Satoshi Yokono

Moderate hypothermia improves imbalances of thromboxane A2 and prostaglandin I2 production after traumatic brain injury in humans.

ObjectiveTo examine the levels of thromboxane B2 (TXB2) and 6-keto prostaglandin F1&agr; (6-keto PGF1&agr;) production in arterial and internal jugular bulb sera in patients with traumatic brain injury (TBI). TBI is associated with arachidonate release and may be associated with an imbalance of vasoconstricting and vasodilating cyclooxygenase metabolites. DesignA prospective, randomized study. SettingThe intensive care unit of a medical university hospital. InterventionsTwenty-six ventilated TBI patents (Glasgow Coma Scale score on admission, ≤8 points) were divided randomly into two groups: a hypothermic group (n = 15), in which the patients were cooled to 32 to 33°C after being giving vecuronium, midazolam, and buprenorphine; and a normothermic group (n = 11), in which the patients’ body temperature was controlled at 36 to 37°C by surface cooling using the same treatment as the hypothermic group. Body temperature control including normothermia was started 3 to 4 hrs after injury. The duration of hypothermia usually lasted for 3 to 4 days, after which the patients were rewarmed at a rate of approximately 1°C per day. Measurements and Main ResultsBlood sampling for TXB2 and 6-keto PGF1&agr; was started shortly after admission in both groups. Arterial TXB2 levels on admission in both groups were elevated remarkably, but not 6-keto PGF1&agr;, thereby causing an imbalance of the prostanoids after injury. In the normothermic group, TXB2 decreased transiently, but this prostanoid increased again 3 days after the injury. In the hypothermic group, such prostanoid differences disappeared shortly after therapy, and the condition was sustained for 10 days. Hypothermia attenuated differences in TXB2 levels between arterial and internal jugular bulb sera, which may reflect reduced cerebral prostanoid production. The Glasgow Outcome Scale score 6 months after the insult in the hypothermic group was significantly higher than that in the normothermic group (p = .04). ConclusionThe current results from a limited number of patients suggest that moderate hypothermia may reduce prostanoid production after TBI, thereby attenuating an imbalance of thromboxane A2 and prostaglandin I2. However, it must be clarified whether the changes in the prostanoid after moderate hypothermia are a secondary effect of other mediator changes or whether they simply represent an epiphenomenon that is mechanistically unrelated to damage in TBI.

Activated cytokine production in patients with accidental hypothermia

We have demonstrated recently that therapeutic moderate hypothermia of 32-33 degrees C, induced by surface cooling under the administration of narcotics, sedatives and muscle relaxant, suppresses cytokine production after traumatic brain injury. We present here the first documented case report of augmented cytokine production in two accidental hypothermia patients, unconscious 84- (acute immersion) and 87- (non-immersion) year-old women, whose rectal temperatures were below 28 degrees C. The victims were artificially ventilated after sedation with midazolam and buprenorphine in accordance with our protocol. Rewarming at the rate of approximately 1 degrees C/h was done by blowing forced-air with appropriate fluid resuscitation. Plasma interleukin(IL)-6 and/or IL-8 levels were measured using ELISA in the patients. In both patients, plasma IL-6 levels on admission were already elevated and the cytokine levels further increased during and after the rewarming period. In the patient with the poorer prognosis, the plasma IL-8 level on admission was not elevated remarkably but after rewarming the level rose significantly. Augmented IL-6 production in accidental hypothermia was sustained for 6 days in the patient with the poorer prognosis but not in the subject with good recovery, who was treated with anti-thrombin III in the early phase. Since the mechanisms for developing accidental hypothermia were different, simple comparisons between the two cases should be limited. But, these findings may suggest a need for testing a hypothesis whether cytokine modulation could be a therapeutic approach worthy of consideration. The results presented here also suggest that in hypothermia, changes in cytokine release may vary depending on procedures such as the anesthetic drugs used, the duration of the therapy, or the rate of rewarming from hypothermia.

400 MHz two-dimensional nuclear Overhauser spectroscopy on anesthetic interaction with lipid bilayer

Interaction between a volatile anesthetic, methoxyflurane, and dipalmitoylphosphatidylcholine (DPPC) vesicle membrane was analyzed by nuclear Overhauser effect (NOE) difference spectroscopy and two-dimensional nuclear Overhauser spectroscopy (NOESY). The NOE difference spectra were obtained by selectively irradiating methoxy protons (hydrophobic end) of the anesthetic: a negative nuclear Overhauser effect of -2.94% was observed with the choline methyl protons of DPPC. The NOESY spectra revealed a cross-peak between the anesthetic methoxy protons and the choline methyl protons. A dipole-dipole interaction exists between the hydrophobic end of the anesthetic and the hydrophilic head group of DPPC. No other cross-peaks were observed. The anesthetic orients itself at the membrane/water interface by interacting with the hydrophilic surface of the DPPC membrane, leaving the hydrophilic end of the anesthetic molecule in the aqueous phase. The preferred residence site of dipolar volatile anesthetics is the membrane/water interface.

Memory Facilitation by Posttraining Exposure to Halothane, Enflurane, and Isoflurane in ddN Mice

The effect of low and high concentrations of halothane, enflurane, and isoflurane on posttraining memory function was studied in male ddN mice. Mice were trained to escape an aversive electric foot shock as an unconditioned stimulus within 3 s after being exposed to light and a buzzer as a conditioned stimulus. Immediately after training (first session: 30 trials), the animals were exposed to halothane, enflurane, or isoflurane avoidance task (second session: 30 trials) 22 h after cessation of exposure. The performance ratios, [B/A] (i.e., A is the score in the first session, and the score in the second) were compared between the anesthetized and for min and then were tested again On the groups and their respective control (nonanesthetized) groups. Mean performance ratios in the control groups ([B/A]c) ranged from 136.8% to 163.9% and those in the aesthetized groups ([B/A]a) ranged from 151.4% to 174.7%. [B/A] in each anesthetized group exceeded [B/A] in its corresponding control group. [B/A]a significantly exceeded [B/A]c by 13.1% in the 1.23 minimum alveolar concentration (MAC) enflurane group (P < 0.05). These results suggest that posttraining exposure to volatile anesthetics facilitates memory.

Dose-dependent effects of propofol on renal sympathetic nerve activity, blood pressure and heart rate in urethane-anesthetized rabbits.

To evaluate the role of the autonomic nervous system in hemodynamic changes after propofol bolus injection, we used direct recordings of renal sympathetic nerve activity to examine the dose-dependent effects of propofol (2.5, 5, 10, and 20 mg/kg) on heart rate, mean blood pressure and renal sympathetic nerve activity in urethane-anesthetized rabbits. The animals were divided into four groups: animals with an intact neuraxis (intact group), cervical vagal nerve-sectioned animals (vagotomy group), carotid sinus and aortic-nerve sectioned animals (SAD group), and animals with SAD plus vagotomy (SADV group). Heart rate did not change significantly even after administration of 2.5 and 5 mg/kg but decreased markedly on 20 mg/kg injection in all groups. The intact and vagotomy groups had augmented renal sympathetic nerve activity with insignificant changes in mean blood pressure after 5 mg/kg injection of the agent. Insignificant changes of renal sympathetic nerve activity but a remarkable decrease of mean blood pressure appeared after 10 mg/kg propofol. Sustained hypotension in parallel with a profound depression of renal sympathetic nerve activity developed at the dose of 20 mg/kg. In SAD and SADV groups, however, dose-dependent depressions of renal sympathetic nerve activity were accompanied by decreases of mean blood pressure. These results suggest the following: (1) propofol-induced hypotensive effects are probably produced by the central-mediated sympathetic depression. (2) The baroreceptor reflex may be preserved at the lower dose of the agent. (3) Heart rate does not change significantly unless a large dose of propofol is used. The difference in effects on heart rate and on mean blood pressure may denote a greater inhibition of sympathetic vascular outflow than of the cardiac sympathetic outflow regulating cardiac rate and contractility. This hypothesis needs further clarification.

Effects of induced hypothermia on renal sympathetic nerve activity and baroreceptor reflex in urethane-anesthetized rabbits.

ObjectiveTo evaluate the role of the autonomic nervous system in hemodynamic changes during induced hypothermia. DesignProspective, randomized animal study. SettingAn animal research laboratory in a medical university. SubjectsA total of 29 anesthetized rabbits. InterventionsAnimals were anesthetized by intraperitoneal urethane. After tracheostomy and administration of gallamine, respiration was maintained by mechanical ventilatory support. The animals were divided into five groups (one control and the four experimental groups); animals were treated with an intact neuraxis and normothermia (control group), animals with an intact neuraxis (intact group), cervical vagotomized animals (vagotomy group), the carotid sinus and aortic nerves denervated animals (SAD group), and animals with SAD plus vagotomy (SADV group). The left renal sympathetic nerves were exposed by a retroperitoneal approach. Measurements and Main ResultsWe examined the effects of surface cooling on HR, mean arterial pressure, central venous pressure, and renal sympathetic nerve activity (RSNA) in the animals. Changes of baroreflex sensitivity and plasma catecholamines were also measured simultaneously. Surface cooling caused progressive and profound decreases in HR in all experimental groups. In all groups, RSNAs increased at the early phase, which were followed by return to the precooling level. ConclusionsHemodynamics and RSNA during induced hypothermia are regulated by mechanisms other than the baroreceptor reflex system, possibly the dermal cold receptors. Suppression of the baroreflex occurred on HR but not on RSNA during hypothermia, which may indicate direct effects of hypothermia on the heart. RSNA responses may be activated earlier than systemic catecholamine responses during induced hypothermia.

Repetitive post-training exposure to enflurane modifies spatial memory in mice

Background Previously the authors found that a single post‐training exposure to enflurane or isoflurane, but not halothane, enhanced memory storage in an active avoidance task, which is a behavior with underlying mechanisms that are poorly understood and still debated. In contrast, spatial tasks are known to depend on hippocampal functions. This study investigated the effects of repetitive post‐training exposure to enflurane on spatial memory in mice. Methods Using an eight‐arm radial maze, 80 mice were trained to eat a pellet placed on the end of each of the eight arms. Training occurred on four consecutive days with one trial per day. The number of errors in the first eight choices was recorded to determine performances for each day of training. Immediately after each training session, mice in the enflurane group received 1 h exposure to 0.5%, 1%, or 2% enflurane in air through a calibrated vaporizer. The performance ratios (the ratio of errors on each day compared with the first day of the 4 days) in the control and the enflurane groups were compared. Results The performance ratios (which equals the mean of the error in the fourth day/the error in the first day) in the control, and 0.5%, 1%, and 2% enflurane groups were 0.66, 0.65, and 0.32 (P < 0.01, vs. control), and 0.46 (P < 0.05, vs. control), respectively. Conclusions Repetitive post‐training exposure to 1% and 2% enflurane significantly enhanced spatial memory in the eight‐arm radial maze task. Enflurane enhances consolidation of spatial memory, possibly by affecting hippocampal activity.

Serum glutathione S-transferase alpha as a measure of hepatocellular function following prolonged anaesthesia with sevoflurane and halothane in paediatric patients

We studied the effects of prolonged anaesthesia (4.3–7.7 h) with sevoflurane and halothane on hepatic function in 14 paediatric patients. Hepatic function was assessed using serum concentrations of liver‐specific glutathione S‐transferase alpha (GSTA) before and 0, 3 and 15 h after the end of anaesthesia. A transient significant increase in GSTA over baseline was observed in the sevoflurane group, but not in the halothane group, and the difference between the groups was not significant. These data suggest that, although statistically insignificant, the use of sevoflurane for prolonged anaesthesia in paediatric patients is more likely than halothane to be involved in damage to hepatic function.

Spontaneous breathing with the use of a laryngeal mask airway in children: comparison of sevoflurane and isoflurane

We compared respiratory parameters during anaesthesia with sevoflurane and isoflurane through a laryngeal mask airway (LMA). Children were anaesthetized with O2 and air with 2.3% (1MAC) sevoflurane (n=20) or 1.5% (1MAC) isoflurane (n=20). After insertion of LMA, patients were allowed to breathe spontaneously and respiratory rate (RR) and PECO2 were measured (presurgery state). After the measurement, anaesthetic concentration was increased to 1.3 MAC (3.0% sevoflurane or 2.0% isoflurane) and surgical stimulation was added. Fifteen min after incision, the measurements were again performed (during surgery). In the sevoflurane group, mean RR and PECO2 were 32 breaths.min−1, and 6.0 kPa (45 mmHg) respectively, before surgery, and 35 breaths.min−1 and 7.0 kPa (52 mmHg) during surgery. In the isoflurane group, mean RR and PECO2 were 32 breaths.min−1 and 6.1 kPa (46 mmHg) respectively, before surgery, and 37 breaths.min−1 and 6.7 kPa (52 mmHg) during surgery. There were no statistical differences between the two anaesthetic groups. Clinical respiratory and cardiovascular parameters during spontaneous breathing with LMA in children are similar during sevoflurane and isoflurane anaesthesia.

Subanesthetic concentrations of volatile anesthetics may enhance acquired avoidance training in ddN mice.

The effects of halothane, enflurane, and isoflurane on avoidance training were assessed in male ddN mice. Animals were trained to escape an aversive unconditioned stimulus (electric foot shock) within 3 s after being exposed to a conditioned stimulus (light and buzzer). Immediately after training (first session), the animals were exposed to halothane, enflurane, isoflurane for 120 min and were then tested again on the avoidance task (second session) 30 min after cessation of the exposure. The performance ratios [B/A] (i.e., A is the score in the first session, and B the score in the second) were compared between the anesthetic groups and their respective control groups. Performance ratios in the control animals ([B/A]c) did not reach 100% except for those corresponding to the 0.5 and 1.0 MAC (minimal alveolar anesthetic concentration) halothane groups. Four of the nine performance ratios in the anesthetic groups ([B/A]a) exceeded 1.0. [B/A]a exceeded [B/A]c by 18.7% in the 0.25 MAC halothane group ( P < 0.05), by 13.5% in the 0.31 MAC enflurane group (i.e., not significant), and by 17.3% in the 0.29 MAC isoflurane group ( P < 0.01). [B/A]a/[B/A]c decreased dose-dependently for each anesthetic group. These results suggest that low concentrations of halothane, enflurane, and isoflurane may enhance the performance of ddN mice in acquired avoidance training performed 30 min after anesthetic exposure.