1214 Crit Care Med 2012 Vol. 40, No. 4 C erebral dysfunction is a com- mon complication of sepsis, and it has been shown to be as- sociated with adverse outcomes (1). Although the exact pathophysiol- ogy remains poorly understood, cerebral endothelial activation and the alteration of the blood-brain barrier (BBB) have been documented in in vivo and in vitro models of the septic brain (2–4). However, the morphologic changes in brain struc- ture associated with sepsis, and the exact cellular pathology underlying BBB dys- function, have not been clearly identified (5, 6). Manipulating the inflammation caus- ing endothelial activation and BBB leak- age has been investigated as a therapeutic target in sepsis-induced brain dysfunc- tion. Different pharmacologic approaches on lipopolysaccharide (LPS)-induced changes in the BBB permeability have previously been investigated in vitro (4). Endothelial cells that had been pretreated with dexamethasone were shown to be more resistant to LPS-induced disruption of the BBB (4). In another trial, LPS has been targeted as a therapy option, and the binding of circulating LPS by the serum amyloid P component was shown to have protective benefits in mice (7). Another therapeutic option for the prevention of sepsis-induced BBB breakdown was demonstrated through the inhibition of complement activation using an anti-C5a antibody (8). The targeting of complex immune ac- tivation in neuroinflammation through the use of immunoglobulin therapy for immunomodulation has been used to treat a variety of inflammatory and au- toimmune diseases (9). Immunoglobulin therapy has become an established treat- ment for an array of neurologic dis- orders, such as chronic inflammatory demyelinating polyneuropathy, multi- focal motor neuropathy, and Guillain- Barré syndrome (10, 11). The effects of Interventions: The effects of immunoglobulin G and immuno- globulins enriched with immunoglobulin A and immunoglobulin M on blood-brain barrier integrity and survival rates in septic rats were comparatively investigated. Measurements: Sepsis was induced by cecal ligation and per- foration in Sprague-Dawley rats. The animals were divided into the following groups: sham, cecal ligation and perforation, ce- cal ligation and perforation plus immunoglobulin G (250 mg/kg, intravenous), and cecal ligation and perforation plus immuno- globulins enriched with immunoglobulin A and immunoglobulin M (250 mg/kg, intravenous). Immunoglobulins were administered 5 mins before cecal ligation and perforation and the animals were observed for behavioral changes for 24 hrs following cecal ligation and perforation. Blood-brain barrier permeability was function- ally and structurally evaluated by determining the extravasation of Evans Blue and horseradish peroxidase tracers, respectively. Immunohistochemistry and Western blotting for occludin were performed. Main Results: The high mortality rate (34%) noted in the sep- tic rats was decreased to 15% and 3% by immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immuno- globulin M, respectively (p , .01). Both immunoglobulin G and im- munoglobulins enriched with immunoglobulin A and immunoglob- ulin M alleviated the symptoms of sickness behavior in the septic rats, with the animals becoming healthy and active. Increased extravasation of Evans Blue into the brain tissue of the septic rats was markedly decreased with the administration of both immuno- globulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M (p , .01). Occludin expression remained essentially unchanged in all groups, including the cecal ligation and perforation group. In the cecal ligation and perforation group, increased luminal and abluminal vesicles containing electron- dense horseradish peroxidase-reaction product were noted in the cytoplasm of endothelial cells located in the hippocampus and the cerebral cortex. Tight junction was ultrastructurally intact, suggesting that the transcellular pathway is responsible for the blood-brain barrier breakdown in sepsis. Following immunoglob- ulin G or immunoglobulins enriched with immunoglobulin A and immunoglobulin M treatment, no ultrastructural evidence of leaky capillaries in the brain was observed in the septic rats, indicat- ing the blockade of the transcellular pathway by immunoglobulins administration. Conclusions: Our study suggests that immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M improve the integrity of the blood-brain barrier and inhibits cecal ligation and perforation-induced symptoms of sickness behavior in rats. (Crit Care Med 2012; 40:1214–1220) KEY WORDS: blood-brain barrier; immunoglobulin A; immuno- globulin G; immunoglobulin M; sepsis Laboratory Investigations Intravenous immunoglobulins prevent the breakdown of the blood- brain barrier in experimentally induced sepsis* Figen Esen, MD; Evren Senturk, MD; Perihan E. Ozcan, MD; Bulent Ahishali, MD; Nadir Arican, MD; Nurcan Orhan; Oguzhan Ekizoglu, MD; Mutlu Kucuk, PhD; Mehmet Kaya, PhD *See also p. 1368. From the Departments of Anesthesiology (FE, ES, PEO), Histology and Embryology (BA), Forensic Medicine (NA), and Physiology (MK), Institute of Experimental Medicine (NO, MK), Istanbul University, and Dr. SadiKonuk Training and Research Hospital (OE), Istanbul, Turkey. Supported, in part, by grants from the Research Foundation of Istanbul University. Project number 2865/2008. The authors have not disclosed any potential con- flicts of interest. For information regarding this article, E-mail: evrensenturk2@yahoo.com Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e31823779ca