The effect of graded hypothermia on hypoxic-ischemic brain damage: a neuropathologic study in the neonatal rat.

Young, Richard S.; Olenginski, Thomas P.; Yagel, Susan K.; Towfighi, Javad

doi:10.1161/01.str.14.6.929

Cited by 82 publications

(32 citation statements)

References 15 publications

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“…This model requires permanent unilateral carotid artery occlusion and temporary systemic hypoxemia to produce focal cerebral infarction and impaired brain development (10) and is feasible in neonatal (PND 7) rats. This model has produced many seminal findings related to hypoxic-ischemic damage in the developing brain related to both mechanism (including: (22,23) and treatment (including: (24)(25)(26), leading to a significant advancement in the understanding of neonatal hypoxia-ischemia. Parallel studies examining mechanisms and treatment in age-appropriate models of pediatric hypoxia-ischemia; however, are lacking.…”

Section: Discussionmentioning

confidence: 99%

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Fink

Alexander

Marco

et al. 2004

Pediatric Critical Care Medicine

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Objective-Develop a clinically relevant model of pediatric asphyxial cardiopulmonary arrest in rats. Design-Prospective interventional study. Setting-University research laboratory.Subjects-Post-natal day (PND) 16-18 rats.Interventions-Anesthetized rats were endotracheally intubated and mechanically ventilated, and vascular catheters were inserted. Vecuronium was administered and the ventilator was disconnected from the rats for 8 min, whereupon rats were resuscitated with epinephrine, sodium bicarbonate, and chest compressions until spontaneous circulation returned. Shams underwent all procedures except asphyxia.Measurements and Main Results-Asphyxial arrest typically occurred by 1 min after the ventilator was disconnected. Return of spontaneous circulation typically occurred <30 sec after resuscitation. An isoelectric electroencephalograph was observed for 30 min after asphyxia and rats remained comatose for 12-24 h. Survival rate in rats after asphyxia was 75%. Motor function measured using beam balance and inclined plane tests was impaired on d 1 and 2, but recovered by d 3, in rats after asphyxia vs. sham injury (n=9/group; P<0.05). Spatial memory acquisition measured using the Morris-water maze on d 7-14 and 28-35 was also impaired in rats after asphyxia vs. sham injury (total latency 379±28 vs. 501±40 sec, respectfully; n=9/group; P<0.05). CA1 hippocampal neuron survival after asphyxia was 39-43% (n=9/group; P<0.001 vs. sham). DNA fragmentation was detected in CA1 hippocampal neurons bilaterally in separate rats on d 3-7 after asphyxia (n=3-4/group). Neurodegeneration detected using Fluorojade-B was seen in bilateral CA1 hippocampi and layer III cortical neurons 3-7 d after asphyxia, with persistent neurodegeneration in CA1 hippocampus detected up to 5 wks after asphyxia. Evidence of DNA or cellular injury was not detected in sham rats.

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Section: Discussionmentioning

confidence: 99%

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Fink

Alexander

Marco

et al. 2004

Pediatric Critical Care Medicine

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“…Cerebral blood flow (CBF) in the hemisphere ipsilateral to the ligated carotid artery does not decrease because of the collateral blood flow via the circle of Willis; however with lower oxygen tension, the CBF in the ipsilateral hemisphere decreases significantly and results in unilateral ischemic injury. The use of 2,3,5-triphenyltetrazolium chloride (TTC) to stain and identify ischemic brain tissue was originally developed for adult models of rodent cerebral ischemia 5 , and is used to evaluate the extent of cerebral infarctin at early time points up to 72 hours after the ischemic event 6 . In this video, we demonstrate the hypoxic-ischemic injury model in postnatal rat brain and the evaluation of the infarct size using TTC staining.…”

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The Hypoxic Ischemic Encephalopathy Model of Perinatal Ischemia

Taniguchi¹,

Andreasson²

2008

JoVE

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Hypoxic-Ischemic Encephalopathy (HIE) is the consequence of systemic asphyxia occurring at birth. Twenty five percent of neonates with HIE develop severe and permanent neuropsychological sequelae, including mental retardation, cerebral palsy, and epilepsy. The outcomes of HIE are devastating and permanent, making it critical to identify and develop therapeutic strategies to reduce brain injury in newborns with HIE. To that end, the neonatal rat model for hypoxic-ischemic brain injury has been developed to model this human condition. The HIE model was first validated by Vannucci et al 1 and has since been extensively used to identify mechanisms of brain injury resulting from perinatal hypoxia-ischemia 2 and to test potential therapeutic interventions 3,4 . The HIE model is a two step process and involves the ligation of the left common carotid artery followed by exposure to a hypoxic environment. Cerebral blood flow (CBF) in the hemisphere ipsilateral to the ligated carotid artery does not decrease because of the collateral blood flow via the circle of Willis; however with lower oxygen tension, the CBF in the ipsilateral hemisphere decreases significantly and results in unilateral ischemic injury. The use of 2,3,5-triphenyltetrazolium chloride (TTC) to stain and identify ischemic brain tissue was originally developed for adult models of rodent cerebral ischemia 5 , and is used to evaluate the extent of cerebral infarctin at early time points up to 72 hours after the ischemic event 6 . In this video, we demonstrate the hypoxic-ischemic injury model in postnatal rat brain and the evaluation of the infarct size using TTC staining. 4. The incision is closed with cyanoacrylate adhesive (Elmers Products Inc, Columbus, OH). The incision is covered with tape and anesthesia is stopped. The pups are returned to their dam and allowed to recuperate for 1-2 hours. 5. Pups are then placed in a hypoxic chamber that contains 8% oxygen balanced with 92% nitrogen for 100 minutes at 37°C. 8% oxygen/92% nitrogen gas(Airgas, Sacramento, CA) flow via a tube into the mouse cage outfitted with a plastic cover. The cover is made to fit to the cage and has two holes of 2 cm in diameter, one of which to receive the tube connected to the 8% oxygen gas tank and another allows the gas to flowout. The chamber is placed in a water bath and is warmed up prior to use and a thermometer inside of it must register 37°C before the start of hypoxia. 6. At the end of 100 minutes of hypoxia, the pups are returned again to their dam for recovery. 7. 24 hours after the end of hypoxia, pups are euthanized by deep anesthesia with isoflurane. Brain tissue is perfused with cold normal saline, followed by a solution of cold 1% TTC in phosphate buffered saline, pH 7.4 (Sigma Chemical Co, St Louis, MO). TTC must be kept protected from light. 8. Brains are removed and cooled for 1-2 minutes on ice, and four coronal sections 3 mm apart (levels 1-4) are cut, beginning rostrally at the level of the opticchiasm and infundibulum, corresponding to the bregma 1...

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“…Moderate decreases of body temperature have also been shown to have a protective effect in experimental brain ischemia (Marshall et al, 1956;Rosomoff, 1957;Kramer et al, 1968;Michenfelder and Theye, 1970;Kopf et al, 1975;Berntman et al, 198 1;Young et al, 1983). To date, however, no investiga tions have documented the effects of small differ ences in intraischemic brain temperature on final histopathological outcome.…”

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confidence: 99%

Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury

Busto

Dietrich

Globus

et al. 1987

J Cereb Blood Flow Metab

1,705

614

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Summary:We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a ther mocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36-37°C by a heating lamp, and striatal temperature prior to ischemia was 36°C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39°C. Postischemic brain tem perature was regulated at 36°C, except for one group in which brain temperature was lowered from 36°C to 33°C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and his topathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological conse quences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the Despite the utility of small animal models of global ischemia, several groups have noted vari ability of outcome from animal to animal (Payan et aI., 1965;Furlow, 1982; Blomqvist et aI., 1984; Harrison et aI., 1985; Vibulsresth et aI., 1987). Al though these variations, in part, may be the conse quence of differences in the severity of ischemia it- 729hippocampus, CA I neurons were consistently damaged at 36°C, but not at 34°C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemi spheres at 36°C, but in only 50% at 34°C. Ischemic neu rons within the central zone of striatum were not ob served in any rats at 34°C, but in all rats at 36°C. In rats whose striatal temperature was not controlled, brain tem perature fell from 36 to 30-31°C during the ischemic in sult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently docu mented within the CAl hippocampal region. These re sults demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during isch emia at all temperatures, small increments of intra ischemic brain temperature markedly accentuate histo pathological changes following 3-day survival; and (c) brain temperature must be controlled above 33°C in order to ensure a consistent histopathological outcome. Low ering of the brain temperature by only a few degrees during ischemia confers a marked protective effect. Key Words: Ischemia-Brain temperature-Rats-Hypo thermia.self, other factors not directly related to the pri mary insult may also play an important role in determining the ultimate histopathological out come.Recen...

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The effect of graded hypothermia on hypoxic-ischemic brain damage: a neuropathologic study in the neonatal rat.

Cited by 82 publications

References 15 publications

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

The Hypoxic Ischemic Encephalopathy Model of Perinatal Ischemia

Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury

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