Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model.

BACKGROUND: Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage. METHODS: Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung. RESULTS: Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1ß, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours. CONCLUSION: Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries. LEVEL OF EVIDENCE: Prospective randomized controlled blinded trial study, Preclinical (animal-based).

Application of Incident Command Structure to clinical trial management in the academic setting: principles and lessons learned.

BACKGROUND: Clinical trial success depends on appropriate management, but practical guidance to trial organisation and planning is lacking. The Incident Command System (ICS) is the 'gold standard' management system developed for managing diverse operations in major incident and public health arenas. It enables effective and flexible management through integration of personnel, procedures, resources, and communications within a common hierarchical organisational structure. Conventional ICS organisation consists of five function modules: Command, Planning, Operations, Logistics, and Finance/Administration. Large clinical trials will require a separate Regulatory Administrative arm, and an Information arm, consisting of dedicated data management and information technology staff. We applied ICS principles to organisation and management of the Prehospital Use of Plasma in Traumatic Haemorrhage (PUPTH) trial. This trial was a multidepartmental, multiagency, randomised clinical trial investigating prehospital administration of thawed plasma on mortality and coagulation response in severely injured trauma patients. We describe the ICS system as it would apply to large clinical trials in general, and the benefits, barriers, and lessons learned in utilising ICS principles to reorganise and coordinate the PUPTH trial. RESULTS: Without a formal trial management structure, early stages of the trial were characterised by inertia and organisational confusion. Implementing ICS improved organisation, coordination, and communication between multiple agencies and service groups, and greatly streamlined regulatory compliance administration. However, unfamiliarity of clinicians with ICS culture, conflicting resource allocation priorities, and communication bottlenecks were significant barriers. CONCLUSIONS: ICS is a flexible and powerful organisational tool for managing large complex clinical trials. However, for successful implementation the cultural, psychological, and social environment of trial participants must be accounted for, and personnel need to be educated in the basics of ICS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02303964 . Registered on 28 November 2014.

Hextend-perfluorocarbon cocktail inhibits mean arterial pressure response in a rabbit shock model.

BACKGROUND: Hextend (HEX) is standard of care resuscitation fluid for combat-related traumatic hemorrhage. Because HEX has limited oxygen-carrying capacity, combination therapy with oxygen therapeutics could improve oxygen delivery after hemodynamic shock. We hypothesized that addition of perfluorocarbon (PFC) to HEX would improve hemodynamics and oxygen delivery marker response in a rabbit model of hemorrhagic shock. METHODS: Anesthetized New Zealand rabbits (n = 23) were randomly allocated to resuscitation with fresh whole blood (FWB), HEX, or HEX plus PFC (HEX + PFC) after 60 min of hemorrhagic hypotension. Mean arterial pressure (MAP) was sampled every 2-3 min for 120 min postinfusion; MAP profiles were modeled by a one-compartment pharmacokinetic model to determine peak MAP (Pmax), time to peak MAP (tmax), and postinfusion MAP persistence. Arterial blood was sampled every 15 min to examine pH, blood gases PO2 and pCO2, metabolites lactate and glucose, methemoglobin (metHb), and electrolytes. RESULTS: Compared with FWB and HEX, HEX + PFC administration resulted in delayed peak MAP and less persistent (P < 0.0001) MAP elevation; metHb was significantly elevated (P < 0.0001) compared with FWB and HEX. There were no significant differences in PO2, pCO2, or pH. Glucose, hematocrit, and hemoglobin of both HEX and HEX + PFC were significantly lower relative to FWB. Lactate clearance was modest and transient for all treatments; base deficit was significantly more negative for HEX + PFC. CONCLUSIONS: Addition of PFC to HEX did not improve hemodynamics or acidosis. Further dose- and volume-range studies are required to test efficacy of PFC in combination with HEX for hemorrhagic shock.