Download MRI: Quality & Safety

Risk of Gadolinium Contrast in
Renal Dysfunction
February 9, 2007
Shannon Bisbee, M.S., NP-C
Nurse Practitioner, Clinical MRI
Beth Israel Deaconess Medical Center
Gadolinium Contrast Agents
Used in MRI, CT, conventional angio
Brightening on T1-weighted images
Gd is toxic!
Chelate used to ‘protect’ the free metal
Gd
Gd
FDA Approved Gadolinium Agents
Generic
Brand
Mfr
Approval
Year
Approx.
Share
Gadopentetate
dimeglumine
Magnevist
Berlex
1988
50%
Gadodiamide
Omniscan
GE
1993
35%
Gadoversetamide
OptiMARK
Tyco /
1999
Mallinckrodt
5%
Gadoteridol
ProHance
Bracco
1992
Gadobenate
dimeglumine
MultiHance Bracco
2004
}
10%
Nephrogenic Systemic Fibrosis (NSF):
The Basics




Originally Nephrogenic Fibrosing Dermopathy (NFD)
Systemic proliferation of connective tissue  NSF
215 cases reported worldwide from 1997-2006
Strong epidemiologic association with Gd
 All FDA-reviewed cases had prior Gd exposure
 Appears to be a class issue (Omniscan > Magnevist, OptiMARK)
 All had renal insufficiency at exposure (most ESRD, on dialysis)
 Associated w/ proinflammatory state11 (e.g., vascular surgery)
 Early data suggests 3-5% incidence w/ Gd in renal failure11
Nephrogenic Systemic Fibrosis (NSF):
The Search for Causation
 No co-factor identified (dialysate, ACEIs,
EPO, etc.)
 Emerging theories of pathogenesis:
Liberation of Gd ion from carrier molecule10
Cutaneous deposition of free Gd ion10
Gd target attracts circulating fibrocytes (CFs)
CFs differentiate to resemble dermal fibroblasts
Half-life of gadodiamide (hours)4
Normal renal function
1.3 h
End-stage renal failure
34.3 h
Hemodialysis (HD)
2.6 h
Peritoneal dialysis (PD)
52.7 h
Patient Safety in 1991…
“… the results suggest that gadolinium enhanced MR
imaging is capable of safely demonstrating tumor
enhancement in patients with renal failure.”6
Radiology 1991; 180:85-89
Patient Safety a Decade Later…
Gd “trigger”
proposed for
NSF (Grobner
First
recognized
case of “NFD”
1997
and Markmann)
2000
First
description of
NSF in the
literature
Apr 2006
May 2006
FDA issues
Public Health
Advisory
FDA revises
Public Health
Advisory
Literature
reports Gd in
NSF skin
biopsies7
Jun 2006
Dec 2006
Jan 2007
Press reports
FDA warning
to “kidney
patients”
Editorial in
Radiology
Danish Medicines
Agency reports 25
cases of Gdassociated NSF
Uses of High Dose Gd
(+/- renal insufficiency):
MRA
Peripheral
Renal
Neuro-onc (site dependent)
X-ray use (k-edge of Gd is
inefficient)
CT
Conventional angio
Nephrogenic Systemic Fibrosis (NSF):
Diagnosis
 Most prominent and visible effects in the skin





Reddened or darkened areas
Texture changes (described as “woody” or peau d’orange)
Tightening, thickening, swelling → joint immobility
Burning, itching, sharp pain
Yellowish scleral plaques
 Skin changes can be insidious -> confused w/ peripheral
edema
 Resembles scleroderma and eosinophilic fasciitis
 Absent: monoclonal gammopathies9, Raynaud phenomenon
and autoantibodies2
 Fibrotic changes can be widespread (liver, lungs, heart)
 Muscle biopsy: ↑ myofibroblasts2
 Skin biopsy: thickened collagen bundles with surrounding
clefts, mucin deposition, ↑ fibroblasts, ↑ CD34+ dendrocytes2
Nephrogenic Systemic Fibrosis (NSF):
Clinical Appearance
Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Accessed 02/01/2007.
Nephrogenic Systemic Fibrosis (NSF):
Prognosis and Treatment
 Course is chronic, progressive, variable
 May be severely debilitating
 Contractures - musculoskeletal
 Wheelchair requirement in some
 Complications may be fatal
 Falls, fractures
 Immobility, pneumonia
 No consistently successful treatment
 Symptoms may improve if renal function improves
 Limited evidence for kidney transplantation, extracorporeal
photopheresis (ECP)
 Also in the literature: oral steroids, plasmapheresis
BIDMC Experience
 Magnevist and MultiHANCE® in use
 Retrospective review of high-dose Gd cases in progress
 First phase review: high-risk population




Studies  40cc Gd
278 studies  40cc Gd from 1999-2006
Approx. 32% (89) involved pts w/ Cr > 1.4
In depth chart review complete for 20/89
 No NSF cases proven at BIDMC thus far
 NSF cases difficult to identify and prove




Retrospective review
Lack of medical records and/or lab results
Complicated medical histories and co-morbidities
Dx requires biopsy
 Outreach to Medicine and Dermatology
Minimizing the Risk of NSF
 Risk : benefit analysis
 Reduce use of Gd in renal disease




FDA recommends avoiding for eGFR < 60 (not evidence-based)
Consider non-contrast protocols
Consider alternate modality (e.g., CT, conventional angiogram)
Minimize dose if Gd is deemed imperative
 Consider alternative agents
 Gd-BOPTA (MultiHANCE®)
 No reports (yet…)
 Can reduce dose (has higher R1)
 HOWEVER…clearance kinetics less favorable (binds protein)
 Hemodialyze patients with ESRD asap
 Gd excretory rates 78%, 96%, 99% from 1st to 3rd HD session5
 When using Gd, maximize pt condition:
 Hold drugs that decrease renal function (e.g., diuretics, NSAIDs)
 Hydrate (consider bicarb – ? role of metabolic acidosis in NSF)
 Informed consent
For Dialysis Patients
Hemo Dialysis (HD)
Peritoneal Dialysis
Consider alternative study
Consider alternative study
2 sessions of HD
1st w/in 3 hrs of Gd
2nd ~ 24 hours after Gd
No functional AV Fistual
Admit for temporary
central venous access
Functional fistula present
For Non-Dialysis Patients
Creatinine
or
eGFR value
In pt
Value w/in 3 days of exam
If worsening trend, day of exam
Out pt
Value < 6months prior to exam
eGFR 45-60
eGFR <45, not on dialysis
Hold Drugs*
for
3 days prior
Hold Drugs*
for
3 days prior
IV Pre -Post Exam**
*diuretics, NSAIDs, and ACE inhibitors (the latter when used with a diuretic)
**Intravenous hydration with sodium bicarbonate for 1hr prior and 6hrs post Gd.
http://home.caregroup.org/departments/radiology/residency/protocols/CT/Visipaque.doc
Hydration & HCO3
 Oral hydration
 1 Liter of H20 by mouth before and after injection of contrast
 Intravenous hydration
 Contact the ordering physician or house staff for orders
 Bicarb
 150mEq of NaHCO3 (e.g. dilute in 1L D5W)
 Pre: 1 hr prior to contrast administration
 @ 3cc/kg/hr and for
 Post: 6 hrs after contrast administration
 @ 1cc/kg/hr
 Modifications possible for pts with renal failure/CHF)
 Encourage oral fluid intake if not on fluid restrictions
 http://home.caregroup.org/departments/radiology/r
esidency/protocols/CT/Visipaque.doc
Perspective – Iodinated Contrast
Risk for severe adverse reactions
0.147% HI-ICM
0.031% NI-ICM (3/10,000)
Death
~ 1/100,000 either high or low osmolality.
Caro AJR 1991 Apr; 156(4): 825-32
Conclusions
Gd is associated with NSF in patients
with renal insufficiency
Risk:Benefit assessment is vital
Guidelines presented will be submitted
for approval – policy and procedures
will be defined
Education across BIDMC is essential
References
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11.
Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at
http://www.icnfdr.org. Accessed 01/17/2007.
Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15:785.
Grobner T: Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy
and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation 21(4): 1104-1108, April 2006.
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 5: 491-502, 1998.
Okada S et al. Safety of gadolinium contrast agent in hemodialysis patient. Acta Radiologica, 2001,
42(3): 339-341.
Rofsky N et al. Renal lesion characterization with gadolinium-enhanced MR imaging: Efficacy and
safety in patients with renal insufficiency. Radiology, July 1991, 180: 85-89.
High WA, Ayers RA, Chandler J, Zito G, and Cowper SE. Gadolinium is detectable within the tissue of
patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56(1):21-26.
Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency.
http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931. Published May 29, 2006. Accessed
February 6, 2007.
Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am
Acad Dermatol. January 2007. 27-30.
Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic
fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance
imaging. J Am Soc Nephrol 2006;17:2359-62.
Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic
fibrosis: Risk factors and incidence estimation. Radiology 2007.
http://radiology.rsnajnls.org/cgi/content/full/2431062144v1. Published January 31, 2007. Accessed
February 1, 2007.