Safe use of contrast media - part 2

Initiatief: NVvR Aantal modules: 13

Management of acute hypersensitivity reactions


What is the optimal treatment for acute hypersensitivity reactions to contrast media?



  • Have the drugs (as a minimum requirement: adrenaline, salbutamol, H1-antihistamine (clemastine) IV, and corticosteroid IV (for example prednisolone), equipment and protocol for treatment of an acute adverse reaction readily available in every room where contrast agents are administered.
  • Adhere to local protocols for accessibility of a resuscitation and emergency response team.
  • Keep every patient with an acute hypersensitivity reaction to CM in a medical environment for at least 30 minutes after contrast agent injection. Moderate and severe reactions need a prolonged observation.


Acute management general principles:

  • Check and stabilize patient according to the ABCDE method.
  • Stop infusing contrast agent and replace IV line with crystalloid.
  • Dyspnoea or stridor: let patient sit up.
  • Hypotension: keep patient in prone position, raise legs.
  • Consider measuring serum tryptase (see recommendations in chapter Laboratory Diagnosis of Hypersensitivity Reactions to Contrast Media).
  • Record acute allergic reactions in allergy registry (see chapter Organisation of Healthcare).

Note: After administration of clemastine the patient may no longer be able (or insured) to drive a car/motorcycle or to operate machinery.


Severe reactions

Cardiac or respiratory arrest:

  • Start CPR.
  • Call the CPR team.

Anaphylactic reaction or stridor:

  • Call rapid response team (SIT-team).
  • Give oxygen 10 to 15L/min with non-rebreathing mask.
  • Give 0.5mg adrenaline IM in lateral upper thigh.
  • Give fluid bolus of crystalloid 500ml IV in 10 minutes, repeat as necessary.
  • Consider nebulizing salbutamol 5mg or budesonide 2mg for stridor.
  • Give clemastine 2mg IV.
  • Consider to add corticosteroid, for example prednisolone 50mg IV.


*Or equivalent dose of other corticosteroid.


50 mg prednisolone is equivalent to:

  • 40 mg methylprednisolone.
  • 8mg dexamethasone.
  • 200mg hydrocortisone.


*Consider adding corticosteroids to prevent a biphasic or protracted anaphylactic reaction if initial symptoms are severe


Moderate reactions

Consider transferring the patient to a department with facilities for monitoring of vital functions.


Isolated bronchospasm:

  • Salbutamol 2.5 to 5mg nebulization in oxygen by facemask 10 to 15 L/min (nebulization is easier to administer and more effective than dose aerosol).
  • In mild cases asthma patients may use their own salbutamol dose aerosol.
  • In case of deterioration give adrenaline 0.5mg IM and consider calling rapid response team.

Isolated facial oedema without stridor:

  • Give oxygen 10 to 15L/min with non-rebreathing mask.
  • Give clemastine 2mg IV.
  • If oedema is severe or near airways or if stridor develops: treat as anaphylaxis.

Isolated urticaria/diffuse erythema:

  • Give clemastine 2mg IV.
  • If accompanied by hypotension: treat as anaphylaxis.

Isolated hypotension:

  • Give bolus of crystalloid 500ml IV, repeat as necessary.
  • If accompanied by bradycardia, consider atropine 0.5mg IV.
  • If accompanied by other symptoms: treat as anaphylaxis.


Mild reactions


  • Mild reactions may only need reassurance.
  • Observe vital signs until symptoms resolve.
  • Do not remove IV access during observation.


  • Prescribing a non-sedating antihistamine, for example desloratadine 5mg PO (once daily) for mild allergic reactions.
  • Ondansetron 4mg IV for protracted vomiting.


Also see the flowchart.


As there are no comparative studies investigating the research question, the recommendations in this national guideline are based mainly on results of observational studies and reviews (for example Cohan, 1996; Bang, 2013; Morzycki, 2017; Boyd, 2017) and of the recommendations of the American College of Radiology 2018 (Manual on Contrast Media v10.3) (ACR, 2018), the European Society of Urogenital Radiology 2018 (electronic v10) (ESUR, 2018), the International Consensus On Drug Allergy 2014 (Demoly, 2014), the World Allergy Organisation (WAO) Anaphylaxis Guidelines 2011, update 2015 (Simons, 2015), the European Association for Allergy and Clinical Immunology (EAACI) Guidelines 2014 (Moraro, 2014), and adapted to the Dutch situation (Het Acute Boekje, NIV 2017).


Because of the diminished frequency of acute adverse reactions to contrast media, there are now fewer opportunities for physicians to recognize and appropriately treat such adverse reactions. Reactions vary from very mild itching to anaphylactic shock. These reactions are often unpredictable; they can happen to people who have not been exposed to contrast media in the past. A mild reaction may be self-limited but can also develop quickly into a severe reaction. When a hypersensitivity reaction to a contrast medium occurs, there may be insufficient time or opportunity to study the treatment protocols and medication doses. It is therefore important for personnel to be prepared for any adverse reaction, to have clear treatment guidelines, and to have access to a rapid response team in case of an emergency. (Segal, 2011).


Because of this diminished frequency and lack of experience in treatment, major guidelines recommend to restricting adrenaline injection in the hands of non-experienced users to intramuscular administration route only.


Risk factors

Patients with a history of previous moderate or severe acute hypersensitivity reaction to an iodine-based contrast medium or gadolinium-based or ultrasound contrast agent, asthma requiring medical treatment and atopy requiring medical treatment are at increased risk (ESUR 2018; ACR 2018).



Use a low-osmolar or iso-osmolar non-ionic iodine-based contrast medium. In patients at risk consider an alternative test not requiring a contrast agent of similar class.


For previous contrast agent reactors: use a different contrast medium/agent, preferably after consultation with a specialist in drug allergy


The radiology department should be prepared for an acute reaction. This requires regular and optimized training of personnel. See Chapter: Organisation of healthcare.



Instead of adrenaline 1:1,000 ampules for IM administration each department may also opt for selecting the (more expensive) adrenaline 1:1,000 auto-injectors, for example EpiPen (Asch 2017).


Acute hypersensitivity reactions often create stress and confusion and appropriate training and clear protocols are advisable. In addition, depending on the location where a patient suffers an acute hypersensitivity reaction to contrast media, the available expertise of the personnel that cares for such a patient may differ. Similarly, the availability of equipment and drugs to treat a (possible serious) hypersensitivity (or anaphylactic) reaction will be different. In a radiology or cardiology department the possibilities are different (and usually more limited) than in a department of emergency medicine or on a hospital ward. In addition, different treatments will have variable modes of action. What is the most appropriate management of a patient with an acute hypersensitivity reaction to contrast media?

Not applicable. There were no studies investigating the research question. The non-comparative studies are briefly described in the table below.


Table 1 Treatment effects of acute adverse reaction

Abbreviations: CM contrast media; CPR Cardio-Pulmonary Resuscitation; IV intravenous;


Total n
(n men)

CM type

Acute reaction(s)




Collins, 2009

9 (3)

LOCM or Gadolinium

Ranged from laryngeal oedema, hypotension,

tachycardia, dyspnoea to hypoxia

All patients received epinephrine; seven 0.1 mg (recommended initial dose) and two 0.3mg.


Oxygen, diphenhydramine, steroids

7/9 discharged in good condition on same day of CM administration

1/9 Intubation during transport to emergency department, admitted to ICU, discharged 5 days later in good condition


1/9 Full cardiac arrest; autopsy showed retroperitoneal haemorrhage as cause of death

4/9 patients had some form of cardiovascular

side effects attributed

to epinephrine (such as “chest tightness”)

Wang, 2008

11 (3)

Non-ionic iodinated contrast media

Ranged from erythema, hypotension, tachycardia,

unresponsiveness, arrhythmia, cardiopulmonary arrest, nausea, diaphoresis, rash, hypotension,

semi-responsiveness, dizziness, gagging and difficulty speaking, bronchospasm, chest pain, generalized seizure to facial oedema

Ranged from CPR, 1 mg of epinephrine IV, 1 mg of atropine IV, 50 mEq of sodium bicarbonate, 1 g 10% calcium chloride, 10 L of O2 by face mask, normal saline, 50% dextrose, 50 mg of diphenhydramine IV, 100 mg of diphenhydramine to 120 mg of methylprednisolone

2/10 returned to their normal baseline conditions within 1 hour.

6/10 manifestations resolved completely within 24 hours, despite their severe symptoms and

often extensive treatment.
2/10 sequelae lasting more than 24 hours

1 unknown outcome

Allergic-type reactions occurred in 545/84,928 (0.6%) of IV injections of nonionic iodinated

contrast media in adults. 221 received treatment.

Power, 2016

85 (sex unknown)


81 mild allergic-like

reactions: urticaria, rash, pruritus, limited erythema, Localized facial oedema, itchy eyes, scratchy throat, sneezing, coughing


3 moderate reactions: erythema over the anterior

chest with dyspnoea, rash and soft palate swelling, pruritic

rash and throat tightness


1 severe: breathing and swallowing

Half of the patient with mild reaction received treatment with oral diphenhydramine


All patients with moderate reactions received treatment with diphenhydramine.



resuscitation effort

All patients were discharged


Piscaglia, 2006

29 (sex unknown)


Ranged from dyspnoea, bronchospasm, slight

hypotension and bradycardia, clouding of consciousness,

lumbar pain, severe

hypotension, cutaneous rash to paraesthesia at the upper limbs

IV corticosteroids, antihistamines, 1 g of hydrocortisone, lying down with both legs raised, lying down.

All patients recovered



To answer the clinical question a systematic literature analysis was performed.


P (Patient): patients with acute hypersensitivity reaction after contrast media administration;

I (Intervention): treatment, antihistamines, corticosteroids, epinephrine, adrenalin, dopamine, norepinephrine, noradrenalin, histamine H1 antagonists, histamine H2 antagonists, H1 antihistamines, H2 antihistamines, adrenergic beta-2 receptor agonists, glucocorticoids, management/treatment of hypersensitivity reactions/allergic reactions after contrast media, antihistamines, volume resuscitation, bronchodilators;

C (Comparison): conservative treatment or comparison of interventions mentioned above;

O (Outcomes): duration of acute reaction, severity of complaints, morbidity, mortality, costs, hospitalization in an IC-unit, length of stay.


Relevant outcome measures

The working group considered morbidity, mortality, and hospitalization in an IC-unit, critical outcome measures for the decision-making process, and duration of acute reaction, length of stay and costs important outcomes for the decision-making process.



The databases Medline (OVID) and Embase were searched from 1s of January 1985 to 28th of December 2017 using relevant search terms for systematic reviews (SRs), randomized controlled trials (RCTs) and observational studies (OBS).


Search terms are shown under the Tab “Literature Search”. The literature search procured 328 hits: 20 SR, 64 RCTs and 224 OBS. Based on title and abstract a total of 47 studies were selected. After examination of full text all studies were excluded, and no studies definitely included in the literature summary.


4 studies describing treatment effects of acute adverse reactions were found. Although these studies did not fulfil the search criteria, a short description is included in the literature summary, due to lack of other evidence. Since no control groups were available, no evidence tables or risk of bias tables or conclusions of these studies are included.

  1. Acute boekje 2017. Een initiatief van de Nederlandse Internisten Vereniging. Available at: Accessed: 11 March 2019
  2. American College of Radiology. ACR Manual on contrast media. V.10.3. Available at: Accessed: 11 March 2019.
  3. Asch D, Pfeifer KE, Arango J, Staib L, Cavallo J, Kirsch JD, Arici M, Pahade J. Benefit of epinephrine autoinjector for treatment of contrast reactions: comparison of errors, administration times, and provider preferences. AJR Am J Roentgenol 2017; 209: W363-W369.
  4. Bang TJ, Suby-Long T, Borgstede JP, et al. University of Colorado radiologist adult contrast reaction smartcard. J Am Coll Radiol 2013; 10: 467-469.
  5. Boyd B, Leder RA, Castillo M. Managing adverse reactions to contrast agents. Magn Reson Imaging Clin North Am 2017; 25: 737-742.
  6. Cohan RL, Leder RA, Ellis JH. Treatment of adverse reactions to radiographic contrast media in adults. Radiol Clin North Am 1996; 34: 1055-1076.
  7. Collins MS, Hunt CH, Hartman RP. Use of IV epinephrine for treatment of patients with contrast reactions: lessons learned from a 5-year experience. AJR Am J Roentgenol 2009; 192: 455-461.
  8. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy 2014; 69: 420-437.
  9. ESUR Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: Accessed: 17 February 2019.
  10. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines of the European Association of Allergy and Clinical Immunology. Allergy 2014; 69: 1026-1045.
  11. Morzycki A, Bhatia A, Murphy KJ. Adverse reactions to contrast material: A Canadian update. Can Assoc Rad J 2017; 68: 167-193.
  12. Piscaglia F, Bolondi L; Italian Society for Ultrasound in Medicine and Biology (SIUMB) Study Group on Ultrasound Contrast Agents. The safety of Sonovue in abdominal applications: retrospective analysis of 23,188 examinations. Ultrasound Med Biol 2006; 32: 1369-1275
  13. Power S, Talbot N, Kucharczyk W, Mandell DM. Allergic-like Reactions to the MR Imaging Contrast Agent Gadobutrol: A Prospective Study of 32 991 Consecutive Injections. Radiology 2016; 281: 72-77.
  14. Segal AJ, Bush Jr. WH. Avoidable errors in dealing with anaphylactoid reactions to contrast media. Invest Radiol 2011, 46: 147-151.
  15. Simons FER, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal 2015; 8:32.
  16. Wang CL, Cohan RL, Ellis JH, Caoli EM, Wang G, Francis IR. Frequency, outcome and appropriateness of treatment of nonionic iodinated contrast media reactions. AJR Am J Roentgenol 2008; 191: 409-415.

Exclusion Table After full text review

Author  and year

Reasons for exclusion

Boyd, 2017

Narrative review. No control arm

Brockow, 2011 20

Narrative review. No control arm

Bush, 1991

Patient group not treated with CM. Does not cover treatment

Cochran, 2005

Expert opinion

Cohan, 1996

Narrative review.

Collins, 2009

Narrative review. No control arm.

Coors, 2006

Narrative review. No control arm.

Davis, 2015

Narrative review. No control arm

Dawson, 2002

Narrative review. No control arm. Does not cover treatment

Drain, 2001

Narrative review. No control arm.

Hash, 1999

Narrative review. No control arm

Hollingswerth, 1991

Patient group not treated with CM

Iyer, 2013

Narrative review. No control arm.

Kounis, 2015

Narrative review. No control arm

Liebhart, 2007

Narrative review. No control arm. Patient group not treated with CM

Marycz, 2014

Narrative review. No control arm

Masch, 2016

Narrative review. No control arm

Meth, 2006

Narrative review. No control arm.

Morcos, 2001

Narrative review. No control arm.

Morcos, 2005

Expert opinion

Morcos, 2005

Narrative review. No control arm.

Morcos, 2006

Narrative review. No control arm.

Morzycki, 2017

Narrative review. No control arm

Namasivayam, 2006a

Narrative review. No control arm. Patient group not treated with CM

Namasivayam, 2006b

Narrative review. No control arm.

Nandwana, 2015

Narrative review. No control arm. Patient group not treated with CM

Nayak, 2009

Narrative review. No control arm.

Newmark, 2012

Narrative review. No control arm

Petscavage, 2012

Patient group not treated with CM

Pumphrey, 2004

Narrative review. No control arm.

Ring, 2010

Narrative review. Patient group not treated with CM

Rose, 2015

Narrative review

Sadler, 1994

Patient group not treated with CM

Seikh, 2013

Expert opinion. Patient group not treated with CM

Shellock, 1993

Patient group not treated with CM

Skowronski, 1987

Patient group not treated with CM

Szebeni, 2004

Narrative review. No control arm.

Thompsen 1998b

Narrative review. No control arm.

Thompsen, 1998a

Narrative review. No control arm.

Thompsen, 2004

More recent guideline available

Thompsen, 2016

Narrative review. No control arm

Toncic, 2009

Narrative review. No control arm. Patient group not treated with CM

Toogood, 1987

Patient group not treated with CM

Wang, 2008

Narrative review. No control arm.

Wang, 2014

No comparison between effectivity of several treatments

Winbery, 2002

Narrative review. No control arm.

Wolkenstein, 1995

Narrative review. No control arm. Patient group not treated with CM

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.



Responsible authors)[2]

Authorisation Year

Next evaluation of validity of guideline

Frequency of evaluation of validity[3]

Who surveys the actuality of this guideline[4]

Relevant factors for changing recommendations[5]

Treatment of acute reactions




5 years


New scientific developments

[1] Name of module

[2] Responsible authors (per module)

[3] Time frame: Once every 6 months, year, two years, five years, longer

[4] Responsible scientific society

[5] 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.


Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Treatment of late reactions to contrast media