Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane.

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. A total of 151 individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G > C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG, and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G > C and rs2031920 C > T, GABRG1 rs279858 T > C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G > A, and rs1801394 A > G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that 9 single nucleotide polymorphisms in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane.

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.

Effects of salbutamol on the kinetics of sevoflurane and the occurrence of early postoperative pulmonary complications in patients with mild-to-moderate chronic obstructive pulmonary disease: A randomized controlled study.

Bronchodilators dilate the bronchi and increase lung volumes, thereby improving respiratory physiology in patients with chronic obstructive pulmonary disease (COPD). However, their effects on sevoflurane kinetics remain unknown. We aimed to determine whether inhaled salbutamol affected the wash-in and wash-out kinetics of sevoflurane and the occurrence of early postoperative pulmonary complications (PPCs) in patients with COPD undergoing elective surgery. This randomized, placebo-controlled study included 63 consecutive patients with COPD allocated to the salbutamol (n = 30) and control groups (n = 33). The salbutamol group received salbutamol aerosol (2 puffs of ~200 µg) 30 min before anesthesia induction and 30 min before surgery completion. The control group received a placebo. Sevoflurane kinetics were determined by collecting end-tidal samples from the first breaths at 1, 2, 3, 4, 5, 7, 10, and 15 min before the surgery (wash-in) and after closing the vaporizer (wash-out). PPCs were recorded for 7 days. The salbutamol group had higher end-tidal to inhaled sevoflurane ratios (p<0.05, p<0.01) than the control group, from 3 to 10 min during the wash-in period, but no significant differences were observed during the wash-out period. The arterial partial pressure of oxygen to the fraction of inhaled oxygen was significantly higher in the salbutamol group at 30 (320.3±17.6 vs. 291.5±29.6 mmHg; p = 0.033) and 60 min (327.8±32.3 vs. 309.2±30.5 mmHg; p = 0.003). The dead space to tidal volume ratios at 30 (20.5±6.4% vs. 26.3±6.0%, p = 0.042) and 60 min (19.6±5.1% vs. 24.8±5.5%, p = 0.007) and the incidence of bronchospasm (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.23-0.67, p = 0.023) and respiratory infiltration (OR 0.52, 95% CI, 0.40-0.65, p = 0.017) were lower in the salbutamol group. In patients with COPD, salbutamol accelerates the wash-in rate of sevoflurane and decreases the occurrence of postoperative bronchospasm and pulmonary infiltration within the first 7 days.

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 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.

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.

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.

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.

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.

Prevalence of Isoelectric Electroencephalography Events in Infants and Young Children Undergoing General Anesthesia.

BACKGROUND: In infants and young children, anesthetic dosing is based on population pharmacokinetics and patient hemodynamics not on patient-specific brain activity. Electroencephalography (EEG) provides insight into brain activity during anesthesia. The primary goal of this prospective observational pilot study was to assess the prevalence of isoelectric EEG events-a sign of deep anesthesia-in infants and young children undergoing general anesthesia using sevoflurane or propofol infusion for maintenance. METHODS: Children 0-37 months of age requiring general anesthesia for surgery excluding cardiac, intracranial, and emergency cases were enrolled by age: 0-3, 4-6, 7-12, 13-18, and 19-37 months. Anesthesia was maintained with sevoflurane or propofol infusion. EEG was recorded from induction to extubation. Isoelectric EEG events (amplitude <20 µV, lasting ≥2 seconds) were characterized by occurrence, number, duration, and percent of isoelectric EEG time over anesthetic time. Associations with patient demographics, anesthetic, and surgical factors were determined. RESULTS: Isoelectric events were observed in 63% (32/51) (95% confidence interval [CI], 49-76) of patients. The median (interquartile range [IQR]) number of isoelectric events per patient was 3 (0-31), cumulative isoelectric time per patient was 12 seconds (0-142 seconds), isoelectric time per event was 3 seconds (0-4 seconds), and percent of total isoelectric over anesthetic time was 0.1% (0%-2.2%). The greatest proportion of isoelectric events occurred between induction and incision. Isoelectric events were associated with higher American Society of Anesthesiologists (ASA) physical status, propofol bolus, endotracheal tube use, and lower arterial pressure during surgical phase. CONCLUSIONS: Isoelectric EEG events were common in infants and young children undergoing sevoflurane or propofol anesthesia. Although the clinical significance of these events remains uncertain, they suggest that dosing based on population pharmacokinetics and patient hemodynamics is often associated with unnecessary deep anesthesia during surgical procedures.

Determination of the minimum alveolar concentration of sevoflurane that blunts adrenergic responses and the effect of a constant rate infusion of ketamine in sheep.

Minimizing sympathetic stimulation under anesthesia prevents activation of the neuroendocrine stress response. The minimum alveolar concentration blunting adrenergic responses in 50% of the population when exposed to a noxious stimulus is defined as MAC-BAR. The purpose of this study was to determine the MAC-BAR of sevoflurane (MAC-BARsevo) in sheep and the MAC-BAR sparing effects of ketamine. Thirteen healthy Dorset-cross adult ewes, 4 ± 1 year old and weighing 74 ± 9 kg, were enrolled in a randomized blinded crossover study design. Ewes were anesthetized twice for MAC-BARsevo determination. After face mask induction with sevoflurane, sheep received intravenous ketamine at 1.5 mg/kg and a constant rate infusion of 1.5 mg/kg/h or an equivalent volume of saline (placebo). After 8 day washout, the other treatment was administered. A bracketing technique was used for MAC-BARsevo determination and values were collected in duplicate. The mechanical stimulus (sponge forceps) was applied at the coronary band for 1 min and blood was collected for ketamine plasma concentrations. The MAC-BARsevo values of each treatment were compared using a paired t-test. Mean MAC-BARsevo of the ketamine and placebo were 2.73 ± 0.23% and 2.77 ± 0.31%, respectively and no significant difference was found (p = .638). Average ketamine plasma concentrations was 1.54 ± 0.18 µg/mL maintained through the study. Ketamine at 1.5 mg/kg, followed by 1.5 mg/kg/h, did not decrease the MAC-BARsevo in sheep. Further studies to determine the effect of higher doses of ketamine on inhalational anesthetic agents and their potential adverse effects are warranted.

Comparison of the Level of Free Hexafluoro-isopropanol in Adults' Blood and the Incidence of Emergence Agitation After Anesthesia With Different Concentrations of Sevoflurane in Laparoscopic Gastrointestinal Surgery: A Randomized Controlled Clinical Trial.

PURPOSE: The aim of the study is to compare the free hexafluoro-isopropanol (HFIP) concentration in adults' blood and the incidence of emergence agitation (EA) after inhaled different concentrations of sevoflurane. METHODS: Sixty adult patients planning to undergo laparoscopic gastrointestinal surgery were randomly assigned to 3 groups. Each group received sevoflurane as the volatile anesthetic at different concentrations: 0.5 minimum alveolar concentration (MAC), 1.0 MAC, and 1.5 MAC. The use of sevoflurane was continued until the end of surgery. Venous blood samples were obtained at 30, 60, 120, and 180 minutes after starting the use of sevoflurane and subsequently at 60, 180, and 300 minutes after discontinuation of volatile anesthetic administration. Blood concentrations of sevoflurane and free HFIP were determined using gas chromatography. The recovery time and the incidence of EA at different time points were evaluated among the 3 groups. FINDINGS: Changes in the blood concentrations of sevoflurane and free HFIP during and after the use of sevoflurane were similar in all 3 groups. The peak blood concentration of free HFIP occurred 60 minutes after onset of sevoflurane anesthesia in all 3 groups (P < 0.05). The lowest level of free HFIP and the longest recovery time were found in the 1.5-MAC group (P < 0.05). No significant difference was found in the incidence of EA or moderate pain among the 3 groups during recovery. IMPLICATIONS: The generation of HFIP would be inhibited when the inhaled sevoflurane concentration increased to 1.5 MAC. However, the incidence of EA during recovery had nothing to do with the inhaled different sevoflurane concentrations (within 1.5 MAC) in adults. ChicCTR.org identifier: ChiCTR-IPD-17011558.

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.

Effect of sevoflurane anesthesia on neuromuscular blockade produced by rocuronium infusion in dogs.

This study evaluated the effect of sevoflurane anesthesia on neuromuscular blockade with rocuronium in dogs. Six healthy beagle dogs were anesthetized four times with a minimum 14-day washout period. On each occasion, the dogs were administered 1.25-, 1.5-, 1.75-, or 2.0-fold of the individualized minimum alveolar concentration (MAC) of sevoflurane and received an infusion of rocuronium (0.5 mg/kg followed by 0.2 mg/kg/hr) for 120 min. Neuromuscular function was monitored with acceleromyography and train-of-four (TOF) stimulation of the left hind limb. Time to achieve TOF count 0 (onset time), time from the onset of neuromuscular blockade to the reappearance of TOF count 4 (blockade period), and time from the onset of rocuronium infusion to attaining a 70 or 90% TOF ratio (TOFR70 or TOFR90) were recorded. There were no significant differences in the onset time, blockade period, and plasma rocuronium concentration between the sevoflurane MAC multiples. The TOFR70 and TOFR90 were dose-dependently prolonged with the sevoflurane MAC multiples. There were significant differences in the TOFR70 and TOFR90 between the 1.25 sevoflurane MAC (median: 55 and 77.5 min, respectively) and 1.75 sevoflurane MAC (122.0 and 122.6 min; P=0.020 and P=0.020, respectively), 1.25 sevoflurane MAC and 2.0 sevoflurane MAC (126.0 and 131.4 min; P=0.020 and P=0.020), and 1.5 sevoflurane MAC (97.5 and 121.3 min) and 2.0 sevoflurane MAC (P=0.033 and P=0.032). In dogs, sevoflurane anesthesia produced dose-dependent prolongation of recovery from neuromuscular blockade produced by rocuronium.

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.

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 intravenous S-ketamine on the MAC of sevoflurane: a randomised, placebo-controlled, double-blinded clinical trial.

BACKGROUND: Ketamine is routinely used in operating theatres, emergency departments, ICUs, and even outpatient units. Despite the widespread use of ketamine, only basic aspects of its interactions with inhalation anaesthetic agents are known, and formal testing of interactions in humans is lacking. The minimum alveolar concentration (MAC) of inhalation anaesthetics is used to guide the depth of anaesthesia, and several drugs are known to influence the MAC. The aim of this study was to investigate whether intravenous application of ketamine influences the MAC of sevoflurane in humans. METHODS: Adult patients undergoing elective surgery were included in this randomised, double-blinded, placebo-controlled study. Patients were assigned to one of three groups, each of which received a bolus of placebo, 0.5 mg kg-1S-ketamine, or 1 mg kg-1S-ketamine followed by an infusion of the same amount per hour after inhalation induction with sevoflurane was performed. The response to skin incision (movement vs non-movement) was recorded. The MAC of sevoflurane was assessed using an up-and-down titration method. RESULTS: Sixty patients aged 30-65 yr were included. Each group consisted of 20 patients. The MAC of sevoflurane was higher in the placebo group (2.1 (sd 0.1) %) than in the low-dose ketamine group (0.9 (0.1)%, P<0.01) and the high-dose ketamine group (0.5 (0.1)%, P<0.01). In addition, the MAC of sevoflurane was higher in the low-dose ketamine group compared with the high-dose ketamine group (P<0.01). CONCLUSIONS: The administration of S-ketamine significantly and dose-dependently reduced the MAC of sevoflurane in humans. CLINICAL TRIAL NUMBER: EudraCT ref. no. 2012-001908-38.