Tomiei Kazama

Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory.

Background: In animal models, neonatal exposure to volatile anesthetics induces neuroapoptosis, leading to memory deficits in adulthood. However, effects of neonatal exposure to desflurane are largely unknown. Methods: Six-day-old C57BL/6 mice were exposed to equivalent doses of desflurane, sevoflurane, or isoflurane for 3 or 6 h. Minimum alveolar concentration was determined by the tail-clamp method as a function of anesthesia duration. Apoptosis was evaluated by immunohistochemical staining for activated caspase-3, and by TUNEL. Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was performed to examine apoptosis comparatively. The open-field, elevated plus-maze, Y-maze, and fear conditioning tests were performed to evaluate general activity, anxiety-related behavior, working memory, and long-term memory, respectively. Results: Minimum alveolar concentrations at 1 h were determined to be 11.5% for desflurane, 3.8% for sevoflurane, and 2.7% for isoflurane in 6-day-old mice. Neonatal exposure to desflurane (8%) induced neuroapoptosis with an anatomic pattern similar to that of sevoflurane or isoflurane; however, desflurane induced significantly greater levels of neuroapoptosis than almost equivalent doses of sevoflurane (3%) or isoflurane (2%). In adulthood, mice treated with these anesthetics had impaired long-term memory, whereas no significant anomalies were detected in the open-field and the elevated plus-maze tests. Although performance in a working memory task was normal in mice exposed neonatally to sevoflurane or isoflurane, mice exposed to desflurane had significantly impaired working memory. Conclusions: In an animal model, neonatal desflurane exposure induced more neuroapoptosis than did sevoflurane or isoflurane and impaired working memory, suggesting that desflurane is more neurotoxic than sevoflurane or isoflurane.

The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data.

BACKGROUND: With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. METHODS: Three compartmental PK models for propofol, called the “Marsh,” the “Schnider,” and the “Schüttler” models, and 1 physiologically based recirculatory model called the “Upton” model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. RESULTS: The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. CONCLUSION: When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

ERK2 Contributes to the Control of Social Behaviors in Mice

Signaling through extracellular signal-regulated kinase (ERK) is important in multiple signal transduction networks in the CNS. However, the specific role of ERK2 in in vivo brain functions is not fully understood. Here we show that ERK2 play a critical role in regulating social behaviors as well as cognitive and emotional behaviors in mice. To study the brain function of ERK2, we used a conditional, region-specific, genetic approach to target Erk2 using the Cre/loxP strategy with a nestin promoter-driven cre transgenic mouse line to induce recombination in the CNS. The resulting Erk2 conditional knock-out (CKO) mice, in which Erk2 was abrogated specifically in the CNS, were viable and fertile with a normal appearance. These mice, however, exhibited marked anomalies in multiple aspects of social behaviors related to facets of autism-spectrum disorders: elevated aggressive behaviors, deficits in maternal nurturing, poor nest-building, and lower levels of social familiarity and social interaction. Erk2 CKO mice also exhibited decreased anxiety-related behaviors and impaired long-term memory. Pharmacological inhibition of ERK1 phosphorylation in Erk2 CKO mice did not affect the impairments in social behaviors and learning disabilities, indicating that ERK2, but not ERK1 plays a critical role in these behaviors. Our findings suggest that ERK2 has complex and multiple roles in the CNS, with important implications for human psychiatric disorders characterized by deficits in social behaviors.

Early Phase Pharmacokinetics but Not Pharmacodynamics Are Influenced by Propofol Infusion Rate

Background:Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. Methods:Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg · kg−1 · h−1. Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. Results:Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. Conclusions:This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg · kg−1 · h−1. The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.

Deletion of ERK1 and ERK2 in the CNS Causes Cortical Abnormalities and Neonatal Lethality: Erk1 Deficiency Enhances the Impairment of Neurogenesis in Erk2-Deficient Mice

Intracellular signaling through extracellular signal-regulated kinase (ERK) is important in regulating cellular functions in a variety of tissues including the CNS. Although ERK1 and ERK2 have a very similar substrate profile and amino acid sequences, there are strikingly different phenotypes between Erk1- and Erk2-deficient mice. Thus, the question arose as to whether these two proteins are functional homologs that compensate for each other, or whether they have distinct functions. Here, we generated double knock-out mice deficient for Erk2 in the CNS, with ubiquitous homozygous deletion of Erk1, and compared the phenotypes of these mice with those of monogenic Erk2-deficient mice. Although we did obtain double knock-out newborn pups, they survived for not >1 d. These pups appeared normal just after parturition. However, they had no milk in their stomachs even 6–7 h after birth. Intracerebral hemorrhages with varying location and severity were observed. The ventricular zones and corpus callosum of the double knock-out pups did not develop adequately. Neuronal size and nuclear morphology in some brain regions were markedly aberrant in the double knock-out pups compared with controls, while deficiency in Erk2 only caused a mild phenotype. These results suggest that total ERK1/2 activity governs cellular behaviors to ensure proper brain development.

Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum.

The effect of isoflurane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) modulated by pargyline, monoamine oxidase inhibitor, was studied using in vivo microdialysis techniques. A microdialysis probe was implanted into the right striatum of male SD rats. Each rat (n=5-6) was given saline or the same volume of 30 or 75 mg kg(-1) pargyline intraperitoneally with or without 1 h isoflurane anesthesia (1 or 3%). Isoflurane anesthesia increased the extracellular concentration of DA in high dose (3%) and increased the metabolite concentrations in a dose-dependent manner. Pargyline administration increased the extracellular concentration of DA and 3-MT, and decreased that of other metabolites. After 30 mg kg(-1) pargyline treatment, 1% isoflurane-induced DA release and increasing of 3-MT were preserved, whereas high dose isoflurane (3%) decreased the concentration of metabolites (DOPAC and HVA), despite of the increase by low dose isoflurane (DOPAC). When 75 mg kg(-1) pargyline was administered, isoflurane anesthesia decreased the concentration of DA and DOPAC. The isoflurane-induced 3-MT increase was preserved in all experiments. Our results suggest that isoflurane anesthesia induced biphasic effect on DA regulation probably by the potentiation of DA release and the inhibition of DA synthesis. Isoflurane might modulate DA homeostasis presynaptically.

Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood.

Background:In animal models, exposure to general anesthetics induces widespread increases in neuronal apoptosis in the developing brain. Subsequently, abnormalities in brain functioning are found in adulthood, long after the anesthetic exposure. These abnormalities include not only reduced learning abilities but also impaired social behaviors, suggesting pervasive deficits in brain functioning. But the underlying features of these deficits are still largely unknown. Methods:Six-day-old C57BL/6 female mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (1.3%) as part of the carrier gas mixture. At 7–9 weeks of age, they were mated with healthy males. The first day after parturition, the maternal behaviors of dams were evaluated. The survival rate of newborn pups was recorded for 6 days after birth. Results:Female mice that received neonatal exposure to sevoflurane could mate normally and deliver healthy pups similar to controls. But these dams often left the pups scattered in the cage and nurtured them very little, so that about half of the pups died within a couple of days. Yet, these dams did not show any deficits in olfactory or exploratory behaviors. Notably, pups born to sevoflurane-treated dams were successfully fostered when nursed by control dams. Mice coadministered of hydrogen gas with sevoflurane did not exhibit the deficits of maternal behaviors. Conclusion:In an animal model, sevoflurane exposure in the developing brain caused serious impairment of maternal behaviors when fostering their pups, suggesting pervasive impairment of brain functions including innate behavior essential to species survival.

A novel continuous cardiac output monitor based on pulse wave transit time

Monitoring cardiac output (CO) is important for the management of patient circulation in an operation room (OR) or intensive care unit (ICU). We assumed that the change in pulse wave transit time (PWTT) obtained from an electrocardiogram (ECG) and a pulse oximeter wave is correlated with the change in stroke volume (SV), from which CO is derived. The present study reports the verification of this hypothesis using a hemodynamic analysis theory and animal study. PWTT consists of a pre-ejection period (PEP), the pulse transit time through an elasticity artery (T1), and the pulse transit time through peripheral resistance arteries (T2). We assumed a consistent negative correlation between PWTT and SV under all conditions of varying circulatory dynamics. The equation for calculating SV from PWTT was derived based on the following procedures. 1. Approximating SV using a linear equation of PWTT. 2. The slope and y-intercept of the above equation were determined under consideration of vessel compliance (SV was divided by Pulse Pressure (PP)), animal type, and the inherent relationship between PP and PWTT. Animal study was performed to verify the above-mentioned assumption. The correlation coefficient of PWTT and SV became r = −0.710 (p < 0.001), and a good correlation was admitted. It has been confirmed that accurate continuous CO and SV measurement is only possible by monitoring regular clinical parameters (ECG, SpO2, and NIBP).

Comparison of a New Cardiac Output Ultrasound Dilution Method With Thermodilution Technique in Adult Patients Under General Anesthesia

OBJECTIVE The purpose of this study was to investigate the reliability of cardiac output (CO) measured by a new ultrasound dilution method (COud) in comparison with CO by pulmonary artery thermodilution (COtd) in adult patients undergoing surgery. DESIGN A prospective study. SETTING A university hospital, single institutional. PARTICIPANTS Twenty-nine adult patients undergoing abdominal surgery. MEASUREMENTS AND MAIN RESULTS After approval of the institutional ethics review board, 29 adult patients were evaluated. After induction, radial and pulmonary artery catheters were inserted. A disposable extracorporeal AV loop was connected between existing arterial and central venous catheters. Reusable ultrasound sensors that measure changes in blood ultrasound velocity after dilution by isotonic saline were clamped onto the arterial and venous limbs of the loop. Ultrasound dilution (UD) measurements (COstatus; Transonic Systems, Inc, Ithaca, NY) were obtained by injecting 30 mL of body-temperature isotonic saline into the venous limb of the AV loop. An average of 3 COud and 5 COtd was obtained for comparison. Bland-Altman plot and correlation analysis were used for statistical comparison. A total of 142 comparison measurements were obtained. The correlation coefficient between the 2 techniques was r = 0.91. Bland-Altman analysis did not produce any significant bias (bias = 0.02, standard deviation = 0.56). The percentage error of these data was 23.53%. CONCLUSIONS COud measurements agreed well with COtd. The results of this study indicated that COud might be interchangeable with conventional COtd in perioperative adult patients.

Effect of remifentanil on plasma propofol concentration and bispectral index during propofol anaesthesia

BACKGROUND Propofol and remifentanil are commonly administered together in clinical anaesthesia, but the effect of remifentanil on the plasma concentration of propofol has yet to be established. The aim of the present study was to investigate the effect of remifentanil on plasma propofol concentrations (Cp) in the absence of surgical stimulation. METHODS Thirty-eight patients undergoing elective gynaecologic surgery were randomly assigned to receive one of the three remifentanil doses (0, 0.5, or 1.0 µg kg⁻¹ min⁻¹). Anaesthesia was induced by a target-controlled infusion of propofol. After tracheal intubation, saline or remifentanil infusion was administered for 15 min. Mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) were recorded and cardiac index (CI), blood volume, and indocyanine green disappearance ratio (K-ICG) were measured using a dye densitogram analyser before and 15 min after saline or remifentanil infusion. Cp was measured using high-performance liquid chromatography. RESULTS HR, K-ICG, and BIS were significantly decreased in the remifentanil 0 µg kg⁻¹ min⁻¹ group. The decrease in MAP, HR, CI, and K-ICG was significantly lower in the remifentanil 0.5 and 1.0 µg kg⁻¹ min⁻¹ groups compared with the remifentanil 0 µg kg⁻¹ min⁻¹ group. Cp was significantly increased after remifentanil administration, but this had no influence on BIS. CONCLUSIONS Remifentanil reduced the CI and increased the Cp, which may be related to a decrease in the K-ICG, but had no significant effect on the BIS.