Shinya Arimura

Renal function in patients with high serum fluoride concentrations after prolonged sevoflurane anesthesia

Background In studies of methoxyflurane-induced nephrotoxicity, renal-concentrating impairment has been observed only when serum inorganic fluoride concentrations exceed 50 micro Meter. Prolonged sevoflurane anesthesia can result in serum inorganic fluoride concentrations in excess of 50 micro Meter. The authors compared renal function after prolonged sevoflurane anesthesia with that after isoflurane anesthesia. In addition, they measured urinary excretion of N-acetyl-beta-glucosaminidase (NAG), a sensitive index of renal tubular damage, during the 3-day period after anesthesia.

Compound A Concentrations During Low-Flow Sevoflurane Anesthesia Correlate Directly with the Concentration of Monovalent Bases in Carbon Dioxide Absorbents

UNLABELLED: Sevoflurane degrades to Compound A, which is nephrotoxic in rats. Potassium hydroxide (KOH) and sodium hydroxide (NaOH) are primary determinants of this degradation reaction. To address this, new carbon dioxide absorbents, such as Amsorb((R)) (A; Armstrong Medical, Coleraine, Northern Ireland), which contains neither KOH nor NaOH, Dragersorb 800 Plus((R)) (D; Drager, Luebeck, Germany), and Medisorb((R)) (M; Datex-Ohmeda, Bromma, Sweden), which contain some NaOH (1% to 2%) and only trace amounts of KOH (0.003%), were recently developed. We compared Compound A concentrations using these three CO(2) absorbents during low-flow (1 L/min) sevoflurane anesthesia in surgical patients, with those using a conventional CO(2) absorbent, Dragersorb 800 (C). The mean Compound A concentrations +/- SD using C, A, D, and M were 18.7 +/- 2.5, 1.8 +/- 0.7, 13.3 +/- 3.5, and 11.2 +/- 2.6 ppm, respectively, with significant differences (P < 0.001; A versus C, A versus D, A versus M, C versus D, C versus M). Amsorb prevented the degradation of sevoflurane to Compound A, whereas Dragersorb 800 Plus and Medisorb decreased the degradation to Compound A. IMPLICATIONS: Sevoflurane degradation to Compound A is decreased by lowering the concentration of monovalent bases in the carbon dioxide absorbent (Dragersorb 800 Plus) [Drager, Luebeck, Germany] and Medisorb) [Datex-Ohmeda, Bromma, Sweden]) and is virtually eliminated in the absence of these bases (Amsorb) [Armstrong Medical, Coleraine, Northern Ireland]).

The interaction between propofol and clonidine for loss of consciousness.

Clonidine premedication reduces the intraoperative requirement for opioids and volatile anesthetics. Clonidine also reduces the induction dose of IV anesthetics. There is no information, however, regarding the effect of oral clonidine premedication on the propofol blood concentrations required for loss of consciousness, and the interaction between propofol and clonidine. We randomly administered target effect-site concentrations of propofol ranging from 0.5 to 5. 0 &mgr;g/mL by using computer-assisted target-controlled infusion to 3 groups of healthy male patients: Control (n = 35), 2.5 &mgr;g/kg Clonidine (n = 36), and 5.0 &mgr;g/kg Clonidine (n = 36) groups. Nothing was administered to the Control group. Clonidine (2.5 or 5.0 &mgr;g/kg) was administered orally 90 min before the induction of anesthesia in the Clonidine groups. After equilibration between the blood and effect-site for 15 min, a verbal command to open their eyes was given two times to the patients. Arterial blood samples for analysis of the serum propofol and clonidine concentrations were taken immediately before verbal commands were given. Measured serum propofol concentrations in equilibrium with the effect-site at which 50% of the patients did not respond to verbal commands (EC50 for loss of consciousness) were determined by logistic regression. The EC50 ± se values in the Control, 2.5 &mgr;g/kg Clonidine, and 5.0 &mgr;g/kg Clonidine groups were 2.67 ± 0.18, 1.31 ± 0.12, and 0.91 ± 0.13 &mgr;g/mL, respectively. The EC50 in the 2.5 and 5.0 &mgr;g/kg clonidine groups was significantly smaller than that in the Control group (P < 0.001). The use of a response surface modeling analysis indicated that there was an additive interaction between measured arterial propofol and clonidine concentrations in relation to loss of consciousness. These results indicate that propofol and clonidine act additively for loss of consciousness.

The Carbon Dioxide Absorption Capacity of Amsorb® is Half That of Soda Lime

A new CO2 absorbent, Amsorb® (A), which does not contain monovalent bases, is ideal because it does not degrade volatile anesthetics to either Compound A (from sevoflurane) or carbon monoxide (from desflurane, enflurane, or isoflurane). The CO2 absorption capacity of A, however, has not been investigated under clinical conditions. In this study, we compared the longevity (time to exhaustion) and CO2 absorption capacity (the volume of CO2 absorbed before CO2 rebreathing occurs) of A under low-flow anesthesia (1 L/min) with those of two soda lime absorbents—Medisorb® (M) and Sodasorb® (S)—by using a 750-mL ADU canister and a 1350-mL Aestiva 3000 canister. In the study with the ADU canister, the longevity of A was 213 ± 71 min, significantly less than those of M (445 ± 125;P < 0.01) and S (503 ± 89;P < 0.001). The CO2 absorption capacity (L/100 g absorbent) of A was 5.5 ± 1.2, significantly less than those of M (10.7 ± 1.7) and S (12.1 ± 1.8;P < 0.001). In the study with the Aestiva 3000 canister, the longevity of A was 218 ± 61 min, significantly less than those of M (538 ± 136) and S (528 ± 103;P < 0.001). The CO2 absorption capacity (L/100 g absorbent) of A was 7.6 ± 1.6, significantly less than those of M (14.4 ± 1.8) and S (14.8 ± 2.3;P < 0.001). These results indicate that the CO2 absorption capacity of A is half that of M or S and that the difference in the CO2 absorption capacity between A and M or S is almost constant, regardless of the canister design.

Early pregnancy does not reduce the C50 of propofol for loss of consciousness

Requirements for inhaled anesthetics decrease during pregnancy. There are no published data, however, regarding propofol requirements in these patients. Because propofol is often used for induction of general anesthesia when surgery is necessary in early pregnancy, we investigated whether early pregnancy reduces the requirement of propofol for loss of consciousness using a computer-assisted target-controlled infusion (TCI). Propofol was administered using TCI to provide stable concentrations and to allow equilibration between blood and effect-site (central compartment) concentrations. Randomly selected target concentrations of propofol (1.5–4.5 &mgr;g/mL) were administered to both pregnant women (n = 36) who were scheduled for pregnancy termination and nonpregnant women (n = 36) who were scheduled for elective orthopedic or otorhinolaryngologic surgery. The median gestation of the pregnant women was 8 wk (range, 6–12 wk). Venous blood samples for analysis of the serum propofol concentration were taken at 3 min and 8 min after equilibration of the propofol concentration. After a 10-min equilibration period of the predetermined propofol blood concentration, a verbal command to open their eyes was given to the patients twice, accompanied by rubbing of their shoulders. Serum propofol concentrations at which 50% of the patients did not respond to verbal commands (C50 for loss of consciousness) were determined by logistic regression. There was no significant difference in C50 ± se of propofol for loss of consciousness between the Nonpregnant (2.1 ± 0.2 &mgr;g/mL) and Pregnant (2.0 ± 0.2 &mgr;g/mL) groups. These results indicate that early pregnancy does not decrease the concentration of propofol required for loss of consciousness.

Oral clonidine premedication reduces the awakening concentration of propofol.

To investigate the effects of oral clonidine premedication on emergence from propofol/fentanyl anesthesia, we studied 72 healthy male patients who were undergoing elective orthopedic surgery: the Control group, the 2.5 &mgr;g/kg Clonidine group, and the 5.0 &mgr;g/kg Clonidine group (n = 24 each). Nothing was administered to the Control group. Clonidine (2.5 or 5.0 &mgr;g/kg) was orally administered 90 min before the induction of anesthesia in the Clonidine groups. Patients were anesthetized with computer-assisted continuous infusion of propofol and fentanyl, with the three groups receiving the same concentrations of propofol (3 &mgr;g/mL) and fentanyl (1 ng/mL) starting 20 to 30 min before the end of surgery. Propofol infusion was then abruptly discontinued at the end of surgery in all patients. After propofol was discontinued, the response to verbal commands was evaluated every 30 s, and arterial blood samples for propofol and clonidine concentrations were taken when the patients opened their eyes. The time required to respond to a verbal command was 14.9 ± 8.3 min for the 5.0 &mgr;g/kg Clonidine group, and this was significantly longer than the Control (8.2 ± 5.0 min) and the 2.5 &mgr;g/kg Clonidine (9.0 ± 3.7 min) groups (P < 0.01). Serum propofol concentration at awakening in the 5.0 &mgr;g/kg Clonidine group was 1.0 ± 0.4 &mgr;g/mL, which was significantly smaller than the Control (1.6 ± 0.4 &mgr;g/mL) and the 2.5 &mgr;g/kg Clonidine (1.4 ± 0.3 &mgr;g/mL) groups (P < 0.01). The blood clonidine concentration was associated with a decrease in the awakening propofol concentration. In conclusion, 5 &mgr;g/kg oral clonidine premedication decreases the awakening propofol concentration and delays arousal from propofol/fentanyl anesthesia.

Temperature and humidity of the Drager Cato anesthetic machine circuit

AbstractPurpose. The DrÄger Cato anesthetic machine (DrÄger, LÜbeck, Germany) effectively humidifies and warms anesthetic gases, because it has a built-in hotplate to heat the breathing system, and expired gas passes through the CO2 absorbent three times during one breath. In the present study, we measured the temperature and absolute humidity (AH) of the anesthetic circuit in the DrÄger Cato machine with and without heat moisture exchangers (HME), and compared them with those in another anesthetic machine, the Aestiva/5 (Datex-Ohmeda, Helsinki, Finland). Methods. Forty-eight adult patients were randomly assigned to one of eight groups according to the anesthetic machine, fresh gas flow (FGF), and the use of HME (n = 6 each): Cato 0.5 l·min−1 without HME (group 1), Cato 1.0 l·min−1 without HME (group 2), Cato 0.5 l·min−1 with HME (group 3), Cato 1.0 l·min−1 with HME (group 4), Aestiva 0.5 l·min−1 without HME (group 5), Aestiva 1.0 l·min−1 without HME (group 6), Aestiva 0.5 l·min−1 with HME (group 7), and Aestiva 1.0 l·min−1 with HME (group 8). The temperature and AH of the anesthetic gases were measured with a Moiscope (S.K.I. Net, Tokyo, Japan), which was placed between the endotracheal tube and the Y-piece of the anesthetic circuit. The HME was placed between the Moiscope and the Y-piece of the anesthetic circuit. The temperature and AH of the anesthetic gases were measured at 5, 10, and 15 min and then every 15 min up to 150 min after tracheal intubation. Results. Among the groups without HME (groups 1, 2, 5, and 6), the inspired temperatures and AH in groups 1 and 2 were significantly higher than those in groups 5 and 6 at all times during the study period (P ≪ 0.01–0.001). The inspired temperatures and AH of the groups with HME (groups 3, 4, 7, and 8), were significantly higher than those in groups 2, 5, and 6 (P ≪ 0.01–0.001). Among the groups with HME, the AH in group 3 was significantly higher than that in group 8 until the final study period. Conclusion. The present study indicates that the DrÄger Cato machine was more effective in warming and humidifying respiratory gas than the Aestiva/5, and that Aestiva/5 without HME does not reach the optimal temperature and humidity ranges, even if minimal flow anesthesia (0.5 l·min−1) is performed.

Expression of ras GTPase-activating protein (GAP) in human normal chorionic villi and hydatidiform mole

Ras GTPase-activating protein (GAP), an important downregulator of Ras activity, has previously been shown to be abundant in human placenta. The expression of p120 and p100 isoforms of GAP in human normal chorionic villi (n=5) and hydatidiform mole (n=5) was investigated to clarify the involvement of Ras GAP in the growth of chorionic villi in the first trimester of pregnancy. Immunoblot analysis revealed that both p120- and p100-GAP isoforms were remarkably less expressed in mole villi than in normal chorionic villi. The expression of p100-GAP significantly reduced in comparison with that of pl20-GAP in mole villi. Northern blot analysis showed that the amount of GAP mRNA reduced in hydatidiform mole less than one-third of that in normal chorionic villi. The GAP activity, measured by the effect of tissue extract on the hydrolysis of Ras-bound GTP, was significantly lower in hydatidiform mole than in normal chorionic villi. These results suggest that Ras GAP may play an important role in the normal growth and differentiation of human chorionic villi in the first trimester.

Phosphorylation of H-ras Proteins by Protein Kinase A

Protein phosphorylation is one of several representative post-translational modifications. Cyclic AMP-dependent protein kinase (PKA) plays the crucial and varying role of signal transduction. On the other hand, ras proteins plays an important role in cell proliferation and growth. Although a previous report showed that H-ras protein was phosphorylated by PKA, the stoichiometry was not determined, so we investigated the stoichiometry of phosphorylation of the protein by PKA. H-ras cDNA inserted into a pGEX-2T expressing vector produced high levels of recombinant H-ras (rH-ras) in a fusion protein with glutathione S-transferase. rH-ras was obtained after cleavage by thrombin. Phosphorylation of ras protein by the catalytic subunit of PKA was performed, and the radioactivity was counted after SDS-PAGE and autoradiography. The results indicate that less than 0.1 mol of phosphate was incorporated per mol of H-ras protein, and suggest that H-ras protein could not be a physiologically meaningful substrate for PKA.

An EGF receptor-mediated signal attenuates the inhibitory effect of LPA on an adenylate cyclase activity

A tyrosine kinase receptor-mediated and a heterotrimeric G protein-coupled receptor-mediated signals have been shown to evoke distinct intracellular signaling events. There has been increasing evidence that cross-talk exists between a tyrosine kinase receptor-mediated and a heterotrimeric G protein-coupled receptor-mediated signal transduction pathways. In the present study, we have studied effects of EGF receptor activation on activities of inhibitory G protein (Gi). We show that the amounts of Gi/Go ADP-ribosylated by islet-activating protein (IAP) increased by 30-40% in the membranes of Rat 1 fibroblast cells pretreated with EGF compared with those without pretreatment. When an effect of lysophosphatidic acid (LPA) stimulation on an adenylate cyclase activity was examined, LPA partly attenuated forskolin-stimulated adenylate cyclase activity via Gi because IAP pretreatment blocked the inhibitory effect of LPA. Pretreatment with EGF reduced the ability of LPA to inhibit the forskolin-stimulated adenylate cyclase activity, while the pretreatment did not have any effects on the forskolin-stimulated activity. Thus, the EGF receptor-mediated signal appears to cause the impairment of Gi function in Rat 1 fibroblast cells.