Long-Term Cognitive Deficits After Subarachnoid Hemorrhage in Rats.

BACKGROUND: Cognitive dysfunction can be a long-term complication following subarachnoid hemorrhage (SAH). Preclinical models have been variously characterized to emulate this disorder. This study was designed to directly compare long-term cognitive deficits in the context of similar levels of insult severity in the cisterna magna double-blood (DB) injection versus prechiasmatic blood (PB) injection SAH models. METHODS: Pilot work identified blood injectate volumes necessary to provide similar mortality rates (20-25 %). Rats were then randomly assigned to DB or PB insults. Saline injection and naïve rats were used as controls. Functional and cognitive outcome was assessed over 35 days. RESULTS: DB and PB caused similar transient rotarod deficits. PB rats exhibited decreased anxiety behavior on the elevated plus maze, while anxiety was increased in DB. DB and PB caused differential deficits in the novel object recognition and novel object location tasks. Morris water maze performance was similarly altered in both models (decreased escape latency and increased swimming speed). SAH caused histologic damage in the medial prefrontal cortex, perirhinal cortex, and hippocampal CA1, although severity of injury in the respective regions differed between DB and PB. CONCLUSION: Both SAH models caused long-term cognitive deficits in the context of similar insult severity. Cognitive deficits differed between the two models, as did distribution of histologic injury. Each model offers unique properties and both models may be useful for study of SAH-induced cognitive deficits.

Isoflurane Induces Transient Impairment of Retention of Spatial Working Memory in Rats.

Postoperative cognitive dysfunction (POCD) occurs in nearly one-third of patients after non-cardiac surgery. Many animal behavior studies have investigated the effect of general anesthesia on cognitive function. However, there have been no studies examining the effects on working memory specifically, with a focus on the retention of working memory. We demonstrate here that isoflurane anesthesia induces deficits in the retention of spatial working memory in rats, as revealed by an increase in isoflurane- induced across-phase errors in the delayed spatial win-shift (SWSh) task with a 30-min delay in an 8-arm radial arm maze on post-anesthesia days (PADs) 1,2,4, and 10. A post-hoc analysis revealed a significant increase in across-phase errors on PAD 1 and recovery on PAD 10 in the isoflurane group. In contrast, within-phase errors independent of the retention of working memory were unaffected by isoflurane. These results demonstrate that isoflurane anesthesia transiently impairs the retention of spatial working memory in rats.

[Intracranial Hemorrhage and Pneumocephalus after Spinal Cord Tumor Resection: A Case Report].

A 75-year-old woman was scheduled for spinal cord tumor resection. General anesthesia was induced and maintained using propofol, remifentanil and fentanyl. Aside from fluctuations in intraoperative blood pres- sure, the surgery was uneventful, but emergence from anesthesia was delayed and the patient showed partial paralysis. Emergent brain CT revealed multiple intracranial hemorrhages and pneumocephalus. Since a large amount of fluid was observed from the drainage tube at the surgical site, loss of cerebrospinal fluid and subsequent low intracranial pressure were considered to be the cause of the hemorrhage and pneumocepha- lus. Intracranial hemorrhage and pneumocephalus are rare complications after spinal surgery, but they can lead to serious neurological dysfunction. Dural tear and/or excessive drainage are considered to be the causes of these complications, and careful observation of the property, amount and rate of drainage is there- fore warranted.

Effect of fentanyl on ischemic depolarization and ischemic neuronal damage of hippocampal CA1 in the gerbil.

PURPOSE: Temporary brain ischemia occurring during surgery under general anesthesia may induce the death of neuronal cells and cause severe neurological deficits. On the other hand, it is not clear whether µ-opioid receptor agonists promote ischemic brain injury. It is known that duration of ischemic depolarization affects the degree of neuronal damage. However, the effects of fentanyl during brain ischemia on ischemic depolarization have not been investigated. Therefore, in the current study, the effects of fentanyl on ischemic neuronal damage and ischemic depolarization were quantitatively evaluated. METHODS: Forty-two male gerbils were randomly assigned to a saline-administered group (control group, n = 21) and a fentanyl-administered group (fentanyl group, n = 21). Fentanyl at 50 µg/kg was first administered over a 10-min period and then 50 µg/kg/h was administered continuously for the fentanyl group. Forebrain ischemia was initiated by occlusion of bilateral common carotid arteries and sustained for 3, 5, or 7 min (n = 7 in each group). Direct-current potentials were measured in bilateral CA1 regions, in which histological evaluation was performed 5 days later. RESULTS: There were no significant differences in onset time, duration of ischemic depolarization, and percentage of neuronal damage between the two groups with any ischemic duration. In the relationships between ischemic time and neuronal damage and those between duration of ischemic depolarization and neuronal damage, there was no significant difference in the percentage of neuronal damage between the two groups. CONCLUSION: Fentanyl at a clinically relevant dose does not affect ischemic depolarization and ischemic neuronal damage.

Dynamic changes in cortical NADH fluorescence in rat focal ischemia: evaluation of the effects of hypothermia on propagation of peri-infarct depolarization by temporal and spatial analysis.

Suppression of peri-infarct depolarizations (PIDs) is one of the major mechanisms of hypothermic protection against transient focal cerebral ischemia. Previous studies have shown the lack of hypothermic protection against permanent focal ischemia. We hypothesized the lack of hypothermic protection was due to the poor efficacy in suppression of PIDs. To examine the hypothesis, we elucidated the effects of hypothermia on the manner of propagation of PIDs with temporal and spatial resolutions using NADH (reduced nicotinamide adenine dinucleotide) fluorescence images by illuminating the parietal-temporal cortex with ultraviolet light. Spontaneously hypertensive rats (n=14) were subjected to permanent focal ischemia by occlusion of the middle cerebral and left common carotid arteries. 2-h hypothermia (30 degrees C) was initiated before ischemia. Although hypothermia delayed the appearance of PIDs, it did not suppress their appearance. Furthermore, 54% of the PIDs enlarged the high-intensity area of NADH fluorescence in the hypothermia group, similar to the normothermia group (53%). The high-intensity area of NADH fluorescence widened by each PID was larger in the hypothermia group than in the normothermia group. These findings suggest that PIDs even in hypothermia are one of the major factors causing growth of infarction, emphasizing the importance of therapy that targets suppression of PIDs even during hypothermia.

Effect of nitrous oxide on neuronal damage and extracellular glutamate concentration as a function of mild, moderate, or severe ischemia in halothane-anesthetized gerbils.

BACKGROUND: The effect of nitrous oxide on ischemic neuronal damage was quantitatively evaluated by use of logistic regression curves. METHODS: Seventy-two gerbils were anesthetized with 1% halothane and randomly assigned to receive 70% nitrous oxide or 70% nitrogen. Forebrain ischemia was performed for 3, 5, or 7 min, and direct-current potential in the hippocampal CA1 region was recorded. Histologic outcome was evaluated 5 days later. Relations of neuronal damage with ischemic duration and duration of ischemic depolarization were determined by logistic regression curves. In some animals, extracellular glutamate concentration was measured every 60 s during forebrain ischemia. RESULTS: Nitrous oxide increased neuronal damage only with 5 min of ischemia (nitrous oxide vs. nitrogen: 78.5 +/- 23.0 vs. 37.3 +/- 12.2%; P < 0.01). The percentages of neuronal damage with 3 and 7 min of ischemia were not different with or without nitrous oxide. Logistic regression curves indicated that nitrous oxide significantly increased neuronal damage during the period from 3.07 to 6.63 min of ischemia. Logistic regression curves also indicated that nitrous oxide increased neuronal damage in the condition of the same duration of ischemic depolarization. Nitrous oxide shortened the ischemic duration necessary for causing 50% neuronal damage by 0.82 min. Dynamic change in extracellular glutamate concentration was not different (mean maximum dialysate glutamate concentration: 4.29 +/- 3.09 vs. 4.63 +/- 1.83 microm). CONCLUSION: Administration of nitrous oxide caused an increase in ischemic neuronal damage, but a significant adverse effect was observed with a limited range of ischemic intervals.

Perioperative Management Center (PERIO) for Neurosurgical Patients.

Perioperative management is critical for positive neurosurgical outcomes. In order to maintain safe and authentic perioperative management, a perioperative management center (PERIO) was introduced to patients of our Neurosurgery Department beginning in June 2014. PERIO involves a multidisciplinary team consisting of anesthesiologists, dentists/dental hygienists/technicians, nurses, physical therapists, pharmacists, and nutritionists. After neurosurgeons decide on the course of surgery, a preoperative evaluation consisting of blood sampling, electrocardiogram, chest X-ray, and lung function test was performed. The patients then visited the PERIO clinic 7-14 days before surgery. One or two days before surgery, the patients without particular issues enter the hospital and receive a mouth cleaning one day before surgery. After surgery, postoperative support involving eating/swallowing evaluation, rehabilitation, and pain control is provided. The differences in duration from admission to surgery, cancellation of surgery, and postoperative complications between PERIO and non-PERIO groups were examined. Eighty-five patients were enrolled in the PERIO group and 131 patients in the non-PERIO group. The duration from admission to surgery was significantly decreased in the PERIO group (3.6 ± 0.3 days), compared to that in the non-PERIO group (4.7 ± 0.2 days). There was one cancelled surgery in the PERIO group and six in the non-PERIO group. Postoperative complications and the overall hospital stay did not differ between the two groups. The PERIO system decreased the duration from admission to surgery, and it is useful in providing high-quality medical service, although the system should be improved so as not to increase the burden on medical staff.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice.

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.

[Living-related liver transplantation in a patient with hepatopulmonary syndrome].

We experienced the perioperative management of the living related liver transplantation (LRLT) in a patient with hepatopulmonary syndrome (HPS). HPS is seen in 15% of patients of the endstage liver failure, and it accompanies the various types of hypoxia. The diagnostic standards of HPS are chronic liver disease usually complicated by portal hypertension with or without cirrhosis, arterial hypoxemia (PaO2 < 70 mmHg or A-aDO2 gradient > 20 mmHg), and intrapulmonary vascular dilation. The present case conformed to the diagnostic standard. But this case was of a mild type of HPS, because PaO2 was elevated after O2 inhalation and extrapulmonary uptake of 99mTcMAA after lung perfusion was lower than 40%. During perioperative period of LRLT, there were no complications such as hypoxia, acute rejection, bleeding and infection. Therefore HPS would be improved after LRLT. In the management of perioperative period it is important to be aware of hypoxia and to evaluate preoperatively the condition of the patient properly.

Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders.

SIGNIFICANCE: Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease. RECENT ADVANCES: Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment. CRITICAL ISSUES: Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders. FUTURE DIRECTIONS: Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.