Clinical Physiology (1992) 12, 409-418
Effects of sulphur hexafluoride on psychomotor performance A. Ostlund, A. Sporrong, D. Linnarsson and F. Lind Environmental Physiology Laboratory, Department of Physiology, Karolinska Institute, Stockholm, Sweden
(Received 23 May 1991; accepted I1 October 1991)
Summary. The narcotic influence of sulphur hexafluoride on mental and psychomotor performance has been studied in 9 subjects at normal atmospheric pressure. Control experiments were performed with air and with nitrous oxide. Psychomotor, perceptual and cognitive abilities were assessed using a computerized test battery. Subjects were exposed to air and six different normoxic gas mixtures: 13, 26, and 39% N 2 0 , and 39, 59, and 79% SF,. Significant performance impairments were found with 13% N 2 0 and gradual further impairment with 26, and 39% NzO.During exposure to 39, 59, and 79% SF, over-all performance was impaired by 5 , lo, and 18%, respectively. Impairment was significant with 59 and 79% SF,. The results indicate that the relative narcotic potency of SF,: N20is about 1:4 in humans. It is concluded that a normoxic SF602 mixture can be inhaled for lung function studies without any harmful effects and that the short-lasting narcotic effect, although detectable with a test battery, would not impair the ability of the subject to perform simple breathing procedures. Key words: inert gas, high density, narcotic potency. Introduction
Sulphur hexafluoride is a synthetic, non-toxic, biochemically inert gas (Lester & Greenberg, 1950) with a low solubility in water and body tissues (Weathersby & Homer, 1980). The gas has a molecular weight of 146 and a density of 6.6 kg m-’ at standard temperature and pressure. A gas mixture with 20.9% oxygen in SF, has a gas density about 4 times that of air at normal ambient pressure. These properties have rendered SF, a very useful tool in respiratory and environmental physiology. In high concentrations it has been used to study the influence of gas density on dynamic lung compliance (Forkert et al., 1975), on maximum flow rates in the airways (Maio & Farhi, 1967), and on the alveolar pressurehlow characteristics of the human lung (Slutsky et al., 1981). Correspondence: A. C)stlund, M.D., Environmental Physiology Laboratory, Department of Physiology, Karolinska Institute, S-104 01 Stockholm, Sweden.
409
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A . Ostlund et al.
The reduced diffusivity of the heavy SF6 molecule, in comparison to a lighter gas such as helium, has been used to investigate the role of diffusion in comparison to convective gas transport of the gas exchange in the lungs (Parker & Nagel, 1971; Martin et al., 1972; Kvale et al., 1975; Wood et al., 1976; Gledhill et al., 1978; van Liew el al., 1981; Hughes et al., 1982). Finally, the low tissue solubility of SF6 has permitted its use as a dilution tracer for lung volume determination (Jonmarker et al., 1985; Larsson et al., 1987; Linnarsson et al., 1987). In those of the above studies, where high SF6 partial pressures of 0 . 7 5 4 8 bar (Parker et al., 1971; Wood et al., 1976; Gledhill et al., 1978) or higher (Maio & Farhi, 1967) were inspired, the subjects noted a mild to moderate degree of narcosis. To our knowledge, however, no quantitative determination of the narcotic effect of SF, in humans has been performed so far. Therefore, the objective of the study described here was to perform such a determination in order to facilitate the continued use of SF6 as an experimental tool in respiratory and environmental physiology, and also in order to extend the data base required for the understanding of the mechanism responsible for the narcotic effect of inert gases. Subjects and methods SUBJECTS
Nine healthy male volunteers were studied. Age, weight, height ranged 28-37 years, 70-95 kg, and 170-186 cm, respectively. All were semi-professional divers familiar with mouthpiece breathing and moderate levels of nitrogen narcosis with hyperbaric air. The experimental protocol utilized in the present study was approved by the Ethics Committee of the Karolinska Institute. GASES AND GAS ANALYSIS
During the experimental sessions with N20, the subjects breathed humidified gases from a low-resistance demand regulator connected to a calibrated proportional mixer. In the SF6-experiment premixed gas was breathed through a mouthpiece and a lowresistance breathing-valve connected to a Douglas bag. Inspired gases were air or normoxic mixtures containing 13,26, and 39% N 2 0 and 39, 59, and 79% SF,. The balance was nitrogen. Inspired and end-expired N 2 0 fractional concentrations were monitored with an infrared N 2 0 analyser (Multicap, Datex Instrumentarium Corp., Helsinki, Finland). The N 2 0 concentrations (13-39%) were chosen to obtain a reference for the test battery from about threshold concentration up to a level where some subjects found it hard to follow instructions and perform a cognitive test. The inhaled SF6-concentrations ranged from 39% up to the highest possible concentration in a normoxic mixture at atmospheric pressure. The demand regulator system for N 2 0 was equipped with a 5-1 reservoir bag. The volume change of this bag activated the demand valve. The SF6 breathing circuit was
SF, and performance
411
designed so that the flow-resistive pressure drop with the much denser 79% SF, mixture was equivalent to that obtained in the experiments with 39% NzO. Special care was taken to ascertain the purity of the SF,, since traces of highly toxic compounds such as S2FI0may be found in impure gas (Greenberg & Lester, 1950). The SF, used in the present study was of the highest obtainable purity and was purchased from a manufacturer (Montefluos, Italy; distributor Alfax, Sweden) who provided certificates of analysis and bioassay for each batch of gas. PERFORMANCE TESTS
Psychomotor and mental performance was assessed with a microcomputer-based test battery. Six speed tests of increasing stimulus complexity were included in the battery. All tests used visual stimuli, presented on a 14-inch colour CRT, and required the same type of joystick motor responses. Self-paced item presentation was used, i.e. the response to one stimulus triggered the presentation of the next. This technique, allowing subjects to work at their own speed, makes the tests sensitive to changes in response-style since performance can be analysed in terms of both speed and accuracy. The test battery was designed to cover a range of fundamental abilities from basic sensory-motor via visuo-spatial to cognitive abilities. Further criteria advanced for the battery were low test inter-correlations, high testretest reliability, and reasonable practice requirements for stable performance making the battery suitable for environmental research using repeated measurement designs. Serial response time (SR). A test of basic psychomotor performance focusing on the processes of stimulus detection and choice discrimination common to all tests in the battery. The stimulus was an airplane symbol and the task was to respond to display position of the stimulus in relation to a centre indicator. Colour-word (CW). A complex response-time task with conflicting stimulus properties. The test is an adaptation of the colour-word confusion part of the Strooptest (Stroop, 1935; Harbeson et al., 1982). The stimulus, an incongruent colour-word combination, was displayed centrally surrounded by the response alternatives, the four colour names, which were presented in a neutral colour. The task was to respond to the colour in which the stimulus was presented ignoring the meaning of the word. Spatial perception (SP). A test of spatial orientation based on the Manikin test (Benson & Gedye, 1963; Bittner ef al., 1983). In this revision of the test an airplane replaced the manikin as stimulus. The airplane was displayed from above or below heading up, down, left, or right, with a missile attached to one of the wings. The task was to respond to the position of the missile as seen from the pilot’s seat. Perceptual speed (PS). A test designed for assessment of the ability to rapidly recognize similarities and differences between visual patterns. The stimuli used were unfilled squares with two rectangular slots of varying depth per vertical side. Each item was a random configuration of a central stimulus figure and four surrounding response figuresof which one was identical to the stimulus figure, the task was to locate this figure.
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A. Ostlund et al.
Acquisition-retention (AR). A test designed for assessment of associative working memory using display-position of 1 unit digits as stimulus. Each trial consisted of a centrally displayed digit surrounded by four different digits randomly assigned to four peripheral display positions. The central digit was sampled from the peripheral digits of the preceding item thus representing a display position in that item. The task was to recall the position in the previous item of the current centre digit and before responding learn the positions of the currently displayed peripheral digits. Grammatical reasoning (GR). An adaptation of Baddeley’s well-known test of logical reasoning based on grammatical transformation (Baddeley , 1968; Carter et al., 1981). The items of the test consist of a letter combination AB or BA, and a sentence making a statement about the order of the letters. The sentence uses the verbs ‘precede’ or ‘follow’ in active or passive form combined with affirmative or negative form, and mentions A or B first which gives statements like ‘A follows B’ and ‘B is not preceded by A’. The task is to determine whether there is consistency or not between the statement and the letter combination presented.
PERFORMANCE MEASURES
Three types of measures were used for performance assessment: (1) Mean response time for correct response as a measure of the speed factor, (2) Fraction of correct responses measuring accuracy, and (3) Number of correct responses, a function of speed and accuracy, as a general performance measure. PROCEDURES
Prior to the N,O-experiment each subject practiced ten times to minimize the influence of learning in the experimental sessions. There were three practice sessions each consisting of three runs of the whole test battery, and one additional practice run on the day of the experiment. The practice sessions were repeated prior to the SF,-experiment which was performed on another occasion. Test presentation order was randomized among the subjects and fixed for each subject over the experimental conditions. Total trial time for the battery was 12-13 min. The subjects were instructed to make as many correct responses as possible in the given time by working as fast and as accurately as possible. In an attempt to keep motivation high among subjects a monetary incentive was used, offering a reward for best performance in each test. All experiments were begun in the morning and were performed in a quiet laboratory where the subject could not be aware of which inspired gas mixture was used. The first run with the test battery was a simulated air control which served as an additional training session. During the following runs the inspired gas was either proper air control or 13,26, or 39% N 2 0 in the first experiment and 39,59, or 79% SF, in the second experiment, in random order.
SF, and performance
413
Each experimental run started with 5 min wash-in of the experimental gas mixture. Between each run the subject rested for at least 30 min. Results SUBJECTIVE EXPERIENCE
The subjects were asked after the experimental session to identify the various gas mixtures based on the degree of intoxication they experienced. In the N20-experiment the subjects could always identify the mixtures with 26% and 39% N 2 0 , but two subjects failed to distinguish between control and 13% N 2 0 . In the SF,-experiment one subject failed to distinguish between control and 39% SF6. None of the subjects felt any discomfort from the high gas density of SF,. No smell or taste was reported. After the cessation of SF6 and N 2 0 inhalation all subjects felt subjectively recovered within about 2 min.
TEST PERFORMANCE
Data from the N 2 0 and SF6 experiments are presented in Table 1 and results from the data analysis made by Student’s t-test are presented in Figs 1-4.
LEARNING EFFECT
The N 2 0 and SF6 experiments took place in that order with a few months interval. To test for a possible learning effect from the first to the second experimental period we compared the number of correct responses during air control. In four of the six test types there was no significant difference between ‘N20’ air control and ‘SF6’ air control. The two tests with highest response frequency, however, showed improved control performance by 11% (SR,P
Effects of sulphur hexafluoride on psychomotor performance A. Ostlund, A. Sporrong, D. Linnarsson and F. Lind Environmental Physiology Laboratory, Department of Physiology, Karolinska Institute, Stockholm, Sweden
(Received 23 May 1991; accepted I1 October 1991)
Summary. The narcotic influence of sulphur hexafluoride on mental and psychomotor performance has been studied in 9 subjects at normal atmospheric pressure. Control experiments were performed with air and with nitrous oxide. Psychomotor, perceptual and cognitive abilities were assessed using a computerized test battery. Subjects were exposed to air and six different normoxic gas mixtures: 13, 26, and 39% N 2 0 , and 39, 59, and 79% SF,. Significant performance impairments were found with 13% N 2 0 and gradual further impairment with 26, and 39% NzO.During exposure to 39, 59, and 79% SF, over-all performance was impaired by 5 , lo, and 18%, respectively. Impairment was significant with 59 and 79% SF,. The results indicate that the relative narcotic potency of SF,: N20is about 1:4 in humans. It is concluded that a normoxic SF602 mixture can be inhaled for lung function studies without any harmful effects and that the short-lasting narcotic effect, although detectable with a test battery, would not impair the ability of the subject to perform simple breathing procedures. Key words: inert gas, high density, narcotic potency. Introduction
Sulphur hexafluoride is a synthetic, non-toxic, biochemically inert gas (Lester & Greenberg, 1950) with a low solubility in water and body tissues (Weathersby & Homer, 1980). The gas has a molecular weight of 146 and a density of 6.6 kg m-’ at standard temperature and pressure. A gas mixture with 20.9% oxygen in SF, has a gas density about 4 times that of air at normal ambient pressure. These properties have rendered SF, a very useful tool in respiratory and environmental physiology. In high concentrations it has been used to study the influence of gas density on dynamic lung compliance (Forkert et al., 1975), on maximum flow rates in the airways (Maio & Farhi, 1967), and on the alveolar pressurehlow characteristics of the human lung (Slutsky et al., 1981). Correspondence: A. C)stlund, M.D., Environmental Physiology Laboratory, Department of Physiology, Karolinska Institute, S-104 01 Stockholm, Sweden.
409
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A . Ostlund et al.
The reduced diffusivity of the heavy SF6 molecule, in comparison to a lighter gas such as helium, has been used to investigate the role of diffusion in comparison to convective gas transport of the gas exchange in the lungs (Parker & Nagel, 1971; Martin et al., 1972; Kvale et al., 1975; Wood et al., 1976; Gledhill et al., 1978; van Liew el al., 1981; Hughes et al., 1982). Finally, the low tissue solubility of SF6 has permitted its use as a dilution tracer for lung volume determination (Jonmarker et al., 1985; Larsson et al., 1987; Linnarsson et al., 1987). In those of the above studies, where high SF6 partial pressures of 0 . 7 5 4 8 bar (Parker et al., 1971; Wood et al., 1976; Gledhill et al., 1978) or higher (Maio & Farhi, 1967) were inspired, the subjects noted a mild to moderate degree of narcosis. To our knowledge, however, no quantitative determination of the narcotic effect of SF, in humans has been performed so far. Therefore, the objective of the study described here was to perform such a determination in order to facilitate the continued use of SF6 as an experimental tool in respiratory and environmental physiology, and also in order to extend the data base required for the understanding of the mechanism responsible for the narcotic effect of inert gases. Subjects and methods SUBJECTS
Nine healthy male volunteers were studied. Age, weight, height ranged 28-37 years, 70-95 kg, and 170-186 cm, respectively. All were semi-professional divers familiar with mouthpiece breathing and moderate levels of nitrogen narcosis with hyperbaric air. The experimental protocol utilized in the present study was approved by the Ethics Committee of the Karolinska Institute. GASES AND GAS ANALYSIS
During the experimental sessions with N20, the subjects breathed humidified gases from a low-resistance demand regulator connected to a calibrated proportional mixer. In the SF6-experiment premixed gas was breathed through a mouthpiece and a lowresistance breathing-valve connected to a Douglas bag. Inspired gases were air or normoxic mixtures containing 13,26, and 39% N 2 0 and 39, 59, and 79% SF,. The balance was nitrogen. Inspired and end-expired N 2 0 fractional concentrations were monitored with an infrared N 2 0 analyser (Multicap, Datex Instrumentarium Corp., Helsinki, Finland). The N 2 0 concentrations (13-39%) were chosen to obtain a reference for the test battery from about threshold concentration up to a level where some subjects found it hard to follow instructions and perform a cognitive test. The inhaled SF6-concentrations ranged from 39% up to the highest possible concentration in a normoxic mixture at atmospheric pressure. The demand regulator system for N 2 0 was equipped with a 5-1 reservoir bag. The volume change of this bag activated the demand valve. The SF6 breathing circuit was
SF, and performance
411
designed so that the flow-resistive pressure drop with the much denser 79% SF, mixture was equivalent to that obtained in the experiments with 39% NzO. Special care was taken to ascertain the purity of the SF,, since traces of highly toxic compounds such as S2FI0may be found in impure gas (Greenberg & Lester, 1950). The SF, used in the present study was of the highest obtainable purity and was purchased from a manufacturer (Montefluos, Italy; distributor Alfax, Sweden) who provided certificates of analysis and bioassay for each batch of gas. PERFORMANCE TESTS
Psychomotor and mental performance was assessed with a microcomputer-based test battery. Six speed tests of increasing stimulus complexity were included in the battery. All tests used visual stimuli, presented on a 14-inch colour CRT, and required the same type of joystick motor responses. Self-paced item presentation was used, i.e. the response to one stimulus triggered the presentation of the next. This technique, allowing subjects to work at their own speed, makes the tests sensitive to changes in response-style since performance can be analysed in terms of both speed and accuracy. The test battery was designed to cover a range of fundamental abilities from basic sensory-motor via visuo-spatial to cognitive abilities. Further criteria advanced for the battery were low test inter-correlations, high testretest reliability, and reasonable practice requirements for stable performance making the battery suitable for environmental research using repeated measurement designs. Serial response time (SR). A test of basic psychomotor performance focusing on the processes of stimulus detection and choice discrimination common to all tests in the battery. The stimulus was an airplane symbol and the task was to respond to display position of the stimulus in relation to a centre indicator. Colour-word (CW). A complex response-time task with conflicting stimulus properties. The test is an adaptation of the colour-word confusion part of the Strooptest (Stroop, 1935; Harbeson et al., 1982). The stimulus, an incongruent colour-word combination, was displayed centrally surrounded by the response alternatives, the four colour names, which were presented in a neutral colour. The task was to respond to the colour in which the stimulus was presented ignoring the meaning of the word. Spatial perception (SP). A test of spatial orientation based on the Manikin test (Benson & Gedye, 1963; Bittner ef al., 1983). In this revision of the test an airplane replaced the manikin as stimulus. The airplane was displayed from above or below heading up, down, left, or right, with a missile attached to one of the wings. The task was to respond to the position of the missile as seen from the pilot’s seat. Perceptual speed (PS). A test designed for assessment of the ability to rapidly recognize similarities and differences between visual patterns. The stimuli used were unfilled squares with two rectangular slots of varying depth per vertical side. Each item was a random configuration of a central stimulus figure and four surrounding response figuresof which one was identical to the stimulus figure, the task was to locate this figure.
412
A. Ostlund et al.
Acquisition-retention (AR). A test designed for assessment of associative working memory using display-position of 1 unit digits as stimulus. Each trial consisted of a centrally displayed digit surrounded by four different digits randomly assigned to four peripheral display positions. The central digit was sampled from the peripheral digits of the preceding item thus representing a display position in that item. The task was to recall the position in the previous item of the current centre digit and before responding learn the positions of the currently displayed peripheral digits. Grammatical reasoning (GR). An adaptation of Baddeley’s well-known test of logical reasoning based on grammatical transformation (Baddeley , 1968; Carter et al., 1981). The items of the test consist of a letter combination AB or BA, and a sentence making a statement about the order of the letters. The sentence uses the verbs ‘precede’ or ‘follow’ in active or passive form combined with affirmative or negative form, and mentions A or B first which gives statements like ‘A follows B’ and ‘B is not preceded by A’. The task is to determine whether there is consistency or not between the statement and the letter combination presented.
PERFORMANCE MEASURES
Three types of measures were used for performance assessment: (1) Mean response time for correct response as a measure of the speed factor, (2) Fraction of correct responses measuring accuracy, and (3) Number of correct responses, a function of speed and accuracy, as a general performance measure. PROCEDURES
Prior to the N,O-experiment each subject practiced ten times to minimize the influence of learning in the experimental sessions. There were three practice sessions each consisting of three runs of the whole test battery, and one additional practice run on the day of the experiment. The practice sessions were repeated prior to the SF,-experiment which was performed on another occasion. Test presentation order was randomized among the subjects and fixed for each subject over the experimental conditions. Total trial time for the battery was 12-13 min. The subjects were instructed to make as many correct responses as possible in the given time by working as fast and as accurately as possible. In an attempt to keep motivation high among subjects a monetary incentive was used, offering a reward for best performance in each test. All experiments were begun in the morning and were performed in a quiet laboratory where the subject could not be aware of which inspired gas mixture was used. The first run with the test battery was a simulated air control which served as an additional training session. During the following runs the inspired gas was either proper air control or 13,26, or 39% N 2 0 in the first experiment and 39,59, or 79% SF, in the second experiment, in random order.
SF, and performance
413
Each experimental run started with 5 min wash-in of the experimental gas mixture. Between each run the subject rested for at least 30 min. Results SUBJECTIVE EXPERIENCE
The subjects were asked after the experimental session to identify the various gas mixtures based on the degree of intoxication they experienced. In the N20-experiment the subjects could always identify the mixtures with 26% and 39% N 2 0 , but two subjects failed to distinguish between control and 13% N 2 0 . In the SF,-experiment one subject failed to distinguish between control and 39% SF6. None of the subjects felt any discomfort from the high gas density of SF,. No smell or taste was reported. After the cessation of SF6 and N 2 0 inhalation all subjects felt subjectively recovered within about 2 min.
TEST PERFORMANCE
Data from the N 2 0 and SF6 experiments are presented in Table 1 and results from the data analysis made by Student’s t-test are presented in Figs 1-4.
LEARNING EFFECT
The N 2 0 and SF6 experiments took place in that order with a few months interval. To test for a possible learning effect from the first to the second experimental period we compared the number of correct responses during air control. In four of the six test types there was no significant difference between ‘N20’ air control and ‘SF6’ air control. The two tests with highest response frequency, however, showed improved control performance by 11% (SR,P
