Ischemia, resuscitation, and reperfusion: Mechanisms of tissue injury and prospects for protection

Krause, Gary S.; Kumar, Kusum; White, Blaine C.; Aust, Steven D.; Wiegenstein, John G.

doi:10.1016/0002-8703(86)90114-6

Cited by 86 publications

(35 citation statements)

References 155 publications

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“…40 Brain death or limitation of active treatment is often the cause of patient demise. 41 Currently, the standard of care for primary cardiac arrest patients who remain comatose after ROSC involves supportive care and serial neurologic examination to determine prognosis. 42 The pathophysiology of ischemic neuronal injury is incompletely understood but is thought to occur through a myriad of mechanisms, including release of excitatory neurotransmitters, dysregulation of calcium homeostasis, and free radical oxidation of cellular components.…”

Section: Discussionmentioning

confidence: 99%

“…43,44 Anoxic brain injury, although related to the length of no circulation time, is an ongoing process after ROSC. 37,41,[43][44][45] Hypothermia is thought to play a neuroprotective role after ROSC by decreasing metabolic demand, 46,47 decreasing the release of excitatory neurotransmitters, 16 and decreasing inflammation. 48 Animal studies since the 1980s [49][50][51][52][53][54][55][56][57] have suggested that mild induced hypothermia may be beneficial as a neuroprotectant after cardiac arrest.…”

Section: Discussionmentioning

confidence: 99%

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Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

Cheung

Green

Magee

2006

CJEM

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Objective: Several randomized controlled trials have suggested that mild induced hypothermia may improve neurologic outcome in comatose cardiac arrest survivors. This systematic review of randomized controlled trials was designed to determine if mild induced hypothermia improves neurologic outcome, decreases mortality, or is associated with an increased incidence of adverse events. Science (1989 to November 2005. For each included study, references were reviewed and the primary author contacted to identify any additional studies. Study selection: Studies that met inclusion criteria were randomized controlled trials of adult patients (>18 years of age) with primary cardiac arrest who remained comatose after return of spontaneous circulation. Patients had to be randomized to mild induced hypothermia (32°C-34°C) or normothermia within 24 hours of presentation. Only studies reporting pre-determined outcomes including discharge neurologic outcome, mortality or significant treatment-related adverse events were included. There were no language or publication restrictions. Data synthesis: Four studies involving 436 patients, with 232 cooled to a core temperature of 32°C-34°C met inclusion criteria. Pooled data demonstrated that mild hypothermia decreased inhospital mortality (relative ratio [RR] 0.75; 95% confidence interval [CI], 0.62-0.92) and reduced the incidence of poor neurologic outcome (RR 0.74; 95% CI, 0.62-0.84). Numbers needed to treat were 7 patients to save 1 life, and 5 patients to improve neurologic outcome. There was no evidence of treatment-limiting side effects. Conclusions: Therapeutically induced mild hypothermia decreases in-hospital mortality and improves neurologic outcome in comatose cardiac arrest survivors. The possibility of treatment-limiting side effects cannot be excluded. RÉSUMÉObjectif : Plusieurs essais comparatifs randomisés ont suggéré qu'une légère hypothermie provoquée peut améliorer le résultat clinique chez les victimes d'arrêt cardiaque dans le coma. La

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

Cheung

Green

Magee

2006

CJEM

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“…Desferroxamine has been used successfully in the treatment of oxidative damage due to iron overload and iron-dependent cytotoxins in systemic organs and a number of animal models (51,(95)(96)(97)(98)(99)(100)(101). Unfortunately, as a consequence of inability to cross the BBB, more suitable lipophylic agents are required.…”

Section: Neuroprotective Therapymentioning

confidence: 99%

The possible role of iron in the etiopathology of parkinson's disease

1993

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The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.

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“…In fact, from the Ϸ70 000 patients per year who are resuscitated after CA, 60% die from extensive brain injury, and only 3% to 10% are able to resume their former lifestyles. 1 Thus, development of novel therapies to protect the brain from the ravages of cerebral ischemia is key to improvement in survival and better outcomes after such a devastating condition.…”

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confidence: 99%

The Arctic Ground Squirrel Brain Is Resistant to Injury From Cardiac Arrest During Euthermia

Dave

Prado

Raval

et al. 2006

Stroke

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Background and Purpose-Hetereothermic mammals tolerate hypoxia during euthermy and torpor, and evidence suggests this tolerance may extend beyond hypoxia to cerebral ischemia. During hibernation, CA1 hippocampal neurons endure extreme fluctuations in cerebral blood flow during transitions into and out of torpor as well as reductions in cerebral blood flow during torpor. In vitro studies likewise show evidence of ischemia tolerance in hippocampal slices harvested from euthermic ground squirrels; however, no studies have investigated tolerance in a clinically relevant model of in vivo global cerebral ischemia. The purpose of the present study was to test the hypothesis that the euthermic Arctic ground squirrel (AGS; Spermophillus parryii) is resistant to injury from asphyxial cardiac arrest (CA). Methods-Estrous-matched female rats were used as a positive control. Female euthermic AGS and rats were subjected to 8-minute CA. At the end of 7 days of reperfusion, AGS and rats were fixed for histopathological assessment. Results-In rats subjected to CA, the number of ischemic neurons was significantly higher (PϽ0.001) compared with control rats in hippocampus and striatum. Cortex was mildly injured. Surprisingly, neuronal counts in AGS were not significantly different in CA and control groups in these brain regions. Conclusion-These data demonstrate that AGS are remarkably tolerant to global cerebral ischemia during euthermia. A better understanding of the mechanisms by which AGS tolerate severe reductions in blood flow during euthermia may provide novel neuroprotective strategies that may translate into significant improvements in human patient outcomes after CA. (Stroke. 2006;37:1261-1265.)

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Ischemia, resuscitation, and reperfusion: Mechanisms of tissue injury and prospects for protection

Cited by 86 publications

References 155 publications

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

The possible role of iron in the etiopathology of parkinson's disease

The Arctic Ground Squirrel Brain Is Resistant to Injury From Cardiac Arrest During Euthermia

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