Background. The extent of secondary organ damage/dysfunction after trauma is determined by the severity of primary mechanical injury and resultant intensity of endogenous secondary injury cascades (e.g. excitotoxicity, oxidant injury, inflammation), which may be worsened by systemic distress (e.g. hypotension, hypoxemia, ischemia). Collectively these posttraumatic insults contribute to brain damage via neural cell death (neurons, axons, glia) and tissue-level pathologies (cerebral edema and progressive neurological impairment). Remote ischemic conditioning (RIC) is a noninvasive intervention produced by alternating cycles of limb ischemia/reperfusion that has been shown to mitigate distant organ injury in animal models of resuscitated hemorrhagic shock (HS) and brain injury (TBI). Objectives. The aim of this randomized controlled trial was to examine the potential neuroprotective effect of RIC on peripheral blood neurological injury biomarker profiles in a cohort of severely injured trauma patients in HS (median ISS = 17) with or without concomitant TBI (AIS head ≥1).
Methods: Healthy controls (n=10) and patients sustaining blunt or penetrating trauma in HS (systolic BP<90mmHG), with (n=8) or without TBI (n=25), were randomized 1:1 to receive either Sham (0mmHg) or RIC intervention (4 cycles of 5-min thigh cuff inflation at 250mmHg followed by 5-min deflation via pneumatic tourniquet). Circulating concentrations of neuroproteomic biomarkers, selected on the basis of their relative brain-specificities and potentials to reflect distinct injury mechanisms, including (1) neuronal cell damage [neuron-specific enolase (NSE), neurogranin, visinin-like protein-1]; (2) astroglial damage [S100B, glial fibrillary acidic protein (GFAP)]; (3) cerebral ischemia/oxidative stress [creatine kinase (CK)-BB], peroxiredoxin]; (4) neuroinflammation [monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-9]; (5) neural repair/plasticity [brain derived neurotrophic factor]; and (6) neurodegeneration [total Tau (T-tau)], were quantified on admission (pre-intervention) and 24-h post-RIC by ELISA. Differences between controls, HS, and HS+TBI on Admission were compared by ANOVA; Sham versus RIC treated trauma patients were evaluated by mixed model analysis. 
Results. Compared to healthy control values, HS alone elevated levels of CKBB (P<0.01), MMP-9 (P<0.01), S100B (P<0.01), and T-Tau (P<0.05) on Admission. Relative to HS alone, patients sustaining HS+TBI exhibited significantly increased levels of GFAP (P<0.01), CK-BB (P<0.05), S100B (P<0.05), T-Tau (P<0.05), and NSE (P<0.05). Overall treatment with RIC in pooled HS patients with or without TBI resulted in reduced NSE levels at 24-h in comparison to Sham patients (P<0.05), but did not alter other biomarker levels.
Conclusions. HS, in the absence of TBI, induced alterations in circulating neurological injury biomarkers. Concomitant hemorrhage and brain injury further exacerbated neurological injury biomarker release. These findings suggest post-injury application of RIC in HS patients has potential to reduce neuronal cell damage as evidenced by reduced NSE levels. Future RIC studies in isolated TBI patients, examining specific neurological injury biomarkers in association with neuroimaging and neurocognitive outcome assessments may also demonstrate neuroprotective effects.

Impact of Remote Ischemic Conditioning on Neurological Biomarker Profiles in Posttraumatic Hemorrhagic Shock Patients with or without Brain Injury