with multiple parameters. Tryptase levels were significantly elevated as compared to a control group of healthy adults


Clement (2018) reported a cohort study in 245 patients with a history of hypersensitivity who were skin tested, of whom 41 were identified as ‘allergic’ to iodinated agents and 10 to gadolinium based ones. Histamine and tryptase concentrations increased with the severity of the reaction.


Comment (2014) described a cohort study where in the realm of forensic pathology beta tryptase measurements for diagnostic purposes were performed in post-mortem serum obtained from femoral blood in 94 patient with different fatalities, among others death following contrast material administration (six cases). Values over 11.4 ng/mL were systematically identified in serum and pericardial fluid following contrast material anaphylaxis and in six cases unrelated to anaphylaxis.

Fellinger (2014) described that a cohort of 15298 individuals was tested for basal tryptase levels. Elevated serum tryptase (> 11.4 ng/mL, mean 20+/- 21 ng/mL) as a predictor of anaphylaxis was evaluated in 900 patients and compared to 900 patients with normal tryptase values. Elevated tryptase levels were significantly associated with adverse reactions to drugs, radio contrast media and insect sting reactions. Anaphylaxis was more common in patients with elevated tryptase levels.


Srivastava (2014) reported a systemic retrospective survey that was carried out in 171 individuals whose data were extracted from the emergency department and specialist allergy clinic records. Thirty-four patients had a grade 1 anaphylaxis reaction, 61 a grade 2 reaction, 27 a grade 3 reaction and six patients a grade 4 reaction. 24 patients could not be graded due to lack of adequate clinical details, 6 patients developed a biphasic response. 50% of cases were diagnosed with idiopathic systemic anaphylaxis and 28% triggered by drugs, foods, and other allergies. Serial tryptase measurements were not available in 117 of the cohort. A weak positive correlation was detected between acute serum tryptase and severity.


Palmiere (2014) performed a retrospective literature analysis on risk factors of causes of anaphylaxis due to contrast media. Moreover, fatal cases investigated in the author’s own institution was evaluated. Only a minority of fatal cases had been previously exposed to contrast compounds. In eight cases with fatal anaphylaxis, post-mortem serum tryptase concentrations ranged from 51 to 979 ng/mL.


In conclusion:

Tryptase is the principal protein component of human mast cell secretory granules.

It was shown to be a marker of mast cell degranulation that is released together with histamine. Detecting elevated levels of tryptase following a suspected hypersensitivity reaction may help to establish the final diagnosis of anaphylaxis. Tryptase levels peak at 0.5 to 1.5 hours and thereafter rapidly decline with a 1.5-2.5 hours half-life (Schwartz, 2006).


The ESUR guidelines suggest that: blood samples for tryptase are taken following suspected anaphylaxis, so that the diagnosis can be established. The minimum recommendation is one sample 1 to 2 hours after the reaction point. Ideally three samples should be obtained, the first one once this visitation is underway the second at 1 to 2 hours after the reaction and the third at 24 hours or during convalescence (ESUR v10)


An elevated level of tryptase is also a hallmark of systemic mastocytosis. Systemic mastocytosis is a risk factor for developing hypersensitivity reactions to multiple agents such as insect venom and drugs that tend to cause mast cell degranulation (ESUR v10). Contrast agents, notably iodinated products, may per se cause some extent of mast cell and/or basophil degranulation. However, the risk of modern contrast agents in mastocytosis seems to be limited (Hermans, 2017). Moreover, since mastocytosis is a rare disease, routine determination of tryptase does not seem warranted, notably not when other signs and symptoms of mastocytosis are absent (urticaria pigmentosa, osteoporosis at early age, insect sting and/or unexplained anaphylactic reactions).


When confronted with a patient responding with a presumed hypersensitivity reaction to infusion of contrast media the first care of course should be for the safety of the patient. However, once the patient is stabilized care should be taken that clinical parameters are documented according to standard procedures. These procedures include exact documentation of infusion materials, medication taken by the patient or given during the procedure and clinical parameters such as such as blood pressure, heart rate, oxygen saturation, auscultation of the lungs, inspection of the oral cavity and of the skin of the patient.


The signs and symptoms of hypersensitivity reactions are not always clear-cut or may be misleading initially. Therefore, objective documentation is sought for. Tryptase is a readily available marker for mast cell/basophil activation; serum levels are normally less than 11.5 ng/mL. Other studies have proposed a somewhat higher cut-off value (14 ng/mL). Elevated levels of serum tryptase occur in both anaphylactic and anaphylactoid (non IgE-mediated) reactions, but a negative test does not fully exclude anaphylaxis. Basal tryptase levels over 20 µg/L are suggestive of systemic mastocytosis. The utility of serum tryptase for the diagnosis of anaphylaxis has been published in the context of the NICE quality standard anaphylaxis 2016 (NICE QS119).


Serum tests in patients suspected of having experienced hypersensitivity reactions to contrast media in the past


Laboratory tests aimed at detecting specific antibodies can be performed by using skin tests and/or an in vitro basophil activation test (BAT) with the suspected compound. In many cases it is not clear to which compound the patient has reacted in the past. Both skin testing and the BAT test may help to select an agent for future safe use. However, the diagnostic accuracy of these methods still is insufficiently documented. The final evaluation of the diagnostic power of these tests is dependent on the comparison with a ‘golden standard’, probably the graded dose challenge.


Concerning the documentation of hypersensitivity reactions to contrast media (grade II and III) patients should be followed up with at least one sample for blood tryptase 1 to 2 hours after the reaction and one at a later time point (ESUR v10).


Testing of baseline levels of tryptase before contrast studies are performed may be useful in patients who have previously developed hypersensitivity reactions to contrast media. Elevated baseline levels of serum tryptase in a steady state situation suggest the presence of a mast cell disorder. Already mildly elevated baseline tryptase levels somewhat increase the risk of anaphylaxis (Fellinger). Indolent systemic mastocytosis (ISM) is considered a risk factor for contrast agent anaphylaxis, but a recent study did not confirm this (Hermans, 2017). ISM is the most frequent form of mast cell disorders; its prevalence in the Netherlands is suggested to be around 1 in 10,000.


Detection of serum tryptase is relatively cheap, routinely performed in many laboratories, serum samples can be stored at -20°C and normal values are well established. If elevated baseline tryptase values are found (>20 µg/L) a further haematological analysis should be performed including C-kit analysis to further specify the type of mast cell disease.


Given the low frequency of hypersensitivity reactions to contrast agents, the low frequency of mastocytosis in the population and the still insufficiently documented sensitivity and specificity of serum tests (incl. BAT), routine testing of all patients prior to injection of contrast agents is not warranted.


It is important to have local protocols that describe which physician is responsible for measuring the tryptase levels during and after a hypersensitivity reaction (see Chapter Organisation of healthcare).


Serum/blood tests can be performed prior to first contact with the agent, immediately after a reaction and after a possible hypersensitivity reaction in the past.


Hypersensitivity reactions to contrast media are described as acute (immediate) or late (delayed). Reactions occurring within one hour after application of the agents are coined as immediate, reactions occurring later are called delayed. As delayed reactions are considered to be caused by cell-mediated immunity, serum/blood tests so far are only considered relevant to confirm the diagnosis of immediate hypersensitivity. Specific diagnosis of delayed type hypersensitivity can be performed using patch tests and/or in vitro tests such as lymphocyte activation test or other laboratory techniques. The latter tests require specialized laboratories. In order to predict the risk of immediate hypersensitivity reactions serum tests could be aimed at detecting specific antibodies (IgE) to contrast media. In reality this has not been shown to be a realistic option, partly due to technical difficulties.


Moreover, for many years reactions to contrast media were considered as not IgE-driven, although occasionally evidence for an IgE mechanism has been put forward (Carr, 1984; Mita, 1998) In recent years however positive skin tests to contrast media in patients having experienced hypersensitivity reactions have suggested a much larger role for specific IgE, at least in some patients (Clement, 2018). It should be noted however that positive skin tests not necessarily imply an IgE mediated mechanism. The same goes for positive results of the basophil activation test (BAT). Although a positive result of this in vitro test usually indicates the presence of specific IgE, it again does not exclude other activation modes of these blood cells. To date there is no commercially available test for directly detecting circulating IgE anti-bodies to contrast media. Application of the BAT to heparin stabilized blood samples of patients shows interesting results but its availability is limited to specialized laboratories. The technique is based on detection of activation of basophils with flow cytometry. CD63 expression serves as a unique marker of identifying activated cells. The technique requires a small amount of fresh blood, less than 0.1 mL. The CD63 marker is located to the same secretory granule that contains histamine, in principle also histamine production could be used as a marker of basophil activation, but determination of histamine is generally more cumbersome than detecting CD63 up regulation (Hoffmann, 2015). Serum tests can also be performed in order to detect a tendency to develop immediate hyper reactivity reactions in general. Serum beta-tryptase (tryptase) is an indicator of mast cell activity and can readily be measured in hospital routine laboratories. Serum histamine determination is unpractical because of its short half-life in circulation. An alternative is detection of histamine metabolites in urine. (N-τ-Methylhistamine). Although this is a reliable parameter (Keyzer, 1984) very few laboratories have this test in their routine repertoire, and there are not enough data available with respect to contrast media. So, this parameter is not further discussed.

Not applicable. There were no studies investigating the research question.

To answer our clinical question a systematic literature analysis was performed for the following research question:

What is the diagnostic value of serum/blood testing for contrast media induced hypersensitivity reactions?


P (Patients): patients with hypersensitivity reactions after undergoing radiological examinations with contrast media;

I (Intervention): serum tests: tryptase, Blood test, basophil activation test;

C (Comparison): Clinical diagnosis of hypersensitivity reaction after contrast administration / no serum tests;

R (Reference test): drug provocation test;

O (Outcomes): correctly confirmed diagnosis of hypersensitivity reaction to
contrast media (sensitivity, specificity, area under the curve, positive predictive value, negative predictive value).


Relevant outcome measures

The working group considered sensitivity and specificity critical outcome measures for the decision-making process; and considered the area under the curve and the positive and negative predictive values important outcome measures.


Search and select (method)

The databases Medline (OVID), Embase and the Cochrane Library were searched from January 1985 to 11th of January 2018 using relevant search terms for systematic reviews (SRs), randomized controlled trials (RCTs) and observational studies (OBS). The literature search resulted in 368 hits: 12 SRs, 17 RCTs and 339 OBS.


Studies were selected based on the following criteria:

  • adult patients with hypersensitivity reaction to radio contrast media;
  • evaluation of diagnostic properties of serum tests to Contrast Media;
  • application of a provocation test to confirm results of cutaneous testing;
  • reports predefined outcome measures: sensitivity, specificity, area under the curve, positive predictive value, negative predictive value;
  • serum tests tryptase and urine-metabolites should be performed within 24 hours after hypersensitivity reaction;
  • no reports of case series or exploratory findings (n≥10).


Based on title and abstract a total of 2 studies were selected. After examination of full text all studies were excluded. Reason for exclusion is reported in exclusion table.


After examination of full text all studies were excluded, and no studies definitely included in the literature summary.

  1. Böhm I, Speck U, Schild HH. Pilot study on basophil activation induced by contrast media. Fundam Clin Pharmacol 2011; 25: 267-276.
  2. Brockow A, et al. Skin test concentrations for systemically administered drugs - an ENDA-EAACI Drug Allergy Interest group position paper. Allergy 2013;68:702-712.
  3. Carr DH, Walker AC. Contrast media reactions: experimental evidence against the allergy theory. Br J Radiol 1984; 57: 469-473.
  4. Clement O, Dewachter P, Mouton-Faivre C, et al. Immediate hypersensitivity to contrast media: the 5-year French CIRTACI study. EClinicalMedicine 2018; 1: 51-61.
  5. Comment L, Reggiani Bonetti L, Mangin P, Palmiere C. Measurement of β-tryptase in postmortem serum, pericardial fluid, urine and vitreous humor in the forensic setting. Forensic Sci Int 2014; 240: 29-33.
  6. ESUR Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: Accessed: 11 march 2019.
  7. Fellinger C, Hemmer W, Wöhrl S, Sesztak-Greinecker G, Jarisch R, Wantke F. Clinical characteristics and risk profile of patients with elevated baseline tryptase. Allergol Immunopathol (Madr) 2014; 42: 544-552.
  8. Hermans MAW, Arends NJT, Gerth van Wijk R, et al. Management around invasive procedures in mastocytosis: an update. Ann Allergy Asthma Immunol 2017; 119: 304-309.
  9. Hoffman HJ, et al. The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease. Allergy 2015: 70;1393 – 1405.
  10. Keyzer JJ, Udding H, De Vries K. Measurement of N-τ-Methylhistamine concentrations in urine as a parameter for histamine release by radiographic contrast media. Diagn Imag Clin Med 1984; 53: 67-72.
  11. Kolenda C, Dubost R, Hacard F, et al. Evaluation of basophil activation test in the management of immediate hypersensitivity reactions to gadolinium-based contrast agents: a five-year experience. J Allergy Clin Immunol Pract 2017; 5: 846-849.
  12. Mangodt, E. A., Van Gasse, A. L., Decuyper, I., et al. In vitro diagnosis of immediate drug hypersensitivity: should we go with the flow? International archives of allergy and immunology, (2015) 168(1), 3-12.
  13. Mita H, Tadkoro K, Akiyama K. Detection of IgE antibody to a radio contrast medium, Allergy 1998 ;53: 1133-1140.
  14. National Institute for Health and Care Excellence. NICE anaphylaxis quality standard (QS 119). London: NICE, 2016.
  15. Palmiere C, Comment L, Mangin P. Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms. Int J Legal Med 2014; 128: 95-103.
  16. Philipse E, Sabato V, Bridts C, et al. Basophil activation in the diagnosis of life-threatening hypersensitivity reaction to iodinated contrast media: case report. Acta Clin Belg 2013; 68: 140-142.
  17. Pinnobphun P, Buranapraditkun S, Kampitak T, Hirankarn N, Klaewsongkram J. The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Ann Allergy Asthma Immunol 2011; 106: 387-393
  18. Salas M, Gomez F, Fernandez TD, Doña I, Aranda A, Ariza A, et al. Diagnosis of immediate hypersensitivity reactions to contrast media. Allergy 2013; 68: 1203-1206.
  19. Srivastava S, Huissoon AP, Barrett V, Hackett S, Dorrian S, Cooke MW, et al. Systemic reactions and anaphylaxis with an acute serum tryptase ≥14 μg/L: retrospective characterisation of aetiology, severity and adherence to
  20. National Institute of Health and Care Excellence (NICE) guidelines for serial tryptasemeasurements and specialist referral. J Clin Pathol 2014; 67; 614-619.
  21. NICE guideline Anaphylaxis. Quality standard (QS119) Published date: March 2016, update aug. 2018.
  22. Schwartz LB. Value of tryptase in anaphylaxis and mastocytosis. Immunol All Clin North Am 2006;26:451-63.
  23. Srivastava S, Huissoon AP, Barrett V, Hackett S, Dorrian S, Cooke MW, et al. Systemic reactions and anaphylaxis with an acute serum tryptase ≥14 μg/L: retrospective characterisation of aetiology, severity and adherence to National Institute of Health and Care Excellence (NICE) guidelines for serial tryptase measurements and specialist referral. J Clin Pathol 2014; 67; 614-619
  24. Steiner, M., Harrer, A., & Himly, M. Basophil reactivity as biomarker in immediate drug hypersensitivity reactions—potential and limitations. Frontiers in pharmacology, 2016. 7, 171.
  25. Thomsen HS, Webb JAW (eds). Contrast Media: Safety Issues and ESUR Guidelines, 3rd edition. Heidelberg, Springer Verlag, 2014.
  26. Trcka J, Schmidt C, Seitz CS, Brocker EB, Gross GE, Trautmann A. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy ? AJR Am J Roentgenol 2008; 190: 666-670.
  27. Zhai L, Guo X, Zhang H, et al. Non-ionic iodinated contrast media related immediate reactions: A mechanism study of 27 patients. Leg Med (Tokyo) 2017; 24: 56-62.

Exclusion table

Author and Year

Reason for exclusion

Böhm, 2005

Narrative review

Bonadonna, 2016

Narrative review

Comment, 2014

Postmortem study, therefore no provocation test and diagnostic accuracy

Fellinger, 2013

No provocation test and diagnostic accuracy

Fisher, 1998

Patientsgroup does not include patients with a reaction to CM

Górska, 2015

Not the right patient group, no provocation test and diagnostic accuracy

Keyzer, 1984

Does not answer research question

Montañez, 2017

Narrative review.

Palmiere, 2014a

Postmortem study, therefore no provocation test and diagnostic accuracy

Palmiere, 2014b

Narrative review and results postmortem study, no diagnostic accuracy

Srivasta, 2014

Patientgroup includes only one patients with a reaction to CM

Ye, 2014

Investigating causes of anaphylaxis

Zhai, 2017

No provocation test and diagnostic accuracy

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 24-06-2020

Laatst geautoriseerd  : 24-06-2020

The board of the Radiological Society of the Netherlands will determine at the latest in 2024 if this guideline (per module) is still valid and applicable. If necessary, a new working group will be formed to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be seen as a reason to commence revisions. The Radiological Society of the Netherlands is considered the keeper of this guideline and thus primarily responsible for the actuality of the guideline. The other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.



Control holder(s)[2]

Year of authorisation

Next assessment actuality guideline[3]

Frequency of assessing actuality[4]

Who monitors actuality[5]

Relevant factors for changes in recommendations[6]

Laboratory tests




5 years


New tests or new information on diagnostic parameters of tests available

[1] Name of module

2 Responsible authors (per module)

3 Year in which the guideline should be assessed for updating

4 Time frame: Once every 6 months, one year, two years, five years, or longer

5 Responsible scientific society

6 Variety of reasons: new drugs, new therapies, et cetera

Initiatief en autorisatie

  • Nederlandse Vereniging voor Radiologie
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging van Spoedeisende Hulp Artsen
  • Nederlandse Vereniging voor Cardiologie
  • Nederlandse Vereniging voor Dermatologie en Venereologie
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging van Ziekenhuisapothekers
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Nederlandse Vereniging voor Intensive Care
  • Patiëntenfederatie Nederland
  • Nederlandse Vereniging voor Allergologie en Klinische Immunologie

Algemene gegevens

The guideline development was assisted by the Knowledge Institute of the Federation Medical Specialists and was financed by the Quality Funds for Medical Specialists (Stichting Kwaliteitsgelden Medisch Specialisten: SKMS).

Doel en doelgroep


The aim of the Part 2 of Safe Use of Contrast Media guidelines is to critically review the present recent evidence with the above trend in mind and tries to formulate new practical guidelines for all hospital physicians to provide the safe use of contrast media in diagnostic and interventional studies. The ultimate goal of this guideline is to increase the quality of care, by providing efficient and expedient healthcare to the specific patient populations that may benefit from this healthcare and simultaneously guard patients from ineffective care. Furthermore, such a guideline should ideally be able to save money and reduce day-hospital waiting lists.



This guideline is intended for all hospital physicians that request or perform diagnostic or interventional radiologic or cardiologic studies for their patients in which CM are involved.

Samenstelling werkgroep

A multidisciplinary working group was formed for the development of the guideline in 2016. The working group consisted of representatives from all relevant medical specialization fields that are involved with intravascular contrast administration.


All working group members have been officially delegated for participation in the working group by their scientific societies. The working group has developed a guideline in the period from May 2016 until July 2019.


The working group is responsible for the complete text of this guideline.


Working group

  • A.J. van der Molen, radiologist, Leiden University Medical Centre, Leiden (chairman)
  • R.W.F. Geenen, radiologist, Noordwest Ziekenhuisgroep (NWZ), Alkmaar
  • T. Leiner, radiologist, University Medical Centre Utrecht, Utrecht (until November 2018)
  • H.M. Dekker, radiologist, Radboud University Medical Centre, Nijmegen
  • I.A. Dekkers, clinical epidemiologist and radiologist in training, Leiden University Medical Centre, Leiden
  • K. van der Putten, nephrologist, Tergooi, Hilversum
  • J.G.R. de Monchy, allergologist, DC-Klinieken, Amsterdam
  • H.R.H. de Geus, internist-intensivist, Erasmus Medical Centre, Rotterdam
  • S.W. Zielhuis, hospital pharmacist, Medical Centre Leeuwarden, Leeuwarden
  • O.R.M. Wikkeling, vascular surgeon, Heelkunde Friesland Groep, location: Nij Smellinghe Hospital, Drachten
  • I. Brummer, emergency physician, Treant Healthcare Group, Emmen
  • M. van der Vlugt, cardiologist, Radboud University Medical Centre, Nijmegen (until April 2018)
  • M. Gotte, cardiologist, Free University Medical Centre, Amsterdam (from July 2018)
  • S.H. Kardaun, dermatologist, University Medical Centre Groningen, Groningen (until March, 2018)


Methodological support

  • I.M. Mostovaya, senior advisor, Knowledge Institute of the Federation Medical Specialists
  • J. Buddeke, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)
  • W. Harmsen, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)


The working group members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that are related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested at the administrative office of the Knowledge Institute of Medical Specialists and are summarised below.


Last name


Other positions

Personal financial interests

Personal relations

Reputation management

Externally financed research

Knowledge valorisation

Other interests


Van der Putten

Internist nephrologist









Van der Vlugt





Chairman of the working group Cardiac MRI & CT and Nuclear imaging of the Netherlands Society of Cardiology






Emergency physician

Instructor OSG/VvAA for courses on echography – paid position

Member of department for burn treatment – unpaid.










Member of commission prevention of PC-AKI






Has held several presentation about contrast media on invitation (GE, BAYER)



Hospital pharmacist


In the past (2013-2015) has participated in an advisory panel on expensive medication for the companies AbbVie and Novartis. Has received an expense allowance for this. Both forms do not produce contrast media that this guideline is about. Currently not active in an advisory panel.







De Geus

Internist-Intensivist Erasmus MC Rotterdam








Ja, 31-03-2016


Radiologist in training and PhD-candidate



Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Ja, 8-7-2016


Vascular surgeon







Not applicable





Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable


Van der Molen

Radiologist at LUMC






Not applicable

One-off royalties Springer Verlag (2014)
Reference work Safety of contrast medicine
One-off payment by Guerbet for (2014)
reference card management of CM reactions (educative material)

Incidental payments for presentations or being day chairman at contrast safety congress (2016 Netherlands + Europe
all firms: GE, Guerbet, Bracco, Bayer



Dermatologist - researcherUniversitair Medisch Centrum Groningen: unpaid

Replacing dermatologist in clinical practice - unpaid
Member of scientific advisory board of Lareb (Dutch center for pharmacovigilance): unpaid









Emergency physician
Treant zorggroep location Emmen and Stadskanaal









Inbreng patiëntenperspectief

It was challenging to find representation for the patient’s perspective, since the guideline does not discuss a specific group of patients with a disease. The Dutch Kidney Patients Association was invited to participate in an advisory board to the working group, but declined since this subject was not specific enough for them to give adequate input; The Dutch Kidney Patients Association did provide written feedback for specific modules during the commentary phase. The Dutch Kidney Patients Association and the Patient Federation of the Netherlands was invited to participate in the invitational conference in which the framework of the guideline was discussed. Furthermore, the concept guideline has been submitted for feedback during the comment process to the Patient Federation of the Netherlands and the Dutch Kidney Patient Association.

Methode ontwikkeling

Evidence based


In the different phases of guideline development, the implementation of the guideline, and the practical enforceability of the guideline were taken into account. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found with the Related Products. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found with the Related Products.



This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0 by the advisory committee of the Quality Counsel. This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (, a broadly accepted instrument in the international community and on the national quality standards for guidelines: “Guidelines for guidelines” (


Identification of subject matter

During the initial phase of the guideline development, the chairman, working group and the advisor inventory the relevant subject matter for the guideline. Furthermore, an Invitational Conference was organized, where additional relevant subjects were discussed. A report of this meeting can be found in Related Products.


Clinical questions and outcomes

During the initial phase of guideline development, the chairman, working group and advisor identified relevant subject matter for the guideline. Furthermore, input was acquired for the outline of the guideline during an Invitational Conference. The working group then formulated definitive clinical questions and defined relevant outcome measures (both beneficial land harmful effects). The working group rated the outcome measures as critical, important and not important. Furthermore, where applicable, the working group defined relevant clinical differences.


Strategy for search and selection of literature

For the separate clinical questions, specific search terms were formulated and published scientific articles were sought after in (several) electronic databases. Furthermore, studies were scrutinized by cross-referencing for other included studies. The studies with potentially the highest quality of research were looked for first. The working group members selected literature in pairs (independently of each other) based on title and abstract. A second selection was performed based on full text. The databases, search terms and selection criteria are described in the modules containing the clinical questions.


Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search, so that risk of bias could be estimated. This is described in the “risk of bias” tables.


Summary of literature

The relevant research findings of all selected articles are shown in evidence tables. The most important findings in literature are described in literature summaries. When there were enough similarities between studies, the study data were pooled.


Grading quality of evidence and strength of recommendations

The strength of the conclusions of the scientific publications was determined using the GRADE-method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see (Atkins, 2004).


GRADE defines four gradations for the quality of scientific evidence: high, moderate, low or very low. These gradations provide information about the amount of certainty about the literature conclusions. (


Formulating conclusions

For diagnostic, etiological, prognostic or adverse effect questions, the evidence was summarized in one or more conclusions, and the level of the most relevant evidence was reported. For intervention questions, the conclusion was drawn based on the body of evidence (not one or several articles). The working groups weighed the beneficial and harmful effects of the intervention.



Aspects such as expertise of working group members, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects were discussed in the paragraph Considerations.


Formulating recommendations

The recommendation answers the clinical question and was based on the available scientific evidence and the most relevant considerations.


Constraints (Organisation of healthcare)

During the development of the outline of the guideline and the rest of the guideline development process, the Organisation of healthcare was explicitly taken into account. Constraints that were relevant for certain clinical questions were discussed in the Consideration paragraphs of those clinical questions. The comprehensive and additional aspects of the Organisation of healthcare were discussed in a separate chapter.


Development of quality indicators

Internal (meant for use by scientific society or its members) quality indicators are developed simultaneously with the guideline. Furthermore, existing indicators on this subject were critically appraised; and the working group produces an advice about such indicators. Additional information on the development of quality indicators is available by contacting the Knowledge Institute for the Federation Medical Specialists. (


Knowledge Gaps

During the development of the guideline, a systematic literature search was performed the results of which help to answer the clinical questions. For each clinical question the working group determined if additional scientific research on this subject was desirable. An overview of recommendations for further research is available in the appendix Knowledge Gaps.


Comment- and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The commentaries were collected and discussed with the working group. The feedback was used to improve the guideline; afterwards the working group made the guideline definitive. The final version of the guideline was offered for authorization to the involved scientific societies and was authorized.



Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-E842.

Medisch Specialistische Richtlijnen 2.0. Adviescommissie Richtlijnen van de Raad Kwalitieit, 2012. Available at:

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available at:

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. Erratum published in: BMJ 2008;336(7654).

Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten.


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