David S. Warner

Oxidants, antioxidants and the ischemic brain

SUMMARY Despite numerous defenses, the brain is vulnerable to oxidative stress resulting from ischemia/reperfusion. Excitotoxic stimulation of superoxide and nitric oxide production leads to formation of highly reactive products, including peroxynitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Use of transgenic mutants and selective pharmacological antioxidants has greatly increased understanding of the complex interplay between substrate deprivation and ischemic outcome. Recent evidence that reactive oxygen/nitrogen species play a critical role in initiation of apoptosis, mitochondrial permeability transition and poly(ADP-ribose) polymerase activation provides additional mechanisms for oxidative damage and new targets for post-ischemic therapeutic intervention. Because oxidative stress involves multiple post-ischemic cascades leading to cell death, effective prevention/treatment of ischemic brain injury is likely to require intervention at multiple effect sites.

Simvastatin Reduces Vasospasm After Aneurysmal Subarachnoid Hemorrhage: Results of a Pilot Randomized Clinical Trial

Background and Purpose— Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH. Methods— Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of ≥1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean VMCA >160 m/sec). Results— There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100&bgr; were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103±41 versus 149±47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20). Conclusion— The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.

Interscalene brachial plexus block with a continuous catheter insertion system and a disposable infusion pump.

Continuous interscalene brachial plexus blockade traditionally requires a hospital stay for local anesthetic infusion, and achieving consistent catheter insertion may be difficult. Incorporating long-acting pain relief from a continuous peripheral nerve block, with a reliable method of catheter insertion, and a self-contained infusion system would be a valuable asset for short-stay care. We compared the efficacy of single injection interscalene brachial plexus blockade to a continuous peripheral nerve block, with an insulated Tuohy system and a disposable infusion pump. Forty adult patients scheduled for open rotator cuff repair were entered in this randomized, double-blinded, placebo-controlled study. Patients received an interscalene brachial plexus blockade and a continuous peripheral nerve catheter as their primary anesthetic and then, were assigned to receive one of two different postoperative infusions: either 0.2% ropivacaine at 10 mL/h via a disposable infusion pump or normal saline at 10 mL/h via a disposable infusion pump (n = 18–20 per group). Visual analog pain scores and postoperative morphine consumption were measured for 24 h. The ropivacaine group showed less pain than the placebo group (P = 0.0001) between 12 and 24 h after the initial injection of local anesthetic. In addition, initial interscalene blockade was successful in all patients and all redosed catheters were functional after 24 h with the continuous catheter insertion system. We conclude that it is possible to achieve a high rate of successful catheter placement and analgesia by using the continuous catheter insertion system and a disposable infusion pump in the ambulatory setting. This method of analgesia may offer improved pain relief after outpatient rotator cuff repair. Implications This study demonstrates that it is possible to achieve successful interscalene brachial plexus continuous catheter insertion and a high degree of persistent analgesia by using a catheter insertion system and a disposable infusion pump administering 0.2% ropivacaine.

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Background and Purpose— Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods— Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. Results— In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatin=74±22 &mgr;m, SAH-vehicle=52±18 &mgr;m, P =0.03; sham-simvastatin=102±8 &mgr;m, sham-vehicle=105±6 &mgr;m). Pretreatment reduced neurological deficits (SAH-simvastatin=25±2, SAH-vehicle=20±2, P =0.005; sham-simvastatin and sham-vehicle=27±0). Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatin=56±12 &mgr;m, SAH-vehicle=45±4 &mgr;m, P =0.03; sham-simvastatin=92±13 &mgr;m, sham-vehicle=99±10 &mgr;m) and reduced neurological deficits (SAH-simvastatin=21±1, SAH-vehicle=19±2, P =0.009). Simvastatin posttreatment did not significantly increase eNOS protein. Conclusions— Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice. The mechanism may be attributable in part to eNOS upregulation.

Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats.

Background and Purpose Mild hypothermia (32–35°C) has been repeatedly shown in laboratory models to reduce damage resulting from global cerebral ischemic insults. Little information is available, however, regarding the protective potential of mild hypothermia against focal ischemia. We designed the present study to determine whether mild hypothermia influences outcome from either temporary or permanent middle cerebral artery occlusion in the rat Methods In experiment 1 (permanent occlusion), mechanically ventilated, halothane-anesthetized spontaneously hypertensive rats underwent permanent ligation of the middle cerebral artery. Pericranial temperature was maintained at either 37°C (n11) or 33°C (n=ll) during the first 2 hours of occlusion. In experiment 2 (temporary occlusion), the vessel was occluded for 1 hour only. Pericranial temperature was controlled at either 37°C (n=12) or 33°C (n= 14) during ischemia and for 1 hour after reperfusion. In both experiments, the rats were allowed to recover, with neurological function scored at 24 and 96 hours after onset of ischemia. Cerebral infarct volume (as determined by nitro blue tetrazolium staining) was planimetrically evaluated 96 hours after onset of ischemia. Results No difference in infarct volume was observed between groups undergoing permanent occlusion (177±53 mm3 for 37°C rats, 167±71 mm3 for 33°C rats [mean±SD]). Although neurologic function correlated with infarct volume at 96 hours (all animals in experiment 1 combined; p<0.01), we were unable to demonstrate an intergroup difference in function. In animals undergoing temporary occlusion, mean±SD infarct volume was 48% less in the hypothermic group (89±54 mm3 for 37°C, 46±31 mm3 for 33°C; p<0.03). Neurological function again correlated with infarct size (p<0.02), but improvement in function approached significance for the hypothermic group (p<0.06) at 24 hours after reperfusion only. Conclusions Benefits from mild hypothermia may be obtained under conditions of temporary but not permanent middle cerebral artery occlusion in the rat

A prospective, comparative trial of three anesthetics for elective supratentorial craniotomy : propofol/fentanyl, isoflurane/nitrous oxide, and fentanyl/nitrous oxide

Background:Different anesthetic agents have different effects on cerebrovascular physiology. However, the importance of these differences In neuroanesthetic practice are unclear. In an effort to determine whether important clinical differences are present, the authors compared three anesthetic techniques in 121 adults undergoing elective surgical removal of a supratentorial, intracranial mass lesion. Methods:Patients were assigned randomly to one of three groups. In group 1 (n=40), anesthesia was induced with propofol and maintained with fentanyl (≊10 µg/kg load, 2-3 µg · kg-1 · h-1 infusion) and propofol (50-300 µg · kg-1 · mln-1). In group 2 (n=40), anesthesia was induced with thiopental and maintained with isoflurane and nitrous oxide. Up to 2 µg/kg fentanyl was given after replacement of the bone flap. In group 3 (n=41), anesthesia was induced with thiopental and maintained with fentanyl (≊10 µg/kg load, 2-3 µg · kg-1 · h1 infusion), nitrous oxide, and low-dose Isoflurane, if required. Blood pressure, heart rate, expired gas concentrations, and ventilatory parameters were recorded automatically in all patients. Epidural intracranial pressure (ICP) was measured via the first burr hole, brain swelling was rated at the time of dural opening, and emergence was monitored closely. Preoperative computed tomography or magnetic resonance imaging scans were evaluated, and pre- and postoperative neurologic exams were performed by a neurosurgeon unaware of group assignments. Total hospital stay (days) and total hospital cost (exclusive of physician charges) also were reviewed. Results:During induction, higher heart rates were seen in isoflurane/nitrous oxide patients, whereas mean arterial pressure was ≊10 mmHg less during the maintenance phase (compared with both other groups). Otherwise, there were few intergroup hemodynamic differences. While there were no clinically important intergroup differences in mean ICP (±SD)—group 1, ICP=12 ± 7 mmHg; group 2,15 ± 12 mmHg; group 3, ICP=11 ± 8 mmHg—more isoflurane/nitrous oxide patients (nine, group 2) had an ICP £24 mmHg than in the other groups (two each). Emergence was, overall, more rapid with fentanyl/nitrous oxide. For example, the median time until the patient could be awakened by quiet verbal command, e.g., “Open your eyes,” was 5 min, versus 10 min in the other groups. There were no relationships between ICP and any measurement of emergence (e.g., time to response to commands). Seven of 41 (17%) fentanyl/nitrous oxide patients vomited In the early postoperative period, compared with only 1 of 40 (2.5%) of those given propofol/fentanyl and 2 of 40 (5%) receiving isoflurane/nitrous oxide (P=0.03). There were no differences in the incidence of new postoperative deficits, total hospital stay, or cost. Conclusions:Although there are modest differences among the three tested anesthetics, short-term outcome was not affected. These results indicate that, despite their respective cerebrovascular effects, all of the anesthetic regimens used were acceptable in these patients undergoing elective surgery.

Sevoflurane and halothane reduce focal ischemic brain damage in the rat : possible influence on thermoregulation

BackgroundThere has been little systematic examination concerning the comparative effects of the anesthetized versus the awake state on outcome from cerebral ischemia. This experiment evaluated infart volume and neurologic function in rats subjected to temporary focal ishemia while anesthetized with either sevoflurane or halothane. Outcome in these animals was compared to that observed in rats maintained unanesthetized during a similar ischemic insult. MethodsAll rats were anesthetized with halothane and surgically prepared for filament occlusion of the middle cerebral artery. After preparation, one group (Halothane) remained anesthetized with approximately 1.4 MAC halothane. In another group (Sevoflurane), halothane was discontinued and substituted with sevoflurane, which was administered until electroencephalographic burst suppression was evident (approximately 1.4 MAC). The final group (A wake) was allowed to awaken immediately after the onset of ischemia. Middle cerebral artery occlusion persisted for 90 min all groups. The middle cerebral artery filament then was removed, and a 96-h survival interval was allowed. Neurologic function and infarct volume were determined. Recent evidence indicates that transient mild hyperthermia occurs in awake rats undergoing filament occlusion of the middle cerebral artery. To examine the potential role of mild hyperthermia in this experiment, a second experiment was performed in which rats anesthetized with halothane underwent 90-min focal ischemia, with pericranial temperatures held at either 38.0° C or 39.2° C. ResultsIntraischemic mean arterial pressure was 20–25 mmHg lower in the two anesthetized groups compared with awake animals. Despite this finding, cortical infarct volumes (mean ± SD; Halothane, 17 ± 32 mm3; Sevoflurane, 36 ± 57 mm3; Awake, 115 ± 104 mm3) and subcortical infarct volumes (mean ±:SD; Halothane, 39 ± 57 mm3; Sevoflurane, 50 ± 29 mm3; Awake, 88 ± 46 mm3) were reduced in both groups of anesthetized rats. This reduction correlated with improved neurologic function. The rats in whom the pericranial temperature was maintained at 39.2° C had a larger total infarct volume (218 ± 81 mm3) and increased neurologic deficits when compared to those in whom the pericranial temperature was maintained at 38.0° C (total infarct volume, 75 ± 77 mm3). ConclusionsBoth halothane and sevoflurane substantially reduced damage in this focal ischemia model when compared to outcome resulting from the same insult induced in awake rats. The reduction in intraischemic mean arterial pressure caused by the anesthetics did not seem contributory to out-come. Brain temperature differences among the groups were not defined. Because small differences in pericranial temperature were shown to have major effects on outcome, further work is required to determine if differences in brain temperature explain the observed protective effects of these anesthetics.

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

BackgroundRemifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.MethodsSixty-three adults gave written informed consent for

Brain Oxygenation and Energy Metabolism: Part I—Biological Function and Pathophysiology

CONTINUOUS OXYGEN DELIVERY and CO2 clearance are paramount in the maintenance of normal brain function and tissue integrity. Under normal conditions, aerobic metabolism is the major source of energy in the brain, but this system may be compromised by the interruption of substrate delivery and disturbances in cerebral metabolism. These disruptions are major factors contributing to ischemic and hypoxic brain damage resulting from traumatic brain injury, stroke, and subarachnoid hemorrhage. There is evidence that mitochondrial function also is reduced after injury. Furthermore, early impairment of cerebral blood flow in patients with severe injury correlates with poor tissue oxygenation and may be an important parameter in secondary damage. Recent advances in brain tissue monitoring in the intensive care unit and operating room have made it possible to continuously measure tissue oxygen tension and temperature, as well as certain aspects of brain metabolism and neurochemistry. Therefore, it is important to understand the physiological process and the pathophysiology produced by these events. This is Part I of a two-part review that analyzes the physiology of cerebral oxygenation and metabolism as well as some of the pathological mechanisms involved in ischemic and traumatic brain injuries. Brain tissue monitoring techniques will be examined in the second article of this two-part series. To understand cerebral oxygenation, it is important to understand cerebral blood flow, energy production, ischemia, acidosis, generation of reactive oxygen species, and mitochondrial failure. These issues provide the basis of knowledge regarding brain bioenergetics and are important topics to understand when developing new approaches to patient care.

Apolipoprotein E-Deficient Mice Have Increased Susceptibility To Focal Cerebral Ischemia

Recent evidence suggests that apolipoprotein E (ApoE) plays a role in neurologic disease. This experiment compared the neurologic and histologic outcome of ApoE-deficient mutant and wild-type mice subjected to a 60- or 90-minute episode of middle cerebral artery filament occlusion and a recovery interval of 24 hours. With 60 minutes of ischemia, there was no mortality. Apolipoprotein E-deficient mice had larger infarcts (cortex: ApoE deficient = 20 mm3 ± 12, wild-type = 9 ± 7 mm3, P = 0.03; subcortex: ApoE deficient = 22 ± 7 mm3, wild-type = 16 ± 7 mm3, P = 0.07). Hemiparesis was less severe in wild-type animals (P = 0.02). After 90 minutes of ischemia, mortality in ApoE-deficient mice (n = 10) was 40% versus 0% in wild-type mice (n = 10; P = 0.09). Intraparenchymal hemorrhage was found in 3 of the 4 dead mice. No difference in cortical (ApoE deficient = 37 ± 8 mm3; wild-type = 31 ± 18 mm3; P = 0.49) or subcortical (ApoE deficient = 30 ± 11 mm3; wild-type = 32 ± 18 mm3; P = 0.78) infarct volumes was present among survivors. ApoE-deficient mice had a prolonged activated partial thromboplastin time and increased fibrinogen concentration. This data supports the hypothesis that apolipoprotein E plays a role in the pathophysiology of ischemic brain damage.