Feasibility of Anesthesia Maintenance With Sevoflurane During Cardiopulmonary Bypass: A Pilot Pharmacokinetics Study.

OBJECTIVE: Adequate maintenance of hypnosis during anesthesia throughout surgery using sevoflurane alone was investigated. In addition, sevoflurane pharmacokinetics during cardiopulmonary bypass were analyzed. DESIGN: This was a pilot pharmacokinetic study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 10 patients aged between 18 and 75 years who underwent elective mitral valve surgery. INTERVENTIONS: The end-tidal and sevoflurane plasma concentrations were measured throughout cardiac surgery procedures involving cardiopulmonary bypass. The sevoflurane plasma concentration was measured using gas chromatography. In addition, the ratio between sevoflurane alveolar concentration and inspired concentration over time (FA/FI) was analyzed to describe wash-in and wash-out curves. MEASUREMENTS AND MAIN RESULTS: Hypnosis was maintained adequately throughout surgery using sevoflurane alone. The bispectral index was maintained between 40 and 60 during cardiopulmonary bypass. The end-tidal sevoflurane was significantly different before and during cardiopulmonary bypass (1.86%±0.54% v 1.30%±0.58%, respectively; p<0.001). However, the sevoflurane plasma concentration was not significantly different before and after cardiopulmonary bypass start-up (40.55 µg/mL [76.62-125.33] before cardiopulmonary bypass and 36.24 µg/mL [56.49-81-42] during cardiopulmonary bypass). This mismatch possibly can be explained by changes that occured after cardiopulmonary bypass start-up, such as reductions of body temperature (36.33°C±0.46°C v 32.98°C±2.38°C, respectively; p<0.001) and hematocrit (35.62%±3.98% v 25.5%±3.08%, respectively; p<0.001). The sevoflurane alveolar concentration varied according to sevoflurane plasma concentration and bispectral index values. No adverse events regarding sevoflurane administration during cardiopulmonary bypass were observed. CONCLUSIONS: Sevoflurane end-tidal values were reliable indicators of adequate anesthesia during all cardiac surgery procedures involving cardiopulmonary bypass.

Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study
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OBJECTIVE: This research studied the influence of different blood lipid components on the rate of alveolar-capillary uptake of sevoflurane. Method: 104 patients aged 20 - 50 years undergoing elective operations under general anesthesia were mechanically ventilated through endotracheal intubation after intravenous injections of midazolam, vecuronium, fentanyl, and etomidate. They inhaled 2% sevoflurane at an oxygen flow of 2 L/min, then the inspired concentrations (FI) and expired concentrations (FA of sevoflurane were recorded at 1, 3, 5, 7, 10, 15, 20, and 30 minutes. These cases were divided into a normal group and an abnormal group according to the lipid levels. Then, based on the lipid criteria, those cases with abnormal lipid levels were classified into a high-triglyceride (TG) and total-cholesterol (TC) group (group TG+TC) and a group with decreased high-density lipoprotein cholesterol (group HDL-C).The values of FA/FI and the times required to reach the titration value FA/FI = 0.8 were calculated were calculated for each group. RESULTS: Compared with the normal group, FA/FI decreased within 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was prolonged in the abnormal group (p < 0.05). The value of FA/FI decreased during 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was longer (p < 0.05) in the group TG+TC. CONCLUSIONS: The increased value of blood/gas partition coefficients (B/G) was caused by the increase in the concentrations of TG and TC in blood lipids.
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Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability, and Cardioprotective Effects During Cardiopulmonary Bypass.

OBJECTIVES: This study aimed to evaluate the pharmacokinetic profiles of sevoflurane and isoflurane during use of minimized extracorporeal circulation to perform coronary artery bypass graft surgery. Furthermore, cardiovascular stability during bypass and the postoperative release of troponins were evaluated. DESIGN: Prospective, randomized study. SETTING: University hospital. PARTICIPANTS: The study comprised 31 adult patients undergoing coronary artery bypass grafting. INTERVENTIONS: The pharmacokinetic measurements of the concentration of the volatile anesthetics in the arterial and venous blood, air inlet, air outlet, and gas exhaust of the extracorporeal circulation were recorded. Secondary end-points were cardiovascular stability during bypass, amount of postoperative release of troponin, time to extubation, time to discharge from the intensive care unit and the hospital, and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: Thirty patients completed the protocol. The pharmacokinetics of isoflurane and sevoflurane were almost identical, with a rapid wash-in (time to reach 50% of arterial steady state) concentration of 0.87±0.97 minutes and 1.14±0.35 minutes for isoflurane and sevoflurane, respectively, and a biphasic venous elimination with a terminal half-life of approximately 10 minutes for both compounds. There was a correlation between the gas inlet and the gas exhaust of the extracorporeal circulation. No difference in cardiovascular stability was found. High-sensitivity troponin concentrations on the first postoperative morning were 0.355±0.312 µg/mL and 0.225±0.111 µg/mL in the isoflurane and sevoflurane groups, respectively (p = 0.147). CONCLUSIONS: The study found similar pharmacokinetics regarding wash-in and wash-out for sevoflurane and isoflurane. In addition, no difference in cardiovascular stability was found. The markers of cardiac damage were not different between the two anesthetics. Based on these data, sevoflurane and isoflurane might be used equivalently in patients undergoing coronary artery bypass graft surgery with extracorporeal circulation.

Sevoflurane Versus Total Intravenous Anesthesia for Isolated Coronary Artery Bypass Surgery With Cardiopulmonary Bypass: A Randomized Trial.

OBJECTIVE: Several studies have suggested that the cardioprotective effects of halogenated anesthetics in cardiac surgery result in reduced cardiac biomarker release compared with total intravenous anesthesia (TIVA). These findings came from relatively small randomized clinical trials and meta-analyses. The authors of this study hypothesized that the beneficial effects of volatile anesthetics translate into a reduced length of hospital stay after coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass. DESIGN: A randomized controlled trial. SETTING: Two university hospitals. PARTICIPANTS: Adult patients undergoing elective CABG surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were assigned randomly to 2 following groups: propofol-based TIVA group (n = 431) and sevoflurane group (n = 437). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was hospital length of stay, and the secondary endpoint included postoperative troponin T and N-terminal pro-brain natriuretic peptide release and mortality. In the sevoflurane group, a reduced length of hospital stay was observed compared with the propofol-based TIVA group (10 [9-11] days v 14 [10-16], p<0.001) as were reductions in cardiac troponin T release (0.18 ng/mL v 0.57 ng/mL at 24 hours, p<0.001), in N-terminal pro-brain natriuretic peptide release (633 pg/mL v 878 pg/mL at 24 hours, p<0.001; 482 pg/mL v 1,036 pg/mL at 48 hours, p<0.001), and in mortality at 1-year follow up (17.8% v 24.8%, p = 0.03). CONCLUSIONS: Anesthesia with sevoflurane reduced cardiac biomarker release and length of hospital stay after CABG with cardiopulmonary bypass surgery compared with propofol-based TIVA with a possible reduction in 1-year mortality.

Effects of sevoflurane and propofol on S100ß and neuron-specific enolase protein levels during cardiopulmonary bypass.

AIM: Cardiopulmonary bypass (CPB) is associated with the release of S100ß and neuron-specific enolase (NSE) indicating cerebral cell injury. The purpose of the present study was to evaluate the effect of propofol and sevoflurane on S100ß and NSE levels in patients undergoing coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Twenty male patients undergoing CABG were randomly allocated into two groups. One group received sevoflurane (GS) and the other received propofol (GP). Arterial blood samples for analysis of S100ß and NSE levels were taken preoperatively (T1), 30 min after initiation of CPB (T2), at the end of CPB (T3), 1 (T4), 6 (T5) and 24 h (T6) postoperatively. RESULTS: S100ß level was significantly higher compared to all analyzed times at T3 in both groups (P < 0.001). S100ß level was significantly higher in GP than GS only at T2 (P = 0.002). NSE level was significantly higher at T3, T4 and T5 than T1 in the GP (P = 0.001, 0.002 and 0.023, respectively), while a significant increase was seen at T3 and T4 in GS group (P = 0.001 and 0.047, respectively). CONCLUSION: Our findings showed that both S100ß and NSE levels similarly increased during CPB and immediately after CPB during sevoflurane and propofol based anesthesia.

Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro.

Tumour cell proliferation, invasion and apoptosis are crucial steps in tumour metastasis. We evaluated the effect of serum from patients undergoing colon cancer surgery receiving thoracic epidural and propofol anaesthesia on colon cancer cell biology. Patients were randomly assigned to receive propofol anaesthesia with a concomitant thoracic epidural (PEA, n = 20) or sevoflurane anaesthesia with opioid analgesia (SGA, n = 20). Venous blood was obtained before induction of anaesthesia and 24 hours postoperatively. The LoVo colon cancer cells were cultured with patient serum from both groups and the effects on proliferation, invasion and apoptosis were measured. Twenty-four hours after surgery, the absorbance value of LoVo cells at 10% serum concentration from PEA was decreased when compared with SGA (0.302 (0.026) vs 0.391 (0.066), p = 0.005). The inhibitory rate of LoVo cells at 10% serum concentration from PEA was higher than that from SGA (p = 0.004) 24 h after surgery. The number of invasive LoVo cells at 10% serum concentration from PEA was reduced when compared with SGA (44 (4) vs 62 (4), p < 0.001). Exposure of LoVo cells to postoperative serum from patients receiving PEA led to a higher luminescence ratio (apoptosis) than those receiving SGA (0.36 (0.04) vs 0.27 (0.05), p < 0.001). Serum from patients receiving PEA for colon cancer surgery inhibited proliferation and invasion of LoVo cells and induced apoptosis in vitro more than that from patients receiving SGA. Anaesthetic technique might influence the serum milieu in a way that affects cancer cell biology and, thereby, tumour metastastasis.

Relationship between Sevoflurane Plasma Concentration, Clinical Variables and Bispectral Index Values during Cardiopulmonary Bypass.

BACKGROUND: Anesthetic administration is increasingly guided by electroencephalography (EEG)-based monitoring, such as the bispectral index (BIS). However, during cardiopulmonary bypass (CPB), factors other than the administered hypnotic agents may influence EEG signals, and their effects on BIS values are unknown. METHODS: This report is a secondary analysis of data from a prospective, controlled interventional study comparing the effect of sevoflurane administration guided by BIS monitoring (group SevoBIS) and constant administration of sevoflurane (group Sevo1.8Vol%) during CPB. Sevoflurane plasma concentration (SPC) was measured using gas chromatography. The relationships of BIS to SPC, CPB pump flow, arterial pressure, hematocrit, temperature, time on CPB, and patient characteristics were analysed. RESULTS: No association was observed between BIS values and SPC in group SevoBIS. In group Sevo1.8Vol%, a 40 µg ml-1 increase in SPC, which encompassed the entire range of observed values of the SPC in this analysis, was associated with a decrease of 3.6 (95% confidence interval (CI): 1.1-6.1) in BIS values (p = 0.005). Each increase in CPB time of 10 minutes was associated with an increase in BIS values of 0.25 (95%CI: 0.11-0.39, p<0.001). Path analysis revealed that the BIS values of SevoBIS patients were 5.3 (95%CI: 3.2-7.5) units higher than those of Sevo1.8Vol% patients (p<0.001), which was the strongest effect on BIS values. Path analysis revealed a slope of 0.5 (95%CI: 0.3-0.7) BIS units per 1°C body temperature (p<0.001). CONCLUSION: BIS monitoring is insensitive to clinically relevant changes in SPC in individual patients during CPB.

Propofol Provides More Effective Protection for Circulating Lymphocytes Than Sevoflurane in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery.

OBJECTIVES: To compare the effects of propofol, sevoflurane, and the combination of the 2 on circulating lymphocytes in patients undergoing off-pump coronary artery bypass graft (OPCAB) surgery. DESIGN: A prospective, randomized study. SETTING: A university hospital. PARTICIPANTS: One hundred five patients undergoing elective OPCAB surgery. INTERVENTIONS: Participants were randomized to receive sevoflurane (group S), propofol (group P), or coadministration (group C) of sevoflurane- and propofol-maintained anesthesia. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained before, during, and after surgery. Caspase-3 and apoptosis-inducing factor in lymphocytes were evaluated by Western blot. During surgery, 5 minutes after revascularization of the left anterior descending artery, 5 minutes after all anastomoses (T4), and after the sternal closure (T5), caspase-3 expression of group S was higher than that of group P (p = 0.02) and group C (p = 0.02). At T4 and T5, expression of active apoptosis-inducing factor in group S was higher than that in the other 2 groups (p = 0.03 and p = 0.04, respectively). 24 hours after surgery, the lymphocyte count of group S (0.55/nL) was lower than that of group P (0.73/nL, p = 0.02) and group C (0.73/nL, p = 0.03). Intensive care unit stay of group S (3.0 days) was longer than that of the other 2 groups (2.2 days, p = 0.02 and 2.1 days, p = 0.01). CONCLUSIONS: OPCAB surgery was associated with postoperative lymphopenia. Regarding a protective effect for circulating lymphocytes, propofol and the combination of sevoflurane- and propofol-maintained anesthesia were both superior to sevoflurane-maintained anesthesia.

Optimal cutoff points of entropy indices for use in predicting responses elicited during determination of minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To investigate values of spectral indices for use in predicting responses in dogs during determination of minimum alveolar concentration (MAC) of sevoflurane. ANIMALS: 15 healthy German Shepherd Dogs. PROCEDURES :Sevoflurane MAC was determined by use of tail clamping. Entropy indices consisting of response entropy and state entropy were recorded during MAC determination. Optimal cutoff points of response entropy and state entropy for use in predicting responses to tail clamping were analyzed with multiple logistic regression. RESULTS: Sevoflurane MAC ranged from 1.8% to 2.6% (mean ± SD, 2.2 ± 0.3%). Response entropy and state entropy were significantly higher during positive responses to tail clamping (88 ± 2 and 76 ± 2, respectively) than during negative responses to tail clamping (63 ± 3 and 52 ± 3, respectively). The difference between the 2 entropy indices did not differ between positive (11 ± 1) and negative (13 ± 1) responses to tail clamping. Response entropy and state entropy served as independent predictors of a positive response, with areas under the curve for receiver operating characteristic curves 0.810 (95% confidence interval, 0.716 to 0.903) and 0.828 (95% confidence interval, 0.741 to 0.916), respectively. Optimal cutoff points to predict a positive response were 75 for response entropy and 65 for state entropy, which corresponded to mean ± SD ORs of 25.2 ± 15.6 and 14.9 ± 7.9, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Response entropy and state entropy were good predictors of responses to tail clamping elicited during determination of sevoflurane MAC in healthy dogs.

Arterial blood and end-tidal concentrations of sevoflurane during the emergence from anesthesia in gynecologic patients.

OBJECTIVE: The end-tidal concentration of inhalation anesthetics is a clinical indicator for predicting the emergence from anesthesia. This study was conducted to assess the relationship between arterial blood and end-tidal sevoflurane concentrations during emergence. METHODS: Thirty-two female American Society of Anesthesiologists physical status I-II patients receiving general anesthesia for elective gynecologic surgery were included. A fixed dose of 3.5% inspiratory sevoflurane in 6 L min-1 oxygen was maintained until the end of surgery. At 20 and 10 minutes before and 0, 5, 10, 15, and 20 minutes after discontinuing sevoflurane, as well as at the time of eye opening by verbal command, defined as awakening, 1 ml arterial blood was obtained to measure its sevoflurane concentration by gas chromatography. Simultaneous inspiratory and end-tidal concentrations of sevoflurane were detected by an infrared analyzer and tested by Bland-Altman agreement analysis. RESULTS: The arterial blood concentrations of sevoflurane were similar to the simultaneous end-tidal concentrations during emergence: 0.36% (0.10) and 0.36% (0.08) sevoflurane at awakening, respectively. The mean time from discontinuing sevoflurane to eye opening was 15.8 minutes (SD 2.9, range 10-26) and was significantly correlated with the duration of anesthesia (52-192 minutes) (P = 0.006) but not with the body mass index or total fentanyl dose. CONCLUSION: The mean awakening arterial blood concentration of sevoflurane was 0.36%. The time to awakening was prolonged in accordance with the anesthetic duration within 3 hours. With well-assisted ventilation during emergence, the sevoflurane end-tidal concentration was nearly equal to its arterial blood concentration, which could be a feasible predictor for awakening.

Simultaneous measurement of methyl tert-butyl ether and tert-butyl alcohol in human serum by headspace solid-phase microextraction gas chromatography-mass spectrometry.

The abundant production of methyl tert-butyl ether (MTBE) and its widespread use have led to an increase in the potential for human exposure. This work described a simple, fast, sensitive, reliable and low-cost method for the simultaneous measurement of MTBE and its metabolite, tert-butyl alcohol (TBA) in human serum by headspace solid-phase microextraction gas chromatography-mass spectrometry. Extraction conditions were optimized and 40 °C, 10 min, 250 rpm and 0.3 g NaCl for a 1 mL sample were the optimal conditions. This method showed good analytical performance in terms of sensitivity with limits of detection in serum (1 mL) of 0.03 µg/L for MTBE and 0.05 µg/L for TBA, accuracy (mean recovery values) from 75.8% to 85.8%, precision (relative standard deviations) <10% and sample stability (biodegradation) <10% after 28 days. A verification experiment proved the reproducibility and stability of this method as well. Finally the method was used to detect 212 specimens, and the internal dose levels for MTBE in human serum were presented in China.

Simultaneous determination of seven taxoids in rat plasma by UPLC-MS/MS and pharmacokinetic study after oral administration of Taxus yunnanensis extracts.

A rapid, sensitive and reliable method has been developed and validated for the simultaneous determination of seven taxoids including 10-deacetylbaccatin III (10-DAB III), baccatin III, 5-epi-canadensene, taxinine M, 10-deacetyltaxol (10-DAT), cephalomannine and paclitaxel in rat plasma using docetaxel as the internal standard (IS). The plasma samples were pretreated by liquid-liquid extraction with methyl tert-butyl ether. The chromatographic separation was achieved on a C18 column (50 mm × 2.1 mm, 1.8 µm, Waters, USA) with a gradient elution program consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. Detection was performed under the selected reaction monitoring (SRM) scan using an electrospray ionization (ESI) in the positive ion mode. The mass transitions were as follows: m/z 567.4→444.9 for 10-DAB III, m/z 609.0→549.3 for baccatin III, m/z 617.4→496.9 for 5-epi-canadensene, m/z 709.6→649.3 for taxinine M, m/z 834.8→307.9 for 10-DAT, m/z 854.5→285.4 for cephalomannine, m/z 876.8→307.3 for paclitaxel and m/z 830.8→549.6 for IS, respectively. All calibration curves exhibited good linearity (r(2)>0.99) over a wide concentration range for all components. The intra-day and inter-day precisions at three different levels were both less than 14.3% in terms of relative standard deviation (RSD) and the accuracies ranged from -8.3% to 14.8% in terms of relative error (RE). The extraction recoveries of the seven compounds ranged from 62.5% to 100.5%. The developed method was successfully applied to the pharmacokinetic study of the seven taxoids in rat plasma after oral administration of the crude extract of the twigs and leaves of Taxus yunnanensis.

Biomarkers of inflammation in major vascular surgery: a prospective randomised trial.

BACKGROUND: Surgery induces inflammation and pro-inflammatory cytokines are associated with post-operative complications. In cardiac surgery, it has been shown that volatile anaesthetics have cardioprotective properties. We explored whether sevoflurane affects the pro-inflammatory response favourably compared with total intravenous anaesthesia (TIVA) after surgery. METHODS: We measured monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9 (MMP-9), C-reactive protein (CRP), vascular cell adhesion molecule 1 (VCAM-1), interleukin (IL)-6 and IL-8 perioperatively and evaluated if the anaesthetic regimen affected these mediators. Our hypothesis was that sevoflurane-based anaesthesia is associated with a reduced release of biomarkers of inflammation compared with TIVA with propofol/remifentanil. RESULTS: In the total population, MCP-1, MMP-9, IL-6 and IL-8 increased 30 min after arrival intensive care unit, compared with before surgery (P < 0.001), whereas CRP and VCAM-1 transiently declined (P < 0.001). From 30 min after arrival intensive care unit to 1st post-operative day, MCP-1 and IL-6 levels declined (P < 0.001), CRP and VCAM-1 increased (P < 0.001), whereas MMP-9 and IL-8 were not significantly altered. Pre-operatively there were no significant differences in any variables between the two anaesthetic groups. Lower levels of MCP-1 and IL-8 (P < 0.001) and higher levels of IL-6 and MMP-9 (P = 0.003) were found in the sevoflurane group, compared with the TIVA group 30 min post-operatively. CRP and VCAM-1 levels did not differ. There were no significant differences between the two anaesthetic groups before surgery or at 1st post-operative day. CONCLUSION: We found an inflammatory response during the observation period, which was modified by the anaesthetic regimen in the early phase. This short-lasting difference is probably too short to support a cardioprotective effect of sevoflurane compared with TIVA in open abdominal aortic surgery.

Blood/Gas partition coefficients for isoflurane, sevoflurane, and desflurane in a clinically relevant patient population.

BACKGROUND: The blood/gas partition coefficient of a certain volatile anesthetic is of clinical importance because it determines its velocity of uptake into and elimination from the body of a patient and thus its pharmacokinetic behavior. To date, the blood/gas partition coefficients of isoflurane, sevoflurane, and desflurane have been measured in small numbers of subjects or in particular study groups, for example, healthy volunteers, patients experiencing a common kind of disease, or mothers immediately after giving birth. The objective of this study was to determine the blood/gas partition coefficients of these volatile anesthetics at 37°C in a larger clinically relevant and adult patient population. Furthermore, we tested whether age, gender, body mass index, hemoglobin concentration, or hematocrit had an influence on the coefficients. METHODS: Blood samples were taken from 120 fasting operative patients with ASA physical status I to III and aged 19 to 86 years. All subjects were randomly enrolled in study groups for the separate determinations of the blood/gas partition coefficients of isoflurane (n = 41), sevoflurane (n = 41), and desflurane (n = 38) by headspace gas chromatography. To check the quality of the measurements, we determined the distilled water/gas partition coefficients of those anesthetics and compared them with previously published values. RESULTS: We found a blood/gas partition coefficient of 1.45 ± 0.12 (mean ± SD) for isoflurane, 0.74 ± 0.06 for sevoflurane, and 0.57 ± 0.04 for desflurane. Values of this study are 5.07%, 12.12%, and 7.55% higher for isoflurane, sevoflurane, and desflurane, respectively, than the previously published mean values (all P ≤ 0.001). There were only trends for small correlations between the blood/gas partition coefficient of isoflurane and hemoglobin concentration (Pearson r = 0.32; P = 0.041) and hematocrit (r = 0.37; P = 0.016). We found no other potentially significant correlations of the partition coefficients with patient age, body mass index, hemoglobin concentration, or hematocrit (all remaining P > 0.069). Furthermore, the coefficients did not differ significantly between female and male patients. The evaluation of the distilled water/gas partition coefficients of isoflurane (0.59 ± 0.04), sevoflurane (0.37 ± 0.04), and desflurane (0.27 ± 0.03) proved the validity of the gas chromatography method used in this study. CONCLUSIONS: The blood/gas partition coefficients of the modern volatile anesthetics, in particular, those of sevoflurane and desflurane, may be higher than that has been hitherto reported. Therefore, their uptake and elimination may occur more slowly in some patients than has been supposed. The blood/gas partition coefficients of isoflurane, sevoflurane, and desflurane measured in this study appear to be representative because they were determined in a clinically and numerically relevant patient cohort.

Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.

BACKGROUND: Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS: Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS: Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION: Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.

Cardiospecific sevoflurane treatment quenches inflammation but does not attenuate myocardial cell damage markers: a proof-of-concept study in patients undergoing mitral valve repair.

BACKGROUND: Inflammation is considered a key mediator of complications after cardiac surgery. Sevoflurane has been shown to quench inflammation and to provide cardioprotection in preclinical studies. Clinical studies using sevoflurane confirm this effect on inflammation but do not consistently show clinical benefits. This paradox may indicate that the contribution of inflammation to postoperative sequalae is less than commonly thought or that systemic doses are too low in their local concentration. To test the latter, we evaluated the effects of intramyocardial sevoflurane delivery. METHODS: Selective myocardial sevoflurane delivery was performed during aortic cross-clamping in patients undergoing valve surgery (n=11). Results were compared with a control group not receiving sevoflurane (n=10). A reference group (n=5) was added to evaluate the effects of systemic sevoflurane delivery. Paired arterial and myocardial venous blood samples were collected at various time points post-reperfusion. Inflammatory mediators and myocardial cell damage were studied. RESULTS: Intramyocardial delivery was superior to systemic delivery in attenuation of interleukin-6 and interleukin-8 (-44% and -25%, respectively; both P=0.001). Myocardial and systemic sevoflurane delivery effectively suppressed surgery-related inflammatory responses including postoperative C-reactive protein levels when compared with controls [63 (47-99) (P=0.01) and 58 (56-81) (P=0.04) compared with 107 (79-144) mg litre(-1)]. Sevoflurane treatment did not reduce postoperative troponin T, creatine kinase, and creatine kinase-MB values. CONCLUSIONS: This proof-of-concept study suggests that intramyocardial delivery compared with the systemic delivery of sevoflurane more strongly attenuates the systemic inflammatory response after cardiopulmonary bypass without reducing postoperative markers of myocardial cell damage. CLINICAL TRIAL REGISTRATION: Nederlands Trial Register NTR2089.