Gadolinium-based Contrast Agents: Patient Safety Concerns

Professional Review Gadolinium-based Contrast Agents: Patient Safety Concerns Christy Foster-Bollman, MAS, R.R.A., R.T.(R)(CT)(MR) Tim K Mackey, MAS, PhD A rare earth metal with paramagnetic properties, gadolinium is useful as a magnetic resonance (MR) imaging contrast agent.1 Because freestate gadolinium is toxic to the human body, it is bound with other agents for stability to ensure the metal is inert when injected into a patient. Gadolinium is the only contrast agent approved by the U.S. Food and Drug Administration (FDA) to image most body organs and tissues during MR imaging. It helps radiologists visualize tumors, infection, differences between normal and scar tissue, and other abnormalities. Although some contrast agents approved for MR to assess only the liver are not gadolinium-based, their use is rare in clinical settings. Gadolinium-based contrast agents (GBCAs) are considered safe for patients with normal kidney function; however, if the patient’s renal function is impaired, GBCAs can increase the risk of nephrogenic systemic fibrosis (NSF), a debilitating disease. NSF rarely occurs in healthy patients. When a patient has renal impairment or delayed renal function, gadolinium can dissociate and bond to other tissues in the body, leading to increased patient safety risks, including NSF. GBCA complexes are divided into 3 classes based on structural and electronic considerations: linear nonionic complexes, linear ionic complexes, and nonionic macrocyclic complexes (see Table 1).2 Imaging with gadolinium began in the 1980s when it was discovered that patients were experiencing contrast-induced nephropathy from 552CT iodinated contrast media. 4 According to the prevailing theory at the time, patients with reduced kidney function would be safe when GBCAs were used; however, gadolinium dosing was applied inconsistently during the early years of MR imaging. Now gadolinium injection volume is based on a calculation called estimated glomerular filtration rate (GFR), which incorporates the patient’s age, weight, and serum creatinine level. Although various estimated GFR calculators are available to determine the appropriate volume of gadolinium to inject, they are used inconsistently in MR imaging. Severe reactions to GBCAs are rare. The most common reactions are brief headache, nausea, and dizziness, as well as dysgeusia, feeling hot, and injection site irritations. 5 Gadolinium toxicity symptoms include pain, dermal changes, cognitive symptoms, balance problems, and edema. 6 Overall, the FDA considers GBCAs to be safe, having received 40 reports of GBCA deaths unrelated to NSF in the United States from 2004 to 2009.2 However, gadolinium was retained in brain tumors of some subjects who underwent MR studies using GBCAs, and gadolinium toxicity can occur even when the patient’s kidney function is normal. 6 Kidney Function Test Limitations The National Kidney Foundation published a list of guidelines for early detection, evaluation, diagnosis, and treatment of kidney disease.7 The foundation assessed the degree of kidney dysfunction by estimated GFR, RADIOLOGIC TECHNOLOGY, May/June 2016, Volume 87, Number 5 Professional Review Foster-Bollman, Mackey Table 1 Gadolinium-based Drugs Drug Class Description Gadobutrol (Gadavist) Macrocyclic nonionic chelate, which binds the gadolinium ion in a cage that gives it added strength as compared to a linear complex3 Considered the safest to transport through the body and is excreted by the kidneys. Newer contrast on the market has not been part of recent FDA risk data, although mechanically it provides additional protection for patients because it chemically bonds differently from other GBCAs.3 Gadodiamide (Omniscan) Linear nonionic complex Detected as having a higher prevalence or odds ratio for NSF in 4 out of 6 studies.2 Gadobenate dimeglumine (MultiHance) Linear ionic complex Had a high prevalence of NSF in 1 in 6 studies.2 Abbreviations: FDA, U.S. Food and Drug Administration; GBCA, gadolinium-based contrast agent; NSF, nephrogenic systemic fibrosis. which it deemed to be the best method for evaluating, classifying, and staging chronic kidney disease, a critical risk component when administering GBCAs.7 The GFR does not measure kidney function; rather, it assesses the number of functional nephrons not related directly to kidney function. Therefore, the GFR helps clinicians determine the degree of renal dysfunction or chronic kidney disease progression. The most common lab value to calculate GFR is serum creatinine, which has been used to evaluate kidney function for many years. However, many variables make serum creatinine levels an unreliable value when assessing overall kidney function (see Box). Medications can interfere with creatinine assay results, which can affect the accuracy of a serum creatinine level.6 Two commonly used formulas inform the GFR: Cockcroft-Gault and Modification of Diet in Renal Disease. Both formulas incorporate the serum creatinine value, along with age, sex, and weight. The CockcroftGault formula uses the inverse of the serum creatinine and the patient’s weight to estimate creatinine clearances. Limitations to using patients’ weight in these calculations include the formula’s characterizing a weight increase as an increase in muscle mass, not body surface area, which can adversely affect the formula’s accuracy. The Modification of Diet in Renal Disease calculator has been reformulated for use with a standard serum creatinine assay. It accounts for age, sex, and patient weight and calculates for African American ethnicity to accommodate higher muscle mass but does not compensate RADIOLOGIC TECHNOLOGY, May/June 2016, Volume 87, Number 5 Box Factors Affecting Serum Creatinine Levels7 Factors that can decrease serum creatinine levels include:  Aging-related decreases in muscle mass.  Sex, specifically female.  Hispanic or Asian ethnicity.  A vegetarian diet. Factors that can increase serum creatinine levels include:  African American ethnicity.  High muscle mass.  Ingesting cooked meats.  Taking potassium-sparing diuretics.  Glucose intake. for ethnicities whose members might have lower muscle mass. Significantly, the Modification of Diet in Renal Disease calculator has built-in adjustments to compensate for body surface area and is considered more accurate than the Cockcroft-Gault formula.7 Adding another layer of complexity to the issue is the variability in the creatinine-based equations that calculate serum creatinine levels. Each laboratory employs its own formula, which could cause variations among patients’ results. For example, a patient could have a 0.8 mg/dL serum creatinine in one facility, and another facility could present it at 1.2 mg/dL. Both measurements fall within the normal range,7 but the difference could be sufficient to change the GFR calculator and shift a patient’s results from normal to a result 553CT Professional Review Gadolinium-based Contrast Agents: Patient Safety Concerns considered renal failure on the chronic kidney disease charts. Nephrogenic Systemic Fibrosis The potential adverse effects of GBCAs in MR imaging were not known until 1997.8 The recognition of NSF began with the identification of a condition called nephrogenic fibrosing dermopathy, in which the skin of patients suffering from renal disease underwent changes.9 Gadolinium deposited in the skin was confirmed after a biopsy was performed on a patient who had scleromyxedema-like cutaneous disease. Postmortem evaluations revealed the fibroses extended into organ systems other than the skin. As a result, the name was changed to nephrogenic systemic fibrosis to reflect the disease process accurately.10 NSF affects the skin and connective tissues such as the lungs, heart, liver, and muscle, including the diaphragm.11 NSF affects patients who have abnormal kidney function. Consequently, its incidence can be associated directly with the combination of gadolinium exposure and impaired renal function. Common signs of NSF include4,10:  Tightening or thickening of the skin.  Reddened or darkening patches with plaques.  A woody texture to the skin, similar to an orange peel.  Swollen hands and feet with blisters.  Burning, itching, or severe sharp pains in the affected area such as the ribs and the hip.  Yellow patches on the eyes. NSF can be debilitating when joints are involved and can be fatal when it involves internal organs.12 The risk of NSF from gadolinium use in MR imaging led the FDA to issue a “black box warning” on all GBCAs in 2007.7 The black box warning is the FDA’s most serious warning, indicating a product’s potential to cause significant patient harm or even death. The warning informs patients and clinicians about the dangers, risks, and safety concerns connected with gadolinium, specifically for patients with acute or chronic renal insufficiency, acute renal insufficiency due to hepatorenal syndrome, or postoperative liver transplant patients with an estimated GFR of less than 30 mL/min/1.73 m2 . Clinicians should avoid using 554CT GBCAs with these patient populations because of the increased chance of NSF.13 The warning also emphasizes the need to screen all patients for renal insufficiency using a patient history questionnaire and laboratory tests to identify patients at risk for NSF.13 In addition, clinicians administering GBCAs should not exceed the recommended dose and must allow time for the contrast to be filtered from the body before the next dose.8 Since the FDA published the black box warning, the number of reported NSF cases has dropped significantly. This could be a result of the FDA’s recommendations to check patients’ estimated GFR before contrast administration and the instructions to avoid using contrast if the patient presents any clinical contraindications to GBCA administration. Despite warnings about GBCA use in medical imaging, patient injury and medical malpractice claims persist, prompting a need for further policy solutions and risk management strategies. However, it might be difficult for a patient to claim that NSF was triggered by a particular injection because patients might receive multiple GBCA injections and could suffer from multiple health issues that mask its adverse effects. Clinical Practice Guidelines The American College of Radiology (ACR) provides guidelines for contrast injections, but a set of universal policies for all facilities that would govern GBCA injection practices is not available. Specifically, the ACR Committee on Drugs and Contrast Media has stated that patients who receive GBCA should be considered at risk for developing NSF, if certain conditions apply.13 ACR guidelines also state that simply asking patients whether they have problems with their kidney function is insufficient because a patient could be experiencing chronic kidney disease and not be aware of it (ie, their kidney disease might be an undiagnosed condition). The ACR also suggests that technologists ask questions to determine whether the patient has underlying kidney disease (see Table 2).13 Asking questions related to kidney disease risk is worthwhile. As people age, their renal function diminishes as part of the body’s natural aging process. A history of renal disease or injury could indicate compromised kidney function or an endangered kidney. Any history of hypertension, especially if uncontrolled, could be a sign RADIOLOGIC TECHNOLOGY, May/June 2016, Volume 87, Number 5 Professional Review Foster-Bollman, Mackey Table 2 American College of Radiology Guidance on GBCA Injection Risk Screening13 Patients At Risk for Nephrogenic Systemic Fibrosis Questions That Help Identify Underlying Kidney Disease 1. On dialysis (of any form). 1. Is the patient older than age 60? 2. Severe or end-stage chronic kidney disease stage 4 or 5, estimated GFR  30 mL/min/1.73 m2 without dialysis. 2. Does the patient have a history of renal disease, including dialysis, kidney transplant, a single kidney, or kidney surgery? 3. Estimated GFR 30-40 mL/min/1.73 m2 without dialysis. 3. Is there a history of known cancer involving the kidney(s)? 4. Acute kidney injury patients with estimated GFR 30-40 mL/min/1.73 m2 also should be considered at risk. Estimated GFR levels can fluctuate from the 30-40 mL/min/1.73 m2 one day and to  30 mL/min/1.73 m2 the next. 4. Is there a history of hypertension requiring medical therapy? 5. Has the patient ever been diagnosed with diabetes mellitus? Abbreviations: GFR, glomerular filtration rate. of underlying kidney issues and possibly the kidney function itself. A patient with diabetes mellitus might have decreased kidney function as a consequence of the disease or medications used to control it.13 The ACR provides a chart to guide radiology staff, including radiologists and radiology nurses, in ordering new estimated GFR laboratory tests for increased risk outpatients before a new MR scan based on risk factors for compromised renal function. Recommendations Clinicians, technologists, and patients face a shared challenge in determining safety with GBCAs. A reliable assessment of the patient includes an accurately measured standard serum creatinine and a GFR formula that is consistent and accepted universally. These could have significant repercussions for patient safety and GBCA-related adverse events. Patients with kidney disease have the right to know that GBCA administration can lead to NSF. To address this challenge, informed consent could be better tailored and applied universally to GBCA administration in a clinical setting. Informed consent is the cornerstone of patients’ rights, and patients have a right to know the potential dangers of any clinical treatment so they can make informed decisions. Because radiologic technologists act on a standing order from a radiologist to inject patients with a GBCA, they are the primary patient interface and might be in the best position to educate them about the potential risk of NSF and administer RADIOLOGIC TECHNOLOGY, May/June 2016, Volume 87, Number 5 targeted informed consent that details the risks and benefits of the MR scan. Alternatively, a radiologist could administer a targeted informed consent form to patients with a GFR of between 30 and 60 because those patients are considered at higher risk for NSF. GBCAs are not as safe as once thought, and patient awareness is lacking. Research shows potential complications resulting from injecting this contrast media.6 Injecting GBCAs without patients’ informed consent puts the patient at heightened risk for adverse events and the facility and the technologist at risk for legal proceedings. Given the risks for all parties, ACR guidance for GBCA-related risks and NSF could be more specific. The ACR is in an optimal position to translate updated guidelines into a patient-centric informed consent form for medical professionals to administer to specific at-risk patients, especially in state jurisdictions that employ the reasonable patient standard for informed consent. The process could begin with ACR members developing a model informed consent form for patients who meet risk criteria for GBCA–associated NSF, targeting states that promote safe injection practices and focus on improving patient safety outcomes. Christy Foster-Bollman, MAS, R.R.A., R.T.(R)(CT) (MR), is program director and assistant professor in the radiologic technology program for San Diego Mesa College, San Diego, California. 555CT Professional Review Gadolinium-based Contrast Agents: Patient Safety Concerns Tim K Mackey, MAS, PhD, is associate program director with the joint master’s degree program in health policy and law for University of California, San Diego School of Medicine and California Western School of Law and assistant professor for the University of California, San Diego School of Medicine Department of Anesthesiology, Division of Global Public Health, San Diego, California. References 1. Decker v GE Healthcare Inc, 770 F3d 378 (6th Cir 2014). 2. Krefting I. Joint meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees. Gadolinium-based contrast agents (GBCAs) & nephrogenic systemic fibrosis (NSF). http://www.fda.gov /downloads/AdvisoryCommittees/CommitteesMeeting Materials/Drugs/CardiovascularandRenalDrugsAdvisory Committee/UCM196218.pdf. Published December 8, 2009. Accessed March 9, 2016. 3. American College of Radiology. Adverse reactions to gadolinium. In: ACR Manual on Contrast Media-Version 9, 2013. 77-80. 4. Cowper SE. Nephrogenic Systemic Fibrosis (ICNSFR) Web site. http://www.icnsfr.org. Updated June 15, 2013. Accessed May 22, 2015. 5. Molan M, Goergen S. Gadolinium contrast medium (MRI contrast agents). InsideRadiology Web site. http://www .insideradiology.com.au/pages/view.php?T_id=38#.VV-E -mTBzGc. Updated May 1, 2009. Accessed March 9, 2016. 6. The Lighthouse Project. Symptoms associated with gadolinium toxicity. Gadolinium Toxicity Web site. http://gadolini umtoxicity.com/help/symptoms/. Published 2015. Accessed March 9, 2016. 7. Lascano ME, Poggio ED. Kidney function assessment by creatinine-based estimation equations. Cleveland Clinic Web site. http://www.clevelandclinicmeded.com/medicalpubs/dis easemanagement/nephrology/kidney-function/default.htm. Published August 2010. Accessed March 9, 2016. 8. Questions and answers on gadolinium-based contrast agents. U.S. Food and Drug Administration Web site. http://www.fda .gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm142889 .htm. Updated July 30, 2014. Accessed March 9, 2016. 9. Deng A, Martin DB, Spillane A, et al. Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling. J Cutan Pathol. 2010;37(2):204-210. doi:10.1111/j.1600 -0560.2009.01301.x. 10. Scheinfeld NS, Cowper S. Nephrogenic systemic fibrosis. Medscape Drugs & Diseases Web site. http://emedicine.med 556CT scape.com/article/1097889-overview. Updated February 8, 2016. Accessed March 9, 2016. 11. Grobner T. Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108. 12. FDA: new warnings required on use of gadolinium-based contrast agents. U.S. Food and Drug Administration Web site. http://www.fda.gov/NewsEvents/Newsroom/PressAnnoun cements/ucm225286.htm. Published September 9, 2010. Accessed March 9, 2016. 13. Gadavist (gadobutrol) injection 1 mmol/mL. Bayer in Radiology Web site. https://www.radiologysolutions.bayer .com/products/mr/contrast/gadavist/. Accessed March 9, 2016. RADIOLOGIC TECHNOLOGY, May/June 2016, Volume 87, Number 5