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Gadolinium Deposition Disease: A New Risk Management Threat
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ORIGINAL ARTICLE
Gadolinium Deposition Disease: A New Risk Management Threat Q8
H. Benjamin Harvey, MD, JD a,b,c , Vrushab Gowda, BS d, Glen Cheng, MD, JD a,e Abstract Gadolinium-based contrast agents (GBCA) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30% of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety profile and attendant medicolegal liability associated with GBCAs changed dramatically in 2016 with the description of gadolinium deposition disease (GDD). Despite being unproven scientifically, a groundswell of GDD-related litigation and personal injury advertising targeting potential GDD patients has occurred. In this article, we describe what GDD is, (2) why GDD has created medicolegal risk, and (3) how can this risk can be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months post-GBCA administration. As such, the authors recommend the use of gadoteridol as the default GBCA and administering other GBCAs, including linear agents, only when clinically necessary. Key Words: Gadolinium, gadolinium deposition disease, lawsuit, liability, risk management J Am Coll Radiol 2019;-:---. Copyright ª 2019 American College of Radiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
INTRODUCTION Contrast agents further enhance the diagnostic power of MRIs and have found particular application in angiography and oncologic imaging. Structurally, they consist of a linear or macrocyclic carrier ligand chelated to a paramagnetic metal ion, which serves to reduce T1 relaxation time and facilitate visualization of perfused structures. These compounds most commonly contain gadolinium(III) as the active material, although iron oxide– and manganese-based agents are also employed [1]. Gadolinium-based contrast agents (GBCAs) have enjoyed wide use since their introduction some 30 years ago, with some 450 million doses administered worldwide to date [2]. They are generally well
a
Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital Department of Radiology, Boston, Massachusetts. c Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts. d Harvard Law School, Cambridge, Massachusetts. e Harvard T.H. Chan School of Public Health, Environmental and Occupational Medicine and Epidemiology. Corresponding author and reprints: H. Benjamin Harvey, MD, JD, Department of Radiology, Massachusetts General Hospital, Institute for Technology Assessment, 175 Cambridge Street, Suite 200, Boston, MA 02114; e-mail: [email protected]. The authors state that they have no conflict of interest related to the maQ 1 terial discussed in this article. b
tolerated and associated with lower rates of adverse events than iodinated contrast agents [3]. Despite their ubiquity, however, GBCAs are not without their risks. Alongside hypersensitivity reactions, acute nephrotoxicity, transient encephalopathy, and nephrogenic systemic fibrosis (NSF) has been identified as a potentially debilitating process associated with GBCA exposure [4]. A newly proposed pathology joined this complement in 2016: gadolinium deposition disease (GDD) [5]. Although shrouded in controversy as to its pathophysiologic mechanism, modifiable risk factors, and even existence as a disease in its own right, GDD has grown salient in the public eye—a fact not lost on personal injury attorneys. The increasing risk exposure created by the advent of GDD bears far-reaching implications for health systems, referring physicians, and radiologists. This article surveys the landscape facing these stakeholders by asking three questions: (1) what GDD is, (2) why GDD creates medicolegal risk, and (3) how this risk can be mitigated.
FROM DEPOSITION TO DISEASE: CORRELATION OR CAUSATION? It has long been known that GBCA administration leaves behind residual gadolinium. Studies have demonstrated its uptake in various tissues, including bone, kidney, and the
Copyright ª 2019 American College of Radiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1546-1440/19/$36.00 n https://doi.org/10.1016/j.jacr.2019.11.009
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brain, even in patients with an intact blood-brain barrier, preserved renal function, and normal hepatic clearance [68]. Interestingly, gadolinium preferentially deposits within the brain in the dentate nuclei and globi pallidi, perhaps conveyed to these structures through the recently discovered glymphatic system [9,10]. Although both linear and macrocyclic GBCAs alike collect within the brain, linear agents (eg, gadopentetate, gadobenate, gadodiamide, gadoxetate) are particularly prone to deposition [11,12]. Not until recently, however, has a pathological consequence to this deposition been suggested. In 2016, Semelka et al first described a constellation of self-reported symptoms in patients who had received GBCAs [5]. Suggesting causation from correlation, the authors postulated this symptomatology to represent GDD and went on to propose diagnostic criteria for this newly proposed disease. To meet the diagnostic criterion for GDD, a patient must exhibit at least three of the following five broad symptom clusters within a period of hours to 2 months post-GBCA administration: (1) peripheral neuropathic pain in either a “glove and stocking” or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain [5,13]. Furthermore, it was proposed that GDD may clinically manifest after the initial infusion of GBCA or after multiple administrations in a dose-dependent manner [14,15]. As the precise mechanism—or even true existence—of the disease has yet to be characterized, a number of theories concerning the pathophysiological basis of GDD have been floated. Some have postulated that gadolinium competitively inhibits calcium channels, thereby interfering with proper neurologic function [16,17]. Separately, GDD symptomatology may causally depend on impaired heavy metal metabolism, itself a consequence of heredity. For instance, data have demonstrated elevated risk among women of European descent, although more robust genelevel studies are needed to more appropriately identify genetic predisposition [18]. Similar to other heavy metal toxicities, chelation treatment has been proposed for GDD. Diethylenetriaminepentaacetic acid has demonstrated clinical benefit, followed by ethylenediaminetetraacetic acid and deferoxamine [19]. GDD, although still unproven, has nonetheless resulted in an impressive regulatory and industry response. Shortly following the initial description of GDD, the ACR and the American Society of Neuroradiology issued a position statement concerning the use of GBCAs, calling for providers to consider “multiple factors . . . when selecting a GBCA, including diagnostic efficacy, relaxivity, rate of adverse reactions, dosing/concentration, and propensity to 2
deposit in more sensitive organs such as the brain” [20]. The US FDA convened the Medical Imaging Drugs Advisory Committee in May and September 2017, which yielded a 692-page transcript of meeting minutes. This panel concluded with “fair uniformity that there is no evidence of a causal relationship between the symptoms and signs in patients with normal renal function and the retention of gadolinium” [21]. Despite this statement, the FDA took the remarkable step of requiring imaging centers to distribute patient Medication Guides to better apprise patients of GBCA-associated risks prior to administration [22]. The European Medicines Agency went one step further by restricting the use of certain linear GBCAs, all the while concluding that “there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients” [23]. The glaring discordance between these regulatory actions and the regulatory-convened scientific panel statements of “no causality” is confusing for medical practitioners, patients, and juries alike.
SYSTEMS-LEVEL SIGNIFICANCE: THE ELEPHANT IN THE COURTROOM Unlike NSF, GDD is marked by a significantly larger risk footprint. The limited epidemiological understanding of this proposed disease process does not permit a fine resolution of population-level data at present. However, recent studies have posited markedly high prevalence of GDD-like symptomatology among patients receiving GBCA. For instance, a recent article from Parillo et al suggests that 13% of patients who received the macrocyclic GBCA gadoterate meglumine experienced GDD-like symptoms [24]. This is alarming, considering that as many as 39 million MRI scans are performed in the United States each year and as many as 12 million of these patients require GBCA administration. A pool of potential plaintiffs growing by over 1 million per annum is sufficiently large for institutional actors to take heed, and large health systems are increasingly making enterprise-level formulary switches primarily to mitigate this risk exposure. In the wake of NSF, personal injury attorneys are no stranger to GBCA-based lawsuits. In fact, a simple web search will show that many personal injury attorneys are already active in the GDD space, including in ongoing multidistrict litigation. Based on case characteristics alone, it is likely that GDD cases will only proliferate over time [25]. There is a vast pool of potential plaintiffs, bearing low costs of capture and still lower barriers to entry. Because GDD clinical diagnostic criteria are largely subjective, their existence is difficult to disprove [5]. Nonspecific and transient constitutional, neurologic, and dermatologic features post-GBCA administration that extend beyond Journal of the American College of Radiology Volume - n Number - n Month 2019
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the formal GDD diagnostic criteria may represent confounding sources of symptomatology leading to an overdiagnosis of GDD post hoc [24]. And finally, the emergence of these symptoms is dispersed over 2 months, which limits diagnostic precision. Notwithstanding the nebulous (and not yet identified) pathologic mechanism of GDD, many courts have to date been unwilling to dismiss GDD personal injury claims. Although defendants have moved to dismiss the claims on the grounds that a scientific consensus is lacking, several courts to date have found that the claims meet a “minimum threshold of plausibility” [26]. These rulings have stymied defendants’ motions to compel the judge to discard these suits owing to a failure to state a claim upon which relief can be granted [27,28]. Moreover, a growing corpus of GDD-related medical literature may now suffice to pass the Daubert standard, which serves to exclude unqualified technical evidence [29-31]. Some trends have emerged from the body of existing GDD lawsuits. The majority apply tort theories of both negligence and strict liability, turning on inadequate labeling and defective design to permit fault-independent recovery [32]. Others advance their claims according to contract doctrine, such as breach of the implied warranty of safety [33]. Although to date most GDD lawsuits attach liability to the GBCA manufacturer, this can fairly be expected to change as the field develops. Looking to the history of NSF litigation by analogy, plaintiffs have in many cases sued a wide range of defendants: government hospitals, state correctional facilities, the Department of Veterans Affairs, as well as individual physicians as private parties [34-36]. A review of GDD lawsuits shows that cases have proceeded irrespective of the fact that GBCA administration is standard of care. This is particularly true when case theories assert negligent choice of GBCA (ie, choosing a GBCA that results in greater brain deposition than necessary). ACR and American Society of Neuroradiology opinions affirming the general safety of these agents to date have not proven dispositive in litigation; likewise, a review of cerebral palsy suits shows that the American College of Obstetrics and Gynecology professional opinion has not historically been accorded decisive weight [37].
RISK MANAGEMENT STRATEGIES: REDUCING BRAIN RETENTION DURING THE EARLY WINDOW Multiple varieties of GBCA exist, each with differing risk profiles. Thus, by choosing the right GBCA, radiologists and referrers likely have the ability to significantly reduce their risk exposure. Experience from NSF lawsuits shows
that litigation has often been mitigated through the use of class II agents and judicious estimated glomerular filtration rate precautions. Although the ACR has yet to articulate specific practice recommendations, this article advocates adoption of a similar approach to GBCA selection to mitigate the risk of GDD. To begin, macrocyclic GBCAs should be used over linear agents whenever appropriate, because it is well established that the latter more avidly deposits within tissues such as the brain and kidneys. Moreover, significant differences between GBCAs also exist within the macrocyclic class of GBCAs. Among macrocyclics, gadoteridol offers significant advantages over its peers from a risk management perspective, with animal studies demonstrating significantly lower retention and more efficient clearance in cerebral, cerebellar, and renal tissue [38,39]. These findings have been replicated in a recent well-conducted confirmatory study and affirmed by Hani Abujudeh, author of the textbook Quality and Safety in Radiology and one of the first Q 2 radiologist to describe NSF. In a recent review article, Dr Abujudeh noted that “an increasing number of health systems [are switching] to gadoteridol given its markedly lower levels of gadolinium retention in the brain and kidneys” [12,40]. The risk management benefits of gadoteridol have also been extolled by attorney and risk management expert Dr Nicholas Argy [41]. From a practical standpoint, a data-driven strategy of risk mitigation grounded in the well-conducted studies described previously is likely to be simultaneously palatable, attractive, and straightforward to both patients and potential juries. Thus, based on the current data, we outline the foregoing strategy for risk mitigation based on the use of gadoteridol as the default GBCA. Such an approach aims to minimize gadolinium retention in the brain during the GDD-sensitive time window of the first 2 months postadministration. This should not be construed as a brightline rule; providers should not hesitate to use other GBCAs, including linear agents when clinically advisable, such as with hepatic or tumor imaging. Moreover, many facilities may not retain a ready supply of gadoteridol; in its absence, providers should consider implementing an informed consent process that alerts the patient, among other things, to the possibility of increased gadolinium retention in the brain compared with other GBCA options and their ability to seek imaging elsewhere if a different GBCA is preferred. One perverse reality of this risk management issue is that the radiologists and referring physicians who are exposed to GDD-related liability are often not the individuals tasked with making the GBCA decision. As such, it is important for physicians to communicate to the pharmacy staff, clinical administrators, and risk managers who make the
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enterprise-level formulary decisions the importance of considering GDD-related liability when selecting a GBCA.
CONCLUSION Q7
Although the science of GDD is uncertain at best, health care providers would nonetheless be well advised to proactively guard against GDD and its attendant liability. The benefits of a risk mitigation strategy could be substantial— including averting costly and disruptive litigation. Based on the current data and regulatory statements, this article advocates for a risk mitigation strategy focused on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months after GBCA administration. As such, the authors recommend the use of gadoteridol as the default GBCA, with other GBCAs, including linear agents, used only when clinically advisable. Caution in GBCA choice now could pay high dividends in avoiding costly GDD claims down the road.
TAKE-HOME POINTS -
Increasing risk exposure created by the advent of GDD bears far-reaching implications for health systems, referring physicians, and radiologists.
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GDD, although still unproven, has nonetheless resulted in an impressive regulatory and industry response, and many courts have to date been unwilling to dismiss GDD personal injury claims.
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Unlike NSF, GDD is marked by a significantly larger risk footprint.
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The preferred risk mitigation strategy is focused on appropriate usage of GBCAs and on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months when GBCAs are needed.
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The authors, in agreement with other risk management experts, recommend the use of gadoteridol as the default GBCA, and the use of other GBCAs, including linear agents, only when clinically necessary.
REFERENCES
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24. Parillo M, Sapienza M, Arpaia F, et al. A structured survey on adverse events occurring within 24 hours after intravenous exposure to gadodiamide or gadoterate meglumine: a controlled prospective comparison study. Invest Radiol 2019;54:191-7. 25. Davis v McKesson Corp., 2019 WL 3532179 (D. Ariz. Aug 2, 2019). 26. Thomas v Bracco Diagnostics Inc., No. CV 19-0493, 2019 WL 4254015 (W.D. La ,July 23, 2019). 27. Gomilla v Bracco Diagnostics, Inc., No. CV 18-10212, 2019 WL 2869077 (E.D. La., July 3, 2019). 28. Legal Information Institute. Federal Rules of Civil Procedure Rule 12. Defenses and objections: when and how presented; motion for judgment on the pleadings; consolidating motions; waiving defenses; pretrial hearing. Available at: https://www.law.cornell.edu/rules/frcp/ rule_12. Accessed September 15, 2019. 29. Hines N. Why technology provides compelling reasons to apply a Daubert analysis to the legal standard of care in medical malpractice Q6 cases. Duke L. and Tech. Rev November 2 2006. 30. Legal Information Institute. Federal Rules of Evidence Rule 702. Testimony by expert witnesses. Available at: https://www.law.cornell. edu/rules/fre/rule_702. Accessed September 15, 2019. 31. Marcum v Adventist Health Sys./W., 345 Or. 237, 252, 193 P.3d 1, 9 (2008). 32. Drescher v Bracco Diagnostics Incorporated et al., 4:2019cv00096, 28: 1332 (D. Ariz., Feb 25, 2019).
33. Smith v GE Health Care, Inc., No. CV 19-0492, 2019 WL 4551622 (W.D. La., Sept 19, 2019). 34. Hedlund v Gov’t of the Virgin Islands, No. ST-13-CV-279, 2015 WL 5439748 (V.I. Super., Sept 10, 2015). 35. Towner v Doe, No. 907-CV-1343 TJM DRH, 2008 WL 324231 (N. D.N.Y., Feb 5, 2008). 36. Andes Estate v. United States, No. 1:19CV00005, 2019 WL 3557885 (W.D. Va., Aug 5, 2019). 37. Sartwelle TP, Johnston JC. Cerebral palsy litigation: change course or abandon ship. J Child Neurol 2015;30:828-41. 38. Bussi S, Coppo A, Botteron C, et al. Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging 2018;47:746-52. 39. Bussi S, Maisano F, Tedoldi F, Kirchin MA. Gadolinium retention and clearance after administration of macrocyclic magnetic resonance contrast agents to rats. Pediatr Radiol 2019;49:1110-1. 40. Hazelton JM, Chiu MK, Abujudeh HH. Nephrogenic systemic fibrosis: a review of history, pathophysiology, and current guidelines. Curr Radiol Rep 2019;7:5. 41. Argy N. Gadolinium risk management: 3 pillars for a sound strategy. Radiology Business. Available at: https://www.radiologybusiness.com/ topics/care-delivery/gadolinium-risk-management-3-pillars-soundstrategy. Published February 19, 2019. Accessed September 15, 2019.
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ORIGINAL ARTICLE
Gadolinium Deposition Disease: A New Risk Management Threat Q8
H. Benjamin Harvey, MD, JD a,b,c , Vrushab Gowda, BS d, Glen Cheng, MD, JD a,e Abstract Gadolinium-based contrast agents (GBCA) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30% of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety profile and attendant medicolegal liability associated with GBCAs changed dramatically in 2016 with the description of gadolinium deposition disease (GDD). Despite being unproven scientifically, a groundswell of GDD-related litigation and personal injury advertising targeting potential GDD patients has occurred. In this article, we describe what GDD is, (2) why GDD has created medicolegal risk, and (3) how can this risk can be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months post-GBCA administration. As such, the authors recommend the use of gadoteridol as the default GBCA and administering other GBCAs, including linear agents, only when clinically necessary. Key Words: Gadolinium, gadolinium deposition disease, lawsuit, liability, risk management J Am Coll Radiol 2019;-:---. Copyright ª 2019 American College of Radiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
INTRODUCTION Contrast agents further enhance the diagnostic power of MRIs and have found particular application in angiography and oncologic imaging. Structurally, they consist of a linear or macrocyclic carrier ligand chelated to a paramagnetic metal ion, which serves to reduce T1 relaxation time and facilitate visualization of perfused structures. These compounds most commonly contain gadolinium(III) as the active material, although iron oxide– and manganese-based agents are also employed [1]. Gadolinium-based contrast agents (GBCAs) have enjoyed wide use since their introduction some 30 years ago, with some 450 million doses administered worldwide to date [2]. They are generally well
a
Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital Department of Radiology, Boston, Massachusetts. c Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts. d Harvard Law School, Cambridge, Massachusetts. e Harvard T.H. Chan School of Public Health, Environmental and Occupational Medicine and Epidemiology. Corresponding author and reprints: H. Benjamin Harvey, MD, JD, Department of Radiology, Massachusetts General Hospital, Institute for Technology Assessment, 175 Cambridge Street, Suite 200, Boston, MA 02114; e-mail: [email protected]. The authors state that they have no conflict of interest related to the maQ 1 terial discussed in this article. b
tolerated and associated with lower rates of adverse events than iodinated contrast agents [3]. Despite their ubiquity, however, GBCAs are not without their risks. Alongside hypersensitivity reactions, acute nephrotoxicity, transient encephalopathy, and nephrogenic systemic fibrosis (NSF) has been identified as a potentially debilitating process associated with GBCA exposure [4]. A newly proposed pathology joined this complement in 2016: gadolinium deposition disease (GDD) [5]. Although shrouded in controversy as to its pathophysiologic mechanism, modifiable risk factors, and even existence as a disease in its own right, GDD has grown salient in the public eye—a fact not lost on personal injury attorneys. The increasing risk exposure created by the advent of GDD bears far-reaching implications for health systems, referring physicians, and radiologists. This article surveys the landscape facing these stakeholders by asking three questions: (1) what GDD is, (2) why GDD creates medicolegal risk, and (3) how this risk can be mitigated.
FROM DEPOSITION TO DISEASE: CORRELATION OR CAUSATION? It has long been known that GBCA administration leaves behind residual gadolinium. Studies have demonstrated its uptake in various tissues, including bone, kidney, and the
Copyright ª 2019 American College of Radiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1546-1440/19/$36.00 n https://doi.org/10.1016/j.jacr.2019.11.009
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brain, even in patients with an intact blood-brain barrier, preserved renal function, and normal hepatic clearance [68]. Interestingly, gadolinium preferentially deposits within the brain in the dentate nuclei and globi pallidi, perhaps conveyed to these structures through the recently discovered glymphatic system [9,10]. Although both linear and macrocyclic GBCAs alike collect within the brain, linear agents (eg, gadopentetate, gadobenate, gadodiamide, gadoxetate) are particularly prone to deposition [11,12]. Not until recently, however, has a pathological consequence to this deposition been suggested. In 2016, Semelka et al first described a constellation of self-reported symptoms in patients who had received GBCAs [5]. Suggesting causation from correlation, the authors postulated this symptomatology to represent GDD and went on to propose diagnostic criteria for this newly proposed disease. To meet the diagnostic criterion for GDD, a patient must exhibit at least three of the following five broad symptom clusters within a period of hours to 2 months post-GBCA administration: (1) peripheral neuropathic pain in either a “glove and stocking” or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain [5,13]. Furthermore, it was proposed that GDD may clinically manifest after the initial infusion of GBCA or after multiple administrations in a dose-dependent manner [14,15]. As the precise mechanism—or even true existence—of the disease has yet to be characterized, a number of theories concerning the pathophysiological basis of GDD have been floated. Some have postulated that gadolinium competitively inhibits calcium channels, thereby interfering with proper neurologic function [16,17]. Separately, GDD symptomatology may causally depend on impaired heavy metal metabolism, itself a consequence of heredity. For instance, data have demonstrated elevated risk among women of European descent, although more robust genelevel studies are needed to more appropriately identify genetic predisposition [18]. Similar to other heavy metal toxicities, chelation treatment has been proposed for GDD. Diethylenetriaminepentaacetic acid has demonstrated clinical benefit, followed by ethylenediaminetetraacetic acid and deferoxamine [19]. GDD, although still unproven, has nonetheless resulted in an impressive regulatory and industry response. Shortly following the initial description of GDD, the ACR and the American Society of Neuroradiology issued a position statement concerning the use of GBCAs, calling for providers to consider “multiple factors . . . when selecting a GBCA, including diagnostic efficacy, relaxivity, rate of adverse reactions, dosing/concentration, and propensity to 2
deposit in more sensitive organs such as the brain” [20]. The US FDA convened the Medical Imaging Drugs Advisory Committee in May and September 2017, which yielded a 692-page transcript of meeting minutes. This panel concluded with “fair uniformity that there is no evidence of a causal relationship between the symptoms and signs in patients with normal renal function and the retention of gadolinium” [21]. Despite this statement, the FDA took the remarkable step of requiring imaging centers to distribute patient Medication Guides to better apprise patients of GBCA-associated risks prior to administration [22]. The European Medicines Agency went one step further by restricting the use of certain linear GBCAs, all the while concluding that “there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients” [23]. The glaring discordance between these regulatory actions and the regulatory-convened scientific panel statements of “no causality” is confusing for medical practitioners, patients, and juries alike.
SYSTEMS-LEVEL SIGNIFICANCE: THE ELEPHANT IN THE COURTROOM Unlike NSF, GDD is marked by a significantly larger risk footprint. The limited epidemiological understanding of this proposed disease process does not permit a fine resolution of population-level data at present. However, recent studies have posited markedly high prevalence of GDD-like symptomatology among patients receiving GBCA. For instance, a recent article from Parillo et al suggests that 13% of patients who received the macrocyclic GBCA gadoterate meglumine experienced GDD-like symptoms [24]. This is alarming, considering that as many as 39 million MRI scans are performed in the United States each year and as many as 12 million of these patients require GBCA administration. A pool of potential plaintiffs growing by over 1 million per annum is sufficiently large for institutional actors to take heed, and large health systems are increasingly making enterprise-level formulary switches primarily to mitigate this risk exposure. In the wake of NSF, personal injury attorneys are no stranger to GBCA-based lawsuits. In fact, a simple web search will show that many personal injury attorneys are already active in the GDD space, including in ongoing multidistrict litigation. Based on case characteristics alone, it is likely that GDD cases will only proliferate over time [25]. There is a vast pool of potential plaintiffs, bearing low costs of capture and still lower barriers to entry. Because GDD clinical diagnostic criteria are largely subjective, their existence is difficult to disprove [5]. Nonspecific and transient constitutional, neurologic, and dermatologic features post-GBCA administration that extend beyond Journal of the American College of Radiology Volume - n Number - n Month 2019
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the formal GDD diagnostic criteria may represent confounding sources of symptomatology leading to an overdiagnosis of GDD post hoc [24]. And finally, the emergence of these symptoms is dispersed over 2 months, which limits diagnostic precision. Notwithstanding the nebulous (and not yet identified) pathologic mechanism of GDD, many courts have to date been unwilling to dismiss GDD personal injury claims. Although defendants have moved to dismiss the claims on the grounds that a scientific consensus is lacking, several courts to date have found that the claims meet a “minimum threshold of plausibility” [26]. These rulings have stymied defendants’ motions to compel the judge to discard these suits owing to a failure to state a claim upon which relief can be granted [27,28]. Moreover, a growing corpus of GDD-related medical literature may now suffice to pass the Daubert standard, which serves to exclude unqualified technical evidence [29-31]. Some trends have emerged from the body of existing GDD lawsuits. The majority apply tort theories of both negligence and strict liability, turning on inadequate labeling and defective design to permit fault-independent recovery [32]. Others advance their claims according to contract doctrine, such as breach of the implied warranty of safety [33]. Although to date most GDD lawsuits attach liability to the GBCA manufacturer, this can fairly be expected to change as the field develops. Looking to the history of NSF litigation by analogy, plaintiffs have in many cases sued a wide range of defendants: government hospitals, state correctional facilities, the Department of Veterans Affairs, as well as individual physicians as private parties [34-36]. A review of GDD lawsuits shows that cases have proceeded irrespective of the fact that GBCA administration is standard of care. This is particularly true when case theories assert negligent choice of GBCA (ie, choosing a GBCA that results in greater brain deposition than necessary). ACR and American Society of Neuroradiology opinions affirming the general safety of these agents to date have not proven dispositive in litigation; likewise, a review of cerebral palsy suits shows that the American College of Obstetrics and Gynecology professional opinion has not historically been accorded decisive weight [37].
RISK MANAGEMENT STRATEGIES: REDUCING BRAIN RETENTION DURING THE EARLY WINDOW Multiple varieties of GBCA exist, each with differing risk profiles. Thus, by choosing the right GBCA, radiologists and referrers likely have the ability to significantly reduce their risk exposure. Experience from NSF lawsuits shows
that litigation has often been mitigated through the use of class II agents and judicious estimated glomerular filtration rate precautions. Although the ACR has yet to articulate specific practice recommendations, this article advocates adoption of a similar approach to GBCA selection to mitigate the risk of GDD. To begin, macrocyclic GBCAs should be used over linear agents whenever appropriate, because it is well established that the latter more avidly deposits within tissues such as the brain and kidneys. Moreover, significant differences between GBCAs also exist within the macrocyclic class of GBCAs. Among macrocyclics, gadoteridol offers significant advantages over its peers from a risk management perspective, with animal studies demonstrating significantly lower retention and more efficient clearance in cerebral, cerebellar, and renal tissue [38,39]. These findings have been replicated in a recent well-conducted confirmatory study and affirmed by Hani Abujudeh, author of the textbook Quality and Safety in Radiology and one of the first Q 2 radiologist to describe NSF. In a recent review article, Dr Abujudeh noted that “an increasing number of health systems [are switching] to gadoteridol given its markedly lower levels of gadolinium retention in the brain and kidneys” [12,40]. The risk management benefits of gadoteridol have also been extolled by attorney and risk management expert Dr Nicholas Argy [41]. From a practical standpoint, a data-driven strategy of risk mitigation grounded in the well-conducted studies described previously is likely to be simultaneously palatable, attractive, and straightforward to both patients and potential juries. Thus, based on the current data, we outline the foregoing strategy for risk mitigation based on the use of gadoteridol as the default GBCA. Such an approach aims to minimize gadolinium retention in the brain during the GDD-sensitive time window of the first 2 months postadministration. This should not be construed as a brightline rule; providers should not hesitate to use other GBCAs, including linear agents when clinically advisable, such as with hepatic or tumor imaging. Moreover, many facilities may not retain a ready supply of gadoteridol; in its absence, providers should consider implementing an informed consent process that alerts the patient, among other things, to the possibility of increased gadolinium retention in the brain compared with other GBCA options and their ability to seek imaging elsewhere if a different GBCA is preferred. One perverse reality of this risk management issue is that the radiologists and referring physicians who are exposed to GDD-related liability are often not the individuals tasked with making the GBCA decision. As such, it is important for physicians to communicate to the pharmacy staff, clinical administrators, and risk managers who make the
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enterprise-level formulary decisions the importance of considering GDD-related liability when selecting a GBCA.
CONCLUSION Q7
Although the science of GDD is uncertain at best, health care providers would nonetheless be well advised to proactively guard against GDD and its attendant liability. The benefits of a risk mitigation strategy could be substantial— including averting costly and disruptive litigation. Based on the current data and regulatory statements, this article advocates for a risk mitigation strategy focused on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months after GBCA administration. As such, the authors recommend the use of gadoteridol as the default GBCA, with other GBCAs, including linear agents, used only when clinically advisable. Caution in GBCA choice now could pay high dividends in avoiding costly GDD claims down the road.
TAKE-HOME POINTS -
Increasing risk exposure created by the advent of GDD bears far-reaching implications for health systems, referring physicians, and radiologists.
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GDD, although still unproven, has nonetheless resulted in an impressive regulatory and industry response, and many courts have to date been unwilling to dismiss GDD personal injury claims.
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Unlike NSF, GDD is marked by a significantly larger risk footprint.
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The preferred risk mitigation strategy is focused on appropriate usage of GBCAs and on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months when GBCAs are needed.
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The authors, in agreement with other risk management experts, recommend the use of gadoteridol as the default GBCA, and the use of other GBCAs, including linear agents, only when clinically necessary.
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