Hypersensitivity Reactions after Nonvascular CM Administration

Laatst beoordeeld: 24-06-2020

Uitgangsvraag

Hypersensitivity Reactions after Nonvascular CM Administration

Aanbeveling

Small amounts of ICM or GBCA can be absorbed by mucosa and enter the systemic circulation after all types of nonvascular CM administration.

 

Hypersensitivity reactions after nonvascular administration of ICM and GBCA can occur, but their incidence is low to very low.

 

No preventive measures are indicated for ERCP or for nonvascular GBCA administration.

 

For other indications using ICM no firm recommendations can be given for patients that have experienced hypersensitivity reactions to CM in the past.

 

In patients that have experienced severe hypersensitivity reactions to CM in the past, alternative imaging or contrast agents should be explored with the radiologist, and a strict indication for examinations using nonvascular CM administration is needed.

 

In patients that have experienced severe hypersensitivity reactions to CM in the past, preventive measures for severe reactions as outlined in the module 'Prophylaxis of hypersensitivity reactions after contrast administration' may be followed prior to examinations using nonvascular CM administration, if possible after laboratory and skin testing by a specialist in drug allergy prior to the examination.

Overwegingen

1. Gastro-intestinal administration

Barium sulphate suspensions are used more and more infrequently in fluoroscopy than in the 1970 and 1990s. Commercial barium sulphate suspensions are inert and not absorbed by the gastrointestinal mucosa. Trace amounts of barium ions may be absorbed by mucosa and stored in soft tissue or bone (Skucas 1997). Hypersensitivity reactions to barium sulphate are exceedingly rare and are usually mild. They have been estimated to occur in about 1 : 1,000,000 cases (Janower, 1986). Yet, severe reactions have been published as case reports in the heyday of barium use, but are exceedingly rare (Seymour, 1997).

 

It is probable that hypersensitivity reactions are not true reactions to barium sulphate but rather to additives of the commercial barium preparations such as methylparaben or carboxymethylcellulose. In addition, they may also be attributed to the use of glucagon in upper or lower GI studies (Gelfand, 1985).

 

Iodine-based contrast media (ICM) are widely used in CT to opacify and/or distend the stomach and bowel structures, either via oral intake, via a nasogastric or nasoduodenal tube, or via direct rectal administration. The use of fluoroscopy of the GI system is rapidly declining. The use of (CT) fistulography for entero-cutaneous fistula is also included here.

 

For high-density (positive) contrast, the older high-osmolar ionic ioxithalamate meglumine and sodium meglumine amidotrizoate are still widely used for this purpose. In CT, water or low-density (negative) CM (Mannitol or PEG) are used more frequently.

 

In contrast to barium sulphate, small amounts of iodine-based CM are absorbed by the gastro-intestinal mucosa (in the order of 0 to 2%) (Sohn, 2002), with relatively more absorption in the upper than in the lower gastrointestinal system. This absorption may be slow. Therefore, also iodine-based CM can elicit hypersensitivity reactions of all severities, both acute and delayed reactions (Miller, 1997; Schmidt, 1998; Davis, 2015; Böhm, 2017). There is no convincing data that inflammation or ischemia of bowel walls lead to more hypersensitivity reactions.

 

Angioedema may also occur in the small bowel and is often under diagnosed as it results in atypical abdominal discomfort (Chen, 2012; Hu, 2012). It is probably more frequently caused by intravascular ICM and GBCA administration, and may be mediated via the gut-associated lymphoid tissue (GALT) in the bowel wall (Böhm, 2017).

 

Because iodine-based CM in CT is usually administered intravenously and orally, the true incidence of gastro-intestinal CM administration is difficult to determine. As published cases are limited to case reports, the incidence is probably very low, much lower than the incidence after intravascular iodine-based CM administration.

 

Gadolinium-based contrast agents (GBCA) are only rarely used for gastrointestinal use in everyday practice. These GBCA can be absorbed by gastro-intestinal mucosa in small amounts. Given the very low incidence of hypersensitivity reactions to intravascular GBCA, the risk of hypersensitivity reactions is largely theoretical.

 

2. Urogenital administration

Iodine-based contrast media are used for a variety of fluoroscopic urologic procedures such as cystography, pyelography, nephrostomography, urinary diversions and neobladders, urodynamic examinations, or retrograde urethrography.

 

As in gastro-intestinal applications, the urothelium can also absorb these CM in small amounts (Davis, 2015), with a potentially higher rate if CM is injected under pressure or if drainage of CM is slow. Therefore, urologic administration can elicit hypersensitivity reactions of variable severity (Weese, 1993; Miller, 1995), even breakthrough reactions (Armstrong, 2005). As shown by one large published series and selected case reports, the incidence of reactions is low (Cartwright, 2008). Nevertheless, in a recent survey with a low response rate by members of the Society of Endourology, hypersensitivity reactions were reported by a considerable number of selected respondents during their careers (Dai ,2018).

 

In hysterosalpingography the incidence of hypersensitivity reactions following use iodine-based CM is very low, even after venous intravasation (Sanfilippo, 1978; Lindequist, 1991; La Fianza, 2005).

 

Gadolinium-based contrast agents are virtually never used directly for urogenital procedures and no data on hypersensitivity is available.

 

3. Biliary system administration

Iodine-based contrast media are mainly used during diagnostic or interventional endoscopic retrograde cholangiopancreatography (ERCP) and in percutaneous transhepatic cholangiography (PTC) with or without drain (PTCD) placements.

 

There is some systemic absorption of CM after ERCP in the biliary tract, in which the contrast can be detected in the kidneys afterwards. Therefore, also biliary procedures may elicit hypersensitivity reactions to iodine-based CM. However, as shown in the largest published series, the incidence of hypersensitivity reactions during ERCP is very low, even in high-risk patients (Dragonov, 2008; Trottier-Tellier, 2018).

 

Gadolinium-based contrast agents are virtually never used directly for biliary procedures and no data on hypersensitivity is available.

 

4. Intra-articular administration

Iodine-based contrast media are frequently used for arthrography, single/double-contrast CT arthrography or to help guide needle placement in MR Arthrography.

 

The intra-articular contrast can be absorbed in small amounts by the synovium. Hypersensitivity reactions have been described with severe reactions occurring in incidental patients (Newberg, 1985; Westesson, 1990; Hugo III, 1998). However, in two large surveys of 126,000 and 262,000 arthrograms the risk of hypersensitivity reactions was low, and most reactions were mild (Newberg, 1985; Hugo III, 1998).

 

Gadolinium-based contrast agents are used for MR arthography in a very diluted amount (2 mmol/L or a 1:250 dilution).

 

Similar to iodine-based CM, trace amounts of GBCA can be absorbed by synovium. However due to the dilution the number of hypersensitivity reactions following MR arthrography is almost non-existent (Schulte-Altedorneburg, 2003).

 

5. Miscellaneous

Iodine-based contrast media are or have been used for a number of miscellaneous procedures like (CT) discography, sialography, et cetera.

 

Hypersensitivity reactions in most of these procedures are not documented well enough to discuss them in this guideline, or have fallen in disfavour.

Inleiding

There was few good data to structurally search and critically assess the literature on hypersensitivity reactions after nonvascular contrast media (CM) administration, such as gastro-intestinal administration, urogenital administration, intrabiliairy administration, and intra-articular administration.

 

Therefore, the guideline committee decided that it was more appropriate to provide an expert-opinion review of the available literature separately and to try to provide recommendations for practice.

Referenties

  1. Armstrong PA, Pazona JF, Schaeffer AJ. Anaphylactoid reaction after retrograde pyelography despite preoperative steroid preparation. Urology 2005; 66: 880.
  2. Böhm I, Morelli J, Nairz K, Silva Hasembank Keller P, Heverhagen JT. Risks of contrast media applied via the gastrointestinal route. Eur J Intern Med 2017; 42: e19-e21
  3. Cartwright R, Cardozo L, Durling R. A retrospective review of a series of video-urodynamic procedures, with respect to the risk of anaphylactoid reactions. Neurourol Urodyn 2008; 27: 559
  4. Chen CK, Chang HT, Chen CW, et al. Dynamic computed tomography of angioedema of the small bowel induced by iodinated contrast medium: prompted by coughing-related motion artifact. Clin Imaging 2012; 36: 386-389
  5. Dai JC, Brisbane WG, Chang HC, Hsi RS, Harper JD. Anaphylactoid reactions after instillation of contrast material into the urinary tract: a survey of contemporary practice patterns and review of the literature. Urology 2018; 122: 58-63.
  6. Davis PL. Anaphylactoid reactions to the nonvascular administration of water-soluble iodinated contrast media. AJR Am J Roentgenol 2015; 204: 1140–1145.
  7. Draganov PV, Forsmark CE. Prospective evaluation of adverse reactions to iodine-containing contrast media after ERCP. Gastrointest Endosc 2008; 68: 1098-1101.
  8. Gelfand DW, Sowers JC, DePonte KA, Sumner TE, Ott DJ. Anaphylactic and allergic reactions during double-contrast studies: is glucagon or barium suspension the allergen? AJR Am J Roentgenol 1985; 144: 405-406.
  9. Hu XH, Gong XY, Hu P. Transient small bowel angioedema due to intravenous iodinated contrast media. World J Gastroenterol 2012; 18: 999–1002.
  10. Hugo III PC, Newberg AH, Newman JS, Wetzner SM. Complications of arthrography. Semin Musculoskelet Radiol 1998; 2: 345–348.
  11. Janower ML. Hypersensitivity reactions after barium studies of the upper and lower gastrointestinal tract. Radiology 1986; 161: 139-140.
  12. La Fianza A, Camilla F. Venous-lymphatic intravasation during hysterosalpingography using hydrosoluble contrast medium: a technique with no complications. J Women’s Imaging 2005; 7: 38–43.
  13. Lindequist S, Justesen P, Larsen C, Rasmussen F. Diagnostic quality and complications of hysterosalpingography: oil- versus water-soluble contrast media--a randomized prospective study. Radiology 1991; 179: 69-74.
  14. Miller KT, Moshyedi AC. Systemic reaction to contrast media during cystography. AJR Am J Roentgenol 1995; 164: 1551.
  15. Miller SH. Anaphylactoid reaction after oral administration of diatrizoate meglumine and diatrizoate sodium solution. AJR Am J Roentgenol 1997; 168: 959–961.
  16. Newberg AH, Munn CS, Robbins AH. Complications of arthrography. Radiology 1985; 155: 605–606.
  17. Sanfilippo JS, Yussman M, Smith O. Hysterosalpingography in the evaluation of infertility: a six year review. Fertil Steril 1978; 30: 636–643.
  18. Schmidt BJ, Foley WD, Bohorfoush AG. Toxic epidermal necrolysis related to oral administration of diluted diatrizoate meglumine and diatrizoate sodium. AJR 1998; 171: 1215–1216.
  19. Schulte-Altedorneburg G, Gebhard M, Wohlgemuth WA, et al. MR arthrography: pharmacology, efficacy and safety in clinical trials. Skelet Radiol 2003; 32: 1–12.
  20. Seymour PC, Kesack CD. Anaphylactic shock during a routine upper gastrointestinal series. AJR Am J Roentgenol 1997;168:957–958.
  21. Skucas J. Anaphylactoid reactions with gastrointestinal contrast media. AJR Am J Roentgenol 1997; 168: 962–964.
  22. Sohn KM, Lee SY, Kwon OH. Renal excretion of ingested Gastrografin: clinical relevance in early postoperative treatment of patients who have undergone gastric surgery. AJR 2002; 178: 1129–1132.
  23. Trottier-Tellier F, Harvey L, Baillargeon JD. Risk evaluation of endoscopic retrograde cholangiopancreatography-related contrast media allergic-like reaction: a single centre experience. Can J Gastroenterol Hepatol 2018; 2018: 6296071.
  24. Weese DL, Greenberg HM, Zimmern PE. Contrast media reactions during voiding cystourethrography or retrograde pyelography. Urology 1993; 41: 81–84.
  25. Westesson PL, Manzione JV. Reaction to nonionic contrast medium during arthrography of the temporomandibular joint. AJR Am J Roentgenol 1990; 154: 1344.

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.

Initiatief en autorisatie

Initiatief:
  • 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 Venerologie
  • 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

Goal

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.

 

Users

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)

Belangenverklaringen

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

Function

Other positions

Personal financial interests

Personal relations

Reputation management

Externally financed research

Knowledge valorisation

Other interests

Signed

Van der Putten

Internist nephrologist

None

None

None

None

None

None

None

14-10-2015

Van der Vlugt

Cardiologist

None

None

None

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

None

None

None

03-01-206

Roodheuvel

Emergency physician

Instructor OSG/VvAA for courses on echography – paid position

Member of department for burn treatment – unpaid.

None

None

None

None

None

None

21-12-2015

Geenen

Radiologist

Member of commission prevention of PC-AKI

None

None

None

None

None

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

25-3-2016

Zielhuis

Hospital pharmacist

None

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.

None

None

None

None

None

8-1-2016

De Geus

Internist-Intensivist Erasmus MC Rotterdam

None

None

None

None

None

None

None

Ja, 31-03-2016

Dekkers

Radiologist in training and PhD-candidate

None

None

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Ja, 8-7-2016

Wikkeling

Vascular surgeon

None

None

None

None

None

None

Not applicable

19-7-2016

Dekker

Radiologist

None

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

10-7-2016

Van der Molen

Chairman
Radiologist at LUMC

None

None

None

None

None

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

6-9-2016

Kardaun

Dermatologist - researcherUniversitair Medisch Centrum Groningen: unpaid

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

None

None

None

None

None

None

24-2-2016

Brummer

Emergency physician
Treant zorggroep location Emmen and Stadskanaal

None

None

None

None

None

None

None

23-2-2018

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

Implementatie

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.

Werkwijze

AGREE

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) (www.agreetrust.org), a broadly accepted instrument in the international community and on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).

 

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 http://www.gradeworkinggroup.org/) (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. (http://www.guidelinedevelopment.org/handbook/).

 

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.

 

Considerations

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. (secretariaat@kennisinstituut.nl).

 

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.

 

References

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: https://richtlijnendatabase.nl/over_deze_site/richtlijnontwikkeling.html.

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: http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

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.