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Several clinical studies have reported promising correlations between propofol concentration in exhaled breath (Ce-pro) and the bispectral index (BIS) in patients, suggesting the potential of exhaled propofol measurement as a non-invasive method for adjusting anesthesia depth. However, these studies are still in the validation phase of instrument effectiveness, often limited by small sample sizes or inappropriate instrument selection, and thus lack convincing results regarding these correlations. In this study, one hundred patients aged 18-65, undergoing elective thyroid surgery under general anesthesia were included. The vacuum ultraviolet photoionization and time-of-flight mass spectrometry was employed to monitor Ce-pro at 20 s intervals, alongside continuous BIS measurement. The association between Ce-pro and BIS was analyzed using linear mixed-effects models, with marginal R 2 used to assess the correlation. The threshold of Ce-pro at awakening was also explored. Additionally, the univariate and multifactorial diagnostic model, including end-of-surgery Ce-pro, were employed to assess the accuracy of predicting delayed recovery. A weak correlation was observed between intraoperative Ce-pro and BIS (marginal R 2 = 0.348). Predictive models utilizing end-of-surgery Ce-pro levels showed good accuracy (area under the curve (AUC) = 0.75, 95% CI: 0.62-0.89, P = 0.003) in predicting delayed recovery, while the model using end-of-surgery Ce-pro combined with gender, sufentanil dosage, the time from the last administration of sufentanil to the end of surgery, and anesthesia duration demonstrated stronger predicting accuracy (AUC = 0.91, 95% CI: 0.85-0.98, P < 0.001). This study suggests that Ce-pro alone may not reliably predict the depth of anesthesia in clinical practice, but shows promising accuracy in predicting delayed recovery from anesthesia., (Creative Commons Attribution license.)

The study objective is to review the literature on the use, pharmacological properties, toxicology, and assay methods for intravenous anesthetic propofol. The scope and forms of propofol use, its pharmacokinetics, biotransformation features, which occurs more than 90% in the liver, and side effects associated with propofol use for anesthesia, are addressed. Propofol infusion syndrome (also known as PrIS) and deaths from propofol overdose due to medical errors, abuse, suicide attempts, and homicide are reported. Propofol identification and assay methods based on high-performance liquid chromatography (HPLC), gas chromatography with mass spectrometry (GC-MS), and liquid chromatography (LC) are described. The features of the methods performance are outlined; biological materials (the study objects) are listed: mainly blood and plasma, as well as urine, bile, hair, etc. The relevance of a comprehensive forensic chemical study of propofol is indicated, though there are few forensic studies of propofol.

Online measuring end-tidal propofol concentration during balanced anesthesia is important for anesthetists to learn the patient's anesthesia depth as exhaled propofol concentration is well related to blood propofol concentration. In previous work, exhaled propofol was detected using acetone assisted negative photoionization ion mobility spectrometer, however, the existence of high concentration sevoflurane interfered the response of propofol. In this work, an anisole assisted photoionization ion mobility spectrometer operated in positive mode was developed to sensitively and selectively measure the end-tidal propofol by eliminating the interferences of exhaled humidity and sevoflurane during balanced anesthesia. Anisole molecular ion is stable enough not to go under proton transfer reaction with water presents in the exhaled breath. Hence, the exhaled humidity related peaks were eliminated and only one propofol product ion peak (K 0  = 1.50 cm 2  V -1  s -1 ) was observed. The relative standard deviation (RSD) ranging from 0.64%-0.91% showed good repeatability and the quantitative range was 0.2-40 ppbv with a response time of 4 s. Finally, the performance of the proposed method was demonstrated by monitoring end-tidal propofol of balanced anesthetized patients during gastric cancer surgery., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The anesthetic side effects of propofol still occur in clinical practice because no reliable monitoring techniques are available. In this regard, continuous monitoring of propofol in breath is a promising method, yet it remains infeasible because there is large variation in the blood/exhaled gas partial pressure ratio (RBE) in humans. Further evaluations of the influences of breathing-related factors on RBE would mitigate this variation., Methods: Correlations were analyzed between breathing-related factors (tidal volume [TV], breath frequency [BF], and minute ventilation [VM]) and RBE in 46 patients. Furthermore, a subset of 10 patients underwent pulmonary function tests (PFTs), and the parameters of the PFTs were then compared with the RBE. We employed a 1-phase exponential decay model to characterize the influence of VM on RBE. We also proposed a modified RBE (RBEM) that was not affected by the different breathing patterns of the patients. The blood concentration of propofol was predicted from breath monitoring using RBEM and RBE., Results: We found a significant negative correlation (R = -0.572; P < .001) between VM and RBE (N = 46). No significant correlation was shown between PFTs and RBE in the subset (N = 10). RBEM demonstrated a standard Gaussian distribution (mean, 1.000; standard deviation [SD], 0.308). Moreover, the predicted propofol concentrations based on breath monitoring matched well with the measured blood concentrations. The 90% prediction band was limited to within ±1 μg·mL., Conclusions: The prediction of propofol concentration in blood was more accurate using RBEM than when using RBE and could provide reference information for anesthesiologists. Moreover, the present study provided a general approach for assessing the influence of relevant physiological factors and will inform noninvasive and accurate breath assessment of volatile drugs or metabolites in blood.

This study estimated the climate footprint of halogenated inhalation anesthetics in Sweden and estimated effects of a decreased use of these compounds. We collected data on sales of desflurane, sevoflurane and isoflurane in Sweden during 2017 and calculated the mass of CO2 equivalents (CO2e) using Global Warming Potential data over 100 years for the compounds. Inhalation anesthetics contributed by 5000 tons of CO2e which corresponds to 0.005 percent of the Swedish climate footprint. By replacing desflurane with sevoflurane the footprint can be reduced by 73 percent. By replacing sevoflurane with intravenous propofol the climate effect can be reduced further by at least 2 orders of magnitude.

Background: Transforming a drug from its commercial form into a ready-to-use drug is common practice, especially in pediatrics. However, the risk of compounding error is real and data on drug stability in practice are not always available., Aims: The aim of this study was to assess, in real conditions, both the error rate and stability of three drugs: ketamine, remifentanil, and sufentanil., Methods: A new rapid and easy-to-use high-performance liquid chromatography method with a diode array detector has been developed and validated to quantify these drugs and detect their degradation products. Over a 1-month period, 151 syringes were collected in the postanesthesia care unit. Seventy-three were stock solution syringes containing a 10-fold dilution of commercial drugs and 78 were serial dilution syringes made from successive dilutions of stock solutions. A comparison between real and expected concentrations as well as the detection of possible degradation products was carried out on these samples., Results: All stock solution syringes had good chemical stability throughout the working day. A 4-µg/mL remifentanil serial dilution syringe, however, had to be discarded as a degradation peak was detected. Overall, 15.3% (95% CI, 9.5-21.1%) of syringes had a drug concentration outside the ±10% acceptability range, that is, 11.0% (95% CI, 3.7-18.2%) and 19.5% (95% CI, 10.6%-28.4%) of stock and diluted syringes respectively, with drug amounts ranging from -25.3% to 22.0%. The highest error rates were observed with sufentanil syringes: 20% and 28% for stock solution and serial dilution, respectively., Conclusion: The study shows that stock solution syringes prepared in advance are chemically stable throughout the day, unlike certain serial dilution syringes, indicating that the latter should be prepared just before administration to ensure chemical stability. Our results show that the error rate for serial dilution syringes is twice that of stock solution. Different safety measures are under discussion and have to be further studied., (© 2018 John Wiley & Sons Ltd.)

Background: The combination of propofol and ketamine is commonly used for total intravenous anesthesia. These drugs can be delivered in different syringes or in the same syringe. We hypothesized that the drugs might separate and different concentrations of each drug could be found in different parts of the syringe during the procedure period when they were mixed in 1 syringe., Methods: Twelve 60-mL polypropylene syringes were prepared by mixing propofol and ketamine as 4 groups on the basis of propofol/ketamine mixture ratios (5:1 and 6.7:1) and propofol solution concentrations. Syringes were placed upright in the vertical position into a rack and kept at room temperature (21.5-22.5°C), in daylight conditions and were not moved for 360 minutes. Samples of the mixture were taken from both the top and the bottom of the syringe. The first 1 mL of the samples was discarded, the following second 1 mL of the samples was filtered using 0.2-μm polytetrafluoroethylene filters and measured twice (n = 6). Samples were taken at the following time intervals: T0, T10, T30, T60, T90, T120, T180, T240, T300, and T360 min. Syringes were checked visually for any color change and separation lines between the drugs., Results: There were no significant differences between the propofol and ketamine concentrations of the top and bottom samples in all 4 groups. In addition, there were no statistically significant changes of propofol and ketamine concentrations of samples over 360 minutes in any of the 4 groups. No visual changes were observed during 6 hours' observation., Conclusion: The results of our measurements demonstrated that mixtures of propofol (1% and 2%) and ketamine at 5:1 and 6.7:1 ratios could be used in terms of mixture homogeneity and stability in a polypropylene syringe during a 6-hour period at room temperature., (© 2018 John Wiley & Sons Ltd.)

Background: In early 2015, clinicians throughout Zambia noted a range of unpredictable adverse events after the administration of propofol, including urticaria, bronchospasm, profound hypotension, and most predictably an inadequate depth of anesthesia. Suspecting that the propofol itself may have been substandard, samples were procured and sent for testing., Methods: Three vials from 2 different batches were analyzed using gas chromatography-mass spectrometry methods at the John L. Holmes Mass Spectrometry Facility., Results: Laboratory gas chromatography-mass spectrometry analysis determined that, although all vials contained propofol, its concentration differed between samples and in all cases was well below the stated quantity. Two vials from 1 batch contained only 44% ± 11% and 54% ± 12% of the stated quantity, whereas the third vial from a second batch contained only 57% ± 9%. The analysis found that there were no hexane-soluble impurities in the samples., Conclusions: None of the analyzed vials contained the stated amount of propofol; however, our analysis did not detect additional contaminants that would explain the adverse events reported by clinicians. Our results confirm the presence of substandard propofol in Zambia; however, anecdotal accounts of substandard anesthetic medicines in other countries abound and warrant further investigation to provide estimates of the prevalence and scope of this global problem.

Propofol is an intravenous anesthetic. Currently, it is not possible to routinely measure blood concentration of the drug in real time. However, multi-capillary column ion-mobility spectrometry of exhaled gas can estimate blood propofol concentration. Unfortunately, adhesion of volatile propofol on plastic materials complicates measurements. Therefore, it is necessary to consider the extent to which volatile propofol adheres to various plastics used in sampling tubing. Perfluoralkoxy (PFA), polytetrafluorethylene (PTFE), polyurethane (PUR), silicone, and Tygon tubing were investigated in an experimental setting using a calibration gas generator (HovaCAL). Propofol gas was measured for one hour at 26 °C, 50 °C, and 90 °C tubing temperature. Test tubing segments were then flushed with N 2 to quantify desorption. PUR and Tygon sample tubing absorbed all volatile propofol. The silicone tubing reached the maximum propofol concentration after 119 min which was 29 min after propofol gas exposure stopped. The use of PFA or PTFE tubing produced comparable and reasonably accurate propofol measurements. The desaturation time for the PFA was 10 min shorter at 26 °C than for PTFE. PFA tubing thus seems most suitable for measurement of volatile propofol, with PTFE as an alternative.

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.

Based on the adsorption of analytes in the sampling loop, a time-resolved dynamic dilution introduction method was developed for negative ion mobility spectrometry to continuously monitor end-tidal propofol without other sample pre-separation. The dynamic dilution characteristics of propofol and moisture in the Teflon sample loop (4 mm o.d. and 2.4 mm i.d., 150 cm length) were both theoretically and experimentally investigated. The prominent absorption differences between propofol and moisture on the inwall of the sample loop allowed their concentrations to be time-resolved during the injection process, realizing sensitive measurement of end-tidal propofol with a response time of 2 s. At the optimized carrier gas flow rate of 700 mL min(-1), the linear response range for propofol was achieved to be 0.2 to 20 ppbv with a limit of detection (LOD) of 65 pptv. Finally, this method was performed on a patient undergoing mastectomy surgery to continuously monitor the end-tidal propofol with an interval of five respirations and the result nicely demonstrated its fast response to the propofol changes.

Background: Although pilot studies have reported that exhaled propofol concentrations can reflect intraoperative plasma propofol concentrations in an individual, the blood/exhaled partial pressure ratio RBE varies between patients, and the relevant factors have not yet been clearly addressed. No efficient method has been reported for the quick evaluation of RBE and its association with inter-individual variables., Methods: We proposed a novel method that uses a surface acoustic wave (SAW) sensor combined with a fast gas chromatograph (GC) to simultaneously detect propofol concentrations in blood and exhaled gas in 28 patients who were receiving propofol i.v. A two-compartment pharmacokinetic (PK) model was established to simulate propofol concentrations in exhaled gas and blood after a bolus injection. Simulated propofol concentrations for exhaled gas and blood were used in a linear regression model to evaluate RBE., Results: The fast GC-SAW system showed reliability and efficiency for simultaneous quantitative determination of propofol in blood (correlation coefficient R(2)=0.994, P<0.01) and exhaled gas (R(2)=0.991, P<0.01). The evaluation of RBE takes <50 min for a patient. The distribution of RBE in 28 patients showed inter-individual differences in RBE (median 1.27; inter-quartile range 1.07-1.59)., Conclusions: Fast GC-SAW, which analyses samples in seconds, can perform both rapid monitoring of exhaled propofol concentrations and fast analysis of blood propofol concentrations. The proposed method allows early determination of the coefficient RBE in individuals. Further studies are required to quantify the distribution of RBE in a larger cohort and assess the effect of other potential factors., Clinical Trial Registration: ChiCTR-ONC-13003291., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

The compound 2,6-diisopropylphenol (Propofol, PRF) is widely used for inducing general anesthesia, but the mechanism of PRF action remains relatively poorly understood at the molecular level. This work examines the possibility that a potential mode of action of PRF is to modulate the lipid order in target membranes. The effect on monolayers and bilayers of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) was probed using Langmuir monolayer isotherms, differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC) and molecular dynamics (MD) simulations. Increasing amounts of PRF in a DPPC monolayer causes a decrease in isothermal compressibility modulus at the phase transition. A partition constant for PRF in DPPC liposomes on the order of K≈1500 M(-1) was found, and the partitioning was found to be enthalpy-driven above the melting temperature (Tm). A decrease in Tm with PRF content was found whereas the bilayer melting enthalpy ΔHm remains almost constant. The last finding indicates that PRF incorporates into the membrane at a depth near the phosphatidylcholine headgroup, in agreement with our MD-simulations. The simulations also reveal that PRF partitions into the membrane on a timescale of 0.5 μs and has a cholesterol-like ordering effect on DPPC in the fluid phase. The vertical location of the PRF binding site in a bacterial ligand-gated ion channel coincides with the location found in our MD-simulations. Our results suggest that multiple physicochemical mechanisms may determine anesthetic potency of PRF, including effects on proteins that are mediated through the bilayer., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Propofol is a widely used, potent intravenous anesthetic for ambulatory anesthesia and long-term sedation. The target steady state concentration of propofol in blood is 0.25-10 μg/mL (1-60 μM). Although propofol can be oxidized electrochemically, monitoring its concentration in biological matrixes is very challenging due to (i) low therapeutic concentration, (ii) high concentrations of easily oxidizable interfering compounds in the sample, and (iii) fouling of the working electrode. In this work we report the performance characteristics of an organic film coated glassy carbon (GC) electrode for continuous monitoring of propofol. The organic film (a plasticized PVC membrane) improved the detection limit and the selectivity of the voltammetric sensor due to the large difference in hydrophobicity between the analyte (propofol) and interfering compounds of the sample, e.g., ascorbic acid (AA) or p-acetamidophenol (APAP). Furthermore, the membrane coating prevented electrode fouling and served as a protective barrier against electrode passivation by proteins. Studies revealed that sensitivity and selectivity of the voltammetric method is greatly influenced by the composition of the PVC membrane. The detection limit of the membrane-coated sensor for propofol in PBS is reported as 0.03 ± 0.01 μM. In serum-like electrolyte solutions containing physiologically relevant levels of albumin (5%) and 3 mM AA and 1 mM APAP as interfering agents, the detection limit was 0.5 ± 0.4 μM. Both values are below the target concentrations used clinically during anesthesia or sedation.

The concentration of propofol in patient's exhaled air is an indicator of the anesthetic depth. In the present study, a membrane inlet ion mobility spectrometer (MI-IMS) was built for the on-line measurement of propofol. Compared with the direct sample introduction, the membrane inlet could eliminate the interference of moisture and improve the selectivity of propofol. Effects of membrane temperature and carrier gas flow rate on the sensitivity and response time have been investigated experimentally and theoretically. Under the optimized experimental conditions of membrane temperature 100 °C and carrier gas flow rate 200 mL min(-1), the calculated limit of detection (LOD) for propofol was 1 ppbv, and the calibration curve was linear in the range of 10-83 ppbv with a correlation coefficient (R(2)) of 0.993. Finally, the propofol concentration in an anaesthetized mouse exhaled air was monitored continuously to demonstrate the capability of MI-IMS in the on-line measurement of propofol in real samples., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Anesthesiologists must consider the entire life cycle of drugs in order to include environmental impacts into clinical decisions. In the present study we used life cycle assessment to examine the climate change impacts of 5 anesthetic drugs: sevoflurane, desflurane, isoflurane, nitrous oxide, and propofol., Methods: A full cradle-to-grave approach was used, encompassing resource extraction, drug manufacturing, transport to health care facilities, drug delivery to the patient, and disposal or emission to the environment. At each stage of the life cycle, energy, material inputs, and emissions were considered, as well as use-specific impacts of each drug. The 4 inhalation anesthetics are greenhouse gases (GHGs), and so life cycle GHG emissions include waste anesthetic gases vented to the atmosphere and emissions (largely carbon dioxide) that arise from other life cycle stages., Results: Desflurane accounts for the largest life cycle GHG impact among the anesthetic drugs considered here: 15 times that of isoflurane and 20 times that of sevoflurane on a per MAC-hour basis when administered in an O(2)/air admixture. GHG emissions increase significantly for all drugs when administered in an N(2)O/O(2) admixture. For all of the inhalation anesthetics, GHG impacts are dominated by uncontrolled emissions of waste anesthetic gases. GHG impacts of propofol are comparatively quite small, nearly 4 orders of magnitude lower than those of desflurane or nitrous oxide. Unlike the inhaled drugs, the GHG impacts of propofol primarily stem from the electricity required for the syringe pump and not from drug production or direct release to the environment., Discussion: Our results reiterate previous published data on the GHG effects of these inhaled drugs, while providing a life cycle context. There are several practical environmental impact mitigation strategies. Desflurane and nitrous oxide should be restricted to cases where they may reduce morbidity and mortality over alternative drugs. Clinicians should avoid unnecessarily high fresh gas flow rates for all inhaled drugs. There are waste anesthetic gas capturing systems, and even in advance of reprocessed gas applications, strong consideration should be given to their use. From our results it appears likely that techniques other than inhalation anesthetics, such as total i.v. anesthesia, neuraxial, or peripheral nerve blocks, would be least harmful to the environment.

The transit of ethanol from blood to breath gas is well characterised. It is used for intraoperative monitoring and in forensic investigations. A further substance, which can be measured in breath gas, is the phenol propofol. After a simultaneous bolus injection, the signals (time course and amplitude) of ethanol and propofol in breath gas were detected by ion molecule reaction-mass spectrometry (IMR-MS) and compared. After approval by the regional authorities, eight pigs were endotracheally intubated after a propofol-free induction with etomidate. Boluses of ethanol (16 μg/kg) and propofol (4 or 2 mg/kg) were infused alone and in combination. For both substances, breath gas concentrations were continuously measured by IMR-MS; the delay time, time to peak and amplitude were determined and compared using non-parametric statistic tests. IMR-MS allows a simultaneous continuous measurement of both substances in breath gas. Ethanol appeared (median delay time, 12 vs 29.5 s) and reached its peak concentration (median time to peak, 45.5 vs 112 s) significantly earlier than propofol. Time courses of ethanol and propofol in breath gas can be simultaneously described with IMR-MS. Differing pharmacological and physicochemical properties of the two substances can explain the earlier appearance and time to peak of ethanol in breath gas compared with propofol., (© Springer-Verlag 2010)

Breath analysis could offer a non-invasive means of intravenous drug monitoring if robust correlations between drug concentrations in breath and blood can be established. In this study, propofol blood and breath concentrations were determined in an animal model under varying physiological conditions. Propofol concentrations in breath were determined by means of two independently calibrated analytical methods: continuous, real-time proton transfer reaction mass spectrometry (PTR-MS) and discontinuous solid-phase micro-extraction coupled with gas chromatography mass spectrometry (SPME-GC-MS). Blood concentrations were determined by means of SPME-GC-MS. Effects of changes in pulmonary blood flow resulting in a decreased cardiac output (CO) and effects of dobutamine administration resulting in an increased CO on propofol breath concentrations and on the correlation between propofol blood and breath concentrations were investigated in seven acutely instrumented pigs. Discontinuous propofol determination in breath by means of alveolar sampling and SPME-GC-MS showed good agreement (R(2)=0.959) with continuous alveolar real-time measurement by means of PTR-MS. In all investigated animals, increasing cardiac output led to a deterioration of the relationship between breath and blood propofol concentrations (R(2)=0.783 for gas chromatography-mass spectrometry and R(2)=0.795 for PTR-MS). Decreasing pulmonary blood flow and cardiac output through banding of the pulmonary artery did not significantly affect the relationship between propofol breath and blood concentrations (R(2)>0.90). Estimation of propofol blood concentrations from exhaled alveolar concentrations seems possible by means of different analytical methods even when cardiac output is decreased. Increases in cardiac output preclude prediction of blood propofol concentration from exhaled concentrations., (© Springer-Verlag 2011)

Propofol is a widely used intravenous agent for induction and maintenance of anesthesia and for sedation in intensive care patients, but it is also associated with abuse and dependency. A simple and sensitive method for the determination of propofol in human whole blood, brain, liver, and adipose tissue by gas chromatography-mass spectrometry using selected-ion monitoring mode is described. Propofol was extracted from 0.2-mL or 0.2-g sample size by a single-step basic extraction procedure using 100 microL heptane with thymol (50 ng) as an internal standard. The calibration curves of the specimens were linear in the concentration range of 10-5000 ng/mL or ng/g, and the limit of detection was 2.5 ng/mL in blood, 5.0 ng/g in brain and liver, and 10 ng/g in adipose tissue. Absolute recovery of propofol was determined in three samples and averaged over 95% for blood and brain, 66% for liver, and 51% for adipose tissue. Within-day and between-day precision was measured in five samples each at 50 and 500 ng/mL or ng/g in all specimens and was determined to be less than 10%. The developed propofol method was applied to a forensic autopsy case where a suspected propofol misinjection occurred eight days prior to death, and the tissue analysis was vital to the case.

This paper presents a disposable microfluidic biochip with on-chip molecularly imprinted biosensors for optical detection of anesthetic propofol. So far, the methods to detect anesthetic propofol in hospitals are liquid chromatography (LC), high-performance liquid chromatography (HPLC), and gas chromatography-mass spectroscopy (GC-MS). These conventional instruments are bulky, expensive, and not ease of access. In this work, a novel plastic microfluidic biochip with on-chip anesthetic biosensor has been developed and characterized for rapid detection of anesthetic propofol. The template-molecule imprinted polymers were integrated into microfluidic biochips to be used for detecting anesthetic propofol optically at 655 nm wavelength after the reaction of propofol with color reagent. Experimental results show that the sensitivity of the microfluidic biochip with on-chip molecularly imprinted polymers (MIPs) biosensor is 6.47 mV/(ppm mm(2)). The specific binding of MIP to non-imprinted polymer (NIP) is up to 456%. And the detection limit of the microsystem is 0.25 ppm with a linear detection range from 0.25 to 10 ppm. The disposable microfluidic biochip with on-chip anesthetic biosensor using molecularly imprinted polymers presented in this work showed excellent performance in separation and sensing of anesthetic propofol molecules. While compared to large-scale conventional instruments, the developed microfluidic biochips with on-chip MIP biosensors have the advantages of compact size, high sensitivity, high selectivity, low cost, and fast response., (2010 Elsevier B.V. All rights reserved.)

Seven patients operated on in a period of two consecutive days in the Havenziekenhuis, Rotterdam, the Netherlands developed symptoms of sepsis following a relatively minor procedure. One patient developed fever and hypotension a few hours after surgery, and developed thrombocytopenia and leucopenia. Postoperative bleeding occurred as a result of the thrombocytopenia, necessitating further surgery. This patient developed serious multi-organ failure, and required prolonged intensive care treatment. The other six patients developed less serious infections, the main symptoms of which were fever, leucopenia, thrombocytopenia and impairment of liver- and kidney function. They recovered quickly. Bacteriological investigation revealed that the infection was caused by extrinsic contamination of the intravenous anaesthetic propofol with Klebsiella pneumoniae and Serratia marcescens. Due to the high risk of contamination of the lipid formulation of this preparation, the use of propofol requires the following measures: syringes should be used just once; vials should be punctured just once; and administration should take place within 12 h after opening the vial or the ampoule. Hygienic working methods are also of crucial importance.

Background: We aimed to measure propofol concentrations in exhaled air with an ion mobility spectrometer coupled to a multicapillary column for pre-separation (MCC-IMS). In addition, we aimed to compare the values of these measurements with serum propofol concentrations, as determined by gas chromatography-mass spectrometry (GC-MS)., Methods: Thirteen patients, ASA I or II, undergoing elective ENT surgery were studied. Anaesthesia was induced with propofol 2.1 (0.7) mg kg(-1), rocuronium 0.5 (0.1) mg kg(-1), and remifentanil 0.5 microg kg(-1) min(-1). After tracheal intubation, anaesthesia was maintained with a continuous infusion of propofol 3.9 (1.8) mg kg(-1) h(-1) and remifentanil 0.5 microg kg(-1) min(-1). Simultaneously, a venous blood sample was obtained. Propofol concentrations in serum were determined by GC-MS and compared with the height of the respective propofol signals achieved by MCC-IMS., Results: Twenty-four pairs of samples were obtained. The comparison of propofol concentrations in exhaled air and serum presented a bias of -10.5% and a precision of +/- 12.3%. With these values, the 95% limits of agreement were 14.1% and -35.1%., Conclusions: MCC-IMS may be a suitable method to determine propofol concentrations in exhaled air, and may be used to predict propofol concentrations in serum.

The interpretation of continuously measured propofol concentration in respiratory gas demands knowledge about the blood gas partition coefficient and pulmonary extraction ratio for propofol. In the present investigation we compared both variables for propofol between goats and pigs during a propofol anaesthesia. In ten goats and ten pigs, expired alveolar gas and arterial and mixed venous blood samples were simultaneously drawn during total intravenous anaesthesia with propofol. The blood gas partition coefficient and pulmonary extraction ratio were calculated for both species. Non-parametric methods were used for statistical inference. The blood gas partition coefficient ranged between 7000 and 646,000 for goats and between 17,000 and 267,000 for pigs. The pulmonary extraction ratio ranged between 32.9% and 98.1% for goats and was higher for pigs, which ranged between -106.0% and 39.0%. The blood gas partition coefficient for propofol exceeded those for other known anaesthetic compounds so that it takes longer to develop a steady-state. The different pulmonary extraction rates in two species suggest that there are different ways to distribute propofol during the lung passage on its way from the blood to breathing gas. This species-specific difference has to be considered for methods using the alveolar gas for monitoring the propofol concentration in plasma.

Many women undergo anaesthetic procedures related to childbirth or during the period of lactation. Most anaesthetic drugs are lipophilic and are thus excreted into breast milk. This article summarises available knowledge regarding anaesthetics, their excretion into breast milk and possible effects on the suckling infant. The consequences of such an exposure are discussed in terms of whether breast-feeding should be allowed or not after anaesthetic procedures.

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.

Objective: To establish an analytical method for the determination of GHB in beverages using GC/MS and LC/MS/MS., Methods: After beverage samples with GHB-d6 as the internal standard were extracted with ethyl acetate, then the extracts were derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), at last the derivateized extracts analyzed by gas chromatography- mass spectrometry. After beverage samples with GHB-d6 as the internal standard were diluted by mobile phase then directly analyzed by LC/MS/MS. Results The limit of detection was 0.2 microg/mL and both relative standard deviations for between-day and within-day assays were < 8.54% in GC/MS. The limit of detection was 2 microg/mL and both relative standard deviations for between-day and within-day assays were <8.62% in LC/MS/MS. Conclusion These methods of qualitative and quantitative analysis were found to be sensitive, accurate, rapid and suitable for the forensic toxicology to test of GHB in real cases.

Background: Propofol (2,6-diisopropylphenol) has some volatility, so it can be detected in expired breath of individuals receiving intravenous propofol. This study measured volatile propofol exhaled by patients and investigated the relation between exhaled and plasma propofol concentrations., Methods: Nineteen patients with American Society of Anesthesiologists physical status I or II who were undergoing elective surgery participated in this two-part study. In study 1 (n = 11), anesthesia was induced with 2 mg/kg propofol, 0.1 mg/kg vecuronium, and 2 microg/kg fentanyl. After intubation, propofol was administered continuously for 60 min at each of three rates: 3, 6, and 9 mg x kg(-1) x h(-1). Blood samples were obtained just before each change in the infusion rate, and the plasma concentrations of propofol were measured. The exhaled propofol concentration was measured continuously by means of proton transfer mass spectrometry. End-tidal propofol concentrations during blood sampling were averaged and compared with plasma propofol concentrations. In study 2 (n = 8), after induction of anesthesia, patients received a bolus injection of 2 mg/kg propofol, and the exhaled propofol concentration was measured., Results: Volatile propofol was detected in expired gas from all study patients. From study 1, the authors obtained 24 paired data points, i.e., concentrations of end-tidal and plasma propofol. With Bland-Altman analysis, bias +/- precision was 5.2 +/- 10.4 with 95% limits of agreement of -15.1 and 25.6. In study 2, the exhaled propofol concentration curve showed an obvious peak in all patients., Conclusions: Agreement between plasma and exhaled propofol concentrations suggests that proton transfer mass spectrometry can be used for real-time propofol monitoring.

The death of a female anaesthesiologist is reported. Although the situation at the scene indicated propofol overdose-related death, self-administration of such high doses of propofol was unlikely, given the pharmacological properties of this drug. The analysis of the situation at the scene and the toxicological analysis in which the blood and liver propofol concentrations were 2.40microg/ml and 0.56microg/g, respectively, supported the conclusion that the death was a consequence of propofol self-administration at therapeutic doses from a person who used the drug on chronic basis seeking to its euphoric effects. However, because the toxic concentrations of propofol in non-intubated patients may be different from those intubated and fully supported in the operating room or in the intensive care unit, a mere interpretation of the blood and tissue concentrations of propofol in the toxicological analysis can confirm the drug intake but it may be of limited diagnostic significance without taking into account this difference.

We hypothesize that aerosolization of anesthetics administered intravenously to patients in the operating room may be an unintended source of exposure to physicians. This may lead to inadvertent sensitization, which is associated with an increased risk for developing addiction. This may contribute to the over-representation of certain specialties among physicians with addiction. We retrospectively reviewed the de-identified demographic information of all licensed physicians treated for substance abuse in the State of Florida since 1980, to determine if medical specialty was associated with addiction in this group of individuals. Then, to identify the potential for exposure, two mass spectrometry assays were developed to detect two intravenously administered drugs, fentanyl and propofol, in air. Since 1980, 7.6% of licensed Florida physicians underwent treatment for addiction. Addiction in anesthesiologists was higher than expected. Opiate abuse was greater in anesthesiologists and surgeons compared to other specialties. Aerosolized fentanyl was detected in the air of the cardiothoracic operating room, in patients' expiratory circuits, and in the headspace above sharps boxes, but not in adjoining hallways. Aerosolized propofol was detected in the expirations of a patient undergoing transurethral prostatectomy. While access and stress may place anesthesiologists and surgeons at greater risk for substance abuse, an additional risk factor may be unintended occupational exposure to addictive drugs. This report provides preliminary evidence of detection of aerosolized intravenous anesthetics using two newly developed analytical methods. We conclude that the potential exists for chronic exposure to low levels of airborne intravenously administered drugs. Further studies are under way to determine the significance of this exposure.

Unlabelled: Because free propofol is thought to be responsible for pain on injection, we investigated the changes in concentrations of free propofol by modifying two kinds of propofol products in a medium- and long-chain triglyceride (MCT/LCT) emulsion and in an LCT emulsion. The techniques used in this study were 1) mixing 2% lidocaine (10:1), 2) mixing 5% dextrose in acetated Ringer's solution to reduce pH (10:1), and 3) changing the temperature to 4 degrees , 20 degrees , and 36 degrees C. The propofol preparations were dialyzed for 24 h, and the receptor medium was analyzed using high-performance liquid chromatography. The concentration of free propofol in propofol MCT/LCT was significantly smaller by 30% than that in propofol LCT. Neither mixing lidocaine nor cooling reduced the concentrations of free propofol in both products, but the concentrations were reduced by a decrease in pH and by an increase in temperature. Because mixing lidocaine can induce instability in an emulsion of propofol and warming can rapidly induce microbial growth, injection of lidocaine before propofol administration is recommended to reduce the pain on injection. The concentrations of free propofol in propofol MCT/LCT were significantly smaller (by approximately 30%-45%) than those in propofol LCT during any situation in this study., Implications: Neither mixing lidocaine nor cooling reduced the concentrations of free propofol in both products but the concentrations were reduced by a decrease in pH and by an increase in temperature. Propofol medium- and long-chain triglycerides had significantly smaller concentrations by approximately 30%-45% than those in propofol long-chain triglycerides during any situation in this study.

Microprocessor-controlled insulin pumps designed for continuous delivery of short-acting insulin analogs into subcutaneous tissues offer several important potential benefits for diabetic patients. The delivery of other substances using these systems is technically feasible. We present a case of homicide involving lethal doses of etomidate and atracurium injected via the victim's insulin pump. This unique situation could be encountered by homicide investigators more frequently as the popularity of these systems continues to grow.

Background: The aim of this paper is to compare the propofol concentration in blood and cerebrospinal fluid (CSF) in patients scheduled for different neurosurgical procedures and anaesthetized using propofol as part of a total intravenous anaesthesia technique., Methods: Thirty-nine patients (ASA I-III) scheduled for elective intracranial procedures, were studied. Propofol was infused initially at 12 mg kg(-1) h(-1) and then reduced in steps to 9 and 6 mg kg(-1) h(-1). During anaesthesia, bolus doses of fentanyl and cis-atracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (FI(O(2))=0.33). Arterial blood and CSF samples for propofol examination were obtained simultaneously directly after intracranial drainage insertion and measured using high-performance liquid chromatography. The patients were divided into two groups depending on the type of neurosurgery. The Aneurysm group consisted of 13 patients who were surgically treated for ruptured intracranial aneurysm. The Tumour group was composed of 26 patients who were undergoing elective posterior fossa extra-axial tumour removal., Results: Blood propofol concentrations in both groups did not differ significantly (P>0.05). The propofol concentration in CSF was 86.62 (SD 37.99) ng ml(-1) in the Aneurysm group and 50.81 (26.10) ng ml(-1) in the Tumour group (P<0.005)., Conclusions: Intracranial pathology may influence CSF propofol concentration. However, the observed discrepancies may also result from quantitative differences in CSF composition and from restricted diffusion of the drug in the CSF.

A 44-year-old female nurse in a department of anesthesiology was found dead at home. An empty bottle of Hypnovel (midazolam 5 mg/5 ml) and a hypodermic syringe were found near the corpse. The nurse was a known abuser of anaesthetic agents for many years. A complete screening for general unknown substances by FPIA, GC/MS, head space GC/MS and HPLC/DAD revealed the simultaneous presence of midazolam, propofol and ethanol in femoral blood. Segmental analysis of a 6-cm-long hair strand revealed the presence of midazolam and propofol in each 2-cm-long segment. Repetitive consumption of the two anaesthetic agents during the last 6 months before the death was therefore demonstrated. These compounds were also detected in pubic and axillary hairs. Self-administration of midazolam and propofol without respiratory assistance and medical control certainly contributed to the death.

This paper proposes an original method for the determination of propofol in biological specimens. For example, hair specimens are cut into small pieces and incubated overnight in Soerensen buffer at 40 degrees C. After headspace preparation of the biological specimens spiked with tetrahydrofurane (internal standard), the analytes are transferred to the gas chromatograph and separated on a HP Wax capillary column. Detection is achieved in SIM mode (propofol: m/z 117, 163 and 178) on a mass spectrometer operating in electronic impact mode. The developed procedure is easy (full-automated), rapid (no extraction- or derivatization-step), sensible and accurate. After validation of the analytical method (linearity, extraction recovery, repeatability, limit of detection), this new procedure was applied to forensic cases.

A simple, rapid and reliable method was developed to determine the concentration of etomidate [ethyl-1-(1-phenylethyl)-1 H-imidazole-5-carboxylate] in mouse brain tissue by gas chromatography-mass spectrometry (GC-MS). Ethyl 5-amino-1-phenyl-4-pyrazolecarboxylate was used as internal standard (IS) and liquid-liquid extraction using ethyl ether as the solvent. The method demonstrated excellent recovery (93%) and a linear calibration range of 50-2500 ng/0.2 g. Intra-day accuracy and precision had an error and coefficient of variation of less than 8.7% and 4.2%, respectively. The limit of detection was 1 ng in mouse brain. Our results suggest that this new method is suitable for the quantitative analysis of etomidate in mouse brain tissue.

Methohexital (MS) determination is based on the formation of insoluble mercury salt on a hanging mercury drop electrode after preaccumulation by adsorption. This property was exploited in developing a highly sensitive stripping voltammetric procedure for the determination of the drug. The anodic current of adsorbed compound is measured by linear sweep anodic stripping voltammetry (LSASV), preceded by a period of preconcentration. The effect of various parameters such as supporting electrolyte composition, pH, initial potential, scan rate, accumulation time and ionic strength are discussed to characterize the interfacial and redox behavior. The detection limit was found to be 2x10(-7) M (56.8 ppb) with 180-s accumulation time. The interference of some amino acids, ascorbic acid and some metal ions was investigated. The application of this method was tested in the determination of methohexital in spiked urine samples. The precision of the method is satisfactory with a relative standard deviation of 2.5%.

Propofol (P) is metabolized in humans by oxidation to 1,4-di-isopropylquinol (Q). P and Q are in turn conjugated with glucuronic acid to the respective glucuronides, propofol glucuronide (Pgluc), quinol-1-glucuronide (Q1G) and quinol-4-glucuronide (Q4G). Propofol and quinol with their glucuronide conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic hydrolysis. The glucuronide conjugates were isolated by preparative HPLC from human urine samples. The glucuronides of P and Q were present in plasma and urine, P and Q were present in plasma, but not in urine. Quinol in plasma was present in the oxidised form, the quinone. Calibration curves of the respective glucuronides were constructed by enzymic deconjugation of isolated samples containing different concentrations of the glucuronides. The limit of quantitation of P and quinone in plasma are respectively 0.119 and 0.138 microg/ml. The limit of quantitation of the glucuronides in plasma are respectively: Pgluc 0.370 microg/ml, Q1G 1.02 microg/ml and Q4G 0.278 microg/ml. The corresponding values in urine are: Pgluc 0.264 microg/ml, Q1G 0.731 microg/ml and Q4G 0.199 microg/ml. A pharmacokinetic profile of P with its metabolites is shown, and some preliminary pharmacokinetic parameters of P and Q glucuronides are given.

Objective: To determine the physicochemical stability of fentanyl in combination with midazolam and either hyoscine butylbromide or metoclopramide, and stored in 30 ml polypropylene syringes., Methods: Solutions containing approximately 40 microg/ ml of fentanyl in combination with midazolam (approximately 600 microg/ml) and either metoclopramide (approximately 700 microg/l) or hyoscine (approximately 850 microg/ml) were prepared from commercial ampoules of the drugs. The solutions were stored, in triplicate, in the dark at 32 degrees C (to simulate usage conditions) for 10 days, and the concentration of each constituent drug was periodically determined using a stability-indicating high-performance liquid chromatography assay., Results: The combinations were relatively stable, with all drugs maintaining over 90% of their initial chemical potency for at least 1 week. There were no evident changes in either the physical appearance or pH values of the solutions over the course of the study., Conclusions: On the basis of physicochemical stability, polypropylene syringes containing fentanyl with midazolam and either hyoscine butylbromide or metoclopramide can be safely prepared and stored at or below 32 degrees C for periods of up to 1 week prior to use by palliative care patients receiving the drugs via a portable subcutaneous infusion device.

Midazolam is increasingly being used for oral sedation in pediatric dentistry. Unfortunately, it is available only as a parenteral formulation in Canada and the United States. Preparation of the parenteral solution for oral use is not uniform and leads the clinician to question the stability of this drug when used in conjunction with these vehicles. Therefore, the purpose of this study was to investigate the chemical stability of parenteral midazolam as an oral formulation to determine its expiry date. This was evaluated using a validated stability-indicating liquid chromatographic method. Midazolam was diluted in orange-flavored syrup to yield concentrations of 0.35, 0.64, and 1.03 mg/ml and then stored at room temperature. Samples were drawn on each of 9 study days (0, 1, 2, 6, 7, 9, 13, 21, and 102) and chromatographed. On each study day, solutions were inspected visually for changes in color, clarity, and appearance of particulate matter. Midazolam concentrations were considered within acceptable limits if they were not less than 90% of the initial concentration. Over the 102-day study period, there was no significant change in concentration in any of the solutions. On day 102, the remaining midazolam was within 7% of the day zero concentration. Therefore, these formulations of midazolam are stable at room temperature for a period of 102 days and would be suitable for clinical use.

Objective: To determine whether administration of opioids to anesthetized cats induced less cardiovascular depression than that induced by an equivalent amount of anesthetic alone, and to measure endocrine responses to a noxious stimulus., Animals: 6 healthy female cats., Procedure: Anesthesia was induced with isoflurane and was maintained for 60 minutes at 1.3 isoflurane MAC. Blood gas tensions, pH, and plasma alfentanil and hormone concentrations, blood pressures, and cardiac output were measured. A noxious stimulus was applied for 5 minutes, while blood acquisition and measurements were repeated. Alfentanil was administered i.v. to achieve estimated plasma concentration of 500 ng/ml, and end-tidal isoflurane concentration was reduced by 35%. After another 60 minutes, blood was obtained and measurements were taken, then a second 5-minute noxious stimulus was applied while blood acquisition and measurements were retaken., Results: Alfentanil administration and reduction of isoflurane concentration significantly increased body temperature, heart rate, mean arterial pressure, mean pulmonary arterial pressure, stroke index, cardiac index, hemoglobin, oxygen delivery index, PvO2 and PvCO2, dopamine, epinephrine (EPI), norepinephrine (NOREPI), and cortisol values, and significantly decreased arterial and venous pH. Application of a noxious stimulus significantly increased heart rate, stroke index, cardiac index, PaO2, oxygen delivery index, arterial and venous pH, and NOREPI values, and decreased bicarbonate, PaCO2, PvCO2, and EPI values. Alfentanil administration blunted cardiac index, PaCO2, oxygen delivery index, arterial pH, PaO2, and EPI, and NOREPI responses to a noxious stimulus., Conclusions: Compared with isoflurane alone, alfentanil administration and reduction of isoflurane MAC improved cardiovascular variables, and blunted respiratory, hormonal, and most hemodynamic responses to a noxious stimulus in cats., Clinical Relevance: Use of the balanced opioid anesthesia regimen induced some beneficial effects in healthy cats; effects were similar to, although greater in nature, than effects induced by a noxious stimulus.

A rapid, accurate and sensitive UV derivative method was described for measuring the Propofol concentration in some biological fluids. Furthermore two alternative procedures, a gaschromatographic and a colorimetric, were also defined, and the results of the three methods, when applied on blood samples spiked with known amounts of analyte, were compared. The samples were preliminary purified by a solid phase extraction on octadecyl C18 cartridge. The UV derivative method was applied to a pharmacokinetic study on pregnant women undergoing cesarean sections. After an induction dose administration of 2.5 mg kg-1, the maternal and umbilical vein blood were found to have comparable concentrations of propofol, with a mean half like of about 3.5 min; on the contrary no detectable levels of the drug were found in amniotic fluid. The drug recoveries > 98% and the response was linear over the range 0.05-40 micrograms ml-1.

Fentanyl and sufentanil are potent narcotic analgesics used only in hospitals as anaesthetic agents. The dependence potential of fentanyl is known. As they are given in doses at the microgram level and their elimination half-life is in the order of a few hours, detection in body fluids is possible only for a short time after administration. Radioimmunological methods are the only ones capable of detecting fentanyl in hair, as normal GC/MS methods for hair analysis are not sensitive enough to detect the drugs after doses in the order of micrograms. We therefore chose GC/MS/MS to analyse fentanyl and sufentanil in two cases where the drugs were given under controlled conditions over several days. The concentration was in the order of less than 100 pg/mg hair.