Isoflurane Improves Long-Term Neurologic Outcome Versus Fentanyl After Traumatic Brain Injury in Rats

Statler, Kimberly D.; Kochanek, Patrick M.; Dixon, C. Edward; Alexander, Henry; Warner, David S.; Clark, Robert S. B.; Wisniewski, Stephen R.; Graham, Steven H.; Jenkins, Larry W.; Marion, Donald W.; Šafář, Peter

doi:10.1089/neu.2000.17.1179

Cited by 99 publications

(70 citation statements)

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“…A 2 min anesthetic washout period was used to reduce the potential confounding effects of general anesthesia (17). At the end of the anesthetic washout, burst suppression was seen on EEG, at which point the ventilator was turned off (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…At 2 min prior to asphyxia isofluorane/N 2 O was discontinued. This anesthetic washout was performed to reduce the confounding effects of inhaled anesthetics (17). Previous pilot experiments testing the anesthetic regimen in uninjured PND 16 -18 rats monitored with scalp electrodes showed that EEG activity began to recover in frequency and amplitude by 2 min, just as animals were emerging from general anesthesia.…”

Section: Methodsmentioning

confidence: 99%

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Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Fink

Alexander

Marco

et al. 2004

Pediatric Critical Care Medicine

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Objective-Develop a clinically relevant model of pediatric asphyxial cardiopulmonary arrest in rats. Design-Prospective interventional study. Setting-University research laboratory.Subjects-Post-natal day (PND) 16-18 rats.Interventions-Anesthetized rats were endotracheally intubated and mechanically ventilated, and vascular catheters were inserted. Vecuronium was administered and the ventilator was disconnected from the rats for 8 min, whereupon rats were resuscitated with epinephrine, sodium bicarbonate, and chest compressions until spontaneous circulation returned. Shams underwent all procedures except asphyxia.Measurements and Main Results-Asphyxial arrest typically occurred by 1 min after the ventilator was disconnected. Return of spontaneous circulation typically occurred <30 sec after resuscitation. An isoelectric electroencephalograph was observed for 30 min after asphyxia and rats remained comatose for 12-24 h. Survival rate in rats after asphyxia was 75%. Motor function measured using beam balance and inclined plane tests was impaired on d 1 and 2, but recovered by d 3, in rats after asphyxia vs. sham injury (n=9/group; P<0.05). Spatial memory acquisition measured using the Morris-water maze on d 7-14 and 28-35 was also impaired in rats after asphyxia vs. sham injury (total latency 379±28 vs. 501±40 sec, respectfully; n=9/group; P<0.05). CA1 hippocampal neuron survival after asphyxia was 39-43% (n=9/group; P<0.001 vs. sham). DNA fragmentation was detected in CA1 hippocampal neurons bilaterally in separate rats on d 3-7 after asphyxia (n=3-4/group). Neurodegeneration detected using Fluorojade-B was seen in bilateral CA1 hippocampi and layer III cortical neurons 3-7 d after asphyxia, with persistent neurodegeneration in CA1 hippocampus detected up to 5 wks after asphyxia. Evidence of DNA or cellular injury was not detected in sham rats.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Fink

Alexander

Marco

et al. 2004

Pediatric Critical Care Medicine

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“…To ensure that anesthetic differences between groups did not produce differential neuroprotective effects (Statler et al, 2000(Statler et al, , 2006, the mice in the sham and CCI-only groups were exposed to an identical duration of anesthesia as those in the HS and CCI + HS groups. We carried out studies until each group had 10 mice for the entire 21-day outcome protocol.…”

Section: Monitoring Protocolmentioning

confidence: 99%

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Hemerka

Dixon

et al. 2012

Journal of Neurotrauma

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Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n = 10/group): sham, HS, controlled cortical impact (CCI), and CCI + HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP] = 25-27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP > 70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n = 60) at 24 h, 7 days, or 21 days (n = 5/group/time point). HS reduced MAP during the shock phase in the HS and CCI + HS groups ( p < 0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI + HS group ( p < 0.05), and were increased in HS versus sham and CCI animals ( p < 0.05). MWM latency was increased on days 14 and 15 after CCI + HS ( p < 0.05). Swim speed and visible platform latency were impaired in the CCI + HS group ( p < 0.05). CCI + HS animals had increased contusion volume versus the CCI group ( p < 0.05). Hemispheric volume loss was increased 33.3% in the CCI + HS versus CCI group ( p < 0.05). CA1 cell loss was seen in CCI + HS and CCI animals at 24 h and 7 days ( p < 0.05). CA3 cell loss was seen after CCI + HS ( p < 0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI + HS animals ( p < 0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.

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“…We hypothesized that the differential results may be attributed to the choice of anesthetic agents, based upon previous studies identifying isoflurane as a neuroprotectant [50,51,52]. To test this hypothesis, neuropathological markers of injury were compared in the brains of Avertin- versus isoflurane-anesthetized mice at 24 h after an equivalent impact severity.…”

Section: Resultsmentioning

confidence: 99%

Long-Term Anesthetic-Dependent Hypoactivity after Repetitive Mild Traumatic Brain Injuries in Adolescent Mice

et al. 2016

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Recent evidence supports the hypothesis that repetitive mild traumatic brain injuries (rmTBIs) culminate in neurological impairments and chronic neurodegeneration, which have wide-ranging implications for patient management and return-to-play decisions for athletes. Adolescents show a high prevalence of sports-related head injuries and may be particularly vulnerable to rmTBIs due to ongoing brain maturation. However, it remains unclear whether rmTBIs, below the threshold for acute neuronal injury or symptomology, influence long-term outcomes. To address this issue, we first defined a very mild injury in adolescent mice (postnatal day 35) as evidenced by an increase in Iba-1- labeled microglia in white matter in the acutely injured brain, in the absence of indices of cell death, axonal injury, and vasogenic edema. Using this level of injury severity and Avertin (2,2,2-tribromoethanol) as the anesthetic, we compared mice subjected to either a single mTBI or 2 rmTBIs, each separated by 48 h. Neurobehavioral assessments were conducted at 1 week and at 1 and 3 months postimpact. Mice subjected to rmTBIs showed transient anxiety and persistent and pronounced hypoactivity compared to sham control mice, alongside normal sensorimotor, cognitive, social, and emotional function. As isoflurane is more commonly used than Avertin in animal models of TBI, we next examined long-term outcomes after rmTBIs in mice that were anesthetized with this agent. However, there was no evidence of abnormal behaviors even with the addition of a third rmTBI. To determine whether isoflurane may be neuroprotective, we compared the acute pathology after a single mTBI in mice anesthetized with either Avertin or isoflurane. Pathological findings were more pronounced in the group exposed to Avertin compared to the isoflurane group. These collective findings reveal distinct behavioral phenotypes (transient anxiety and prolonged hypoactivity) that emerge in response to rmTBIs. Our findings further suggest that selected anesthetics may confer early neuroprotection after rmTBIs, and as such mask long-term abnormal phenotypes that may otherwise emerge as a consequence of acute pathogenesis.

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Isoflurane Improves Long-Term Neurologic Outcome Versus Fentanyl After Traumatic Brain Injury in Rats

Cited by 99 publications

References 50 publications

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Long-Term Anesthetic-Dependent Hypoactivity after Repetitive Mild Traumatic Brain Injuries in Adolescent Mice

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