Cerebral Edema and Neurological Recovery after Traumatic Brain Injury Are Worsened if Accompanied by a Concomitant Long Bone Fracture.

Progression of severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation, but it is unknown how a concomitant bone fracture (FX) affects this progression. Enoxaparin (ENX), a low molecular weight heparin often used for venous thromboembolic prophylaxis, decreases penumbral leukocyte (LEU) mobilization in isolated TBI and improves neurological recovery. We investigated if TBI accompanied by an FX worsens LEU-mediated cerebral inflammation and if ENX alters this process. CD1 male mice underwent controlled cortical impact (CCI) or sham craniotomy with or without an open tibial FX, and received either ENX (1 mg/kg, three times/day) or saline for 2 days following injury. Randomization defined four groups (Sham, CCI, CCI+FX, CCI+FX+ENX, n = 10/group). Two days after CCI, neurological recovery was assessed with the Garcia Neurological Test (GNT); intravital microscopy (LEU rolling and adhesion, microvascular leakage) and blood hemoglobin levels were also evaluated. Penumbral cerebral neutrophil sequestration (Ly-6G immunohistochemistry [IHC]) were evaluated post-mortem. In vivo LEU rolling was greater in CCI+FX (45.2 ± 4.8 LEUs/100 µm/min) than in CCI alone (26.5 ± 3.1, p = 0.007), and was suppressed by ENX (23.2 ± 5.5, p = 0.003 vs. CCI + FX). Neurovascular permeability was higher in CCI+FX (71.1 ± 2.9%) than CCI alone (42.5 ± 2.3, p < 0.001). GNT scores were lower in CCI+FX (15.2 ± 0.2) than in CCI alone (16.3 ± 0.3, p < 0.001). Hemoglobin was lowest in the CCI+FX+ENX group, lower than in Sham or CCI. IHC demonstrated greatest polymorphonuclear neutrophil (PMN) invasion in CCI+FX in uninjured cerebral territories. A concomitant long bone FX worsens TBI-induced cerebral LEU mobilization, microvascular leakage, and cerebral edema, and impairs neurological recovery at 48 h. ENX suppresses this progression but may increase bleeding.

A concomitant bone fracture delays cognitive recovery from traumatic brain injury.

BACKGROUND: Brain injury progression after severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation but it is unknown how a concomitant bone fracture (BF) affects this progression. Enoxaparin (ENX) decreases penumbral leukocyte mobilization after TBI and improves neurologic recovery. We hypothesized that a concomitant BF worsens learning/memory recovery weeks after TBI and that ENX improves this recovery. METHODS: CD1 male mice underwent controlled cortical impact or sham craniotomy with or without tibial fracture, receiving either daily ENX (0.8 mg/kg) or saline for 14 days after injury. Randomization defined four groups (Sham, TBI only, TBI + Fx, TBI + Fx + ENX, n = 5/each). Body weight loss and neurologic recovery (Garcia Neurologic Test, max score = 18) were assessed each day. Mouse learning (swimming time [s] and total distance [m] to reach the submerged platform Days 14 to 17 after TBI) and memory (swimming time [s] in platform quadrant after platform removed [probe]) was assessed by the Morris water maze. Ly-6G (cerebral neutrophil sequestration) and glial fibrillary acidic protein were evaluated by immunohistochemistry in brain tissue post mortem. Analysis of variance with Tukey's post hoc test determined significance (p < 0.05). RESULTS: A concurrent BF worsened Garcia Neurologic Test scores post-TBI Days 2 to 4 (p < 0.01) as compared with TBI only, and ENX reversed this worsening on Day 4 (p < 0.01). Learning was significantly slower (greater swimming time and distance) in TBI + Fx versus TBI only on Day 17 (p < 0.01). This was despite similar swimming velocities in both groups, indicating intact extremity motor function. Memory was similar in isolated TBI and Sham which was significantly better than in TBI + Fx animals (p < 0.05). Glial fibrillary acidic protein-positive cells in penumbral cortex were most prevalent in TBI + Fx animals, significantly greater than in Sham (p < 0.05). CONCLUSION: A long BF accompanying TBI worsens early neurologic recovery and subsequent learning/memory. Enoxaparin may partially counter this and improve neurologic recovery.

Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury.

BACKGROUND: Unfractionated heparin administered immediately after traumatic brain injury (TBI) reduces brain leukocyte (LEU) accumulation, and enhances early cognitive recovery, but may increase bleeding after injury. It is unknown how non-anticoagulant heparins, such as 2,3-O desulfated heparin (ODSH), impact post-TBI cerebral inflammation and long-term recovery. We hypothesized that ODSH after TBI reduces LEU-mediated brain inflammation and improves long-term neurologic recovery. METHODS: CD1 male mice (n = 66) underwent either TBI (controlled cortical impact [CCI]) or sham craniotomy. 2,3-O desulfated heparin (25 mg/kg [25ODSH] or 50 mg/kg [50ODSH]) or saline was administered for 48 hours after TBI in 46 animals. At 48 hours, intravital microscopy visualized rolling LEUs and fluorescent albumin leakage in the pial circulation, and the Garcia Neurologic Test assessed neurologic function. Brain edema (wet/dry ratio) was evaluated post mortem. In a separate group of animals (n = 20), learning/memory ability (% time swimming in the Probe platform quadrant) was assessed by the Morris Water Maze 17 days after TBI. Analysis of variance with Bonferroni correction determined significance (p < 0.05). RESULTS: Compared with CCI (LEU rolling: 32.3 ± 13.7 LEUs/100 µm per minute, cerebrovascular albumin leakage: 57.4 ± 5.6%), both ODSH doses reduced post-TBI pial LEU rolling (25ODSH: 18.5 ± 9.2 LEUs/100 µm per minute, p = 0.036; 50ODSH: 7.8 ± 3.9 LEUs/100 µm per minute, p < 0.001) and cerebrovascular albumin leakage (25ODSH: 37.9 ± 11.7%, p = 0.001, 50ODSH: 32.3 ± 8.7%, p < 0.001). 50ODSH also reduced injured cerebral hemisphere edema (77.7 ± 0.4%) vs. CCI (78.7 ± 0.4 %, p = 0.003). Compared with CCI, both ODSH doses improved Garcia Neurologic Test at 48 hours. Learning/memory ability (% time swimming in target quadrant) was lowest in CCI (5.9 ± 6.4%) and significantly improved in the 25ODSH group (27.5 ± 8.2%, p = 0.025). CONCLUSION: 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.

Effectiveness of cadaver-based educational seminar for trauma surgery: skills retention after half-year follow-up.

Aim: In Japan, trauma surgery training remains insufficient, and on-the-job training has become increasingly difficult because of the decreasing number of severe trauma patients and the development of non-operative management. Therefore, we assessed whether a 1-day cadaver-based seminar is effective for trauma surgery training. Methods: Data were collected from 11 seminars carried out from January 2013 to March 2014, including a 10-point self-assessment of confidence levels (SACL) for 21 surgical skills and an evaluation of the contents before, just after, and a half-year after the seminar. Statistical analysis was undertaken using the paired t-test at P < 0.0167. Results: A total of 135 participants were divided into three groups based on experience and clinical careers. The SACL improved in all skills between before and just after the seminar, however, they decreased between just after and a half-year after the seminar. The SACL did not change significantly in all skills between just after and a half-year after the seminar in highly experienced and experienced group members belonging to an emergency center. Conclusions: A cadaver-based seminar provided more self-confidence just after the seminar for participants at all experience levels. This effect was not maintained after a half-year, except in participants who can practice the skills at an emergency center. Practicing and participating in the seminar repeatedly is suggested to be effective for skills retention in trauma surgery.

Empirical research on the utility of a preparation manual for a disaster medical response drill.

PURPOSE: It is difficult for emergency physicians to plan and execute a disaster medical response drill while conducting their daily work activities. Readily available drill preparation manuals are therefore essential, alongside assessment methods to ensure quality. Here, we propose email text analysis as a manual assessment method, and investigate its validity. METHODS: The preparation status of two similar large-scale disaster medical response drills were compared. All email texts exchanged during the preparation stage were analyzed, and frequently appearing words (quality element) and word counts (quantity element) were compared between Drill 1, which was organized without a manual, and Drill 2, organized with a manual. RESULTS: Word frequency analysis revealed that the key components of the manual (visualization of necessary work, preparation of documents in a certain format, and clarification of aims of the drill) contributed to the effectiveness of the preparation process for Drill 2. Furthermore, work volume during the preparation for Drill 2 was decreased by 41.9% from that during the preparation for Drill 1. CONCLUSION: Preparation of a high-quality manual is crucial so that emergency physicians can plan and execute a disaster medical response drill. Email text analysis can serve as an objective method assessing the quality of manuals.

Early heparin administration after traumatic brain injury: Prolonged cognitive recovery associated with reduced cerebral edema and neutrophil sequestration.

BACKGROUND: Early administration of unfractionated heparin (UFH) after traumatic brain injury (TBI) reduces early in vivo circulating leukocytes (LEUs) in peri-injury penumbral brain tissue, enhancing cognitive recovery 2 days after injury. It remains unclear how long this effect lasts and if this is related to persistently accumulating LEUs in penumbral brain tissue. We hypothesized that UFH reduces LEU brain tissue sequestration resulting in prolonged cognitive recovery. METHODS: CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. Unfractionated heparin (75 or 225 U/kg) or vehicle was repeatedly administered after TBI. Neurologic function (Garcia Neurological Test [maximum score = 18]) and body weight loss ratios were evaluated at 24 hours to 96 hours after TBI. Brain and lung wet-to-dry ratios, hemoglobin levels, and brain LEU sequestration (Ly6G immunohistochemistry) were evaluated 96 hours postmortem. Analysis of variance with Bonferroni correction determined significance (p < 0.05). RESULTS: Compared with untreated CCI animals (24 hours, 14.7 ± 1.0; 48 hours, 15.5 ± 0.7; 72 hours, 15.0 ± 0.8; 96 hours, 16.5 ± 0.9), UFH75 (24 hours, 16.0 ± 1.0, p < 0.01; 48 hours, 16.5 ± 0.7, p < 0.05; 72 hours, 17.1 ± 0.6, p < 0.01; 96 hours, 17.4 ± 0.7, p < 0.05) increased cognitive recovery throughout the entire observation period after TBI. At 48 hours, UFH225 significantly worsened body weight loss (10.2 ± 4.7%) as compared with uninjured animals (5.5 ± 2.9%, p < 0.05). Both UFH75 (60.8 ± 40.9 PMNs per high-power field [HPF], p < 0.05) and UFH225 (36.0 ± 17.6 PMNs/HPF, p < 0.01) significantly decreased brain neutrophil sequestration found in untreated CCI animals (124.2 ± 44.1 PMNs/HPF) 96 hours after TBI. Compared with untreated CCI animals (78.8 ± 0.8%), UFH75 (77.3 ± 0.6%, p = 0.04) reduced cerebral edema to uninjured levels (77.4 ± 0.6%, p = 0.04 vs. CCI). Only UFH225 (10.6 ± 1.2 g/dL) resulted in lower hemoglobin than in uninjured animals (13.0 ± 1.2 g/dL, p < 0.05). CONCLUSIONS: 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.

Procalcitonin levels predict to identify bacterial strains in blood cultures of septic patients.

BACKGROUND: We examined whether the values obtained from principal component analysis (PCA) on laboratory tests can be used to predict bacterial infections and identify bacterial strains in blood culture (BC). METHOD: This study is a single-center retrospective analysis of 315 patients suspected of having sepsis. We applied PCA on procalcitonin (PCT) and laboratory test biomarkers, namely, platelet (PLT), white blood cell, and C-reactive protein (CRP) as well as BC. RESULTS: Principal component analysis showed that PCT, CRP, and PLT contributions to component 1 were associated with bacterial infection. The number of patients who had BC-negative results, gram-positive cocci (GPC), and gram-negative rods (GNRs) were 124, 28, and 19, respectively. The mean value of component 1 in GNR-positive patients was 1.58±1.41 and was significantly higher than that in GPC-positive patients (0.28±0.87; P<.0001). Furthermore, the mean values of component 1 in both GNR- and GPC-positive patients were significantly higher than that in BC-negative patients (-0.31±0.65; P<.0001 and P<.002, respectively). One certain range showing higher value more than 2.00 for component 1 and -1.00 for component 2 only included GNR-positive patients. There were no BC-positive patients who showed less than -1.00 for component 1. CONCLUSION: The present results obtained by PCA on laboratory tests involving PCT, PLT, white blood cell, and CRP suggest the potential of PCA-obtained values to not only predict bloodstream infection but also identify bacterial strains. This provides some clinical significance in the management of sepsis in acute care.

Unfractionated heparin after TBI reduces in vivo cerebrovascular inflammation, brain edema and accelerates cognitive recovery.

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.

Does enoxaparin interfere with HMGB1 signaling after TBI? A potential mechanism for reduced cerebral edema and neurologic recovery.

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.

Middle latency auditory-evoked potential index monitoring of cerebral function to predict functional outcome after emergency craniotomy in patients with brain damage.

BACKGROUND: At 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. METHODS: The 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. RESULTS: Thirty-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). CONCLUSION: We believe that MLAEPi satisfactorily denotes cerebral function and predicts outcomes after emergency craniotomy in patients with DOC, which was caused by acute brain damage.

Anti-NMDAR encephalitis: case report and diagnostic issues.

Case: A 20-year-old woman developed acute psychotic symptoms and altered level of consciousness. She presented with neck stiffness, tremulous arms, facial dyskinesia, and distension of the lower abdomen. Pelvic magnetic resonance imaging showed bilateral ovarian teratomas. Anti-N-methyl-D-aspartate receptor antibodies were detected in her cerebrospinal fluid. Outcome: Resection of the tumors and immunotherapy were carried out. She gradually recovered and was discharged with few neurological deficits on the 105th day of hospitalization. Conclusion: Our survey of 63 previous reports describing 92 cases revealed that 21.7% of the patients were sent to emergency departments and 59.8% of the patients were managed in intensive care units. Emergency physicians and intensivists should be aware of this disorder, as they may encounter undiagnosed disorders in patients with epileptic attacks, acute psychotic signs, dyskinesia, or hypoventilation in the course of the illness.

Middle latency auditory-evoked potential index for predicting the degree of consciousness of comatose patients in EDs.

INTRODUCTION: Digitized assessment of the degree of consciousness is a universal challenge in emergency departments (EDs) and intensive care units (ICUs). The middle latency auditory-evoked potential index (MLAEPi) monitor aepEX plus (Audiomex, Glasgow, Scotland, UK) is the first mobile middle latency auditory-evoked potential monitor. We speculated that the initial MLAEPi determined on arrival at EDs could indicate cerebral function and predict the degree of consciousness of comatose patients. METHODS: We used MLAEPi-related data from 50 comatose patients with disturbance of consciousness (DOC), 50 patients with cardiopulmonary arrest (CPA), and 50 healthy volunteers (control). Comatose patients were defined as those with an initial Glasgow Coma Scale score of 8 or less. The CPA group consisted of patients who arrived at EDs without restoration of spontaneous circulation. Among the patients with DOC who underwent sedation at EDs, the change in the MLAEPi was evaluated between arrival at the ED and ICU admission. RESULTS: The initial MLAEPi was significantly lower in the DOC group than in the control group but significantly higher in the DOC group than in the CPA group. Among the comatose patients, the receiver operating characteristic curve for the initial MLAEPi showed an area under the curve of 0.93 (P < .01) for the DOC group. Thirty patients with DOC underwent sedation at EDs, and the initial MLAEPi was significantly higher than those at other periods during emergency care. CONCLUSION: The MLAEPi (simple numerical value) may be used to evaluate the degree of consciousness in comatose patients while performing emergency care in EDs.