Immunopathology of terminal complement activation and complement C5 blockade creating a pro-survival and organ-protective phenotype in trauma.

BACKGROUND AND PURPOSE: Traumatic haemorrhage (TH) is the leading cause of potentially preventable deaths that occur during the prehospital phase of care. No effective pharmacological therapeutics are available for critical TH patients yet. Here, we identify terminal complement activation (TCA) as a therapeutic target in combat casualties and evaluate the efficacy of a TCA inhibitor (nomacopan) on organ damage and survival in vivo. EXPERIMENTAL APPROACH: Complement activation products and cytokines were analysed in plasma from 54 combat casualties. The correlations between activated complement pathway(s) and the clinical outcomes in trauma patients were assessed. Nomacopan was administered to rats subjected to lethal TH (blast injury and haemorrhagic shock). Effects of nomacopan on TH were determined using survival rate, organ damage, physiological parameters, and laboratory profiles. KEY RESULTS: Early TCA was associated with systemic inflammatory responses and clinical outcomes in this trauma cohort. Lethal TH in the untreated rats induced early TCA that correlated with the severity of tissue damage and mortality. The addition of nomacopan to a damage-control resuscitation (DCR) protocol significantly inhibited TCA, decreased local and systemic inflammatory responses, improved haemodynamics and metabolism, attenuated tissue and organ damage, and increased survival. CONCLUSION AND IMPLICATIONS: Previous findings of our and other groups revealed that early TCA represents a rational therapeutic target for trauma patients. Nomacopan as a pro-survival and organ-protective drug, could emerge as a promising adjunct to DCR that may significantly reduce the morbidity and mortality in severe TH patients while awaiting transport to critical care facilities.

Distal organ inflammation and injury after resuscitative endovascular balloon occlusion of the aorta in a porcine model of severe hemorrhagic shock.

BACKGROUND AND OBJECTIVE: Resuscitative Endovascular Balloon Occlusion of Aorta (REBOA) has emerged as a potential life-saving maneuver for the management of non-compressible torso hemorrhage in trauma patients. Complete REBOA (cREBOA) is inherently associated with the burden of ischemia reperfusion injury (IRI) and organ dysfunction. However, the distal organ inflammation and its association with organ injury have been little investigated. This study was conducted to assess these adverse effects of cREBOA following massive hemorrhage in swine. METHODS: Spontaneously breathing and consciously sedated Sinclair pigs were subjected to exponential hemorrhage of 65% total blood volume over 60 minutes. Animals were randomized into 3 groups (n = 7): (1) Positive control (PC) received immediate transfusion of shed blood after hemorrhage, (2) 30min-cREBOA (A30) received Zone 1 cREBOA for 30 minutes, and (3) 60min-cREBOA (A60) given Zone 1 cREBOA for 60 minutes. The A30 and A60 groups were followed by resuscitation with shed blood post-cREBOA and observed for 4h. Metabolic and hemodynamic effects, coagulation parameters, inflammatory and end organ consequences were monitored and assessed. RESULTS: Compared with 30min-cREBOA, 60min-cREBOA resulted in (1) increased IL-6, TNF-α, and IL-1ß in distal organs (kidney, jejunum, and liver) (p < 0.05) and decreased reduced glutathione in kidney and liver (p < 0.05), (2) leukopenia, neutropenia, and coagulopathy (p < 0.05), (3) blood pressure decline (p < 0.05), (4) metabolic acidosis and hyperkalemia (p < 0.05), and (5) histological injury of kidney and jejunum (p < 0.05) as well as higher levels of creatinine, AST, and ALT (p < 0.05). CONCLUSION: 30min-cREBOA seems to be a feasible and effective adjunct in supporting central perfusion during severe hemorrhage. However, prolonged cREBOA (60min) adverse effects such as distal organ inflammation and injury must be taken into serious consideration.

Ceruloplasmin and Hypoferremia: Studies in Burn and Non-Burn Trauma Patients.

OBJECTIVE: Normal iron handling appears to be disrupted in critically ill patients leading to hypoferremia that may contribute to systemic inflammation. Ceruloplasmin (Cp), an acute phase reactant protein that can convert ferrous iron to its less reactive ferric form facilitating binding to ferritin, has ferroxidase activity that is important to iron handling. Genetic absence of Cp decreases iron export resulting in iron accumulation in many organs. The objective of this study was to characterize iron metabolism and Cp activity in burn and non-burn trauma patients to determine if changes in Cp activity are a potential contributor to the observed hypoferremia. MATERIAL AND METHODS: Under Brooke Army Medical Center Institutional Review Board approved protocols, serum or plasma was collected from burn and non-burn trauma patients on admission to the ICU and at times up to 14 days and measured for indices of iron status, Cp protein and oxidase activity and cytokines. RESULTS: Burn patients showed evidence of anemia and normal or elevated ferritin levels. Plasma Cp oxidase activity in burn and trauma patients were markedly lower than controls on admission and increased to control levels by day 3, particularly in burn patients. Plasma cytokines were elevated throughout the 14 days study along with evidence of an oxidative stress. No significant differences in soluble transferrin receptor were noted among groups on admission, but levels in burn patients were lower than controls for the first 5 days after injury. CONCLUSION: This study further established the hypoferremia and inflammation associated with burns and trauma. To our knowledge, this is the first study to show an early decrease in Cp oxidase activity in burn and non-burn trauma patients. The results support the hypothesis that transient loss of Cp activity contributes to hypoferremia and inflammation. Further studies are warranted to determine if decreased Cp activity increases the risk of iron-induced injury following therapeutic interventions such as transfusions with blood that has undergone prolonged storage in trauma resuscitation.