Yasutaka Oda

Serum glial fibrillary acidic protein as a predictive biomarker of neurological outcome after cardiac arrest

AIM OF THE STUDY Serum glial fibrillary acidic protein (GFAP) has recently been identified as a specific predictor of brain damage and neurological outcome in patients with head trauma. In this study, serum GFAP was assessed as a predictor of neurological outcome in post-cardiac-arrest (PCA) patients. METHODS This study was a retrospective, single-medical-center analysis, conducted in the intensive care unit of a university hospital. Forty-four sequential PCA patients with cardiogenic or non-cardiogenic arrest were included. The patients were treated with or without therapeutic hypothermia (TH). Serum samples were collected from the patients at 12, 24, and 48h after the return of spontaneous circulation (ROSC). Serum GFAP concentrations were measured by enzyme-linked immunosorbent assay and compared in patients with good and poor neurological outcomes, evaluated over a period of 6 months using Glasgow Outcome Scale. RESULTS Serum GFAP was significantly higher in patients with a poor outcome at 12 and 24h without TH and at 48h with TH (P<0.05). GFAP (>0.1ngdL(-1)) was a specific predictor of poor neurological outcome at 6 months with or without TH treatment. CONCLUSIONS Although this study is preliminary, serum GFAP after ROSC reflected a poor neurological outcome in PCA patients.

Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis

PURPOSE Acute renal failure (ARF) is the most important complication of rhabdomyolysis. Serial measurements of blood myoglobin might be useful for predicting rhabdomyolysis-induced ARF. METHODS Thirty patients with rhabdomyolysis were examined. The causes of rhabdomyolysis were trauma, burns, and ischemia, among others. Serial blood myoglobin levels were measured by immunochromatography, and the peak value was determined. The relationship between blood myoglobin levels and the incidence of ARF was evaluated. RESULTS The median peak blood myoglobin level was 3335 ng/mL. Acute renal failure occurred in 12 patients (40%). Nine patients (30%) underwent renal replacement therapy. Peak creatine kinase and peak blood myoglobin levels in the ARF group were significantly higher than those in the non-ARF group. Three patients in the ARF group were treated with renal replacement therapy before occurrence of uremia because of extremely high levels of blood myoglobin (>10,000 ng/mL). Receiver operating characteristic analysis showed that the area under the curve for blood myoglobin that predicted ARF was 0.88, and the best cutoff value for blood myoglobin was 3865 ng/mL. CONCLUSIONS The peak value for blood myoglobin might be a good predictor of rhabdomyolysis-induced ARF. Early renal protective therapies should be considered for patients with rhabdomyolysis at high risk of ARF.

In vivo real-time measurement of superoxide anion radical with a novel electrochemical sensor

The dynamics of superoxide anion (O(2)(-)) in vivo remain to be clarified because no appropriate method exists to directly and continuously monitor and evaluate O(2)(-) in vivo. Here, we establish an in vivo method using a novel electrochemical O(2)(-) sensor. O(2)(-) generated is measured as a current and evaluated as a quantified partial value of electricity (Q(part)), which is calculated by integration of the difference between the baseline and the actual reacted current. The accuracy and efficacy of this method were confirmed by dose-dependent O(2)(-) generation in xanthine-xanthine oxidase in vitro in phosphate-buffered saline and human blood. It was then applied to endotoxemic rats in vivo. O(2)(-) current began to increase 1 h after lipopolysaccharide, and Q(part) increased significantly for 6 h in endotoxemic rats, in comparison to sham-treated rats. These values were attenuated by superoxide dismutase. The generation and attenuation of O(2)(-) were indirectly confirmed by plasma lipid peroxidation with malondialdehyde, endothelial injury with soluble intercellular adhesion molecule-1, and microcirculatory dysfunction. This is a novel method for measuring O(2)(-) in vivo and could be used to monitor and treat the pathophysiology caused by excessive O(2)(-) generation in animals and humans.

Prediction of the neurological outcome with intrathecal high mobility group box 1 and S100B in cardiac arrest victims: A pilot study

OBJECTIVES To investigate whether high mobility group box 1 (HMGB1) and S100B in cerebrospinal fluid (CSF) and the serum predict the neurological outcome in patients resuscitated from out-of-hospital cardiac arrest (OHCA). MATERIALS AND METHODS This study was designed as a prospective observational study. Twenty-five patients, who received standard cardiopulmonary resuscitation and post-resuscitation intensive care, were enrolled in this study. The patients were divided into two groups according to Glasgow-Pittsburgh Cerebral Performance categories (CPCs) at 6 months after return of spontaneous circulation (ROSC), Group G (n = 7, CPC 1 or 2) and Group P (n = 18, CPC ≥ 3). Their blood samples were taken at 6, 24, and 48h after ROSC. The patients, whose CSF was sampled at 48h, were also divided into either sub-Group G (n = 6) or sub-Group P (n = 8) at 6 months after ROSC. RESULTS HMGB1 and S100B in CSF in sub-Group P were significantly higher than those in sub-Group G (HMGB1, <1.0 vs. 12.4 ng/ml, P = 0.009; S100B, 2.68 vs. 84.2 ng/ml, P = 0.007, respectively). HMGB1 in CSF was strongly correlated with S100B (σ = 0.81, P = 0.001). HMGB1 was elevated in serum at 6h and normalized within 48 h after ROSC without any significant differences between the two groups. Serum S100B in Group P was significantly higher than that in Group G at each time point. CONCLUSIONS The significant elevations of HMGB1 and S100B in CSF, and S100B in serum are associated with the neurologically poor outcome in OHCA patients.

The Combination of Either Tempol or FK506 with Delayed Hypothermia: Implications for Traumatically Induced Microvascular and Axonal Protection

Following traumatic brain injury (TBI), inhibition of reactive oxygen species and/or calcineurin can exert axonal and vascular protection. This protection proves optimal when these strategies are used early post-injury. Recent work has shown that the combination of delayed drug administration and delayed hypothermia extends this protection. Here we revisit this issue in TBI using the nitroxide antioxidant Tempol, or the immunophilin ligand FK506, together with delayed hypothermia, to determine their effects upon cerebral vascular reactivity and axonal damage. Animals were subjected to TBI and treated with Tempol at 30 or 90 min post-injury, or 90 min post-injury with concomitant mild hypothermia (33°C). Another group of animals were treated in the same fashion with the exception that they received FK506. Cranial windows were placed to assess vascular reactivity over 6 h post-injury, when the animals were assessed for traumatically induced axonal damage. Vasoreactivity was preserved by early Tempol administration; however, this benefit declined with time. The coupling of hypothermia and delayed Tempol, however, exerted significant vascular protection. The use of early and delayed FK506 provided significant vascular protection which was not augmented by hypothermia. The early administration of Tempol provided dramatic axonal protection that was not enhanced with hypothermia. Early and delayed FK506 provided significant axonal protection, although this protection was not enhanced by delayed hypothermia. The current investigation supports the premise that Tempol coupled with hypothermia extends its benefits. While FK506 proved efficacious with early and delayed administration, it did not provide either increased vascular or axonal benefit with hypothermia. These studies illustrate the potential benefits of Tempol coupled to delayed hypothermia. However, these findings do not transfer to the use of FK506, which in previous studies proved beneficial when coupled with hypothermia. These divergent results may be a reflection of the different animal models used and/or their associated injury severity.

The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims

OBJECTIVES To evaluate the changes in inflammatory cytokines, such as interleukin (IL)-8 and IL-6, in the cerebrospinal fluid (CSF) and serum, and to identify any correlations with the neurological outcomes in patients resuscitated from cardiopulmonary arrest (CPA). MATERIALS AND METHODS This study was designed as a prospective clinical trial. Thirteen patients, who were resuscitated from out-of-hospital CPA and survived for more than 48 h, were enrolled in this study. Arterial blood was taken from the patients at 48 h after the return of spontaneous circulation (ROSC) and CSF was taken by lumbar puncture at the same time. RESULTS In the CSF, the median levels of IL-8 and IL-6 in the patients resuscitated from CPA were significantly higher than those in the control subjects (1311 pg/ml vs 82 pg/ml, P<0.001; 2040 pg/ml vs 1 pg/ml, P<0.001, respectively). The Glasgow Outcome Scale (GOS) score evaluated at 6 months after the ROSC correlated significantly with the levels of IL-8 and IL-6. The cutoff values and sensitivity values with 100% specificity for the prediction of an unfavorable neurological outcome were 1423 pg/ml and 86% for IL-8, and 2708 pg/ml and 86% for IL-6, respectively. CONCLUSION We demonstrated the cutoff values of IL-8 and IL-6 in the CSF to predict the neurological outcome in the patients resuscitated from CPA. The excessive inflammatory cytokine reactions in the brain might therefore be related to the poor neurological outcome in patients with post-resuscitation encephalopathy.

A clinical perspective of sepsis-associated delirium

The term sepsis-associated encephalopathy (SAE) has been applied to animal models, postmortem studies in patients, and severe cases of sepsis. SAE is considered to include all types of brain dysfunction, including delirium, coma, seizure, and focal neurological signs. Clinical data for sepsis-associated delirium (SAD) have been accumulating since the establishment of definitions of coma or delirium and the introduction of validated screening tools. Some preliminary studies have examined the etiology of SAD. Neuroinflammation, abnormal cerebral perfusion, and neurotransmitter imbalances are the main mechanisms underlying the development of SAD. However, there are still no specific diagnostic blood, electrophysiological, or imaging tests or treatments specific for SAD. The duration of delirium in intensive care patients is associated with long-term functional disability and cognitive impairment, although this syndrome usually reverses after the successful treatment of sepsis. Once the respiratory and hemodynamic states are stabilized, patients with severe sepsis or septic shock should receive rehabilitation as soon as possible because early initiation of rehabilitation can reduce the duration of delirium. We expect to see further pathophysiological data and the development of novel treatments for SAD now that reliable and consistent definitions of SAD have been established.

Analysis of magnetic resonance imaging (MRI) morphometry and cerebral blood flow in patients with hypoxic-ischemic encephalopathy.

The aim of this study was to analyze magnetic resonance imaging (MRI) morphometry and cerebral blood flow (CBF) in patients with hypoxic-ischemic encephalopathy, and determine the viability of such measurements for predicting cerebral outcome. The subjects were 26 patients with histories of cardiopulmonary resuscitation who had subsequently developed encephalopathy. We examined the CBF using stable xenon-computed tomography (Xe-CT) and MR images in the subacute period (8-20 days). Three signal-change patterns in the basal ganglia emerged in the MRI study. The first pattern, isointense areas evident in both the T1-weighted image (T1WI) and the T2-weighted image (T2WI), was observed in four patients with favorable outcomes. The second pattern, iso- or hypointense areas evident in the T1WI and hyperintense areas evident in the T2WI, was observed in six patients with favorable outcomes and three patients with poor outcomes. The third pattern, hyperintense areas evident in both the T1WI and T2WI, was observed in 13 patients with poor outcomes. Hemispheric CBFs were 38.9+/-4.6 (mean (SD)) ml/100 g/min in patients with favorable outcomes and 25.3+/-4.3 ml/100 g/min in patients with poor outcomes (p < 0.01). The CBF increase after acetazolamide administration was 13.3+/-3.4 ml/100 g/min in patients with favorable outcomes and 6.8+/-5.6 ml/100 g/min in patients with poor outcomes ( p < 0.05). The presence of hyperintense lesions in the basal ganglia in T1WI, low hemispheric CBF ( < 30 ml/100 g/min), and low acetazolamide reactivity ( < 10 ml/100 g/min) are all factors associated with poor outcome in patients with hypoxic-ischemic encephalopathy.

Fever Control Management Is Preferable to Mild Therapeutic Hypothermia in Traumatic Brain Injury Patients with Abbreviated Injury Scale 3–4: A Multi-Center, Randomized Controlled Trial

In our prospective, multi-center, randomized controlled trial (RCT)-the Brain Hypothermia (B-HYPO) study-we could not show any difference on neurological outcomes in patients probably because of the heterogeneity in the severity of their traumatic condition. We therefore aimed to clarify and compare the effectiveness of the two therapeutic temperature management regimens in severe (Abbreviated Injury Scale [AIS] 3-4) or critical trauma patients (AIS 5). In the present post hoc B-HYPO study, we re-evaluated data based on the severity of trauma as AIS 3-4 or AIS 5 and compared Glasgow Outcome Scale score and mortality at 6 months by per-protocol analyses. Consequently, 135 patients were enrolled. Finally, 129 patients, that is, 47 and 31 patients with AIS 3-4 and 36 and 15 patients with AIS 5 were allocated to the mild therapeutic hypothermia (MTH) and fever control groups, respectively. No significant intergroup differences were observed with regard to age, gender, scores on head computed tomography (CT) scans, and surgical operation for traumatic brain injury (TBI), except for Injury Severity Score (ISS) in AIS 5. The fever control group demonstrated a significant reduction of TBI-related mortality compared with the MTH group (9.7% vs. 34.0%, p = 0.02) and an increase of favorable neurological outcomes (64.5% vs. 51.1%, p = 0.26) in patients with AIS 3-4, although the latter was not statistically significant. There was no difference in mortality or favorable outcome in patients with AIS 5. Fever control may be considered instead of MTH in patients with TBI (AIS 3-4).

Effects of mechanical chest compression device with a load-distributing band on post-resuscitation injuries identified by post-mortem computed tomography.

OBJECTIVE To determine the effects of cardiopulmonary resuscitation (CPR) with AutoPulse™ (LDB-CPR) on post-resuscitation injuries identified by post-mortem computed tomography (PMCT). AutoPulse™ is a novel mechanical chest-compression device with a load-distributing band (LDB) that may affect post-resuscitation injury identified by PMCT. METHODS We conducted a retrospective cohort study of non-traumatic adult out-of-hospital cardiac arrest patients whose death was confirmed in our emergency department between October 2009 and September 2014. Patients were divided according to whether LDB-CPR (LDB-CPR group) or manual CPR only (manual CPR only group) was performed. The background characteristics and post-resuscitation injuries identified by PMCT were compared between both groups. Logistic regression was used to identify risk factors for posterior rib fracture and abdominal injury. RESULTS Overall, 323 patients were evaluated, with 241 (74.6%) in the LDB-CPR group. The total duration of CPR was significantly longer in the LDB-CPR group than in the manual CPR only group. Posterior rib fracture, hemoperitoneum, and retroperitoneal hemorrhage were significantly more frequent in the LDB-CPR group. The frequencies of anterior/lateral rib and sternum fracture were similar in both groups. Pneumothorax tended to be more frequent in the LDB-CPR group, although not significantly. LDB-CPR was an independent risk factor for posterior rib fracture (odds ratio 30.57, 95% confidence interval 4.15-225.49, P=0.001) and abdominal injury (odds ratio 4.93, 95% confidence interval 1.88-12.95, P=0.001). CONCLUSIONS LDB-CPR was associated with higher frequencies of posterior rib fracture and abdominal injury identified by PMCT. PMCT findings should be carefully examined after LDB-CPR.