Takefumi Inada

Effect of propofol and isoflurane anaesthesia on the immune response to surgery.

There are two major subpopulations of peripheral helper T lymphocytes: T helper 1 (Th1) and T helper 2 (Th2) cells. Surgical stress increases the number of Th2 cells, and decreases that of Th1 cells, resulting in a decrease in the Th1/Th2 ratio, and, consequently, in suppressed cell‐mediated immunity. Since anaesthesia can suppress the stress response to surgery, it may inhibit the decrease in the Th1/Th2 ratio. Using flow cytometry, we studied whether propofol anaesthesia (n = 9) or isoflurane anaesthesia (n = 9) had more effect on the decrease in the Th1/Th2 ratio after surgery in patients undergoing craniotomy. The Th1/Th2 ratio decreased significantly after isoflurane anaesthesia (p = 0.011), while it did not change after propofol anaesthesia. The ratio was significantly lower with isoflurane than propofol (p = 0.009). Propofol anaesthesia attenuated the surgical stress‐induced adverse immune response better than isoflurane anaesthesia.

Enhancement of Antitumor Immunity after Propofol Treatment in Mice

Propofol and midazolam are the most widely used sedatives in the intensive care setting after surgery. We studied whether these sedatives had any antitumor immunity effects in mice. Mice were given intraperitoneal injections of propofol or midazolam and subcutaneous inoculation of tumor cells (EL4). Then, spleen cells were collected and the in vitro activity of cytotoxic T lymphocytes (CTL) was measured using flow cytometry. The in vitro activity of CTL against EL4 was significantly greater after propofol injection compared with its vehicle (Intralipid) or saline. Midazolam had no effect on CTL activity. We also studied whether tumor growth in vivo was affected by the administration of propofol. Tumor growth was significantly suppressed in mice that were given propofol, compared with tumor growth in mice given saline. Therefore, it is concluded that propofol may have a beneficial effect on antitumor immunity in mice.

Orotracheal intubation through the laryngeal mask airway in paediatric patients with Treacher-Collins syndrome

The laryngeal mask airway (LMA) is useful as an airway intubator (conduit) for an intubating tracheal bougie or fibreoptic bronchoscope, over which a tracheal tube is passed. However, in our paediatric patients with Treacher‐Collins syndrome, only the latter technique was successful. This was attributed to the fact that a posteriorly protruded tongue displaced the LMA, made the glottis move considerably anterior and interfered with the attempts to enter the trachea with a bougie. Downward displacement of the epiglottis, which can sometimes impair the intubation technique through the LMA, was not observed in our patients. Partial obstruction of a tracheal tube within the LMA occurred in one of the patients.

Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol

The intravenous anesthetic propofol has a number of well-known nonanesthetic effects, including anti-oxidation and anti-emesis. Another interesting nonanesthetic effect of propofol may be its cyclooxygenase (COX)-inhibiting activity. This activity may have important clinical implications, as propofol could have antitumor properties through COX inhibition. Propofol could counteract the activity of COX, which elicits, via its major product prostaglandin E2, (1) tumor growth stimulation, (2) increased tumor survival, (3) enhanced tumor invasiveness, (4) stimulation of new vessel formation, and (5) tumor evasion of host immune surveillance through suppression of immune cell functions. Indeed, accumulated evidence indicates that propofol suppresses the proliferation, motility, and invasiveness of tumors in vitro and in vivo. Therefore, propofol could be a particularly suitable anesthetic for use during the perioperative period for cancer surgery. However, whether the COX-inhibiting activity of propofol is related to the reported antitumor properties of propofol is not known. Definitive evidence remains to be provided.

Xenon Inhibits but N2o Enhances Ketamine-induced c-fos Expression in the Rat Posterior Cingulate and Retrosplenial Cortices

Both nitrous oxide (N2O) and xenon are N-methyl-d-aspartate receptor antagonists that have psychotomimetic effects and cause neuronal injuries in the posterior cingulate and retrosplenial cortices. We investigated the effect of xenon, xenon with ketamine, N2O, and N2O with ketamine on c-Fos expression in the rat posterior cingulate and retrosplenial cortices, a marker of psychotomimetic effects. Brain sections were prepared, and c-Fos expression was detected with immunohistochemical methods. A loss of microtubule-associated protein 2, a marker of neuronal injury, was also investigated. The number of Fos-like immunoreactivity positive cells by ketamine IV at a dose of 5 mg/kg under 70% N2O (128 ± 12 cells per 0.5 mm2) was significantly more than those under 30% (15 ± 2 cells per 0.5 mm2) and 70% xenon (2 ± 1 cells per 0.5 mm2). Despite differences in c-fos immunoreactivity, there was no loss of microtubule-associated protein 2 immunoreactivity in any group examined. Xenon may suppress the adverse neuronal effects of ketamine, and combined use of xenon and ketamine seems to be safe in respect to neuronal adverse effects. Implications Xenon may suppress adverse neuronal effects of ketamine. Conversely, combined use of N2O and ketamine may increase the risk of neuronal adverse effects, such as psychotomimetic effects.

Propofol and Midazolam Inhibit Gastric Emptying and Gastrointestinal Transit in Mice

We studied the effect of propofol and midazolam on gastric emptying and gastrointestinal transit in mice. Ten minutes after intraperitoneal injection of propofol or midazolam, 0.2 mL of saline containing fluorescent microbeads was infused into the stomach. Thirty minutes later, the gastrointestinal tract was excised, and gastric emptying and gastrointestinal transit were calculated by measuring the quantity of fluorescent microbeads in the gastrointestinal tract by using a flow cytometer. At a dose that produced a light level of sedation (mice righted themselves within 2 s), both drugs significantly, but weakly, inhibited gastric emptying to a similar degree (propofol: P < 0.001 versus control value; 95% confidence interval [CI] for difference, 4.9%–20.2%; midazolam: P < 0.001 versus control value; 95% CI for difference, 7.8%–14.7%). Midazolam, but not propofol, delayed gastrointestinal transit (P < 0.001). At a larger dose that produced a deeper level of sedation (absence of righting reflex >10 s), both drugs significantly inhibited gastric emptying (propofol: P < 0.001; 95% CI for difference, 31.4%–61.2%; midazolam: P < 0.001; 95% CI for difference, 30.8%–61.1%) and gastrointestinal transit (P < 0.001 for both drugs).

Edaravone, a free radical scavenger, mitigates both gray and white matter damages after global cerebral ischemia in rats.

Recent studies have shown that similar to cerebral gray matter (mainly composed of neuronal perikarya), white matter (composed of axons and glias) is vulnerable to ischemia. Edaravone, a free radical scavenger, has neuroprotective effects against focal cerebral ischemia even in humans. In this study, we investigated the time course and the severity of both gray and white matter damage following global cerebral ischemia by cardiac arrest, and examined whether edaravone protected the gray and the white matter. Male Sprague-Dawley rats were used. Global cerebral ischemia was induced by 5 min of cardiac arrest and resuscitation (CAR). Edaravone, 3 mg/kg, was administered intravenously either immediately or 60 min after CAR. The morphological damage was assessed by cresyl violet staining. The microtubule-associated protein 2 (a maker of neuronal perikarya and dendrites), the beta amyloid precursor protein (the accumulation of which is a maker of axonal damage), and the ionized calcium binding adaptor molecule 1 (a marker of microglia) were stained for immunohistochemical analysis. Significant neuronal perikaryal damage and marked microglial activation were observed in the hippocampal CA1 region with little axonal damage one week after CAR. Two weeks after CAR, the perikaryal damage and microglial activation were unchanged, but obvious axonal damage occurred. Administration of edaravone 60 min after CAR significantly mitigated the perikaryal damage, the axonal damage, and the microglial activation. Our results show that axonal damage develops slower than perikaryal damage and that edaravone can protect both gray and white matter after CAR in rats.

Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis.

The treatment of sepsis may require mechanical ventilation of the lungs and sedation. Because neutrophils are the most important effector cells for protecting against sepsis, and propofol and midazolam are the most widely used anesthetics for sedation, we studied the effects of these two anesthetics on the neutrophil function during sepsis. Sepsis was induced in rats by cecal ligation and puncture. At either 4 h or 24 h after cecal ligation and puncture, blood and peritoneal neutrophils were obtained, incubated with the test anesthetics, and the hydrogen peroxide (H2O2) production and CD11b/c expression were determined by flow cytometry. In both early (at 4 h) and late (at 24 h) sepsis, propofol and midazolam depressed H2O2 production by blood and peritoneal neutrophils at clinical concentrations. Propofol caused more depression than midazolam (P < 0.005). In both early and late sepsis, the effect of the anesthetics on the up-regulation of the stimulation-induced CD11b/c expression on blood neutrophils was minimal at clinical concentrations. If these results ultimately become clinically relevant, midazolam may be preferable to propofol for sedation during sepsis. Implications In septic patients, mechanical ventilation of the lungs is sometimes needed, and propofol and midazolam are widely used for sedation. Midazolam was less inhibitory for neutrophil function than propofol during sepsis; thus, midazolam may be preferable to propofol for sedation during sepsis for preserving the neutrophil function to combat sepsis.

Changes in tracheal tube position during laparoscopic cholecystectomy

The distance from the carina to the tip of the tracheal tube was measured with a fibreoptic bronchoscope in 21 consecutive patients undergoing elective laparoscopic cholecystectomy. After placement of an Eschmann tracheal tube with a printed intubation guide mark at the vocal cords, the distance was 28 (15) [5–54]mm (mean (SD) [range]). The tube was then repositioned so that the distance was 34 (3) [30–40]mm from tip of the tube to the carina. After creation of pneumoperitoneum, the distance was significantly decreased to 26 (5) [17–35] mm (p < 0.005), which was not significantly altered by subsequent moving of the patient to the reverse Trendelenburg and left lateral tilt position. The maximum distance of tube migration was 8 (4) [0–15]mm. Four out of 21 patients would have been at risk of bronchial intubation after pneumoperitoneum if the tube had not been repositioned. Placement of the tube according to the guide mark is not recommended for laparoscopic cholecystectomy.

The differential effects of nitrous oxide and xenon on extracellular dopamine levels in the rat nucleus accumbens: a microdialysis study.

Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the action of various psychotropic and addictive drugs, such as antagonists of the N-methyl-d-aspartate subtype of the glutamate. Although both nitrous oxide and xenon are N-methyl-d-aspartate receptor antagonists, they differ in their potential for producing neuropsychological toxicity; therefore, we decided to examine their effects on both spontaneous and ketamine-induced extracellular dopamine levels in the NAC. A microdialysis probe was implanted into the NAC in each of 35 rats, which were randomly assigned to one of six groups: exposure to 40% O2, exposure to 60% nitrous oxide (0.27 MAC), exposure to 43% xenon (0.27 MAC) for 60 min, and three groups exposed to either 40% O2, 60% nitrous oxide, or 43% xenon for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure. Perfusate samples were collected every 20 min, and the dopamine levels were measured using a high-performance liquid chromatography system. Nitrous oxide, but not xenon, significantly increased the dopamine level. Ketamine significantly increased the dopamine level, and this was significantly inhibited by xenon, but not by nitrous oxide. These data suggest that the difference in neuropsychological activity between nitrous oxide and xenon is partly due to their differential effects on the mesolimbic dopamine system.