Gadolinium Deposition in the Body and T1w Hyperintensity in the Brain

Laatst beoordeeld: 24-06-2020

Uitgangsvraag

What is the clinical relevance of gadolinium-based contrast agent (GBCA) induced T1w hyperintensity of the nucleus dentatus and the globus pallidus in the brain?

Aanbeveling

Ensure a strict indication for gadolinium-enhanced MRI and use EMA-approved GBCA in all patients to minimize possible gadolinium deposition.

Overwegingen

The following is a short overview of the current state of gadolinium retention in the brain and body. See also the Introduction to Safe Use of Gadolinium-Based Contrast Agents.

 

Increased SI due to Gd deposition

Two autopsy studies, both published in 2015, showed that the increased SI on T1-weighted sequences (T1w) in the dentate nucleus and globus pallidus was indeed due to the presence of retained Gd (Kanda, 2015; McDonald, 2015). The majority of the Gd was localized in the perivascular spaces (4), whereas a much smaller fraction crossed the blood-brain barrier and was situated in the neural interstitium and cellular organelles (Fingerhut, 2018; McDonald 2015; McDonald, 2017_1; McDonald, 2017_2).

 

Difference between linear and macrocyclic chelates

Subsequent studies confirmed progressive T1 SI increases after intravenous administration of linear GBCA (Errante, 2014; Kanda, 2015_1; Radbruch, 2015; Ramalho, 2015; Quattrocchi, 2015; Quattrocchi, 2015_1). The majority of the publications do not show dose-dependent changes in T1w SI after macrocyclic GBCA exposure (Cao, 2016; Kanda, 2015_1; Kromrey, 2017; Radbruch, 2017; Ramalho, 2015; Quattrocchi, 2015_1; Tibussek, 2017). Others report a weak T1w SI increase after administration of macrocyclic GBCA (Bjornerud, 2017; Kang, 2018; Rossi, 2017; Spelndiani, 2018; Stojanov, 2016;). A study of human brain tissue demonstrated measurable Gd after single dose intravenous administration of both linear and macrocyclic chelates (Murata, 2016). Significant less Gd retention was observed after macrocyclic chelate exposure, compared to linear chelate exposure (Murata, 2016).

 

These results led to a European Medicines Agency (EMA) directory regarding GBCA, stating to suspend the use of linear GBCA in order to prevent any risks that could potentially be associated with Gd brain deposition (EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans, 2019). Only the liver specific linear GBCA gadoxetate and gadobenate are allowed to be used in these situations where they meet a specific diagnostic need (EMA’s final opinion confirms restrictions on use of linear GBCA in body scans, 2017).

 

Gd deposition in other tissues than brain.

Besides the brain and skin in patients with NSF, Gd retention has been reported in many other tissues including the bone, muscles, tendons, nerves, blood vessels and visceral organs (Gibby, 2004; Murata, 2016; Sanyal, 2011).

 

Pathophysiology of Gd deposition

Stability of Gd chelates is determined by their thermodynamic and kinetic stability. Thermodynamic stability of a chemical system means that this system is neither consuming nor releasing heat, i.e. thermal energy. In the absence of a change in thermal energy, the system is not undergoing a chemical reaction. Kinetic stability refers to the fact that a chemical reaction can occur at a certain speed. If a chemical system is kinetically stable, it means that reactions within this system occur very slowly. In general, macrocyclic GBCA have higher thermodynamic and kinetic stability constants and are therefore more stable than linear Gd chelates and therefore release less amount of Gd3+ out of the chelate (McDonald, 2018). Very little is known about the fate of free Gd3+ within the human body, and how biologically active and potentially toxic chemical forms of retained Gd in tissues are formed (McDonald, 2018). After intravenous injection in patients with normal kidney function, 73% to 99% of the dose is excreted within 24 hours after injection. Biodistribution data of GBCA suggest the presence of a longer lasting phase of residual excretion from other tissues, from which Gd is slowly eliminated (McDonald, 2018). The potential toxicities of this small pool of retained Gd are largely unknown (McDonald, 2018).

 

Clinical importance of Gd deposition

After hundred millions of Gd chelate administered doses, 139 patients with normal or minimally impaired kidney function reported effects that they associate with Gd exposure. The symptoms include chronic pain, fatigue, dermal changes, musculoskeletal disturbances, cognitive impairment, and visual impairment (Burke, 2016). An association between these symptoms and Gd chelate exposure has been postulated and the term “gadolinium deposition disease” has been proposed (Semelka, 2016). The Food and Drug Administration (FDA) could not find a causal relationship between Gd deposition and symptoms. If Gd deposition is associated with clinical harm, the harm is likely to be rare or occult for the vast majority of exposed patients (McDonald, 2018).

 

Future directions

Today, many question marks exist when it comes to the explanation of how Gd deposition occurs and what the clinical consequences, if any, are. In 2018, a research roadmap on Gd deposition was proposed, with the highest priorities to determine a) if Gd deposition adversely affects the function of human tissues, b) if deposition is causally associated with short- or long-term clinical manifestations of disease and c) if vulnerable populations are at greater risk for developing clinical disease (McDonald, 2018).

Inleiding

In 2014, Kanda observed progressive unenhanced T1-weighted (T1w) signal intensity (SI) increases in the dentate nucleus and globus pallidus in patients who received at least 6 doses of Gadolinium (Gd) chelates (Kanda, 2014). This publication triggered a huge amount of research on this subject, which is still going on today. Weekly, new publications arise, which make it impossible to give an up to date overview in this guideline. The broad outlines of gadolinium deposition will be discussed.

Samenvatting literatuur

Not Applicable.

Zoeken en selecteren

To answer our clinical question a systematic literature analysis was performed. This was an orientatational search, to examine the clinical relevance of the T1w hyperintensity of the nucleus dentatus and the globus pallidus.

 

P (Patient): patients who have repeatedly received gadolinium-based contrast agents and have signs of gadolinium retention such as T1w hyperintensity of the nucleus dentatus and the globus pallidus, but also gadolinium retention in the bones, liver and skin;

I (Intervention): not applicable;

C (Comparison): not applicable;

O (Outcomes): signal intensity, signal increase, hyperintensity, hypersignal. Central torso and peripheral arm and leg pain. Distal arm and leg skin thickening. Rubbery subcutaneous tissues. Clouded mentation or brain fog.

 

Relevance of outcome measures

Signal intensity, signal increase, hyperintensity, hypersignal were considered critical outcomes and central torso, peripheral arm and leg pain, distal arm and leg skin thickening and rubbery subcutaneous tissues and clouded mentation or brain fog were considered important outcome measures.

 

Methods

The databases Medline (OVID), Embase and the Cochrane Library were searched from 1st of January 1996 to 11th of November 2018 using relevant search terms for systematic reviews (SRs), randomized controlled trials (RCTs) and observational studies (OBS).

 

The literature search produced 722 hits. A total of 99 abstracts were selected. When the full texts were examined, none of them fulfilled the selection criteria. Based on this, it was concluded that no conclusions on the clinical aspect could be drawn. Based on the literature, the narrative review shown below was written by the guideline committee.

Referenties

  1. Bjornerud A, Vatnehof SAS, Larsson C, Due-Tonnessen P, Hol PK, Groote IR. Signal enhancement of the dentate nucleus at unenhanced MR imaging after very high cumulative doses of the macrocyclic gadolinium-based contrast agent gadobutrol: an observational study. Radiology 2017; 285: 434 – 444.
  2. Burke LM, Ramalho M, Al Obaidy M, Chang E, Jay M, Semelka RC. Self-reported gadolinium toxicity: a survey of patients with chronic symptoms. Magn Reson Imaging 2016; 34: 1078 – 1080.
  3. Cao Y, Huang DQ, Shih G, Prince MR. Signal change in the dentate nucleus on T1-weigthed MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR 2016; 206: 414 – 419.
  4. European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans (21 July 2017). Available at: https://www.ema.europa.eu/en/documents/referral/gadolinium-article-31-referral-emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents_en-0.pdf Accessed: 11 July 2019.
  5. Fingerhut S, Sperling M, Holling M, Niederstadt T, Allkemper T, Radbruch A, et al. Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls, while the neuropil is not affected: an autopsy study. Acta Neuropathol 2018; 136: 127-138.
  6. Gibby WA, Gibby KA, Gibby WA. Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol 2004; 39: 138 – 142.
  7. Kanda T, Ishii K, Kawaguchi H, Ketajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: Relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014; 270: 834 – 841.
  8. Kanda T, Fukusato T, Matsuda M et al. Gadolinium-based contrast agents accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 2015; 276: 228-232.
  9. Kanda T_1, Osawa M , Oba H, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015; 275: 803 – 809.
  10. Kang KM Choi SH, Hwang M, Yun TJ, Kim JH, Sohn CH. T1 shortening in the globus pallidus after multiple administrations of gadobutrol: assessment with a multidynamic multiecho sequence. Radiol 2018; 287: 258 – 266.
  11. Kromrey ML, Liedtke KR, Ittermann T, et al. Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years. Eur Radiol 2017; 27: 772 – 777.
  12. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015; 275: 772 – 782.
  13. McDonald JS_1, McDonald RJ, Jentoft ME, et al. Intracranial gadolinium deposition following gadodiamide-enhanced magnetic resonance imaging in pediatric patients: a case-control study. JAMA Pediatr 2017; 171; 705 – 707.
  14. McDonald RJ_2, McDonald JS, Kallmes DF, et al. Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without intracranial abnormalities. Radiology 2017; 285; 546 – 554.
  15. McDonald RJ, Levine D, Weinreb J, Kanal E, Davenport MS, Ellis JH, et al. Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology 2018; 289: 517-534.
  16. Murata N, Gonzalez-Cuyar LF, Murata K, et al. Macrocyclic and other non-group 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue: preliminary results from 9 patients with normal renal function. Invest Radiol 2016; 51: 447 – 453
  17. Quattrocchi CC_1, Mallio CA, Errante Y, Beomonte Zobel B. High T1 signal intensity in dentate nucleus after multiple injections of linear gadolinium chelates. Radiology 2015; 276: 616 – 617.
  18. Quattrocchi CC_2, Mallio CA, Errante Y et al. Gadodiamide and dentate nucleus T1 hyperintensity in patients with meningioma evaluated by multiple follow-up contrast-enhanced magnetic resonance examinations with no systemic interval therapy. Invest Radiol 2015; 50: 470 – 472.
  19. Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015; 275: 783 – 791.
  20. Radbruch A, Haase R, Kieslich PJ, et al. No signal intensity increase in the dentate nucleus on unenhanced T1-weigthed MR images after more than 20 serial injections of macrocyclic gadolinium-based contrast agents. Radiology 2017; 282: 699 – 707.
  21. Ramalho J, Castillo M, AlOaidy M, et al. High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology 2015; 276: 836 – 844.
  22. Rossi Espagnet MR, Bernardi B, Pasquini L, Figa-Talamanca L, Toma P, Napolitano A. Signal intensity at unenhanced T1-weigthed magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children. Pediatr Radiol 2017; 47: 1345 – 1352.
  23. Sanyal S, Marckmann P, Scherer S, Abraham JL. Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis: an autopsy-based review. Nephrol Dail Transplant 2011; 26: 3616 – 3626.
  24. Semelka RC, Ramalho J, Vakharia A, et al. Gadolinium deposition disease: initial description of a disease that has been around for a while. Magn Reson Imaging 2016; 34: 1383 – 1390.
  25. Splendiani A, Perri M, Marsecano C, et al. Effects of serial macrocyclic-based contrast materials gadoterate meglumine and gadobutrol administration on gadolinium-related dentate nuclei signal increases on unenhanced T1-weigthed brain: a retrospective study in 158 multiple sclerosis (MS) patients. Radiol Med 2018; 123: 125 – 134.
  26. Stojanov DA, Aracki-Trenkic A, Vojinovic S, Benedeto-Stojanov D, Ljubisavljevic S. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol. Eur Radiol 2016; 26: 807 – 815.
  27. Tibussek D, Rademacher C, Caspers J, et al. Gadolinium brian deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology 2017; 285: 223 – 230.

Evidence tabellen

Table of Excluded studies after reading full text

Author and year

Reason for exclusion

Abraham, 2008

Does not meet selection criteria.

Aruyani 2018

Does not meet selection criteria.

Adin, 2018

Does not meet selection criteria.

Arsenault, 1996

Does not meet selection criteria.

Bae, 2017

Does not meet selection criteria.

Behzadi, 2018

Does not meet selection criteria.

Bhargava, 2018

Does not meet selection criteria.

Bjornerund, 2017

Does not meet selection criteria.

Bolles, 2018

Does not meet selection criteria.

Boyken, 2018

Does not meet selection criteria.

Cao, 2016

Does not meet selection criteria.

Cao, 2016_1

Does not meet selection criteria.

Conte, 2017

Does not meet selection criteria.

Costa, 2018

Not an original article.

Costa, 2018_1

Does not meet selection criteria.

DiGregorio 2018

Does not meet selection criteria.

Errante, 2014

Does not meet selection criteria.

Fingerhut, 2018

Does not meet selection criteria.

Fingerhut, 2018_1

Does not meet selection criteria.

Flood 2017

Does not meet selection criteria.

Frenzel, 2017

Does not meet selection criteria

Frettelier, 2018

Does not meet selection criteria.

Guo, 2018

Does not meet selection criteria.

Hinoda, 2017

Does not meet selection criteria.

Hu, 2016

Does not meet selection criteria.

Huckle, 2016

Not an original article, narrative review.

Ichiwana, 2017

Does not meet selection criteria.

Idee, 2018

Does not meet selection criteria.

Idee, 2018_1

Does not meet selection criteria.

Jaulant, 2018

Does not meet selection criteria.

Jost, 2016

Does not meet selection criteria.

Kahn, 2017

Does not meet selection criteria.

Kanda, 2014

Does not meet selection criteria.

Kanda, 2015

Does not meet selection criteria.

Kang, 2018

Does not meet selection criteria.

Kang, 2018_1

Does not meet selection criteria.

Kasper, 2018

Does not meet selection criteria.

Khant, 2017

Does not meet selection criteria.

Kim, 2018

Does not meet selection criteria.

Kinner, 2018

Does not meet selection criteria.

Kralik, 2018

Does not meet selection criteria.

Kromrey, 2017

Does not meet selection criteria.

Kuno, 2017

Does not meet selection criteria.

Langer, 2017

Does not meet selection criteria.

Lee 2017

Does not meet selection criteria.

Lohrke, 2017

Does not meet selection criteria.

Lord, 2018

Does not meet selection criteria.

Malhotra, 2018

Does not meet selection criteria.

Maria, 2018

Does not meet selection criteria.

McDonald, 2018

Does not meet selection criteria.

McDonald, 2017

Does not meet selection criteria.

McDonald, 2017

Does not meet selection criteria.

Moser, 2018

Does not meet selection criteria.

Murata, 2016

Does not meet selection criteria.

Olchowy, 2017

Does not meet selection criteria, no comparative studies included in review.

Ozturk, 2018

Does not meet selection criteria.

Pasquini, 2018

Does not meet selection criteria.

Perrotta, 2017

Does not meet selection criteria.

Pinter, 2016

Does not meet selection criteria

Pulcino, 2018

Does not meet selection criteria.

Quattrocchi, 2018

Does not meet selection criteria.

Quattrocchi, 2015

Does not meet selection criteria.

Radbruch, 2018

Does not meet selection criteria.

Radbruch, 2017

Does not meet selection criteria.

Radbruch 2017_1

Does not meet selection criteria.

Radbruch, 2015

Does not meet selection criteria.

Radbruch, 2015

Does not meet selection criteria.

Ramalho, 2017

Does not meet selection criteria.

Ramalho, 2016

Does not meet selection criteria.

Ramalho, 2016_1

Does not meet selection criteria.

Ramalho 2016_2

Does not meet selection criteria.

Ramalho, 2015

Does not meet selection criteria.

Rasschaert, 2018

Does not meet selection criteria.

Raynaldo, 2018

Does not meet selection criteria.

Renz, 2018

Does not meet selection criteria.

Roberts, 2017

Does not meet selection criteria.

Roberts, 2017_1

Does not meet selection criteria.

Rossi, 2017

Does not meet selection criteria.

Runge 2017

Does not meet selection criteria.

Ryo, 2018

Does not meet selection criteria.

Schlemm, 2017

Does not meet selection criteria.

Schneider, 2016

Does not meet selection criteria

Splendiani, 2018

Does not meet selection criteria.

Swaminathan, 2016

Does not meet selection criteria.

Tamrazi, 2018

Does not meet selection criteria.

Tamrazi, 2018_1

Does not meet selection criteria.

Taoka, 2018

Does not meet selection criteria.

Taoka, 2018_1

Does not meet selection criteria..

Tedeschi, 2018

Does not meet selection criteria.

Tedeschi 2018_1

Does not meet selection criteria.

Thomsen, 2016

Does not meet selection criteria.

Tibussek, 2017

Does not meet selection criteria.

Weberling, 2015

Does not meet selection criteria.

Xia, 2014

Does not meet selection criteria.

Yoo, 2018

Does not meet selection criteria.

Young, 2017

Does not meet selection criteria.

Young, 2018

Does not meet selection criteria, patient population consists of children.

Young, 2018_1

Does not meet selection criteria.

Zhang, 2017

Does not meet selection criteria.

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.

 

Module[1]

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]

GBCA deposition

NVvR

2019

2021

2 years*

NVvR

New information on GBCA deposition

*Note: This topic will be covered in more detail in Safe Use of Contrast Media, part 3.


[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

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.

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