Guidelines on the Administration of Intravenous Gadolinium-Containing Contrast Media

Updated 9/1/2011

Formulated by the UCSF Department of Radiology MRI Safety Committee, and based on FDA recommendations, ACR guidelines, and published medical literature

Overview

• Risk of gadolinium administration in patients with impaired kidney function

• Choice of gadolinium-containing contrast medium

• Approach to intravenous gadolinium use in patients with impaired kidney function
• Role of dialysis after gadolinium administration in patients with renal impairment

• Creatinine testing prior to gadolinium administration

• Estimated glomerular filtration rate (eGFR) calculation
• eGFR and intravenous gadolinium administration
• Pediatric eGFR and intravenous gadolinium administration
• Off-label use of contrast media and power injectors
• Gadolinium use in pregnancy
• Useful Links

Risk of gadolinium administration in patients with impaired kidney function

Historically, the administration of intravenous gadolinium-containing contrast media was considered safe in patients with impaired renal function. In 2006, the FDA first reported the association of a serious and debilitating condition known as nephrogenic systemic fibrosis (NSF) with the prior administration of gadolinium. NSF is a rare but serious systemic disease characterized by fibrosis of the skin and other tissues throughout the body. NSF is generally seen in the middle-aged, but has also been reported in the elderly and pediatric population. The exact etiology of this disease is unclear but most of the reported cases of NSF have been documented in patients who received intravenous gadolinium and have severe acute or chronic renal failure, with a glomerular filtration rate (GFR) < 30. Only two cases of NSF have been reported in patients with a GFR > 30¹. In 2009, the FDA determined that moderate renal impairment (eGFR of 30-60) was NOT a risk factor for NSF, reversing the position it had taken in December 2006, and stated² “The December information was based upon reports of NSF among patients with purportedly moderate renal insufficiency.  Since issuing the information in December 2006, FDA has received new information regarding these patients.  Additional details have clarified that the patients actually were in acute renal failure at the time they received a gadolinium based contrast agent. Considering this clarification, FDA has not received reports of NSF among patients with normal renal function or moderate renal insufficiency”. Many of the reported cases of NSF have been in patients before or after liver transplant. Other co morbidities have been described in patients who developed NSF, including acute pro-inflammatory states, metabolic acidosis, increased iron, calcium or phosphate levels, immunosuppression, vasculopathy, high dose erythropoietine therapy and infection³. Many published series have suggested an increased risk of NSF development in patients exposed to high doses and multiple doses of gadolinium, however cases with single doses (0.1mmol/kg) have also been reported. A recent meta-analysis including the seven major papers about NSF reported an odds ratio of 26.7 (95% CI = 10.3-69.4) for development of NSF after gadolinium administration in patients with impaired renal function (GFR < 30)⁴. The incidence of NSF in patients with severe renal dysfunction (GFR < 30) varies from 0.19 to 4%^5-7. As of October 2007, of the 431 of the cases reported from the FDA Freedom of Information system to the authors of a review paper in the topic, 283 were associated with Omniscan, 125 were associated with Magnevist, 20 were associated with Opti-MARK, 9 were associated with ProHance (8 of which were also exposed to other agents), and 10 were associated with MultiHance (8 of which were also exposed to other agents)⁸. A recent publication from a single institution has recently demonstrated a positive impact of screening for NSF risk factors prior to administration of gadolinium. After guidelines based on ACR/FDA recommendations where applied, the incidence of the disease fell from 36.5/100,000 patients to 4/100,000 patients⁹.

Key point: Nephrogenic systemic fibrosis (NSF) is associated with the administration of intravenous gadolinium. The primary risk factor is renal failure (patient on dialysis or with a GFR < 30). 

1. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007; 243:148-157.
2. FDA Drug Safety Newsletter. Updated 8/13/2009. Available at http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm142889.htm.
3. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media.
4. Agarwal R, Brunelli SM, Williams K, Mitchell MD, Feldman HI, Umscheid CA. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant 2009;24: 856-863.
5. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007;188: 586-592.
6. Hope TA, Herfkens RJ, Denianke KS, Leboit PE, Hung YY, Weil E. Nephrogenic Systemic Fibrosis in Patients With Chronic Kidney Disease Who Received Gadopentetate Dimeglumine. Invest Radiol 2009.
7. Shabana WM, Cohan RH, Ellis JH, et al. Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am J Roentgenol 2008;190:736-741.
8. Penfield JG, Reilly RF. Nephrogenic systemic fibrosis risk: is there a difference between gadolinium-based contrast agents? Semin Dial 2008; 21:129-134.
9. Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA. Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases. Radiology 2009;250: 371-377.

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Choice of gadolinium-containing contrast medium

The ACR recognizes three categories of gadolinium-containing contrast media with respect to risk of nephrogenic systemic fibrosis¹. These are listed below. For simplicity, only those agents approved for use in the United States by the FDA are included:

• Agents associated with the greatest number of NSF cases
  • Gadodiamide (Omniscan)
  • Gadopentetate dimeglumine (Magnevist)
  • Gadoversetamide (OptiMARK)
• Agents associated with few, if any, unconfounded cases of NSF
  • Gadobenate dimeglumine (MultiHance)
  • Gadoteridol (ProHance)
• Agents which have only recently appeared on the market in the US
  • Gadofosveset (Ablavar)
  • Gadoxetic acid (Eovist)

This categorization suggests that gadobenate dimeglumine (MultiHance) or gadoteridol (ProHance) are preferable agents for patients at high risk for nephrogenic systemic fibrosis (i.e., eGFR < 30), and gadobenate dimeglumine (MultiHance) is available at UCSF for use in such selected patients, but should only be used when there is a compelling clinical indication and should only be given as a single dose. It should be noted that the FDA does not differentiate between gadolinium containing contrast media with respect to the risk of NSF, regarding the evidence as insufficient to make a definitive determination². Based on the FDA approach and our departmental experience, we continue to use gadopentetate dimeglumine (Magnevist) as our routine gadolinium containing contrast medium.

Key point: Gadopentetate dimeglumine (Magnevist) is the routine gadolinium containing contrast medium used in our department. Gadobenate dimeglumine (MultiHance) is available for use in patients at high risk for nephrogenic systemic fibrosis (i.e., eGFR < 30).

1. FDA Drug Safety Newsletter, 9/13/2010. Available at http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm.
2. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media.
3. FDA Drug Safety Newsletter. Updated 8/13/2009. Available at http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm142889.htm

 

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Approach to intravenous gadolinium use in patients with impaired kidney function

The relative risk to benefit of intravenous gadolinium in patients with severely impaired kidney function should be carefully considered by the referring physician and radiologist with input from a nephrologist if necessary. Particular caution should be considered in patients with acute renal failure or evidence of co-existing severe liver disease. No patient should be denied any imaging investigation that is critical to clinical management, which takes precedent over any other cautionary measures. Informed consent should be obtained by the radiologist if intravenous gadolinium is to be given to high risk patients.

Key point: Gadolinium should only be given to a patient who is on dialysis or has a GFR < 30 if the imaging study is considered critical to clinical management AND informed consent has been obtained by a radiologist.

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Role of dialysis after gadolinium administration in patients with renal impairment

Dialysis does not protect patients from developing NSF¹. Studies have shown that the serum concentration of gadolinium is significantly decreased after hemodialysis, however, there is no information regarding residual tissue amounts². Theoretically, the sooner the dialysis session is performed the less amount of contrast agent is deposited in the tissues. Therefore, all patients already receiving dialysis treatment should be scheduled for dialysis as soon as practical following the gadolinium-enhanced MRI and preferably within 24 hours. This should be arranged by the requesting physician in consultation with the patient’s outpatient nephrologist and dialysis unit. Routine MRI studies should be scheduled in the morning and dialysis scheduled in the afternoon following the study; radiology scheduling staff will give morning slot priority to dialysis patients. Administration of hemodialysis promptly after gadolinium may require altering the patient’s regular outpatient dialysis schedule and advance communication several days in advance with the nephrologist and dialysis unit. There is general consensus that a patient with chronic kidney disease who is not already dialysis dependent should not be started on dialysis after administration of gadolinium for precautionary purposes only, since there is no data to support the benefits of this intervention.

Key point: Dialysis should preferably be performed within 24 hours of gadolinium administration to patients already on dialysis. The institution of dialysis is not required in patients with severe renal impairment who are not already on dialysis after gadolinium administration.

1. Broome DR, Cottrell AC, Kanal E. Response to "Will dialysis prevent the development of nephrogenic systemic fibrosis after gadolinium-based contrast administration?" AJR Am J Roentgenol 2007;189: W234-235.
2. Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998; 5: 491-502.

 

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Creatinine testing prior to gadolinium administration

Laboratory results should be checked for the most recent serum creatinine on ALL patients (by the technologist performing the study). For patients with the following risk factors, serum creatinine with calculation of eGFR should be performed within 6 weeks of the MRI study:

• Age over 60 years
• History of “kidney disease” as an adult, including tumor and transplant
• Family history of kidney failure or disease
• Diabetes treated with insulin or other prescribed medications
• Hypertension (high blood pressure) requiring medication
• Multiple myeloma
• Solid organ transplant
• History of severe hepatic disease/liver transplant/pending liver transplant. For patients in this category only, it is recommended that the patient's GFR assessment be nearly contemporaneous with the MR examination for which the gadolinium is to be administered.

 

Routine creatinine testing prior to contrast administration is NOT necessary in all patients^1,2. With the exception of age and hypertension (see below), the indications for creatinine testing in the above guidelines are those suggested by the ACR¹. However, these recommendations should be considered in the light of several confounding factors:

1. In a study of 2034 outpatients who all had routine creatinine testing prior to outpatient CT, 66 patients had a creatinine of 2.0 or above². All but 2 of the 66 had one or more of 8 risk factors that were chosen based on published literature (history of renal insufficiency or renal disease, diabetes mellitus, advanced age, male gender, nephrotoxic-drug use, chemotherapy, HIV/AIDS, solitary kidney). The two cases that would have been “missed” by a policy of selective creatinine testing had a creatinine of 2.0 and 2.2. Two particularly notable findings in this study were that age alone was not an important risk factor, and that both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes were important risk factors.
2. The use of age as a risk factor and the choice of threshold are both controversial, with conflicting data in the literature. Community based studies of serum creatinine suggest age, hypertension, and diabetes are important predictors of creatinine elevation^3-5. In addition, many centers use age (with variable thresholds) to determine the need for creatinine testing and this practice is also engrained in the department culture at UCSF.
3. Standard practice is variable and often based on little to no evidence¹⁵. For example, there is little data on whether in-patients are substantively different to outpatients.
4. Arguably, the list of medications should be expanded to include chemotherapy, since many of these drugs are nephrotoxic¹⁶.
5. In general, these guidelines are simply guidelines, and strict adherence in every case may not be in the patient's best interest. Physician discretion and judgment are paramount, and commonsense should be applied to individual patient's circumstances.  Conversely, it may be prudent to check creatinine in a sick debilitated patient even if they do not have any of the specific factors listed above.

 

Key point: Routine creatinine testing prior to contrast administration is NOT necessary in all patients; the major indications are age over 60, history of preexistent renal insufficiency, diabetes mellitus, or hypertension.

1. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media.
2.  Tippins RB, Torres WE, Baumgartner BR, Baumgarten DA. Are screening serum creatinine levels necessary prior to outpatient CT examinations? Radiology 2000;216: 481-484.
3. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study. Arch Intern Med 1999;159: 1785-1790.
4. Passos VM, Barreto SM, Lima-Costa MF. Detection of renal dysfunction based on serum creatinine levels in a Brazilian community: the Bambui Health and Ageing Study. Braz J Med Biol Res 2003;36: 393-401.
5. Coresh J, Wei GL, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2001;161: 1207-1216.

 

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Estimated glomerular filtration rate (eGFR) calculation

Creatinine levels are commonly used to estimate kidney function but may be influenced by a number of factors including patient race, gender and muscle mass. The estimated glomerular filtration rate (eGFR) is a calculation based upon serum creatinine level but takes into account some of these factors (age, gender and to some extent race). Although eGFR is also only an approximation of kidney function it is thought to be more representative than serum creatinine alone. A serum creatinine level is required for determination of eGFR. UCSF clinical laboratories now generate eGFR with creatinine levels in STOR for adults at Parnassus and Mt Zion. When available, creatinine level and eGFR value will be entered by the radiology staff into the on-line memo box on Imagecast prior to performance of the study. The eGFR , physician requisition, and the scan protocol will be checked for clearance by the MR technologist, prior to the administration gadolinium. Alternatively, if required eGFR may be made using the new formula for eGFR calculation based on the IDMS referenced creatinine method.You can find an online calculator for eGFR with this newer formula at http://www.kidney.org/professionals/KDOQI/gfr_calculator.cfm. The calculation of eGFR requires the creatinine level (mg/dL), age, race (African-American versus other) and gender of the patient. 

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eGFR and intravenous gadolinium administration

Risk category	Clinical features	Approach
HIGH RISK	eGFR < 30 or on dialysis Hepatorenal syndrome Perioperative liver transplantation period1	Not recommended If gadolinium essential use lowest possible dose with approval of attending radiologist Informed consent must be obtained* Consult Nephrology for early hemodialysis if on hemodialysis
LOW RISK	eGFR 30-60	Use minimum/single dose with approval of any radiologist**
NEGLIGIBLE RISK	eGFR > 60	In general, use single dose gadolinium

*If no alternative imaging technique is possible and gadolinium contrast enhanced MRI is considered critical to patient care, informed consent should be obtained by a radiologist using the green surgical procedure form (number 862-001Z).  A lower risk gadolinium agent such as Multihance should be used.  Annotation must be made in the memo field of Imagecast by the Radiologist obtaining consent. When the study is dictated the dictating Radiologist should look at Imagecast and include that consent was obtained in the dictated report.

**The decision to administer gadolinium in a patient with moderate renal impairment (eGFR of 30-60) will always require review by a radiologist, to ensure that the risk/benefit balance merits the administration of contrast. This is a matter of physician judgment and is made on an individualized case by case basis; rigid criteria cannot be formulated to account for every conceivable scenario and are not appropriate in this setting. That said, patients with an eGFR closer to 30 are obviously of greater concern that those with an eGFR closer to 60. For example, while the FDA no longer regards moderate renal impairment (eGFR of 30-60) as a risk factor for NSF¹, the ACR has suggested patients with an eGFR of 30-45 should be treated with greater caution². The ACR also notes that acute renal impairment may be more concerning than chronic renal impairment, so that an eGFR that has recently declined to 40 may be more worrying than a chronically low eGFR of 40. Radiologists deciding to administer gadolinium to patients with an eGFR in the 30-45 range should adjust their risk/benefit analysis accordingly, requiring a more compelling clinical indication and performing a more detailed review of prior renal function. For example, a declining or fluctuating eGFR of 35 would be of more concern than a persistently stable eGFR of 35.

1. FDA Drug Safety Newsletter. Updated 8/13/2009. Available at http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm142889.htm.
2. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media. 

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Pediatric eGFR and intravenous gadolinium administration

The National Kidney Disease Education Program web site has an automatic calculator.

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Off-label use of contrast media and power injectors

Excerpt from the ACR Manual on contrast media¹: “Radiologists commonly use contrast media for clinical purpose not contained in the labeling, i.e. off label use. By definition such usage is not FDA approved and the legal ramifications are unclear. Physicians have some latitude in using gadolinium chelates off label as guided by clinical circumstances but must be prepared to justify such usage in individual cases eg MR angiography, cardiac applications and pediatric applications in patients younger than 2 years. No gadolinium chelate is approved in the United States for use in a power injector”. Although gadolinium administration via a power injector is a commonly accepted practice, it is technically an off-label use of the power injector.

1. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media. 

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Gadolinium and Pregnancy

See departmental policy at http://www.radiology.ucsf.edu/patient-care/patient-safety/ct-mri-pregnancy#terarisk2.

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Useful Links

• ACR Contrast Manual (pdf)
• Contrast Doses for Pediatric Patients
• eGFR Caluclators:  GFR Calculator for Adults (for patients 18 and older) and GFR Calculator for Children, from the National Kidney Disease Education Program website.
• Risk of Teratogenesis from Gadolinium
• Use of Contrast Media During Lactation

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