BACKGROUND
Enoxaparin (ENX) has been shown to reduce cerebral edema and improve
neurologic recovery after traumatic brain injury (TBI), through blunting of
cerebral leukocyte (LEU) recruitment. High mobility group box 1 (HMGB1)
protein may induce inflammation through LEU activation. We hypothesized that
ENX after TBI reduces LEU-mediated edema through blockade of HMGB1
signaling.
METHODS
Twenty-three CD1 mice underwent severe TBI by controlled cortical
impact and were randomized to one of four groups receiving either monoclonal
antibody against HMGB1 (MAb) or isotype (Iso) and either ENX (1 mg/kg) or
normal saline (NS): NS + Iso (n = 5), NS + MAb (n = 6), ENX + Iso (n = 6),
ENX + MAb (n = 6). ENX or NS was administered 2, 8, 14, 23 and 32 hours
after TBI. MAb or Iso (25 μg) was administered 2 hours after TBI. At
48 hours, cerebral intravital microscopy served to visualize live LEU
interacting with endothelium and microvascular fluorescein
isothiocyanate–albumin leakage. The Neurological Severity Score (NSS)
graded neurologic recovery; wet-to-dry ratios determined cerebral/lung
edema. Analysis of variance with Bonferroni correction was used for
statistical analyses.
RESULTS
ENX and MAb similarly reduced in vivo pial LEU rolling without
demonstrating additive effect. In vivo albumin leakage was greatest in
vehicle-treated animals but decreased by 25% with either MAb or ENX but by
50% when both were combined. Controlled cortical impact–induced
cerebral wet-to-dry ratios were reduced by MAb or ENX without additive
effect. Postinjury lung water was reduced by ENX but not by MAb. Neurologic
recovery at 24 hours and 48 hours was similarly improved with ENX, MAb, or
both treatments combined.
CONCLUSION
Mirroring ENX, HMGB1 signaling blockade reduces LEU recruitment,
cerebrovascular permeability, and cerebral edema following TBI. ENX further
reduced lung edema indicating a multifaceted effect beyond HMGB1 blockade.
Further study is needed to determine how ENX may play a role in blunting
HMGB1 signaling in brain injury patients.
BACKGROUND
Severe traumatic brain injury (TBI) may increase the risk of venous thromboembolic complications; however, early prevention with heparinoids is often withheld for its anticoagulant effect. New evidence suggests low molecular weight heparin reduces cerebral edema and improves neurological recovery after stroke and TBI, through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post-TBI. We hypothesized that UFH after TBI reduces cerebral edema by reducing LEU-mediated inflammation and improves neurological recovery.
METHODS
CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. UFH (75 U/kg or 225 U/kg) or vehicle (VEH, 0.9% saline) was administered 2, 11, 20, 27, and 34 hours after TBI. At 48 hours, pial intravital microscopy through a craniotomy was used to visualize live brain LEUs interacting with endothelium and microvascular fluorescein isothiocyanate–albumin leakage. Neurologic function (Garcia Neurological Test, GNT) and body weight loss ratios were evaluated 24 and 48 hours after TBI. Cerebral and lung wet-to-dry ratios were evaluated post mortem. ANOVA with Bonferroni correction was used to determine significance (p < 0.05).
RESULTS
Compared to positive controls (CCI), both UFH doses reduced post-TBI in vivo LEU rolling on endothelium, concurrent cerebrovascular albumin leakage, and ipsilateral cerebral water content after TBI. Additionally, only low dose UFH (75 U/kg) improved GNT at both 24 and 48 hours after TBI. High dose UFH (225 U/kg) significantly increased body weight loss above sham at 48 hours. Differences in lung water content and blood pressure between groups were not significant.
CONCLUSIONS
UFH after TBI reduces LEU recruitment, microvascular permeability, and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery whereas higher UFH may worsen functional recovery. Further study is needed to determine if this is caused by increased bleeding from injured brain with higher UFH doses.
A long BF accompanying TBI worsens early neurologic recovery and subsequent learning/memory. Enoxaparin may partially counter this and improve neurologic recovery.
2,3-O desulfated heparin after TBI reduces cerebral LEU recruitment, microvascular permeability and edema. 2,3-O desulfated heparin may also improve acute neurologic recovery leading to improved learning/memory ability weeks after injury.
Heparin after TBI reduces tissue LEU sequestration and edema in injured brain for up to 4 days. This is associated with persistent improved cognitive recovery, but only when low-dose UFH is given. Early administration of UFH following TBI may blunt LEU-related cerebral swelling and slow progression of secondary brain injury.
BackgroundAt present, no satisfactory reports on the monitoring of cerebral function to predict functional outcomes after brain damage such as traumatic brain injury (TBI) and stroke. The middle latency auditory-evoked potential index (MLAEPi) monitor (aepEX plus®, Audiomex, UK) is a mobile MLAEP monitor measuring the degree of consciousness that is represented by numerical values. Hence, we hypothesized that MLAEPi predicts neurological outcome after emergency craniotomy among patients with disturbance of consciousness (DOC), which was caused by brain damage.MethodsThe afore-mentioned patients who underwent emergency craniotomy within 12 h of brain damage and were subsequently monitored using MLAEPi were enrolled in this study. DOC was defined as an initial Glasgow Coma Scale score < 8. MLAEPi was measured for 14 days after craniotomy. Neurological outcome was evaluated before discharge using a cerebral performance category (CPC) score and classified into three groups: favorable outcome group for a CPC score of 1 or 2, unfavorable outcome group for a score of 3 or 4, and brain dead (BD) group for a score of 5.ResultsThirty-two patients were included in this study (17 with TBIs and 15 with acute stroke). Regarding outcome, 10 patients had a favorable outcome, 15 had an unfavorable outcome, and 7 were pronounced BD. MLAEPi was observed to be significantly higher on day 5 than that observed immediately after craniotomy in cases of favorable or unfavorable outcome (63 ± 3.5 vs. 36 ± 2.5 in favorable outcome; 63 ± 3.5 vs. 34 ± 1.8 in unfavorable outcome). MLAEPi was significantly lower in BD patients than in those with a favorable or unfavorable outcome on day 3 (24 ± 4.2 in BD vs. 52 ± 5.2 and 45 ± 2.7 in favorable and unfavorable outcome, respectively) and after day 4. MLAEPi was significantly higher in patients with a favorable outcome than in those with a favorable or unfavorable outcome after day 6 (68 ± 2.3 in favorable outcome vs. 48 ± 2.3 in unfavorable outcome).ConclusionWe believe that MLAEPi satisfactorily denotes cerebral function and predicts outcomes after emergency craniotomy in patients with DOC, which was caused by acute brain damage.
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