Effects of normothermic versus mild hyperthermic forebrain ischemia in rats.

Dietrich, W. Dalton; Busto, Raul; I, Isabel Valdés; Loor, Y

doi:10.1161/01.str.21.9.1318

Cited by 310 publications

(116 citation statements)

References 31 publications

(13 reference statements)

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“…Результаты доклинических исследова-ний свидетельствуют о наличии взаимосвязи между гипертермией и исходом инсульта, и, согласно надеж-ным экспериментальным данным, гипертермия усу-губляет ишемическое повреждение головного мозга [5][6][7]. В качестве независимого прогностического маркера лихорадку (температуру тела >38°C) вклю-чили в валидизированные прогностические модели для прогнозирования летальности и функциональ-ного исхода после острого ишемического инсульта [8,9].…”

Section: Discussionunclassified

“…Data from preclinical studies provided a link between hyperthermia and stroke outcomes, and robust experimental evidence for detrimental effects of hyperthermia on ischemic brain injury is available. [5][6][7] Fever (temperature Ͼ38°C) has been included as an independent prognostic marker in validated prognostic models for prediction of mortality and functional outcome after an acute ischemic stroke. 8,9 A recent meta-analysis suggested that pyrexia after stroke was significantly associated with mortality and morbidity.…”

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Effect of Hyperthermia on Prognosis After Acute Ischemic Stroke

Saini

Saqqur

Kamruzzaman

et al. 2009

Stroke

108

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FRCPC; on behalf of the VISTA Investigators Background and Purpose-Experimental studies have shown that hyperthermia is a determinant of poor outcome after ischemic stroke. Clinical studies evaluating the effect of temperature on poststroke outcome have, however, been limited by small sample sizes. We sought to evaluate the effect of temperature and timing of hyperthermia on outcome after ischemic stroke. Methods-Data of 5305 patients in acute stroke trials from the Virtual International Stroke Trials Archive (VISTA) data set were analyzed. Data for temperatures at baseline, eighth, 24th, 48th, and 72nd hours, and seventh day were assessed in relation to outcome (poor versus good) based on the modified Rankin Scale at 3 months. Hyperthermia was defined as temperature Ͼ37.2°C and poor outcome as 90-day modified Rankin Scale Ͼ2. Hazard ratios with 95% CIs were reported for hyperthermia in relation to the outcome. Logistic regression models, in relation to hyperthermia, were fitted for a set of preselected covariates at different time points to identify predictors/determinants of hyperthermia. Results-The average age of patients was 68.0Ϯ11.9 years, 2380 (44.9%) were females, and 42.3% (2233) received thrombolysis using recombinant tissue plasminogen activator. After adjustment, hyperthermia was a statistically significant predictor of poor outcome. The hazard ratios (95% CI) for poor outcome in relation to hyperthermia at different time points were: baseline 1.2 (1.0 to 1.4), eighth hour 1.7 (1.2 to 2.2), 24th hour 1.5 (1.2 to 1.9), 48th hour 2.0 (1.5 to 2.6), 72nd hour 2.2 (1.7 to 2.9), and seventh day 2.7 (2.0 to 3.8). Gender, stroke severity (National Institutes of Health Stroke Scale score Ͼ16), white blood cell count, and antibiotic use were significantly associated with hyperthermia (PՅ0.01). Conclusions-Hyperthermia, in acute ischemic stroke, is associated with a poor clinical outcome. The later the hyperthermia occurs within the first week, the worse the prognosis. Severity of stroke and inflammation are important determinants of hyperthermia after ischemic stroke. In patients with acute ischemic stroke, aggressive measures to prevent and treat hyperthermia could improve the clinical outcomes.

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Section: Discussionunclassified

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Effect of Hyperthermia on Prognosis After Acute Ischemic Stroke

Saini

Saqqur

Kamruzzaman

et al. 2009

Stroke

108

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“…Because such a therapy was not used in any thermoregulatory study in the past (Table 1), some animals were likely to die in those studies. Knowing that even mild hyperthermia strongly exaggerates neural damage and increases the related mortality rate (15), it is reasonable to suspect that hyperthermic animals were more likely to die after OVLT lesioning than normo-or hypothermic animals in the early studies.…”

Section: Hyperthermia Induced By Ovlt Lesionmentioning

confidence: 99%

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

Romanovsky

Sugimoto²,

Simons³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Romanovsky, Andrej A., Naotoshi Sugimoto, Christopher T. Simons, and William S. Hunter. The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments. Am J Physiol Regul Integr Comp Physiol 285: R420-R428, 2003. First published April 24, 2003 10.1152/ajpregu.00757. 2002The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many "side effects" not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by ϳ2°C) and long-lasting (Ͼ3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1␤ (500 ng/kg iv) was tested. The shamoperated rats developed typical monophasic fevers (ϳ0.5°C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39-40°C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain. fever; adipsia; third ventricle; median preoptic nucleus THERE IS LITTLE DOUBT that the febrile response is regulated by the central nervous system (CNS), but the mechanisms by which peripherally originating pyrogenic signals reach the brain remain unclear. At least four possibilities have been proposed. First, pyrogenic cytokines, such as IL-1␤, access the CNS by carriermediated transport across the blood-brain barrier (BBB) (2). Second, circulating pyrogens bind to the cerebral vascular endothelium and stimulate production of fever mediators, most importantly PGE 2 , by endothelial cells; endotheliocytes release PGE 2 into the brain tissue (10). Third, pyrogens act on neural terminals in peripheral tissues and convey febrigenic signals to the CNS via sensory fibers, e.g., those of the vagus nerve (7, 74). Fourt...

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“…Hypothermia during HI has been shown to prevent or delay HI brain injury (9,(13)(14)(15)(16)(17). However, evidence for a potential beneficial effect of postinsult hypothermia in neonatal animal models of HI has been conflicting, with studies showing varying degrees of protection for different periods and depths of hypothermia (18 -20).…”

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Improved Neuroprotection with Hypothermia Delayed by 6 Hours Following Cerebral Hypoxia-Ischemia in the 14-Day-Old Rat

et al. 2002

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Since hypothermia may be a potential treatment for perinatal cerebral hypoxic-ischemic injury, we used an established neonatal model of hypoxia-ischemia to determine the time after injury at which cooling had the best protective effect. Fourteen-day-old Wistar rats were subjected to right carotid artery ligation and hypoxia (8% O 2 for 90 min). Immediately at the end of hypoxia (defined as 0h), animals were either maintained at normal body temperature until sacrifice (normothermia) or subjected to hypothermia. In a preliminary study, the effects of a reduction in temperature and the duration of such cooling were investigated; animals were cooled (until brain temperature reached 33°C or 30°C) for 2, 4, or 6 h commencing immediately after hypoxia. In a second study, animals were cooled (brain temperature 30°C) for 6 h commencing at either 0, 2, 4, or 6 h after the end of hypoxia. Sham-operated animals were used as controls. Twentyfour hours after hypoxia-ischemia, cerebral energy metabolism was measured by phosphorus magnetic resonance spectroscopy, and at 5 d cerebral infarction was measured by planimetry. In normothermic animals the ratio of phosphocreatine/inorganic phosphate (PCr/Pi) had fallen markedly 24 h following hypoxiaischemia. In contrast, animals cooled between 6 and 12 h displayed high PCr/Pi ratios similar to those in control animals. Similarly, after 5 d, infarct area was significantly reduced only in animals cooled between 6 and12 h after injury. These results indicate that cooling between 6 and 12 h after hypoxia-ischemia is more effective in reducing cerebral injury than other cooling regimes and suggest that the physiologic events during this period are critical for understanding cerebral infarction. Term infants who suffer significant hypoxia-ischemia (HI) during birth later develop cerebral injury and neurodevelopmental impairment that may in the severest cases prove fatal. Studies using phosphorus magnetic resonance spectroscopy ( 31 P MRS) have demonstrated that these babies usually possess normal cerebral energy metabolism soon after resuscitation, but impaired oxidative phosphorylation, measured as the ratio of the concentrations of phosphocreatine/inorganic phosphate (PCr/Pi), develops some 24 h later as demonstrated by a low PCr/Pi that persists for many days (1). This delayed impairment of energy metabolism was not due to continued HI, nor was it associated with intracellular acidosis (2), but its magnitude was linearly related to the severity of later impairment and reduced brain growth (3).A similar pattern of changes has been observed in neonatal animal models of HI (4 -6). Recently, we have shown that changes comparable to those observed in human term infants occur in a neonatal rat model of HI (5, 7). Thus, in the 7-day-old rat, HI produces a severe disruption of cerebral energy metabolism during the insult, which resolves on reoxygenation. However, there is a second decline in energy metabolites beginning some 10 to 12 h after the insult (5, 7). The decrease in PCr/Pi at 10 to 12...

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Effects of normothermic versus mild hyperthermic forebrain ischemia in rats.

Cited by 310 publications

References 31 publications

Effect of Hyperthermia on Prognosis After Acute Ischemic Stroke

Effect of Hyperthermia on Prognosis After Acute Ischemic Stroke

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

Improved Neuroprotection with Hypothermia Delayed by 6 Hours Following Cerebral Hypoxia-Ischemia in the 14-Day-Old Rat

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