A straightforward method for determination of the sevoflurane metabolite hexafluoroisopropanol in urinary occupational medical samples by headspace-gas chromatography mass spectrometry.

Biological monitoring of the unmodified sevoflurane and its metabolite hexafluoroisopropanol (HFIP) in urine samples was proposed to determine the individual exposure levels of the medical staff. In this study, a method for simultaneous determination of both compounds in urine using static headspace-gas chromatography-mass spectrometry (HS-GC-MS) was developed. The method is linear over a broad concentration range from 1 to 1000 µg/L (r2 > 0.999) and shows high precision. Limits of quantification (LOQ) are 0.6 µg/L for sevoflurane and 3 µg/L for HFIP, representing an excellent sensitivity without the necessity of analyte enrichment. The method was successfully applied in a German pilot-study to monitor both compounds in samples from medical personnel working in operating theatres. Urinary concentrations of HFIP ranged between < LOQ and 145 µg/L, while sevoflurane was below the LOD in all samples.

Comparison of 3 Methods to Assess Occupational Sevoflurane Exposure in Abdominal Surgeons: A Single-Center Observational Pilot Study.

BACKGROUND: Studies demonstrated that operating room personnel are exposed to anesthetic gases such as sevoflurane (SEVO). Measuring the gas burden is essential to assess the exposure objectively. Air pollution measurements and the biological monitoring of urinary SEVO and its metabolite hexafluoroisopropanol (HFIP) are possible approaches. Calculating the mass of inhaled SEVO is an alternative, but its predictive power has not been evaluated. We investigated the SEVO burdens of abdominal surgeons and hypothesized that inhaled mass calculations would be better suited than pollution measurements in their breathing zones (25 cm around nose and mouth) to estimate urinary SEVO and HFIP concentrations. The effects of potentially influencing factors were considered. METHODS: SEVO pollution was continuously measured by photoacoustic gas monitoring. Urinary SEVO and HFIP samples, which were collected before and after surgery, were analyzed by a blinded environmental toxicologist using the headspace gas chromatography-mass spectrometry method. The mass of inhaled SEVO was calculated according to the formula mVA = cVA·(Equation is included in full-text article.)·t·ρ VA aer. (mVA: inhaled mass; cVA: volume concentration; (Equation is included in full-text article.): respiratory minute volume; t: exposure time; and ρ VA aer.: gaseous density of SEVO). A linear multilevel mixed model was used for data analysis and comparisons of the different approaches. RESULTS: Eight surgeons performed 22 pancreatic resections. Mean (standard deviation [SD]) SEVO pollution was 0.32 ppm (0.09 ppm). Urinary SEVO concentrations were below the detection limit in all samples, whereas HFIP was detectable in 82% of the preoperative samples in a mean (SD) concentration of 8.53 µg·L (15.53 µg·L; median: 2.11 µg·L, interquartile range [IQR]: 4.58 µg·L) and in all postoperative samples (25.42 µg·L [21.39 µg·L]). The mean (SD) inhaled SEVO mass was 5.67 mg (2.55 mg). The postoperative HFIP concentrations correlated linearly to the SEVO concentrations in the surgeons' breathing zones (ß = 216.89; P < .001) and to the calculated masses of inhaled SEVO (ß = 4.17; P = .018). The surgeon's body mass index (BMI), age, and the frequency of surgeries within the last 24 hours before study entry did not influence the relation between HFIP concentration and air pollution or inhaled mass, respectively. CONCLUSIONS: The biological SEVO burden, expressed as urinary HFIP concentration, can be estimated by monitoring SEVO pollution in the personnel's individual breathing zone. Urinary SEVO was not an appropriate biomarker in this setting.

Occupational exposure to nitrous oxide during procedural pain control in children: a comparison of different inhalation techniques and scavenging systems.

BACKGROUND: Nitrous oxide (N2 O 50% in oxygen) is commonly used for painful procedures in children. Potential negative health effects associated with chronic workplace exposure limit its use. Safe occupational N2 O exposure concentrations are below 25 ppm environmental concentration as a time-weighted average (TWA) and below 200 ppm as a short-time exposure level (STEL) of 15 min. AIM: The aim was to assess occupational exposure of staff during nitrous oxide administration to children using different inhalation delivery devices and scavenging systems. METHODS: Staff nitrous oxide exposure during use of a double face mask (DFM) with or without a demand valve (DV) was compared with a conventional single face mask (FM). We also compared exposure using the hospital central scavenging system with a portable evacuation system. N2 O concentrations, representing exposure values, were monitored within proximity to staff. Urine N2 O concentration was measured in staff administering the N2 O at the end of the procedural session. RESULTS: The mean and median values of TWA and STEL within the working area were lower than recommended values in the DFM (10.8, 11.6 ppm for TWA; 13.9, 11.0 ppm for STEL) and DFM-DV groups (2.3, 2.8 ppm for TWA; 4.4, 3.5 ppm for STEL) using the portable evacuation system. The N2 O urine exposure in DFM-DV group was lower than DFM group: a mean difference of 9.56 ppm (95% CI 2.65-16.46). Staff N2 O urinary concentrations were within safe biological limits in both the DFM and DFM-DV groups. High exposure concentrations to N2 O were recorded in all FM and FM-DV environmental and biological samples. CONCLUSIONS: The DFM system, with or without a DV, connected to a portable evacuation system during N2 O administration to children for painful procedures kept N2 O levels within the local environment below recommended limits.

Biomonitoring occupational sevoflurane exposure at low levels by urinary sevoflurane and hexafluoroisopropanol.

This study aimed to correlate environmental sevoflurane levels with urinary concentrations of sevoflurane (Sev-U) or its metabolite hexafluoroisopropanol (HFIP) in order to assess and discuss the main issues relating to which biomarker of sevoflurane exposure is best, and possibly suggest the corresponding biological equivalent exposure limit values. Individual sevoflurane exposure was measured in 100 healthcare operators at five hospitals in north-east Italy using the passive air sampling device Radiello(®), and assaying Sev-U and HFIP concentrations in their urine collected at the end of the operating room session. All analyses were performed by gas chromatography-mass spectrometry. Environmental sevoflurane levels in the operating rooms were also monitored continuously using an infrared photoacoustic analyzer. Our results showed very low individual sevoflurane exposure levels, generally below 0.5 ppm (mean 0.116 ppm; range 0.007-0.940 ppm). Sev-U and HFIP concentrations were in the range of 0.1-17.28 µg/L and 5-550 µg/L, respectively. Both biomarkers showed a statistically significant correlation with the environmental exposure levels (Sev-U, r=0.49; HFIP, r=0.52), albeit showing fairly scattered values. Sev-U values seem to be influenced by peaks of exposure, especially at the end of the operating-room session, whereas HFIP levels by exposure on the previous day, the data being consistent with the biomarkers' very different half-lives (2.8 and 19 h, respectively). According to our results, both Sev-U and HFIP are appropriate biomarkers for assessing sevoflurane exposure at low levels, although with some differences in times/patterns of exposure. More work is needed to identify the best biomarker of sevoflurane exposure and the corresponding biological equivalent exposure limit values.

[Air and biomonitoring of occupational exposure to anesthetic gases in the health care workers of a large hospital in Milan]. / Il monitoraggio ambientale e biologico dell'esposizione professionale a gas anestetici presso le sale operatorie di un grande ospedale milanese.

In this study exposure to anesthetic gases in health care workers of a hospital of Milan was investigated. The evaluation focused on the period 2007-2010 and was performed by environmental monitoring (20 operating rooms and 54 samples) and biological monitoring (180 workers and 242 urine samples). Mean airborne exposure was 3:15 and 0.34 ppm for nitrogen protoxide (N2O) and sevorane; in end-of-exposure urine samples the concentration of N2O and hexafluoroisopropanol, metabolite of sevorane, were 4.85 mg/L and 0.21 mg/L, with 80 and 21% of values below the quantification limit. Sevorane monitoring exceeded or equaled the environmental limit value of 0.5 ppm and the biological exposure index in 17 and 11% of measures. There were no observed exceedances of the limit for N2O. The anesthetist and scrub nurse were tasks with greater exposure. There was a significant correlation between airborne halogenated gases and urinary hexafluoroisopropanol. The results of this study indicates that further efforts are needed to improve the hygienic conditions in the investigated hospital.

Exposure of personnel to sevoflurane during paediatric anaesthesia: influence of professional role and anaesthetic procedure.

BACKGROUND AND OBJECTIVE: This study was performed to determine the individual exposure of paediatric operating theatre personnel to sevoflurane and to evaluate the impact of inhalation induction and various airway approaches on exposure to airborne sevoflurane. METHODS: Mean individual environmental (workplace air) exposure to sevoflurane and a biomarker of exposure (urinary sevoflurane) were monitored in 36 subjects (10 anaesthetists, 10 surgeons, 12 nurses and 4 auxiliary personnel) working in two paediatric operating rooms. RESULTS: Environmental and urinary values were significantly greater in anaesthetists compared with other groups, with median values of 0.65ppm (interquartile range 1.36; 95th percentile 4.36) for breathing zone sevoflurane and 2.1 microgL(-1) urine (interquartile range 2.6; 95th percentile 7.6) for urinary sevoflurane. Anaesthetists exceeded the 2ppm maximum allowed environmental concentration recommended by the National Institute for Occupational Safety and Health in 4 of 22 cases (18.1%). A positive correlation was found between the number of patients undergoing inhalational induction each day and mean values of breathing zone and urinary sevoflurane. An increase in the number of daily laryngeal mask insertions, or the use of rigid bronchoscopy, are statistically related to higher environmental and urinary values (P < 0.01 and <0.00001 for breathing zone sevoflurane, P < 0.05 and <0.01 for urinary sevoflurane, respectively). CONCLUSIONS: Anaesthesia with sevoflurane can pose a hazard of chronic exposure with anaesthetists having the highest risk. Endotracheal intubation offers considerable protection against exposure. Routine anaesthesia using a standard facemask, a laryngeal mask or rigid bronchoscopy are risk factors for increased anaesthetic exposure.

Use of 19F-nuclear magnetic resonance and gas chromatography-electron capture detection in the quantitative analysis of fluorine-containing metabolites in urine of sevoflurane-anaesthetized patients.

1: The use of fluorine-19 nuclear magnetic resonance (19F-NMR) and gas chromatography-electron capture detection (GC-ECD) in the analysis of fluorine-containing products in the urine of sevoflurane-exposed patients was explored. 2: Ten patients were anaesthetized by sevoflurane for 135-660 min at a flow rate of 6 l min(-1). Urine samples were collected before, directly after and 24 h after discontinuation of anaesthesia. 3: 19F-NMR analysis of the urines showed the presence of several fluorine-containing metabolites. The main oxidative metabolite, hexafluoroisopropanol (HFIP)-glucuronide, showed two strong quartet signals in the 19F-NMR spectrum. HFIP concentrations after beta-glucuronidase treatment were quantified by (19)F-nuclear magnetic resonance. Concentrations directly after and 24 h after discontinuation of anaesthesia were 131 +/- 41 (mean +/- SEM) and 61 +/- 19 mol mg(-1) creatinine, respectively. Urinary HFIP excretions correlated with sevoflurane exposure. 4: Longer scanning times enabled the measurement of signals from two compound A-derived metabolites, i.e. compound A mercapturic acid I (CAMA-I) and compound A mercapturic acid II (CAMA-II), as well as products from beta-lyase activation of the respective cysteine conjugates of compound A. The signals of the mercapturic acids, 3,3,3-trifluoro-2-(fluoromethoxy)-propanoic acid and 3,3,3-trifluorolactic acid were visible after combining and concentrating the patient urines. CAMA-I and -II excretions in patients were completed after 24 h. 5: Since 19F-nuclear magnetic resonance is not sensitive enough, urinary mercapturic acids concentrations were quantified by gas chromatography-electron capture detection. CAMA-I and -II urinary concentrations were 2.3 +/- 0.7 and 1.4 +/- 0.4 mol mg(-1) creatinine, respectively. Urinary excretion of CAMA-I showed a correlation with sevoflurane exposure, whereas CAMA-II did not. 6. The results show that 19F-nuclear magnetic resonance is a very selective and convenient technique to detect and quantify HFIP in non-concentrated human urine. 19F-nuclear magnetic resonance can also be used to monitor the oxidative biotransformation of sevoflurane in anaesthetized patients. Compound A-derived mercapturic acids and 3,3,3-trifluoro-2-(fluoromethoxy)-propanoic acid and 3,3,3-trifluorolactic acid, however, require more sensitive techniques such as gas chromatography-electron capture detection and/or gas chromatography-mass spectrometry for quantification.

[Biological monitoring of occupational exposure to sevoflurane]. / Monitoraggio biologico dell'esposizione professionale a sevoflurane.

Sevoflurane has been used in the last few years in brief surgical operations, either alone or in combination with nitrous oxide. Occupationally exposed groups include anesthesiologists, surgeons and operating room nurses. In 1977 the National Institute for Occupational Safety and Health (NIOSH) recommended that occupational exposure to halogenated anesthetic agents (halothane, enflurane, and isoflurane), when used as the sole anesthetic, should be controlled so that no worker would be exposed to time-weighted average concentrations greater than 2 ppm during anesthetic administration. When halogenated anesthetics are associated with nitrous oxide, NIOSH recommends that the limit value should not exceed 0.5 ppm. We think these recommendations can be extended to sevoflurane. Metabolism of sevoflurane is catalyzed by cytochrome P-450; this involves oxidation of the fluoromethyl side chain of the molecule, followed by glucuronidation. Two urinary metabolites of sevoflurane have been identified: inorganic fluoride (which, however, is not specific) and a non-volatile compound that yields hexafluoroisopropanol (HFIP) when digested with the enzyme beta-glucuronidase. In order to investigate the role of urinary HFIP as an indicator of occupational exposure to sevoflurane (CI, ppm), CI was measured in 145 members of 18 operating room staffs. The measurements of the time-weighted average of CI in the breathing zone were made by means of diffusive personal samplers. Each sampler was exposed during the whole working period. Sevoflurane was desorbed with CS2 from charcoal and the concentrations were measured on a gas chromatograph (GC) equipped with a mass selective detector (MSD). The GC was equipped with a 25 meter cross-linked phenylmethylsilicon column (internal diameter 0.2 mm). GC conditions were as follows: injector column temperature = 200 degrees C; column temperature = 30 degrees C; carrier gas = helium; injection technique of samples = splitless. The analytical conditions for the MSD were the following: ion mass monitored = 131 m/e; dwell time = 50 msec; selected ion monitoring window time = 0.1 amu; electromultiplier = 400 V. Urine samples were collected near the end of the shift and were analyzed for HFIP by head-space gas chromatography after glucuronide hydrolysis. 0.5 ml of urine and 1.5 ml of 10 M sulfuric acid were added to 21.8 ml headspace vials. The vials were immediately capped, vortexed, and loaded into the headspace autosampler. Samples were maintained at 100 degrees C for 30 min, after which glucuronide hydrolysis was 99% complete. Analyses were performed on a GC equipped with a MSD. The analytical conditions for urine analysis were as follows: cross-linked 5% phenylmethylsilicon column (internal diameter 0.2 mm, length 25 m); column temperature = 35 degrees C; carrier gas = helium. The analytical conditions for the MSD were: monitored ions = 51.05 and 99; dwell time = 100 ms; selected ion monitoring window time = 0.1 amu; electromultiplier voltage = 2000 Volt. With our analytical procedure, the detection limit of HFIP in urine was 20 micrograms/L. The variation coefficient (CV) for HFIP measurement in urine was 8.7% (on 10 determinations; mean value = 1000 micrograms/L). The median value of CI was 0.77 ppm (Geometric Standard Deviation = 4.08; range = 0.05-27.9 ppm). The correlation between CI and HFIP (Cu, microgram/L) was: Log Cu (microgram/L) = 0.813 x Log CI (ppm) + 2.517 (r = 0.79, n = 145, p < 0.0001). On the basis of the equation it was possible to establish tentatively the biological limit values corresponding to the respective occupational exposure limit values proposed for sevoflurane. According to our experimental results, HFIP values of 488 micrograms/L and 160 micrograms/L correspond to airborne sevoflurane concentrations of 2 and 0.5 ppm respectively.

Solid-phase microextraction gas chromatographic-mass spectrometric method for the determination of inhalation anesthetics in urine.

Solid-phase microextraction (SPME) has been applied to the headspace sampling of inhalation anesthetics (i.e. nitrous oxide, isoflurane and halothane) in human urine. Analysis was carried out by gas chromatography-mass spectrometry using a capillary column with a divinylbenzene porous polymeric stationary phase. A SPME divinylbenzene-Carboxen-polydimethylsiloxane coated fiber, 2 cm long, was used, and its performances were compared with those of a Carboxen-PDMS in terms of sensitivity, extraction efficiency, extraction time, fiber coating-urine distribution coefficient. For both fibers, linearity was established over four orders of magnitude, limits of detection were below 100 ng/l for nitrous oxide and below 30 ng/l for halogenated. Precision calculated as %RSD was within 3-13% for all intra- and inter-day determinations. The method was applied to the quantitative analysis of anesthetics in the urine of occupationally exposed people (operating room personnel).