‘Four pillars’ of high signal-intensity contrast agents

Dr Henrik Michaely

Associate professor of radiology and section chief of vascular and abdominal imaging, Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre, Mannheim, Germany

The role of high signal-intensity contrast agents in diagnostic imaging is growing, which is largely attributable to their diagnostic accuracy at lower and safer doses compared with conventional agents.1 However, further fine-tuning of four key aspects – ‘stability, safety, image quality and efficacy’ – could help radiologists to select the most appropriate agent and its optimal dose.

This short article will give an overview of these key aspects, paying particular attention to gadobutrol as a case study in magnetic resonance imaging (MRI).

Stability: a unique way of looking at safety
Complex stability is often overlooked when considering the choice of a contrast agent. However, we now know that contrast agents containing gadolinium (Gd3+) in linear structures are much more unstable than agents, such as gadobutrol, which contain Gd3+ in rigid macrocyclic structures. Linear structures are composed of open-chains, which are more likely to unfold and to release metal ions, whereas macrocyclic structures are more rigid; the metal ion is caged and would need to break from several sites in order to be released (Figure 1).

Less stable chelates can also undergo transmetallation (metal exchange) with other anions such as calcium during renal elimination, leading to release of toxic Gd3+. In patients with renal impairment, excretion of the contrast agents is prolonged and transmetallation is more likely to occur leading to a greater release of Gd3+ ions.

In one preclinical study, gadoversetamide with its linear structure released nearly 30% of total Gd3+ within 15 days under normal physiological conditions. This release increased to nearly 50% when phosphate was added, mirroring the situation found in patients with end-stage renal disease.2 In comparison, gadobutrol with its rigid macrocyclic structure showed negligible release (<0.1%) of total Gd3+ within the same time-period; furthermore, there was no enhanced release when phosphate was added.

The release of Gd3+ ions can lead to a build-up in tissues, causing fibrosis and fibroblast proliferation.3,4 This is a particular problem in renal patients where Gd3+ accumulation has been associated with the development of nephrogenic systemic fibrosis (NSF) – an acquired disorder which predominantly affects the skin in these patients.5

Not surprisingly, various guidelines including those published by the European Medicines Agency,6 now grade the different contrast agents in order to minimise the risk of NSF. Agents with stable macrocyclic structures (gadobutrol, gadoteridol and gadoterate) are classified as low-risk for the development of NSF compared with agents such as gadoversetamide, which is high-risk.

The American College of Radiology has recently produced similar guidelines based on the numbers of NSF cases.7 However, further studies are warranted to support the use of low-risk agents in patients with renal impairment. The GRIP (Gadobutrol in Renally Impaired Patients) study is already underway, which is a prospective international study to determine the risk of NSF in patients with chronic renal failure (CRF) IV or CRF V.

Framing the body
High signal-intensity gadolinium-based contrast agents can offer enhanced contrast and detailed perfusion information in MRI across several body areas.8 The image quality and efficacy of these agents is determined by physicochemical characteristics such as relaxivity and gadolinium content.

The combination of high gadolinium concentration and high relaxivity9,10 observed with gadobutrol (1.0 mmol/l) results in a higher T1-shortening compared with 0.5 molar contrast agents (Figure 2).9,11 The smaller injection volume, and therefore sharper bolus peak, that can be achieved with this agent may also optimise newer, faster imaging techniques such as magnetic resonance angiography (MRA).12

Neuro-imaging
In brain imaging, intra-individual studies comparing gadolinium-contrast agents have shown that the beneficial features of gadobutrol over other agents (i.e. greater T1 shortening) and the higher dose delivered (as shown in animal glioma models) can improve lesion detection, but there is little difference in terms of timing of image acquisition.13,14

A retrospective study of 27 patients with brain metastasis having undergone gamma knife surgery (GKS) showed that 130 lesions were detected with double-dose gadopentetate dimeglumine (Gd-DTPA)-MRI (0.2 mmol/l/kg bodyweight), but the use of double-dose gadobutrol (also 0.2 mmol/l/kg bodyweight)-MRI identified a further 25 lesions.15

In another study which used equivalent gadobutrol and Gd-DTPA doses (i.e. 0.1 mmol/l/kg bodyweight), a total of 67 metastatic lesions were detected with gadobutrol compared with 65 lesions using Gd-DTPA. Lesion conspicuity was also improved with gadobutrol in ten of 27 cases, while equivalent results for gadobutrol and Gd-DTPA were seen in 17 cases.16

In a comparison of gadobutrol with Gd-DOTA, both at a dose of 0.1 mmol/l/kg bodyweight in 131 patients with neoplastic lesions, a total of 42 out of 131 examinations were rated as ‘better’ with gadobutrol compared with 16 for Gd-DOTA. Gadobutrol also gave significantly higher lesion-to-brain signal ratios and 10% higher relative signal enhancement.17

MRI and multiple sclerosis
MRI with gadolinium contrast agents has also proven effective for enhancing in the diagnosis and follow-up of multiple sclerosis (MS) patients. Consensus guidelines for MS diagnosis recommend a simple, standardised protocol using gadolinium contrast-enhanced T1 MRI for all patients. The guidelines note the advantages for diagnosis of an agent such as gadobutrol, which offers high T1-shortening and delayed lesion enhancement over time.18

Although the standard (and indicated) dose of contrast agent in central nervous system (CNS) imaging is 0.1 mmol/l/kg bodyweight, increasing the dose of agents such as gadobutrol to 0.3 mmol/l/kg bodyweight can also improve tumour contrast and visualisation further, resulting in a higher detection rate for brain metastases, especially small lesions, as well as enhanced accuracy for the diagnosis of MS.15-17,19,20 For patients with suspected solitary metastasis, the higher dose (0.3 mmol/l/kg bodyweight) allows either exclusion or improved detection of additional metastatic lesions.

However, increasing the dose of any gadolinium-contrast agent must be balanced against the risk of fibroblast proliferation. The linear gadolinium contrast agents (e.g. gadodiamide, Gd-DTPA) have been shown to stimulate fibroblast proliferation at lower doses (i.e. 0.1 mmol/l) than macrocyclic contrast agents (e.g. gadoterate and gadoteridol) (5 mmol/l). In addition to emphasising the impact of molecular structure, these findings indicate that the lowest effective dose should be used and repeat contrast enhanced-MRI should be kept to a minimum over a short time-period.4

Liver and kidney imaging
Gadobutrol (1.0 mmol/l) has also been shown to be non-inferior – and, in some cases, superior – to standard contrast agents in liver and kidney imaging. In a randomised study of 572 patients with known or suspected liver lesions, gadobutrol (1.0 mmol/l) was compared with Gd-DTPA (0.5 mmol/l)-MRI at a standard dose of 0.1 mmol/l/kg bodyweight. Non-inferiority was demonstrated for gadobutrol in diagnostic efficacy rates (i.e. accuracy, sensitivity and specificity), and both agents had sensitivity and specificity ranges up to 90%.21

In a separate study, there was evidence that the lesion signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) may be superior with gadobutrol than Gd-DTPA in patients with small hepatocellular carcinomas.22 In another randomised comparator study of gadobutrol (1.0 mmol/l) and Gd-DTPA (0.5 mmol/l)-MRI in 471 patients with known or suspected renal lesions, the diagnostic accuracy was 83.7% for gadobutrol and 87.3% for Gd-DTPA; sensitivity and specificity for both agents was around 85%.23

Future possibilities with gadobutrol
Several studies24-26 have demonstrated the potential role of gadobutrol in whole-body angiography, including improved delineation of arterial morphology and small vessels compared with other contrast agents (Figure 3).

Three-dimensional MRA abdominal examination of five healthy volunteers revealed a better CNR with gadobutrol and gadobenate dimeglumine (Gd-BOPTA) compared with Gd-DTPA (Figure 4).25 The robustness of vasculature imaging with gadobutrol (0.1 mmol/l/kg bodyweight) was shown in continuous table movement (CTM) with temporal resolution time-resolved (TWIST) MRA in patients with symptoms of peripheral arterial occlusive disease.

This imaging approach may have a broad clinical use and could also aid in determining the degree of stenosis.27 Gadobutrol-enhanced fast MRI (imaging time of 17 seconds) was shown to be non-inferior to multidetector CT angiography in classifying arterial stenoses.28 MRA with gadobutrol (0.1 mmol/l/kg bodyweight) also provides a sharper contrast bolus in imaging of neck vessels with higher SNR and CNR values than 0.5 molar gadolinium-contrast agents; this may reduce the overestimation of stenosis observed with 0.5 molar agents.19

High signal-intensity contrast agents such as gadobutrol may also find a promising new avenue in the imaging of lesions in areas such as the pancreas, bile duct and breast.29-31

In summary, high signal-intensity contrast agents such as gadobutrol have a number of benefits related to safety and efficacy:

• 
Stability: macrocyclic contrast agents such as gadobutrol are more stable than linear contrast agents. 

  The release of toxic Gd3+ ions by macrocyclic agents under physiological conditions is negligible. This could minimize the risk of NSF. The doses needed to cause fibroblast proliferation are also much higher for macrocyclic than linear agents, and are above the levels used in clinical practice.
• 
Safety: the standard, recommended dose of gadovist (i.e. 0.1 mmol/l/kg bodyweight) is safe and well tolerated, with an adverse event profile similar to other contrast agents. An observational study in more than 14,000 patients showed that gadobutrol (1.0 mmol/l) was well-tolerated in MRI and MRA of all body regions.32 

  Increasing the dose up to 0.3 mmol/l/kg bodyweight can improve lesion visualisation further, but the safety margin is likely to be around 2-3 times higher.33
• 
Image quality: Gadobutrol has a unique combination of high relaxivity and high gadolinium concentration, which contributes to greater T1-shortening and improved image quality.
• 
Efficacy: The physicochemical characteristics of gadobutrol, including T1-shortening, translate to superior efficacy, with clinically relevant benefits such as improved lesion visualisation and stenosis assessment.

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