Biomedical subjects

David S Warner

Publications and source records attributed to David S Warner.

At least 55 records · Page 3Linked to original sources

PubMed2003

Severe hypotension is not essential for isoflurane neuroprotection against forebrain ischemia in mice.

BACKGROUND: Volatile anesthetics provide protection in experimental models of global cerebral ischemia. To date, all models evaluated have included profound systemic arterial hypotension as a component of the ischemic insult. This study was designed to determine if isoflurane protection persists in a global insult devoid of hypotension. METHODS: C57BL/6J mice having a high incidence of posterior communicating artery atresia were anesthetized with isoflurane (1.2%) or fentanyl/N2O and subjected to bilateral carotid artery occlusion for 15 min or 20 min with normotension (80-110 mmHg mean arterial pressure) or for 10 min with hypotension (35 mmHg mean arterial pressure). Three days later, neurologic function and histologic damage were assessed. Other mice underwent measurement of intraischemic cerebral blood flow (4-iodo-N-methyl-[14C]antipyrine autoradiography) or plasma norepinephrine. RESULTS: Isoflurane reduced the percentage of hippocampal CA1 dead neurons (e.g., 10 min bilateral carotid occlusion + hypotension: 43 +/- 18 (isoflurane) vs. 67 +/- 20 (fentanyl/N2O), P = 0.003; 20 min bilateral carotid occlusion + normotension: 49 +/- 27 (isoflurane) vs. 71 +/- 22 (fentanyl/N2O), P = 0.003). Isoflurane also reduced CA3 damage and improved neurologic function under all conditions. Intraischemic forebrain blood flow was similar during bilateral carotid occlusion plus normotension for the two anesthetic states. Plasma norepinephrine values were greater when hypotension was added to the ischemic insult. CONCLUSIONS: Isoflurane resulted in improved neurologic function and reduced histologic damage regardless of the presence or absence of systemic hypotension during the ischemic insult. This indicates that beneficial effects of isoflurane are most likely attributable to direct effects at the neuronal level as opposed to indirect effects resulting from interactions with profound hypotension.

Anesthetics, Inhalation↗

PubMed2003

Lack of evidence for apoptosis as a cause of delayed onset paraplegia after spinal cord ischemia in rabbits.

UNLABELLED: The mechanisms for delayed onset paraplegia after transient spinal cord ischemia are not fully understood. We investigated whether apoptotic motor neuron death is involved in its development. Spinal cord ischemia was induced for 15 min by occlusion of the abdominal aorta in rabbits. At 8, 24, or 48 h after reperfusion, hind limb motor function was assessed, and the lumbar spinal cord was examined morphologically (hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining) and biochemically (breakdown products of alpha-fodrin and patterns of DNA changes). At each time point, 14 rabbits were studied (7 for histopathology and 7 for biochemical analysis). Six rabbits served as sham controls. Delayed motor dysfunction developed in two thirds of the rabbits. The motor neurons in the rabbits with motor dysfunction (not paraplegia) showed swelling and a finely granular dispersed Nissl substance. In paraplegic rabbits, destruction of the gray matter and prominent inflammatory cell infiltration were observed. No apoptotic motor neuron was found in any rabbit. There was neither detectable increase in a caspase-3-mediated breakdown product of alpha-fodrin, nor DNA laddering in any rabbit. The results suggest that apoptosis has a negligible role in the pathophysiology of delayed paraplegia in the spinal cord ischemia model examined. IMPLICATIONS: Although the possibility of apoptotic motor neuron death cannot be completely excluded, delayed onset paraplegia after transient spinal cord ischemia is largely associated with necrotic cell death.

Anesthesia↗

PubMed2003

gamma-Aminobutyric acid-A receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures.

UNLABELLED: The mechanisms by which anesthetics such as isoflurane reduce cell death in rodent models of cerebral ischemia remain incompletely defined. Reduction in glutamate excitotoxicity explains some but not all of isoflurane's neuroprotection. Because isoflurane potentiates gamma-aminobutyric acid (GABA) receptor-mediated ion fluxes and GABA(A) receptor agonists have neuroprotective effects, we hypothesized that GABA(A) receptors contribute to isoflurane neuroprotection. As a model of cerebral ischemia and recovery, we used rat hippocampal slice cultures. Survival of CA1, CA3, and dentate neurons was examined 2 and 3 days after 1-h combined oxygen-glucose deprivation (OGD) at 37 degrees C. To define the role of GABA(A) receptors in mediating protection, the effect of 1% isoflurane on cell survival was examined in the presence of the GABA(A) antagonist bicuculline during OGD. Cell death was measured with propidium iodide fluorescence. Isoflurane and the selective GABA(A) agonist muscimol (25 micro M) reduced cell death after OGD to values similar to slices not exposed to OGD, with the exception that muscimol did not reduce cell death in CA3 neurons 2 days after OGD. The GABA(A) antagonist bicuculline reduced the neuroprotective effects of isoflurane on hippocampal neurons 2 and 3 days after OGD. We conclude that GABA(A) receptors contribute to neuroprotection against OGD produced by isoflurane in the hippocampal slice model. Based on this and other studies, it is likely that neuroprotection produced by isoflurane is multifactorial and includes actions at both GABA(A) and glutamate receptors and possibly other mechanisms. IMPLICATIONS: Isoflurane is neuroprotective in rodent brain ischemia models, but the mechanisms for this effect remain incompletely defined. In organotypic cultures of rat hippocampus, we show that protection of CA1, CA3, and dentate neurons by 1% isoflurane from death caused by oxygen and glucose deprivation involves GABA(A) receptors.

Anesthetics, Inhalation↗

PubMed2003

Possible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: During vasospasm after subarachnoid hemorrhage (SAH), cerebral blood vessels show structural changes consistent with the actions of vascular mitogens. We measured platelet-derived vascular growth factors (PDGFs) in the cerebrospinal fluid (CSF) of patients after SAH and tested the effect of these factors on cerebral arteries in vivo and in vitro. METHODS: CSF was sampled from 14 patients after SAH, 6 patients not suffering SAH, and 8 normal controls. ELISA was performed for PDGF-AB, transforming growth factor-beta1, and vascular endothelial growth factor. A mouse model was used to compare cerebral vascular cell proliferation and PDGF staining in SAH compared with sham-operated controls. Normal human pial arteries were incubated for 7 days in vitro, 2 groups with human blood clot and 1 with and 1 without PDGF antibodies. RESULTS: PDGF-AB concentrations in CSF from SAH patients were significantly higher than those from non-SAH patients and normal controls, both during the first week after SAH and for all time points measured. Smooth muscle and fibroblast proliferation was observed after SAH in the mouse model, and this cellular replication was observed in conjunction with PDGF protein at the sites of thrombus. In human pial arteries, localized thrombus stimulated vessel wall proliferation, and proliferation was blocked by neutralizing antibodies directed against PDGFs. CONCLUSIONS: Vascular mitogens are increased in the CSF of patients after SAH. Proliferation of cells in the vascular wall is associated with perivascular thrombus. Cellular proliferation and subsequent vessel wall thickening may contribute to the syndrome of delayed cerebral vasospasm.

Adolescent↗

PubMed2002

Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity.

Superoxide plays a role in blood pressure regulation in certain vascular diseases, however, its involvement in regulating basal blood pressure is uncertain. Vascular superoxide concentrations are limited by extracellular superoxide dismutase (EC-SOD), which is highly expressed in the vasculature of most animal species. Metalloporphyrins are low molecular weight, synthetic, redox-active, catalytic antioxidants that act as SOD mimetics. We evaluated the effects of metalloporphyrins on blood pressure in different animal species. The metalloporphyrin AEOL10113 (5-10 micro /kg iv), but not native or polyethylene glycol-CuZnSOD, caused a dose-dependent reduction in blood pressure in anesthetized rats. AEOL10113 had no effect on blood pressure in mice (wild-type or EC-SOD knockouts), guinea pigs, dogs, or baboons at doses up to 5 mg/kg iv Structure-activity studies indicated that metalloporphyrins with high SOD activity were more effective in lowering rat blood pressure than low-activity analogs. The blood pressure effect of AEOL10113 was not attributable to the release of manganese, nor was it affected by inhibitors of nitric oxide synthase (L-NAME) and guanylate cyclase (ODQ, 8-bromo-cGMP, and methylene blue) or nitric oxide scavengers (HbAo). Chlorpheniramine attenuated the effect, suggesting that the blood pressure response in rats is related to histamine release rather than the protection of nitric oxide.

Animals↗

PubMed2002

A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke.

Oxidative stress is a major source of injury from cerebral ischemia and reperfusion. We hypothesized that a catalytic antioxidant AEOL 10150 [manganese (III) meso-tetrakis (di-N-ethylimidazole) porphyrin] would attenuate changes in brain gene expression in a mouse model of transient middle cerebral artery occlusion (MCAO). C57BL/6J mice were subjected to either sham surgery or 60 min of right MCAO. AEOL 10150 or phosphate-buffered saline was given intravenously 5 min after onset of reperfusion (n = 6 per group). Six hours later, parenchyma within the MCA distribution was harvested. RNA from the six brains in each group was pooled and mRNA expression determined using an Affymetrix murine MG_U74A v. 2.0 expression microarray. Each experiment was performed three times. The largest changes in expression occurred in stress response and inflammatory genes such as heat shock protein, interleukin-6, and macrophage inflammatory protein-2. Treatment with AEOL 10150 attenuated only the increase in expression of inflammatory genes. This suggests that AEOL 10150 protects brain by attenuating the immune response to ischemia and reperfusion.

Animals↗

PubMed2002

Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia.

Reactive oxygen species play a role in the response of brain to ischemia. The effects of metalloporphyrin catalytic antioxidants (AEOL 10113 and AEOL 10150) were examined after murine middle cerebral artery occlusion (MCAO). Ninety minutes after reperfusion from 90 min MCAO in the rat, AEOL 10113, AEOL 10150, or vehicle were given intracerebroventricularly. AEOL 10113 and AEOL 10150 similarly reduced infarct size (35%) and neurologic deficit. AEOL 10113 caused behavioral side effects at twice the neuroprotective dose while AEOL 10150 required a 15-fold increase from the neuroprotective dose to cause behavioral changes. AEOL 10150, given 6 h after 90 min MCAO, reduced total infarct size by 43% without temperature effects. Brain AEOL 10150 elimination t(1/2) was 10 h. In the mouse, intravenous AEOL 10150 infusion post-MCAO reduced both infarct size (25%) and neurologic deficit. Brain AEOL 10150 uptake, greater in the ischemic hemisphere, was dose- and time-dependent. AEOL 10150 had direct effects on proteomic events and ameliorated changes caused by ischemia. In primary mixed neuronal/glial cultures exposed to 2 h of O(2)/glucose deprivation, AEOL 10150 reduced lactate dehydrogenase release dose-dependently and selectively preserved aconitase activity in concentrations consistent with neuroprotection in vivo. AEOL 10150 is an effective neuroprotective compound offering a wide therapeutic window with a large margin of safety against adverse behavioral side effects.

Animals↗

PubMed2002

Allopregnanolone attenuates N-methyl-D-aspartate-induced excitotoxicity and apoptosis in the human NT2 cell line in culture.

Progesterone modulates gamma-aminobutyric acid and excitatory amino acid neurotransmitter systems and has neuroprotective properties in models of hypoxia-ischemia. This study examined the in vitro effects of allopregnanolone, the active progesterone metabolite, in models of N-methyl-D-aspartate (NMDA)-induced necrosis and apoptosis. Cultured NT2 neurons were exposed to 1 mM NMDA. Lactate dehydrogenase (LDH) release was measured 24 h later. NMDA at a concentration of 1 mM produced a 39 +/- 19% release of total LDH. Exposure to 10 microM allopregnanolone prior to NMDA exposure reduced LDH release by 51% (P = 0.0028). NMDA stimulated apoptotic cell changes defined by terminal dUTP nick-end labeling (TUNEL) and 5,5', 6,6'-tetrachloro-1,1,3,3'-tetra ethlybenzimidazolycarbocyanide iodide staining were reduced to baseline values by both 10 microM allopregnanolone and 100 microM MK-801. Pretreatment with allopregnanolone (0-10 microM) reduced the percentage of TUNEL-positive cells in a dose-dependent manner (EC(50) = 2.7 +/- 0.1 nM). Physiologic concentrations of allopregnanolone provided protection against both necrotic and apoptotic injury induced by NMDA excitotoxicity.

Apoptosis↗

PubMed2002

Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema.

Apolipoprotein E has been implicated in modifying neurological outcome after traumatic brain injury, although the mechanisms by which this occurs remain poorly defined. To investigate the role of endogenous apolipoprotein E following acute brain injury, noninvasive magnetic resonance imaging was performed on anesthetized mice following closed head injury. Effacement of the lateral ventricle was used as a radiographic surrogate for cerebral edema. At 24 hours following injury, apolipoprotein E-deficient animals had a greater degree of cerebral edema as compared to matched controls. In addition, the brains of apolipoprotein E-deficient animals had a significantly greater upregulation of tissue necrosis factor alpha messenger ribonucleic acid as compared to controls as early as 1-hr post injury. Thus, modulation of the endogenous central nervous system inflammatory response may be one mechanism by which apolipoprotein E affects outcome following acute brain injury.

Acute Disease↗

PubMed2002

Apolipoprotein E protects against NMDA excitotoxicity.

Preclinical and clinical evidence implicates a role for endogenous apolipoprotein E in modifying the response of the brain to focal and global ischemia. To investigate whether apoE modulates the neuronal response to glutamate excitotoxicity, we exposed primary neuronal glial cultures and a neuronal cell line to biologically relevant concentrations of apolipoprotein E prior to NMDA exposure. In both of these paradigms, apolipoprotein E exerted partial protective effects. At neuroprotective concentrations, however, apolipoprotein E failed to block NMDA-induced calcium influx to the same magnitude as the NMDA receptor antagonist MK-801. These results suggest that one mechanism by which apolipoprotein E modifies the central nervous system response to ischemia may be by reducing glutamate-induced excitotoxicity.

Animals↗

PubMed2002

A comparison of the remifentanil and fentanyl adverse effect profile in a multicenter phase IV study.

STUDY OBJECTIVE: To compare the frequency of adverse effects of remifentanil and fentanyl in a large and diverse patient population. DESIGN: Prospective, randomized, open-label study. SETTING: Multicenter study including academic and community hospitals. PATIENTS: 2,438 adult patients (1,496 outpatients and 942 inpatients) scheduled for elective surgical procedures under general endotracheal anesthesia of at least 30-minute duration. INTERVENTIONS: Patients were randomly assigned to receive either intravenous (IV) remifentanil (n = 1,229) 0.5 microg/kg/min for induction and tracheal intubation followed by an infusion rate of 0.25 microg/kg/min or fentanyl (n = 1,209) administered according to the anesthesiologist's usual practice. Anesthesia was maintained with propofol and/or isoflurane (with or without nitrous oxide) titrated according to protocol. Transition analgesia with either morphine or fentanyl was administered in the remifentanil and, at the anesthesiologist's discretion, in the fentanyl group. MEASUREMENTS: The overall nonspecific and specific (i.e., opioid-related) adverse effects were recorded. MAIN RESULTS: Remifentanil was associated with more intraoperative hypotension than fentanyl (p < 0.05). All four cases (0.3%) of muscle rigidity occurred in the remifentanil-treated outpatients. There were no significant differences between the two drugs with respect to other adverse events (i.e., episodes of hypertension, bradycardia, respiratory depression, and apnea). CONCLUSIONS: In the doses used, both remifentanil and fentanyl have a similar frequency of adverse effects except for the higher frequency of hypotension associated with the use of remifentanil.

Adult↗

PubMed2002

Ambulatory discharge after long-acting peripheral nerve blockade: 2382 blocks with ropivacaine.

UNLABELLED: Discharging patients with a long-acting peripheral nerve block remains controversial. Concerns about accidental injury of the limb or surgical site because of an insensate extremity are common despite a lack of data on the subject. We report a study examining the efficacy and complications of discharge after long-acting block. This prospective study included 1791 patients receiving an upper or lower extremity nerve block with 0.5% ropivacaine and discharged the day of surgery. Efficacy (conversion to general anesthesia and opioid use), persistent motor or sensory weakness, complications, satisfaction, and unscheduled health care visits were assessed in the postanesthesia care unit (PACU) and at 24 h and 7 days postoperatively using a detailed questionnaire. There were 2382 blocks placed: 1119 upper extremity blocks and 1263 lower extremity blocks. Efficacy was demonstrated by a small conversion to general anesthesia (1%-6%) and a lack of patients requiring opioids in the PACU (89%-92%). A large percentage of patients continued to use opioids at 7 days (17%-22%). Despite the requirement for opioids, satisfaction with the anesthesia experience was high at 24 h and 7 days (Liekert scale [1-5] mean at 24 h, 4.88 +/- 0.44; mean at 7 days, 4.77 +/- 0.69) and most (98%) would choose the same anesthetic again. Thirty-seven patients (1.6%) were identified with symptoms or complaints at 7 days. After review, 6 of them (0.25%) had a persistent paresthesia that may have been related to the block or discharge. We conclude that long-acting peripheral nerve blockade may be safely used in the ambulatory setting with a high degree of efficacy, safety, and satisfaction. This technique is associated with an infrequent incidence of neurologic complications and injuries. Given the frequent incidence of persistent pain at 7 days, prolongation of the analgesia would be beneficial. IMPLICATIONS: This study demonstrates that long-acting peripheral nerve blockade may be safely used in the ambulatory setting with a high degree of efficacy and satisfaction. This technique is associated with an infrequent incidence of neurologic complications and injuries despite discharge with an insensate extremity. The frequent incidence of pain at 7 days suggests that longer-acting local anesthetics are still needed.

Ambulatory Surgical Procedures↗

PubMed2002

Peripheral nerve blockade with long-acting local anesthetics: a survey of the Society for Ambulatory Anesthesia.

UNLABELLED: Despite the growth of ambulatory anesthesia and the renewed popularity of regional techniques, there is little current information concerning outpatient regional anesthesia practices or attitudes about discharge with an insensate extremity. We present results from a survey sent to all members of the Society for Ambulatory Anesthesia (SAMBA). The survey was mailed in January 2001 to 2373 SAMBA members, along with a self-addressed stamped return envelope. After 3 mo, 1078 surveys were returned (response rate 45%). Respondents indicated that they were most likely to perform axillary (77%), interscalene (67%), and ankle blocks (68%) on ambulatory patients. They were less likely to perform lower extremity conduction blocks in ambulatory patients (femoral blocks, 40%; all other types of blocks, <23%]. Eighty-five percent of respondents discharged patients with long-acting blocks, but this was mainly limited to three types. Of the 16% who never or rarely discharged patients with long-acting blocks, the primary reasons were concern about patient injury (49%) and the inability for patients to care for themselves (28%). Only 22% of office-based anesthesiologists would perform upper extremity blocks and only 28% would perform lower extremity blocks (P < 0.001). This survey demonstrates that use of regional anesthesia in outpatients is common but restricted to a few techniques. Discharge with an insensate upper extremity is prevalent but discharge with an insensate lower extremity is not common and remains controversial. Despite the reasoning for the reported practices, randomized data are necessary to confirm the validity of these concerns. IMPLICATIONS: This survey demonstrates that use of regional anesthesia in outpatients is common but restricted to a few techniques. Discharge with an insensate upper extremity is common but discharge with an insensate lower extremity is not prevalent and remains controversial.

Adult↗

PubMed2002

Differential cerebral gene expression during cardiopulmonary bypass in the rat: evidence for apoptosis?

UNLABELLED: Cardiopulmonary bypass (CPB) is associated with a spectrum of cerebral injuries. The molecular changes in the brain that might contribute to these injuries are not clearly known. We sought to determine whether the expression of apoptotic genes is increased after CPB in the rat. Rats (n = 7) were subjected to 90 min of normothermic CPB. A group of sham-operated rats (n = 7) served as non-CPB controls. After a 3-h post-CPB period of recovery, their brains were removed, homogenized, and processed for messenger RNA (mRNA) extraction. By using a ribonuclease protection assay, the ratios of both pro- and antiapoptotic mRNA (bcl-x, bcl-2, bax, caspase 2, and caspase 3) to the housekeeping glyceraldehyde phosphate dehydrogenase (GAPDH) gene were determined. Additionally, Western immunoblotting was performed to detect the presence of activated caspase 3, a protein central in the apoptotic process. Compared with the non-CPB controls, the CPB group had significantly increased levels of apoptotic/GAPDH mRNA ratios (bcl-x, 0.414 +/- 0.152 CPB versus 0.251 +/- 0.051 non-CPB, P = 0.048; caspase 2, 0.030 +/- 0.014 CPB versus 0.018 +/- 0.005 non-CPB, P = 0.048; bax, 0.106 +/- 0.035 CPB versus 0.066 +/- 0.009 non-CPB, P = 0.009; bcl-2, 0.011 +/- 0.006 CPB versus 0.006 +/- 0.002 non-CPB, P = 0.035). However, no activated caspase 3 protein was detected in either group. Elucidating the molecular biological sequelae of CPB may aid in the understanding of the pathophysiology of cardiac surgery-associated cerebral injury and, in doing so, may be useful in identifying potential therapeutic targets for pharmacologic neuroprotection. IMPLICATIONS: Cardiopulmonary bypass (CPB) appears to induce transcription of pro- and antiapoptotic genes in the rat brain, but caspase-mediated apoptosis itself does not appear to be activated. Elucidating the molecular biological sequelae of CPB may aid in the understanding of the pathophysiology of cardiac surgery-associated cerebral injury and, in doing so, may be useful in identifying potential therapeutic targets for pharmacologic neuroprotection.

Anesthesia↗

PubMed2002

Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Endothelial damage and intimal proliferation occur in vasospastic cerebral arteries after subarachnoid hemorrhage (SAH). In the peripheral vasculature, endothelial damage increases intimal matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) levels, causing neointimal proliferation. We hypothesized that serum von Willebrand factor (vWF) (a marker of endothelial cell death), MMP-9, and VEGF levels could serve as prognostic markers in predicting the occurrence of cerebral vasospasm. METHODS: Venous serum vWF, MMP-9, and VEGF levels were prospectively measured daily, for 12 days or until the onset of vasospasm, for 45 consecutive patients admitted with SAH (n = 38) or admitted for elective aneurysm clipping (control subjects, n = 7). The development of transcranial Doppler flow velocities of more than 180 cm/s and/or new focal neurological deficits with angiographically confirmed vasospasm was considered the onset of vasospasm. To establish whether these markers were specific for vasospasm versus ischemia, blood samples were obtained from a concurrent group of 42 patients within 24 hours after stroke onset unrelated to SAH. RESULTS: Fifty-seven percent of patients (22 of 38 patients) developed vasospasm, 4 to 11 days after SAH (median, 7 d). Mean peak serum vWF, MMP-9, and VEGF levels were increased in the SAH prevasospasm cohort, compared with the SAH nonvasospasm cohort (vWF, 5526 +/- 929 versus 4934 +/- 599 ng/ml, P = 0.01; MMP-9, 705 +/- 338 versus 438 +/- 154 ng/ml, P = 0.006; VEGF, 0.12 +/- 0.06 versus 0.06 +/- 0.06 ng/ml, P = 0.023). Mean peak vWF, MMP-9, and VEGF levels for the focal ischemia cohort (vWF, 4645 +/- 875 ng/ml, P = 0.01; MMP-9, 250 +/- 308 ng/ml, P = 0.001; VEGF, 0.03 +/- 0.04 ng/ml, P = 0.001) were markedly lower in comparison with the SAH prevasospasm cohort and were unchanged in comparison with the control cohort. vWF levels of more than 5500 ng/ml, VEGF levels of more than 0.12 ng/ml, and MMP levels of more than 700 ng/ml each independently increased the odds of subsequent vasospasm (18-, 20-, and 25-fold, respectively). CONCLUSION: The development of cerebral vasospasm after SAH was preceded by increases in serum vWF, MMP-9, and VEGF levels. Increased serum vWF, MMP-9, and VEGF levels could accurately predict the onset of cerebral vasospasm after SAH. These factors were not elevated by SAH alone or in a separate cohort of patients with ischemic stroke, suggesting that these factors might play a role in the pathogenesis of human cerebral vasospasm.

Aged↗

PubMed2002

A randomized, double-blind comparison of ondansetron versus placebo for prevention of nausea and vomiting after infratentorial craniotomy.

Ondansetron was compared with placebo for nausea and vomiting prophylaxis after fentanyl/isoflurane/relaxant anesthesia and infratentorial craniotomy. Eight milligrams intravenous ondansetron or vehicle was administered at skin closure. Nausea, emesis, and antiemetic use were recorded at 0, 0.5, 1, 4, 8, 12, 24, and 48 hours. There were no significant intergroup differences for nausea incidence at any interval, but cumulatively the placebo group was 3.2 times more likely to develop nausea during the first 12 hours (P = .04). Nausea incidence was bimodal in both groups, peaking during the first 1 to 4 hours. A nadir occurred at 8 to 12 hours, but nausea increased during the next 36 hours. By 48 hours, approximately 40% of patients in both groups were still nauseated. Reduced vomiting frequency was seen with ondansetron at 4, 8, 12, and 24 hours (P < .05). Despite rescue antiemetics, emesis occurred in an irregular pattern with episodes still observed in 35% of placebo patients at 48 hours. For ondansetron, emesis was infrequent for the first 12 hours but then a persistent increase was observed (48 hours, 22%). The incidence of rescue antiemetic use was 65% for both groups. There was no effect of gender. Nausea and vomiting are frequent and protracted after infratentorial craniotomy. Administration of single-dose ondansetron (8 mg intravenously) at wound closure was partially effective in reducing acute nausea and vomiting but had little delayed benefit. Scheduled prophylactic administration of antiemetic therapy during the first 48 hours after infratentorial craniotomy should be evaluated for efficacy and safety.

Adolescent↗

PubMed2002

Pharmacological correction of hypothermic P(50) shift does not alter outcome from focal cerebral ischemia in rats.

Hypothermia decreases the arterial PO(2) at which hemoglobin is 50% saturated (P(50)), increasing hemoglobin O(2)-binding affinity. We used RSR13, a synthetic allosteric modifier of hemoglobin that increases P(50), to study the role of altered hemoglobin O(2)-binding affinity in mild hypothermic neuroprotection. RSR13 (150 mg/kg iv) restored P(50) to normothermic values. Rats underwent 70 min of middle cerebral artery occlusion (MCAO) at 30.0, 34.0, or 37.5 degrees C with hemoglobin saturation held at 98-100%. The 34.0 degrees C group received RSR13 or vehicle before ischemia. After 7 days of recovery, infarct volumes were reduced in all hypothermic groups, without evidence of a detrimental effect on infarct size or neurological score as a result of P(50) correction. To examine for a beneficial effect of P(50) correction, ischemia duration was increased to 120 min in rats maintained at 34.0 degrees C. Correction of P(50) by RSR13 did not alter cerebral infarct sizes or neurological scores. The decrease in P(50), caused by mild hypothermia, could not be associated with infarct size or neurological deficit resulting from ischemic brain hypoxia in rats.

Aniline Compounds↗

PubMed2002

Attenuation of cerebral vasospasm after subarachnoid hemorrhage in mice overexpressing extracellular superoxide dismutase.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) increases production of vascular extracellular superoxide anion (*O2-). We examined whether overexpression of murine extracellular superoxide dismutase (EC-SOD) alters SAH-induced cerebral vasospasm, oxidative stress, and neurological outcome. METHODS: Mice exhibiting a 2-fold increase in vascular EC-SOD and wild-type (WT) littermates were subjected to sham surgery or SAH by perforation of the right anterior cerebral artery. Neurological deficits were scored 72 hours later. Middle cerebral artery (MCA) diameter was measured or immunohistochemically stained for nitrotyrosine. RESULTS: MCA diameter (mean+/-SD) was greater in EC-SOD versus WT mice after SAH but not sham surgery (EC-SOD SAH=56+/-10 microm; WT SAH=38+/-13 microm [P<0.01]; EC-SOD sham=99+/-16 microm; WT sham=100+/-15 microm). SAH decreased median (range) neurological score (scoring scale, 9 to 39; no deficit=39) versus shams, but there was no difference between EC-SOD and WT groups (EC-SOD SAH=26 [23 to 30]; WT SAH=23 [19 to 29] [P=0.27]; EC-SOD sham=39 [39]; WT sham=39 [39]). Sensory-motor deficits correlated with MCA diameter (P<0.001) but worsened primarily between 60 and 50 micro m, plateauing below this threshold. The percentage of mice with MCA nitrotyrosine staining increased after SAH in WT (sham=29%; SAH=100% [P<0.05]) but not EC-SOD (sham=33%; SAH=44% [P=0.80]) mice. CONCLUSIONS: Endogenous overexpression of EC-SOD attenuated vasospasm and oxidative stress but failed to reduce neurological deficits after SAH. Extracellular *O2- likely plays a direct role in the etiology of vasospasm.

Animals↗