title: Hypersensitivity reactions to intravenous lipid emulsion in swine: relevance for lipid resuscitation studies.
abstract: BACKGROUND
  Reports in the recent experimental literature have provided contradicting results in different animal species regarding the efficacy of IV lipid emulsion (ILE) in the reversal of cardiovascular and central nervous system symptoms of local anesthetic and other lipophilic drug overdoses. In particular, ILE seemed to be effective in rats, rabbits, dogs, and humans, but not in swine, for which it not only failed to reverse the adverse effects of anesthetics, but the animals also developed a generalized cutaneous mottling or a dusky appearance immediately after ILE, suggestive of another type of toxicity. The latter symptoms arise in complement (C) activation-related pseudoallergy, a hypersensitivity reaction to particulate drugs and agents.
  
  
  METHODS
  Ten Yorkshire swine (15-20 kg) were sedated with ketamine and anesthetized with isoflurane. ILE 1.5 and 5 mL/kg 20% was administered via the ear vein while pulmonary arterial pressure, systemic arterial blood pressure, electrocardiogram, and end-tidal CO2 were recorded continuously. Thromboxane was measured in blood collected at baseline and 2 and 10 minutes after injections. Complement activation by lipid emulsion was also assessed in vitro with soluble terminal complement complex (SC5b-9) and sheep red blood cell assays.
  
  
  RESULTS
  Significant increases were observed in the pulmonary pressure (median [interquartile range]) within minutes after the administration of ILE, both at doses 1.5 and 5 mL/kg (15 [12-16.5] to 18.5 [16-20] mm Hg, P = 0.0058 and 15.5 [13-17.25] to 39.5 [30.5-48.5], respectively). The systemic arterial blood pressure increased, and the heart rate decreased after both injections. Thromboxane B2 concentration (median [interquartile range]) in the blood plasma increased from a baseline of 617.3 [412.4-920] to 1132 [597.9-1417] pg/mL (P = 0.0055) and from 1276 [1200-2581] to 4046 [2946-8442] pg/mL (P = 0.0017) after the administration of 1.5 and 5 mL/kg ILE, respectively. Intralipid did not cause in vitro complement activation in human serum.
  
  
  CONCLUSIONS
  ILE causes clinically significant hemodynamic changes in pigs, in concert with significant increases in the plasma thromboxane concentration. However, the in vitro tests did not confirm involvement of the complement system in human sera, leaving the underlying mechanism of these findings in doubt. Nonetheless, the observed hemodynamic and biochemical effects of ILE serve as a caveat that the pig is not an ideal model for the study of interventions involving ILE.
authors.affiliation: From the *Defense and Veterans Center for Integrative Pain Management; †Department of Anesthesiology, Uniformed Services University; ‡Department of Anesthesiology, Walter Reed National Military Medical Center, Bethesda, Maryland; §Washington University in St. Louis, St. Louis, Missouri; ∥Seroscience Ltd.; ¶Nanomedicine Research and Education Center, Semmelweis University Budapest, Budapest; and #Department of Nanobiotechnology, Institute of Theoretical Health Sciences, Miskolc University, Miskolc, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Bedocs
authors.forename: John
authors.initials: J
authors.lastname: Capacchione
authors.forename: Lauren
authors.initials: L
authors.lastname: Potts
authors.forename: Ryan
authors.initials: R
authors.lastname: Chugani
authors.forename: Zsoka
authors.initials: Z
authors.lastname: Weiszhar
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
authors.forename: Chester C
authors.initials: CC
authors.lastname: Buckenmaier
mesh_terms: D000707:Anaphylaxis / Q000209:etiology; D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D003875:Drug Eruptions / Q000209:etiology / Q000276:immunology; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000503:physiopathology*; D005217:Fat Emulsions, Intravenous / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects; D012151:Resuscitation; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D005217:Fat Emulsions, Intravenous; D013929:Thromboxane B2