Veilig gebruik van contrastmiddelen

Initiatief: NVvR Aantal modules: 48

Strategieën voor dosisreductie van GBCA


Op welke manier kan de dosis van gadoliniumhoudende contrastmiddelen worden geminimaliseerd zonder de diagnostische accuratesse te verminderen?


De volgende categorieën werden gedefinieerd:

  1. Potentiële dosisreductiestrategieën voor neurobeeldvorming met gadoliniumhoudend contrastmiddel
  2. Potentiële dosisreductiestrategieën voor cardiovasculaire beeldvorming met gadoliniumhoudend contrastmiddel
  3. Potentiële dosisreductiestrategieën voor musculoskeletale beeldvorming met gadoliniumhoudend contrastmiddel
  4. Potentiële dosisreductiestrategieën voor abdominale beeldvorming met gadoliniumhoudend contrastmiddel
  5. Potentiële dosisreductiestrategieën voor mammabeeldvorming met gadoliniumhoudend contrastmiddel


1. Potentiële dosisreductiestrategieën voor neurobeeldvorming met gadoliniumhoudend contrastmiddel


De resultaten van de LEADER-75 studie geven aan dat de dosis van gadoliniumhoudende contrastmiddelen (gadobutrol) kan worden gereduceerd tot 75% van de standaarddosering (0.075 mmol/kg lichaamsgewicht (equivalent aan 0.075 ml/kg lichaamsgewicht)) bij patiënten met verdenking op laesies in de hersenen.


Het gebruik van deep learning gebaseerde methoden voor dosisreductie van gadoliniumhoudende contrastmiddelen bij patiënten met verdenking op laesies in de hersenen kan op basis van de huidige literatuur niet worden aanbevolen.


2. Potentiële dosisreductiestrategieën voor cardiovasculaire beeldvorming met gadoliniumhoudend contrastmiddel


Beeldvorming met standaarddosering wordt aanbevolen bij patiënten met klinische indicaties voor de toediening van gadoliniumhoudende contrastmiddelen bij cardiale MRI.


MRA-technieken zonder contrastmiddel (v.b. time-of-flight MRA) zijn op grote schaal beschikbaar en kunnen worden gebruikt voor accurate evaluatie van de graad van stenose van de supra-aortale vaten.


ECG-gated MRA sequenties zijn op grote schaal beschikbaar en worden aanbevolen in plaats van lage dosis contrastmiddel-versterkte MRA technieken voor de evaluatie van aorta dimensies.


3. Potentiële dosisreductiestrategieën voor musculoskeletale beeldvorming met gadoliniumhoudend contrastmiddel


Beeldvorming met standaarddosering wordt aanbevolen bij patiënten met klinische indicaties voor de toediening van gadoliniumhoudende contrastmiddelen bij musculoskeletale MRI.


4. Potentiële dosisreductiestrategieën voor abdominale beeldvorming met gadoliniumhoudend contrastmiddel




Er is toenemend bewijs dat biparametrische protocollen (T2w + DWI) zouden kunnen worden gebruikt als alternatief voor multiparametrische (T2w + DWI + DCE) protocollen voor de detectie van prostaatkanker.




Beeldvorming met standaarddosering wordt aanbevolen bij patiënten met klinische indicaties voor de toediening van gadoliniumhoudende contrastmiddelen bij MRI van de lever.


5. Potentiële dosisreductiestrategieën voor mammabeeldvorming met gadoliniumhoudend contrastmiddel


Beeldvorming met standaarddosering wordt aanbevolen bij patiënten met klinische indicaties voor het toedienen van gadoliniumhoudende contrastmiddelen bij MRI van de mammae.


Narrative literature analysis


Gadolinium reduction strategies for neuroimaging


Most studies published on Gd reduction strategies are primarily focused on static contrast- enhanced (CE) T1-weighted (T1w) imaging. Several studies have compared the use of half- dose imaging (e.g., 0.05 mmol/kg body weight) to full dose (e.g., 0.1 mmol/kg body weight) imaging in neuro MRI protocols. Initial studies compared the diagnostic certainty of detecting brain metastasis for different doses of GBCA. These have shown that for spin-echo MR imaging high dose GBCA was an efficient way to improve the detection of brain metastases, in particular of small metastases (Åkeson, 1995). However, other studies in the same period showed that half dose imaging with magnetization transfer did not lead to significant differences in contrast enhancement for extra-axial tumours (e.g. meningiomas) upon visual inspection when compared with standard dose imaging (Haba, 2001; Han, 1998).


At 3.0 T half-dose imaging using gadopentetate has shown to yield in significantly higher contrast-to-noise ratio (1.3-fold higher) compared to full-dose imaging at 1.5 T (Krautmacher, 2005). However, it should be not that the older studies addressing half dose imaging such as the 1995 study by Åkeson used linear GBCA’s which are currently no longer on available on the European Market because of suspended marketing authorizations due to the potential risk of gadolinium retention in the human body (Åkeson, 1995). This also applies to the study by Khoury Chalouhi et al. which performed an intraindividual and interindividual comparison between 0.075 mmol/kg and 0.1 mmol/kg of gadoterate meglumine for cranial MRI because of the higher relaxivity of this GBCA agent (Khoury Chalouhi, 2014). Also two recent studies evaluated the use of half dose imaging of the high- relaxivity linear GBCA gadobenate dimeglumine decmonstrated that half dose compared to full dose imaging was non-inferior with regard to visual lesion delineation, internal morphology, and contrast enhancement at 1.5 T and 3.0 T (DeLano, 2021), and small or ring- enhancing metastases can be better visualized on half-dose gadobenate dimeglumine delayed CE T2 FLAIR for than on half dose CE-T1w brain MRI scans (Jin, 2021). It should be noted that the findings of studies on linear GBCA’s cannot be extrapolated to the macrocyclic GBCAs that are currently used in neuroimaging because of the restricted use within the EU.


With regard to macrocyclic agents, the literature on reduced contrast dose is still limited and mainly based on the recent findings of the LEADER-75 trial. The LEADER-75 trial is an international prospective multicentre open-label crossover study that evaluated the use of three-quarter dose high-relaxivity gadobutrol (0.075 mmol/kg) compared with standard- dose gadoterate (0.1 mmol/kg) in adults with known or suspected CNS pathology undergoing CE brain imaging at 1.5T and 3T (Liu, 2021). Efficacy analysis in 141 patients found that improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images. The authors used a 20% noninferiority margin for three primary efficacy measures using mean

readings (p ≤ 0.025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. The sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. No differences in mean reader confidence (3.3 ± 0.6 for both reduced-dose gadobutrol and standard-dose gadoterate) and reader preference were found (95% CI, -0.10 to 0.11). Albeit that the LEADER-75 trial is the first study to demonstrate convincing evidence for reduced dose imaging for macrocyclic GBCA in neuroimaging with out compromising reader confidence and reader preference, there are several knowledge gaps that remain. These include the potential influence of field strength, the potential differences in CE in CNS pathologies that were underrepresented in the LEADER-75 sample (e.g. 41% of the sample consisted of meningiomas and 24% of metastases), and influence of sequence design and acquisition.


In addition to static CE-T1W for brain imaging, reduced dose imaging has also been investigated for brain perfusion using dynamic susceptibility contrast (DSC). In DSC half dose imaging has shown to lead to a more accurate arterial input function (Filice, 2017) and CBV maps of comparable diagnostic quality as the corresponding images acquired with a full dose imaging (Crisi, 2017). However, in acute stroke half-dose DSC imaging was found to result in poor image quality in 40.7% of the cases receiving half-dose GBCA (0.1 ml/kg gadobenate dimeglumine body weight) vs. 6.3% of patients who received full GBCA dose (0.2 ml/kg gadobenate dimeglumine body weight), and may thus adversely affect stroke patient triage for thrombectomy (Heit, 2021). For DSC MRI in neuroimaging the field dependency remains to be investigated, and reduced dose imaging for this application remains controversial.


More recently, several recent studies have evaluated the clinical performance of deep learning (DL)–based methods for brain MRI reducing contrast dose up to 10-fold (Gong, 2021). However the missing enhancement in small lesions indicates the need for further improvements in DL based algorithms or dosage design (Ammari, 2022; Luo, 2021). To date, DL strategies to minimize the dosage of GBCAs in brain MRI are still in its infancy and additional studies on the (potential) loss of diagnostic information are warranted.


Beyond reducing GBCA dose, the omission of the need of GBCA-based sequences in MRI scan protocols is also widely studied, in particular for the follow-up of extra-axial brain masses. The majority of the studies have focused on vestibular schwannomas, including evaluation of the diagnostic accuracy of non-CE gradient-echo constructive interference in steady state (CISS) and coronal T2w imaging in the setting of screening (Abele, 2014). A recent meta-analysis evaluated non-CE imaging for diagnosis and monitoring of vestibular schwannomas (Kim, 2019). In this meta-analysis six studies evaluated measurement difference, five articles focused on diagnostic accuracy and eight studied adverse effects. The studies showed that a non-CE MRI scan protocol with T2w imaging is highly accurate and highly reliable for diagnosing and monitoring vestibular schwannoma in comparison with CE-T1w imaging. In addition to vestibular schwannomas, also for meningiomas it has been shown that dimensions measured on pre-contrast T2 have similar results compared to measurements on CE-T1w imaging (Rahatli, 2019). One study leaving out CE-sequences in MRI protocols in children (Marsault, 2019). This study investigated the use of non-CE MRI for the follow-up of optic pathway gliomas in children, suggesting that tumour volume variation may be sufficient to assess optic pathway glioma progression (Marsault, 2019).


In addition to extra-axial masses, another disease group in which comparative studies on non-CE versus CE MRI protocols have been evaluated is multiple sclerosis. For multiple sclerosis three studies have evaluated the use of MRI protocols using non-contrast sequences for the detection of new brain lesions on follow-up imaging (Eichinger, 2021). These studies indicate that considering the very low incidence rate of new enhancing lesions in patients with non-progressive disease on follow-up, the routine administration of contrast in follow-up MRI scans is of limited value and does not change the diagnosis interval of disease progression. Finally, one study was identified that compared the use of non-CE MRI protocols to protocols using GBCAs for stroke. This study evaluated non-CE MR venography compared to conventional CE-T1w imaging and 3D gradient echo CE-T1w imaging, demonstrating that unenhanced MR venography had slightly lower sensitivity, specificity and accuracy for detecting cortical venous and/or dural sinus thrombosis (Sari, 2015) compared to the contrast-enhanced protocols.


Gadolinium reduction strategies for cardiovascular imaging


Thoracic aorta


Sequence designs such state-state free pression (SSFP) that enable combining non-breath- hold acquisitions with cardiac gating and respiratory triggering are widely used for vascular imaging with high resolution and high contrast between blood in the aorta and coronaries compared to surrounding tissue (Amano, 2008; Deshpande, 2001; François, 2008; Krishnam, 2008). International joint-society guidelines in the field of cardiology, cardiothoracic surgery and imaging have stated that non-CE MRA and CE-MRA are both acceptable imaging studies to measure the aorta in patients with thoracic aorta disease and adults with congenital heart disease (Baumgartner, 2010; Hiratzka, 2016). Direct comparison between non-CE MRA to CE-MRA for the assessment of the dimensions of the thoracic aorta has been performed in several studies demonstrating that diagnostic image quality can be achieved without the need for Gadolinium (Bannas, 2013; Groth, 2012; Pennig, 2021; Veldhoen, 2017; Von Tengg-Kobligk, 2009).


Supra-aortic vasculature


Several studies have compared various non-CE MRA techniques for blood flow-related luminography, such as gradient-echo based time-of-flight (ToF), with CE-MRA for evaluating stenosis of the supra-aortic arteries. These studies show that non-CE MRA techniques are promising alternatives for stenosis grading, in particular for distinguishing surgically treatable internal carotid artery stenosis, without significantly compromising image quality or diagnostic accuracy (Babiarz, 2009; Lim, 2008; Liu, 2019; Peters, 2019; Zhang, 2020).


With regard to half dose imaging, half-dose (0.05 mmol/kg body weight) CE MRA and full- dose (0.1 mmol/kg body weight) CE-MRA have been evaluated with regard to SNR, CNR at both 1.5 T and 3T, demonstrating that dose-reduction of cervical CE-MRA is feasible at 3T without compromising angiographic quality with regard to stenosis evaluation (Dehkharghani, 2015). Low dose time-resolved CE-MRA has been evaluated compared to non-contrast ToF MRA and high-resolution CE-MRA, showing that time-resolved MRA has a good image quality and accurate stenosis grading compared to high-resolution CE-MRA and might be more useful than ToF-MRA (Lee YJ, 2015).


Two studies evaluated ultralow-dose Gd (2-3 mL) time-resolved MRA versus standard dose (0.1 mmol/kg) CE-MRA for the evaluation of supra-aortic arterial stenosis at 3T. These showed that image quality and diagnostic agreement for stenotic disease in ultralow dose time-resolved MRA scans using 2-3 mL were not inferior to standard dose CE-MRA (Bak, 2017; Lohan, 2009). However, Gd doses below 2 mL were considered limited in spatial resolution leading to a tendency of overestimating stenosis grade. Also for Gd doses as low as 0.047 mmol/kg MRA of the supra-aortic arteries can be performed at 3T, without compromising image quality, acquisition speed, or spatial resolution (Tomasian, 2008).

However, it should be noted that the imaging quality at local centres will depend on the local MRI physics expertise to implement non-CE MRA or ultra-low CE-MRA techniques.


Abdominal vasculature, peripheral arteries, and vascular malformations


For the abdominal aorta and pelvic vasculature only one study was identified that compared low dose (Takahashi, 2004) to standard dose CE MRA. Three studies have been published that evaluated hepatic vasculature using non-contrast MRA compared to CE sequences (Kumar, 2021; Luk, 2017; Puippe, 2012), indicating that CE-MRI is not superior in depicting hepatic anatomy.


Several comparative studies have been published that evaluated non-contrast MRA for the assessment of renal artery stenosis, in particular balances steady-state free precession MR angiography (b-SSFP MRA) has shown promise in diagnosing renal artery stenosis (Aydin, 2017; Braidy, 2012; Glockner, 2010; Khoo, 2011; Lal, 2021; Maki, 2007). Also the three- dimensional Fast Imaging Employing Steady-State Acquisition (3D-FIESTA) sequence has been compared to CE-MRA and digital subtraction angiography (Gaudiano, 2014), suggesting that also 3D FIESTA sequence could be a useful tool in evaluating RAS. Further studies are needed to evaluate whether non-contrast MRA can truly replace CE-MRA to determine the presence of significant renal artery stenosis. Five studies were identified that evaluated non- contrast MRA for the evaluation of peripheral arterial occlusive disease. Although some studies were promising with regard to potential of non-contrast MRA techniques (Hodnett, 2011; Knobloch, 2021; Thierfelder, 2014), also concerns were expressed with regard to the rate of non-diagnostic vessel segments being considerably higher for non-contrast MRA than for CE-MRA (Diop, 2013; Schubert, 2016).


A specific indication of vascular imaging is the evaluation of vascular malformations. There is limited information in this disease group. One study evaluated a low dose CE protocol for diagnostic accuracy for treatment planning and follow-up but did not compare to standard dose MRI (Anzidei, 2011). For coil-embolized intra-cranial aneurysms it has been suggested that non-contrast ToF MRA can be used as a diagnostic alternative to CE ToF MRA (Behme, 2016).




With regards to cardiac imaging, various studies have been published that evaluated the possibilities of non-contrast imaging for various applications. This is of particular relevance in cardiac imaging considering that high-risk populations with chronic kidney disease often are referred for cardiac imaging due to concomitant cardiovascular disease as part of cardiorenal syndrome. Few studies have evaluated the possibilities of detecting myocardial fibrosis using non-Gd protocols (Graham-Brown, 2018) or with lowered Gd dose using higher-relaxivity contrast media such as gadobenate dimeglumine (Cheong, 2015; Galea, 2014). With regards to these studies, it can be concluded that the need of GBCA is of great relevance for the detection of myocardial disease as the distribution of the Gd chelate to the increased extracellular volume in the equilibrium phase is the pathophysiological marker of delayed enhancement imaging, which as this moment cannot be reliable replaced by existing non-contrast sequences.


Although low dose GBCA protocols can visualize myocardial fibrosis, standard dose protocols did result in overall better image quality and should be routinely preferred (Galea, 2014). One study evaluated non-contrast coronary MRA for the detection of significant coronary artery disease combined with subsequent Gd adenosine stress perfusion imaging of the heart (Heer, 2013), indicating that additional stress perfusion imaging with Gd substantially improved the diagnostic accuracy of detecting significant coronary artery disease. A specific group in which the application of reduced dose (Faggioni, 2012; Montalt-Tordera, 2021) and non-CE protocols (Chang, 2013; Elzayat, 2018; Isaak, 2021) have been evaluated are patients with congenital heart disease. For visualization of anatomy of the great vessels in congenital heart disease, non-contrast MRA protocols can be used as alternative to contrast-enhanced (CE) MRA protocols. One study described the potential of DL for the improvement of contrast in low-dose MRA studies in patients with congenital heart disease (Montalt- Tordera, 2021).


Gadolinium reduction strategies for musculoskeletal imaging


Four studies were identified that evaluated half dose imaging for musculoskeletal indications involving the assessment of synovitis or tenosynovitis (Schueller-Weidekamm, 2013), bone and soft-tissue disease in children (Colafati, 2018), bone and soft tissue tumours (Costelloe, 2011) and the evaluation of cartilage. These studies indicate that half dose GBCA protocols may be used while maintaining image quality (Rehnitz, 2020), however the limited number of studies indicate the need for additional research on this topic.


Studies evaluating the added value of GBCAs to musculoskeletal imaging protocols were mainly focused on detecting synovitis in patients with osteoarthritis and in spinal imaging. Albeit non-CE sequences can visualize synovitis, these are limited with an underestimation for detecting synovitis in patients with osteoarthritis (Crema, 2013; de Vries, 2021; Eshed, 2015) and inflammatory arthritis (Hemke, 2013). A recent meta-analysis aimed at determining the correlation between knee synovitis assessed on non-CE and CE MRI with histology in patients with knee osteoarthritis found that CE MRI scores correlated best with inflammatory infiltrates of synovial tissue, while paucity of current evidence warrants further studies on non-contrast for detecting knee synovitis (Shakoor, 2020).


With regards to spinal imaging, only three studies have been published that evaluated the added diagnostic value of Gd to spinal imaging protocols. One study investigated the differentiation of epidural fibrosis from disc herniation (Passavanti, 2020), one the characterization of vertebral marrow infiltrative lesions (Zidan, 2014), and one debated the added value of post-Gd images in contrast to non-enhanced scans for diagnosis of spondylitis and its complications (Prasetyo, 2020).


Gadolinium reduction strategies for body imaging




Several studies in the past few years have been performed that have investigated the performance of non-CE MRI of the prostate versus CE prostate MRI protocols. These studies have focused on the sensitivity and specificity of detecting prostate cancer using non- contrast imaging protocols (T2w + DWI [diffusion weighted imaging] sequences) compared to CE-imaging protocols (T2w + DWI + DCE [dynamic contrast enhanced imaging]). For the non-contrast imaging protocols the ranges for sensitivity and specificity of detecting clinically significant prostate cancer were respectively 63%-95% and 71-88%, compared to sensitivity and specificity ranging between 73-95% and 45-85% for protocols including Gd (Alabousi, 2019; Bass, 2021; Cuocolo, 2021; Knaapila, 2020; Kuhl, 2017; Liang, 2020; Niu, 2018; Park, 2021; Tamada, 2021). An overview of the main studies investigating the performance of non-contrast MRI of the prostate vs contrast MRI was recently summarized by Pecoraro (2021). For intra-procedural prostate imaging for identification of ablation zone extent, non-contrast T2*w-MRI in one study has shown to be comparable to CE T1w-MRI suggesting that this might be a method for repeated intra-procedural monitoring of the thermal ablation zone without the need for Gd (Sun, 2021). With regard to lowered Gd dose strategies for prostate cancer, only one small study in 17 patients was identified that evaluated whether administration of low doses of Gd for DCE MRI can be as effective as a standard dose in distinguishing prostate cancer from benign tissue (He, 2018).




Several studies have been performed that compared half-dose imaging with standard-dose imaging in liver MRI. Most studies focused on gadobenate dimeglumine which has high T1 relaxivity and can be used for both dynamic and delayed liver MRI. A blinded intra-individual study evaluating standard and low dose liver MRI with gadobenate, found that albeit the standard dose yields greater relative enhancement, there is overall little improvement in subjective image quality (Kamali, 2020). Evaluation of enhancement patterns and characterization showed that half-dose and standard-dose liver MRI with gadopentetate dimeglumine found that 62 out of 64 lesions (97%) were identically characterized based on similar contrast enhancement compared to standard-dose gadodiamide (De Corato, 1999).


One study comparing half-dose gadobenate dimeglumine to standard dose gadopentetate dimeglumine showed that the half-dose imaging resulted in similar diagnostic information on dynamic imaging as well as the possibility of delayed imaging in the hepatobiliary phase (Schneider, 2003). Quarter-dose (0.025 mmol/kg) with gadobenate dimeglumine was compared retrospectively for image quality with half-dose imaging for abdominal MRI in patients at risk for nephrogenic systemic fibrosis, showing that the overall enhancement quality of the quarter dose was rated as good in all phases of enhancement, but was significantly lower than that for half-dose imaging (De Campos, 2011).


A recent meta-analysis study for surveillance MRI of hepatocellular carcinoma (HCC) using shortened MRI protocols (also referred to as abbreviated MRI) assessed the pooled sensitivity and specificity of contrast-enhanced hepatobiliary phase (HBP) abbreviated MRI (T2w, DWI, CE-T1w in HBP) and non-contrast abbreviated MRI (T2w, DWI, T1w dual-gradient echo imaging) (Kim, 2021). In this study there was a good overall diagnostic performance for detecting both any-stage HCC and early-stage HC, and the contrast-enhanced HBP abbreviated MRI showed a significantly higher sensitivity for detecting HCC than the non- contrast abbreviated MRI (87% vs. 82%) but had a significantly lower specificity (93% vs. 98%) (p = 0.03). The main limitation of the non-contrast abbreviated MRI is the relatively low lesion-to-liver contrast.


Also for liver metastases detection, non-contrast MRI protocols have been studied indicating that in particular DWI is an important sequence that improved mean specificity, positive predictive, negative predictive, and accuracy values for lesions either as small or greater than 1 cm (Colagrande, 2016). A comparative study in 175 patients with histologically confirmed 401 liver metastases and 73 benign liver lesions found no significant differences in sensitivity (range = 95.2-99.6%), specificity (range = 77.3-100%), positive predictive value (range = 92.9-100%) or negative predictive value (range = 87.5-95.7%) between the non- contrast MRI and the full MRI protocol with contrast (Hwang, 2019). These studies indicate that non-contrast liver MRI that includes DWI may serve as an alternative to contrast- enhanced MRI for detecting and characterizing liver metastases in patients with relatively high risk of liver metastases.


Finally, one study in patients with suspected possible choledocholithiasis evaluated the comparative performance of non-contrast MRI with half-Fourier acquisition single-shot turbo spin echo (HASTE) versus contrast-enhanced MRI/3D-magnetic resonance cholangiopancreatography (MRCP) (Kang, 2017). In this study the abbreviated non-contrast MRI with HASTE and full contrast-enhanced MRI/3D-MRCP resulted in high accuracy for choledocholithiasis (91.1-94.3% vs. 91.9-92.7%) and no differences in sensitivity or specificity were found, indicating that in patients with suspected choledocholithiasis, performance of non-contrast abdominal MRI with HASTE is similar to contrast-enhanced MRI with 3D-MRCP, offering potential for decreased scanning time and improved patient tolerability (Kang, 2017).


Other body imaging applications


Only few studies have been published that evaluate non-contrast MRI protocols for other body applications such as renal (Mawi, 2021), pancreatic (Lee, 2019), gastro-intestinal (Cattapan, 2019; Goshima, 2009; Kim SJ, 2019), and adnexal (Sahin, 2021) imaging. Albeit these studies are promising about the possibility of leaving out Gd-based sequences in MRI protocols without compromising diagnostic confidence, more studies are needed before specific recommendations on non-contrast MRI strategies for body imaging can be made.


Also for MRI studies with low dose strategies for renal renography and urography more evidence is needed (Bayrak, 2002).


Gadolinium reduction strategies for breast imaging


Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is the most sensitive technique in breast imaging for the detection of breast cancer, however an increasing number of studies have investigated the potential of unenhanced or abbreviated MRI protocols without the need for GBCA in breast cancer imaging. In total seven studies were found that evaluated the application of non-contrast breast MRI protocols versus breast MRI protocols that include Gd based sequences. Although non-contrast sequences such as STIR and DWI have good specificity for the detection of breast cancer (Belli, 2016; Khalil, 2020; Telegrafo, 2015), reduced diagnostic performance for small lesions (<10 mm) limits the application of non-contrast breast MRI (Belli, 2016). Combining unenhanced MRI of the breast with additional breast tomosynthesis may improve the diagnostic accuracy of non- contrast breast MRI protocols (Girometti, 2020; Rizzo, 2021).


Some initial evaluation of the application of non-contrast breast MRI protocols has been performed in the context of evaluation of treatment response of neoadjuvant chemotherapy (Cavallo, 2019). One study evaluated high spectral and spatial resolution MRI (Medved, 2011) indicating the need for further research on new MRI sequences. In addition, protocols with reduced GBCA dose need further investigation. In the present literature search one study was identified that investigated a half dose Gd protocol for breast MRI. This study in 40 patients evaluated whether half dose gadobutrol (0.05 mmol/kg) was able to detect biopsy-proven breast cancers imaged at 3T using DCE MRI. All 49 breast cancers (of which approximately a quarter were smaller than 2 cm) were detectable using half dose gadobutrol on 3T MRI and did not differ in conspicuity scores (Melsaether, 2019).




In general, it can be concluded that the evidence for non-CE imaging in applications where CE imaging is considered standard of care is still too scarce to be able to draw conclusions and for this reason in this section only remarks summarizing the body of literature are provided, and no active recommendations are formulated. Few comparative studies on reduced dose imaging have been performed from which the following can be recommended:


1. Potential dose-reduction strategies for neuroimaging with gadolinium-based contrast agents


Findings of the LEADER-75 trial indicate that the dose of gadolinium-based contrast agents (gadobutrol) may be reduced to up to 75% of the standard dose (0.075 mmol/kg bodyweight, equivalent to 0.075 ml/kg bodyweight) in patients with suspected brain lesions.


The use of deep learning based methods for gadolinium dose reduction in patients suspected with brain metastasis is not recommended based on the current literature.


2. Potential dose-reduction strategies for cardiovascular imaging with gadolinium- based contrast agents


The use of standard dose imaging is recommended in patients with clinical indications for the administration of gadolinium-based contrast agents in in cardiac MRI.


Non-CE MRA techniques (e.g., time-of-flight MRA) and are widely available and can be used for accurate evaluation of stenosis grade of the supra-aortic vasculature.


Non-CE ECG-gated MRA sequences are widely available and recommended over (low- dose) CE MRA techniques for the evaluation of aortic dimensions.


3. Potential dose-reduction strategies for musculoskeletal imaging with gadolinium- based contrast agents


The use of standard dose imaging is recommended in patients with clinical indications for the administration of gadolinium based contrast agents in musculoskeletal imaging.


4. Potential dose-reduction strategies for abdominal imaging with gadolinium-based contrast agents




There is increasing evidence that biparametric (T2w + DWI) protocols may be used as an alternative to multiparametric (T2w + DWI + DCE) protocols for the detection of prostate cancer (See also guideline on Prostate Cancer).




The use of standard dose imaging is recommended in patients with clinical indications for the administration of gadolinium based contrast agents in liver MRI.


5. Potential dose-reduction strategies for breast imaging with gadolinium-based contrast agents


The use of standard dose imaging is recommended in patients with clinical indications for the administration of gadolinium based contrast agents in breast MRI.



There is an increasing interest in the reduction of the use of gadolinium-based contrast agents (GBCAs) for clinical safety reasons, environmental aspects, logistics, and health care costs. Two main strategies for the reduction of GBCAs are imaging by using a lower dose (e.g., half-dose imaging or lower) than the standard used dose of gadolinium (Gd) of 0.1 mmol/kg body weight for contrast-enhanced (CE) MRI, as well as leaving out GBCA in MRI scan protocols to answer specific clinical questions. Leaving out GBCA involves specific clinical scenario’s for various organ systems, and such approaches are to be discussed further within multi-disciplinary expert panels.

For this chapter it was decided not to perform a systematic literature analysis.

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  117. Von Tengg-Kobligk H, Ley-Zaporozhan J, Henninger V, Grünberg KM, Giesel FL, Böckler D, et al. Intraindividual assessment of the thoracic aorta using contrast and non-contrast- enhanced MR angiography. RöFo Fortschritte Röntgenstr. 2009; 181(3): 230–236.
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Autorisatiedatum en geldigheid

Laatst beoordeeld  : 28-11-2022

Laatst geautoriseerd  : 28-11-2022

Geplande herbeoordeling  :


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.



  • Radiological Society of the Netherlands (NVvR)

In association with

  • Netherlands Association of Internal Medicine (NIV)
  • The Dutch Association of Neurosurgery (NVvN)
  • The Dutch Society of Allergology and Clinical Immunology (NVvAKI)
  • The Dutch Society of Cardiology (NVVC)
  • The Dutch Society of Clinical Chemistry and Laboratory Medicine (NVKC)
  • The Dutch Society of Endocrinology (NVE)
  • The Dutch Society of Neurology (NVN)
  • The Dutch Society of Obstetrics and Gynaecology (NVOG)
  • The Dutch Society of Surgery (NVvH) / The Dutch Society of Vascular Surgery (NVvV)

Initiatief en autorisatie

  • Nederlandse Vereniging voor Radiologie
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Cardiologie
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Neurochirurgie
  • Nederlandse Vereniging voor Neurologie
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Nederlandse Vereniging voor Allergologie en Klinische Immunologie
  • Nederlandse Vereniging voor Endocrinologie
  • Nederlandse Vereniging voor Vaatchirurgie

Algemene gegevens

General Information

The Kennisinstituut van de Federatie Medisch Specialisten ( 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


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 ( and were summarised below.


Last name


Other positions

Personal financial


Personal relations

Reputation management

Externally financed


Knowledge valorisation

Other interests



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







Received consultancy fees from Guerbet, 2019-


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


Member of contrast media safety

committee, European

Society of Urogenital

Radiology (no payment)







April 11th, 2020, Reaffirmed October 12th,


No restrictions

Houwen T, van der

Internist - Immunologist - Allergologist, Amsterdam UMC, also seconded allergologist in Huid Medisch









July 11th, 2022 Reaffirmed October 12th, 2022

No restrictions

Kerstens MN

Internist- endocrinologist, UMCG

Chairman Bijniernet (no payment)







July 1st, 2020, reaffirmed October 25th,


No restrictions

Krabbe JG

Clinical chemist, Medisch Spectrum Twente








September 1st, 2020,

Reaffirmed October 13th, 2022

No restrictions

Luijtgaarden KM, van de

Vascular surgeon, Maasland Ziekenhuis








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



Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no







Received consultancy fees from Guerbet, 2019-


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)







April 7th, 2020, Reaffirmed October 13th,


No restrictions

Uyttenboogaart M

Neurologist and neuro- interventionalist UMCG

Advisor International Federation of Orthopaedic Manipulative Physical Therapist / Nederlandse Vereniging Manuele Therapie



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


Work package leader CONTRAST

(Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology



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-








April 7th, 2020, Reaffirmed October 19th, 2022

No restrictions

Wolk S, van der

Gynaecologist- obstetrician, Haga Ziekenhuis








June 30th, 2021, reaffirmed October 25th,


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 ( In addition, patient information on safe use of contrast media in pregnancy and lactation was developed for, a platform to inform patients about health and disease.



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’.




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


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 (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 (


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.



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 ( 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.



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.

Zwangerschap en lactatie