Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study.

INTRODUCTION: Severe infections in intensive care patients show high morbidity and mortality rates. Linezolid is an antimicrobial drug frequently used in critically ill patients. Recent data indicates that there might be high variability of linezolid serum concentrations in intensive care patients receiving standard doses. This study was aimed to evaluate whether standard dosing of linezolid leads to therapeutic serum concentrations in critically ill patients. METHODS: In this prospective observational study, 30 critically ill adult patients with suspected infections received standard dosing of 600 mg linezolid intravenously twice a day. Over 4 days, multiple serum samples were obtained from each patient, in order to determine the linezolid concentrations by liquid chromatography tandem mass spectrometry. RESULTS: A high variability of serum linezolid concentrations was observed (range of area under the linezolid concentration time curve over 24 hours (AUC24) 50.1 to 453.9 mg/L, median 143.3 mg*h/L; range of trough concentrations (Cmin) < 0.13 to 14.49 mg/L, median 2.06 mg/L). Furthermore, potentially subtherapeutic linezolid concentrations over 24 hours and at single time points (defined according to the literature as AUC24 < 200 mg*h/L and Cmin < 2 mg/L) were observed for 63% and 50% of the patients, respectively. Finally, potentially toxic levels (defined as AUC24 > 400 mg*h/L and Cmin > 10 mg/L) were observed for 7 of the patients. CONCLUSIONS: A high variability of linezolid serum concentrations with a substantial percentage of potentially subtherapeutic levels was observed in intensive care patients. The findings suggest that therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01793012. Registered 24 January 2013.

Determination of breath isoprene allows the identification of the expiratory fraction of the propofol breath signal during real-time propofol breath monitoring.

Real-time measurement of propofol in the breath may be used for routine clinical monitoring. However, this requires unequivocal identification of the expiratory phase of the respiratory propofol signal as only expiratory propofol reflects propofol blood concentrations. Determination of CO2 breath concentrations is the current gold standard for the identification of expiratory gas but usually requires additional equipment. Human breath also contains isoprene, a volatile organic compound with low inspiratory breath concentration and an expiratory concentration plateau. We investigated whether breath isoprene could be used similarly to CO2 to identify the expiratory fraction of the propofol breath signal. We investigated real-time breath data obtained from 40 study subjects during routine anesthesia. Propofol, isoprene, and CO2 breath concentrations were determined by a combined ion molecule reaction/electron impact mass spectrometry system. The expiratory propofol signal was identified according to breath CO2 and isoprene concentrations and presented as median of intervals of 30 s duration. Bland-Altman analysis was applied to detect differences (bias) in the expiratory propofol signal extracted by the two identification methods. We investigated propofol signals in a total of 3,590 observation intervals of 30 s duration in the 40 study subjects. In 51.4 % of the intervals (1,844/3,590) both methods extracted the same results for expiratory propofol signal. Overall bias between the two data extraction methods was -0.12 ppb. The lower and the upper limits of the 95 % CI were -0.69 and 0.45 ppb. Determination of isoprene breath concentrations allows the identification of the expiratory propofol signal during real-time breath monitoring.

Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial.

Importance: Proposed biosimilar natalizumab (biosim-NTZ) PB006 is the first biosimilar monoclonal antibody therapy developed for multiple sclerosis (MS) treatment. Objective: To evaluate matching efficacy, safety, and immunogenicity between biosim-NTZ and reference natalizumab (ref-NTZ) in patients with relapsing-remitting MS (RRMS). Design, Setting, and Participants: The Antelope trial was a phase 3, parallel-group, randomized, active-controlled study, conducted between October 2019 and March 2021, with last patient follow-up visit on August 23, 2021. The study took place in 48 centers in 7 countries. Of 531 patients with RRMS aged 18 to 60 years screened, 266 were excluded before randomization in line with study criteria. Eligible participants had 1 or more documented relapse within the previous year and either 1 or more gadolinium-enhancing T1-weighted or 9 or more T2-weighted brain lesions, Kurtzke Expanded Disability Status Scale score of 0 to 5.0 (inclusive), and John Cunningham virus index of 1.5 or less at screening. One patient withdrew consent before dosing. Interventions: Intravenous infusions every 4 weeks of biosim-NTZ, 300 mg, or ref-NTZ, 300 mg (1:1 randomization), from week 0 to week 44 (end-of-study visit: week 48). At week 24, the ref-NTZ group was rerandomized and 30 patients were switched to biosim-NTZ for the remainder of the study. Main Outcomes and Measures: The primary end point was the cumulative number of new active lesions on magnetic resonance imaging (new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double counting) over 24 weeks. Additional end points included further magnetic resonance imaging parameters, annualized relapse rate, and Kurtzke Expanded Disability Status Scale score. Safety, tolerability, and immunogenicity assessments included adverse events, laboratory evaluations, and positivity for anti-John Cunningham virus antibodies and antinatalizumab antibodies. Results: A total of 264 participants (mean [SD] age, 36.7 [9.38] years; 162 [61.4%] female) received treatment with biosim-NTZ (n = 131) or ref-NTZ (n = 133). At week 24, the model-based mean difference in cumulative number of new active lesions between biosim-NTZ and ref-NTZ treatment groups was 0.17 (least square means [SE]: biosim-NTZ, 0.34 [0.34]; ref-NTZ, 0.45 [0.28]; 95% CI, -0.61 to 0.94 within the prespecified margins of ±2.1). No significant differences between treatment groups were observed across secondary efficacy end points, safety, tolerability, or immunogenicity assessments. Conclusions and Relevance: Biosim-NTZ matched ref-NTZ in efficacy, safety, and immunogenicity for patients with RRMS in the tested setting. This phase 3 trial supports proposed biosim-NTZ as a biosimilar alternative to ref-NTZ for treating RRMS. Trial Registration: ClinicalTrials.gov Identifier: NCT04115488.

Time course of expiratory propofol after bolus injection as measured by ion molecule reaction mass spectrometry.

Propofol in exhaled breath can be detected and monitored in real time by ion molecule reaction mass spectrometry (IMR-MS). In addition, propofol concentration in exhaled breath is tightly correlated with propofol concentration in plasma. Therefore, real-time monitoring of expiratory propofol could be useful for titrating intravenous anesthesia, but only if concentration changes in plasma can be determined in exhaled breath without significant delay. To evaluate the utility of IMR-MS during non-steady-state conditions, we measured the time course of both expiratory propofol concentration and the processed electroencephalography (EEG) as a surrogate outcome for propofol effect after an IV bolus induction of propofol. Twenty-one patients scheduled for routine surgery were observed after a bolus of 2.5 mg kg(-1) propofol for induction of anesthesia. Expiratory propofol was measured using IMR-MS and the cerebral propofol effect was estimated using the bispectral index (BIS). Primary endpoints were time to detection of expiratory propofol and time to onset of propofol's effect on BIS, and the secondary endpoint was time to peak effect (highest expiratory propofol or lowest BIS). Expiratory propofol and changes in BIS were first detected at 43 ± 21 and 49 ± 11 s after bolus injection, respectively (P = 0.29). Peak propofol concentrations (9.2 ± 2.4 parts-per-billion) and lowest BIS values (23 ± 4) were reached after 208 ± 57 and 219 ± 62 s, respectively (P = 0.57). Expiratory propofol concentrations measured by IMR-MS have similar times to detection and peak concentrations compared with propofol effect as measured by the processed EEG (BIS). This suggests that expiratory propofol concentrations may be useful for titrating intravenous anesthesia.

Effect of an acute consumption of a moderate amount of ethanol on plasma endocannabinoid levels in humans.

AIMS: Animal experiments have shown that the endocannabinoid system (ECS) plays an important role in the regulation of ethanol intake. We investigated these effects in healthy volunteers who consumed a moderate amount of ethanol (red wine) and measured plasma levels of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) to test whether alcohol consumption influences the ECS in humans. Grape juice or plain non-sparkling water served as non-alcoholic control liquids. METHODS: In total, 55 adults were enrolled in this study and assigned to one of three groups drinking either 250 ml of red wine (28.0 g of ethanol, <0.8 g of sugar and 187.5 kcal), grape juice (41.0 g of sugar, 187.5 kcal) or plain water within 10 min. Twenty minutes and 45 min thereafter, AEA, 2-AG, ethanol and glucose levels were determined from venous plasma samples. RESULTS: AEA, 2-AG and plasma glucose levels were significantly reduced after red wine consumption. AEA had its maximal decline at 20 min (from 0.23 ± 0.12 to 0.18 ± 0.07 ng/ml, P < 0.01), whereas the nadir of 2-AG was seen after 45 min and dropped from 6.68 ± 4.13 to 5.49 ± 3.22 ng/ml (P < 0.05). Grape juice highly affected blood glucose level after 20 min, with a return to baseline after 45 min. ECs remained almost unchanged by this intervention. Water intake had no significant effect on AEA (0.21 ± 0.08 at baseline and 0.19 ± 0.06 after 45 min) but resulted in a gradual reduction in 2-AG concentrations which became significant at 45 min when compared with baseline. CONCLUSIONS: The consumption of a moderate amount of red wine reduces plasma AEA and 2-AG concentrations, whereas the volume and caloric equivalent of the sugar containing, non-alcoholic liquid grape juice does not affect plasma ECs. Plain water has a differential effect on the ECS by reducing 2-AG concentrations without affecting AEA.

Neurokinin-1 and novel serotonin antagonists for postoperative and postdischarge nausea and vomiting.

PURPOSE OF REVIEW: This review will address novel options for the prevention and treatment of postoperative and postdischarge nausea and vomiting (PONV and PDNV) after ambulatory anesthesia. In particular, this paper will review the characteristics of neurokinin-1 receptor antagonists (NK1-RAs) and the new serotonin receptor antagonist (5HT3-RA) palonosetron. Finally, we will discuss strategies for prophylaxis and treatment of PONV and PDNV that address the unique concerns in ambulatory surgery patients. RECENT FINDINGS: First, although PONV has previously been recognized to be a problem for inpatients, new research suggests that the incidence of PDNV after ambulatory surgery may be as high as 35%. Second, NK1-RAs, including aprepitant, the first approved member of this family, are significantly more efficacious than any other antiemetic for the prevention of vomiting. They are however not more effective than other interventions for the control of nausea. Third, the next generation of 5HT3-RAs, such as palonosetron, does not affect the QT interval and has a half-life of 40 h that should be advantageous for the prevention of PDNV. SUMMARY: Because of the high incidence of PDNV, a predictive model for PDNV would be helpful to determine appropriate antiemetic interventions for each individual patient. Drugs that may be particularly favorable are the novel NK1-RA aprepitant and the next generation 5HT3-RA palonosetron.

Propofol Breath Monitoring as a Potential Tool to Improve the Prediction of Intraoperative Plasma Concentrations.

INTRODUCTION: Monitoring of drug concentrations in breathing gas is routinely being used to individualize drug dosing for the inhalation anesthetics. For intravenous anesthetics however, no decisive evidence in favor of breath concentration monitoring has been presented up until now. At the same time, questions remain with respect to the performance of currently used plasma pharmacokinetic models implemented in target-controlled infusion systems. In this study, we investigate whether breath monitoring of propofol could improve the predictive performance of currently applied, target-controlled infusion models. METHODS: Based on data from a healthy volunteer study, we developed an addition to the current state-of-the-art pharmacokinetic model for propofol, to accommodate breath concentration measurements. The potential of using this pharmacokinetic (PK) model in a Bayesian forecasting setting was studied using a simulation study. Finally, by introducing bispectral index monitor (BIS) measurements and the accompanying BIS models into our PK model, we investigated the relationship between BIS and predicted breath concentrations. RESULTS AND DISCUSSION: We show that the current state-of-the-art pharmacokinetic model is easily extended to reliably describe propofol kinetics in exhaled breath. Furthermore, we show that the predictive performance of the a priori model is improved by Bayesian adaptation based on the measured breath concentrations, thereby allowing further treatment individualization and a more stringent control on the targeted plasma concentrations during general anesthesia. Finally, we demonstrated concordance between currently advocated BIS models, relying on predicted effect-site concentrations, and our new approach in which BIS measurements are derived from predicted breath concentrations.

Liver resection in the elderly: significance of comorbidities and blood loss.

OBJECTIVE: Liver resection is increasingly performed in elderly patients who are suspected of increased postoperative morbidity (PM) and reduced overall survival (OS). Patient selection based on the identification of age-adjusted risk factors may help to decrease PM and OS. DESIGN AND PARTICIPANTS: Prospectively collected data of 879 patients undergoing elective hepatic resection were analyzed. This population was stratified into three age cohorts: >70 years (n = 228; 26 %), 60-69 years (n = 309; 35 %), and <60 years (n = 342; 39 %). Multivariate survival analysis was performed. RESULTS: The incidence of severe (p < 0.01) and non-surgical (p < 0.001) postoperative complications was higher in older compared to younger patients. Major estimated blood loss (EBL; p = 0.039) and comorbidities (p = 0.002) independently increased PM. EBL was comparable between all age cohorts. However, preexisting comorbidities, major EBL, and postoperative complications markedly decreased OS in contrast to younger patients. Adjusted for age, independent predictors of OS were comorbidities (HR = 1.51; p = 0.001), major hepatectomy (HR = 1.33; p = 0.025), increased EBL (HR = 1.32; p = 0.031), and postoperative complications (HR = 1.64; p < 0.001). CONCLUSION: Although increased age should not be a contraindication for liver resection, this study accents the avoidance of major blood loss in elderly patients and a stringent patient selection based on preexisting comorbidities.

Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis.

Opioids are a key risk factor for postoperative nausea and vomiting (PONV). As intravenous (i.v.) acetaminophen reduces postoperative pain and opioid requirements, one would expect i.v. acetaminophen to be associated with a lower incidence of opioid-induced side effects, including PONV. We conducted a systematic search using Medline and Cochrane databases supplemented with hand search of abstract proceedings to identify randomized-controlled trials of i.v. acetaminophen. Inclusion criteria were (a) randomized for i.v. acetaminophen vs a placebo control, (b) general anesthesia, and (c) reported or obtainable PONV outcomes. Primary outcome was postoperative nausea and secondary outcome was postoperative vomiting. We included 30 studies with 2364 patients (1223 in the acetaminophen group, 1141 in the placebo group). The relative risk (95% confidence interval) was 0.73 (0.60-0.88) for nausea and 0.63 (0.45-0.88) for vomiting. Data showed significant heterogeneity for both nausea (P=0.02, I(2)=38%) and vomiting (P=0.006, I(2)=47%), but were homogeneous when studies were grouped according to timing of first administration: i.v. acetaminophen reduced nausea when given prophylactically either before surgery, 0.54 (0.40-0.74), or before arrival in the postanesthesia care unit, 0.67 (0.55-0.83); but not when given after the onset of pain, 1.12 (0.85-1.48). When i.v. acetaminophen was given prophylactically, the reduction of nausea correlated with the reduction of pain (odds ratio 0.66, 0.47-0.93), but not with reduction in postoperative opioids (odds ratio 0.89, 0.64-1.22). Prophylactically administered i.v. acetaminophen reduced PONV, mainly mediated through superior pain control.

Breath isoprene concentrations in persons undergoing general anesthesia and in healthy volunteers.

Human breath contains an abundance of volatile organic compounds (VOCs). Analysis of breath VOC may be used for diagnosis of various diseases or for on-line monitoring in anesthesia and intensive care. However, VOC concentrations largely depend on the breath sampling method and have a large inter-individual variability. For the development of breath tests, the influence of breath sampling methods and study subject characteristics on VOC concentrations has to be known. Therefore, we investigated the VOC isoprene in 62 study subjects during anesthesia and 16 spontaneously breathing healthy volunteers to determine (a) the influence of artificial and spontaneous ventilation and (b) the influence of study subject characteristics on breath isoprene concentrations. We used ion molecule reaction mass spectrometry for high-resolution breath-by-breath analysis of isoprene. We found that persons during anesthesia had significantly increased inspiratory and end-expiratory isoprene breath concentrations. Measured isoprene concentrations (median [first quartile-third quartile]) were in the anesthesia group: 54 [40-79] ppb (inspiratory) and 224 [171-309] ppb (end-expiratory), volunteer group: 14 [11-17] ppb (inspiratory) and 174 [124-202] ppb (end-expiratory). Higher end-tidal CO(2) concentrations in ventilated subjects were associated with higher expiratory isoprene levels. Furthermore, inspiratory and end-expiratory isoprene concentrations were correlated during anesthesia (r = 0.603, p < 0.001). Multivariate analysis showed that men had significantly higher end-expiratory isoprene concentrations than women. Rebreathing of isoprene from the anesthesia machine possibly accounts for the observed increase in isoprene in the anesthesia group.

Pharmacologic management of postoperative nausea and vomiting.

INTRODUCTION: As advances in the safety and efficacy of surgery and anesthesia have been made, other complications such as postoperative nausea and vomiting (PONV) have become more apparent. PONV occurs after 30% of all surgeries, and incidences as high as 80% have been reported among patients at high risk. AREAS COVERED: This review provides a brief overview of the etiology and mechanisms of emesis and of known risk factors for PONV. It also covers pharmacologic therapies, appropriate management strategies, prophylactic strategies, multimodal therapy and rescue treatment. EXPERT OPINION: The main triggers for PONV are general anesthesia with inhalational anesthetics and opioids. When given to susceptible patients, e.g., females, the risk may be as high as 80%. In such patients, opioid-free regional anesthesia would be the most logical approach. However, if general anesthesia is needed, we prefer total intravenous anesthesia as it eliminates the use of inhalational anesthetics and reduces the risk for PONV. Importantly, efficacy of antiemetic interventions is independent as long as interventions have different mechanisms. Thus, for practical purposes, we prefer to titrate the use of antiemetics according to the validated Apfel simplified risk score. If a patient has 0, 1, 2, 3 or 4 of the four risk factors, we apply a similar number of antiemetic strategies.

Prevention of pain on injection of propofol: systematic review and meta-analysis.

OBJECTIVE: To systematically determine the most efficacious approach for preventing pain on injection of propofol. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Library, www.clinicaltrials.gov, and hand searching from the reference lists of identified papers. STUDY SELECTION: Randomised controlled trials comparing drug and non-drug interventions with placebo or another intervention to alleviate pain on injection of propofol in adults. RESULTS: Data were analysed from 177 randomised controlled trials totalling 25,260 adults. The overall risk of pain from propofol injection alone was about 60%. Using an antecubital vein instead of a hand vein was the most effective single intervention (relative risk 0.14, 95% confidence interval 0.07 to 0.30). Pretreatment using lidocaine (lignocaine) in conjunction with venous occlusion was similarly effective (0.29, 0.22 to 0.38). Other effective interventions were a lidocaine-propofol admixture (0.40, 0.33 to 0.48); pretreatment with lidocaine (0.47, 0.40 to 0.56), opioids (0.49, 0.41 to 0.59), ketamine (0.52, 0.46 to 0.57), or non-steroidal anti-inflammatory drugs (0.67, 0.49 to 0.91); and propofol emulsions containing medium and long chain triglycerides (0.75, 0.67 to 0.84). Statistical testing of indirect comparisons showed that use of the antecubital vein and pretreatment using lidocaine along with venous occlusion to be more efficacious than the other interventions. CONCLUSIONS: The two most efficacious interventions to reduce pain on injection of propofol were use of the antecubital vein, or pretreatment using lidocaine in conjunction with venous occlusion when the hand vein was chosen. Under the assumption of independent efficacy a third practical alternative could be pretreatment of the hand vein with lidocaine or ketamine and use of a propofol emulsion containing medium and long chain triglycerides. Although not the most effective intervention on its own, a small dose of opioids before induction halved the risk of pain from the injection and thus can generally be recommended unless contraindicated.

Transdermal scopolamine for the prevention of postoperative nausea and vomiting: a systematic review and meta-analysis.

BACKGROUND: Transdermal scopolamine (TDS) is a potential long-acting prophylactic antiemetic initially developed to prevent motion sickness. TDS is a centrally acting anticholinergic agent that was approved in 2001 by the US Food and Drug Administration for the prevention of postoperative nausea and vomiting (PONV). Although TDS has been reported to be clinically efficacious in the prevention of PONV, several adverse events (AEs), such as sedation, dry mouth, blurred vision, central cholinergic syndrome, and confusion (particularly in elderly patients with mild cognitive impairment), are potential concerns. OBJECTIVE: The aim of this study was to explore the efficacy and tolerability of TDS in the prevention of PONV in adults. METHODS: A systematic search of PubMed, EMBASE, and the Cochrane Library for randomized controlled trials in adults that compared the effects of TDS and placebo on postoperative nausea, vomiting, and PONV was conducted in March 2009, and an update was conducted in July 2010. Without any language restrictions, a search with the following terms was performed: postoperative, postoperative, postanesthe*, postanaesthe*, post-anesthe*, post-anaesthe*, anesthesia, anaesthesia, surgery, surgeries, surgical, nausea, vomiting, emesis, retching, scopolamine, and hyoscine. Identified studies were then hand-searched for further relevant literature. RESULTS: Data from 25 randomized controlled trials were analyzed (N = 3298). In the postanesthesia care unit, TDS was associated with a significantly reduced risk for postoperative nausea compared with placebo (relative risk [RR] = 0.77; 95% CI, 0.61-0.98; P = 0.03). TDS was also associated with a significantly reduced risk for postoperative nausea (RR = 0.59; 95% CI, 0.48-0.73; P < 0.001), postoperative vomiting (RR = 0.68; 95% CI, 0.61-0.76; P < 0.001), and PONV (RR = 0.73; 95% CI, 0.60-0.88; P = 0.001) during the first 24 hours after the start of anesthesia. TDS appeared to be effective compared with placebo in the prevention of postoperative nausea when treatment was initiated the night before (early application) (RR = 0.56; 95% CI, 0.41-0.75; P < 0.001) or on the day of surgery (late application) (RR = 0.61; 95% CI, 0.47-0.79; P < 0.001). TDS was associated with a higher prevalence of visual disturbances at 24 to 48 hours compared with placebo (RR = 3.35; 95% CI, 1.78-6.32). Analyses of confusion and other AEs did not show a significant association with TDS. CONCLUSIONS: In this systematic review and metaanalysis, TDS was associated with significant reductions in PONV with both early and late patch application during the first 24 hours after the start of anesthesia. TDS was associated with a higher prevalence of visual disturbances at 24 to 48 hours after surgery, but no other AEs, compared with placebo.

Formation of the N-methylpyridinium ether derivative of propofol to improve sensitivity, specificity and reproducibility of its detection in blood by liquid chromatography-mass spectrometry.

In spite of comparatively high therapeutic concentrations in blood, the quantitation of propofol may cause analytical challenges due to its pharmacokinetic (e.g. short half life, high distribution volume) and physicochemical (significant volatility) particularities. Moreover, a considerable and concentration dependent protein binding and a substance association to erythrocytes result in an irreproducible distribution between whole blood and serum. A possible redistribution in stored samples needs to be compensated during sample preparation or included into the result interpretation. The new analytical approach is based on a formation of N-methylpyridinium derivatives of propofol and corresponding internal standards and permits a significant ( approximately 300 fold) increase of detection limits in LC-MS/MS. Derivatization is achieved by a direct conversion of the acetonitrile supernatant of a protein precipitation with 2-fluoro-1-methyl-pyridinium-p-toluene-sulfonate using triethylamine as catalyst. The derivative exhibits a high solvent stability and provides--in contrast to the unchanged parent compound--a sufficient number of diagnostic qualifier fragments to fulfil common identification criteria. By using 2-tert-butyl-6-methylphenol as internal standard (instead of the commonly applied thymol), a better compensation of matrix effects could be achieved. Owing to its high robustness, appropriate quantitation limits (LLOQ approximately 13 ng/mL), minimum sample amount and preparation effort, the assay could efficiently be applied for quantitative propofol analyses in pharmacokinetic studies with high sampling rates.

Real-time monitoring of propofol in expired air in humans undergoing total intravenous anesthesia.

BACKGROUND: The physicochemical properties of propofol could allow diffusion across the alveolocapillary membrane and a measurable degree of pulmonary propofol elimination. The authors tested this hypothesis and showed that propofol can be quantified in expiratory air and that propofol breath concentrations reflect blood concentrations. This could allow real-time monitoring of relative changes in the propofol concentration in arterial blood during total intravenous anesthesia. METHODS: The authors measured gas-phase propofol using a mass spectrometry system based on ion-molecule reactions coupled with quadrupole mass spectrometry which provides a highly sensitive method for on-line and off-line measurements of organic and inorganic compounds in gases. In a first sequence of experiments, the authors sampled blood from neurosurgery patients undergoing total intravenous anesthesia and performed propofol headspace determination above the blood sample using an auto-sampler connected to the mass spectrometry system. In a second set of experiments, the mass spectrometry system was connected directly to neurosurgery patients undergoing target-controlled infusion via a T piece inserted between the endotracheal tube and the Y connector of the anesthesia machine, and end-expiratory propofol concentrations were measured on-line. RESULTS: A close correlation between propofol whole blood concentration and propofol headspace was found (range of Pearson r, 0.846-0.957; P < 0.01; n = 6). End-expiratory propofol signals mirrored whole blood values with close intraindividual correlations between both parameters (range of Pearson r, 0.784-0.985; n = 11). CONCLUSION: Ion-molecule reaction mass spectrometry may allow the continuous and noninvasive monitoring of expiratory propofol levels in patients undergoing general anesthesia.

Effects of general anesthesia on anandamide blood levels in humans.

BACKGROUND: The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans. METHODS: The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia). RESULTS: Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance). CONCLUSION: General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.