Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.

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 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.

Postoperative recovery of patients with differential requirements for sevoflurane after abdominal surgery: A prospective observational clinical study.

ABSTRACT: An association between animals and volatile anaesthetic requirements has been shown; however, evidence related to the postoperative outcome of human patients is lacking. Our aim was to investigate whether there is a difference in the requirement for sevoflurane among people undergoing gastrointestinal surgery.We observed 390 adult patients who underwent gastrointestinal surgery with an American Society of Anesthesiologists physical status of I or II with an expected surgery duration of > 2 hours. We used the bispectral index (BIS) to guide the regulation of end-tidal sevoflurane concentration (ETsevo). The mean ETsevo from 20 minutes after endotracheal intubation to 2 hours after the start of surgery was calculated for all patients. Differential sevoflurane requirements were identified according to ETsevo. The BIS, ETsevo, heart rate, mean arterial pressure, dose of sufentanil and cisatracurium, tracheal extubation time, incidence of intraoperative awareness, and incidence of postoperative nausea and vomiting were compared between patients with a low requirement for sevoflurane (group L) and patients with a high requirement for sevoflurane (group H).The mean ETsevo of the 390 patients was 1.55% ±â€Š0.26%. Based on our definition, patients with an ETsevo of < 1.29% were allocated to the low requirement group (group L; n = 69), while patients with an ETsevo of > 1.81% were allocated to the high requirement group (group H; n = 78). The ETsevo of group L was significantly lower than the ETsevo of group H (1.29% ±â€Š0.014% vs 1.82% ±â€Š0.017%, P < .001). There was no significant difference in the ETsevo, BIS, heart rate, mean arterial pressure, dose of sufentanil and cisatracurium, tracheal extubation time, incidence of intraoperative awareness, and incidence of postoperative nausea and vomiting. The tracheal extubation time in the L group was significantly shorter than that in the H group. No intraoperative awareness occurred.There was a significant difference in the requirement for sevoflurane in adult patients. The tracheal extubation time in group L was significantly shorter than that in group H.

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 Volatile Anesthetics on Postoperative Ischemic Stroke Incidence.

Background Preclinical studies suggest that volatile anesthetics decrease infarct volume and improve the outcome of ischemic stroke. This study aims to determine their effect during noncardiac surgery on postoperative ischemic stroke incidence. Methods and Results This was a retrospective cohort study of surgical patients undergoing general anesthesia at 2 tertiary care centers in Boston, MA, between October 2005 and September 2017. Exclusion criteria comprised brain death, age <18 years, cardiac surgery, and missing covariate data. The exposure was defined as median age-adjusted minimum alveolar concentration of all intraoperative measurements of desflurane, sevoflurane, and isoflurane. The primary outcome was postoperative ischemic stroke within 30 days. Among 314 932 patients, 1957 (0.6%) experienced the primary outcome. Higher doses of volatile anesthetics had a protective effect on postoperative ischemic stroke incidence (adjusted odds ratio per 1 minimum alveolar concentration increase 0.49, 95% CI, 0.40-0.59, P<0.001). In Cox proportional hazards regression, the effect was observed for 17 postoperative days (postoperative day 1: hazard ratio (HR), 0.56; 95% CI, 0.48-0.65; versus day 17: HR, 0.85; 95% CI, 0.74-0.99). Volatile anesthetics were also associated with lower stroke severity: Every 1-unit increase in minimum alveolar concentration was associated with a 0.006-unit decrease in the National Institutes of Health Stroke Scale (95% CI, -0.01 to -0.002, P=0.002). The effects were robust throughout various sensitivity analyses including adjustment for anesthesia providers as random effect. Conclusions Among patients undergoing noncardiac surgery, volatile anesthetics showed a dose-dependent protective effect on the incidence and severity of early postoperative ischemic stroke.

Prediction of expiratory desflurane and sevoflurane concentrations in lung-healthy patients utilizing cardiac output and alveolar ventilation matched pharmacokinetic models: A comparative observational study.

ABSTRACT: The Gas Man simulation software provides an opportunity to teach, understand and examine the pharmacokinetics of volatile anesthetics. The primary aim of this study was to investigate the accuracy of a cardiac output and alveolar ventilation matched Gas Man model and to compare its predictive performance with the standard pharmacokinetic model using patient data.Therefore, patient data from volatile anesthesia were successively compared to simulated administration of desflurane and sevoflurane for the standard and a parameter-matched simulation model with modified alveolar ventilation and cardiac output. We calculated the root-mean-square deviation (RMSD) between measured and calculated induction, maintenance and elimination and the expiratory decrement times during emergence and recovery for the standard and the parameter-matched model.During induction, RMSDs for the standard Gas Man simulation model were higher than for the parameter-matched Gas Man simulation model [induction (desflurane), standard: 1.8 (0.4) % Atm, parameter-matched: 0.9 (0.5) % Atm., P = .001; induction (sevoflurane), standard: 1.2 (0.9) % Atm, parameter-matched: 0.4 (0.4) % Atm, P = .029]. During elimination, RMSDs for the standard Gas Man simulation model were higher than for the parameter-matched Gas Man simulation model [elimination (desflurane), standard: 0.7 (0.6) % Atm, parameter-matched: 0.2 (0.2) % Atm, P = .001; elimination (sevoflurane), standard: 0.7 (0.5) % Atm, parameter-matched: 0.2 (0.2) % Atm, P = .008]. The RMSDs during the maintenance of anesthesia and the expiratory decrement times during emergence and recovery showed no significant differences between the patient and simulated data for both simulation models.Gas Man simulation software predicts expiratory concentrations of desflurane and sevoflurane in humans with good accuracy, especially when compared to models for intravenous anesthetics. Enhancing the standard model by ventilation and hemodynamic input variables increases the predictive performance of the simulation model. In most patients and clinical scenarios, the predictive performance of the standard Gas Man simulation model will be high enough to estimate pharmacokinetics of desflurane and sevoflurane with appropriate accuracy.

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.

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.

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.

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.

Implementation of a Pharmacokinetic Model for Inhaled Anesthetics Into a Software-Based Anesthesia Workstation for LLEAP-Compatible Simulators.

INTRODUCTION: Laerdal Learning Application (LLEAP)-compatible simulation manikins lack some specific functions that can be useful in anesthesia simulation scenarios. Our objective was to develop a software-based anesthesia workstation with a pharmacokinetic model for inhaled anesthetics for this simulation platform. METHODS: A Windows Presentation Foundation application that emulates an Aespire anesthesia workstation was created. The Gas Man simulator (Med Man Simulations) was used as a reference for the pharmacokinetic model. A concordance analysis was made between the results obtained by our model and the reference, in open and semiclosed circuit, in both 70- and 140-kg patients. RESULTS: The mean of the differences between the compartments was less than 0.01 vol% in all circumstances. The percentile rank P2.5 to P97.5 was less than 0.5 vol% in all compartments, except for the open circuit compartment. CONCLUSIONS: No significant differences were found between both pharmacokinetic models. We consider that our software-based anesthesia workstation can be useful for simulating mechanical ventilation and halogenated administration in different scenarios.

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.

Minimal alveolar concentration for deep sedation (MAC-DS) in intensive care unit patients sedated with sevoflurane: A physiological study.

BACKGROUND: Volatile anaesthetic agents, especially sevoflurane, could be an alternative for sedating ICU patients. In the operating theatre, volatile anaesthetic agents are monitored using minimal alveolar concentration (MAC). In ICU, MAC may be used to assess sedation level and may replace clinical scale especially when they are unusable. Therefore, we sought to investigate the minimal sevoflurane end-tidal concentration to achieved deep sedation in critical ill patients: MAC-deep sedation (MAC-DS). METHODS: In a prospective interventional study, we included patients with a Richmond Assessment Sedation Score (RASS) of 0 without any sedation. We stepwise increased sevoflurane concentration level before assessing for deep sedation (RASS≤-3). MAC-DS was defined as the minimal sevoflurane MAC fraction or sevoflurane expiratory fraction (FeSevo) to get 90% and 95% of patients in deep sedation (MAC-DS 90 and MAC-DS 95, respectively). RESULTS: Between June and November 2014, 30 patients were included (median age=60 years [interquartile range: 47-69]). Increasing sevoflurane MAC was correlated with a decrease in RASS values (r=-0.83, P<0.001). MAC-DS 90 and MAC-DS 95 were achieved at 0.42 MAC (CI 95 [0.38-0.46]) and 0.46 MAC (CI 95 [0.42-0.51]), respectively. FeSevo to achieve MAC-DS 90 and MAC-DS 95 was 0.72 (CI 95 [0.65-0.79]) and 0.80 (CI 95 [0.72-0.89]), respectively. CONCLUSION: In this physiological study involving 30 ICU patients, MAC-DS, end-tidal sevoflurane concentration to get 95% of patients in deep sedation determined over more than 500 observations, is achieved at 0.8% of expired fraction of sevoflurane or at 0.5 age-adjusted MAC.

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.

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.

Development of a simple method for differential delivery of volatile anesthetics to the spinal cord of the rabbit.

Emulsified volatile anesthetic can be directly injected into the circulation and eliminated from blood through lungs. Taking advantage of the unique pharmacokinetics of the emulsified volatile anesthetics, we aimed to develop a less traumatic method to differentially deliver them to the spinal cord of rabbit. Sixteen New Zealand White rabbits were randomly assigned to the isoflurane or sevoflurane group. A catheter was placed into the descending aorta, and emulsified isoflurane (8mg/kg/h) or sevoflurane (12mg/kg/h) was given respectively. The concentration and partial pressure of the anesthetics in the jugular and femoral vein were measured. Our results showed that the partial pressure for isoflurane was 3.91±1.11 mmHg and 12.61±1.60 mmHg (1.0MAC), and for sevoflurane was 3.89±1.00 mmHg and 19.92±1.84mmHg (1.0MAC), in the jugular vein and femoral vein, respectively. There was significant difference between jugular and femoral vein partial pressure for both isoflurane and sevoflurane groups (both P < 0.001). In conclusion, a simple and minimally invasive method has been successfully developed to selectively deliver isoflurane and sevoflurane to the spinal cord in the rabbit. Before the anesthetics taking action on the brain, 69% of isoflurane and 81% of sevoflurane were removed through lungs. This method can be used to investigate sites and mechanisms of volatile anesthetic action.

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.