Rationales for Non-standard GBCA Dosing-Low?-High?-When? and Why?: A Literature-based Study

The current standard dose of extracellular, multipurpose gadolinium-based contrast agents (GBCAs) of 0.1 mmol Gd/kg body weight (bw) was first suggested in 1984, 40 years ago. Although the safety and efficacy of both higher and lower doses ("non-standard dosing") have been extensively investigated over the years, the recent introduction of high-relaxivity macrocyclic GBCAs provides, for the first time, a viable lower-dose alternative.

To systematically explore published rationales for nonstandard dosing of GBCAs and discuss the potential future impact of high-relaxivity contrast agents.

A systematic literature review was conducted using Embase and MEDLINE/PubMED, covering studies published from 1991 to 2024. Publications were categorized by clinical indication, administered GBCA dose, study design, and rationale for nonstandard dosing. The dose of 0.1 mmol Gd/kg body weight was defined as the "standard" reference for comparison.

Eighty-seven publications comparing different nonstandard dosing regimens with the standard dose were finally selected, which included 43 high-dose and 58 low-dose studies. The rationales for using high-dose administration were to achieve better contrast (25/43; 58%) and to improve lesion detection (15/43; 35%). These high-dose studies were performed primarily in the CNS until 2006. Twenty-nine studies (29/43; 67%) reported improved outcomes compared with standard dose, and 1 study (1/43; 2%) reported comparable outcomes. Rationales for using low-dose administration were related to (1) NSF (31/58; 53%); (2) Gd exposure (23/58; 40%); (3) cost (22/58; 38%); (4) unspecified safety (22/58; 38%); (5) Gd retention/presence (19/58; 33%); and (6) the environment (7/58; 12%). From 1991 to 2006, cost was the primary rationale for lower dose administration. From 2008, NSF was noted, from 2017 onward, Gd retention/presence emerged as an identified rationale, and most recently, to minimize environmental impact. Forty-nine of 58 (84%) investigating low-dose regimens reported comparable outcomes, 7 studies (12%) reported inferior outcomes compared with standard dose. However, 36 of the 49 low-dose studies reporting comparable outcomes modified not only the dose but additionally other parameters, or they applied a study design potentially impacting study strength. To reliably allow for a substantially lower dose across a broad range of indications, the next generation of high-relaxivity low-dose GBCAs (gadopiclenol, gadoquatrane) was developed.

For over 34 years, there has been a consistent demand to lower GBCA doses, with an increasing number of rationales over time. The high-relaxivity, low-dose mGBCAs show promise for reducing Gd dose while maintaining high image quality, potentially defining a new standard dose.