Katsuhiro Nagata

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 &mgr;g) 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.

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.

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.

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.

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.

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

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.

Predictors of neurological outcome in the emergency department for elderly patients following out-of-hospital restoration of spontaneous circulation

Aims. Survival rates for cardiac arrest in acute medicine are higher following out-of-hospital restoration of spontaneous circulation (OH-ROSC). However, data pertaining to OH-ROSC is limited in the elderly population. We aimed to assess the predictors of neurological outcome among elderly patients with OH-ROSC.Methods. We retrospectively analyzed the data of patients 65 years and older who achieved OH-ROSC and who presented to the emergency department (ED) between 2009 and 2013. The following parameters were considered: age, sex, medical history, vital signs, blood values, initial electrical rhythm, witnessed cardiac arrest, bystander cardiopulmonary resuscitation, resuscitation duration, attempted defibrillation, and neurological outcome. Neurological outcomes were evaluated 3 months after cardiac arrest, using the cerebral performance category (CPC) score, and were classified into two groups: favorable outcome (CPC = 1–2) and unfavorable outcome (CPC = 3–5).Results. Fifty-five patients were studied, of which 21 and 34 patients were classified as having favorable and unfavorable outcomes, respectively. The following values were associated with favorable outcomes: resuscitation duration, initial cardiac rhythm, base excess, pH, lactate levels, the motor response on the Glasgow Coma Scale (GCS), and the number of patients with GCS ≤8 (p < 0.01). Logistic regression analysis confirmed that motor response scores and lactate levels were independent predictors of neurological outcomes.Conclusions. Lactate levels and GCS motor response measured immediately at ED arrival are likely to be useful to assess the neurological outcomes among elderly patients with OH-ROSC.

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.

Middle latency auditory evoked potential index for prediction of post-resuscitation survival in elderly populations with out-of-hospital cardiac arrest

Background. Out-of-hospital cardiac arrest (OHCA) is associated with a high mortality rate in the elderly. Although most reports have investigated among elderly patients with OHCA until 1990s, non-invasive monitorings cannot presently predicted cerebral resuscitation during cardiopulmonary resuscitation (CPR). Findings of a previous study suggest that monitoring of middle latency auditory evoked potentials (MLAEP) during CPR could provide an indicator of effective post-resuscitation survival. Objectives. We speculated that the MLAEP index (MLAEPi), measured in an emergency room, can predict post-resuscitation survival among elderly patients with OHCA. Methods. This prospective study included 31 elderly patients aged ≥65 years with OHCA who received basic life support (BLS) and did not achieve restoration of spontaneous circulation (ROSC) until arrival at the emergency center between December 2010 and December 2011. All patients were administered advanced cardiac life support (ACLS) in the emergency room. Initial MLAEPi was measured using an MLAEP monitor (aepEX plus®, Audiomex, UK) during the first cycle of ACLS. Prediction of the post-resuscitation survival was investigated. Results. Eight patients who achieved ROSC were admitted to our hospital and 23 did not achieve ROSC in the emergency room. Initial MLAEPi was significantly higher in patients with than without ROSC (median, 33 vs. 26, p = 0.02). Three survivors, among patients with ROSC, were discharged from our hospital (survivors) and 5 died during hospitalization (non-survivors). Initial MLAEPi was significantly higher in survivors than in non-survivors (median, 35 vs. 28, p = 0.03) or patients without ROSC (median, 35 vs. 26, p < 0.01). Conclusions. MLAEPi satisfactorily denotes cerebral function and predicts postresuscitation survival in elderly populations.

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.