Insulin alters cytokine content in two pivotal organs after brain death: a porcine model A. BARKLIN 1,2 , A. LARSSON 2,3 , C. VESTERGAARD 2,4 , A. KJAERGAARD 1,5 , L. WOGENSEN 2,5 , O. SCHMITZ 6,7 and E. TØNNESEN 1,2 1 Department of Anaesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark, 2 Institute of Clinical Medicine, Aarhus University, Aarhus,Denmark, 3 Department of Anaesthesiology and Intensive Care, Aalborg Hospital, Aarhus University Hospital, Aarhus, Denmark, 4 Department of Dermatology, 5 Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark, 6 Department of Pharmacology, University of Aarhus, Aarhus, Denmark and 7 Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark Background: To optimize the quantity and quality of organs available for transplantation, it is crucial to gain further insight into the treatment of brain dead organ donors. In the current study we hypothesized that insulin treatment after brain death alters cytokine content in the heart, liver, and kidney. Methods: Sixteen brain dead pigs (35–40 kg) were treated with either (1) no insulin [brain dead without insulin treatment treatment (BD)], or (2) insulin infusion intrave- nously (i.v.) at a constant rate of 0.6 mU/kg/min during 360 min [brain dead with insulin treatment (BD1I)]. Blood glucose was clamped at 4.5 mmol/l by infusion of 20% glucose. Blood samples for insulin, glucose, catechola- mines, free fatty acids, and glucagon were obtained during the experimental period. Six hours after brain death biop- sies were taken from the heart, liver, and kidney. These were analyzed for cytokine mRNA and proteins [tumor necrosis factor-a (TNF-a), interleukin (IL)-6, and IL-10]. Results: The BD1I compared with the BD animals had lower IL-6 concentrations in the right ventricle of the heart ( P 5 0.001), in the renal cortex (P 5 0.04) and in the renal medulla (P 5 0.05), and lower IL-6 mRNA in the renal medulla ( P 5 0.0002). Furthermore, the BD1I animals had lower concentrations in the renal medulla of IL-10 ( P 5 0.01), and tended to have lower TNF- a in the renal cortex (P 5 0.06) than the BD animals. In the right ventricle of the heart TNF-a mRNA and IL-10 mRNA were higher in the BD1I than in the BD group (P 5 0.002 and 0.004). Conclusion: Insulin has anti-inflammatory effects on cytokine concentration in the heart and kidney after brain death. Accepted for publication 3 December 2007 Key words: Insulin; hyperinsulinemia; brain death; inflam- mation; cytokines; catecholamines; organ; heart; liver; kidney; experimental animal model. r 2008 The Authors Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation O RGAN transplantation is often the only avail- able treatment option for patients with end- stage diseases. However, one of the limitations associated with transplantation is the lack of avail- able organs. A reason for this is non-optimal organ management in brain-dead donors (1, 2). To in- crease quality and quantity of organs for transplan- tations, we need further studies of the treatment of brain-dead organ donors. Organ function after transplantation is correlated to inflammatory markers in the donor organ before transplantation. In a human study the expression of the adhesion molecules, [vascular cell adhesion molecule-1 (VCAM-1)] and [intercellular cell adhe- sion molecule (ICAM-1)] in donor kidney, detected by immunohistochemistry, is associated with infer- ior kidney graft function after transplantation (3). Another study states that the expression of tumor necrosis factor-a (TNF-a) in the donor heart pre- dicts right ventricular failure after transplantation (4). Therefore, it might be desirable to treat donors in order to decrease organ inflammation before the organ harvest. Optimally, this treatment should be commenced as early as possible, and not deferred until the final diagnosis of brain death is estab- lished. Thus, for ethical reasons, the treatment should also be beneficial for patients with severe cerebral injury who are not brain dead. Strict glucose control by insulin therapy demon- strates anti-inflammatory effects in clinical and experimental studies (5–7), and has been proven to improve the outcome in medical and surgical patients in the ICU (8, 9). Indeed, in patients with isolated brain injury, strict glucose control is 628 Acta Anaesthesiol Scand 2008; 52: 628–634 Printed in Singapore. All rights reserved r 2008 The Authors Journal compilation r 2008 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA doi: 10.1111/j.1399-6576.2008.01606.x