Analytische interferentie van contrastmiddelen met klinische laboratoriumtesten
Uitgangsvraag
Hoe kunnen contrastmiddelen (CM) interferentie geven op vaak toegepaste laboratorium testen?
- Interferentie door jodiumhoudende CM
- Interferentie door gadoliniumhoudende CM
Aanbeveling
Bloedanalyse
Wees bewust dat een potentiële interferentie van CM op laboratoriumtesten bestaat, en dat dit cruciaal is om onnodige work-up van patiënten te voorkomen.
Zoals bij alle laboratoriumtesten moeten de resultaten worden geïnterpreteerd in relatie tot de medische geschiedenis en het klinische onderzoek van de patiënt.
Consulteer de laboratoriumarts wanneer er discrepanties zijn tussen de klinische presentatie en de uitslagen van laboratoriumtesten.
Voer bloedonderzoeken uit voordat toediening van CM plaatsvindt of stel bloedonderzoek uit voor niet-spoedeisende klinische laboratoriumtesten voor een periode van*:
- Tenminste 4 uur en optimaal 12 uur na toediening van CM bij patiënten met een normale nierfunctie (eGFR > 60 mL/min/1.73 m2)
- Tenminste 16 uur en optimaal 48 uur na toediening van CM bij patiënten met een gereduceerde nierfunctie (eGFR 30-60 mL/min/1.73 m2)
- Tenminste 60 uur en optimaal 168 uur na toediening van CM bij patiënten met een ernstig gereduceerde nierfunctie (eGFR < 30 mL/min/1.73 m2)
*Zie ook 10.1 Meerdere onderzoeken met contrastmiddelen bij patiënten met normale of gereduceerde nierfunctie
Urine-analyse
Voer urineonderzoek uit voordat toediening van CM plaatsvindt of stel urineonderzoek uit voor niet-spoedeisende klinische laboratoriumtesten voor een periode van**:
- Tenminste 24 uur na toediening van CM bij patiënten met een normale nierfunctie (eGFR > 60 mL/min/1.73 m2)
- Tenminste 48 uur na toediening van CM bij patiënten met een gereduceerde nierfunctie (eGFR 30-60 mL/min/1.73 m2)
- Tenminste 168 uur na toediening van CM bij patiënten met een ernstig gereduceerde nierfunctie (eGFR < 30 mL/min/1.73 m2)
** Criteria zijn gebaseerd op bijna complete eliminatie van CM
Overwegingen
1. Iodine-based contrast media interference with laboratory tests
The effect of iodine-based contrast media (ICM) on clinical assays has not been systematically studied extensively. Depending on method and ICM used, interference may be clinically relevant (Morcos, 2005). M-protein analysis is paramount in the diagnosis and monitoring of monoclonal gammopathy (Dimopoulos, 2021). Several studies report interference of ICM on the spectrophotometric detection of monoclonal protein analysis by capillary zone electrophoresis with spectrophotometric detection (CZE-UV) (Quirós, 2018). ICM absorb UV-light at a similar wavelength as the peptide bonds in m-proteins, thereby mimicking the presence of (M-)proteins in the commonly used CZE analysis with UV detection. In contrast, Capaldo and co-workers (Capaldo, 2021) demonstrated that the opposite may also occur, i.e., masking an M-protein peak. In the M-protein analysis by CZE- UV, a duplication in the beta-2 fraction which was at first assigned to ICM (iomeprol) interference and the beta-1 fraction did not display any M-protein peak. Further analysis demonstrated that the iomeprol peak should appear in the beta-1-fraction and not in the beta-2-fraction. After 6 days, a new urine sample demonstrated a m-protein in the beta-1- fraction, which was masked by the iomeprol interference.
Otnes and co-workers investigated in vitro the analytical interference of two specific ICM, iodixanol and iomeprol (Otnes, 2017). They reported in the high, but clinically relevant, concentration range of the ICMs, either a positive bias (colorimetric calcium assay) or a negative bias, i.e., colorimetric iron, magnesium, and zinc assay as well as in the direct potentiometric sodium assay. Other assays did not show any interference with both ICMs. In another study, Lin and co-workers (Lin, 2006) investigated the interference of ICM on two cardiac Troponin I immunoassays (Opus Magnum (Behring Diagnostics) and the Access (Beckman Coulter, Inc)) in patients undergoing coronary angiography. In two in-vivo and two in-vitro experiments, they demonstrated a clinically relevant interference of the ICM on the cardiac levels on the Opus system, especially in the samples obtained directly after the coronary angiography procedure. The interference was absent in the sample after 30 minutes from patients with normal kidney function and lasted longer than 30 min in patients with reduced kidney function. In contrast the Access did not show any interference in the in vivo experiments. In the same study, in vitro experiments of 12 different ICMs showed a similar interference on the Opus system for all ICMs and only one (Lipiodol) on the Access system. A similar interference by iohexol on endocrine immunoassays was observed by Loh and co-workers in in-vitro experiments (Loh, 2013). They reported that soon after contrast administration iohexol may affect follicle stimulating hormone (FSH), luteinizing hormone (LH), plasma renin activity (PRA) and thyrotropin (TSH) measurements by different manufacturers. The interference on immunoassays may be explained by either the presence of an unidentified antigenic site on the contrast medium molecule blocking or cross-reacting with antibodies, dilutional effects due to the high osmolar aspects of iohexol and/or, as described before, due to spectrophotometric aspects of the ICM, interfering with UV- detection.
Next to the photometric aspects of ICM, the higher refractive index of the ICMs interference may occur in urinary analysis, e.g., specific gravity measurement (Glasson, 2012; Oyaert, 2021; Strassinger, 2008).
Besides interference on laboratory testing, sample integrity and quality may be impacted (Lippi, 2014). Since, due to the presence of ICM in the blood, the density of blood is altered, thereby potentially influencing gel cell separator characteristics resulting in incorrect plasma or serum collection (Daves, 2012; Kaleta, 2012; Spiritus, 2003).
Table 10.2.1 shows commonly demonstrated ICM interference on clinical laboratory tests. Unfortunately, there are not many systematic studies addressing CM interference on clinical laboratory tests and recommendations (Stacul, 2018) rely mainly on CM elimination. ESUR for instance recommends performing blood and urine clinical tests prior to administration of the GBCA, to circumvent interference and incorrect assessment of the patient. Post-imaging non-emergency blood and urine analysis should be delayed until the CM concentration in blood and/or urine is not present anymore. In emergency testing, blood and urine analysis can be performed, though clinicians and laboratory specialists should be aware of potential interference of CM. As is with all laboratory tests, the results should be interpreted in
relationship with the patient’s medical history and clinical examination.
Table 10.2.1 Clinical and/or analytical significant analyte interference of specific ICMs
Iodine-based Contrast Media |
||||
Analyte |
Method/technique |
Name ICM |
Observed Interference (bias) |
Reference |
Albumin |
Colorimetric assay |
Iodixanol |
↑ |
Otnes, 2017 |
Aldosterone |
Radioimmunoassay with I125-tracer |
Iohexol |
↓ |
Loh, 2013 |
Bicarbonate |
Enzymatic assay |
Iomeprol, iodixanol |
↓ |
Otnes, 2017 |
Calcium |
Colorimetric assay |
Iomeprol, iodixanol |
↑ |
Otnes, 2017 |
Chloride |
Ion selective electrode |
Iohexol |
↓ |
Sankaran, 2019 |
Cortisol |
Immunoassay with spectrophotometric detection |
Iohexol |
↑ |
Loh, 2013 |
C-peptide |
Immunoassay with spectrophotometric detection |
Iohexol |
↓ |
Loh, 2013 |
Erythrocytes in urine |
Fluorescence flow cytometry |
Iomeprol |
↑ |
Oyaert, 2021 |
Follicle Stimulating Hormone |
Immunoassay with spectrophotometric detection |
Iohexol |
↓ |
Loh, 2013 |
Insulin |
Immunoassay with spectrophotometric detection |
Iohexol |
↓ |
Loh, 2013 |
Iron |
Colorimetric assay |
Iodixanol |
↑ |
Otnes, 2017 |
LDH |
Enzymatic assay |
Iodixanol |
↓ |
Otnes, 2017 |
Leukocytes in urine |
Fluorescence flow cytometry |
Iomeprol |
↑ |
Oyaert, 2021 |
Luteinizing Hormone |
Immunoassay with spectrophotometric detection |
Iohexol |
↓ |
Loh, 2013 |
Magnesium |
Colorimetric assay |
Iomeprol |
↓ |
Otnes, 2017 |
M-proteins |
CZE-UV |
Iomeprol, iohexol, meglumine iotroxate, sodium meglumine amidotrizoate, Ioversol, Iopromide, Iobitridol, Iopamidol, Ioxitalamic acid, Ioversol |
↑, ↓ |
Arranz-Pena, 2004; Capaldo, 2021; Vermeersch, 2006; |
Potassium |
Potentiometric assay |
Iodixanol, Iomeprol |
↑ |
Otnes, 2017 |
Renin activity |
Radioimmunoassay with I125-tracer |
Iohexol |
↓ |
Loh, 2013 |
Sodium |
Potentiometric assay, Ion selective electrode |
Iometrol, iodixanol, iohexol |
↓ |
Otnes, 2017; Sankaran, 2019 |
Specific gravity in urine |
Refractometry |
Iomeprol, iohexol, iodixanol |
↑ |
Giasson, 2012; Oyaert, 2021 |
Thyroid Stimulating Hormone |
Immunoassay with spectrophotometric detection |
Iohexol |
↓ |
Loh, 2013 |
Troponin I |
Immuno-enzymatic assay |
11 ICMs, a.o. Iopromide, ioversol, iohexol |
↑ |
Lin, 2006 |
Zinc |
Colorimetric assay |
Iodixanol |
↓ |
Otnes, 2017 |
N.B. Interference may be manufacturer/analyser specific. For detailed information see references.
2. Gadolinium-based contrast agent interference with laboratory tests
Since the introduction of gadolinium-based contrast agents (GBCA) in 1983, these contrast agents have been used extensively. Several interferences on laboratory tests have been described, ranging from commonly used laboratory tests (Lippi, 2014) to more specialized laboratory tests (Day, 2019). One of the most reported clinically relevant interferences is the interference of GBCAs, especially gadodiamide (Normann, 1995; Prince, 2003; Prince, 2004; Zhang, 2006) and gadoversetamide (Lin, 1999) on serum calcium measurement by specific colorimetric methods, irrespective of the molecular configuration of the CA (i.e., linear or cyclic and ionic or non-ionic) (Prince, 2003). Depending on the colorimetric method used the potential bias could be either absent, positive, or negative. In principle, other methods to measure calcium, e.g., Inductively Coupled plasma Mass Spectrometry (ICP-MS) does not demonstrate clinically relevant interference.
In an in-vitro study Proctor and co-workers (Proctor, 2004) investigated the analytical interference of four GBCAs on multiple analytes and multiple analysers. They demonstrated that depending on the specific GBCA a positive and negative analytical interference is observed, which is most prominent in Angiotensin Converting Enzyme (ACE), calcium, iron, total iron binding capacity (TIBC), magnesium and zinc. Mechanistically, all the affected analytes are either endogenous divalent cations or somehow use divalent cations in the reaction of the laboratory test. Gd3+ can interact with the analyte of interest (e.g., transmetallation), thereby potentially interrupting the analytical process or in colorimetric assays by binding with the chromophore (Yan, 2014). In an in-vitro experiment, Otnes and co-workers demonstrated a similar interference by the GBCAs gadoxetate disodium, gadoterate meglumine, and gadobutrol on iron and zinc (negative bias) assays. Other 29 clinical tests did not display any clinically relevant interference by these GBCAs (Otnes, 2017).
In the field of trace elements and heavy metals, ICP-MS is the golden standard. Gd3+ may interfere also with this technique in multiple ways, i.e., space-charge effects, interference in the mass spectrometry analysis by double charged ions and polyatomic interference (Day, 2019). The latter can be circumvented by applying the correct analytical technique. In the study, Day and co-workers shared their experience with the clinical impact of GBCA interference in their clinical metal’s laboratory. Especially in the analysis of selenium by ICP- MS is complicated by the presence of 156Gd which may be doubly charged in the ionization process and therefore has a similar m/z ratio. Moreover, the presence of excess of Gd ions may interfere with the ionization process, suppressing ions of analytes, e.g., trace elements or (toxic) heavy metals and internal standards used.
It is worth noting that many studies report interference of gadodiamide and gadoversetamide on calcium assays but these GBCAs no longer available on the European market.
Table 10.2.2 shows commonly described GBCA interference on clinical laboratory tests. Assay interference by GBCAs can be contrast agent specific, analyte specific and method specific.
Table 10.2.2 Clinical and/or analytical significant analyte interference of specific GBCA.
Gadolinium Based Contrast Agents |
||||
Analyte |
Method/technique |
Name GBCA |
Observed interference (bias) |
Reference |
ACE |
Colorimetric enzymatic reaction |
Gadodiamide, gadoversetamide |
↓ |
Proctor, 2004 |
Calcium |
Several colorimetric assays |
Gadodiamide, gadoversetamide |
↓ |
Proctor, 2004; Yan, 2014 |
Iron |
Colorimetric assay |
Gadodiamide, gadoversetamide, gadopentetate dimeglumine, gadoxetate disodium |
↓,↑ |
Otnes, 2017; Proctor, 2004 |
Magnesium |
|
Gadodiamide, gadoversetamide |
↓,↑ |
Proctor, 2004 |
Selenium |
ICP-MS |
Not specified |
↑ |
Harrington, 2014; Ryan, 2014 |
TIBC |
Colorimetric assay |
Gadodiamide, gadoversetamide |
↑ |
Proctor, 2004 |
Troponin I |
Immuno-enzymatic assay |
Gadopentetate dimeglumine |
↑ |
Lin, 2006 |
Zinc |
Colorimetric assay |
Gadodiamide, gadoversetamide, gadopentetate dimeglumine, gadoteridol, gadoxetate disodium |
↓ |
Otnes, 2017; Proctor, 2004 |
N.B. Interference may be manufacturer/analyser specific. For detailed information see references. Note: Gadodiamide and gadoversetamide are currently not on the market in the EU.
Recommendations
Recommendations are similar to the recommendations in the ESUR guideline version 10.0 (ESUR, 2018; Morcos, 2005) and based on pharmacokinetics and elimination recommendations in Chapter 10.1 Safe time intervals between contrast-enhanced studies.
Blood Analysis
Be aware that the potential interference of contrast media on laboratory tests is crucial to prevent adverse patient work-up. As with all laboratory tests, the results should be interpreted in relationship with the patient’s medical history and clinical examination.
Consult the laboratory specialist if there are any discrepancies between clinical presentation and laboratory tests. |
Perform clinical laboratory testing prior to administrating contrast media or delay blood collection for non-emergency clinical laboratory testing* for:
|
Urine Analysis
Perform urine clinical laboratory tests prior to contrast media administration. Another option is to delay urine collection for at least**:
|
Onderbouwing
Achtergrond
Radiological imaging with (or without) contrast media (CM) and laboratory tests are commonly used complimentary tools in the diagnosis and monitoring of patients. In terms of efficient patient work-up, these tools are often planned together. Though most clinicians are not aware, several studies have reported interference of iodine-based contrast media (ICM) and gadolinium-based contrast agents (GBCA) with several clinical laboratory tests.
Awareness of these interferences is important since they may pose a potential threat by misdiagnosing and/or incorrect monitoring of patients, denying or delaying their treatment or initiating/continuing undesirable treatment (Doorenbos, 2003). These clinically relevant interferences are specific for the contrast media administered as well as for the specific technique/method used for the analysis of the biomarker (Otnes, 2017).
N.B. (Patho)physiological responses of the body, represented by specific biomarkers, e.g., thyroid function (Bednarczuk, 2021), coagulation status (Aspelin, 2006; Lukasiewicz, 2012), due to the administration of contrast agents are outside of the scope of this chapter.
Referenties
- Arranz-Pena ML, Gonzalez-Sagrado M, Olmos-Linares AM, Fernandez-Garcia N, Martin-Gil FJ. Interference of iodinated contrast media in serum capillary zone electrophoresis. Clin Chem 2000; 46: 736-737.
- Aspelin P, Stacul F, Thomsen HS, Morcos SK, van der Molen AJ, Members of the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR). Effects of iodinated contrast media on blood and endothelium. Eur Radiol 2006; 16(5): 1041-1049.
- Bednarczuk T, Brix TH, Schima W, Zettinig G, Kahaly G. 2021 European Thyroid Association guidelines for the management of iodine-based contrast media-induced thyroid dysfunction. Eur Thyroid J. 2021; 10(4): 269-284.
- Capaldo C, El Aouni MC, Laurelli D, Leven C, Carré JL. Detection of monoclonal protein by capillary zone electrophoresis can be challenged by iodinated contrast agent interference: a case report. Biochem Med (Zagreb) 2021; 31(2): 021001.
- Daves M, Lippi G, Cosio G, Raffagnini A, Peer E, Dangella A, et al., An unusual case of a primary blood collection tube with floating separator gel. J Clin Lab Anal. 2012; 26(4): 246-247.
- Day P, Erdahl S, Eckdahl S, Bornhorst J, Jannetto PJ. Gadolinium-based contrast agents: A clinically significant analytical interference in inductively coupled plasma mass spectrometry elemental analysis. Ann Clin Biochem. 2019; 56(6): 638-645.
- Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow- up. Ann Oncol 2021; 32(3): 309-322.
- Doorenbos CJ, Ozyilmaz A, van Wijnen M. Severe pseudohypocalcemia after gadolinium- enhanced magnetic resonance angiography. N Engl J Med 2003; 349(8): 817-818.
- European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10, 2018. Available at: [URL] Accessed: 1 April 2022.
- Giasson J, Chen Y. A discrepant urine specific gravity. Clin Chem 2012; 58(4): 797.
- Harrington CF, Walter A, Nelms S, Taylor A. Removal of the gadolinium interference from the measurement of selenium in human serum by use of collision cell quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS). Ann Clin Biochem 2014; 51(Pt 3): 386-391.
- Kaleta EJ, Jaffe AS, Baumann NA, Block DR. A case of floating gel. Clin Chem 2012; 58(11): 1604-1605.
- Lin J, Idee JM, Port M, Diai A, Berthommier C, Robert M, et al. Interference of magnetic resonance imaging contrast agents with the serum calcium measurement technique using colorimetric reagents. J Pharm Biomed Anal 1999; 21(5): 931-943.
- Lin CT, Lee HC, Voon WC, Yen HW, Tang MH, Chin TT, et al. Positive interference from contrast media in cardiac troponin I immunoassays. Kaohsiung J Med Sci 2006; 22(3): 107-113.
- Lippi G, Daves M, Mattiuzzi C. Interference of medical contrast media on laboratory testing. Biochem Med (Zagreb) 2014; 24(1): 80-88.
- Loh TP, Mok SF, Ang BW, Chuah TY, Sethi SK. Non-ionic radiologic contrast (iohexol) interferes with laboratory measurements of endocrine hormones. Pathology 2013; 45(5): 527-529.
- Lukasiewicz A, Lebkowska U, Galar M. Effect of iodinated low-osmolar contrast media on the hemostatic system after intraarterial and intravenous contrast administration. Adv Med Sci 2012; 57(2): 341-347.
- Morcos SK, Thomsen HS, Exley CM; Members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). Contrast media: interactions with other drugs and clinical tests. Eur Radiol 2005; 15(7): 1463-1468.
- Normann PT, Froysa A, Svaland M. Interference of gadodiamide injection (Omniscan) on the colorimetric determination of serum calcium. Scan J Clin Lab Invest 1995; 55(5): 421- 426.
- Otnes S, Fogh-Andersen N, Rømsing J, Thomsen HS. Analytical interference by contrast agents in biochemical assays. Contrast Media Mol Imaging 2017; 2017: 1323802.
- Oyaert MN, De Buyzere ML, Verstraete KL, Speeckaert MM, Delanghe JR. Iodine containing contrast media and urinary flow cytometry: an unknown interference in automated urine sediment analysis. Clin Chem Lab Med 2021; 59(8): e335-e337.
- Prince MR, Erel HE, Lent RW, Blumenfeld J, Kent KC, Bush HL, et al. Gadodiamide administration causes spurious hypocalcemia. Radiology 2003; 227(3): 639-646
- Prince MR, Choyke PL, Knopp MV. More on pseudohypocalcemia and gadolinium-enhanced MRI. N Engl J Med 2004; 350(1): 87-88.
- Proctor KA, Rao LV, Roberts WL. Gadolinium magnetic resonance contrast agents produce analytic interference in multiple serum assays. Am J Clin Pathol 2004; 121(2): 282-292.
- Quirós C, Cillero AI, Bretaña L, García M, Prieto B, Álvarez FV. In vivo interference of Ioversol in serum and urine capillary electrophoresis: an optimized protocol for sample collection. Clin Chem Lab Med 2018; 26;56(2): e53-e55.
- Ryan JB, Grant S, Walmsley T, Florkowski CM, George PM. Falsely elevated plasma selenium due to gadolinium contrast interference: a novel solution to a preanalytical problem. Ann Clin Biochem 2014; 51(6): 714-716.
- Sankaran S, Saharia GK, Naik S, Mangaraj M. Effect of iodinated contrast media on serum electrolyte concentrations in patients undergoing routine contrast computed tomography scan procedure. Int J Appl Basic Med Res 2019; 9(4): 217-220.
- Stacul F, Bertolotto M, Thomsen HS, Pozzato G, Ugolini D, Bellin MF, et al. ESUR Contrast Media Safety Committee. Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines. Eur Radiol 2018; 28(2): 683-691.
- Strasinger SK, Di Lorenzo MS. Urinalysis and body fluids. 5th ed. Philadelphia: F.A. Davis, 2008.
- Spiritus T, Zaman Z, Desmet W. Iodinated contrast media interfere with gel barrier formation in plasma and serum separator tubes. Clin Chem 2003; 49(7): 1187-1189.
- Vermeersch P, Mariën G, Bossuyt X. Pseudoparaproteinemia related to iomeprol administration after angiocardiography: Detection in the beta fraction by capillary zone electrophoresis. Clin Chem 2006; 52(12): 2312–2313.
- Yan R, Tarr H, McNally M, Cartier LJ, Chen Y. Interference of gadolinium-based contrast agents on colorimetric calcium assays. Clin Biochem 2014; 47(7-8): 648-653.
- Zhang HL, Ersoy H, Prince MR. Effects of gadopentetate dimeglumine and gadodiamide on serum calcium, magnesium, and creatinine measurements. J Magn Reson Imaging 2006; 23(3): 383-387.
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 28-11-2022
Laatst geautoriseerd : 28-11-2022
Geplande herbeoordeling : 01-12-2023
Validity
The Radiological Society of the Netherlands (NVvR) will determine around 2027 if this guideline (per module) is still valid and applicable. If necessary, the scientific societies will form a new guideline group 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 a reason to commence revisions. The Radiological Society of the Netherlands is the owner of this guideline and thus primarily responsible for the actuality of the guideline. 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.
Algemene gegevens
General Information
The Kennisinstituut van de Federatie Medisch Specialisten (www.kennisinstituut.nl) assisted the guideline development group. The guideline was financed by Stichting Kwaliteitsgelden Medisch Specialisten (SKMS) which is a quality fund for medical specialists in The Netherlands.
Samenstelling werkgroep
Guideline development group (GDG)
A multidisciplinary guideline development group (GDG) was formed for the development of the guideline in 2020. The GDG consisted of representatives from all relevant medical specialization fields which were using intravascular contrast administration in their field.
All GDG members have been officially delegated for participation in the GDG by their scientific societies. The GDG has developed a guideline in the period from June 2020 until November 2022. The GDG is responsible for the complete text of this guideline.
Guideline development group
- Dekkers I.A. (Ilona), clinical epidemiologist and radiologist, Leiden University Medical Center, Leiden
- Geenen R.W.F. (Remy), radiologist, Noordwest Ziekenhuisgroep, Alkmaar
- Kerstens M.N. (Michiel), internist-endocrinologist, University Medical Centre Groningen
- Krabbe J.G. (Hans), clinical chemist-endocrinologist, Medisch Spectrum Twente, Enschede
- Rossius M.J.P. (Mariska), radiologist, Erasmus Medical Centre, Rotterdam
- Uyttenboogaart M. (Maarten), neurologist and neuro-interventionalist, University Medical Centre Groningen
- van de Luijtgaarden K.M. (Koen), vascular surgeon, Maasstad Ziekenhuis, Rotterdam
- van der Molen A.J. (Aart), chair guideline development group, radiologist, Leiden University Medical Center, Leiden
- van der Wolk S.L. (Sabine), gynaecologist-obstetrician, Haga Ziekenhuis, Den Haag
- van de Ven A.A.J.M. (Annick), internist-allergologist-immunologist, University Medical Centre Groningen (until 1.7.2022)
- van der Houwen, T.B. (Tim), internist-allergologist-immunologist, Amsterdam University Medical Center (from 1.7.2022)
Invited experts
- van Maaren M.S. (Maurits), internist-allergologist-immunologist, Erasmus MC, Rotterdam
Belangenverklaringen
Conflicts of interest
The GDG members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that were 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 from the administrative office of Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl) and were summarised below.
Last name |
Function |
Other positions |
Personal financial interests |
Personal relations |
Reputation management |
Externally financed research |
Knowledge valorisation |
Other interests |
Signed |
Actions |
Dekkers IA |
Radiologist, LUMC |
Clinical Epidemiologist
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)
Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no payment) |
No |
No |
No |
No |
No |
Received consultancy fees from Guerbet, 2019- 2022 |
July 24th, 2020, Reaffirmed October 12th, 2022 |
No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention specific medication, not of working mechanism, nor of side effects. |
Geenen RWF |
Radiologist, Noordwest ziekenhuisgroep /Medisch specialisten Noordwest |
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment) |
No |
No |
No |
No |
No |
No |
April 11th, 2020, Reaffirmed October 12th, 2022 |
No restrictions |
Houwen T, van der |
Internist - Immunologist - Allergologist, Amsterdam UMC, also seconded allergologist in Huid Medisch Centrum |
None |
None |
None |
None |
None |
None |
None |
July 11th, 2022 Reaffirmed October 12th, 2022 |
No restrictions |
Kerstens MN |
Internist- endocrinologist, UMCG |
Chairman Bijniernet (no payment) |
No |
No |
No |
No |
No |
No |
July 1st, 2020, reaffirmed October 25th, 2022 |
No restrictions |
Krabbe JG |
Clinical chemist, Medisch Spectrum Twente |
No |
No |
No |
No |
No |
No |
No |
September 1st, 2020, Reaffirmed October 13th, 2022 |
No restrictions |
Luijtgaarden KM, van de |
Vascular surgeon, Maasland Ziekenhuis |
No |
No |
No |
No |
No |
No |
No |
August 1st, 2020, reaffirmed October 26th, 2022 |
No restrictions |
Molen AJ, van der |
Radiologist LUMC |
Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)
Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no payment) |
No |
No |
No |
No |
No |
Received consultancy fees from Guerbet, 2019- 2022 |
July, 24th, 2020 Reaffirmed October 12th, 2022 |
No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention Specific medication, not of working mechanism, nor of side effects. |
Rossius MJP |
Radiologist Erasmus Medical Centre |
Medical coordinator (no payment) |
No |
No |
No |
No |
No |
No |
April 7th, 2020, Reaffirmed October 13th, 2022 |
No restrictions |
Uyttenboogaart M |
Neurologist and neuro- interventionalist UMCG |
Advisor International Federation of Orthopaedic Manipulative Physical Therapist / Nederlandse Vereniging Manuele Therapie |
No |
No |
Subsidy Hart Stichting for CONTRAST (Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology: financing of 2 PhD students by the Hart Stichting / PPS Allowance |
Work package leader CONTRAST (Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology |
No |
No |
June 30th, 2020, reaffirmed October 26th, 2022 |
No restrictions: the CONTRAST consortium wp8 is only about organisation and treatment of stroke. Stroke is not in this guideline. |
Ven AAJM, van de |
Internist- allergologist- immunologist, UMCG |
Education and research related to work as internist- allergist |
No |
No |
No |
No |
No |
No |
April 7th, 2020, Reaffirmed October 19th, 2022 |
No restrictions |
Wolk S, van der |
Gynaecologist- obstetrician, Haga Ziekenhuis |
No |
No |
No |
No |
No |
No |
No |
June 30th, 2021, reaffirmed October 25th, 2022 |
No restrictions |
Inbreng patiëntenperspectief
Input of patient’s perspective
The guideline does not address a specific adult patient group, but a diverse set of diagnoses. Therefore, it was decided to invite a broad spectrum of patient organisations for the stakeholder consultation. The stakeholder consultation was performed at the beginning of the process for feedbacking on the framework of subjects and clinical questions addressed in the guideline, and during the commentary phase to provide feedback on the concept guideline. The list of organisations which were invited for the stakeholder consultation can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). In addition, patient information on safe use of contrast media in pregnancy and lactation was developed for Thuisarts.nl, a platform to inform patients about health and disease.
Implementatie
Implementation
During different phases of guideline development, implementation and practical enforceability of the guideline were considered. 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 in the ‘Appendices to modules’. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found in the ‘Appendices to modules’.
Werkwijze
Methodology
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 (www.kwaliteitskoepel.nl). 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 based 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 GDG identified the relevant subject matter for the guideline. The framework is consisted of both new matters, which were not yet addressed in part 1 and 2 of the guideline, and an update of matters that were subject to modification (for example in case of new published literature). Furthermore, a stakeholder consultation was performed, where input on the framework was requested.
Clinical questions and outcomes
The outcome of the stakeholder consultation was discussed with the GDG, after which definitive clinical questions were formulated. Subsequently, the GDG formulated relevant outcome measures (both beneficial and harmful effects). The GDG rated the outcome measures as critical, important and of limited importance (GRADE method). Furthermore, where applicable, the GDG defined relevant clinical differences.
Search and select
For clinical questions, specific search strategies were formulated, and scientific articles published in several electronic databases were searched. First, the studies that potentially had the highest quality of research were reviewed. The GDG selected literature in pairs (independently of each other) based on the title and abstract. A second selection was performed by the methodological advisor based on full text. The databases used, selection criteria and number of included articles can be found in the modules, the search strategy in the appendix.
Quality assessment of individual studies
Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search. For systematic reviews, a combination of the AMSTAR checklist and PRISMA checklist was used. For RCTs the Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University were used, and for cohort studies/observational studies the risk of bias tool by the CLARITY Group at McMaster University was used. The risk of bias tables can be found in the separate document Appendices to modules.
Summary of literature
The relevant research findings of all selected articles were shown in evidence tables. The evidence tables can be found in the separate document Appendices to modules. The most important findings in literature were 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 included studies 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 levels for the quality of scientific evidence: high, moderate, low, or very low. These levels provide information about the certainty level of the literature conclusions (http://www.guidelinedevelopment.org/handbook).
The evidence was summarized in the literature analysis, followed by one or more conclusions, drawn from the body of evidence. The level of evidence for the conclusions can be found above the conclusions. Aspects such as expertise of GDG members, local expertise, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects are discussed in the paragraph justifications. The recommendations provide an answer to the clinical question or help to increase awareness and were based on the available scientific evidence and the most relevant justifications.
Appendices
Internal (meant for use by scientific society or its members) quality indicators were developed with the guideline and can be found in the separate document Appendices to modules. In most cases, indicators were not applicable. For most questions, additional scientific research on the subject is warranted. Therefore, the GDG formulated knowledge gaps to aid in future research, which can be found in the separate document Appendices to modules.
Commentary and authorisation phase
The concept guideline was subjected to commentaries by the involved scientific societies. The list of parties that participated in the commentary phase can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). The commentaries were collected and discussed with the GDG. The feedback was used to improve the guideline; afterwards the GDG made the guideline definitive. The final version of the guideline was offered to the involved scientific societies for authorization and was authorized.
Literature
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 Kwaliteit, 2012. Available at: [URL].
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: [URL].
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- 1110. Erratum published in: BMJ 2008;336(7654).
Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten, 2020.