Management of Patients with Acute Subdural Hemorrhage During Treatment with Direct Oral Anticoagulants.

BACKGROUND: Anticoagulation therapy is a major risk factor for unfavorable patient outcomes following (traumatic) intracranial hemorrhage. Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic diseases. Data on patients treated for acute subdural hemorrhage (SDH) during anticoagulation therapy with DOAC are limited. METHODS: We analyzed the medical records of consecutive patients treated at our institution for acute SDH during anticoagulation therapy with DOAC or vitamin K antagonists (VKA) during a period of 30 months. Patient characteristics such as results of imaging and laboratory studies, treatment modalities and short-term patient outcomes were included. RESULTS: A total of 128 patients with preadmission DOAC (n = 65) or VKA (n = 63) intake were compared. The overall 30-day mortality rate of this patient cohort was 27%, and it did not differ between patients with DOAC or VKA intake (26% vs. 27%; p = 1.000). Similarly, the rates of neurosurgical intervention (65%) and intracranial re-hemorrhage (18%) were comparable. Prothrombin complex concentrates were administered more frequently in patients with VKA intake than in patients with DOAC intake (90% vs. 58%; p < 0.0001). DOAC treatment in patients with acute SDH did not increase in-hospital and 30-day mortality rates compared to VKA treatment. CONCLUSIONS: These findings support the favorable safety profile of DOAC in patients, even in the setting of intracranial hemorrhage. However, the availability of specific antidotes to DOAC may further improve the management of these patients.

Thrombin contributes to the injury development and neurological deficit after acute subdural hemorrhage in rats only in collaboration with additional blood-derived factors.

BACKGROUND: Acute subdural hemorrhage (ASDH) is a severe consequence of traumatic brain injury. The occurrence of subdural blood increases the lethality of these patients independent of the amount of blood or elevated intracranial pressure. Thrombin is one of the potential harmful blood components. Possible harmful effects of thrombin are mediated via the Protease-activated-receptor-1 (PAR1) and thus, translating the acute Thrombin release after ASDH into cell loss. The objectives of the present study were twofold, namely to examine (1) the impact of direct thrombin inhibition in the acute phase after hemorrhage on the long-term histological and functional deficits and (2) the early inhibition of PAR1 activation by thrombin with the selective antagonist SCH79797 on lesion volume at 14 days after ASDH. The effects of thrombin on the lesion size were investigated in two separate experiments via (1) direct thrombin inhibition in the subdural infused blood (Argatroban 600 µg) as well as by (2) intraventricular injection of the PAR-1 antagonist SCH79797 (1 µg or 5 µg). Lesion volume and behavior deficits using a neurological deficit score and a motor function test (beam balance test) were analyzed as outcome parameters at 14 days after injury. RESULTS: 59 Male Sprague-Dawley rats received a subdural infusion of 300 µl autologous blood or sham operation. Lesion volume at 14 days after ASDH tended to be smaller in the Argatroban-treated group when compared to the vehicle group (8.1 ± 1.1 vs. 10.1 ± 2.3 mm2, n.s.). Motor deficits in the beam balance test were not significantly less severe in the Argatroban-treated group. Animals treated with SCH79797 also showed a trend towards dose-dependent decreased lesion volume in comparison to the vehicle-treated group (1 µg: 4.3 ± 0.7 mm3; 5 µg: 3.8 ± 1.1 mm3; vehicle: 6.5 ± 2.0 mm3, n.s). CONCLUSIONS: Thrombin inhibition in the subdural blood and local cerebral blockade of PAR-1 cause a tendency towards reduced lesion volume or functional recovery. All results show a trend in favor of the acute treatment on the outcome parameters. Our results suggests that thrombin could be an important blood-derived factor during acute subdural hemorrhage that translates its deleterious effects in concert with other blood-induced factors.

Acute subdural hematoma in patients on oral anticoagulant therapy: management and outcome.

OBJECTIVE Isolated acute subdural hematoma (aSDH) is increasing in older populations and so is the use of oral anticoagulant therapy (OAT). The dramatic increase of OAT-with direct oral anticoagulants (DOACs) as well as with conventional anticoagulants-is leading to changes in the care of patients who present with aSDH while receiving OAT. The purpose of this study was to determine the management and outcome of patients being treated with OAT at the time of aSDH presentation. METHODS In this single-center, retrospective study, the authors analyzed 116 consecutive cases involving patients with aSDH treated from January 2007 to June 2016. The following parameters were assessed: patient characteristics, admission status, anticoagulation status, perioperative management, comorbidities, clinical course, and outcome as determined at discharge and through 6 months of follow-up. Oral anticoagulants were classified as thrombocyte inhibitors, vitamin K antagonists, and DOACs. Patients were stratified based on which type of medication they were taking, and subgroup analyses were performed. Predictors of unfavorable outcome at discharge and follow-up were identified. RESULTS Of 116 patients, 74 (64%) had been following an OAT regimen at presentation with aSDH. The patients who were taking oral anticoagulants (OAT group) were significantly older (OR 12.5), more often comatose 24 hours postoperatively (OR 2.4), and more often had ≥ 4 comorbidities (OR 3.2) than patients who were not taking oral anticoagulants (no-OAT group). Accordingly, the rate of unfavorable outcome was significantly higher in patients in the OAT group, both at discharge (OR 2.3) and at follow-up (OR 2.2). Of the patients in the OAT group, 37.8% were taking a thrombocyte inhibitor, 54.1% a vitamin K antagonist, and 8.1% DOACs. In all cases, OAT was stopped on discovery of aSDH. For reversal of anticoagulation, patients who were taking a thrombocyte inhibitor received desmopressin 0.4 µg/kg, 1-2 g tranexamic acid, and preoperative transfusion with 2 units of platelets. Patients following other oral anticoagulant regimens received 50 IU/kg of prothrombin complex concentrates and 10 mg of vitamin K. There was no significant difference in the rebleeding rate between the OAT and no-OAT groups. The in-hospital mortality rate was significantly higher for patients who were taking a thrombocyte inhibitor (OR 3.3), whereas patients who were taking a vitamin K antagonist had a significantly higher 6-month mortality rate (OR 2.7). Patients taking DOACs showed a tendency toward unfavorable outcome, with higher mortality rates than patients on conventional OAT or patients in the vitamin K antagonist subgroup. Independent predictors for unfavorable outcome at discharge were comatose status 24 hours after surgery (OR 93.2), rebleeding (OR 9.8), respiratory disease (OR 4.1), and infection (OR 11.1) (Nagelkerke R2 = 0.684). Independent predictors for unfavorable outcome at follow-up were comatose status 24 hours after surgery (OR 12.7), rebleeding (OR 3.1), age ≥ 70 years (OR 3.1), and 6 or more comorbidities (OR 3.1, Nagelkerke R2 = 0.466). OAT itself was not an independent predictor for worse outcome. CONCLUSIONS An OAT regimen at the time of presentation with aSDH is associated with increased mortality rates and unfavorable outcome at discharge and follow-up. Thrombocyte inhibitor treatment was associated with increased short-term mortality, whereas vitamin K antagonist treatment was associated with increased long-term mortality. In particular, patients on DOACs were seriously affected, showing more unfavorable outcomes at discharge as well as at follow-up. The suggested medical treatment for aSDH in both OAT and no-OAT patients seems to be effective and reasonable, with comparable rebleeding and favorable outcome rates in the 2 groups. In addition, prior OAT is not a predictor for aSDH outcome.

The dangerous gamble of heparinization within two weeks of nonoperative traumatic acute subdural hematoma in patients with increased stroke risk: a case series.

BACKGROUND: In traumatic acute subdural hematoma (aSDH) management, systemic anticoagulation is contraindicated, particularly during the first 2 weeks. We present two cases of patients with nonoperative aSDH whose stroke risk led to heparinization within 2 weeks of the initial hemorrhage and examine their outcomes to illustrate the risks and benefits associated with systemic anticoagulation. MATERIALS AND METHODS: Two elderly males, on warfarin at baseline who developed traumatic nonoperative aSDH were heparinized within 2 weeks of aSDH onset. RESULTS: One patient showed a decreased SDH volume on Day 19. The second patient developed sudden onset headache with fixed/dilated pupils on Day 5. In this patient, a CT scan of the brain revealed marked enlargement of the aSDH from 0.9 to 2.4 cm with midline shift of 1.5 cm, and uncal herniation that was incompatible with life. CONCLUSION: Heparinization within two weeks of aSDH may cause SDH enlargement resulting in rapidly fatal neurologic deterioration. Further study is needed to more definitively address this issue.

Impact of Antithrombotic Medications and Reversal Strategies on the Surgical Management and Outcomes of Traumatic Acute Subdural Hematoma.

OBJECTIVE: Careful hematologic management is required in surgical patients with traumatic acute subdural hematoma (aSDH) taking antithrombotic medications. We sought to compare outcomes between patients with aSDH taking antithrombotic medications at admission who received antithrombotic reversal with patients with aSDH not taking antithrombotics. METHODS: Retrospective review identified patients with traumatic aSDH requiring surgical evacuation. The cohort was divided based on antithrombotic use and whether pharmacologic reversal agents or platelet transfusions were administered. A 3-way comparison of outcomes was performed between patients taking anticoagulants who received pharmacologic reversal, patients taking antiplatelets who received platelet transfusion, and patients not taking antithrombotics. Multivariable regressions, adjusted for injury severity, further investigated associations with outcomes. RESULTS: Of 138 patients who met inclusion criteria, 13.0% (n = 18) reported taking anticoagulants, 16.7% (n = 23) reported taking antiplatelets, and 3.6% (n = 5) reported taking both. Patients taking antiplatelets who received platelet transfusion had longer intraoperative times (P = 0.040) and higher rates of palliative care consultations (P = 0.046) compared with patients taking anticoagulants who received pharmacologic reversal and patients not taking antithrombotics. Across groups, no significant differences were found in frequency of in-hospital intracranial hemorrhage and venous thromboembolism, length of hospital stay, rate of inpatient mortality, or follow-up health status. In multivariable analysis, intraoperative time remained longest for the antiplatelets with platelet transfusion group. Other outcomes were not associated with patient group. CONCLUSIONS: Among surgical patients with traumatic aSDH, those taking antiplatelet medications who receive platelet transfusions experience longer intraoperative procedure times and higher rates of palliative care consultation. Comparable outcomes were observed between patients receiving antithrombotic reversal and patients not taking antithrombotics.

Rapid disappearance of acute subdural hematoma due to abrogated hyper-fibrinolytic activity by tranexamic acid: Case report.

RATIONALE: Acute subdural hematoma (ASDH) occurs after tearing of bridging veins within the dura resulting in the accumulation of blood between the arachnoid and dura layers within 72 hours after traumatic head injury. Also, antigen fibrin D-dimer (DD) is the principal enzymatic degradation product of cross-linked fibrin by plasmin. We observed that early tranexamic acid (TXA) treatment resolved hyper-fibrinolysis and rapid disappearance ASDH. PATIENTS CONCERNS: A 48-year-old female presented with unconsciousness for 2 hours after head trauma. Her Glasgow Coma Scale score was >8 points. DIAGNOSIS: Computed tomography scan established ASDH with midline shift and brainstem compression and surgery was scheduled. Also, laboratory results indicated high DD spike of 34,820 µg/L and a reduction in plasma fibrinogen 1 hour after the injury. INTERVENTION: She was treated with intravenous TXA immediately after admission. OUTCOMES: Her DD spike decreased remarkably in 48 hours with associated rapid disappearance of ASDH thereby averting surgical intervention. She recovered fully with no long-term complications. LESSONS: Historically, hyper-fibrinolysis is associated with poor outcome in head trauma. However, early initiation of TXA which is noninvasive treatment modality for ASDH could avert surgery and reduce cost, anesthesia, and other complications associated with surgery.

Effect of Pre-Management Antithrombotic Agent Use on Outcome after Traumatic Acute Subdural Hematoma in the Elderly: A Systematic Review.

Traumatic acute subdural hematomas (ASDH) are common in elderly patients (age ≥65 years) and are associated with a poorer prognosis compared with younger populations. Antithrombotic agent (ATA) use is also common in the elderly; however, the influence that pre-morbid ATA has on outcome in ASDH is poorly understood. We hypothesized that pre-morbid ATA use significantly worsens outcomes in elderly patients presenting with traumatic ASDH. English language medical literature was searched for articles relating to ATA use in the elderly with ASDH. Data were collated and appraised where possible. Analyses of study bias were performed. Twelve articles encompassing 2038 patients were included; controls were poorly described in the included studies. Pre-morbid ATA use was seen in 1042 (51.1%) patients and 18 different ATA combination therapies were identified, with coumarins being the most common single agent used. The newer direct oral anticoagulants were evaluated in only two studies. ATA use was associated with a lower presenting Glasgow Coma Scale (GCS) score but not hematoma volume on computed tomography (CT) or post-operative hematoma re-accumulation. No studies connected ATA use with patient outcomes without the presence of confounders and bias. Reversal strategies, bridging therapy, recommencement of ATA, and comparison groups were poorly described; accordingly, our hypothesis was rejected. ATA reversal methods, identification of surgical candidates, optimal surgery methods, and when or whether ATA should be recommenced following ASDH resolution remain topics of debate. This study defines our current understanding on this topic, revealing clear deficiencies in the literature with recommendations for future research.

Venous thromboembolic pharmacological prophylaxis in severe traumatic acute subdural hematomas: Early prophylaxis is effective and safe.

BACKGROUND: The purpose of this study was to evaluate the optimal timing and type of pharmacological venous thromboembolism prophylaxis (VTEp) in patients with severe blunt head trauma with acute subdural hematomas (ASDH). METHODS: Matched cohort study using ACS-TQIP database (2013-2016) including patients with isolated ASDH. Outcomes of matched patients receiving early prophylaxis (EP, ≤48 h) and late prophylaxis (LP, >48 h) were compared with univariable and multivariable regression analysis. RESULTS: In 1,660 matched cases VTE complications (3.1% vs 0.5%, p < 0.001) were more common in the LP compared to the EP group. Multivariable regression analysis identified EP as an independent protective factor for VTE complications (OR 0.169, p < 0.001) but not mortality (p = 0.260). The adjusted risk for delayed craniectomy was not associated with EP compared to LP (p = 0.095). LMWH was independently associated with a lower mortality (OR 0.480, p = 0.008) compared to UH. CONCLUSIONS: Early VTEp (≤48 h) does not increase the risk for craniectomies and is independently associated with fewer VTE complications in patients with isolated ASDH. LMWH was independently associated with a lower mortality compared to UH.

Timing of Restarting Anticoagulation and Antiplatelet Therapies After Traumatic Subdural Hematoma-A Single Institution Experience.

BACKGROUND: There is a paucity of information regarding the optimal timing of restarting antiplatelet therapy (APT) and anticoagulation therapy (ACT) after traumatic subdural hematoma (tSDH). Therefore, we sought to report our experience at a single level 1 trauma center with regard to restarting APT and/or ACT after tSDH. METHODS: A total of 456 consecutive records were reviewed for unplanned hematoma evacuation within 90 days of discharge and thrombotic/thromboembolic events before restarting APT and/or ACT. RESULTS: There was no difference in unplanned hematoma evacuation rate in patients not receiving APT or ACT (control) compared with those necessitating APT and/or ACT (6.4% control, 6.9% APT alone, 5.8% ACT alone, 5.4% APT and ACT). There was an increase in post-tSDH thrombosis/thromboembolism in patients needing to restart ACT (1.9% APT alone, P = 0.53 vs. control; 5.8% ACT alone, P = 0.04 vs. control; 16% APT and ACT; P < 0.001 vs. control). Subgroup analysis revealed that patients with coronary artery disease necessitating APT and patients with atrial fibrillation necessitating ACT had higher thrombosis/thromboembolism rates compared with controls (1.0% control vs. 6.1% coronary artery disease, P = 0.02; 1.0% control vs. 10.1% atrial fibrillation, P < 0.001). The median restart time of ACT was approximately 1 month after trauma; APT was restarted 2-4 weeks after trauma depending on clinical indication. CONCLUSIONS: Patients requiring reinitiation of APT and/or ACT after tSDH were at elevated risk of thrombotic/thromboembolic events but not unplanned hematoma evacuation. Therefore, patients should be followed closely until APT and/or ACT are restarted, and consideration for earlier reinitiation of blood thinners should be given on a case-by-case basis.

Fast point-of-care coagulometer guided reversal of oral anticoagulation at the bedside hastens management of acute subdural hemorrhage.

BACKGROUND: Emergency reversal of the international normalized ratio (INR) in patients who develop nontraumatic subdural hemorrhage (SDH) due to oral anticoagulants (OAC) represents a primary treatment strategy but it is difficult to predict the amount of prothrombin complex concentrate (PCC) needed for reversal treatment. Moreover, repeated INR testings in central laboratories (CL) are time consuming. The usefulness of point-of-care INR coagulometers (POC) to test the success of INR reversal in OAC-SDH has not yet been investigated. METHODS: Prospectively, INR reversal was performed by administering PCC to patients suffering from acute SDH-OAC using a predefined dosing schedule. Accuracy and time gained by using POC were assessed and compared with CL measurements. RESULTS: A total of 10 patients were treated according to the protocol (male: 5). Bland-Altman analysis between POC and CL revealed a mean INR deviation of 0.013 for initial INR values and of 0.081 during reversal treatment. Using POC, the median initial net time gain (accounting for clinical examination and CT) for the start of PCC was 21 min. Median total time for POC-documented reversal was 27 min, as compared to 70 min for CL. The shortest interval between head CT and start of emergency SDH evacuation surgery was 37 min. By employing stepwise POC-guided reversal of the anticoagulatory effect of OAC, the calculated PCC dose could be reduced by 25% in the median. CONCLUSIONS: Using POC to measure INR values and patient-adapted PCC administration is a fast and economic method to reverse anticoagulation in patients with acute OAC-SDH.

Acute subdural hematoma: potential soccer injury in an otherwise healthy child.

A 16-year-old adolescent boy presented with headache, dizziness, loss of consciousness, and a tonic-clonic seizure after heading a soccer ball in a competitive match. A computed tomographic scan of the head revealed an acute subdural hematoma with a mass effect. The patient was emergently referred to a tertiary care facility where he eventually recovered completely with conservative care. No predisposing medical conditions were found. To the best of our knowledge, this is the first report of an intracranial hemorrhage secondary to the heading of a soccer ball alone in an otherwise healthy child without any underlying predisposing central nervous system abnormalities.

Coagulopathy and inhospital deaths in patients with acute subdural hematoma.

OBJECT: Acute subdural hematoma (SDH) is one of the most lethal forms of intracranial injury; several risk factors predictive of a worse outcome have been identified. Emerging research suggests that patients with coagulopathy and intracerebral hemorrhage have a worse outcome than patients without coagulopathy but with intracerebral hemorrhage. The authors sought to determine if such a relationship exists for patients with acute SDH. METHODS: The authors conducted a retrospective analysis of consecutive patients admitted to a neurosciences intensive care unit with acute SDH over a 4-year period (January 1997-December 2001). Demographic data, laboratory values, admission source, prior functional status, medical comorbidities, treatments received, and discharge disposition were recorded, as were scores on the Acute Physiology, Age, and Chronic Health Evaluation III (APACHE III). Coagulopathy was defined as an internal normalized ratio>1.2 or a prothrombin time>or=12.7 seconds. Univariate and multivariate analyses were performed on 244 patients to determine factors associated with worse short-term outcomes. RESULTS: The authors identified 248 patients with acute SDH admitted to the neurointensive care unit during the study period, of which 244 had complete data. Most were male (61%), and the mean age of the study population was 71.3+/-15 years (range 20-95 years). Fifty-three patients (22%) had coagulopathy. The median APACHE III score was 43 (range 11-119). Twenty-nine patients (12%) died in the hospital. Independent predictors of inhospital death included APACHE III score (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.4-13.4, p=0.011) and coagulopathy (OR 2.7, 95% CI 1.1-7.1, p=0.037). Surgical evacuation of acute SDH was associated with reduced inhospital deaths (OR 0.2, 95% CI 0.1-0.6, p=0.003). CONCLUSIONS: Coagulopathy is independently associated with inhospital death in patients with acute SDH. Time to treatment to correct coagulopathy using fresh frozen plasma and/or vitamin K was prolonged.

Recombinant activated factor VII for a warfarinised Jehovah's Witness with an acute subdural haematoma.

Recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) is a haemostatic agent first developed for bleeding associated with haemophilia and trauma, but for which the indications continue to expand. Recent reports have suggested efficacy for various types of intracranial haemorrhage and for patients with abnormalities of coagulation. We report a warfarin-anticoagulated Jehovah's Witness patient with an acute subdural haematoma for whom rFVIIa was used perioperatively. The haematoma was surgically evacuated without excessive blood loss and the patient eventually made a good recovery, returning to independent self-care.

Effects of diclofenac sodium on the hippocampus of rats with acute subdural hematoma: histological, stereological, and molecular approach.

This study was aimed at evaluating the potential effects of acute subdural hematoma (ASDH) and diclofenac sodium (DS) therapy following ASDH on the rat hippocampus. Twenty-four male Sprague Dawley rats were used and divided into four groups. 0.1 ml of non-heparinized autologous blood from the tail vein of the animals in the non-treatment group (NTG) and treatment group (TG) was injected into the subdural space. The TG received intramuscular diclofenac sodium at a 15 mg/kg dose daily from the postoperative second hour to the seventh day after the operation. The control group (CG) and sham group (SG) were used for control and sham operations, respectively. On the postoperative eighth day, all animals were sacrificed, and the hippocampi of all animals were stereologically and histologically evaluated. Also blood samples of the animals were biochemically analyzed. As a result of the study, the mean number of neurons in CA1, CA2, and CA3 regions of the hippocampus and the total number of neurons were decreased in the hippocampus samples of the NTG and especially the TG subjects. When comparing the second blood samples, there was no difference between the levels of adrenaline and serotonin among the groups. However, after the operation, noradrenalin levels in the treatment group were found to be higher than those of the sham and control groups (p < 0.05). In the NTG and TG, histopathological findings were observed such as Nissl condensation as well as completely dead and indistinguishable neurons with abnormally shaped, shrunken cytoplasm and nuclei. Also necrotic areas on the specimens of the TG were seen. In immunohistochemical sections, c-FOS positivity was decreased in the NTG and especially the TG. Otherwise, PGC-1 positive cells were increased in the NTG and especially the TG. In this study, it was shown for the first time by means of stereological techniques that using DS after ASDH caused a decrease in the number of hippocampal neurons (CA1, CA2, and CA3 regions).

Effects of mild hypothermia and alkalizing agents on brain injuries in rats with acute subdural hematomas.

Brain ischemia is the leading pathopysiological mechanism in the development of secondary brain damage after acute subdural hematoma (SDH). Hypothermia has been employed as an effective cerebroprotective treatment on brain injuries, but the control of the general condition is very difficult under hypothermia, and various severe complications have been reported. Cerebral acidosis in the ischemic area is one of the important factors augmenting the brain edema formation. Tris-(hydroxymethyl)-aminomethane (THAM) has been used as an alkalizing agent for acidosis on brain injury and is reported to be effective. In the present study, we used a rat acute SDH model to assess the effect of mild (35 degrees C) hypothermia and THAM combined treatment on brain water content, brain ischemia, and blood-brain barrier (BBB) permeability at 4 h after hematoma induction. Mild hypothermia did not significantly reduce the brain water content beneath the hematoma (79.5 +/- 0.2%) compared to normothermia (80.2 +/- 0.2%), but mild hypothermia combined to THAM resulted in a significant reduction (78.7 +/- 0.0%; p < 0.01). Combined with mild hypothermia, THAM treatment significantly reduced the Evan's blue extravasation (35 +/- 7 ng/g wet tissue; p < 0.05) compared to normothermia (63 +/- 7 ng/g wet tissue). Furthermore, the volume of infarction at 24 h after the hematoma induction (54 +/- 3 mm(3); p < 0.01) was significantly smaller by the combined treatment compared with normothermia (70 +/- 2 mm(3)). The present findings indicate that mild hypothermia of 35 degrees C combined with THAM presents a potent cerebroprotective strategy. The protection of the BBB is one of the possible cerebroprotective mechanisms in this rat acute SDH model.

Tempol, a novel stable nitroxide, reduces brain damage and free radical production, after acute subdural hematoma in the rat.

Recent studies have shown that there is increased production of deleterious free radicals following acute subdural hematoma (ASDH). Scavenging them may therefore be of therapeutic benefit. Nitroxides are new, low molecular weight, cell permeable superoxide dismutase mimics. This study investigated the neuroprotective effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) following ASDH in the rat. Twenty-one male Sprague-Dawley rats were used in two studies: (1) a volumetric study of ischemic brain damage (n = 10); and (2) a microdialysis study measuring free radical generation after ASDH (n = 11). Ten minutes after induction of hematoma, the animals received 10 mg/kg Tempol or vehicle intravenously. In the volumetric study, 4 h after treatment, the rats were perfused, the brain removed, cut into serial 12-microm coronal sections, and stained. Ischemic areas were measured in eight predetermined stereotactic planes. In the microdialysis study, free radical production was measured using the salicylate trapping technique by quantifying 2,3-dihydrobenzoic acid (2,3-DHBA) and 2,5-DHBA using HPLC. In the volumetric study, Tempol treatment significantly reduced infarct volumes; 100.2 +/- 15.7 mm3 in Tempol-treated animals compared with 171.5 +/- 13.6 mm3 in controls (42% reduction, p = 0.0005). The microdialysis study demonstrated an early twofold increase of free radical production at 30 min, and returning to the baseline levels in controls. However, in Tempol-treated animals, this early surge was attenuated, and all measured values remained around the baseline levels throughout the experiments. Tempol thus provides significant neuroprotective effect in a rat model of ASDH, related to attenuation of superoxide radical production. The use of these low molecular weight, cell-permeable agents, which readily cross the blood-brain barrier and enter cells, thus appears indicated for acute pathologies, ASDH.

Chemical shift imaging of mannitol in acute cerebral ischemia. Case report.

The effectiveness of mannitol for the treatment of cerebral edema after stroke has long been debated, and the diffusion of mannitol through a disrupted blood-brain barrier has been the focus of many contradictory studies. The authors present a unique case in which chemical shift imaging was used to demonstrate the accumulation of mannitol in an area of stroke underlying a subdural hematoma in a patient with end-stage renal disease being treated with hemodialysis. A metabolite map for the xenobiotic mannitol was created from the data and demonstrated the accumulation of mannitol when hemodialysis was interrupted prematurely. Metabolite maps were also used to show removal of the mannitol with the reestablishment of hemodialysis. It is concluded that mannitol can accumulate in an area of infarction, and that chemical shift imaging can be used to illustrate this process.

The neuroprotective effect of diazoxide is mediated by mitochondrial ATP-dependent potassium channels in a rat model of acute subdural hematoma.

Acute subdural hematoma (ASDH) results in neuronal death due to mitochondrial dysfunction and a subsequent cascade of apoptotic and necrotic events. We previously demonstrated that mitochondrial ATP-dependent potassium (mitoK(ATP)) channels have a major role in cerebral ischemic preconditioning in vivo and in vitro. However, the role of the mitoK(ATP) channel has not been investigated in the context of ASDH. Thus, the purpose of this study was to determine whether the mitoK(ATP) channel mediates neuroprotection in a rat model of ASDH. Male Wistar rats were subjected to subdural infusion of 400 µL autologous venous blood. The rats were assigned to four experimental groups pretreated intraventricularly 15 minutes before ASDH with (1) vehicle (n=10); (2) the mitoK(ATP) channel agonist diazoxide (n=9); (3) diazoxide plus the selective mitoK(ATP) channel antagonist 5-hydroxydecanoate (5-HD) (n=6); or (4) 5-HD alone (n=6). Infarct volume was assessed at 4 days after ASDH. Brain edema formation was also measured. Pretreatment with diazoxide significantly reduced infarct volume and brain edema formation after ASDH. However, the effects of diazoxide were abolished by co-treatment with 5-HD. 5-HD alone increased infarct volume. These data suggest that the mitoK(ATP) channel is an important mediator of the neuroprotective effects of cerebral preconditioning in a rat model of ASDH.