title: Adverse skin reactions to iodinated x-ray contrast agents in healthy rats.
abstract: OBJECTIVE
  The aim of this preclinical study on healthy Sprague-Dawley rats was to determine whether differences exist in the induction of adverse skin reactions after the intravenous administration of a monomeric and 2 dimeric iodinated nonionic contrast agents.
  
  
  METHODS
  After intravenous injection of iopromide (monomeric), iodixanol (dimeric), and iotrolan (dimeric) at a dose of 4 g iodine/kg of body weight, mechanical ear volume measurements (10 minute after injection) and intravital microscopy (baseline, 5 minutes after injection) of the ear with the near-infrared dye indocyanine green were performed to determine the volume change and plasma extravasation. Histopathological analysis (20 minutes, 1 hour, and 3 hours after injection) was performed to diagnose alterations in the skin. Blood plasma was analyzed to identify elevated levels of histamine (5 minutes after injection) and inflammatory markers (a multianalyte profile of 58 markers; 1 hour and 3 hours after injection).
  
  
  RESULTS
  Only iodixanol induced immediate angioedema formation, with a 100% incidence rate and with slight mast cell infiltration in the ear, muzzle, and paws. The ear showed a 53% volume increase and strong extravasation of plasma proteins into the interstitium, which correlated with highly (11-fold) increased plasma histamine levels 5 minutes after injection. Elevated levels of tumor necrosis factor-α (7.1-fold), macrophage inflammatory protein (MIP)-1α (3.2-fold), and MIP-2 (7.7-fold) were identified 1 hour after the iodixanol injection. Increased levels (fold-change) of MIP-1β (14; 6.3), monocyte chemotactic protein-1 (3.3; 3.7), monocyte chemotactic protein-3 (2.4; 3.0), stem cell factor (1.7; 2), vascular endothelial growth factor (2; 2.1), and interferon gamma-induced protein-10 (4.1; 39.1) were identified 1 hour and 3 hours after the iodixanol administration, respectively. The level of these molecules remained unchanged after the iopromide and iotrolan injections (except for stem cell factor).
  
  
  CONCLUSIONS
  A reversible anaphylactoid-like reaction in healthy Sprague-Dawley rats was observed after the iodixanol administration but not after the monomeric iopromide or dimeric iotrolan injections. Therefore, we conclude that the induction of adverse skin reactions is not per se because of a class effect of dimeric contrast agent.
authors.affiliation: From the *Institute for Vegetative Physiology, Charité-Universitätsmedizin; †Indication Expansion, and ‡MR and CT Contrast Media Research, Bayer Healthcare AG; and §Institute for Animal Pathology, Berlin, Germany.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Lenhard
authors.forename: Ekkehard
authors.initials: E
authors.lastname: May
authors.forename: Christine
authors.initials: C
authors.lastname: Morgenroth
authors.forename: Gregor
authors.initials: G
authors.lastname: Jost
authors.forename: Wolfram
authors.initials: W
authors.lastname: Haider
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
mesh_terms: D000799:Angioedema / Q000139:chemically induced; D000818:Animals; D003287:Contrast Media / Q000009:adverse effects*; D007275:Injections, Intravenous; D007472:Iohexol / Q000009:adverse effects / Q000031:analogs & derivatives*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects*; D014283:Triiodobenzoic Acids / Q000009:adverse effects*; D014965:X-Rays
chemical_list: D003287:Contrast Media; D014283:Triiodobenzoic Acids; C033300:iotrolan; D007472:Iohexol; C038192:iopromide; C044834:iodixanol