Given the recent attention to the potential adverse effects of high dose gadolinium MRI studies, we evaluated the current status of GBCA use for CMR as presented in the peer-reviewed literature, emphasizing trends before and after nephrogenic fibrosis guidelines were issued in 2008. This meta-analysis showed that the median GBCA dose for English peer reviewed publications for CMR (19,934 patients) was 0.2 mmol/kg. Further, no change in mean or median gadolinium dose was present before, versus after the FDA issued GBCA black box warnings (p > 0.05). To date, only 1 multi-center, dose ranging trial has been conducted for a single gadolinium contrast agent (gadoversetaminde) for LGE . For perfusion CMR, two dose ranging multi-center trials for gadopentetate dimeglumine have been published in the literature, with "optimal" gadolinium dose ranging from 0.05 to 0.15 mmol/kg [17, 18], The gadolinium dose reported in the literature for perfusion CMR varies between 0.1-0.2. (Table 6) [16–18]. It remains to be seen if future CMR studies will incorporate and report lower gadolinium doses.
CMR is widely available and has been validated at 0.2 mmol/Kg for detection of scar [3, 4] and at a range of doses for myocardial ischemia using stress/rest perfusion protocol [5–7]. The most frequent topics in the peer-reviewed literature focused on myocardial infarction [19, 20] and viability [21, 22], cardiomyopathy [23–25], ischemia [26, 27], and myocarditis . It seems quite clear that these published, investigational studies have routinely used higher doses of GBCAs than FDA labeling. A limitation of this report is that we are unable to determine if the pattern of GBCA use with CMR in published studies reflects the broader routine clinical pattern of practice for GBCA use.
Patients with cardiovascular disease must be screened for risk factors that are associated with NSF. In addition to the major risk factor of renal failure, an additional risk factor for NSF might to be multiple/high dose gadolinium enhanced MRI examinations. In particular, Adujudeh et al [29–31], Perez et al  and others have shown that patients who receive higher cumulative doses of gadopentetate dimeglumine have a higher risk of developing NFS compared with those who received lower doses. Patients who have cardiovascular disease may have other medical conditions that require MRI examination. Thus, the relatively high dose of GBCA used for CMR studies may be particularly relevant for patients who may also undergo non-cardiovascular MRI.
The accepted approach to determination of the minimally effective GBCA dose is evaluation in multi-center phase II and III studies. For LGE, only one contrast agent (gadoversetamide) has been subject to a combined phase II/III evaluation. That study concluded that a gadolinium dose of 0.2 mmol/kg gadoversetamide was appropriate for LGE CMR. For myocardial perfusion, Wolff et al indicated that the appropriate dose for a single perfusion evaluation was 0.05 mmol/kg with gadopentetate dimeglumine . Giang et al showed that gadolinium doses of 0.10 or 0.15 of gadopentetate dimeglumine were optimal for perfusion CMR. Since that time however, considerable advances have been made in both hardware and software.
Approximately 23% of peer-reviewed publications regarding gadolinium enhanced CMR had incomplete or inaccurate information related to GBCAs. "Gadolinium DTPA," a nonspecific description of the specific contrast agent, was frequently described as the type of contrast media that was administered. In order to maintain patient safety, it is essential that gadolinium contrast agents be accurately reported in the medical record. Contrast agents for MRI are currently treated the same as all other hospital medications by the United States Joint Commission on Accreditation of Healthcare Organizations. These standards require accurate recording and reconciliation of the type, route and dose of administration. The American College of Radiology standards for the practice of MRI also indicates that radiology reports should record type, route and dose of gadolinium administration. With the advent of NSF, it is likely that improved reporting of gadolinium type may take place in the future.
Dose and efficacy studies for GBCAs focused on CMR have rarely been performed. One factor is likely the high cost of multi-center trials which is typically borne by the drug manufacturer. Thus, peer-reviewed literature and individual physician experience from single-site experience will probably continue to guide clinical practice. In principle, the lowest drug dose that is diagnostically efficacious is recommended by regulatory authorities. Without well-controlled clinical trials, the lowest gadolinium dose that is efficacious is essentially unknown for most of the available CMR contrast agents. Recently, there have been attempts to use lower gadolinium dose in large multi-center studies, such as EuroCMR (gadolinium dose < 0.16 mmol/kg) . In addition, the Multi-Ethnic Study of Atherosclerosis (MESA) protocol for LGE CMR involving approximately 3000 study participants requires a gadolinium dose of 0.15 mmol/kg; a higher dose of 0.2 mmol/kg was not recommended by the MESA renal working group due to safety concerns in an elderly, volunteer population (D. Bluemke, J Lima, personal communication).
It is clear that improved reporting of contrast media administration for CMR publications needs immediate attention in the peer reviewed literature. We strongly recommend that authors, editors and reviewers of peer-reviewed journals demand standardization of GBCA reporting in the literature. Professional societies that are particularly concerned about the use of CMR, such as the Society of Cardiovascular Magnetic Resonance (SCMR) and the International Society for Magnetic Resonance in Medicine (ISMRM), could provide education and guidelines for practice in this regard. For CMR, it is important to report not only the weight based dose of the GBCA (mmol/kg or ml/Kg) and the chemical name and manufacturer, but also the delay time for imaging. Generic statements such as "gadolinium DTPA" should be avoided.
There are several limitations of this study. We limited our search to articles with abstracts and those published in English with specific MeSh terms from PubMed. Thus, our review probably does not reflect the worldwide use of gadolinium contrast agents. In addition, the FDA black box warning in 2007 was issued by a United States agency. We hypothesized that CMR publications appearing after 2008 were likely to be influenced by this warning. However, warnings about gadolinium use were slightly different in Europe although they were also issued about this same time. In addition, FDA-approved GBCA medication label changes took place only in early 2008. It is possible that changes in gadolinium dose policies in research studies may take longer to appear in the literature than our inclusion literature date of December, 2010. The observation of discernable trend in dose reduction for CMR over this period might be a reflection of changing referral patterns for CMR: patients with renal failure are no longer being referred for GBCA studies and there is less consideration for low dose by CMR physicians in a somewhat healthier population.
In conclusion, we report that CMR studies in the peer-reviewed published literature routinely use higher gadolinium doses than FDA label indicated dose. Clinical trials should be supported to determine the appropriate doses of gadolinium enhancement of the myocardium.