The use of gadolinium-based contrast agents in Ghana with a focus on residual intracranial gadolinium deposition
A B S T R A C T
Introduction: The aim of the survey was to identify current practice of the use of gadolinium-based contrast agents (GBCAs) in the wake of recent reports on gadolinium deposition in the brain following repeated administration of GBCAs.Method: A total of 13 facilities in Ghana with magnetic resonance imaging (MRI) departments were contacted via email with a two-page questionnaire.Results: A response rate of 69.2% (n ¼ 9) was achieved. Gadodiamide (Omniscan) was the most commonly used GBCA. Slightly more than half of respondents were aware of residual deposition of GBCAs in the brain. Majority of the respondents were aware of GBCA deposition in individuals with abnormal renal function, but not aware of its deposition in those with normal renal function. A great majority of the respondents do not record the type and dose of GBCA after each intravenous adminis- tration, and such information is not provided in MRI reports. More than half of the respondents do not check eGFR prior to the administration of GBCA even when a high-risk agent is used.Conclusion: Gadodiamide (Omniscan) a high-risk agent remains the most commonly used GBCA in Ghana. Awareness of current findings of GBCA deposition in the brain following repeated doses are not encouraging as revealed in this study. The need to adopt international standard guidelines into practice cannot be overemphasized in order to reduce the potential long-term effect of this deposition.
Introduction
Since its first approval in 1988 by the U.S. Food and Drug Administration (FDA) and now 9 in total, gadolinium-based contrast agents (GBCAs) have been used internationally over a quarter century in more than 300 million patients providing crucial, life-saving medical information.1,2 In fact they have become indispensable adjuncts to MRI.1 However, since the year 2000 when Cowper et al.3 issued the first report of 14 cases of nephrogenic systemic fibrosis (NSF), a rare but potentially fatal acquired sys- temic disease thought to occur predominantly in patients with severe renal insufficiency, there have been much concern about the safety profile of GBCA. From then till 2006, all GBCAs were still considered to be extremely safe. Then in 2006, Grobner4 and Marckmann et al.5 established an association between NSF and GBCAs. This was in contrast to previously held notion established by Prince et al.6 that unlike iodine-based contrast media, GBCAs were not nephrotoxic. Nevertheless, since the middle of 2009, specifically in the developed countries, NSF has been almost completely eliminated following the establishment and implementation of restrictive guidelines such as screening patients for potential presence of renal disease, judicious use of GBCAs among patients with compromised renal function, by performing unenhanced studies or half-dose GBCA studies in patients at high risk, and by reducing or avoiding high-risk GBCAs in patients with substantial renal disease.2,7
Again, we were awakened with a report of gadolinium deposition in specific areas of brain tissues after repeated doses of GBCAs over their lifetimes, even in the absence of clinically evident disease (i.e. Renal or liver disease) and in the setting of an intact blood brain barrier.2 This eye-opening report, first revealed by Kanda et al.8 noted residual gadolinium deposition in patients with normal renal function, which was characterized by dose-related T1 short- ening in the globus pallidus (GP) and the dentate nuclei (DN) in patients who had been intravenously administered repeated pre- vious doses of gadodiamide (Omniscan) and/or gadopentetate dimeglumine (Magnevist). Following this report, other authors9e14 confirmed this novel observation. Indeed, in two recent studies12,15 of autopsy specimens, it was proven that T1 shortening results from gadolinium retention in neuronal tissues of the GP, DN, thalamus, and pons. Overall, gadodiamide (Omniscan) is the agent most associated with this finding7e9,12,14; however, reports have also been shown with gadopentetate dimeglumine (Magnevist).
In a recent survey on the use of GBCAs in Ghana,16 it was revealed that gadodiamide (Omniscan), a high risk GBCA accounted for 67% of first-line agents, i.e. being the preferred standard, or first choice. Gadodiamide has been widely reported in the literature to be the agent most associated with NSF; yet it was found to be the most commonly used agent in many MRI facilities nationwide.16 The aim of the present nationwide survey was to identify current practice of the use of GBCAs in the wake of recent reports on gadolinium deposition in the brain following repeated administration of GBCAs.Initially, an online search was carried out to identify all healthcare facilities that owned MRI scanner for in vivo imaging. The main resources for this identification were tertiary hospitals, private hospital/clinics, and standalone diagnostic centres. In addition, assistance was provided by radiography professionals personally known to be performing MRI in identifying facilities that owned MRI scanners. This search resulted in a total of 13 func- tioning MRI facilities that were identified and approached nation- wide. This number represented the total number of MRI scanners in Ghana. Email addresses and telephone numbers of the contact persons within each MRI department were sourced from radiog- raphy colleagues who were familiar with these persons. A two-page close-ended questionnaire was directly addressed to the contact persons via email for completion, as they were the Heads- of-department (Directors) of the MRI unit, and were actively responsible in the day to day management or work practice of the department.17 Subsequently, the contact persons were prompted via the popular social media “WhatsApp” about the need to com- plete the questionnaire. Follow-ups were done via WhatsApp and phone calls to remind the contacts on the need to complete the questionnaire after a week. There was no need for approval from an ethical committee; however, a participant information leaflet and consent form was provided and participants were assured that the result of the study would only be used for the purpose of the study, and that their participation in the study was voluntary, anonymous, and confidential. The questionnaires were sent in May 2017 and responses received before the end of July 2017. Data were collated and descriptively analyzed using a 2013 Microsoft Excel Professional Plus.
Results
A total number of 13 MRI facilities were identified and approached to participate in the study. Completed questionnaires were returned by 9 MRI facilities resulting in an overall response of 69.2% (n 9).In Table 1, majority of the respondents 5 (56%) indicated they use Omniscan.
Table 2 demonstrates the knowledge and practice of adminis- tration of GBCAs in current practice. The questionnaire provided two response categories: Yes and No. The study demonstrated that all respondents administer the same GBCA in MR imaging of all body parts. Slightly more than half were aware of reports of gad- olinium deposition in the brain after four or more contrast MRI scans. Majority (6[67%]) were not aware that GBCA(s) remain in individuals with normal renal function. Contrarily, the same ma- jority were aware that GBCA(s) remain in individuals with abnormal renal function for great majority (7[78%]) lack depart- mental protocol on the administration of GBCA with regards to its residual deposition in the brain. All indicated that there was no information on how to reassess the necessity of repetitive admin- istration of GBCA(s). Again, the majority (7[78%]) indicated that they do not record the type and dose of GBCA after each intrave- nous administration, and none of the respondents provide details of the type and dose of GBCA on MRI reports. Majority (6[67%]) ask patients if they have had previous intravenous administration of GBCA(s) and type. Also, all respondents indicated they often attend to patients who undergo multiple MRI examinations that involve repeating doses of GBCA. With regards to the awareness of state- ments issued by international organizations concerning GBCA deposition in the brain: 5(56%) were aware of that of the ACR-ASNR, only 2(22%) and 4(44%) were aware of that of the US FDA and the EMA respectively. Finally, 5(56%) do not check eGFR of patients prior to the administration of a GBCA. Table 3 illustrates responses of participants on what they considered as best practices with regards to the administration of GBCAs. A Likert scale was used. The study revealed that 6(67%) agreed the type of the GBCA and the diagnostic efficacy be considered. All respondents agreed that the following be consid- ered: the rate of adverse reactions, dosing/concentration, and propensity to deposit in more sensitive organs be considered respectively. Interesting, 7(78%) agreed that linear agents be avoi- ded. However, 7(78%) strongly disagreed that GBCAs should be avoided entirely. All respondents (9[100%]) agreed that: macrocy- clic agents should be administered at low doses; the clinical benefit of the diagnostic information of GBCA-MRI should be weighed against the potential risk of deposition in the brain; and attention should be given to paediatrics who may require GBCA adminis- tration over the course of their lifetime.
Discussion
A response rate of 69.2% (n 9) was achieved from both public and private healthcare centres (Table 1). The majority of responses were from public tertiary healthcare facilities. In the current study, we found that gadodiamide (Omniscan) was the most commonly used GBCA (Table 1) despite its widely reported association with NSF18e20 and recently, intracranial deposition after repeated dos- es.7e9,12,14 This finding is similar to a previous study conducted in Ghana.16 Even though gadopentetate dimeglumine (Magnevist) has also been found to be associated with intracranial deposition of gadolinium,8,10 this agent is currently not in use in Ghana. Both GBCAs however, have been identified as high risk agents by the ACR21 and ESUR.22 Commercially available GBCAs differ in the structure of their chelate (linear vs. macrocyclic) and in their charge (ionic vs. non-ionic). These properties determine the ease with which free gadolinium is released from the gadoliniumechelate complex. When the properties of structure and charge are considered together, ionic and macrocyclic agents have the highest affinity for gadolinium, the risk of gadolinium dissociating from its chelate increases for non-ionic and linear agents23,24; while ionic linear chelates and non-ionic cyclic chelates probably fall between these two ends of the spectrum.25 In their response to knowledge and practice of administration of GBCAs (Table 2), all respondents indicated they use their GBCAs for MR imaging of all body parts. Indeed, apart from gadobenate dimeglumine (MultiHance) and gadoxetic acid (Primovist/Eovist) which are liver-specific agents, and gadofoveset trisodium (Vasovist/Ablavar) which is a blood-specific agent, all others are not organ specific.
The present survey demonstrates that slightly more than half of respondents were aware of reports of residual depo- sition of GBCAs in the brain after repeated doses. Studies of gado- linium deposition are increasingly being reported in the medical literature. The lack of awareness by some of the respondents might stem from their inaccessibility to current information or simply put, lack of interest on issues surrounding GBCAs. Even though 67% of the respondents indicated they were aware of reports of GBCA deposition in individuals with abnormal renal function, similar percentage were not aware of reports of its deposition in those with normal renal function. Evidence points out that the first report8 on deposition of gadolinium in neuronal tissues was noted in patients with normal renal function. This observation was similarly reported by other authors.9e14 In light of this observation, it is important that departmental protocols reflect this current finding and precautions to be taken before intravenous administration of any type of GBCAs. Precautions include confirming that the requested contrast- enhanced MR examination is truly indicated, considering the un- known risks of previously unanticipated residual gadolinium in our decisions as to which agent to administer, how much to administer, and whether to administer it at all.1 In addition, macrocyclic agents are more preferable than linear agents, and extra caution is required when administering GBCAs in children and young adults e low doses should be administered to minimize the cu- mulative gadolinium deposition over their lifetime. It was indicated that 78% of the respondents indicated their lack of inclusion of such protocol. This is not so surprising as authors16 reported in their previous study that out of a total of 12 MRI facilities, only 5 (42%) had a departmental protocol for the administration of GBCAs with regards to its association with NSF.
In spite of the recommendation of best practices in the literature concerning recording the type and dose of GBCA after each intra- venous administration, and providing such information on MRI reports,2 the present survey demonstrated that this practice is not followed as 78% of the respondents indicated that such information are not provided in MRI reports. The provision of such vital infor- mation is emphasized in the wake of recent reports of gadolinium deposition and because its phenomenon remains a relatively un- defined clinical phenomenon.2 Interestingly, it was revealed that 67% of the respondents indicated they ask patients if they have had a previous intravenous administration of a GBCA and type; how- ever, all respondents indicated their lack of information on how to reassess the necessity of repetitive administration of GBCAs; even though they attend to patients who undergo multiple MRI exami- nations that involve repeating doses of GBCA. According to stan- dard practice, it is important to obtain this vital information from patients prior to administration of GBCAs.21 Awareness of the statements issued by international organizations, i.e. ACR-ASNR,2 U.S. FDA, and EMA’s PRAC26,27 however varied among re- spondents. One way or the other, about half of the respondents were aware of statements issued by one of these organizations. More than half of the respondents do not check eGFR at all prior to the administration of GBCA, even when a high-risk agent is used. This was previously reported16 and is contrary to the ESUR22 guideline. According to the ACR21 guideline, although not so ‘rigid’ like that of the ESUR22 also supports checking eGFR when high-risk agents i.e. gadodiamide (Omniscan) is to be administered in at-risk outpatients who may have renal function impairment only when risk factors (history of renal disease [dialysis, kidney transplant, single kidney, kidney surgery, and history of known cancer involving any of the kidneys], history of hypertension requiring medical therapy, and a history of diabetes mellitus) are identified. For at-risk in patients, the ACR21 recommends obtaining eGFR within 2 days prior to planned administration of a high-risk agent.
Due to the reason that eGFR is more accurate than serum creatinine at predicting true GFR,28 it is gaining attention as a potentially better marker of contrast-induced nephropathy risk.29,30 In their responses to consideration for GBCA usage for best practices (Table 3), 67% 0f the respondents agreed that there is the need to consider the type of the GBCA and their diagnostic efficacy. All respondents agreed that the rate of adverse reactions, dosing/ concentration, and propensity to deposit in more sensitive organs i.e. brain be considered. This is supported by the ACR.21 Interesting, 78% agreed that linear agents be avoided for use in clinical MRI; however, most (78%) of them disagreed with the avoidance of the use of GBCAs entirely. These responses seem to reflect the varied positions taken by both the ACR26 and the EMA PRAC.27 The widely agreed practices as indicated by all respondents were: the use macrocyclic agents at low dose; considering the clinical benefit of the diagnostic information that MRI may provide against unknown potential risk of gadolinium deposition in the brain for each indi- vidual patient; and paying attention to paediatrics and other pa- tients who may receive many GBCA-MRI studies over the course of their lifetime. These practices fall in line with international guidelines.
In conclusion, in the wake of increasing reports of intracranial deposition of gadolinium after repeated doses, gadodiamide (Omniscan) a high-risk agent remains the most commonly used GBCA in Ghana. Awareness of reports of current findings of GBCA deposition in the brain following repeated doses is not encouraging as revealed in this study. It is therefore important to be particularly aware that GBCA deposition can occur in individuals with abnormal renal function or normal renal function, and the propensity for deposition is much attributed to the use of linear agents i.e. gado- diamide. The need to adopt international standard guidelines into practice cannot be overemphasized in order to reduce the potential long-term effect of this EGFR-IN-7 deposition.