Eiichi Suehiro

Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation.

In the clinical and laboratory setting, multiple reports have suggested the efficacy of hypothermia in blunting the damaging consequences of traumatic brain injury (TBI). With the use of posttraumatic hypothermia, it has been recognized that the time of initiation and duration of hypothermia are important variables in determining the degree of neuroprotection provided. Further, it has been recently recognized that the rate of posttraumatic rewarming is an important variable, with rapid rewarming exacerbating neuronal/axonal damage in contrast to slow rewarming which appears to provide enhanced neuroprotection. Although these findings have been confirmed in the brain parenchyma, no information exists for the cerebral microcirculation on the potential benefits of posttraumatic hypothermia followed by either slow or rapid rewarming. In the current communication we assess these issues in the pial circulation using a well-characterized model of TBI. Rats were prepared for the placement of cranial widows for direct assessment of the pial microcirculation prior to and after the induction of impact acceleration injury followed by moderate hypothermia with either subsequent slow or rapid rewarming strategies. The cranial windows allowed for the measurement of pial vessel diameter to assess ACh-dependent and CO2 reactivity in the chosen paradigms. ACh was applied topically to assess ACh-dependent dilation, while CO2 reactivity was assessed by changing the concentration of the inspired gas. Through this approach, it was found that posttraumatic hypothermia followed by slow rewarming maintained normal arteriolar vascular responses in terms of ACh-dependent dilation and CO2 reactivity. In contrast, arterioles subjected to TBI followed by normothermia or hypothermia and rapid rewarming showed impaired vasoreactivity in terms of their ACh-dependent and CO2 responses. This study provides additional evidence of the benefits of posttraumatic hypothermia followed by slow rewarming, demonstrating for the first time that the previously described neuroprotective effects extend to the cerebral microcirculation.

Preoperative Prediction of Outcome in 283 Poor-Grade Patients with Subarachnoid Hemorrhage: A Project of the Chugoku-Shikoku Division of the Japan Neurosurgical Society

Background: The management of patients with poor-grade subarachnoid hemorrhage (SAH) continues to be controversial. The objective of this study was to examine predictors of outcome of poor-grade SAH after surgical obliteration of the aneurysm. Methods: The study was performed as a retrospective review of 283 patients with poor-grade SAH who underwent surgical obliteration of the aneurysm at multiple centers in Chugoku and Shikoku, Japan. Results: A favorable outcome at discharge was achieved in 97 of the 283 patients (34.3%). Age (p < 0.001), World Federation of Neurosurgical Societies (WFNS) grade V at admission (p = 0.002), improvement in WFNS grade after admission (p = 0.002), Fisher grade (p = 0.039) and a low-density area (LDA) associated with vasospasm on computed tomography (CT; p < 0.001) showed a significant association with outcome. Further analysis of WFNS grades indicated that most patients who only improved to preoperative grade IV from grade V at admission did not have a favorable outcome. Multivariate analysis identified age (especially of ≧65 years; p < 0.001), WFNS grade V (p < 0.001) and LDA associated with vasospasm on CT (p < 0.001) as predictors of a poor outcome, and improvement in WFNS grade (p = 0.001) as a predictor of a favorable outcome after surgical obliteration of the aneurysm. Conclusions: Advanced age, WFNS grade V, improvement in WFNS grade, and LDA associated with vasospasm on CT were found to be independent predictors of clinical outcome, whereas rebleeding, early aneurysm surgery and treatment modality (surgical clipping or Guglielmi detachable coil embolization) were not independently associated with outcome in patients with poor-grade aneurysm.

Uncomplicated Rapid Posthypothermic Rewarming Alters Cerebrovascular Responsiveness

Background and Purpose— Recently, we focused on the cerebrovascular protective effects of moderate hypothermia after traumatic brain injury, noting that the efficacy of posttraumatic hypothermia is related to the rate of posthypothermic rewarming. In the current communication, we revisit the use of hypothermia with varying degrees of rewarming to ascertain whether, in the normal cerebral vasculature, varying rates of rewarming can differentially affect cerebrovascular responsiveness. Methods— Pentobarbital-anesthetized rats equipped with a cranial window were randomized to 3 groups. In 1 group, a 1-hour period of hypothermia (32°C) followed by slow rewarming (over 90 minutes) was used. In the remaining 2 groups, either a 1- or 2-hour period of hypothermia was followed by rapid rewarming (within 30 minutes). Vasoreactivity to hypercapnia and acetylcholine was assessed before, during, and after hypothermia. Additionally, the vascular responses to sodium nitroprusside (SNP) and pinacidil, a KATP channel opener, were also examined. Results— Hypothermia itself generated modest vasodilation and reduced vasoreactivity to all utilized agents. The slow rewarming group showed restoration of normal vascular responsivity. In contrast, hypothermia followed by rapid rewarming was associated with continued impaired responsiveness to acetylcholine and arterial hypercapnia. These abnormalities persisted even with the use of more prolonged (2-hour) hypothermia. Furthermore, posthypothermic rapid rewarming impaired the dilator responses of SNP and pinacidil. Conclusions— Posthypothermic rapid rewarming caused cerebral vascular abnormalities, including a diminished response to acetylcholine, hypercapnia, pinacidil, and SNP. Our data with acetylcholine and SNP suggest that rapid rewarming most likely causes abnormality at both the vascular smooth muscle and endothelial levels.

Angiogram-negative subarachnoid hemorrhage in the era of three dimensional rotational angiography

BACKGROUND Three dimensional rotational angiography (3DRA) is a powerful method for depicting intracranial vascular lesions because of its 3D imaging capability. The purpose of this study was to analyse if 3DRA had reduced the incidence of angiogram-negative subarchnoid haemorrhage (SAH) and which type of aneurysm tended to be overlooked with conventional digital subtraction angiography. METHOD Angiogram-negative SAH was defined as present in those patients with SAH who had no demonstrable lesion revealed by more than two adequate cerebral angiograms. From January 1, 1992, to December 31, 2004, angiography was performed on 247 patients at the Yamaguchi University Hospital. Digital subtraction angiography (DSA) alone was used for 105 patients (DSA group) from 1992 to 2000. After the technology of 3DRA was introduced to our hospital in 2000, 142 patients were evaluated by 3DRA and DSA together (3DRA group). FINDINGS The incidence of angiogram-negative SAH was 9/105 (8.6%) in the DSA group and 6/142 (4.2%) in the 3DRA group. 3DRA revealed six aneurysms not depicted by the conventional DSA, including a basilar tip aneurysm, anterior cerebral artery aneurysm and a basilar tip aneurysm originating from a previously clipped aneurysm. CONCLUSION Three dimensional RA is more sensitive in detecting aneurysms, but in our study still produced a 4.2% rate of angiogram-negative SAH. Three dimensional RA has some advantages for evaluation, especially of complicated sites and previously clipped aneurysms because of its three dimensional imaging capability.

Multicenter Prospective Cohort Study on Volume Management After Subarachnoid Hemorrhage Hemodynamic Changes According to Severity of Subarachnoid Hemorrhage and Cerebral Vasospasm

Background and Purpose— Systemic circulation management has not been established for patients with poor grade aneurysmal subarachnoid hemorrhage (SAH) or delayed cerebral ischemia (DCI) after SAH. The aims of the study were to examine hemodynamic variables in these patients and to establish treatment strategies. Methods— A multicenter prospective cohort study of hemodynamic variables from days 1 to 14 was performed using a transpulmonary thermodilution system (PiCCO Plus). Parameters were analyzed by Mann–Whitney test. Multivariate analysis was performed to identify parameters involved in onset of DCI. Results— The subjects were 204 patients, including 138 with poor grade SAH (World Federation of Neurological Surgeons grades IV and V) and 52 who developed DCI. The extravascular lung water index, pulmonary vascular permeability index, and systemic vascular resistance index were significantly greater in patients with poor grade SAH compared with those with good grade SAH (World Federation of Neurological Surgeons I–III) on day 2 (P=0.049, P=0.039, and P=0.038). Cardiac index was significantly lower in patients with poor grade SAH on days 1 and 2 (P=0.027 and P=0.011). In patients with DCI, the global end-diastolic volume index was significantly lower than in those without DCI on days 3 to 5 (P=0.0053; P=0.048; and P=0.048). In multivariate analysis, median global end-diastolic volume index, cardiac index, and systemic vascular resistance index at an early stage of SAH (days 3–6) were independently related to onset of DCI (P=0.023, P=0.013, and P=0.003). Conclusions— Patients with poor grade SAH developed heart failure–like afterload mismatch at an early stage, and those with DCI had decreased global end-diastolic volume index (hypovolemia) in the early stage of SAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000003794.

Systemic Administration of Argatroban Reduces Secondary Brain Damage in a Rat Model of Intracerebral Hemorrhage: Histopathological Assessment

This study investigated the effects of argatroban, a thrombin inhibitor, on brain edema and inflammation in a rat intracerebral hemorrhage (ICH) model. ICH was induced by injecting collagenase IV into the right caudate nucleus. Argatroban was administered intraperitoneally. Argatroban reduced brain edema from 44.6 to 14.3 µl at 72 h. Infiltration of polymorphonuclear leukocytes at 24 h and monocyte/macrophage at 24 and 72 h was significantly suppressed by argatroban. Argatroban did not increase the volume of hematoma. Systemic administration of argatroban reduced secondary brain damage including edema and inflammation in a rat ICH model.

Survey of brain temperature management in patients with traumatic brain injury in the Japan neurotrauma data bank.

The goal of this study was to evaluate the clinical characteristics and effects of brain temperature management in patients with severe traumatic brain injury (TBI). A total of 1091 patients were registered from the Japan Neurotrauma Data Bank Project 2009. Those with a Glasgow Coma Scale (GCS) score of 9 or more, a GCS score of 3, bilateral dilated pupils, or cardiopulmonary arrest on arrival were excluded. This left a total of 401 patients. Patients were classified into three groups: no temperature management, with no intervention for brain temperature (225 patients, 56.1%), intensive normothermia (129 patients, 32.2%), and hypothermia (47 patients, 11.7%). Patient age, GCS score, pupillary abnormality, Injury Severity Score (ISS), intracranial pressure (ICP) monitoring, and outcome according to CT classification (Traumatic Coma Data Bank classification) on admission were examined. Patients were significantly older in the no temperature management group (average age 61.5 years) compared with normothermia (53.6 years) and hypothermia (46.9 years). ICP monitoring was significantly decreased in 85.1% of patients with hypothermia, 42.6% with normothermia, and 14.7% in no temperature management group. Favorable outcome rate was significantly higher with hypothermia (52.4%) compared with normothermia (26.9%) and no temperature management (20.7%) with evacuated mass lesions in contrast to diffuse injury. Multivariate analysis in patients with evacuated mass lesions showed that GCS (≥6 pts), and hypothermia were independent factors related to a favorable outcome. Appropriate thermoregulation of the brain for individual patients with various types of TBI are important.

Recovered neuronal viability revealed by Iodine-123-iomazenil SPECT following traumatic brain injury.

We evaluated cortical damages following traumatic brain injury (TBI) in the acute phase with [123I] iomazenil (IMZ) single photon emission computed tomography (SPECT). In all, 12 patients with cerebral contusion following TBI were recruited. All patients underwent IMZ SPECT within 1 week after TBI. To investigate the changes in distribution of IMZ in the cortex in the chronic phase, after conventional treatment, patients underwent IMZ SPECT again. A decrease in the accumulation of radioligand for the central benzodiazepine receptor in the cortex corresponding to the contusion revealed with computed tomography (CT) scans and magnetic resonance imaging (MRI) were shown on IMZ SPECT in the acute phase in all patients. In 9 of 12 patients (75%), images of IMZ SPECT obtained in the chronic phase of TBI showed that areas with a decreased distribution of IMZ were remarkably reduced in comparison with those obtained in the acute phase. Both CT scans and MRI showed a normal appearance of the cortex morphologically, where the binding potential of IMZ recovered in the chronic phase. Reduced binding potential of radioligand for the central benzodiazepine receptor is considered to be an irreversible reaction; however, in this study, IMZ accumulation in the cortex following TBI was recovered in the chronic phase in several patients. [123I] iomazenil SPECT may have a potential to disclose a reversible vulnerability of neurons following TBI.

Diverse Effects of Hypothermia Therapy in Patients with Severe Traumatic Brain Injury Based on the Computed Tomography Classification of the Traumatic Coma Data Bank

A multicenter randomized controlled trial of patients with severe traumatic brain injury who received therapeutic hypothermia or fever control was performed from 2002 to 2008 in Japan (BHYPO). There was no difference in the therapeutic effect on traumatic brain injury between the two groups. The efficacy of hypothermia treatment and the objective of the treatment were reexamined based on a secondary analysis of the BHYPO trial in 135 patients (88 treated with therapeutic hypothermia and 47 with fever control). This analysis was performed to examine clinical outcomes according to the CT classification of the Traumatic Coma Data Bank on admission. Clinical outcomes were evaluated with the Glasgow Outcome Scale and mortality at 6 months after injury. Good recovery and moderate disability were defined as favorable outcomes. Favorable outcomes in young patients (≤50 years old) with evacuated mass lesions significantly increased from 33.3% with fever control to 77.8% with therapeutic hypothermia. Patients with diffuse injury III who were treated with therapeutic hypothermia, however, had significantly higher mortality than patients treated with fever control. It was difficult to control intracranial pressure with hypothermia for patients with diffuse injury III, but hypothermia was effective for young patients with an evacuated mass lesion.

Mild Hypothermia Inhibits Exogenous Glutamate-Induced Increases in Nitric Oxide Synthesis

The purpose of this study was to investigate changes in nitric oxide (NO) synthesis induced by exogenous glutamate perfusion into the cerebral cortex, and the effects of mild hypothermia on this glutamate-induced NO synthesis. Glutamate-induced cortical lesions were produced by perfusion of 0.5 M glutamate solution via a microdialysis probe, and the extracellular concentrations of NO end-products (nitrite and nitrate) were measured by microdialysis in normothermic (37 degrees C) and hypothermic (32 degrees C) rats. The levels of NO end-products in the normothermia group were elevated markedly by glutamate perfusion, and this change was completely attenuated by the induction of hypothermia. The glutamate-induced increases were also attenuated markedly by both Nomega-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI). These results suggest that the perfusion of exogenous glutamate into the cortex induces NO synthesis, that is derived primarily from the activity of neuronal NO synthase. These results also demonstrate that hypothermia prevents this glutamate-induced increase in NO, suggesting that the protection afforded by the hypothermic condition is most likely linked to its inhibition of the glutamate-induced NO synthesis.