Feasibility of endovascular and surface cooling strategies in acute stroke.

BACKGROUND: Therapeutic hypothermia (TH) is a promising treatment of stroke, but limited data are available regarding the safety and effectiveness of cooling methodology. We investigated the safety of TH and compared the cooling capacity of two widely used cooling strategies - endovascular and surface cooling. METHODS: COOLAID Oresund is a bicentre randomized trial in Copenhagen (Denmark) and Malmö (Sweden). Patients were randomized to either TH (33°C for 24 h) in a general intensive care unit (ICU) or standardized stroke unit care (control). Cooling was induced by a surface or endovascular-based strategy. RESULTS: Thirty-one patients were randomized. Seven were cooled using endovascular and 10 using surface-based cooling methods and 14 patients received standard care (controls). 14 (45%) patients received thrombolysis. Pneumonia was recorded in 6 (35%) TH patients and in 1 (7%) control. 4 TH patients and 1 control developed massive infarction. 1 TH patient and 2 control suffered asymptomatic haemorrhagic transformation. Mortality was comparable with 2 (12%) in the TH group and 1 (7%) among controls. Mean (SD) duration of hospital stay was 25.0 days (24, 9) in TH and 22.5 days (20.6) in control patients (P = 0.767). Mean (SD) induction period (cooling onset to target temperature) was 126.3 min (80.6) with endovascular cooling and 196.3 min (76.3) with surface cooling (P = 0.025). CONCLUSIONS: Therapeutic hypothermia with general anaesthesia is feasible in stroke patients. We noticed increased rates of pneumonia, while the length of hospital stay remained comparable. The endovascular cooling strategy provides a faster induction period than surface cooling.

The influence of body temperature on infarct volume and thrombolytic therapy in a rat embolic stroke model.

The effect of body temperature on cerebral infarcts and thrombolytic therapy was investigated in 91 rats embolized in the right carotid territory. Hypothermia of 32 degrees C for 2 h with preembolic onset (n = 15) or hyperthermia of 39 degrees C for 2 h with postembolic onset (n = 22) was compared to normothermic controls (n = 17). After 48 h of survival, neuropathological evaluation with measurement of infarct volume was performed. Median infarct volume in percent of affected hemisphere volume was 11% (9-21, quartiles) in rats treated with hypothermia alone, compared to 46% (14-59, quartiles) in normothermic controls (P = 0.04). Hyperthermia for 2 h increased median infarct volume to 65% (37-75, quartiles). There was a positive and significant correlation between infarct volume and body temperature (R = 0.53, P = 0.0002, n = 54). Mortality rate was significantly higher among rats treated with hyperthermia compared to normothermic controls (P = 0.005). A subset of 37 rats exposed to the same temperature regimen were treated with tissue plasminogen activator (20 mg/kg i.v. during 45 min) 2 h after embolization. Judged by posttreatment carotid angiography, hyperthermic rats (n = 11) had the best degree of recanalization (P = 0.03) compared to controls (n = 17), but median infarct volume in this group was (58% (27-67, quartiles)) significantly larger (P < 0.02) than normothermic (21% (15-39, quartiles), n = 14) and hypothermic (13% (7-31, quartiles), n = 12) rats treated with thrombolytic therapy. Thrombolytic therapy following 2 h of hypothermia, could not improve the effect of hypothermia alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancing the efficacy of thrombolysis by AMPA receptor blockade with NBQX in a rat embolic stroke model.

Efficacy and safety of combined alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor blockade and thrombolytic therapy with human recombinant tissue plasminogen activator (TPA) was tested in a rat embolic stroke model. Sixty-three rats were embolized in the right internal carotid territory with a 200 microliters suspension of microclots formed by alternate moving of 150 microliters whole blood and 50 microliters of thrombin between two interconnected syringes for 4 min. Sixteen embolized rats served as controls, and 16 rats were treated with NBQX immediately after embolization. Thirty-one rats were treated with TPA 2 h following embolization, and in 16 of these rats additional NBQX treatments were initiated 90 min following embolization. Hemispheric cerebral blood flow (CBF) was measured by an intraarterial 133Xenon injection method before and after embolization. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after 2 days, evaluated neuropathologically, and infarct volumes were measured. Median CBF was reduced by 70-77% in the affected hemispheres following embolization. Significant recanalization occurred in all groups except those treated with NBQX. TPA-treated rats had significantly better reperfusion compared to controls judged by angiography 3 h following embolization (P = 0.04). NBQX alone and TPA alone caused insignificant reduction in infarct volume but, when combined, total infarct volume was reduced by 77% compared to controls (P = 0.02). Separate measurement of cortical infarct revealed significantly smaller infarcts (P = 0.05) in the combined treatment group compared to the TPA treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral blood flow measurement during embolization of the rat brain using the xenon injection method.

The purpose of this study was to investigate if cerebral blood flow (CBF) was influenced by the volume of the bolus using the intracarotid 133Xenon method in anesthetized rats, and to evaluate the effect of intracarotid embolization on hemispheric CBF. In 18 male Sprague-Dawley rats hemispheric CBF was calculated from recorded clearance of an intracarotid injected 50 microliters bolus of 133Xenon. A second clearance recording was done after the injection of a 200 microliter bolus of 133Xenon. Then the 18 animals were divided in 3 subsets each of 6 animals. In the first subset of 6 animals a bolus of 200 microliters 133Xenon was given, clearance was recorded before and after the injection of a suspension of microemboli. In all the above experiments within 90 sec after the initial bolus of 133Xenon, 20 microliters 133Xenon remaining in the carotid catheter was flushed into the brain by saline or the suspension of emboli. In the second subset of 6 rats the distribution of 133Xenon in various parts of the brain and head was examined after killing the animals 35 sec after injection of a 200 microliter bolus of 133Xenon. The third subset of 6 rats was treated as the second subset, except for the size of the bolus which was 50 microliters of 133Xenon. The calculated CBF values were independent of the volume of the bolus. At the post-mortem examination 76% of the radioactivity was located in the right hemisphere and majority of the remainder in the head outside the brain. The clearance curve was not monoexponential, but flattened out within the initial 30 sec when clearance from areas with CBF dominated the initial 15-second period, then clearance form areas with lower CBF values were more prominent in the following 15-second period. Embolization significantly reduced right hemispheric CBF to 0.26 (0.09-0.50) of the value immediately before embolization. The findings demonstrate applicability of CBF measurements using the intra-arterial 133Xenon injection method during embolization of the rat brain, provided a second bolus of 133Xenon is given before the embolization.

[Thrombolytic treatment of acute cerebral infarction]. / Trombolysebehandling af akut cerebralt infarkt.

INTRODUCTION: Thrombolytic therapy of acute ischaemic stroke within three hours of the onset of symptoms is approved by health authorities in the USA and Canada, but not in Europe. METHODS: We report seven patients treated with recombinant tissue plasminogen activator (rtPA) within three hours of the onset of stroke according to an open protocol following internationally accepted guidelines. RESULTS: Three patients with initial severe neurological deficits made an almost complete recovery within the first 24 hours after treatment. Two patients had a partial remission, and two patients had no benefit. There were no bleeding complications. DISCUSSION: The present results are in accordance with the Cochrane Library's analysis of published data regarding thrombolytic therapy.

Influence of different fixation procedures on the quantification of infarction and oedema in a rat model of stroke.

In pharmacodynamic studies using focal ischaemia models, the size of the infarct measured by quantitative histology is the most important outcome measure. Precise, unbiased and reproducible assessment of infarct volume is of foremost importance. A frequent problem in interventional stroke models is the evaluation of infarcts in animals found dead, where instant post-mortem fixation of the brain cannot be performed. The purpose of this study was to investigate possible bias from perfusion, immediate and 3-h post-mortem delayed immersion fixation on the measured volumes of cerebral infarction, oedema and hemispheres in a rat embolic stroke model. Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. After survival for 24 h, the animals were divided into three groups: group 1 - immediate perfusion fixation; group 2 - immediate immersion fixation of the brain; and group 3 - animals left dead for 3 h at room temperature before removal of the brain for immersion fixation. Following histological preparation and evaluation, the volumes of the hemispheres and infarction were measured by quantitative histology and planimetry. Brains fixed by immersion were 7% larger than the perfusion-fixed brains. Delaying the immersion fixation for 3 h may increase hemisphere volume by a further 12%. Independent of the fixation procedure, the size of infarction was approximately 40% of the ipsilateral hemisphere, and the oedema was approximately 11% of the size of the infarct. The used planimetric technique was accurate with measured values within +/- 2% of the factual value. In conclusion, sizes of hemispheres, infarction and oedema in absolute volume measures are influenced by the effect of unwanted variation of brain size caused by biological factors and artificial shrinkage caused by fixation, dehydration and heat treatment of the specimens. Infarction and oedema expressed relatively in per cent of hemisphere and infarct, respectively, are robust measures independent of the investigated fixation procedures.

[Can acute stroke be treated with hypothermia?]. / Kan akut apopleksi behandles med hypotermi?

In animal stroke models, treatment with mild hypothermia (30-34 degrees C) for 3-4 hours may reduce the size of cerebral infarction if started within three hours of the initiation of cerebral ischaemia. The mechanism by which hypothermia exerts its neuroprotective effect is unknown, but experimental studies have shown the release of neurotoxic excitatory amino acids and free oxygen radicals to be reduced during hypothermic ischaemia. In patients with acute stroke, body temperature above 37.5 degrees C are associated with poor outcome, and temperatures below 36.5 degrees C with improved outcome, compared to normothermic patients. Due to the unpleasantness of cooling and side effects as shivering, hypothermia may not be tolerated by stroke patients without sedation of light anaesthesia which may increase the risk of hypotension and respiratory complications. However, lowering body temperature by 1-2 degrees C may suffice to improve functional outcome in acute stroke patients, and such mild hypothermia should be tested in randomized controlled clinical trials.

Effect of hypothermia and delayed thrombolysis in a rat embolic stroke model.

Effect of hypothermia on cerebral infarcts was studied in rats embolized in the right carotid territory. Thirty-four served as normothermic controls receiving saline infusion only. In 16 rats hypothermia of 32 degrees C was induced by cooling with a fan, followed by embolization. The rats were kept hypothermic for the following 3 h before body temperature was raised to 37 degrees C. In 26 rats, treatment with human recombinant tissue plasminogen activator (20 mg/kg i.v. during 45 min), started 2 h after embolization. Finally, 14 rats were treated similarly with hypothermia for 3 h followed by additional rt-PA treatment starting after 2 h. Thrombolytic therapy reduced median infarct volume from 19.5% of affected hemisphere among controls to 4.6% (p = 0.006) in the treated group. Three hours of hypothermia reduced infarct volume to 1.6% (p = 0.0007). Additional rt-PA could not demonstrate further improvement in this experimental setting.

Thrombolytic and anticoagulation treatment in a rat embolic stroke model.

OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilaterally and assigned to: (i). controls, (ii). rt-PA 6 mg/kg, (iii). PENTA 0.5 mg/kg, (iv). PENTA 0.5 mg/kg and rt-PA 6 mg/kg. After 2 days animals were killed, the brains removed and evaluated microscopically. RESULTS: The median infarct size measured in percentage of the affected hemisphere was 25% in the control group, 4% (P < 0.01, Mann Whitney) in group 2, 19% (n.s.) in group 3, and 10% (P < 0.05) in group 4. rt-PA, and rt-PA combined with PENTA also promoted functional recovery. CONCLUSION: The present study found no effect of 0.5 mg/kg PENTA treatment. Compared with rt-PA treatment alone, 0.5 mg/kg PENTA alone or combined with rt-PA did not significantly increase mortality or tendency for hemorrhage.

The course of blood pressure in acute stroke is related to the severity of the neurological deficits.

OBJECTIVES: To evaluate how soon after stroke the diagnosis of hypertension could be established. METHODS: In a prospective study including 1192 patients with acute stroke within 6 h, blood pressure was measured serially at 2-h intervals during the first 24 h. Results are presented as mean arterial blood pressure (MAP). The Scandinavian Stroke Scale (SSS) assessed the neurological deficit. RESULTS: In 779 patients with mild to moderate ischaemic stroke or transient ischaemic attack (TIA) and SSS > 25, MAP was 118 mmHg (CI 95%: 116-119 mmHg) on admission and 109 mmHg (CI 95%: 108-110 mmHg) 4 h later (paired t-test, P < 0.001). No such early decrease was observed in 228 patients with severe cerebral infarction (CI). In mild to moderate ischaemic stroke or TIA, MAP at 24 h was not different from MAP at 3 months in paired t-test. CONCLUSIONS: Blood pressure 24 h after admission in patients with mild to moderate CI or TIA was representative of the patient's blood pressure 3 months after stroke. A diagnosis of arterial hypertension can be established a few days after stroke.

Disparity in regional cerebral blood flow during electrically induced seizure.

This is a presentation of 2 cases in which the intraictal regional cerebral blood flow distribution was measured with the 99mTc-HMPAO single photon emission computerized tomography technique during an electrically induced seizure. Although the seizure was verified as generalized on electroencephalography, the regional neuronal activity expressed as rCBF unexpectedly was markedly asymmetrical in one of the cases. These findings demonstrated that the 99mTc-HMPAO technique makes it possible to discriminate intraictal variation in cortical and subcortical activation between the hemispheres during electroencephalography-verified generalized seizures.

Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model.

BACKGROUND AND PURPOSE: We sought to evaluate the effects of the combination of cytidine-5'-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model. METHODS: Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg, (5) rtPA 5 mg/kg plus citicoline 250 mg/kg, and (6) rtPA 5 mg/kg plus citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily. RESULTS: The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared with 22% (5% to 52%; P=NS) in group 2, 11% (5% to 34%; P=NS) in group 3, 24% (12% to 31%; P=NS) in group 4, 11% (3% to 22%; P=0.02) in the combined group 5, and 19% (9% to 51%; P=NS) in group 6. The infarct size was significantly reduced in the combined citicoline+rtPA-treated groups to a median of 13% (5% to 30%; P<0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery. CONCLUSIONS: These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model.