No abstract

This review addresses current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion. The mechanism for radical production remains speculative in large part because of the difficulty of measuring radical species in vivo. Breakdown of lipid membranes during ischemia leads to accumulation of free fatty acids. Decreased energy stores during ischemia result in the accumulation of adenine nucleotides. During reperfusion, metabolism of free fatty acids via the cyclooxygenase pathway and metabolism of adenine nucleotides via the xanthine oxidase pathway are the most likely sources of oxygen radicals. Although leukocytes have been found to accumulate in some models of ischemia and reperfusion, their mechanistic role remains in question. Therapeutic strategies aimed at decreasing brain injury have included administration of radical scavengers at the time of reperfusion. Efficacy of traditional oxygen radical scavengers such as superoxide dismutase and catalase may be limited by their inability to cross the blood-brain barrier. Lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and because of their presence in membrane structures where peroxidative reactions can be halted.

Administration of anesthetic agents fundamentally shifts the responsibility for maintenance of homeostasis from the patient and their intrinsic physiological regulatory mechanisms to the anesthesiologist. Continuous delivery of oxygen and nutrients to the brain is necessary to prevent irreversible injury and arises from a complex series of regulatory mechanisms that ensure uninterrupted cerebral blood flow. Our understanding of these regulatory mechanisms and the effects of anesthetics on them has been driven by the tireless work of pioneers in the field. It is of paramount importance that the anesthesiologist shares this understanding. Herein, we will review the physiological determinants of cerebral blood flow and how delivery of anesthesia impacts these processes.

This review will focus on inhalational anesthetic neuroprotection during cerebral ischemia and inhalational anesthetic preconditioning before ischemic brain injury. The limitations and challenges of past and current research in this area will be addressed before reviewing experimental and clinical studies evaluating the effects of inhalational anesthetics before and during cerebral ischemia. Mechanisms underlying volatile anesthetic neuroprotection and preconditioning will also be examined. Lastly, future directions for inhalational anesthetics and ischemic brain injury will be briefly discussed.

Summary: Female reproductive hormones are consid ered to be protective agents in atherosclerotic vascular disease and stroke. The present study determined if there are unique cerebrovascular responses in female animals to global cerebral ischemia and if 17J3-estradiol is impor tant to postischemic outcome in brain. Three groups of anesthetized, sexually mature rabbits were treated with normotensive four-vessel occlusion (6 min) and 3 h of reperfusion: females chronically instrumented with 1713-estradiol implants (EFEM; n = 8, plasma estradiol level = 365 ± 48 pg/ml), untreated females (FEM; n = 8, estradiol = 13 ± 3 pg/ml), and untreated males (M; n = 8, estradiol < limit of radioimmunoassay). CBF (micro spheres) and somatosensory evoked potential (SEP) am plitude were measured during ischemia/reperfusion. Baseline hemispheric blood flow and regional flow distri-The incidence of atherosclerotic vascular disease in premenopausal women is less than in men, but this difference disappears after menopause (Bush and Miller, 1987; Wolf et aI., 1987; Barrett-Connor and Bush, 199 1; Sivenius et aI. , 199 1). These obser vations have historically been interpreted as evi dence that female reproductive hormones confer vascular protection in ischemic heart disease and stroke. However, it is unclear if estrogen per se is critical to stroke risk or by what mechanism protec tion is achieved. Further, the presence of vascular responses unique to the female in an ongoing cere- 666bution were not altered by chronic estradiol treatment. Hemispheric blood flow was equivalently reduced during ischemia in FEM and M (6 ± 1 and 9 ± 2 ml min -I 100 g-I, respectively); however postischemic hyperemia was greater in FEM than M (CBF = 25 7 ± 27 and 18 3 ± 27 ml min -1 100 g -I. However, EFEM experienced higher CBF during ischemia (e.g., 13 ± 2ml min-1100 g-l) and less hyperemia (134 ± 4 ml min -I 100 g-I in hemi spheres) in numerous brain regions than FEM. CBF at 3 h reperfusion was not different among the groups. Recov ery of SEPs was incomplete and similar in all groups. We conclude that chronic exogenous 17J3-estradiol treatment increases CBF during global incomplete ischemia and ameliorates postischemic hyperemia in the female animal.

Traumatic spinal cord injury is frequently associated with brain injury and with alterations in respiratory and cardiovascular function that require critical care management. Complications include respiratory failure, atelectasis, pneumonia, neurogenic shock, autonomic dysreflexia, venous thromboembolism, and sepsis. While complications may be managed with supportive care, the goal of ameliorating neurologic outcome has proved elusive. Methylprednisolone, when instituted <8 hours after traumatic spinal cord injury, was associated in two clinical trials with statistically significant improvements in motor scores at 6 months and 1 year; however, critical reappraisal of these data raises questions about their validity and clinical relevance. Until more evidence of clinically effective therapies is available, acute management must be driven by pathophysiologic principles, with emphasis on interventions that attenuate secondary neurologic injury; these include the rational use of immobilization, cautious airway management, and promotion of cord perfusion and oxygenation with the appropriate level of hemodynamic and respiratory support. Clinical trials of pharmacologic neuroprotection have yielded disappointing results, but the ongoing elucidation of spinal cord repair and regenerative mechanisms suggests new therapeutic prospects.

Background-Peripheral nerve blocks (PNB's) with local anesthetics (LA's) are commonly performed to provide surgical anesthesia or postoperative analgesia. Nerve injury resulting in persistent numbness or weakness is a potentially serious complication. LA's have previously been shown to damage neuronal and Schwann cells via several mechanisms. We sought to test the

Background and Purpose-The potent 1 -receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) provides neuroprotection in experimental stroke. We tested the hypothesis that PPBP attenuates striatal tissue damage after middle cerebral artery occlusion (MCAO) by a mechanism involving reduction of ischemia-evoked nitric oxide (NO) production. Furthermore, we determined whether the agent fails to protect ischemic brain when neuronal nitric oxide synthase (nNOS) is genetically deleted or pharmacologically inhibited (selective nNOS inhibitor, 7-nitroindazole [7-NI]). Methods-Halothane-anesthetized adult male Wistar rats were subjected to 2 hours of MCAO by the intraluminal filament occlusion technique. All physiological variables were controlled during the ischemic insult. In vivo striatal NO production was estimated via microdialysis by quantification of local, labeled citrulline recovery after labeled arginine infusion. In a second series of experiments, nNOS null mutants (nNOSKOs) and the genetically matched wild-type (WT) strain were treated with 90 minutes of MCAO. Brains were harvested at 22 hours of reperfusion for measurement of infarction volume by triphenyltetrazolium chloride histology. Results-PPBP attenuated infarction volume at 22 hours of reperfusion in cerebral cortex and striatum and markedly attenuated NO production in ischemic and nonischemic striatum during occlusion and early reperfusion. Treatment with 7-NI mimicked the effects of PPBP. In WT mice, infarction volume was robustly decreased by both PPBP and 7-NI, but the efficacy of PPBP was not altered by pharmacological nNOS inhibition in combined therapy. In contrast, PPBP did not decrease infarction volume in nNOSKO mice. Conclusions-These data suggest that the mechanism of neuroprotection of PPBP in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity. (Stroke. 2001;32: 1613-1620.)