Adenosine, Lidocaine and Mg2+ (ALM) resuscitation fluid protects against experimental traumatic brain injury

Background Currently no drug therapy prevents secondary injury progression after TBI. Our aim was to investigate the effects of small-volume intravenous adenosine, lidocaine and Mg2+ (ALM) resuscitation fluid after moderate-TBI in a rat fluid-percussion injury model. Methods Anesthetized, mechanically-ventilated male Sprague–Dawley rats (449±5g) were randomly assigned to one of four groups: 1) Sham (craniotomy without TBI), 2) No-Treatment, 3) Saline-controls or 4) ALM therapy (all n=16). A subdural probe was implanted in n=8 animals per group to measure cerebral blood flow. Fifteen minutes after moderate-TBI was induced with lateral FPI (2.57 atm), a single 3% NaCl±ALM bolus (0.7 ml/kg) was injected IV, and after 60 min (Phase 1), 0.9% NaCl±ALM stabilization ‘drip’ (0.5 ml/kg/hour) was administered for 3 hours (Phase 2). Results Mortality (without subdural brain probe) was 25% (saline-controls), and 0% (ALM). Sixty-minutes after bolus, ALM significantly increased cardiac function, cortical blood flow (CBF) (~3-fold) and blunted systemic inflammation compared to saline-controls. Three hours after infusion 'drip', ALM improved left-ventricular function, supported higher CBF, decreased pro-inflammatory cytokines systemically (IL-1β, TNF-α, RANTES), increased anti-inflammatory cytokines in brain tissue (IL-10, IL-4), lowered brain injury markers (NSE, Syndecan-1, HMGB-1), reduced coagulopathy, increased platelet aggregation, and maintained baseline fibrinogen levels. Saline-controls were pro-inflammatory (brain, heart, lung and blood) and hypocoagulable with neurogenic right heart enlargement. Survival-time significantly correlated with plasma NSE (p=0.001) and CBF at 180 min (p=0.009), and CBF correlated with brain anti-inflammatory cytokines (p=0.001-0.034). Conclusion After moderate-TBI, ALM resuscitation fluid increased survival and protected against early secondary injury by reducing coagulopathy, inflammation and platelet dysfunction. Level of Evidence Level 1 Randomized animal study Funding Statement: This work was supported by USSOCOM, IACUC protocol A2118, USAMRMC proposal SO13004 under Award No. W81XWH-15-1-0002. The opinions, interpretations, conclusions are those of the authors and are not necessarily endorsed by the US Department of Defense. Author Disclosure Statement: GPD is the inventor of the ALM concept for cardiac surgery, trauma and sepsis, and has no competing financial interests. HLL has no competing financial interests. To whom correspondence should be addressed: Email: geoffrey.dobson@jcu.edu.au Fax: +61 747 816 279 Phone: +61 407 550 235 © 2018 Lippincott Williams & Wilkins, Inc.

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