Yoshihiro Momota

Rate of CSF formation and resistance to reabsorption of CSF during sevoflurane or remifentanil in rabbits.

Information on the effects of sevoflurane on the rate of cerebrospinal fluid (CSF) formation (Vf) and resistance to reabsorption of CSF (Ra) is incomplete, and no such information is available for remifentanil. The present study examined the dose-related effects of sevoflurane and remifentanil on Vf and Ra in rabbits. Eight rabbits were studied during isoflurane 1.4% (baseline) and sevoflurane 1.4%, 2.5%, and 3.7%, and eight were studied during isoflurane 1.4% (baseline) and remifentanil 0.30, 0.67, and 1.00 microg x kg(-1) x min(-1) in randomized order. Ventriculocisternal perfusion at two CSF pressure states for each experimental condition was used to determine Vf and Ra. There was no dose-response relation for Vf (10.4+/-2.5, 9.0+/-2.0, and 10.0+/-3.0 microl x min(-1)) or Ra (0.81+/-0.33, 1.35+/-0.54, and 0.84+/-0.27 cm H2O x microl(-1) x min) between the three sevoflurane concentrations. There also was no dose-response relation for Vf (7.8+/-1.2, 8.8+/-3.0, and 6.5+/-2.3 microl x min(-1)) or Ra (1.07+/-0.54, 1.23+/-0.50, and 1.13+/-0.51 cm H2O x microl(-1) x min) between the three remifentanil doses. Vf and Ra during either sevoflurane or remifentanil were not significantly different from Vf and Ra during the two isoflurane baseline conditions (Vf = 8.5+/-2.5 and 9.8+/-1.3 microl x min(-1), and Ra = 0.97+/-0.36 and 1.38+/-0.55 cm H2O x microl(-1) x min, mean +/- SD). Vf and Ra are of interest because they influence CSF volume, intracranial pressure, and/or intracranial elastance. In our model, sevoflurane or remifentanil did not significantly alter Vf or Ra.

Posttreatment with propofol terminates lidocaine-induced epileptiform electroencephalogram activity in rabbits: effects on cerebrospinal fluid dynamics.

There are no controlled studies to determine whether propofol given after the onset of lidocaine-induced seizures (posttreatment) stops lidocaine-induced seizures. In this study, we determined whether posttreatment with propofol abolishes lidocaine-induced epileptiform electroencephalogram (EEG) activity as effectively as does midazolam, and cerebrospinal fluid (CSF) dynamics during lidocaine-induced epileptiform EEG activity and its treatment. EEG activity and CSF dynamics were determined in two groups of anesthetized rabbits at each of four experimental conditions: baseline, lidocaine-induced epileptiform activity, treatment with midazolam (n = 6) or propofol (n = 6), and return to baseline. The analog EEG signal was converted into a set of digital parameters using aperiodic analysis, and CSF dynamics were determined using ventriculocisternal perfusion. Propofol (3.8 +/- 1.3 mg/kg) stopped epileptiform activity, as did midazolam (2.0 +/- 1.7 mg/kg). The rates of CSF formation or reabsorption and resistances to CSF reabsorption or flow at the arachnoid villi did not differ among conditions or between groups. Our results indicate that propofol and midazolam both terminate epileptiform activity without changing CSF dynamics. Implications: Propofol may be an alternative to benzodiazepines for treating lidocaine-induced epileptiform electroencephalogram activity in patients. (Anesth Analg 1998;87:900-6)

Trabecular outflow facility and formation rate of aqueous humor during anesthesia with sevoflurane-nitrous oxide or sevoflurane-remifentanil in rabbits.

UNLABELLED In the present study, we examined the effect of sevoflurane and remifentanil on intraocular pressure (IOP) and fluid dynamics. Twenty-eight rabbits were anesthetized with halothane, and IOP was measured via a 25-gauge needle in the anterior chamber. Rabbits were then assigned to one of four groups, and halothane was replaced with sevoflurane 1% (n = 7), 2% (n = 7), 3% (n = 7), or 1% + remifentanil 0.65 microg kg(-1) x min(-1) i.v. (n = 7). In all groups, a series of intraocular infusions was made into the anterior chamber, and IOP, trabecular outflow facility, the rate of aqueous humor formation, and intraocular compliance were determined. With sevoflurane only, intraocular compliance decreased (55 +/- 14, 39 +/- 22, 31 +/- 17 nL/mm Hg; P < 0.05) as the concentration of sevoflurane increased. With sevoflurane 1% + remifentanil, intraocular compliance was significantly increased (100.1 +/- 30.5 nL/mm Hg; P < 0.05) compared with sevoflurane 1%, 2%, or 3%. Trabecular outflow facility, rate of aqueous humor formation, and IOP did not differ among groups, and IOP was similar to values obtained during halothane anesthesia. IMPLICATIONS The dose-related effects of sevoflurane on intraocular compliance did not produce significant intraocular pressure differences. Adding remifentanil to sevoflurane increased intraocular compliance. Sevoflurane or sevoflurane + remifentanil causes a decrease in intraocular pressure compared with the average of previously reported values in awake rabbits, and the magnitude of the decrease is similar to that previously reported in rabbits anesthetized with ethyl urethane, pentobarbital, or halothane alone or in combination with propofol, cocaine, or lidocaine.

Induction of autophagy restores the loss of sevoflurane cardiac preconditioning seen with prolonged ischemic insult

Sevoflurane preconditioning against myocardial ischemia-reperfusion injury is lost if the ischemic insult is too long. Emerging evidence suggests that induction of autophagy may also confer cardioprotection against ischemia-reperfusion injury. We examined whether induction of autophagy prolongs sevoflurane preconditioning protection during a longer ischemic insult. Isolated guinea pigs hearts were subjected to 30 or 45 min ischemia, followed by 120 min reperfusion (control). Anesthetic preconditioning was elicited with 2% sevoflurane for 10 min prior to ischemia (SEVO-30, SEVO-45). Chloramphenicol (autophagy upregulator, 300 µM) was administered starting 20 min before ischemia and throughout reperfusion in SEVO-45 (SEVO-45+CAP). To inhibit autophagy, 3-methyladenine (10 μM) was administered during sevoflurane administration in SEVO-45+CAP. Infarct size was determined by triphenyltetrazolium chloride stain. Tissue samples were obtained before ischemia to determine autophagy-related protein (microtubule-associated protein light chain I and II: LC3-I, II), Akt and glycogen synthase kinase 3β (GSK3β) expression using Western blot analysis. The effect of autophagy on calcium-induced mitochondrial permeability transition pore (MPTP) opening in isolated calcein-loaded mitochondria was assessed. Electron microscopy was used to detect autophagosomes. Infarct size was significantly reduced in SEVO-30, but not in SEVO-45. Chloramphenicol restored sevoflurane preconditioning lost by 45 min ischemia. There were more abundant autophagozomes and LC3-II expression was significantly increased in SEVO-45+CAP. Induction of autophagy before ischemia enhanced GSK3β phosphorylation and inhibition of calcium-induced MPTP opening. These effects were abolished by 3-methyladenine. Pre-ischemic induction of autophagy restores sevoflurane preconditioning lost by longer ischemic insult. This effect is associated with enhanced inhibition of MPTP by autophagy.

Concentrations of lidocaine and monoethylglycine xylidide in brain, cerebrospinal fluid, and plasma during lidocaine-induced epileptiform electroencephalogram activity in rabbits: the effects of epinephrine and hypocapnia.

UNLABELLED When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO(2). In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO(2) on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg. kg(-1). min(-1) with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 microg/mL with hypocapnia and 2 microg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 microg/mL without epinephrine and by 14 microg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain. IMPLICATIONS Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.

Sevoflurane Confers Additive Cardioprotection to Ethanol Preconditioning Associated With Enhanced Phosphorylation of Glycogen Synthase Kinase-3β and Inhibition of Mitochondrial Permeability Transition Pore Opening

OBJECTIVE The purposes of this study were to investigate whether sevoflurane (SEVO) enhances moderate-dose ethanol (EtOH) preconditioning and whether this additional cardioprotection is associated with glycogen synthase kinase-3β (GSK-3β), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 70-kDa ribosomal s6 kinase-1 (p70s6K), and/or mitochondrial permeability transition pore (MPTP) opening. DESIGN In vitro study using an isolated heart Langendorff preparation. SETTING University research laboratory. PARTICIPANTS Male guinea pigs (n = 170). INTERVENTIONS Isolated perfused guinea pig hearts underwent 30-minute ischemia and 120-minute reperfusion (control). The EtOH group received 5% EtOH in the drinking water for 8 weeks. Anesthetic preconditioning was elicited by a 10-minute exposure to 2% SEVO in EtOH (EtOH + SEVO group) or non-EtOH (SEVO group) hearts. The inhibition of GSK-3β phosphorylation and mTOR was achieved with LY294002 and rapamycin, respectively. GSK-3β, Akt, mTOR, and p70s6K expressions were determined by western blot. Calcium-induced MPTP opening was assessed in isolated calcein-loaded mitochondria. MEASUREMENTS AND MAIN RESULTS After ischemia-reperfusion, the EtOH, SEVO, and EtOH + SEVO groups had higher left ventricular developed pressure recovery and lower end-diastolic pressure versus the control group. Infarct size was smaller in the EtOH and SEVO groups versus control and even smaller in the EtOH + SEVO group. Phosphorylation of GSK-3β and Akt, but not mTOR and p70s6K, was increased in the EtOH and SEVO groups. Phosphorylation of GSK-3β, but not mTOR and p70s6K, was further increased in the EtOH + SEVO group. The EtOH and SEVO groups exhibited a smaller calcium-induced MPTP opening, and the EtOH + SEVO presented an even smaller MPTP opening. CONCLUSIONS SEVO and chronic EtOH preconditioning offer additive cardioprotection. This effect is associated with an increased GSK-3β phosphorylation and an inhibition of MPTP opening.

A highly reproducible model of cerebral ischemia/reperfusion with extended survival in CB-17 mice

To simulate the clinical and pathologic situation in patients with stroke, as well as to evaluate future potential therapeutic approaches, it is essential to have a highly reproducible model that displays long-term survival. Though a range of rodent models has been employed in the literature, there are questions regarding reproducibility, especially in terms of ischemic zone (i.e., degree of ischemia) and long-term survival. We have developed a highly reproducible stroke model that produces a consistent ischemic zone as a result of direct transient occlusion of the middle cerebral artery (MCA) in CB-17 (CB-17/Icr-+/+Jcl) mice. The model employs a thin monofilament to twist the artery resulting in complete interruption of blood flow. Transient ischemia can be induced for up to 240min and the survival rate at 7 days post-ischemia was more than 60%, even in mice subjected to 240min of transient ischemia resulting in hemorrhagic infarction in most animals. Our method can be used to model several pathologic conditions, such as reversible reperfusion injury, delayed neuronal death, necrotic brain injury and hemorrhagic infarction. We believe this preclinical model provides a step forward for testing future therapeutic approaches applicable to patients with ischemic brain injury.

Changes in blood pressure during induction of anesthesia and oral and maxillofacial surgery by type and timing of discontinuation of antihypertensive drugs.

The purpose of this study was to evaluate the effects of an antihypertensive drug class and the timing of discontinuation of antihypertensive therapy on blood pressure during oral and maxillofacial surgery for 129 patients on antihypertensive therapy receiving general anesthesia. Blood pressures at loss of response to stimulation and 5-15 minutes after intubation were significantly lower than those before induction, although the type of antihypertensive therapy did not affect changes in blood pressure. No significant correlation was observed between systolic blood pressure (SBP) on the ward and change in SBP during surgery, though patients with higher blood pressure on the ward tended to exhibit larger differences between SBP on the ward and the lowest SBP during surgery. Frequency of use of vasopressors during surgery was significantly higher in patients who discontinued antihypertensive therapy on the day before surgery than in those who continued antihypertensive therapy on the day of surgery. These findings suggest that appropriate preoperative antihypertensive therapy is important for minimizing change in blood pressure during surgery and preventing perioperative complications. Patients undergoing antihypertensive therapy should be carefully monitored perioperatively by observation for interactions between antihypertensive and anesthetic agents and minimizing interruption schedules for antihypertensive therapy.

Effect of sevoflurane on intracranial pressure, sagittal sinus pressure, and the intracranial volume-pressure relation in cats.

The effect of sevoflurane on intracranial pressure (ICP), sagittal sinus pressure (SSP), and the intracranial volume-pressure (V-P) relation was examined in cats. In experiment 1, on nine cats, changes in ICP and SSP were studied for 180 min during anesthesia with 1 MAC sevoflurane (2.6%, inspired) and 50% nitrous oxide (N2O) in oxygen (O2). ICP significantly (p <0.01) increased from 8.4 +/- 3.8 cm H2O (mean +/- SD), the control level to 10.6 +/- 5.1 cm H2O immediately after the administration of sevoflurane. ICP was unchanged for the subsequent 120 min but then increased significantly (p <0.05) 140 min after administration, being 15.5 +/- 9.0 cm H2O at 180 min. There were no changes in SSP or blood gases. In experiment 2, the rapid injection technique of mock cerebrospinal fluid was used to determine the intracranial V-P relation in ten cats. Measures of V-P relationships included (a) ICP before volume injection (Po), (b) peak ICP caused by volume injection (Pp), (c) intracranial compliance (C) calculated as the ratio of change of intracranial volume Delta V) to change of ICP (Delta P), and (d) the pressure volume index (PVI) calculated as the ratio of Delta V to log Pp/Po. The subjects were divided into two groups, one administered 2.6% sevoflurane and 50% N2O in O2 (n = 6) and the other 50% N2O in O2 (n = 4). Each cat in both groups was given two bolus injections into the lateral ventricle at 180 min after the start of anesthesia. Then, C and PVI were calculated. C and PVI in the group treated with sevoflurane were significantly (p <0.05) lower than in the other group. These findings suggest that prolonged use of sevoflurane increases the intracranial elastance.

Functional recovery by application of human dedifferentiated fat cells on cerebral infarction mice model

Elderly people whose daily activities have declined due to a cerebrovascular disorder may suffer from dysphagia and may find oral hygiene difficult. Therefore, it is important to establish an effective therapy for the underlying cerebrovascular disorder. Dedifferentiated fat cells (DFAT) were obtained from mature adipocytes isolated from human buccal adipose pads in a ceiling culture. DFAT expressed the neural markers Nestin and SOX2. Flow cytometric analysis revealed that the cells had properties similar to mesenchymal stem cells. Although the transplantation of DFAT did not change the infarction area and volume ratios in a murine cerebral infarction model, functional recovery was observed in behavioral tests. Furthermore, DFAT administered to mice were later detected in cerebral infarctions. It therefore appears that transplanted DFAT affect the brain after infarction and contribute to the promotion of functional recovery. This finding may provide new cell replacement therapy options for treating disorders of the central nervous system.