S2k guideline diagnosis and treatment of carbon monoxide poisoning.

Carbon monoxide (CO) can occur in numerous situations and ambient conditions, such as fire smoke, indoor fireplaces, silos containing large quantities of wood pellets, engine exhaust fumes, and when using hookahs. Symptoms of CO poisoning are nonspecific and can range from dizziness, headache, and angina pectoris to unconsciousness and death. This guideline presents the current state of knowledge and national recommendations on the diagnosis and treatment of patients with CO poisoning. The diagnosis of CO poisoning is based on clinical symptoms and proven or probable exposure to CO. Negative carboxyhemoglobin (COHb) levels should not rule out CO poisoning if the history and symptoms are consistent with this phenomenon. Reduced oxygen-carrying capacity, impairment of the cellular respiratory chain, and immunomodulatory processes may result in myocardial and central nervous tissue damage even after a reduction in COHb. If CO poisoning is suspected, 100% oxygen breathing should be immediately initiated in the prehospital setting. Clinical symptoms do not correlate with COHb elimination from the blood; therefore, COHb monitoring alone is unsuitable for treatment management. Especially in the absence of improvement despite treatment, a reevaluation for other possible differential diagnoses ought to be performed. Evidence regarding the benefit of hyperbaric oxygen therapy (HBOT) is scant and the subject of controversy due to the heterogeneity of studies. If required, HBOT should be initiated within 6 h. All patients with CO poisoning should be informed about the risk of delayed neurological sequelae (DNS).

Implant for Augmentation of Cerebral Blood Flow Trial-1 (ImpACT-1). A single-arm feasibility study evaluating the safety and potential benefit of the Ischemic Stroke System for treatment of acute ischemic stroke.

BACKGROUND: The Ischemic Stroke System is a novel device designed to deliver stimulation to the sphenopalatine ganglion(SPG).The SPG sends parasympathetic innervations to the anterior cerebral circulation. In rat stroke models, SPG stimulation results in increased cerebral blood flow, reduced infarct volume, protects the blood brain barrier, and improved neurological outcome. We present here the results of a prospective, multinational, single-arm, feasibility study designed to assess the safety, tolerability, and potential benefit of SPG stimulation inpatients with acute ischemic stroke(AIS). METHODS: Patients with anterior AIS, baseline NIHSS 7-20 and ability to initiate treatment within 24h from stroke onset, were implanted and treated with the SPG stimulation. Patients were followed up for 90 days. Effect was assessed by comparing the patient outcome to a matched population from the NINDS rt-PA trial placebo patients. RESULTS: Ninety-eight patients were enrolled (mean age 57years, mean baseline NIHSS 12 and mean treatment time from stroke onset 19h). The observed mortality rate(12.2%), serious adverse events (SAE)incidence(23.5%) and nature of SAE were within the expected range for the population. The modified intention to treat cohort consisted of 84 patients who were compared to matched patients from the NINDS placebo arm. Patients treated with SPG stimulation had an average mRS lower by 0.76 than the historical controls(CMH test p = 0.001). CONCLUSION: The implantation procedure and the SPG stimulation, initiated within 24hr from stroke onset, are feasible, safe, and tolerable. The results call for a follow-up randomized trial (funded by BrainsGate; clinicaltrials.gov number, NCT03733236).

Organ-Protective Intensive Care in Organ Donors.

BACKGROUND: The ascertainment of brain death (the irreversible, total loss of brain function) gives the physician the opportunity to limit or stop further treatment. Alternatively, if the brain-dead individual is an organ donor, the mode of treatment can be changed from patient-centered to donationcentered. Consensus-derived recommendations for the organ-protective treatment of brain-dead organ donors are not yet available in Germany. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, and on the authors' clinical experience. RESULTS: Brain death causes major pathophysiological changes, including an increase in catecholamine levels and a sudden drop in the concentration of multiple hormones, among them antidiuretic hormone, cortisol, insulin, and triand tetraiodothyronine. These changes affect the function of all organ systems, as well as the hemodynamic state and the regulation of body temperature. The use of standardized donor management protocols might well increase the rate of transplanted organs per donor and improve the quality of the transplanted organs. In addition, the administration of methylprednisolone, desmopressin, and vasopressin could be a useful supplement to treatment in some cases. Randomized controlled trials have not yet demonstrated either improved organ function or prolonged survival of the transplant recipients. CONCLUSION: The evidence base for organ-protective intensive care is weak; most of the available evidence is on the level of expert opinion. There is good reason to believe, however, that the continuation of intensive care, in the sense of early donor management, can make organ transplantation more successful both by increasing the number of transplantable organs and by improving organ quality.

Cooling Activity is Associated with Neurological Outcome in Patients with Severe Cerebrovascular Disease Undergoing Endovascular Temperature Control.

BACKGROUND: Neuroprotection through targeted temperature management is currently investigated in patients with severe brain injury in multiple trials. Feedback devices have been shown to precisely reach and maintain target temperature by constantly adjusting cooling activity. We analyzed the association between cooling activity expressed as cool bath temperatures and functional neurological outcome. METHODS: Data were retrospectively analyzed from a prospective randomized trial on controlled prophylactic normothermia (i.e., 36.5 °C) in patients with severe cerebrovascular disease. Body core temperature of patients who had been randomized to the endovascular group, was controlled using an endovascular cooling device. Cool bath temperature was analyzed over a period of 168 h. Functional neurological outcome was evaluated at 180 days using the modified Rankin Scale. RESULTS: 51 of 102 patients included were randomized to the endovascular group. Cool bath temperature data were available from 47/51 patients. Patients with lower cool bath temperatures reflecting high cooling activity had a more favorable neurological outcome at 180 days (mRS 0-2) than patients with low cooling activity (p < 0.05). We did not find a significant correlation between cool bath temperature and inflammatory markers. CONCLUSION: High cooling activity of an endovascular feedback device is associated with favorable outcome in patients with severe cerebrovascular disease.

Clevidipine rapidly and safely reduces blood pressure in acute intracerebral hemorrhage: the ACCELERATE trial.

BACKGROUND: Intracerebral hemorrhage (ICH) causes 10-15% of primary strokes, with mortality related to hematoma volume. Blood pressure (BP) reduction may attenuate hematoma expansion. ACCELERATE (the Evaluation of Patients with Acute Hypertension and Intracerebral Hemorrhage with Intravenous Clevidipine Treatment) is a pilot study representing the first evaluation of safety and efficacy of intravenous clevidipine for the rapid treatment of hypertension in ICH patients. METHODS: ICH patients with a systolic BP (SBP) >160 mm Hg who present within 6 h (n = 27) or 12 h (n = 10) of symptoms were prospectively enrolled, treated with open-label clevidipine until SBP ≤160 mm Hg was achieved and then titrated to keep target SBP between 140-160 mm Hg. RESULTS: A total of 35 patients with baseline median Glasgow Coma Scale score of 12, median NIH Stroke Scale score of 14, mean SBP of 186 mm Hg and a mean time from onset of symptoms of 5.5 h received clevidipine. Median time to achieve SBP target range was 5.5 min. All patients achieved target SBP within 30 min; 96.9% achieved target SBP with clevidipine monotherapy. CT scans showed minimal hematoma volume change for the overall population (median change 0.01 ml, -2.9%). Mild/moderate hypotension was reported in 3 patients and resolved with dose reduction or drug discontinuation. CONCLUSION: Clevidipine monotherapy was effective and safe for rapid BP reduction in this cohort of critically ill ICH patients. Overall, patients showed minimal hematoma expansion with BP reduction, suggesting that rapid BP control with clevidipine may have a beneficial impact on hematoma expansion and warrants further investigation.

Autonomic reactions and peri-interventional alterations in body weight as potential supplementary outcome parameters for thromboembolic stroke in rats.

BACKGROUND: Since several neuroprotectives failed to reproduce promising preclinical results under clinical conditions, efforts emerged to implement clinically relevant endpoints in animal stroke studies. Thereby, insufficient attention was given on autonomic reactions due to experimental stroke, although clinical trials reported on high functional and prognostic impact. This study focused on autonomic consequences and body weight changes in a translational relevant stroke model and investigated interrelations to different outcome measurements. METHODS: Forty-eight rats underwent thromboembolic middle cerebral artery occlusion (MCAO) while recording heart rate (HR) and mean arterial pressure (MAP). After assessing early functional impairment (Menzies score), animals were assigned to control procedure or potentially neuroprotective treatment with normobaric (NBO) or hyperbaric oxygen (HBO). Four or 24 hours after ischemia onset, functional impairment was re-assessed and FITC-albumin administered intravenously obtaining leakage-related blood-brain barrier (BBB) impairment. Body weight was documented prior to MCAO and 4 or 24 hours after ischemia onset. RESULTS: During MCAO, HR was found to increase significantly while MAP decreased. The amount of changes in HR was positively correlated with early functional impairment (P = 0.001): Severely affected animals provided an increase of 15.2 compared to 0.8 beats/minute in rats with low impairment (P = 0.048). Regarding body weight, a decrease of 9.4% within 24 hours after MCAO occurred, but treatment-specific alterations showed no significant correlations with respective functional or BBB impairment. CONCLUSIONS: Future studies should routinely include autonomic parameters to allow inter-group comparisons and better understanding of autonomic reactions due to experimental stroke. Prospectively, autonomic consequences might represent a useful outcome parameter enhancing the methodological spectrum of preclinical stroke studies.

Long-lasting neuronal loss following experimental focal cerebral ischemia is not affected by combined administration of tissue plasminogen activator and hyperbaric oxygen.

Acute focal cerebral ischemia and consecutive energy failure are accompanied by neuronal death in regions with impaired cerebral blood flow. Several translational attempts of potential neuroprotective agents have failed, hence extended perspectives are required regarding the regional differences of neuronal impairment and glial involvement by using clinically relevant stroke models. This study aimed on neuronal loss following experimental focal cerebral ischemia, considering tissue plasminogen activator (tPA) as established treatment in stroke and hyperbaric oxygenation (HBO) as potential neuroprotective co-treatment. Wistar rats were subjected to embolic middle cerebral artery occlusion and underwent either treatment with tPA only, combined tPA+HBO, or no treatment. Neuronal impairment was assessed by Neuronal Nuclei (NeuN) staining in 4 ischemia-related areas and at 4 different time points after stroke induction (24hours, 7, 14 and 28 days). Additionally, spatial relationships between neuronal loss and gliosis were revealed by triple fluorescence staining of neurons, astrocytes and microglia, comparing the ipsi- and contra-lesional hemisphere. Analyzing the ischemic injury in general, a shell-like distribution of neuronal damage was observed, starting in the ischemic core and diminishing over the general ischemic area to the ischemic border zone and the primary non-affected area. This pattern remained detectable up to 4weeks after ischemia induction. Surprisingly, tPA and tPA+HBO did not markedly affect the post-ischemic course of neuronal impairment. Further studies are needed to investigate the effects of treatment with tPA or potential neuroprotective agents on neuronal integrity, with emphasis on the separation of intact neurons from those undergoing apoptosis or necrosis.

Safety of Tirofiban in acute Ischemic Stroke: the SaTIS trial.

BACKGROUND AND PURPOSE: Tirofiban is a highly selective, fast-acting nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist with a short half-life time. Glycoprotein IIb/IIIa antagonists are effective for the treatment of acute coronary syndromes proven in large clinical trials. Safety and efficacy in patients with ischemic stroke are uncertain. This was addressed in the Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial. METHODS: Two hundred sixty patients with acute ischemic stroke were randomized in a placebo-controlled, prospective, open-label treatment, blinded outcome reading multicenter trial. Subjects with a National Institutes of Health Stroke Scale between 4 and 18 received intravenously either tirofiban or placebo within 3 to 22 hours after symptom onset for 48 hours. The primary end point was the rate of cerebral bleeding as measured in follow-up CT scans 2 to 7 days after inclusion. The secondary end point was clinical efficacy within 1 week (National Institutes of Health Stroke Scale, modified Rankin Scale) and after 5 months (Barthel Index, modified Rankin Scale). RESULTS: The rate of cerebral hemorrhagic transformation (I/II) and parenchymal hemorrhage (I/II) did not differ between both groups (tirofiban 36 of 120; placebo 33 of 124: OR, 1.18; 95% CI, 0.66 to 2.06). Mortality after 5 months was significantly lower in patients treated with tirofiban (3 of 130 [2.3%] versus 11 of 126 [8.7%]; OR, 4.05; 95% CI, 1.1 to 14.9). No difference in neurological/functional outcome was found after 1 week and after 5 months. CONCLUSIONS: We conclude that tirofiban might be safe in acute moderate ischemic stroke even when administered within a large time window after symptom onset and might save lives in the late outcome. Clinical Trial Registration- URL: www.strokecenter.org/trials/. Trial name: SaTIS. Enrollment began before July 1, 2005.

Combined systemic thrombolysis with alteplase and early hyperbaric oxygen therapy in experimental embolic stroke in rats: relationship to functional outcome and reduction of structural damage.

INTRODUCTION: The only causal therapy in ischemic stroke is thrombolysis with recombinant tissue plasminogen activator (rtPA), but it is feasible only for few patients, and new therapies are needed. This study investigates the effects of systemic thrombolysis with rtPA combined with hyperbaric oxygen therapy (HBOT) in embolic stroke in rats. METHODS: In 22 male Wistar rats, an embolic ischemic stroke was induced. The animals were randomized to one of four groups: control, thrombolysis alone, HBOT sequential or HBOT parallel with thrombolysis. HBOT (2.4 ATA, 1 h) started 45 min (sequential) or 120 min (parallel) after stroke. rtPA was given intravenously 120 min after stroke onset. Functional tests were performed after stroke induction and after treatment. After 6 h infarct volume and intracerebral hemorrhagic complications were assessed. RESULTS: Compared to the control group only the combination of HBOT and thrombolysis significantly improved the functional outcome (p=0.03) and reduced the infarct volume (p=0.01), whereas thrombolysis alone did not show a significant benefit. In all treatment groups there was a trend towards fewer hemorrhagic transformations. CONCLUSION: Hyperbaric oxygen in combination with thrombolysis shows neuroprotection in acute ischemic stroke in rats by reducing infarct volume and improving functional outcome in the early poststroke period.

Early outcome and blood-brain barrier integrity after co-administered thrombolysis and hyperbaric oxygenation in experimental stroke.

BACKGROUND: After promising results in experimental stroke, normobaric (NBO) or hyperbaric oxygenation (HBO) have recently been discussed as co-medication with tissue plasminogen activator (tPA) for improving outcome. This study assessed the interactions of hyperoxia and tPA, focusing on survival, early functional outcome and blood-brain barrier (BBB) integrity following experimental stroke. METHODS: Rats (n = 109) underwent embolic middle cerebral artery occlusion or sham surgery. Animals were assigned to: Control, NBO (60-minute pure oxygen), HBO (60-minute pure oxygen at 2.4 absolute atmospheres), tPA, or HBO+tPA. Functional impairment was assessed at 4 and 24 hours using Menzies score, followed by intravenous application of FITC-albumin as a BBB permeability marker, which was allowed to circulate for 1 hour. Further, blood sampling was performed at 5 and 25 hours for MMP-2, MMP-9, TIMP-1 and TIMP-2 concentration. RESULTS: Mortality rates did not differ significantly between groups, whereas functional improvement was found for NBO, tPA and HBO+tPA. NBO and HBO tended to stabilize BBB and to reduce MMP-2. tPA tended to increase BBB permeability with corresponding MMP and TIMP elevation. Co-administered HBO failed to attenuate these early deleterious effects, independent of functional improvement. CONCLUSIONS: The long-term consequences of simultaneously applied tPA and both NBO and HBO need to be addressed by further studies to identify therapeutic potencies in acute stroke, and to avoid unfavorable courses following combined treatment.

The P2 receptor antagonist PPADS supports recovery from experimental stroke in vivo.

BACKGROUND: After ischemia of the CNS, extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations due to cell damage and subsequent increase of membrane permeability. ATP may cause cellular degeneration and death, mediated by P2X and P2Y receptors. METHODOLOGY/PRINCIPAL FINDINGS: The effects of inhibition of P2 receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on electrophysiological, functional and morphological alterations in an ischemia model with permanent middle cerebral artery occlusion (MCAO) were investigated up to day 28. Spontaneously hypertensive rats received PPADS or vehicle intracerebroventricularly 15 minutes prior MCAO for up to 7 days. The functional recovery monitored by qEEG was improved by PPADS indicated by an accelerated recovery of ischemia-induced qEEG changes in the delta and alpha frequency bands along with a faster and sustained recovery of motor impairments. Whereas the functional improvements by PPADS were persistent at day 28, the infarct volume measured by magnetic resonance imaging and the amount of TUNEL-positive cells were significantly reduced by PPADS only until day 7. Further, by immunohistochemistry and confocal laser scanning microscopy, we identified both neurons and astrocytes as TUNEL-positive after MCAO. CONCLUSION: The persistent beneficial effect of PPADS on the functional parameters without differences in the late (day 28) infarct size and apoptosis suggests that the early inhibition of P2 receptors might be favourable for the maintenance or early reconstruction of neuronal connectivity in the periinfarct area after ischemic incidents.

Influence of prophylactic, endovascularly based normothermia on inflammation in patients with severe cerebrovascular disease: a prospective, randomized trial.

BACKGROUND AND PURPOSE: We analyzed the impact of long-term endovascularly based prophylactic normothermia versus conventional temperature management on inflammatory parameters in patients with severe cerebrovascular disease. METHODS: This was a prospective, randomized, controlled trial comparing the course of inflammatory parameters between the 2 treatment arms: (1) prophylactically endovascular long-term normothermia; and (2) conventional, stepwise fever management with antiinflammatory drugs and surface cooling. Inclusion criteria were (1) spontaneous subarachnoid hemorrhage with Hunt-Hess grade between 3 and 5; (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score of ≤ 10; or (3) complicated cerebral infarction requiring intensive care unit treatment with a NIH Stroke Scale score of ≥ 15. Treatment period was 336 hours in subarachnoid hemorrhage patients and 168 hours in patients with complicated stroke or intracerebral hemorrhage patients. RESULTS: A total of 102 patients (56 female) were enrolled during a 3.5-year period. Overall median total fever burden during the course of treatment was 0.0°C hour and 4.3°C hours in the catheter and conventional group, respectively (P < 0.0001). C-reactive protein and interleukin-6 were significantly elevated in the endovascular group (P < 0.05). Nonsteroidal antiinflammatory drugs, used as additional treatment of fever, significantly reduced mean C-reactive protein in endovascular treated patients (P < 0.01). CONCLUSIONS: The proinflammatory cytokines C-reactive protein and interleukin-6 were significantly elevated in patients receiving prophylactic endovascularly based long-term normothermia. Nonsteroidal antiinflammatory drugs significantly affected the course of proinflammatory parameters; thus, future trials should investigate the role of nonsteroidal antiinflammatory drugs in severe cerebrovascular disease patients and their interaction with temperature management. Clinical Trial Registration-Trial not registered; enrollment began before July 2005.

AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke.

BACKGROUND AND PURPOSE: Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. METHODS: Four intravenous dose regimens (total cumulative doses of 30-180 µg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. RESULTS: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm³. CONCLUSIONS: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points.

A novel quantification of blood-brain barrier damage and histochemical typing after embolic stroke in rats.

Treatment strategies in acute ischemic stroke are still limited. Considering numerous translation failures, research is tending to a preferred use of human-like animal models, and a more-complex perspective of tissue salvaging involving endothelial, glial and neuronal components according to the neurovascular unit (NVU) concept. During ischemia, blood-brain barrier (BBB) alterations lead to brain edema and hemorrhagic transformation affecting NVU components. The present study aims on a novel quantification method of BBB damage and affected tissue following experimental cerebral ischemia, closely to the human condition. Wistar rats underwent embolic middle cerebral artery occlusion, followed by an intravenous application of fluorescein isothiocyanate (FITC)-tagged albumin (≈70kDa) and/or biotinylated rat IgG (≈150kDa) as BBB permeability markers. Both fluorescent agents revealed similar leakage and allow quantification of BBB permeability by fluorescence microscopy, and after immunohistochemical conversion into a permanent diaminobenzidine label at light-microscopical level. The following markers were identified for sufficient detection of NVU components: Rat endothelial cell antigen-1 (RECA) and laminin for vessels, Lycopersicon esculentum and Griffonia simplicifolia agglutinin for vessels and microglial subpopulations, ionized calcium binding adaptor molecule 1 (Iba1), CD68 and CD11b for macrophages, activated microglia, monocytes and neutrophils, S100ß for astroglia, as well as NeuN and HuC/D for neurons. This is the first report confirming the usefulness of simultaneously applied FITC-albumin and biotinylated rat IgG as BBB permeability markers in experimental stroke, and, specifying antibodies and lectins for multiple fluorescence labeling of NVU components. Newly elaborated protocols might facilitate a more-complex outcome measurement in drug development for cerebral ischemia.

Recombinant human erythropoietin in the treatment of acute ischemic stroke.

BACKGROUND AND PURPOSE: Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. METHODS: This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40,000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. RESULTS: Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. CONCLUSIONS: Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Microplasmin is a recombinant truncated form of human plasmin. It has demonstrated efficacy in experimental animal models of stroke and tolerability in healthy volunteers. We tested the tolerability of microplasmin in patients with acute ischemic stroke. METHODS: In a multicenter, double-blind, randomized, placebo-controlled Phase II trial, 40 patients with ischemic stroke were treated with either placebo or active drug between 3 and 12 hours after symptom onset in a dose-finding design. Ten patients received placebo, 6 patients received a total dose of 2 mg/kg, 12 patients received a total dose of 3 mg/kg, and 12 patients received a total dose of 4 mg/kg. We studied the pharmacodynamics of microplasmin and its effect on the clinical and hemodynamic parameters of the patients. MRI was used as a surrogate marker and matrix metalloproteinases serum concentrations were used as markers of neurovascular integrity. The study was underpowered to detect clinical efficacy. RESULTS: Microplasmin induced reversible effects on markers of systemic thrombolysis and neutralized alpha(2)-antiplasmin by up to 80%. It was well tolerated with one of 30 treated patients developing a fatal symptomatic intracerebral hemorrhage. No significant effect on reperfusion rate or on clinical outcome was observed. Matrix metalloproteinase-2 levels were reduced in microplasmin-treated patients. CONCLUSIONS: Microplasmin was well tolerated and achieved neutralization of alpha(2)-antiplasmin. Further studies are warranted to determine whether microplasmin is an effective therapeutic agent for ischemic stroke.

Prophylactic, endovascularly based, long-term normothermia in ICU patients with severe cerebrovascular disease: bicenter prospective, randomized trial.

BACKGROUND AND PURPOSE: We sought to study the effectiveness and safety of endovascular cooling to maintain prophylactic normothermia in comparison with standardized, stepwise, escalating fever management to reduce fever burden in patients with severe cerebrovascular disease. METHODS: This study was a prospective, randomized, controlled trial with a blinded neurologic outcome evaluation comparison between prophylactic, catheter-based normothermia (CoolGard; ie, body core temperature 36.5 degrees C) and conventional, stepwise fever management with anti-inflammatory drugs and surface cooling. Patients admitted to 1 of the 2 neurointensive care units were eligible for study inclusion when they had a (1) spontaneous subarachnoid hemorrhage with Hunt & Hess grade between 3 and 5, (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score or=15. RESULTS: A total of 102 patients (56 female) were enrolled during a 3.5-year period. Fifty percent had a spontaneous subarachnoid hemorrhage, 40% had a spontaneous intracerebral hemorrhage, and 10% had a complicated cerebral infarction. Overall median total fever burden during the course of treatment was 0.0 degrees C hour and 4.3 degrees C hours in the catheter and conventional groups, respectively (P<0.0001). Prophylactic normothermia did not lead to an increase in the number of patients who experienced a major adverse event. No significant difference was found in mortality and neurologic long-term follow-up. CONCLUSIONS: Long-term, catheter-based, prophylactic normothermia significantly reduces fever burden in neurointensive care unit patients with severe cerebrovascular disease and is not associated with increased major adverse events.

Long-term functional and neurological outcome after simultaneous treatment with tissue-plasminogen activator and hyperbaric oxygen in early phase of embolic stroke in rats.

The combination of hyperbaric oxygen therapy (HBO) and recombinant tissue-plasminogen activator (tPA) is of interest in the treatment of acute ischemic stroke with a view to combine positive effects of both strategies. We investigated neurological and functional outcome after early treatment with HBO additional to tPA in ischemic stroke. Focal cerebral ischemia was induced using an embolic stroke model in 87 male Wistar rats. Animals were randomized to therapy with tPA+HBO, tPA alone, or control. Menzies score, Beam walk, and the Corner test were assessed for a period of 4 weeks following ischemia. Within the first 24 h neurological deficits improved in all groups but most pronounced in animals treated with tPA+HBO. Thereafter, a deterioration of neurological deficits occurred in the tPA+HBO group with significant differences at day 7, 8, 18, and 24 (P<0.05). Surprisingly, Beam walk and Corner test results did not differ significantly between all groups. This first report of early simultaneous treatment with tPA and HBO in experimental embolic stroke with 4-week follow-up confirms previous studies reporting positive effects of HBO shortly after the ischemia. Following the acute phase, combined tPA and HBO resulted in deterioration of neurological deficits without affecting functional recovery. Future studies should focus on interactions of tPA and HBO on molecular level leading to delayed damage to brain tissue at risk.

Effectiveness and safety of transcranial laser therapy for acute ischemic stroke.

BACKGROUND AND PURPOSE: We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial-2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke. METHODS: This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score. RESULTS: We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group (P=0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of <16 showed a favorable outcome at 90 days on the primary end point (P<0.044). Mortality rates and serious adverse events did not differ between groups with 17.5% and 17.4% mortality, 37.8% and 41.8% serious adverse events for TLT and sham, respectively. CONCLUSIONS: TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

BACKGROUND: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). METHODS: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. FINDINGS: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). INTERPRETATION: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. FUNDING: PAION Deutschland GmbH; Forest Laboratories.