The influence of body temperature on infarct volume and thrombolytic therapy in a rat embolic stroke model (original) (raw)
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The beneficial effect of mild hypothermia in a rat model of repeated thromboembolic insults
Acta Neuropathologica, 2004
The post-thrombotic brain has recently been reported to have an enhanced vulnerability to a second embolic insult. Although postischemic hypothermia is neuroprotective in global and focal ischemia models, the effect of mild hypothermia on outcome after thromboembolic insults has not been evaluated. This study therefore determined whether brain hypothermia (33°C) was neuroprotective against repeated thromboembolic insults. Photochemically induced non-occlusive common carotid artery thrombosis (CCAT) leading to platelet embolization to the brain was induced in anesthetized rats (n=35). Thirty minutes after CCAT, brain temperature was maintained at normothermic (37°C) or hypothermic (33°C) levels for 4 h followed by a slow rewarming period (1.5 h). Three days later, rats underwent a secondary CCAT insult under normothermic conditions and were allowed to survive for an additional 3 days prior to perfusion fixation and quantitative histopathological assessment. Compared to normothermic animals, mild hypothermia after the first embolic insult produced a significant reduction (P>0.05) in overall infarct volume. Hypothermia reduced total infarct volume from 7.55±2.32 mm 3 (mean ± SEM) in normothermic rats to 2.56±0.88 mm 3 in hypothermic animals undergoing repeated insults. Histopathological analysis also demonstrated less evidence for focal hemorrhage in the cooled groups. These data demonstrate that mild hypothermia is protective in a thromboembolic stroke model. In addition, post-thrombotic hypothermia decreases the histopathological vulnerability of the post-thrombotic brain to secondary embolic insults. These findings may be important in the prevention of stroke in patients at risk.
Immediate or delayed mild hypothermia prevents focal cerebral infarction
Brain Research, 1992
Thc protcclivc cft'eet of mild hypothcrmia was studied in rodent models of both permanent and transient local cerebral ischemia. In Expt. I, Wislar rats were exposed to h h permanent ischemia by bilateral occlusion of both common carotid arteries and right middle cerebral artery. In Expt. 2. animals werc exposed to 3 h tr:|llsicnl ischcmi;i followed by 21 h rcperfusion, and in Expt, 3, 3 h transient ischemia was followed by 69 h of rcpcrfusion. Expt. 4 used 3 h transient ischcmia followed by 3 h reperfusion, In Expt. I, animals maintained at 37°(" rectal (normothermia) suffered a mc:m infarct volume (± S.D,) of 142 ± 44 mm ~ (n = 6), which was reduced for those exposed to permanent hypothermic (32°C) ischcmia to 56±64 mm ~ (n = I01 (P < 0,05), In Expl. 2, normothermic ischemia and reperfusion resulted in an infarction of 211:t:35 mm "~ (n ~ fit. lntra.ischemic hypothertni:t (32°C) ftdlowed by 21 h of normothermic reperfusion resulted in 17± 12 mm 3 of infarctkm (n =9) (P < {|,0011, I lypothcrmia for either tile first or second 1,5 h of the 3 h ischemic insult reduced the infarct wdume to 116± 76 mm ~ (n = 6) (P < 0,051 or It)8 :t: 73 mm ~ (n ~ 7) (P < 4),01 ), respectively, Delaying the induction of hypothermia by 1.5 It and subsequently maintaining the tcntpcraturc at 320( ` durint~ the first 1,5 h of repcrfusion resulted in a reduction in infarct volume to 56 ± 66 mm 3 (n ,= 7) ( P < 11.01). In Expt. 3. hypt~lllcrmic ischcmiu followed hy prolonged reperfusion (3 days) resulted in 31 ± 25 mm ' (n -7) of infarction, versus 198 ± 28 mm ' (P < 0.001) in normothermic controls (n ~ 7). In Expt. 4, normotherntic ischemi:t ;rod rcperfusion resulted in a mean infarct volumu of 166 t 27 mnr ~ (n -7). Delaying the onset of hypolhcrmia unlil just prior to rcpcrfusion resulted in a reduction in infarc! volume to 65 ~ 54 mm ~ (n -5) (P < {HIS), llypcrthermic ischemia I.t0"( '1 increased injury, 245 ~ 1' 14 ntm ,~ (n-5)(P < 0,115), These results dcntonstraic that mild inlra-lschemic temperature reductions can attenuate cortical infarction with hoth perma.cnt and trLmsicnt focal tschemia, Furtherntorc, followin8 transient t'ocal ischemia. delayed hyptltl'tcrntia can still result in amelioration of Injury,
Mild Hypothermia: Therapeutic Window after Experimental Cerebral Ischemia
Neurosurgery, 1996
THE TREATM ENT O F cerebral ischemia remains a formidable challenge in neuroscience today. Mild hypothermia has been shown to be an effective neuroprotective agent. Despite the great volume of published research, the therapeutic window of mild hypothermia has not been precisely elucidated. Using a model of reversible focal cerebral ischemia in the rat, this study was undertaken to define the optimal duration of hypothermic application and the maximal postischemic delay in hypothermic application before which optimal therapeutic effect is noted. Focal ischemia was induced by temporary occlusion of the middle cerebral artery and both carotid arteries in Sprague Dawley rats for a period of 3 hours. In the first study, mild hypothermia (32-33°C) was induced at the onset o t ischemia in four groups of rats for varying lengths of time ranging from 1 to 4 hours. The animals were killed after 3 days, and their brains were sliced and stained. Infarcted volume was measured using a computerized im age analyzer. The infarct volumes were 211 ± 4.5, 214.2 ± 8.0, 199.5 ± 5.3, 1 71.3 ± 9.1, and 169.8 ± 6.5 mmj (m ean ± standard error of the mean, n = 6 per group) for the control, 1-hour, 2-hour, 3-hour, and 4-hour groups, respectively. On the basis of the results from the above study, a 3-hour duration of hypothermia was then applied to animals at 0, 15, 30, or 45 minutes after the ischemic onset. The volumes of infarction for these four respective groups were: 171.3 ± 9.1, 173 ± 5.7, 179.3 ± 5.2, and 206.2 ± 8.4 mm* (mean ± standard error of the m ean, n = 6 per group). These results demonstrated that optimal duration of mild hypothermia was at least 3 hours (P < 0.001) when applied within the first 30 minutes after the onset of ischemia (P < 0.001).
Hypothermia and stroke: the pathophysiological background
Pathophysiology, 2003
Hypothermia to mitigate ischemic brain tissue damage has a history of about six decades. Both in clinical and experimental studies of hypothermia, two principal arbitrary patterns of core temperature lowering have been defined: mild (32-35 • C) and moderate hypothermia (30-33 • C). The neuroprotective effectiveness of postischemic hypothermia is typically viewed with skepticism because of conflicting experimental data. The questions to be resolved include the: (i) postischemic delay; (ii) depth; and (iii) duration of hypothermia. However, more recent experimental data have revealed that a protected reduction in brain temperature can provide sustained behavioral and histological neuroprotection, especially when thermoregulatory responses are suppressed by sedation or anesthesia. Conversely, brief or very mild hypothermia may only delay neuronal damage. Accordingly, protracted hypothermia of 32-34 • C may be beneficial following acute cerebral ischemia. But the pathophysiological mechanism of this protection remains yet unclear. Although reduction of metabolism could explain protection by deep hypothermia, it does not explain the robust protection connected with mild hypothermia. A thorough understanding of the experimental data of postischemic hypothermia would lead to a more selective and effective clinical therapy. For this reason, we here summarize recent experimental data on the application of hypothermia in cerebral ischemia, discuss problems to be solved in the experimental field, and try to draw parallels to therapeutic potentials and limitations.
Experimental Neurology, 2008
Mild hypothermia reduces injury in models of global and focal cerebral ischemia even when initiated after the insult. Neuroprotection depends critically upon the duration of hypothermia with longer treatments often being more efficacious. However, the ideal treatment duration is not known for most insults and this knowledge would facilitate clinical studies. Thus, we compared 12, 24 and 48 h of systemic hypothermia (33°C vs. normothermia) initiated 1 h after permanent middle cerebral artery occlusion (pMCAO), which was produced by permanent occlusion of the carotid arteries and cauterization of the distal MCA in rat. Behavioral recovery and lesion volume were determined 7 days after pMCAO. All three treatments significantly and equally attenuated neurological deficits (e.g., forelimb placing response). Conversely, stepping error rate in the horizontal ladder test was significantly reduced only by the 24-h (18.7%) and 48-h treatments (11.7%) compared to normothermic rats (34.4%), and the 48-h treatment was significantly better than the 12-h treatment (28.8%). Similarly, brain injury was significantly reduced by 24-h (78.8 mm 3 lesion volume) and 48-h (66.8 mm 3) treatments compared to normothermia (142.6 mm 3), and the 48-h treatment was significantly better than the 12-h duration (114.6 mm 3). In separate experiments cerebral edema was measured via wet-dry weight measurements and significantly reduced by hypothermia (e.g., from 83.7% water in the injured cortex of normothermic rats to 81.4% in rats cooled for one day), but for this there were no significant duration effects. In summary, prolonged hypothermia treatment provides superior protection overall, but this is not explained by reductions in edema.
Stroke; a journal of cerebral circulation, 2016
Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke. Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke. PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages an...
Antihyperthermic Treatment in the Management of Malignant Infarction of the Middle Cerebral Artery
Journal of Clinical Medicine
Malignant infarction of the middle cerebral artery (m-MCA) is a complication of ischemic stroke. Since hyperthermia is a predictor of poor outcome, and antihyperthermic treatment is well tolerated, our main aim was to analyze whether the systemic temperature decrease within the first 24 h was associated with a better outcome. Furthermore, we studied potential biochemical and neuroimaging biomarkers. This is a retrospective observational analysis that included 119 patients. The temperature variations within the first 24 h were recorded. Biochemical laboratory parameters and neuroimaging variables were also analyzed. The temperature increase at the first 24 h (OR: 158.97; CI 95%: 7.29–3465.61; p < 0.001) was independently associated with a higher mortality. Moreover, antihyperthermic treatment (OR: 0.08; CI 95%: 0.02–0.38; p = 0.002) was significantly associated with a good outcome at 3 months. Importantly, antihyperthermic treatment was associated with higher survival at 3 months ...