Indian Journal of Dermatology
: 2012  |  Volume : 57  |  Issue : 3  |  Page : 246-

Author's Reply

Zhitong Zou 
 From the Department of Radiology, Weill Medical College of Cornell University, Ithaca, New York, USA; and Chinese Peoples' Liberation Army General Hospital, Beijing, China

Correspondence Address:
Zhitong Zou
From the Department of Radiology, Weill Medical College of Cornell University, Ithaca, New York, USA; and Chinese Peoples«SQ» Liberation Army General Hospital, Beijing, China

How to cite this article:
Zou Z. Author's Reply.Indian J Dermatol 2012;57:246-246

How to cite this URL:
Zou Z. Author's Reply. Indian J Dermatol [serial online] 2012 [cited 2021 Apr 10 ];57:246-246
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Full Text


Thank you for pointing out the limitations of assessing data on the rates of adverse events for various classes of gadolinium chelates. These limitations apply to both allergic reactions and nephrogenic systemic fibrosis (NSF). Since the publication of our NSF review article, [1] several studies have added additional scientific basis for the concept of a lower rate of immediate adverse events for linear nonionic gadolinium chelates. [2],[3],[4],[5],[6],[ 7] In particular, Prince et al. [2] reviewing experience in 158,796 gadolinium-based contrast agent (GBCA) enhanced examinations from two major institutions found an order of magnitude with a lower rate of immediate adverse events for the linear, nonionic agents, compared to the linear ionic agents and gadoteridol, a macrocyclic agent. Prince also reviewed the deaths from allergic reactions reported to the US food and drug administration (FDA), capturing the experience from 51 million GBCA administrations over a six-year period. These data also show that the lowest death rate is with linear nonionic gadolinium chelates.

Lee et al. [6] reviewing immediate anapylaxis in 141,623 patients showed a lower adverse events rate for gadodiamide, a linear nonionic chelate, compared to gadobenate, an ionic chelate (0.00013 vs. 0.00221; P<0.001). Taketomi-Takahashi et al.'s [4] review of 13,252 gadolinium administrations showed an adverse events rate of 0.14% for gadodiamide compared to 0.55% for Gd:DTPA, a linear ionic chelate. At the latest Yale NSF symposium, Raisch et al. [5] from the RADAR group, using a completely different analysis of tapping into FDA and legal databases, in addition to the published literature, showed projected reaction rates for gadodiamide and gadoversetamide (two linear nonionic agents) of 0.16 and 2.248, compared to rates of 5.03 and 11.41 for Gd:DTPA and gadobenate, two linear ionic agents, and 16.16 for gadoterate, an ionic macrocyclic agent.

We agree that the retrospective analysis of adverse events is not as good as the randomized, prospective, double-blinded trials. However, for the <1 in a million incidence of death from immediate allergic-type reactions to gadolinium and now nearly non-existent NSF, the randomized, double-blinded, prospective trials are not practical and we are forced to rely on retrospective data. Currently published prospective, controlled, double-blinded clinical trials do not confirm that all marketed GBCAs are similar with respect to hypersensitivity reactions, because they are massively underpowered. Interpreting failure to observe a statistically significant difference as proof that there is no difference is a common statistical error. Note that the US FDA has also made some differentiation among the GBCAs, giving a contraindication for three linear ionic agents, gadobenate, gadoxetate, and gadofosveset, in patients with a known history of allergic reaction to GBCA, while the nonionic GBCAs have no such contraindication. The growing abundance of evidence that nonionic linear GBCAs have a lower immediate adverse events rate compared to the ionic agents is not surprising, given that the same relationship exists for iodinated-based contrast agents.


1Zou Z, Ma L. Nephrogenic systemic fibrosis: Review of 408 biopsy-confirmed cases. Indian J Dermatol 2011;56:65-73.
2Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol 2011;196:W138-43.
3Bruder O, Schneider S, Nothnagel D, Pilz G, Lombardi M, Sinha A, et al. Acute adverse reactions to gadolinium-based contrast agents in CMR: Multicenter experience with 17,767 patients from the EuroCMR Registry. JACC Cardiovasc Imaging 2011; 4:1171-6.
4Taketomi-Takahashi A, Matsumoto N, Tsushima Y, Amanuma M, Endo K. Eye of the Beholder: Physical properties of intravenous contrast and their appearance on various imaging modalities. Presented at: Radiological Society of North America 2010 Scientific Assembly and Annual Meeting; Chicago, Illinois, United States; 2010 Nov 28-Dec 3.
5Raisch DW, Garg V, Samaras AT, Saddleton EE, Laumann AE, McKoy JM, et al. Anaphylactoid reactions associated with gadolinium vs. iodinated agents contrast media plus safety signal detection in the FDA's adverse event reporting system. Presented at: 5 th Annual Symposium on Nephrogenic Systemic Fibrosis and Allied Systemic Fibrosing Disorders; Orange, Connecticut, United States; 2011 May 20-21.
6Lee W, Han MH, Jung J, Kang H, Cho S, Chung T. Immediate type hypersensitivity reaction to gadolinium-based MR contrast media. Presented at: 23 rd International Magnetic Resonance Angiography Club; Banff, Alberta, Canada; 2011 Sep 24-28.
7Nacif M. Overview of contrast agents and dose, safety (non-NSF). Presented at: Society for Cardiovascular Magnetic Resonance 15 th Annual Scientific Sessions; Orlando, Florida, United States; 2012 Feb 2-5.