Methods for Defining the Neuroprotective Properties of Xenon.

Xenon has features that make it an ideal general anesthetic agent; cost and scarcity mitigate xenon's widespread use in the operating room. Discovery of xenon's cytoprotective properties resulted in its application to thwart ongoing acute neurologic injury, an unmet clinical need. The discovery that xenon's neuroprotective effect interacts synergistically with targeted temperature management (TTM) led to its investigation in clinical settings, including in the management of the postcardiac arrest syndrome, in which TTM is indicated. Following successful demonstration of xenon's efficacy in combination with TTM in a preclinical model of porcine cardiac arrest, xenon plus TTM was shown to significantly decrease an imaging biomarker of brain injury for out of hospital cardiac arrest victims that had been successfully resuscitated. With the development of an efficient delivery system the stage is now set to investigate whether xenon improves survival, with good clinical outcome, for successfully resuscitated victims of a cardiac arrest.

Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model.

Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

[The mechanisms of adaptation in severe trauma to the brain under conditions protecting it from hypoxia with pharmacological preparations and hyperbaric oxygenation]. / Mekhanizmy adaptatsii pri tiazheloi travme golovnogo mozga v usloviiakh zashchity ego ot gipoksii farmakologicheskimi preparatami i giperbaricheskoi oksigenatsiei.

From analysis of the adaptation mechanisms forming in severe brain trauma in 49 patients during its protection from hypoxia by combined administration of subnarcotic doses of sodium oxybutyrate and sodium thiopental in a bolus and an early course of hyperbaric oxygenation (HBO) the authors revealed the adaptation and disadaptation processes determining the outcome of the treatment. Since activation of the system of stress realizing biogenic amines promotes disadaptation processes, whatever the outcome, it is recommended to begin HBO after their stabilization. The character of changes of the lactate and pyruvate levels in blood flowing to and from the brain allowed the authors to distinguish the occurrence of a negative A-B gradient according to pyruvate after the first trial HBO session as a market of adaptation and a biochemical criterion of the expediency of prescribing a course of HBO.

[The effect of S-adenosyl-L-methionine sulfate tosylate (FO-1561) on survival time in various brain damage models].

The effect of S-adenosyl-L-methionine sulfate tosylate (FO-1561) on survival time in various brain damage models (cerebral anoxia or ischemia) was studied. 1) In KCN-induced or normobaric anoxia of ddY mice, FO-1561 (30-100 mg/kg as amount of S-adenosyl-L-methionine) administered intravenously 15-30 min prior to the treatment showed significant increase of survival time dose-dependently. 2) In asphyxic anoxia of Wistar rats, FO-1561 (100 mg/kg) administered intravenously 15 min prior to the treatment (cessation of artificial respiration) delayed the time until the disappearance of electrocorticogram. 3) In cerebral ischemia of Mongolian gerbils, FO-1561 (50 mg/kg) injected five times at 1 hr interval intraperitoneally 3 hr after the unilateral ligation of common carotid arteries showed significant increase of survival time. These results suggested that FO-1561 may be effective in ameliorating cerebral anoxic or ischemic damage, without observing any side effects like sedation and motor depression which pentobarbital showed with the effective doses in these damage models.

The role of ethanol in diluents of drugs that protect mice from hypoxia.

This study evaluates the hypothesis that ethanol alone, or in diluents for drugs used to protect hypoxic mice, is responsible in part for an increased tolerance to hypoxia (4-5% oxygen). The change in hypoxic tolerance following i.v. or i.p. administration of ethanol, diazepam, nimodipine and various diluent components was measured. Diazepam (50 mg/kg i.v.) increased hypoxic tolerance to 700 +/- 47% (n = 11) of saline control, its diluent increased hypoxic tolerance to 468 +/- 60% (n = 10) of saline control but the ethanol component of the diluent accounted for almost half of this diluent effect. Nimodipine (2 mg/kg i.p.), a calcium antagonist, increased tolerance to 180 +/- 18% of control (n = 19) and nimodipine diluent showed an even greater increase to 226 +/- 25% of control (n = 15). In this case essentially all of the protective effect of nimodipine diluent (81.3%) is accounted for by ethanol. Dose response curves indicate the maximum ethanol induced increase in hypoxic tolerance was approximately 335% of control at a dose of 2.4 g/kg. Buffers, etc. in the diluents evidently add to the protective effect of ethanol. Our data clearly indicate ethanol is the important component of some treatments which protect mice from hypoxia. The pharmacological activity of ethanol, even when used in a diluent, should not be ignored in evaluating therapeutic intervention for protection from hypoxia.