Exposure to Sevoflurane and Nitrous Oxide During Four Different Methods of Anesthetic Induction

Klaus H. Hoerauf, MD*, Thomas Wallner, MD†, Ozan Akc¸a, MD†‡, Reza Taslimi, MD†, and Daniel I. Sessler, MD†‡§ʈ Departments of Anesthesia and General Intensive Care (*B) and (†A), ‡Outcomes Research™, and §Ludwig Boltzmann Institute for Clinical Anesthesia and Intensive Care, University of Vienna, Vienna, Austria; and ʈDepartment of Anesthesia, University of California San Francisco, San Francisco, California

The National Institute for Occupational Safety and were generally Ͻ20 ppm sevoflurane and 100 ppm ni- Health-recommended exposure levels for nitrous oxide trous oxide. During maintenance, median values were exposure are 25 ppm as a time-weighted average over near 2 ppm sevoflurane and 50 ppm nitrous oxide in all the time of exposure. The exposure limit for haloge- groups. Sevoflurane concentrations during inhaled in- nated anesthetics (without concomitant nitrous oxide duction frequently exceeded the National Institute for exposure) is 2 ppm. Inhaled sevoflurane provides an Occupational Safety and Health-recommended expo- alternative to IV induction of anesthesia. However, the sure ceiling of 2 ppm but mostly remained Ͻ20 ppm. inadvertent release of anesthetic gases into the room is Exposure during the maintenance phase of anesthesia likely to be greater than that with induction involving also frequently exceeded the 2-ppm ceiling. We con- IV anesthetics. We therefore evaluated anesthesiologist clude that operating room anesthetic vapor concentra- exposure during four different induction techniques. tions are increased during inhaled inductions and Eighty patients were assigned to one of the induction remain increased with laryngeal mask ventilation. groups to receive: 1) sevoflurane and nitrous oxide Implications: We compared waste gas concentrations from a rebreathing bag, 2) sevoflurane and nitrous ox- to sevoflurane and nitrous oxide during four different ide from a circle circuit, 3) propofol 3 mg/kg, and induction methods. During inhaled induction with a 4) thiopental sodium 5 mg/kg. Anesthesia was main- rebreathing bag or a circle circuit system, waste gas con- tained with sevoflurane and nitrous oxide via a laryn- centrations frequently exceed National Institute for Oc- geal mask. Trace concentrations were measured di- cupational Safety and Health limits of 2 ppm sevoflu- rectly from the breathing zone of the anesthesiologist. rane and 50 ppm nitrous oxide. Therefore, we During induction, peak concentrations of sevoflurane recommend that people at risk (e.g., women of child- and nitrous oxide with the two IV methods rarely ex- bearing age) should pay great attention when using this ceeded 2 ppm sevoflurane and 50 ppm nitrous oxide. technique. Concentrations during the two inhalation methods (Anesth Analg 1999;88:925–9)

ome contamination of the operating rooms by high concentrations of inhaled anesthetics are used; in- waste anesthetic gases is unavoidable when anes- haled induction of anesthesia, for example, is especially S thetic gases are used. The amount of contamina- problematic (1,2). The health consequences of environ- tion increases when unsealed airway devices and/or mental exposure to operating room anesthetic vapor concentrations are controversial (3). However, there is considerable epidemiological evidence that trace concen- Supported by NIH Grant GM58273, the Joseph Drown Founda- trations of anesthetics are associated with spontaneous tion (Los Angeles, CA), the Fonds zur Fo¨rderung der Wissen- abortion and infertility (4,5). schaftlichen Forschung (Vienna, Austria), Apotheus Laboratories, Ltd., and Abbott GesmbH (Vienna, Austria). Apotheus Laboratories European and United States health authorities recom- manufactures a mask designed to restrict waste-anesthetic gas ex- mend exposure limits for volatile anesthetics (Table 1). posure among postanesthesia care personnel; Abbott GesmbH dis- Although an occupational exposure standard for tributes propofol and sevoflurane. sevoflurane has not been established by regulatory agen- The authors do not consult for, accept honoraria from, or own stock or stock options in any anesthesia-related company. cies, a maximal level of 20 ppm has been set by the Accepted for publication December 22, 1998. manufacturer without a detailed justification (data pro- Address correspondence to Dr. Klaus Hoerauf, Department of vided by manufacturer). This is higher than the Euro- Anesthesia and General Intensive Care (B), University of Vienna, Wa¨hringer-Gu¨ rtel 18–20, A-1090 Vienna, Austria. Address e-mail to pean recommended exposure limits for other volatile [email protected]. anesthetics (6). In contrast, the United States National

Table 1. Recommended Occupational Exposure Levels for Anesthetic Vapors in Various Countries

N2O Halothane Enflurane Isoflurane Sevoflurane Desflurane Austria – 5 – – – – Denmark 100 5 2 – – – France – 2 – – – – Germany 100 5 20 – – – Great Britain 100 10 50 50 – – Italy 100 – – – – – Norway 100 5 2 2 – – Sweden 100 5 10 10 – – Switzerland 100 5 10 10 – – US-NIOSH 25 2 2 2 2 2 US-ACGIH 50 50 75 – – –

Current threshold values as time-weighted averages in parts per million. NIOSH values refer to the time of exposure during anesthetic administration; all others refer to an 8-h work day time-weighted average. NIOSH ϭ National Institute for Occupational Safety and Health, ACGIH ϭ American Conference of Governmental and Industrial Hygienists.

Institute of Environmental Health and Safety (NIOSH) studies (10), operating room anesthetic vapor concentra- recommends a time-weighted average of 25 ppm for tions of sevoflurane and nitrous oxide samples were nitrous oxide and a ceiling of 2 ppm for volatile anes- determined at 1-min intervals with a Bru¨ el & Kjaer 1301 thetics, although it these levels were set long before the (Naerum, Denmark) photoacoustic infrared spectrome- introduction of sevoflurane (7,8). ter. The lower detection limit with this system is 0.09 The aim of our study was to evaluate time-dependent ppm for sevoflurane and 0.1 ppm for nitrous oxide. changes in air contamination by waste anesthetic gases Before the study, the system was calibrated for each gas, during four different anesthetic induction techniques. e.g., with 20.8 ppm sevoflurane in pure nitrogen to pro- vide an accuracy of Ϯ2% over the entire relevant range. Appropriate compensations were included to neutralize the potential confounding effects of humidity, air pres- Methods sure, and temperature. We similarly compensated for We measured trace concentrations of sevoflurane and potential interactions among sevoflurane, nitrous oxide, nitrous oxide during the induction, maintenance, and water, and carbon dioxide. recovery from anesthesia in 80 patients scheduled for The time course of each anesthetic procedure was gynecological procedures. The details of induction and divided into four periods: preinduction, induction, maintenance are described in an accompanying article maintenance, and recovery. Cumulative values were (9). Briefly, four different methods of induction were calculated for 5 min for preinduction and induction, performed: 1) sevoflurane and nitrous oxide from a re- whereas a 10-min cumulative value was calculated for breathing bag (Sevo/Bag), 2) sevoflurane and nitrous the maintenance and recovery periods. Results are oxide from a circle system on a conventional anesthesia presented as medians with 10th, 25th, 75th, 90th, and machine (Sevo/Circle), 3) propofol 3 mg/kg (propofol), outliers ranging within the 95th percentiles. Values and 4) thiopental sodium 5 mg/kg (thiopental). were compared using nonparametric tests (Mann- Ͻ A laryngeal mask was used to secure the airway Whitney U-test); P 0.05 was considered statistically during anesthesia. Anesthesia was then maintained significant. with clinically necessary amounts of sevoflurane in 60% nitrous oxide in oxygen. Great care was taken throughout induction and anesthesia to maintain the Results best possible mask seal, to avoid excessive peak in- Typical time courses of the waste gas concentrations spiratory pressure, and to minimize occupational ex- during preinduction, induction, maintenance, and recov- posure to operating room anesthetic vapor concentra- ery of anesthesia are presented in Figures 1 and 2. Cu- tions. The study was conducted in an operating room mulative data during the different parts of anesthesia that had 17 air exchanges/h, with all ventilation being and for each group are presented as box plots in Figures fresh air. The anesthesia machine was connected to a 3 and 4. Violations of different threshold values of 0.5, 2, scavenging system, which, in turn, was connected to 20, and Ͼ20 ppm sevoflurane, and of 25, 50, 100, and the hospital vacuum system, which aspirated at a rate Ͼ100 ppm nitrous oxide according to the different inter- of 45 L/min. national occupational standards (Table 1) as a percent- Ambient gas was sampled continuously from a Teflon age of time are presented in Table 2. tube (Merck, Vienna, Austria) fixed to the shoulder of During induction, peak concentrations of sevoflu- the anesthesiologist (breathing zone). As in previous rane and nitrous oxide with the two IV methods rarely ANESTH ANALG HOERAUF ET AL. 927 1999;88:925–9 EXPOSURE TO SEVOFLURANE AND N2O

Figure 1. Typical nitrous oxide concentrations recorded from the shoulder of the anesthesiologist with each induction technique. The time course is divided into the following periods: preinduction (1–5 min), induction (6–10 min), maintenance (11–20 min), and recovery (Ͼ21 min). Figure 3. Distribution of the trace concentrations of nitrous oxide for the different periods of anesthesia in all four groups. Box plots show the 10th, 25th, 75th, and 90th percentile; circles identify outliers up to the 95th percentile. The 25th and 75th percentiles are indicated by the lower and upper border of the box; the 10th and 90th percentiles are indicated by the lower and upper error bar.

Figure 2. Typical sevoflurane concentrations recorded from the shoulder of the anesthesiologist with each induction technique. The time course is divided into the following periods: preinduction (1–5 min), induction (6–10 min), maintenance (11–20 min), and recovery (Ͼ21 min). exceeded 2 ppm sevoflurane and 50 ppm nitrous oxide. Peak concentrations of sevoflurane during the two Figure 4. Distribution of the trace concentrations of sevoflurane for inhalation methods rarely exceeded 20 ppm (Table 2). the different periods of anesthesia in all four groups. Box plots show the 10th, 25th, 75th, and 90th percentile; circles identify outliers up Overall, the concentrations of sevoflurane and nitrous to the 95th percentile. The 25th and 75th percentiles are indicated by oxide during induction were significantly lower in the the lower and upper border of the box; the 10th and 90th percentiles IV groups (thiopental and propofol) than the inhala- are indicated by the lower and upper error bar. tion groups (Sevo/Bag and Sevo/Circle). The range of the waste gases during induction was greater in the Sevo/Circle than in the Sevo/Bag group, but the dif- Discussion ference was not statistically significant. Nine major studies of anesthetic vapor concentrations Median waste gas concentrations during mainte- between 1971 and 1985 indicated that occupational nance were approximately 2 ppm sevoflurane and exposure to unscavenged waste anesthetic gases is approximately 50 ppm nitrous oxide in all groups. associated with adverse effects in healthcare workers During the recovery period, median waste gas con- (11–19). In contrast, seven other studies failed to iden- centrations were similar in all groups, near 1 ppm tify a statistically significant correlation (20–26). Al- sevoflurane and approximately 25 ppm nitrous oxide though these studies were criticized for design limita- (Figs. 3 and 4). tions, meta-analyses identified substantial basis for 928 HOERAUF ET AL. ANESTH ANALG EXPOSURE TO SEVOFLURANE AND N2O 1999;88:925–9

Table 2. Percentage of Time Exceeding Recommended Exposure Limits Thiopental Propofol Sevo/Circle Sevo/Bag Ͻ0.5 0.5–2 2–20 Ͼ20 Ͻ0.5 0.5–2 2–20 Ͼ20 Ͻ0.5 0.5–2 2–20 Ͼ20 Ͻ0.5 0.5–2 2–20 Ͼ20 Sevoflurane Preinduction 46 50 4 0 44 42 14 0 36 54 10 0 54 41 5 0 Induction 48 42 10 0 41 49 9 1 14 25 51 10 14 44 32 10 Maintenance 22 56 21 1 16 50 33 1 9 33 53 4 14 44 41 1 Recovery 32 58 10 0 24 51 24 1 25 49 26 0 26 52 22 0

Ͻ25 25–50 50–100Ͼ100 Ͻ25 25–50 50–100Ͼ100 Ͻ25 25–50 50–100Ͼ100 Ͻ25 25–50 50–100Ͼ100

N2O Preinduction 97 3 0 0 97 3 0 0 99 1 0 0 100 0 0 0 Induction 79 15 1 5 82 8 5 6 32 23 26 19 62 11 12 15 Maintenance 26 28 29 17 14 31 26 29 3 36 31 30 29 31 22 18 Recovery 59 26 11 4 51 28 14 7 57 20 10 13 63 24 9 4

Concentrations were averaged over the relevant study period in each case. Sevoflurane concentrations can be directly compared with the relevant recommended ceiling exposure limits. Nitrous oxide concentrations cannot be directed compared with recommended exposure limits because the limits for this agent are expressed in terms of a time-weighted average over an 8-h work day. concern, even when analysis was restricted to the best rooms reportedly comply with NIOSH-recommended available data (27–29). The major identified toxicities exposure limits (32,33). The operating room anesthetic were spontaneous abortion (relative risk roughly 1.3– vapor concentrations we observed during mask in- 1.9) and infertility. When assessing the value of these duction in adults were considerably lower than the epidemiological studies, however, it should be taken levels reported during pediatric anesthesia (31) and into consideration that it had been impossible to draw were comparable to values obtained during triple a direct connection between the level of exposure and vital-capacity inhaled inductions (2). untoward health response because most studies Nitrous oxide concentrations were relatively high lacked exposure measurement. This may be important during maintenance anesthesia (Ϸ40–57 ppm) in all because universal adoption of scavenging systems did groups. These high values are presumably from leak- not occur until 1980. age from laryngeal mask airways (30). Because me- Nevertheless, most international health authorities dian values were near the 2-ppm NIOSH limit, it is have set occupational standards ranging from a low to apparent that half the values exceeded this value. a relatively high level, demonstrating the lack of con- However, most measurements were well within the sensus in this field. For example, NIOSH has specified European recommendations. that it is unable to identify a safe level of exposure for Operating room anesthetic vapor concentrations waste anesthetic gases. It therefore recommends that would presumably be higher with lower air turnover the risk be minimized by “reducing exposures to the and a smaller fraction of fresh air. For example, rela- greatest extent possible” (8). The NIOSH recommen- tively high concentrations have even been observed in dations for nitrous oxide exposure are now 25 ppm, as poorly ventilated postanesthesia care units (34). In this a time-weighted average. Interestingly, the recommended exposure level for nitrous oxide in Europe is respect, it is worth noting that air exchange in the considerably higher: 50–100 ppm as a time-weighted operating room we studied far exceeds current recom- average over an 8-h working day. The exposure limit mendations by the American Institute of Architects for halogenated anesthetics (without concomitant ni- and the United States Department of Health and Hu- trous oxide exposure) is 2 ppm (7), whereas, with man Services, which specify six air exchanges per concomitant nitrous oxide exposure, it should not ex- hour, with only two being fresh (35). ceed 0.5 ppm. The European community has yet to In summary, we conclude that inhaled induction establish exposure limits for sevoflurane; however, the techniques with sevoflurane and nitrous oxide in recommended levels for other volatile anesthetics and adults violate NIOSH-recommended exposure levels nitrous oxide are higher than those in the United approximately 50% of the time. Sevoflurane concen- States (30). trations also frequently exceeded 2 ppm during main- Nitrous oxide and halogenated anesthetic concen- tenance of anesthesia with laryngeal mask airways. trations in unscavenged operating rooms exceed However, operating room anesthetic vapor concentra- NIOSH-recommended exposure limits (31), whereas tions rarely exceeded the higher European exposure gas concentrations in properly scavenged operating limits. ANESTH ANALG HOERAUF ET AL. 929 1999;88:925–9 EXPOSURE TO SEVOFLURANE AND N2O

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