Anti-Inflammatory Therapy with High Dose Insulin in Brain Dead Organ Donors

Abstract

Introduction: Brain death is a major stress on the body that is associated with a massive inflammatory response. Severe inflammation can lead to increased graft immunogenicity and increased risk of graft dysfunction. In addition, to the maintenance of normoglycaemia Insulin therapy has expressed anti-inflammatory effects in clinical and experimental studies. The objective is determining if high dose insulin therapy can suppress inflammation and maintain normoglycaemia in brain dead donors. Methods: Pilot study with an open-label prospective-controlled design. Fifteen brain dead organ donors were recruited including 6 study donors and 9 control donors. Insulin therapy was delivered to the study donors using the hyperinsulinemic normoglycaemic clamp (HNC) and was maintained for a minimum of 6 hours and continued till organ retrieval. The anti-inflammatory effect was measured by the change in the cytokine levels in the plasma of these donors. Categorical and continuous variables were expressed as summary statistics (n, median, mean, range, standard deviation) for all donors in both groups. Fisher's exact and Wilcoxon test were performed to assess differences between the groups and a p-value < 0.1 was considered significant. Results: There was no significant difference in donor characteristics between the 2 groups. CVA was the most common cause of brain death (60%). The study group had normal glucose levels (median 4.8 mmol/L) compared to the control group (median 9.0 mmol/L) (p< 0.001). There were no periods of severe hypoglycemia (glucose < 2.5 mmol/l). The levels of several pro-inflammatory mediators including; IL-6, TGF-α and MCP-1 were significantly decreased after 6 hours of treatment compared to their baseline values in the study group (p=0.03), (p=0.03) and (p=0.09), respectively. We observed an opposite trend in circulating levels of the anti-inflammatory factor IL-10 in the study group. The levels of inflammatory markers did not demonstrate a significant change after 6 hours compared to their baseline values in the control group. Conclusion: High dose insulin therapy in the form of HNC was successful in the maintenance of normoglycaemia in brain dead organ donors, without severe hypoglycaemia. Furthermore, the therapy had anti-inflammatory effects on donors, as expressed by decreased the levels of several pro-inflammatory cytokines in the study group.Table: [General demographics and characteristics of donors]Table: [change of cytokine levels at ST1 (after 6hrs)]