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David S Warner

Publications and source records attributed to David S Warner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures.

Prolonged exposure of postnatal day (PND) 7 rat pups to anesthetics, which act via N-methyl-D-aspartate antagonism and/or gamma-amino butyric acid enhancement, causes neurodegeneration and persistent behavioral deficits. We studied these findings in vitro and determined whether the age of rat pups used for study or duration of anesthetic exposure modulates resultant neurodegeneration. Organotypic hippocampal slices (OHSs) were prepared from rat pups on PNDs 4, 7, and 14 and cultured 7 or 14 days in vitro. The slices were exposed to 1.5% isoflurane or fresh gas for durations of 1, 3, or 5 h. Hippocampal CA1, CA3, and dentate gyrus neuronal survival was assessed 3 days later. Neuronal cell death was greatest in OHSs prepared from PND 7 rat pups (P < 0.001) and was most evident after 5 h exposure to isoflurane (P < 0.001). By eliminating variables such as hemodynamics, nutrition, oxygenation, and carbon dioxide elimination, this in vitro investigation supports both an age- and duration-dependent relationship between 1.5% isoflurane exposure and perinatal neuronal death.

Anesthetics, Inhalation↗
PubMed2005

Peripheral nerve block techniques for ambulatory surgery.

Peripheral nerve blocks (PNBs) have an increasingly important role in ambulatory anesthesia and have many characteristics of the ideal outpatient anesthetic: surgical anesthesia, prolonged postoperative analgesia, and facilitated discharge. Critically evaluating the potential benefits and supporting evidence is essential to appropriate technique selection. When PNBs are used for upper extremity procedures, there is consistent opioid sparing and fewer treatment-related side effects when compared with general anesthesia. This has been demonstrated in the immediate perioperative period but has not been extensively investigated after discharge. Lower extremity PNBs are particularly useful for procedures resulting in greater tissue trauma when the benefits of dense analgesia appear to be magnified, as evidenced by less hospital readmission. The majority of current studies do not support the concept that a patient will have difficulty coping with pain when their block resolves at home. Initial investigations of outpatient continuous peripheral nerve blocks demonstrate analgesic potential beyond that obtained with single-injection blocks and offer promise for extending the duration of postoperative analgesia. The encouraging results of these studies will have to be balanced with the resources needed to safely manage catheters at home. Despite supportive data for ambulatory PNBs, most studies have been either case series or relatively small prospective trials, with a narrow focus on analgesia, opioids, and immediate side effects. Ultimately, having larger prospective data with a broader focus on outcome benefits would be more persuasive for anesthesiologists to perform procedures that are still viewed by many as technically challenging.

Ambulatory Surgical Procedures↗
PubMed2005

Magnesium neuroprotection is limited in humans with acute brain injury.

Based on the results of preclinical models, magnesium sulfate (MgSO4) has gained attention as a putative neuroprotective agent. The negative results of a large-scale, randomized clinical trial using MgSO4 in acute stroke have tempered the initial enthusiasm for a neuroprotective benefit of the ion. Additional, large-scale clinical trials in stroke and other forms of brain injury are underway. This article reviews the central nervous system (CNS) physiology of Mg++, disordered Mg++ homeostasis in acute brain injury, preclinical and preliminary clinical foundations of current clinical trials, and the data regarding the CNS bio-availability of MgSO4 an important requisite for neuroprotective therapy. Although human studies have confirmed that moderate hypermagnesemia is well-tolerated and feasible, only modest elevation of cerebrospinal fluid (CSF) [Mg++] occurs. This modest increment of CSF [Mg++] in brain-injured humans occurs in the range of 10 to 19%. However, experimental evidence has yet to establish whether this modest elevation is sufficient for neuroprotection. Because of the limited CNS passage of the ion, further experimental work is needed to define the neuroprotective threshold of [Mg++] in the injured brain.

Brain Injuries↗
PubMed2004

Mouse spinal cord compression injury is ameliorated by intrathecal cationic manganese(III) porphyrin catalytic antioxidant therapy.

This study evaluated the effects of the cationic manganese(III) tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin catalytic antioxidant Mn(III)TDE-2-ImP5+ (AEOL 10150) on outcome from spinal cord compression (SCC) in the mouse. C57BL/6J mice were subjected to 60 min thoracic SCC after discontinuation of halothane anesthesia. In Experiment 1, mice were given intravenous Mn(III)TDE-2-ImP5+ (0.5 mg/kg bolus followed by 1 mg kg(-1) h(-1) for 24 h), methylprednisolone (30 mg/kg bolus followed by 5.4 mg kg(-1) h(-1) for 24 h), or vehicle (n = 25 per group). In Experiment 2, mice were given intrathecal Mn(III)TDE-2-ImP5+ (2.5 or 5.0 microg/kg) or vehicle (n = 18 per group). In both experiments, treatment began 5 min post-SCC onset. Rotarod performance was measured on post-SCC days 3, 7, 14, and 21. On post-SCC day 21, the spinal cord was histologically examined and a total damage score was calculated. Neither intravenous Mn(III)TDE-2-ImP5+ nor methylprednisolone altered rotarod performance (accelerated rate P = 0.11, fixed rate P = 0.11) or mean +/- S.D. total damage score (Mn(III)TDE-2-ImP5+ = 21 +/- 9, methylprednisolone = 24 +/- 8, vehicle = 22 +/- 10; P = 0.47; shams = 0). Intrathecal Mn(III)TDE-2-ImP5+ (both 2.5 and 5.0 microg) given at SCC-onset improved rotarod performance (P = 0.05) and total damage score (2.5 microg = 19 +/- 10, P = 0.04; 5.0 microg =19 +/- 8, P = 0.03) versus vehicle (26 +/- 10). These studies demonstrate sustained benefit from manganese(III) porphyrin catalytic antioxidant therapy after SCC. However, efficacy was dependent upon route of administration suggesting that bioavailability is critical in defining efficacy.

Animals↗
PubMed2004

Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity.

Apolipoprotein E (ApoE) deficiency has been shown to adversely affect outcome after transient cerebral ischemia and head trauma. Since oxidative stress contributes to these injuries, the ability of ApoE to reduce irreversible oxidative damage was studied in primary mixed neuronal-glial cell cultures. Cells (13-16 days in vitro) were exposed to 50 microM hydrogen peroxide (H2O2) for 30 min, and toxicity was determined by the release of lactate dehydrogenase (LDH) 24 h after exposure. The presence of recombinant human ApoE2 (100, 300, or 1000 nM) in the culture media partially protected against oxidative injury. This protection was not reversed by pre-treatment with receptor associated protein. The NMDA receptor antagonist, MK-801, also provided partial protection against H2O2 toxicity. The degree of protection was similar to that conferred by ApoE treatment. The protective effects of ApoE and MK-801 were not additive; no ApoE protection was observed in cultures treated with MK-801 prior to H2O2 exposure. ApoE treatment had no effect on H2O2 stimulated glutamate release, but did increase the rate of glutamate uptake via the high affinity glutamate transporter in H2O2 treated cultures. Pre-treatment with ApoE also conferred partial protection against glutamate-induced LDH release. Taken together, these findings suggest that ApoE protects mixed neuronal-glial cell cultures against irreversible oxidative injury from H2O2 by reducing secondary glutamate excitotoxicity.

Animals↗
PubMed2004

A no-laminectomy spinal cord compression injury model in mice.

The purpose of this study was to develop a minimally invasive recovery model of spinal cord injury in the C57Bl/6J mouse. Without laminectomy, the epidural space was exposed by disruption of the T10-T11 interspinous ligament. Perpendicular to the rostral-caudal axis of the spine, a 1.5-mm silicone tube (O.D. 0.047 in.) was placed in the T11 epidural space. Prior to placement, a suture was passed through the tube allowing withdrawal of the tube after discontinuation of anesthesia. After 1, 30, 60, or 120 min (n = 5-8) of spinal cord compression (SCC), the tube was withdrawn. Neurological function was measured at 1, 3, 7, and 14 days after injury followed by histologic analysis. BBB locomotor score, rotarod latency, and screen grasping were worsened in a SCC duration-dependent manner (p < 0.0001). With increasing SCC duration, the number of histologically normal neurons in the ventral horns decreased (p < 0.0001) while the cross-sectional area of spinal cord with pancellular necrosis increased (p < 0.0001). Increased duration of SCC caused progressive rostral-caudal spread of histologic damage. The results indicate that this is a simple, reliable model with neurologic and histologic injury highly dependent on SCC duration. This model may be useful for study of spinal cord injury in genetically modified mice in the absence of anesthetic confounds while leaving the vertebral column intact.

Animals↗
PubMed2004

Effects of isoflurane versus fentanyl-nitrous oxide anesthesia on long-term outcome from severe forebrain ischemia in the rat.

BACKGROUND: This study examined long-term outcome from severe forebrain ischemia in the rat, as a function of anesthetic given during the ischemic injury. METHODS: Rats were subjected to 10 min of near-complete forebrain ischemia while anesthetized with either 1.4% isoflurane or 70% nitrous oxide-fentanyl. Neurologic and histologic outcomes were measured at 5 days, 3 weeks, or 3 months after ischemia. RESULTS: At 5 days, isoflurane-anesthetized rats had less damage than did fentanyl-nitrous oxide-anesthetized rats (mean +/- SD, percent alive hippocampal CA1 neurons = 58+/-29 vs. 20+/-16, respectively; P = 0.011). This was accompanied by improved motor function in the isoflurane group (P = 0.002). At 3 weeks, there was no difference between groups for either outcome variable (percent alive CA1 neurons = 35+/-26 and 36+/-28 for isoflurane and fentanyl-nitrous oxide, respectively). Similarly, at 3 months, there was no difference between groups (percent alive CA1 neurons = 56+/-27 and 60+/-27 for isoflurane and fentanyl-nitrous oxide, respectively). Morris water maze performance at 3 months was similar between anesthetic groups and was also similar to sham performance. The percent alive CA1 neurons in the fentanyl-nitrous oxide group increased with duration of recovery (P = 0.004). There were no differences among isoflurane groups over time (5 days vs. 3 weeks, P = 0.26; 5 days vs. 3 months, P = 0.99; 3 week vs. 3 months, P = 0.32). CONCLUSIONS: This study found no change in the percent alive CA1 hippocampal neurons as a function of duration of recovery from severe forebrain ischemia in isoflurane anesthetized rats. In contrast, the percent alive CA1 neurons in fentanyl-nitrous oxide-anesthetized rats tripled over 3 months of recovery. The natural history of long-term responses to forebrain ischemia requires further study before conclusions can be drawn with respect to the permanence of isoflurane neuroprotection.

Anesthesia↗
PubMed2004

Intraischemic nitrous oxide alters neither neurologic nor histologic outcome: a comparison with dizocilpine.

N-Methyl-D-aspartate receptor antagonism contributes to the anesthetic action of nitrous oxide (N(2)O). We examined the effects of the N-methyl-D-aspartate antagonists N(2)O and dizocilpine on outcome from filament occlusion of the middle cerebral artery (MCAO). Rats breathed 70% nitrogen/30% oxygen or 70% N(2)O/30% oxygen during MCAO. A third group breathed 70% nitrogen/30% oxygen and was given dizocilpine (0.25 mg/kg IV). After 75 min of MCAO, the rats recovered for 3 or 14 days. Pericranial temperature was maintained at 37.5 degrees C +/- 0.2 degrees C during ischemia and for 20 h postischemia. N(2)O did not alter neurologic scores at 3 days (N(2)O, 21 +/- 6; nitrogen, 22 +/- 8; P = 0.95; 0 = normal; 48 = maximal deficit; mean +/- sd; n = 15) or 14 days (N(2)O, 13 +/- 6; nitrogen, 12 +/- 6; P = 0.93; n = 15-16) postischemia. N(2)O had no effect on infarct size at 3 days (N(2)O, 162 +/- 45 mm(3); nitrogen, 162 +/- 61 mm(3); P > 0.99) or 14 days (N(2)O, 147 +/- 56 mm(3); nitrogen, 151 +/- 62 mm(3); P = 0.99) postischemia. Dizocilpine treatment caused smaller infarcts (3 days: 66 +/- 49 mm(3), P < 0.0001 versus nitrogen; 14 days: 84 +/- 50 mm(3), P < 0.006 versus nitrogen) and reduced the neurologic deficit (3 days: 10 +/- 10, P = 0.002 versus nitrogen; 14 days: 6 +/- 7, P = 0.006 versus nitrogen). N(2)O (70%) had no effect on either behavioral or histologic outcome from transient focal cerebral ischemia when compared with results in rats breathing 70% nitrogen. These results indicate that normobaric N(2)O does not alter the response of rat brain to a focal ischemic insult.

Animals↗
PubMed2004

Apoptosis is not enhanced in primary mixed neuronal/glial cultures protected by isoflurane against N-methyl-D-aspartate excitotoxicity.

Volatile anesthetics reduce acute excitotoxic cell death in primary neuronal/glial cultures. We hypothesized that cells protected by isoflurane against N-methyl-d-aspartate (NMDA)-induced necrosis would instead become apoptotic. Primary mixed neuronal/glial cultures prepared from fetal rat brain were exposed to dissolved isoflurane (0 mM, 0.4 mM [1.8 minimum alveolar anesthetic concentration], or 1.6 mM [7 minimum alveolar anesthetic concentration]) and NMDA (0 or 100 microM) at 37 degrees C for 30 min. Dizocilpine (10 microM) plus 100 microM NMDA served as a positive control. Necrosis and apoptosis were assessed at 24 and/or 48 h after exposure by using Hoechst/propidium iodide staining, terminal-deoxynucleotidyl transferase end-nick labeling, DNA fragmentation enzyme-linked immunoabsorbence, and caspase-3 activity assays. NMDA increased the number of necrotic cells. Isoflurane (1.6 mM) and dizocilpine partially reduced cellular necrosis but did not increase the number of morphologically apoptotic or apoptotic-like cells resulting from exposure to 100 microM NMDA at 24 h. At 48 h, no evidence was found to indicate that cells protected by isoflurane had become apoptotic or apoptotic-like. However, cells protected by dizocilpine against necrosis showed evidence of caspase-3-mediated apoptosis. These in vitro data do not support the hypothesis that isoflurane protection against acute excitotoxic necrosis results in apoptosis.

Anesthetics, Inhalation↗
PubMed2004

Oxidants, antioxidants and the ischemic brain.

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.

Antioxidants↗
PubMed2004

Changes in magnetization transfer MRI correlate with spreading depression-induced astroglial reactivity and increased protein expression in mice.

OBJECTIVE: Gliosis refers to a range of glial cell transformations that vary according to specific brain pathologic states. Disease, however, is not a prerequisite for gliosis because glial reactivity may also be seen in regions of increased physiologic activity. Our study tests the hypothesis that high-field-strength magnetization transfer MRI is a sensitive technique for detecting transient glial reactivity after experimental spreading depression, a relatively benign perturbation unaccompanied by cell injury. MATERIALS AND METHODS: Unilateral neocortical spreading depression was elicited in mouse cerebral hemispheres and confirmed by transcranial blood flow and extracellular potential measurements. After 3 days, mice were imaged at 4 T using magnetization transfer techniques. Astroglial reactivity was determined immunohistochemically, and protein expression in control and experimental hemispheres was compared using proteomic techniques. RESULTS: Sixteen ([mean +/- SD] +/- 3) spreading depressions (n = 10) were recorded in experimental hemispheres. Spreading depression was never observed in control hemispheres. At 3 days, an 8% decrease (p < 0.05, n = 4) in magnetization transfer signal intensity was measured in experimental hemispheres, which was associated with a 37% increase (p < 0.001, n = 4) in the intensity of glial fibrillary acidic protein staining. Proteomic analysis performed 3 days after the induction of spreading depression showed upregulation of at least 56 proteins, including extracellular and intracellular elements. CONCLUSION: Magnetization transfer at 4.0-T MRI is a sensitive method for detecting glial reactivity and changes in protein expression not associated with cell injury. These results suggest magnetization transfer MRI techniques may have potential for detecting glial reactivity in physiologic processes such as learning and in early disease states.

Animals↗
PubMed2003

APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response.

Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo. In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human APOE3 and APOE4 genes after intravenous administration of lipopolysaccharide. Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNFalpha and IL-6 as compared with their APOE3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE. Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE-(133-149)) similarly suppressed both systemic and brain inflammatory responses in mice after lipopolysaccharide administration. These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses. Moreover, because exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or central nervous system inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.

Amino Acid Sequence↗
PubMed2003

The difficulties of ambulatory interscalene and intra-articular infusions for rotator cuff surgery: a preliminary report.

PURPOSE: Rotator cuff repair may result in severe postoperative pain. We compared a continuous intra-articular infusion to a continuous interscalene block with ropivacaine for patients undergoing outpatient rotator cuff repair. METHODS: Seventeen patients were randomized to one of two groups: 1) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative intra-articular infusion or; 2) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative continuous interscalene infusion. Infusions were 0.2% ropivacaine at 10 mL x hr(-1) for both groups. Infusions were maintained for 48 hr. Patients were discharged on the day of surgery. Verbal analogue pain scores (VAS) and postoperative oxycodone consumption were measured for 48 hr. RESULTS: Eight patients (47%; four in each group) had side effects or logistical problems complicating care. The mean VAS scores at rest and with movement in the postanesthesia care unit and at 12 hr, 24 hr, and 48 hr were not different (P > 0.1). Inadequate analgesia was reported in 50-75% of all study patients. Time until first oxycodone use was similar between groups 829 min +/- 432 (interscalene) and 999 min +/- 823 (intra-articular; P = 0.6). Total oxycodone consumption was also similar 49 mg +/- 48 and 59 mg +/- 51 (P = 0.7), respectively. CONCLUSIONS: This study demonstrates the difficulties of ambulatory interscalene and intra-articular infusion for rotator cuff surgery. The high VAS scores and need for additional medical care suggest that intra-articular administration may not be reasonable for this magnitude of surgery. Further refinement of the perineural local anesthetic infusion is necessary to consistently provide analgesia after ambulatory rotator cuff surgery.

Amides↗
PubMed2003

The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice.

BACKGROUND: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion. METHODS: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated. RESULTS: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2 versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2 versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3 versus 59 +/- 11 mm3, respectively; P = 0.0009). CONCLUSIONS: In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.

Administration, Inhalation↗