[Assessment of occupational exposure of medical personnel to inhalatory anesthetics in Poland]. / Ocena narazenia zawodowego personelu medycznego na anestetyki wziewne w Polsce.

BACKGROUND: Despite common use of inhalatory anesthetics, such as nitrous oxide (N2O), halothane, sevoflurane, and the like, occupational exposure to these substances in operating theatres was not monitored in Poland until 2006. The situation changed when maximum admissible concentration (MAC) values for anesthetics used in Poland were established in 2005 for N2O, and in 2007 for sevoflurane, desflurane and isoflurane. The aim of this work was to assess occupational exposure in operating rooms on the basis of reliable and uniform analytical procedures. MATERIAL AND METHODS: The method for the determination of all anesthetics used in Poland, i.e. nitrous oxide, sevoflurane, isoflurane, desflurane, and halothane, was developed and validated. The measurements were performed in 2006-2010 in 31 hospitals countrywide. The study covered 117 operating rooms; air samples were collected from the breathing zone of 146 anesthesiologists, and 154 nurses, mostly anaesthetic. The measurements were carried out during various surgical operations, mostly on adult patients but also in hospitals for children. RESULTS: Time weighted average concentrations of the anesthetics varied considerably, and the greatest differences were noted for N2O (0.1-1438.5 mg/m3); 40% of the results exceeded the MAC value. Only 3% of halothane, and 2% of sevoflurane concentrations exceeded the respective MAC values. CONCLUSIONS: Working in operating theatres is dangerous to the health of the operating staff. The coefficient of combined exposure to anesthesiologists under study exceeded the admissible value in 130 cases, which makes over 40% of the whole study population. Most of the excessive exposure values were noted for nitrous oxide.

Human biomarkers in breath by photoacoustic spectroscopy.

Photoacoustic spectrometry provides a novel approach to the analysis of human breath biomarkers. This unique methodology has specific applications for determination of ethylene oxide, nitrous oxide, ammonia as well as other compounds of interest including sevoflurane, halothane, isoflurane, methane, ethane and propofol. The advantages and disadvantages of photoacoustic spectrometry for this purpose are evaluated.

Field application of SPME as a novel tool for occupational exposure assessment with inhalational anesthetics.

Occupational exposure to inhalational anesthetics occurs routinely in operating rooms. It could induce serious health hazards and diseases. This exposure assessment is a crucial step in determining risks. In this study, a pen-shaped holder for solid-phase microextraction (SPME) sampler was successfully applied as a time-weighted average sampling tool for workshift exposure assessment of operation room staff to halothane. It proved to be very convenient for use in occupational environments such as operation rooms. Samples were analyzed by a gas chromatography-mass spectrometry. The validity of the SPME method was checked in real-world conditions with Occupational Safety and Health Administration (OSHA) 103 standard method for the determination of inhalational anesthetics. A good agreement between OSHA 103 and SPME methods was obtained and results demonstrated no statistically significant differences in anesthetic concentrations determined by the two analytical methods (p ≥ 0.05). It is concluded that SPME in retracted mode could successfully be applied in occupational exposure assessment purposes.

An unusual case of anesthetic abuse by a full-face gas mask.

The authors report a case of sniffing of halothane (Narcotan) by a 32-year-old man, master of pharmacy, through the military full-face gas mask. The liquid halothane had been applied on the scrubber of the gas mask and voluntarily inhaled. The sniffer was found dead in his flat, with the gas mask still fixed and sealed on his face. Because the authors have not encountered any report of such a case in the literature, they present and discuss this case in this article.

NMR investigations of amyloid-ß peptide interactions with propofol at clinically relevant concentrations with and without aqueous halothane solution.

Oligomerization of amyloid-ß peptide (Aß) is an important stage in Alzheimer's disease. Recently, it has been shown that in an experimental model, smaller sized anesthetics (e.g., isoflurane, desflurane, etc.) induce Aß oligomerization. Using state-of-the-art solution nuclear magnetic resonance, spectroscopic studies on Aß interaction with propofol indicated that propofol does not interact with the G29, A30, and I31 residues of Aß peptide at a clinically relevant concentration (0.083 mM), and no Aß oligomerization was observed after 69 days. However, Aß oligomerization was observed when treated with propofol (clinically relevant concentration) coadministered with aqueous halothane solution. Furthermore, dose dependence studies at various propofol concentrations (0.32 mM, 2.07 mM, and 53.4 mM) indicate the effect of propofol concentration on Aß oligomerization revealing the hydrophobic nature of interactions between propofol with these critical residues (G29, A30, and I31). These experimental findings reaffirm that smaller molecular sized anesthetics (e.g., halothane) do play a leading role in Aß oligomerization.

El halotano como contaminante del aire en el ambiente de trabajo / Halothane as a pollutant in the occupational environment

El halotano es un agente anestésico inhalatorio volátil empleado en algunos procedimientos quirúrgicos. En este trabajo nos propusimos compilar información a partir de la literatura existente relacionada con el personal expuesto, efectos sobre la salud, métodos de muestreo y análisis, así como estudios realizados en este campo. Esta revisión muestra que la presencia de concentraciones elevadas en los puestos de trabajo puede ocasionar daños a la salud de los trabajadores expuestos, por lo que es necesario establecer una metodología adecuada de evaluación y control a este contaminante dentro del sistema de vigilancia(AU)

Halothane is an inhaling volatile anesthetic used in some surgical procedures. In this work it was our purpose to compile information through the existent literature related to exposed personnel, effects to health, and methods of sampling and analysis, as well as studies done in this field. This review shows that the presence of high concentrations in working places can cause damage to the health of the exposed workers, so it is necessary to establish an adequate method of evaluation and control of this contaminant within the vigilance system(AU)

Clinically relevant concentration determination of inhaled anesthetics (halothane, isoflurane, sevoflurane, and desflurane) by 19F NMR.

Biophysical studies of protein-anesthetic interactions using nuclear magnetic resonance (NMR) spectroscopy are often conducted by the addition of micro amounts of neat inhaled anesthetic which yields much higher than clinically relevant (0.2-0.5 mM) anesthetic concentrations. We report a 19F NMR technique to measure clinically relevant inhaled anesthetic concentrations from saturated aqueous solutions of these anesthetics (halothane, isoflurane, sevoflurane, and desflurane). We use a setup with a 3-mm NMR tube (containing trifluoroacetic acid as standard), coaxially inserted in a 5-mm NMR tube containing anesthetic solution under investigation. All experiments are conducted in a 5-mm NMR probe. We also have provided standard curves for four inhaled anesthetics using NMR technique. The standard curve for each of these anesthetics is helpful in determining the prerequisite amount of aqueous anesthetic solution required to prepare clinically relevant concentrations for protein-anesthetic interaction studies.

Apparent 'electrocatalytic' activity of multiwalled carbon nanotubes in the detection of the anaesthetic halothane: occluded copper nanoparticles.

The electrocatalytic detection of the anaesthetic halothane on a multiwalled carbon nanotube modified glassy carbon electrode is reported with a low limit of detection of 4.6 microM. A thorough investigation of the underlying cause of this apparent catalytic effect is undertaken by comparing the response of various carbon electrodes including glassy carbon, basal- and edge-plane pyrolytic graphite electrodes (bppg and eppg respectively) to increasing additions of halothane. The reduction of halothane is shifted by 250-300 mV to more negative potentials at an eppg electrode than that observed at the GC-CNT electrode. Therefore the results of this investigation show that, surprisingly, the electrocatalysis is not solely due to the introduction of edge-plane-like defect sites on the carbon nanotubes as is commonly found for many other substrates showing favourable voltammetry at nanotube modified electrodes. Instead, we reveal that in this unusual case the electroactive sites for the reduction of halothane are due to the presence of copper nanoparticles occluded within the carbon nanotubes during their production, which are never completely removed by standard purification techniques such as acid washing. This is only the third known case where apparent electrocatalysis by carbon nanotube modified electrodes is due to occluded metal-related nanoparticles within the nanotube structure, rather than the active sites being the edge-plane-like defect sites on the nanotubes. Furthermore this is the first case where the active sites are nanoparticles of copper metal, rather than metal oxide nanoparticles (namely oxides of iron(II)/(III)) as was found to be the case in the previous examples.

Effect of halothane on lung carcinoma cells A 549.

The halogenated hydrocarbons, such as halothane, are widely used as anesthetics in clinical practice; however their application is often accompanied with metabolic, cardiovascular and respiratory complications. One of the possible factors for this negative outcome might be the severe toxicity of these agents. In this paper, we investigate in vitro effects of halothane on human lung carcinoma A 549 cells, namely on their cytotoxicity, adhesive properties and metabolic activity. The cytotoxicity response of lung carcinoma A 549 cells to halothane was determined by lactate dehydrogenase (LDH) assay (for cytotoxicity), by detachment assay after adhesion to type IV collagen (for cell adhesive properties) and by surface tension measurements of culture medium (for cell metabolic activity). Regarding the cytotoxicity, the determined maximal non-toxic concentration of halothane on A 549 cells, given here as volume percentages (vol.%) was 0.7 vol.% expressed as aqueous concentration in the culture medium. Direct measurement of the actual halothane concentration in the culture medium showed that 0.7 vol.% corresponds to 1.05 mM and 5.25 aqueous-phase minimum alveolar concentration (MAC). Concentrations equal or higher than 1.4 vol.% (2.1 mM; 10.5 MAC) of halothane provoked complete detachment (cell death), or reduction of initial adhesion to collagen IV in half of the cell population. Surfactant production of A 549 cells, registered up to 48 h after halothane treatment, was inhibited by halothane concentrations as low as 0.6 vol.% (0.9 mM; 4.5 MAC). Our results demonstrate that sub toxic halothane concentrations of 0.6 vol.% inhibits surfactant production; concentrations in the range 0.8-1.4 vol.% induce membrane damages and concentrations equal and higher than 1.4 vol.%--cell death of approximately 50% of the cells.

Low-affinity analytical chromatography for measuring inhaled anesthetic binding to isolated proteins.

The direct measure of volatile anesthetic binding to protein is complicated by weak affinity and therefore rapid kinetics. Consequently, several puted targets for these clinically important drugs have only functional data to support a direct mode of action. While several methods for measuring some aspects of binding are available, all have significant limitations. We introduce the use of analytical chromatography for the purpose of directly measuring volatile anesthetic binding to protein, and show that it can provide estimates of both affinity and stoichiometry for proteins that can be obtained in fairly high purity and mass. Using this approach we characterize halothane binding to serum albumin as low affinity and multisite, and to myoglobin or cytochrome C as strictly nonspecific. This approach will be useful in directly characterizing equilibrium, solution binding to isolated proteins in preparation for more time-consuming methods with structural resolution.

Bioactivation and cytotoxicity of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) in isolated rat hepatocytes.

The bioactivation and cytotoxicity of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), a replacement for some ozone-depleting chlorofluorocarbons, were investigated using freshly isolated hepatocytes from non-induced male rats. A time- and concentration-dependent increase in the leakage of lactate dehydrogenase and a concentration-dependent loss of total cellular glutathione were observed in cells incubated with 1, 5 and 10 mM HCFC-123 under normoxic or hypoxic (about 4% O2) conditions. Lactate dehydrogenase leakage was completely prevented by pretreating the cell suspension with the free radical trapper N-t-butyl-alpha-phenylnitrone. The aspecific cytochrome P450 (P450) inhibitor, metyrapone, totally prevented the lactate dehydrogenase leakage from hepatocytes, while two isoform-specific P450 inhibitors, 4-methylpyrazole and troleandomycin (a P450 2E1 and a P450 3A inhibitor, respectively), provided a partial protection against HCFC-123 cytotoxicity. Interestingly, pretreatment of cells with glutathione depletors, such as phorone and diethylmaleate, did not enhance the HCFC-123-dependent lactate dehydrogenase leakage. Two stable metabolites of HCFC-123, 1-chloro-2,2,2-trifluoroethane and 1-chloro-2,2-difluoroethene, were detected by gas chromatography/mass spectrometry analysis of the head space of the hepatocyte incubations carried out under hypoxic and, although at a lower level, also normoxic conditions, indicating that reductive metabolism of HCFC-123 by hepatocytes had occurred. The results overall indicate that HCFC-123 is cytotoxic to rat hepatocytes under both normoxic and hypoxic conditions, due to its bioactivation to reactive metabolites, probably free radicals, and that P450 2E1 and, to a lower extent, P450 3A, are involved in the process.

Rapid analysis of halothane in biological samples using headspace solid-phase microextraction and gas chromatography-mass spectrometry--a case of a double homicide.

A simple, rapid, and sensitive method for the analysis of halothane in biological samples was developed. The procedure describes the extraction of halothane from blood, liver, kidney, brain, urine, bile, and stomach contents by headspace solid-phase microextraction (HS-SPME) followed by capillary gas chromatography coupled with mass spectrometry (GC-MS). The recovery in blood samples after addition of ammonium sulfate and sulfuric acid was 72% compared to a sample prepared in water (100%). Linearity was established over a concentration range of 0.1-100 mg/kg of spiked blood samples with an excellent coefficient of correlation (0.996) and a limit of detection of 0.004 mg/kg. The time for analysis was approximately 40 min per sample including the extraction step. The procedure was used for quantitation of halothane in various samples in a case of a double homicide. HS-SPME in combination with GC-MS was an effective method for the determination and quantitation of halothane in biological material.

Occupational exposure to inhaled anaesthetics: a follow-up study on anaesthetists of an eastern European university hospital.

BACKGROUND: Although no dose-response relationship for the health risks associated with the occupational exposure to inhaled anaesthetics exists, public health authorities recommend threshold values. The aim of the present study was to assess if and to what extent these threshold values are exceeded in an eastern European university hospital before and after measures had been taken to reduce occupational exposure. METHODS: At nine workplaces occupational exposure of anaesthetists to nitrous oxide and halothane or isoflurane was measured by means of photoacoustic infrared spectrometry. The measurements were carried out in 1996 and were repeated in 1997 after the installation of active scavenging devices at five workplaces and an air-conditioning system at one workplace. RESULTS: Occupational exposure to nitrous oxide and halothane or isoflurane was lower in 1997 compared to 1996. In 1997 most of the nitrous oxide values still exceeded the threshold value of 100 ppm, whereas most of the halothane and isoflurane values were already below the threshold values of 5 ppm and 10 ppm in 1996. CONCLUSION: The measures taken were effective in reducing waste gas exposure. Nevertheless, further efforts are necessary, especially for nitrous oxide, to reach western European standards. These efforts comprise structural measures such as active scavenging devices and air-conditioning systems at all workplaces, the use of total intravenous anaesthesia, low-flow anaesthesia and an appropriate working technique.

Concentrations of anaesthetic gases in hospital operating theatres.

Occupational exposure to anaesthetic gases (halothane, forane and nitrous oxide) was assessed in hospitals located in Lódz and its satellite towns. Individual dosimetry and stationary sampling methods were employed. The samples of air from workplaces were analysed by gas chromatography with mass detection or flow ionisation (halothane, forane) and by infra-red spectroscopy method (nitrous oxide). The concentrations of halothane and accompanying substances (ethanol, isopropanol and diethyl ether) indicate that Polish OELs were met in the majority of the hospitals. As Polish hygiene standards for forane and nitrous oxide are no available, the concentration values were compared with Swedish and German OELs. The comparison revealed that forane concentrations did not exceed Swedish OEL but nitrous oxide did exceed German maximum allowable levels.

Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.

OBJECTIVE: Halothane undergoes both oxidative and reductive metabolism by cytochrome P450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism. METHODS: Patients (n = 9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations. RESULTS: The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 +/- 20 micromol vs 116 +/- 78 micromol) and bromide (17 +/- 11 micromol vs 53 +/- 49 micromol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations. CONCLUSIONS: These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors.

Staff exposure to anaesthetic gases in theatre and non theatre areas.

Environmental monitoring of anaesthetic gases was carried out in theatre areas in eight hospitals as well as in Delivery suites, radiology, radiotherapy and Dental suites. High staff exposures occurred in nontheatre areas although exposures in theatres were generally satisfactory. Environmental control measures are required where staff exposures exceed legal standards.

Factitious halothane detection during trigger-free anesthesia in a malignant hyperthermia susceptible patient.

PURPOSE: To discuss the problems encountered when halothane was detected in a presumed 'clean' patient circuit during the 'trigger-free' anesthetic management of a known Malignant Hyperthermia Susceptible (MHS) patient for routine orthopedic surgery. CLINICAL FEATURES: A 29-yr-old MHS woman had a wrist arthroscopy/exploration/fusion under general anesthesia. During the course of the 'trigger-free' anesthetic the respiratory gas analyser detected end-tidal halothane in the patient circuit. The patient was disconnected from the circuit as attempts to identify the source of the readings were undertaken. After ruling out the presence of halothane by various clinical manoeuvre the patient was reconnected to the circuit without sequelae. CONCLUSION: By exclusion the problem was presumed to be a factitious reading resulting from the respiratory gas analyser incorrectly identifying patient-expired methane as halothane.

Homicidal poisoning with halothane.

A double homicide by smothering with halothane-moistened towels is described and the blood and tissue concentrations of halothane are discussed in comparison to the literature.

[Evaluation of exposure to halothane and ethyl alcohol among technicians responsible for maintenance of anesthesia equipment]. / Ocena narazenia konserwatorów sprzetu anestezjologicznego na halotan i pary etanolu.

The authors discuss the measurements of exposure to halotane and ethyl alcohol among technicians responsible for maintenance of anaesthesiological instruments that occurs at various stages of maintenance work and in an operating room.

Concentration measures of volatile anesthetics in the aqueous phase using calcium sensitive electrodes.

Volatile anesthetic concentrations have been difficult to measure, but are an important experimental parameter for in vitro studies of anesthetic actions. Calcium sensitive electrodes were investigated as a means of continuously monitoring anesthetic concentrations in artificial cerebrospinal fluids (ACSF). Anesthetic-induced Ca2+ electrode signals were compared at room (22 degrees C) and physiological (35 degrees C) temperatures. Electrophysiological measures of anesthetic effects on synaptic potentials provided a bioassay. Halothane and isoflurane produced negative changes in calcium electrode potentials which were linearly related to concentrations over a clinically useful range (0.5-1.5 MAC). Anesthetic-induced voltages persisted in nominally zero Ca2+ ACSF and even in deionized water. A good correlation (r>0.9) was found for calcium electrode measures of anesthetic concentration and synaptic response depression produced by halothane, at both 22 and 35 degrees C. These results support three conclusions: (1) calcium sensitive electrodes provide a useful measure of volatile anesthetic concentrations in aqueous solution. (2) Care must be taken when using these electrodes for Ca2+ concentration measurements, if a volatile anesthetic is also to be used, since the anesthetic could introduce an appreciable error (>50%). (3) A temperature change of 13 degrees C had surprisingly little effect on Ca2+ electrode responses or on synaptic depression produced by anesthetics.