Editorial for “Relationship Between Patient-friendly Audiovisual Systems and MRI Contrast Agent to Adverse Reactions”

Gadolinium (Gd) is a rare earth metal commonly used to enhance magnetic resonance imaging (MRI). A paramagnetic element with seven unpaired electrons, Gd generates a magnetic field in the same direction and radiofrequency as imposed by the MR scanner.¹ The induced electromagnetism then strengthens nuclear spin and expedites energy release from excited protons, creating an image with sharper contrast in brightness between tissue parts of varying proton densities. Today, about one in three MRI scans employs gadolinium-based contrast agents (GBCA) to improve image quality.²

Administered through intravenous injection, most GBCAs coat the heavy metal with organic ligands to prevent it from harming the body. The detoxified compounds are then considered safe, with most molecules urinated out within 24 hours after injection.³ Notwithstanding, mild adverse events (AE), for example, headache, nausea/vomiting, hives (urticaria), are reported in 0.2%–4% of cases (possibly caused by freed Gd ions or elevated local concentrations of the compound).^2,3 Such physiological/allergic reactions are observed to go hand in hand with patient anxiety due to claustrophobia or unsettling machine noise.⁴ Meanwhile, patients are reported to generally relax in the presence of an audiovisual (AV) system that plays soothing music and varies lighting during MRI as a distraction.⁵ Could such a system be useful in mitigating GBCA’s side effects, possibly by reducing patient stress?

To answer this question in the current issue of JMRI, Nitta et al.⁶ report an observational study, which compares the incidence of GBCA-related AEs with and without a patient-friendly AV system during head-and-neck MRIs in 2016–2021. Only 8 (0.7%) out of 1159 patients in the AV group experienced AEs, compared with 57 (1.6%) out of 3673 in the control, slashing the risk by more than half (P = 0.03; Table 2). Although the lack of randomization means some patient factors are imbalanced between the two groups (Table 1), the effect size and statistical significance stay virtually unchanged in multiple logistic regression adjusting for these factors (Table 3). Besides, certain imbalances favor the control rather than treatment, for example, the higher proportion of females in the AV group, who are more susceptible to (sex hormone-mediated) allergic reactions to GBCA.⁷ Nevertheless, unmeasured confounding can certainly creep in to throw a causal link into question. For example, patients who are more open-minded, thus less prone to anxiety in unfamiliar surroundings, may be more likely to volunteer for the novel AV systems, predisposing them to a better outcome. Most importantly, as pointed out by the authors, scan rooms with and without AV systems differ in other aspects as well (this being an observational study). These include the scanner type, presence/absence of a monitor showing scan progress, and size of the room, all of which could contribute to the differential outcomes observed between the two groups.

The time is ripe for a randomized controlled trial (RCT). The RCT should pit the use versus no-use of AV systems in otherwise identical set-ups. Should other factors, for example, a scan monitor or a more spacious room, be thought useful, a multifactorial design would allow us to evaluate their individual as well as (possibly synergistic) joint effects. Patients recruited through informed consent would not only pass an ethical requirement but also ensure that they come from the target population who are open to both options and thus of interventional interest. Possible noncompliance should be handled in principled ways (eg, intent-to-treat) to avoid the bias-prone imbalances that undermine the comparability of assigned groups.⁸ Lastly, randomization would make it easier to investigate the role of stress alleviation in mediating the reduction of GBCA-related AEs by patient-friendly AV systems—in observational settings, the potential mediator would be inextricably linked with treatment choice.⁹

A more difficult question remains as to the long-term toxicity of GBCA. In 2017, the US Food and Drug Administration issued a warning about Gd retention in patient body for years after taking GBCA, likely a result of it breaking loose from the binding compound and thereby evading renal clearance.¹⁰ In rare cases, this may lead to nephrogenic systemic fibrosis, a debilitating disorder characterized by thickening of the skin.¹⁰ Unlike the immediate side effects, Gd buildup is insidious and hard to measure, with symptoms rare and concentrated in subgroups with pre-existing renal impairments. To study its effects and find treatments, biochemists, clinicians, epidemiologists, and data scientists need to bring their complementary skills to the table and work together as a team.