High early phase hemoglobin level is associated with favorable neurological outcome in patients with severe traumatic brain injury.

BACKGROUND: The appropriate hemoglobin (Hb) level threshold for the early phase (i.e. from Emergency Department to ICU admission) in patients with severe traumatic brain injury (TBI) is still unknown. Therefore, we aimed to examine the association between Hb levels during the early phase and neurological outcomes in patients with severe TBI using data from the Brain Hypothermia (B-HYPO) Study Group. METHODS: We performed a post-hoc analysis of the B-HYPO study (a prospective, multicenter, randomized controlled trial on patients with severe TBI who received either mild therapeutic hypothermia [MTH; 32.0 °C-34.0 °C] or fever control [35.5 °C-37.0 °C]). We calculated Hb levels during early phase by the formula: (admission Hb + Hb on day 1) / 2. The primary outcome was the association between during early phase Hb levels and 6-month neurological outcome after the TBI based on the Glasgow Outcome Scale scores (a measure of functional recovery defined as moderate disability or good recovery). RESULTS: We reviewed data from 130 patients and found favorable neurological outcomes in 48.5% of them. We found significant differences between the favorable and unfavorable neurological outcome groups in terms of their Hb levels on admission and on day 1. But, we found no Hb level differences after day 3 (including 1 day after rewarming). Our multivariable analysis showed that Hb levels during early phase were significantly associated with favorable neurological outcomes (odds ratio, 1.387; 95% confidence interval, 1.057-1.858; P = 0.018). CONCLUSIONS: High early phase Hb levels are associated with favorable neurological outcomes after severe TBI.

Fluorescence tumor imaging by i.v. administered indocyanine green in a mouse model of colitis-associated colon cancer.

Fluorescence tumor imaging using exogenous fluorescent tumor-targeting agents has potential to improve early tumor detection. The fluorescent contrast agent indocyanine green (ICG) is used in medical diagnostics. The aim of the present study is to investigate the tumor imaging capability and the imaging mechanism of i.v. administered ICG in a mouse model of colitis-associated colon cancer. To do this, an azoxymethane/dextran sodium sulfate-induced colon cancer mouse model was used. Ex vivo imaging experiments were carried out 1 hour after i.v. injection of ICG. The ICG fluorescence was observed in the colon tumor tissues, with sufficient tumor to normal tissue ratio, correlating with tumor malignancy. In the tumor tissues, ICG fluorescence was localized in the vascular interstitial tissue. Immunofluorescence microscopy revealed that tumor cells formed tight junctions normally, suggesting an inability of tumor cellular uptake of ICG. In contrast, tumor tissues increased the CD31-immunoreactive endothelial cell area, and accumulated stromal cells immunoreactive for COX-2 and tumor cell population immunoreactive for inducible nitric oxide synthase. In vivo vascular permeability assay revealed that prostaglandin E2 promoted the endothelial cell permeability of ICG. In conclusion, our data indicated that fluorescence contrast-enhanced imaging following i.v. administered ICG can be applied to the detection of colon tumors in a mouse colitis-associated colon cancer model. The tumor tissue preference of ICG in the present model can be attributed to the enhanced vascular leakage of ICG involving inflammatory mediators, such as COX-2 and inducible nitric oxide synthase, in conjunction with increased tumor vascularity.

Mild decrease in heart rate during early phase of targeted temperature management following tachycardia on admission is associated with unfavorable neurological outcomes after severe traumatic brain injury: a post hoc analysis of a multicenter randomized controlled trial.

BACKGROUND: The association between isolated admission heart rate (HR) and prognosis has been discussed, but not that between gross HR change and neurological outcome in patients with severe traumatic brain injury (TBI). In the acute phase of severe TBI, HR is influenced by several factors (e.g., pain, sympathetic activation, hypovolemia, fever, body temperature). Therefore, admission HR and gross HR change should be examined in patients with TBI treated with a well-designed protocol, such as was done in the Brain Hypothermia (B-HYPO) Study. METHODS: This was a post hoc analysis of the B-HYPO Study, which was conducted as a prospective, multicenter, randomized controlled trial in patients with severe TBI receiving mild therapeutic hypothermia (MTH; 32.0 °C-34.0 °C) or fever control (35.5 °C-37.0 °C) in Japan. Patients with MTH were examined, and HR change (%HR) in the early MTH phase was calculated as follows: [admission HR - HR at day 1]/admission HR × 100. Patients were divided into six groups, using admission HR (< 80, 80-99, ≤ 100) and median of %HR; i.e., group (Admission HR < 80 and %HR ≥ 18.6); group (Admission HR < 80 and %HR < 18.6); group (Admission HR 80-99 and %HR ≥ 18.6); group (Admission HR 80-99 and %HR < 18.6); group (Admission HR ≥100 and %HR ≥ 18.6); and group (Admission HR ≥100 and %HR < 18.6). The primary outcome was an adjusted predicted probability of unfavorable neurological outcome at 6 months after TBI according to Glasgow Outcome Scale score, which is a measure of functional recovery and defined as severe disability, persistent vegetative state, and death. RESULTS: Overall, 79 patients with MTH (52.7% of the original trial) were examined; among these, unfavorable neurological outcomes were observed in 53.2%. Among all the groups, group (Admission HR ≥100 and %HR < 18.6) exhibited the highest proportion of unfavorable outcomes, and 82.3% of patients had an adjusted predicted probability of unfavorable outcomes, whereas those in group (Admission HR < 80 and %HR ≥ 18.6) developed only 22.8% (p = 0.04). CONCLUSIONS: Mild HR decrease during the early phase of targeted temperature management following tachycardia at admission can be associated with unfavorable neurological outcomes after severe TBI.

Isolation of a non-urea-producing sake yeast strain carrying a discriminable molecular marker.

In the fermentation industry, the traceability of microorganisms during the process is important to ensure safety and efficacy. Ethyl carbamate, a group-2A carcinogen, is produced from ethanol and urea during the storage of food/alcoholic beverages. We isolated non-urea-producing sake yeast car1 mutants carrying a discriminable molecular marker, and demonstrated, by the use of PCR assays, that these mutants are useful for traceability analysis and identification during the sake brewing process.

In Vitro Comparative Study of Near-Infrared Photoimmunotherapy and Photodynamic Therapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a new phototherapy that utilizes a monoclonal antibody (mAb) against cancer antigens and a phthalocyanine dye, IRDye700DX (IR700) conjugate (mAb-IR700). Photodynamic therapy (PDT) is a combination therapy that utilizes photoreactive agents and light irradiation as well as NIR-PIT. In the present study, we compared these therapies in vitro. The characterization of cellular binding/uptake specificity and cytotoxicity were examined using two mAb-IR700 forms and a conventional PDT agent, talaporfin sodium, in three cell lines. As designed, mAb-IR700 had high molecular selectivity and visualized target molecule-positive cells at the lowest concentration examined. NIR-PIT induced necrosis and damage-associated molecular patterns (DAMPs), a surrogate maker of immunogenic cell death. In contrast, talaporfin sodium was taken up by cells regardless of cell type, and its uptake was enhanced in a concentration-dependent manner. PDT induced cell death, with the pattern of cell death shifting from apoptosis to necrosis depending on the concentration of the photosensitizer. Induction of DAMPs was observed at the highest concentration, but their sensitivity differed among cell lines. Overall, our data suggest that molecule-specific NIR-PIT may have potential advantages compared with PDT in terms of the efficiency of tumor visualization and induction of DAMPs.

Trastuzumab-based near-infrared photoimmunotherapy in xenograft mouse of breast cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel form of cancer treatment using conjugates of antibody against overexpressed antigens in cancers and photoabsorber IRDye700DX. HER2 is overexpressed in various cancers, for which molecular targeted therapy such as trastuzumab has been developed. The present study investigated the efficacy potential of HER2-targeted NIR-PIT using trastuzumab-IRDye700DX conjugate (Tra-IR700) in HER2-positive breast cancer. We first examined the reactivity of Tra-IR700 and the cytotoxicity of NIR-PIT in vitro. HER2-positive BT-474 and SK-BR-3 cells and HER2-negative BT-20 cells were used. Tra-IR700 fluorescence was only observed in HER2-positive breast cancer cell lines, and the fluorescence was localized to the cell surface. Furthermore, HER2-positive breast cancer cell lines treated with NIR-PIT showed swelling and blebbing shortly after irradiation, and eventually increased PI-positive dead cells. Next, tumor accumulation of Tra-IR700 and tumor damage by NIR-PIT were examined in vivo. Tra-IR700 was administered intravenously to a xenograft model in which BT-474 cells were implanted subcutaneously in BALB/c nude mice. Tra-IR700 fluorescence was the highest in tumor tissue 1 day after administration, and the fluorescence was localized to the cell membrane of tumor cells. At this time point, NIR-PIT resulted in diffuse necrosis of tumor tissues 1 day after irradiation. These results suggest that NIR-PIT with Tra-IR700 induces a highly selective therapeutic effect in a HER2-positive breast cancer model. NIR-PIT using Tra-IR700 is expected to be a novel treatment for HER2-positive cancers, including breast cancer.

Zinc is a novel intracellular second messenger.

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcepsilon receptor I [FcepsilonRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcepsilonRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger.

Benefits of Hypothermia for Young Patients with Acute Subdural Hematoma: A Computed Tomography Analysis of the Brain Hypothermia Study.

Therapeutic hypothermia for severe traumatic brain injury (TBI) has been repeatedly studied, but no past studies have assessed the detailed head computed tomography (CT) findings. We sought to investigate individual CT findings of severe TBI patients treated with targeted temperature management utilizing the head CT database obtained from the Brain Hypothermia study. Enrolled patients underwent either mild therapeutic hypothermia (32.0°C-34.0°C) or fever control (35.5°C-37.0°C). We assessed individual head CT images on arrival and after rewarming and investigated the correlations with outcomes. The initial CT data were available for 125 patients (hypothermia group = 80, fever control group = 45). Baseline characteristics and CT findings, such as hematoma thickness and midline shift, were similar in all aspects between the two groups. The favorable outcomes in the hypothermia and fever control groups were 38 (47.5%) and 24 (53.3%; p = 0.53) for all 125 patients, respectively; 21 (46.7%) vs. 10 (38.5%; p = 0.50) for 71 patients with acute subdural hematoma (SDH), respectively; and 12 (75.0%) vs. 4 (36.4%; p = 0.045) in 27 young adults (≤50 years) with acute SDH, respectively. There was a trend toward favorable outcomes for earlier time to reach 35.5°C (190 vs. 377 min, p = 0.052) and surgery (155 vs. 180 min, p = 0.096) in young patients with acute SDH. The second CT image revealed progression of the brain injury. This study demonstrated the potential benefits of early hypothermia in young patients with acute SDH, despite no difference in CT findings between the two groups. However, the small number of cases involved hindered the drawing of definitive conclusions. Future studies are warranted to validate the results.

Sake lees fermented with lactic acid bacteria prevents allergic rhinitis-like symptoms and IgE-mediated basophil degranulation.

We tested the effect of oral administration of fermented sake lees with lactic acid bacteria (FESLAB) on a murine model of allergic rhinitis upon immunization and nasal sensitization with ovalbumin (OVA). We used Lactobacillus paracasei NPSRIk-4 (isolated from sake lees), and L. brevis NPSRIv-8 (from fermented milk) as starter strains to produce the FESLAB. Oral FESLAB administration resulted in the development of significantly fewer sneezing symptoms than those seen in sham control animals given sterile water. We also found that FESLAB suppressed the allergen-induced degranulation of RBL2H3 rat basophilic leukemia cells.

Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer.

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.

Prognostic Significance of the Difference Between Mixed and Jugular Venous Oxygen Saturation After Severe Traumatic Brain Injury: A Post Hoc Analysis of the Brain Hypothermia Study.

BACKGROUND: In patients postcardiac arrest, it has been reported that the small value of the difference between mixed venous oxygen saturation (Svo2) and jugular venous oxygen saturation (Sjvo2) is associated with poor neurologic outcome. However, the importance of the difference between mixed venous oxygen saturation and jugular venous oxygen saturation (ΔSo2 [v - jv]) remains unknown in severe traumatic brain injury (TBI). The aim of this study was to examine whether ΔSo2 (v - jv) is associated with neurologic outcome and mortality in patients with severe TBI. METHODS: We conducted post hoc analyses of the Brain Hypothermia Study, a multicenter randomized controlled trial of mild therapeutic hypothermia for the treatment of severe TBI. The value of ΔSo2(v - jv) on day 1 and day 3 was compared between survivors (n = 65) and nonsurvivors (n = 25) or between patients with favorable (n = 47) and unfavorable (n = 43) neurologic outcomes. RESULTS: The reduction in ΔSo2 (v - jv) on day 3 was -2.0% (range, -6.9% to 6.5%) in the nonsurvivor group and 6.3% (range, -2.5% to 16.7%) in the survivor group. The difference was statistically significant (P = 0.03). The same tendencies were observed in the nonsurvivor group on day 1 and in the unfavorable neurologic outcome group on day 1 and day 3, but the difference was not significant. CONCLUSIONS: The reduction in ΔSo2(v - jv) on day 3 was associated with high mortality in patients with severe TBI.

Stat3 Controls Cell Movements during Zebrafish Gastrulation.

Vertebrate axis formation requires both the correct specification of cell fates and the coordination of gastrulation movements. We report that the zebrafish signal transducer and activator of transcription 3 (Stat3) is activated on the dorsal side by the maternal Wnt/beta-catenin pathway. Zebrafish embryos lacking Stat3 activity display abnormal cell movements during gastrulation, resulting in a mispositioned head and a shortened anterior-posterior axis, but show no defects in early cell fate specification. Time course analysis, cell tracing, and transplantation experiments revealed that Stat3 activity is required cell autonomously for the anterior migration of dorsal mesendodermal cells and non-cell autonomously for the convergence of neighboring paraxial cells. These results reveal a role for Stat3 in controlling cell movements during gastrulation.

STAT3 noncell-autonomously controls planar cell polarity during zebrafish convergence and extension.

Zebrafish signal transducer and activator of transcription 3 (STAT3) controls the cell movements during gastrulation. Here, we show that noncell-autonomous activity of STAT3 signaling in gastrula organizer cells controls the polarity of neighboring cells through Dishevelled-RhoA signaling in the Wnt-planar cell polarity (Wnt-PCP) pathway. In STAT3-depleted embryos, although all the known molecules in the Wnt-PCP pathway were expressed normally, the RhoA activity in lateral mesendodermal cells was down-regulated, resulting in severe cell polarization defects in convergence and extension movements identical to Strabismus-depleted embryos. Cell-autonomous activation of Wnt-PCP signaling by DeltaN-dishevelled rescued the defect in cell elongation, but not the orientation of lateral mesendodermal cells in STAT3-depleted embryos. The defect in the orientation could be rescued by transplantation of shield cells having noncell-autonomous activity of STAT3 signaling. These results suggest that the cells undergoing convergence and extension movement may sense the gradient of signaling molecules, which are expressed in gastrula organizer by STAT3 and noncell-autonomously activate PCP signaling in neighboring cells during zebrafish gastrulation.

High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage.

BACKGROUND: High-mobility group box 1 protein (HMGB1) is a nuclear factor that is a potent proinflammatory mediator, and may trigger increases in other inflammatory cytokines. The inflammatory cytokines in the cerebrospinal fluid (CSF) of patients with subarachnoid hemorrhage (SAH) have been reported previously, but HMGB1 has not. In this study, we measured HMGB1 and the inflammatory cytokines in the CSF of patients with SAH. METHODS: CSF samples were collected on days 3, 7, and 14 from the drainage tubes of the postaneurysm clips of 39 patients with SAH. HMGB1, interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-alpha) were measured in the CSF, and compared between the patients with favorable (good recovery and moderate disability) and unfavorable outcomes (severe disability, vegetative state, and death) at 3 months. RESULTS: In the unfavorable outcome group, HMGB1 (P = 0.017), IL-6 (P = 0.003), IL-8 (P = 0.041), and TNF-alpha (P = 0.002) were significantly increased. HMGB1 correlated significantly with IL-6, IL-8, and TNF-alpha (R = 0.672, 0.421, and 0.697, respectively). CONCLUSIONS: HMGB1 was increased in the CSF of SAH patients with an unfavorable outcome, as were the other cytokines. These results suggest that HMGB1 and cytokines are related to the brain damage observed after SAH. HMGB1 might play a key role in the inflammatory response in the CNS of SAH patients.

Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Our previous studies have demonstrated that oxidative DNA injury occurs in the brain after intracerebral hemorrhage (ICH). We therefore examined whether edaravone, a free-radical scavenger, could reduce ICH-induced brain injury. METHODS: These experiments used pentobarbital-anesthetized, male Sprague-Dawley rats that received an infusion of either 100 microL autologous whole blood (ICH), FeCl(2), or thrombin into the right basal ganglia. The rats were humanely killed 24 hours later. There were 4 sets of experiments. In the first, the dose-dependent effects of edaravone on ICH-induced brain injury were examined by measuring brain edema and neurologic deficits. In the second set, apurinic/apyrimidinic abasic sites and 8-hydroxyl-2'-deoxyguanosine, which are hallmarks of DNA oxidation, were investigated after treatment for ICH. In the third, the effect of delayed treatment with edaravone on ICH-induced injury was determined, whereas the fourth examined the effects of edaravone on iron- and thrombin-induced brain injury. RESULTS: Systemic administration of edaravone immediately or 2 hours after ICH reduced brain water content 24 hours after ICH compared with vehicle (P<0.05). Edaravone treatment immediately or 2 hours after ICH also ameliorated neurologic deficits (P<0.05). Edaravone also attenuated ICH-induced changes in apurinic/apyrimidinic abasic sites and 8-hydroxyl-2'-deoxyguanosine and reduced iron- and thrombin-induced brain injury. CONCLUSIONS: Edaravone attenuates ICH-induced brain edema, neurologic deficits, and oxidative injury. It also reduces iron- and thrombin-induced brain injury. These results suggest that edaravone is a potential therapeutic agent for ICH.

Hyperbaric oxygen therapy for consciousness disturbance following head injury in subacute phase.

BACKGROUND: Hyperbaric oxygen (HBO) therapy has been shown to improve outcome after brain injury, however its mechanisms are not understood. The purpose of the present study was to investigate the effect of hyperbaric oxygen (HBO) therapy on the cerebral circulation and metabolism of patients with disturbances in consciousness after head injury in the subacute phase. METHODS: Seven head injury patients underwent HBO treatment after leaving the intensive care unit. Oxygen (100% O2, 2.7 atm absolute) was delivered to patients in a hyperbaric chamber for 60 min every 24 h (total five treatments/patient). Cerebral circulation monitoring (mean flow velocity: mFV, and pulsatility index: PI at horizontal portion of middle cerebral artery by transcranial Doppler) and cerebral metabolism monitoring (arterio-jugular venous difference of oxygen: AJDO2 and jugular venous lactate: lac-JV) before and after the series of treatments were evaluated. FINDINGS: Both PI and lac-JV were significantly decreased after HBO theatment, while there were no significant changes in mFV and AJDO2. The decreased PI and lac-JV after HBO therapy might indicate that this treatment couples cerebral circulation and metabolism. CONCLUSIONS: The measurement of cerebral circulation and metabolism parameters, especially PI and lac-JV, is useful for estimation of effect of HBO therapy in patients with distubances in consciousness after head injury in the subacute phase.

Cerebral metabolism monitoring during hypothermia following resuscitation from cardiopulmonary arrest.

BACKGROUND: The aim of the present study was to evaluate cerebral metabolism monitoring during therapeutic hypothermia for global ischemic brain damage after cardiopulmonary resuscitation (CPR). METHODS: Jugular venous sampling and positron emission tomography (PET) were used. Seven comatose patients with cardiopulmonary arrest underwent hypothermia treatment as soon as possible after CPR. The body temperature of these patients was maintained at 34 degrees C for 72 h. Rewarming was performed at a rate of 1 degrees C/day. To monitor jugular venous saturation (SjO2) and lactate (lac-JV), a fiberoptic catheter was inserted into the jugular bulb. Oxygen extraction fraction (OEF) was calculated using the difference between arterial oxygen saturation (SaO2) and SjO2. 18F-fluorodeoxyglucose (FDG) PET was performed to investigate cerebral glucose metabolism at the end of therapeutic hypothermia. FINDINGS: The OEF was significantly increased at the end of hypothermia in four patients with favorable outcome on the Glasgow Outcome Scale (hypothermia onset 15.3 +/- 2.0% vs. hypothermia end 30.3 +/- 2.8%, P < 0.05). In three patients with unfavourable outcome (severe or worse on the Glasgow Outcome Scale), end hypothermia OEF tended to be low. There was also a reduction in FDG uptake in these three patients with unfavourable outcome. The lac-JV was significantly decreased at the end ofhypothermia treatment compared with hypothermia onset (27.7 +/- 7.4 vs. 6.0 +/- 3.0 mg/dL, P < 0.05). CONCLUSIONS: The measurement of cerebral metabolism parameters, especially OEF, might be useful for estimation of hypothermia therapy in patients with unconsciousness after resuscitation after cardiac arrest.

Severe and Recurrent Hypoglycemia Caused by Garenoxacin in a Patient not Taking Hypoglycemic Drugs.

Quinolones are known to induce hypoglycemia, although there is no written report of garenoxacin-induced hypoglycemia. We herein report a case of garenoxacin-induced hypoglycemia in a patient not taking hypoglycemic drugs. An 89-year-old Japanese woman with type 2 diabetes and chronic renal insufficiency requiring hemodialysis was admitted to the emergency department in a comatose state. Her serum glucose measured 1 mg/dL on arrival. The patient had not taken any hypoglycemic drugs recently and had never experienced a hypoglycemic episode. She had received a four-day course of garenoxacin treatment before the emergency admission. Clinicians should therefore recognize the potential risk of hypoglycemia during garenoxacin therapy.

Slow rewarming improved the neurological outcomes of prolonged mild therapeutic hypothermia in patients with severe traumatic brain injury and an evacuated hematoma.

Mild therapeutic hypothermia (MTH) is expected to improve the neurological outcomes of patients with severe traumatic brain injury (TBI). However, there are no standard protocols for managing the temperature of patients with severe TBI in order to improve their neurological outcomes. We conducted a post hoc analysis of the B-HYPO study, a randomized controlled trial of MTH in patients with TBI in Japan. We evaluated the impact of MTH methods on neurological outcomes. Ninety-seven patients who received MTH were included in the present analyses. The neurological outcomes were compared among subgroups of patients divided by cutoff values for the induction, maintenance, and rewarming times of MTH in all patients, in patients with diffuse injury, and in patients with an evacuated hematoma. The proportion of patients with a good neurological outcome was significantly different between patients with an evacuated hematoma divided into subgroups by the cutoff value of rewarming time of 48 h (>48 h vs. ≤ 48 h: 65% vs. 22%; odds ratio: 6.61; 95% confidence interval: 1.13-38.7, P = 0.0498). Slow rewarming for >48 h might improve the neurological outcomes of prolonged MTH in patients with TBI and an evacuated hematoma. Further studies are needed to investigate the optimal rewarming protocol in patients with TBI.

Therapeutic hypothermia in patients with coagulopathy following severe traumatic brain injury.

BACKGROUND: Coagulopathy in traumatic brain injury (TBI) has been associated with poor neurological outcomes and higher in-hospital mortality. In general principle of trauma management, hypothermia should be prevented as it directly worsens coagulopathy. Therefore, we examined the safety of mild therapeutic hypothermia (MTH) in patients with coagulopathy following severe TBI. METHODS: We re-evaluated the brain hypothermia (B-HYPO) study data based on coagulopathy and compared the Glasgow Outcome Scale scores and survival rates at 6 months using per protocol analyses. Coagulopathy was defined as an activated partial thromboplastin time (APTT) > 60 s and/or fibrin/fibrinogen degradation product levels (FDP) > 90 µg/mL on admission. Baseline characteristics, coagulation parameters, and outcomes were compared between the control and MTH groups with or without coagulopathy. RESULTS: In patients with coagulopathy, 12 patients were allocated to the control group (35.5-37.0 °C) and 20 patients to the MTH group (32-34 °C). In patients without coagulopathy, 28 were allocated to the control group and 59 patients were allocated to the MTH group. In patients with coagulopathy, favorable neurological outcomes and survival rates were comparable between the control and MTH groups (33.3% vs. 35.0%, P = 1.00; 50.0% vs. 60.0%, P = 0.72) with no difference in complication rates. On admission, no significant differences in APTT or FDP levels were observed between the two groups; however, APTT was significantly prolonged in the MTH group compared to the control group on day 3. DISCUSSION: Based on our study, MTH did not seem to negatively affect the outcomes in patients with coagulopathy following severe TBI on admission; therefore, the present study indicates that MTH may be applicable even in patients with severe TBI and coagulopathy. CONCLUSIONS: Our study suggests that in comparison to control, MTH does not worsen the outcome of patients with coagulopathy following severe TBI. TRIAL REGISTRATION: UMIN-CTR, No. C000000231 , Registered 13 September 2005.