The effect of oral pregabalin on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To investigate the effect of three different doses of oral pregabalin on minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective, randomized, placebo-controlled, blinded, crossover trial. ANIMALS: A group of eight healthy adult cats aged 24-48 months. METHODS: Cats were randomly assigned to three oral doses of pregabalin (low dose: 2.5 mg kg-1, medium dose: 5 mg kg-1, high dose: 10 mg kg-1) or placebo 2 hours before MACISO determination, with the multiple treatments administered with a minimum 7 day washout period. Anesthesia was induced and maintained with isoflurane in oxygen until endotracheal intubation was achieved, and maintained with isoflurane with volume-controlled ventilation. MACISO was determined in triplicate using the bracketing technique and tail clamp method 120 minutes after pregabalin or placebo administration. Physiologic variables (including heart rate and blood pressure) recorded during MACISO determination were averaged and compared between the pregabalin and placebo treatments. One-way analysis of variance and the Friedman test were used to assess the difference for normally and non-normally distributed data, respectively. The Tukey test was used as a post hoc analysis. Values of p < 0.05 were considered significant. RESULTS: The MACISO with the medium- and high-dose pregabalin treatments were 1.33 ± 0.21% and 1.23 ± 0.17%, respectively. These were significantly lower than MACISO after placebo treatment (1.62 ± 0.13%; p = 0.014, p < 0.001, respectively), representing a decrease of 18 ± 9% and 24 ± 6%. The mean plasma pregabalin concentration was negatively correlated with MACISO values. Physiologic variables did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Doses of 5 or 10 mg kg-1 pregabalin, administered orally 2 hours before determining MACISO, had a significant isoflurane-sparing effect in cats.

Effect of Global Ventilation to Perfusion Ratio, for Normal Lungs, on Desflurane and Sevoflurane Elimination Kinetics.

BACKGROUND: Kinetics of the uptake of inhaled anesthetics have been well studied, but the kinetics of elimination might be of more practical importance. The objective of the authors' study was to assess the effect of the overall ventilation/perfusion ratio (VA/Q), for normal lungs, on elimination kinetics of desflurane and sevoflurane. METHODS: The authors developed a mathematical model of inhaled anesthetic elimination that explicitly relates the terminal washout time constant to the global lung VA/Q ratio. Assumptions and results of the model were tested with experimental data from a recent study, where desflurane and sevoflurane elimination were observed for three different VA/Q conditions: normal, low, and high. RESULTS: The mathematical model predicts that the global VA/Q ratio, for normal lungs, modifies the time constant for tissue anesthetic washout throughout the entire elimination. For all three VA/Q conditions, the ratio of arterial to mixed venous anesthetic partial pressure Part/Pmv reached a constant value after 5 min of elimination, as predicted by the retention equation. The time constant corrected for incomplete lung clearance was a better predictor of late-stage kinetics than the intrinsic tissue time constant. CONCLUSIONS: In addition to the well-known role of the lungs in the early phases of inhaled anesthetic washout, the lungs play a long-overlooked role in modulating the kinetics of tissue washout during the later stages of inhaled anesthetic elimination. The VA/Q ratio influences the kinetics of desflurane and sevoflurane elimination throughout the entire elimination, with more pronounced slowing of tissue washout at lower VA/Q ratios.

Effects of the reservoir bag disconnection on inspired gases during general anesthesia: a simulator-based study.

BACKGROUND: Fresh gas decoupling is a feature of the modern anesthesia workstation, where the fresh gas flow (FGF) is diverted into the reservoir bag and is not added to the delivered tidal volume, which thus remains constant. The present study aimed to investigate the entraining of the atmospheric air into the anesthesia breathing circuit in case the reservoir bag was disconnected. METHODS: We conducted a simulator-based study, where the METI HPS simulator was connected to the anesthesia workstation. The effect of the disconnected reservoir bag was evaluated using oxygen (O2) and air or oxygen and nitrous oxide (N2O) as a carrier gas at different FGF rates. We disconnected the reservoir bag for 10 min during the maintenance phase. We recorded values for inspiratory O2, N2O, and sevoflurane. The time constant of the exponential process was estimated during reservoir bag disconnection. RESULTS: The difference of O2, N2O and sevoflurane concentrations, before, during, and after reservoir bag disconnection was statistically significant at 0.5, 1, and 2 L/min of FGF (p < 0.001). The largest decrease of the inspired O2 concentrations (FIO2) was detected in the case of oxygen and air as the carrier gas and an FGF of 1 L/min, when oxygen decreased from median [25th-75th percentile] 55.00% [54.00-56.00] to median 39.50% [38.00-42.50] (p < 0.001). The time constant for FIO2 during reservoir bag disconnection in oxygen and air as the carrier gas, were median 2.5, 2.5, and 1.5 min in FGF of 0.5, 1.0, and 2 L/min respectively. CONCLUSIONS: During the disconnection of the anesthesia reservoir bag, the process of pharmacokinetics takes place faster compared to the wash-in and wash-out pharmacokinetic properties in the circle breathing system. The time constant was affected by the FGF rate, as well as the gradient of anesthetic gases between the anesthesia circle system and atmospheric air.

Effects of different remifentanil target concentrations on MACBAR of sevoflurane in patients with liver dysfunction under carbon dioxide pneumoperitoneum stimulus: A randomized controlled trial.

WHAT IS KNOWN AND OBJECTIVE: Remifentanil can effectively decrease the sevoflurane concentration to block sympathetic adrenergic response to CO2 pneumoperitoneum stimulus,and liver dysfunction will significantly reduce the MACBAR (minimum alveolar concentration for blocking adrenergic response) of sevoflurane. However, the effects of different remifentanil concentrations on the MACBAR of sevoflurane in patients with liver dysfunction are unclear. The aim of this study was to observe the effects of different remifentanil concentrations by intravenous target-controlled infusion on the MACBAR of sevoflurane in patients with grade B liver dysfunction under carbon dioxide pneumoperitoneum stimulus. METHODS: Seventy-five patients with grade B liver dysfunction undergoing elective laparoscopic surgery were selected, and randomly divided into three groups with remifentanil plasma target concentrations of 0 (group R0 ), 1 (group R1 ) and 2 (group R2 ) ng/ml. Anaesthesia was induced by intravenous injection of propofol 2-3 mg/kg, remifentanil 2 µg/kg and cisatracurium 0.15 mg/kg. All groups were inhaled different concentrations of sevoflurane. The determination of sevoflurane MACBAR in each group was used a method of sequential-allocation technique, and venous blood samples were taken before and after the creation of carbon dioxide pneumoperitoneum to determine plasma adrenaline and noradrenaline concentrations. RESULTS AND DISCUSSIONS: The MACBAR of sevoflurane in groups R0 , R1 and R2 was 4.83%, 3.00% and 2.10%, respectively. The MACBAR of sevoflurane was significantly difference among the three groups. When a similar effect of MACBAR had achieved in each group, no significant differences were found in the changes of plasma adrenaline and noradrenaline concentrations before and after the creation of pneumoperitoneum. What is new and conclusion Target-controlled infusion of different concentrations of remifentanil can reduce sevoflurane MACBAR during pneumoperitoneum stimulation in patients with liver dysfunction in some degree. However, the changes of plasma adrenaline and noradrenaline concentrations are consistent in the three groups when patient's stress response was inhibited at the same degree.

Effect of low-dose ketamine on MACBAR of sevoflurane in laparoscopic cholecystectomy: A randomized controlled trial.

WHAT IS KNOWN AND OBJECTIVE: Low-dose ketamine can reduce the minimum alveolar concentration of sevoflurane necessary to block the adrenergic response (MACBAR ) in animals. However, the effects of low-dose ketamine on the sevoflurane MACBAR in patients undergoing laparoscopic surgery are unclear. The aim of this study was to investigate the effects of three different low doses of ketamine on the MACBAR of sevoflurane in patients undergoing laparoscopic cholecystectomy. METHODS: One hundred patients who underwent laparoscopic cholecystectomy were enrolled. After general anaesthesia induction and tracheal intubation, patients received sevoflurane anaesthesia in combination with a loading dose of saline followed by infusion or a loading dose of 0.5 mg/kg ketamine followed by a continuous infusion of 5 (K1 group), 10 (K2 group) and 20 µg/kg/min (K3 group). The target concentration of end-tidal sevoflurane was maintained for at least 20 minutes before carbon dioxide pneumoperitoneum stimulus. The MACBAR of sevoflurane in each group was determined by using an up-and-down sequential allocation technique. RESULTS AND DISCUSSION: Seventy-one patients completed the study. The values of MACBAR for sevoflurane were 5.3% in the K0 , 4.8% in K1 , 3.3% in K2 and 3.2% in K3 groups. The use of ketamine significantly reduced the MACBAR of sevoflurane compared to sevoflurane alone. The K2 and K3 groups showed significantly lower values of MACBAR than that in the K1 group. However, a higher dose of ketamine in the K3 group did not further reduce the sevoflurane MACBAR . The mean arterial blood pressure (MAP) values before pneumoperitoneum in the K2 and the K3 groups were significantly higher compared to those in the K0 and K1 groups. Compared with the values before pneumoperitoneum, the heart rate and MAP after pneumoperitoneum were significantly increased. Overall, the haemodynamics remained stable during the study period in all groups. WHAT IS NEW AND CONCLUSION: A loading dose of 0.5 mg/kg ketamine followed by a continuous infusion of 10.0 µg/kg/min led to a significant decrease in the MACBAR of sevoflurane in patients undergoing laparoscopic cholecystectomy.

A pharmacodynamic model of tidal volume and inspiratory sevoflurane concentration in children during spontaneous breathing.

PURPOSE: High concentrations of sevoflurane causes respiratory depression, mainly due to the decrease in tidal volume (TV) during spontaneous ventilation. The purpose of this study was to identify clinical variables that affect the relationship between TV and sevoflurane concentration, and to establish a population pharmacodynamic modelling approach to TV and sevoflurane concentration in children. A prospective observational study involving 48 patients (≤ 6 years of age) scheduled to undergo general anesthesia using laryngeal mask airway was performed. When the inspiratory sevoflurane concentration reached 2 vol%, the vaporizer was increased to 4 vol% for 5 min, then sevoflurane was decreased to 2 vol% for 5 min. During the study period, TV, end-tidal carbon dioxide, and sevoflurane concentration were recorded every 30 s. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the TV-sevoflurane concentration relationship. To collapse hysteresis of the pharmacokinetic and pharmacodynamic relationship, the semicompartmental model was applied which does not require a structural model for equilibration delay causing the hysteresis. TV decreased with increasing inspiratory sevoflurane concentrations. Hysteresis between the TV and sevoflurane concentration was observed and was accounted for when the model was developed. Initial TV and maximal reduction in TV were related to body weight. The γ (a steepness of the concentration-response relation curve) was 8.78 and the keo, (a first-order rate constant determining the equilibrium between the end-tidal sevoflurane concentration and effect site sevoflurane concentration) was 2.27 min-1. Changes in TV were correlated with sevoflurane concentration with spontaneous breathing during sevoflurane anesthesia. The initial and maximal TV were related to body weight, in a pediatric population.

End-tidal to Arterial Gradients and Alveolar Deadspace for Anesthetic Agents.

BACKGROUND: According to the "three-compartment" model of ventilation-perfusion ((Equation is included in full-text article.)) inequality, increased (Equation is included in full-text article.)scatter in the lung under general anesthesia is reflected in increased alveolar deadspace fraction (VDA/VA) customarily measured using end-tidal to arterial (A-a) partial pressure gradients for carbon dioxide. A-a gradients for anesthetic agents such as isoflurane are also significant but have been shown to be inconsistent with those for carbon dioxide under the three-compartment theory. The authors hypothesized that three-compartment VDA/VA calculated using partial pressures of four inhalational agents (VDA/VAG) is different from that calculated using carbon dioxide (VDA/VACO2) measurements, but similar to predictions from multicompartment models of physiologically realistic "log-normal" (Equation is included in full-text article.)distributions. METHODS: In an observational study, inspired, end-tidal, arterial, and mixed venous partial pressures of halothane, isoflurane, sevoflurane, or desflurane were measured simultaneously with carbon dioxide in 52 cardiac surgery patients at two centers. VDA/VA was calculated from three-compartment model theory and compared for all gases. Ideal alveolar (PAG) and end-capillary partial pressure (Pc'G) of each agent, theoretically identical, were also calculated from end-tidal and arterial partial pressures adjusted for deadspace and venous admixture. RESULTS: Calculated VDA/VAG was larger (mean ± SD) for halothane (0.47 ± 0.08), isoflurane (0.55 ± 0.09), sevoflurane (0.61 ± 0.10), and desflurane (0.65 ± 0.07) than VDA/VACO2 (0.23 ± 0.07 overall), increasing with lower blood solubility (slope [Cis], -0.096 [-0.133 to -0.059], P < 0.001). There was a significant difference between calculated ideal PAG and Pc'G median [interquartile range], PAG 5.1 [3.7, 8.9] versus Pc'G 4.0[2.5, 6.2], P = 0.011, for all agents combined. The slope of the relationship to solubility was predicted by the log-normal lung model, but with a lower magnitude relative to calculated VDA/VAG. CONCLUSIONS: Alveolar deadspace for anesthetic agents is much larger than for carbon dioxide and related to blood solubility. Unlike the three-compartment model, multicompartment (Equation is included in full-text article.)scatter models explain this from physiologically realistic gas uptake distributions, but suggest a residual factor other than solubility, potentially diffusion limitation, contributes to deadspace.

Circadian differences in emergence from volatile anaesthesia in mice: involvement of the locus coeruleus noradrenergic system.

BACKGROUND: Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. METHODS: The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. RESULTS: MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. CONCLUSION: Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.

Pharmacokinetics and clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia.

This study determined the pharmacokinetics and compared the clinical effects of xylazine and dexmedetomidine in horses recovering from isoflurane anesthesia. Six healthy horses aged 8.5 ± 3 years and weighing 462 ± 50 kg were anesthetized with isoflurane for 2 hr under standard conditions on two occasions one-week apart. In recovery, horses received 200 µg/kg xylazine or 0.875 µg/kg dexmedetomidine intravenously and were allowed to recover without assistance. These doses were selected because they have been used for postanesthetic sedation in clinical and research studies. Serial venous blood samples were collected for quantification of xylazine and dexmedetomidine, and the pharmacokinetic parameters were calculated. Two individuals blinded to treatment identity evaluated recovery quality with a visual analog scale. Times to stand were recorded. Results (mean ± SD) were compared using paired t tests or Wilcoxon signed-ranked test with p < .05 considered significant. Elimination half-lives (62.7 ± 21.8 and 30.1 ± 8 min for xylazine and dexmedetomidine, respectively) and steady-state volumes of distribution (215 ± 123 and 744 ± 403 ml/kg) were significantly different between xylazine and dexmedetomidine, whereas clearances (21.1 ± 17.3 and 48.6 ± 28.1 ml/minute/kg), times to stand (47 ± 24 and 53 ± 12 min) and recovery quality (51 ± 24 and 61 ± 22 mm VAS) were not significantly different. When used for postanesthetic sedation following isoflurane anesthesia in healthy horses, dexmedetomidine displays faster plasma kinetics but is not associated with faster recoveries compared to xylazine.

Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

Minimum anesthetic concentration of isoflurane and sparing effect of midazolam in Quaker parrots (Myiopsitta monachus).

OBJECTIVE: To determine the effects of midazolam on the minimum anesthetic concentration (MAC) reduction of end-tidal isoflurane concentration (Fe'Iso) measured using an electrical stimulus in Quaker parrots (Myiopsitta monachus). STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A group of six adult Quaker parrots, weighing 98-124 g. METHODS: Birds were anesthetized with isoflurane in oxygen delivered by mask, then tracheally intubated and mechanically ventilated. Three treatments were applied with a 4 day interval between anesthetic events. Each anesthetized bird was administered midazolam (1 mg kg-1; treatment MID1), midazolam (2 mg kg-1; treatment MID2) or electrolyte solution (control) intramuscularly. The treatments were administered using a replicated Latin square design and the observers were blinded. Based on a pilot bird, the starting Fe'Iso was 1.8%. After equilibration for 10 minutes, a supramaximal stimulus was delivered using an electrical current (20 V and 50 Hz for 10 ms) and birds were observed for non-reflex movement. The Fe'Iso was titrated by 0.1% until a crossover event was observed. The MAC was estimated using logistic regression. RESULTS: The MAC of isoflurane (MACISO) was estimated at 2.52% [95% confidence interval (CI), 2.19-2.85] with a range of 1.85-2.65%. MACISO in MID1 was 2.04% (95% CI, 1.71-2.37) and in MID2 was 1.81% (95% CI, 1.48-2.14); reductions in MACISO from control of 19% (p = 0.001) and 28% (p < 0.001), respectively. Heart rate, temperature, sex and anesthetic time were not different among treatments. CONCLUSIONS: Midazolam (1-2 mg kg-1) intramuscularly resulted in a significant isoflurane-sparing effect in response to a noxious stimulus in Quaker parrots without observable adverse effects. CLINICAL RELEVANCE: Midazolam can be used as part of a balanced anesthetic approach using isoflurane in Quaker parrots, and potentially in other psittacine species.

Plasma dopamine concentrations following dopamine infusion to isoflurane-anesthetized New Zealand White rabbits.

OBJECTIVE: To determine the pharmacokinetics of dopamine following a short infusion in isoflurane-anesthetized rabbits. STUDY DESIGN: Prospective, descriptive pharmacokinetic study. ANIMALS: A group of six adult female New Zealand White rabbits weighing 4.4 ± 0.2 kg. METHODS: Rabbits were anesthetized with isoflurane in oxygen and maintained at 1.2 × minimum alveolar concentration of isoflurane (2.3% atmosphere). Dopamine (30 µg kg-1 minute-1) was infused for 10 minutes. Arterial blood was sampled prior, during and following the infusion at various intervals for 1 hour. RESULTS: A one-compartment model with baseline concentration best fitted the time-plasma dopamine concentration data. Estimated typical population value (interindividual variability) for volume of distribution and clearance were 10.3 (232%) L kg-1 and 9.9 (508%) L minute-1 kg-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: There was a large degree of interindividual variation in the disposition of dopamine. The large volume of distribution and high metabolic clearance rate reported for dopamine in this study likely explains the lack of clinical efficacy of dopamine in rabbits at doses up to 30 µg kg-1 minute-1.

Sevoflurane EC50 for intravenous cannulation attempt and movement in children.

BACKGROUND: Intravenous cannulation at lighter planes of anaesthesia can lead to adverse respiratory and haemodynamic events. So far, there is no consensus on optimum end tidal sevoflurane concentration required for intravenous cannulation in children. We aimed to evaluate the optimum end tidal concentration at which an intravenous cannulation can be successfully attempted without movements in paediatric patients after inhalational induction of general anaesthesia. MATERIAL AND METHODS: In this clinical trial, paediatric subjects of either sex aged 1-3 years, weighing 7-15 kg having American Society of Anaesthesiologists physical status I/II of undergoing elective cataract surgery were included. After inhalational induction of general anaesthesia with 8% sevoflurane and 100% oxygen, end tidal sevoflurane concentration was maintained at 2% for 4 minutes for the first child. This was followed by intravenous cannulation attempted by an experienced anesthesiologist. The intravenous cannulation was considered to be unsuccessful if there was "movement" and successful if there was "no movement" in response to the stimuli of cannulation. End-tidal concentration was increased/decreased (step-size 0.2% for sevoflurane) using Dixon and Massey up and down method in the next patient depending upon previous patient's response. RESULTS: The sevoflurane EC50 for successful intravenous cannulation is 1.32% ± 1.0%. Pearson correlation (r) between weight of the child and response to intravenous cannulation was found to be 0.40 with P value of 0.008. CONCLUSION: Intravenous cannulation can be accomplished without movements at end tidal sevoflurane of 1.3% in children aged 1-3 years in 50% of children.

Electroencephalographic (EEG) density spectral array monitoring in children during sevoflurane anaesthesia: a prospective observational study.

Electroencephalographic density spectral array monitoring has been developed to facilitate the interpretation of unprocessed electroencephalogram signals. The primary aim of this prospective observational study, performed in a tertiary children's hospital, was to identify the clinical applicability and validity of density spectral array monitoring in infants and children during sevoflurane anaesthesia. We included 104 children, aged < 6 years, undergoing elective surgery during sevoflurane anaesthesia. We investigated the correlation between non-steady state end-tidal sevoflurane and the expression of the four electroencephalogram frequency bands ß, α, θ and δ, representing density spectral array. Patients were divided into three age groups (< 6 months, 6-12 months, > 12 months). There was a significant correlation between end-tidal sevoflurane and density spectral array in the age groups 6-12 months (p < 0.05) and 1-6 years (p < 0.0001). In infants < 6 months of age, the relative percentages of density spectral array did not correlate with end-tidal sevoflurane. The main finding was that different end-tidal concentrations of sevoflurane produce age-dependent changes in the density spectral array power spectrum. In infants younger than 6 months-old, α and ß coherence are absent, whereas θ and δ oscillations have already emerged. In cases where anaesthesia was too deep, this presented as burst suppression on the electroencephalogram, θ disappeared, leaving the electroencephalographic activity in the δ range. Future research should address this issue, aiming to clarify whether the emergence of θ oscillations in infants helps to prevent sevoflurane overdosing.

Effect of One-Lung Ventilation on Blood Sevoflurane and Desflurane Concentrations.

OBJECTIVE: To determine the blood sevoflurane and desflurane concentrations during one-lung ventilation (OLV). DESIGN: Randomized, single-blind study. SETTING: Single university hospital. PARTICIPANTS: The study comprised 24 patients, 35 to 70 years old who were scheduled for either a major abdominal surgery or thoracotomy. INTERVENTIONS: The patients were divided into the following 4 groups: sevoflurane two-lung ventilation (TLV), sevoflurane OLV, desflurane TLV, and desflurane OLV. Vaporizers were set at 1.5% sevoflurane or 6% desflurane. MEASUREMENTS AND MAIN RESULTS: In the TLV groups, blood samples were taken in 10-minute intervals starting 40 minutes after the start of TLV (T1-T9) for blood gas analysis and gas chromatography. In the OLV groups, the first sample was collected at 40 minutes of TLV (T1), and other samples were collected in 10-minute intervals from the start of OLV (T2-T9). Saturation of peripheral oxygen (SpO2), hemodynamic variables, and inspired and end-tidal volatiles were recorded. The fraction uptake of the volatile agents (F) was calculated for each patient at the same time points. The mean arterial sevoflurane concentration in the sevoflurane OLV group at T1 decreased from 40.7 ± 4.4 to 30.2 ± 2.5 µg/mL at T3 (p = 0.014, 26% decrease). In the OLV desflurane group, the mean arterial desflurane concentration at T1 declined from 224.6 ± 44.8 to 159.8 ± 32 µg/mL at T3 (p=0.018, 29% decrease). However, the reduction of sevoflurane concentration compared with that of desflurane at T3 was not statistically significant (p = 0.31). In addition, the fraction uptake of the volatile agents values significantly increased at the start of OLV (p = 0.001). CONCLUSION: An OLV procedure causes a decrease in the both arterial and venous blood concentrations of sevoflurane and desflurane. This reduction is believed to be due to ventilation-perfusion mismatch.

Optimizing target control of the vessel rich group with volatile anesthetics.

The ability to monitor the inspired and expired concentrations of volatile anesthetic gases in real time makes these drugs implicitly targetable. However, the end-tidal concentration only represents the concentration within the brain and the vessel rich group (VRG) at steady state, and very poorly approximates the VRG concentration during common dynamic situations such as initial uptake and emergence. How should the vaporization of anesthetic gases be controlled in order to optimally target VRG concentration in clinical practice? Using a generally accepted pharmacokinetic model of uptake and redistribution, a transfer function from the vaporizer setting to the VRG is established and transformed to the time domain. Targeted actuation of the vaporizer in a time-optimal manner is produced by a variable structure, sliding mode controller. Direct mathematical application of the controller produces rapid cycling at the limits of the vaporizer, further prolonged by low fresh gas flows. This phenomenon, known as "chattering", is unsuitable for operating real equipment. Using a simple and clinically intuitive modification to the targeting algorithm, a variable low-pass boundary layer is applied to the actuation, smoothing discontinuities in the control law and practically eliminating chatter without prolonging the time taken to reach the VRG target concentration by any clinically significant degree. A model is derived for optimum VRG-targeted control of anesthetic vaporizers. An alternate and further application is described, in which deliberate perturbation of the vaporization permits non-invasive estimation of parameters such as cardiac output that are otherwise difficult to measure intra-operatively.

Effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of five healthy adult male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. MACISO was determined in duplicate in five cats, before and during administration of atipamezole (250 µg kg-1 followed by 250 µg kg-1 hour-1) using the bracketing technique and tail clamping. Estimates of MACISO obtained before and during administration of atipamezole were compared using a two-tailed paired t test. RESULTS: MACISO during atipamezole administration (mean ± standard deviation 2.73% ± 0.07%) was significantly larger than before atipamezole administration (1.95% ± 0.13%; p < 0.0001). CONCLUSION AND CLINICAL RELEVANCE: The role of α2-adrenoceptors in inhaled anesthetic-induced immobility may be larger than previously thought. Antagonism of an α2-adrenoceptor agonist during inhalation anesthesia may result in an increase in MAC disproportionate to the MAC reduction induced by the agonist.

Effects of midazolam and nitrous oxide on the minimum anesthetic concentration of isoflurane in the ball python (Python regius).

OBJECTIVE: To evaluate the effects of midazolam and nitrous oxide (N2O) on the minimum anesthetic concentration of isoflurane (MACISO) in ball pythons. STUDY DESIGN: Prospective, crossover, randomized, semi-blinded study. ANIMALS: A total of nine healthy adult female ball pythons (Python regius) weighing 2.76 ± 0.73 kg. METHODS: In each snake, three protocols were evaluated with 2 week washouts: treatment MID-O2, midazolam (1 mg kg-1) administered intramuscularly (IM) and anesthesia induced with isoflurane-oxygen; treatment SAL-O2, saline (0.2 mL kg-1) IM and anesthesia with isoflurane-oxygen; and treatment SAL-N2O, saline IM and anesthesia with isoflurane and 50% nitrous oxide (N2O):50% oxygen. In each treatment, isoflurane was administered by face mask immediately after premedication. Snakes were endotracheally intubated and inspired and end-tidal isoflurane concentrations were monitored. The study design followed a standard bracketing technique, and the MACISO was determined using logistic regression. Electrical stimulation using a Grass stimulator connected to the base of the tail (50 V, 50 Hz, 6.5 ms pulse-1) was used as the supramaximal stimulus. Blood-gas analysis was performed on cardiac blood collected immediately following intubation and after the last stimulation. Blood-gas variables were compared over time and between treatments using linear mixed models. RESULTS: MACISO at a body temperature of 30.1 ± 0.4 °C was 1.11% (95% confidence interval, 0.94-1.28%) in SAL-O2 and was significantly decreased to 0.48% (0.29-0.67%) in MID-O2 (p < 0.001) and to 0.92% (0.74-1.09%) in SAL-N2O (p = 0.016). PO2 was significantly lower in MID-O2 and SAL-N2O than in SAL-O2. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam significantly decreased the MACISO by 57% in ball pythons, whereas addition of N2O resulted in a modest, although significant, decrease (17%). MACISO in ball pythons was lower than those previously reported in reptiles.

Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone.

OBJECTIVE: To compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. STUDY DESIGN: Prospective, randomized, crossover controlled trial. ANIMALS: A group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation). METHODS: Dogs were allocated to two treatments: LHR (HR: 45-75 beats minute-1) and HHR (HR: 100-130 beats minute-1). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg-1 followed by 0.02-0.10 mg kg-1 hour-1) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 µg kg-1) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05. RESULTS: A three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute-1 kg-1) was 33.2 (24.0-48.0) and 61.3 (44.5-72.7), maximum concentration (ng mL-1) 33.6 (23.4-36.6) and 20.0 (16.7-28.0), apparent volume of the rapid peripheral compartment (mL kg-1) 436 (352-723) and 925 (499-1887), apparent volume at steady state (mL kg-1) 4064 (3453-6546) and 7195 (5077-8601), cardiac index (CI; mL minute-1 m-2) 2.83 (1.98-3.67) and 4.91 (3.22-6.09) and HR (beats minute-1) 68 (49-72) and 120 (102-129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs.

Effects of dexmedetomidine, with or without vatinoxan (MK-467), on minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effects of dexmedetomidine, with or without vatinoxan, on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. Dexmedetomidine was administered using a target-controlled infusion system to achieve 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Additionally, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve a target plasma concentration of 4 µg mL-1. Pulse rate (PR), respiratory rate, systolic arterial pressure (SAP), hemoglobin oxygen saturation, body temperature, end-tidal partial pressure of carbon dioxide and drug concentrations were measured. MACISO was determined at each target plasma dexmedetomidine concentration using the bracketing method and the tail clamp technique. Pharmacodynamic models were fitted to the plasma dexmedetomidine concentration-MACISO. Pharmacodynamic parameters were tested for equivalence, and if rejected, for difference. RESULTS: Dexmedetomidine alone decreased MACISO in a plasma concentration-dependent manner. Maximum reduction was 77 ± 4%; the dexmedetomidine concentration producing 50% of the maximum decrease (IC50) was 0.77 ng mL-1. Vatinoxan increased MACISO in the absence of dexmedetomidine, decreased the potency of dexmedetomidine for its MACISO-reducing effect (IC50 = 12 ng mL-1) and lessened the maximum MACISO reduction (60 ± 14%). PR decreased less and SAP increased less when dexmedetomidine was administered with vatinoxan compared with saline. CONCLUSION AND CLINICAL RELEVANCE: Vatinoxan altered the effect of dexmedetomidine on MACISO. A high plasma dexmedetomidine concentration in the presence of vatinoxan resulted in a large decrease in MACISO, with attenuation of dexmedetomidine-induced cardiovascular effects. The vatinoxan-dexmedetomidine combination may provide clinical benefits in isoflurane-anesthetized cats.