Oxygen Part Pressure Interrelated Hypoxia

Transcription

1 Int Arch Occup Environ Health (2003) 76: DOI /s ORIGINAL ARTICLE Peter Angerer Æ Dennis Nowak Working in permanent hypoxia for fire protection impact on health Received: 3 May 2002 / Accepted: 28 August 2002 / Published online: 31 January 2003 Ó Springer-Verlag 2003 Abstract Objectives: A new technique to prevent fires is continuous exchange of oxygen with nitrogen which leads to an oxygen concentration of between 15% and 13% in the ambient air. This paper reviews the effect of shortterm, intermittent hypoxia on health and performance of people working in such atmospheres. Methods: We reviewed the effect of ambient air hypoxia on human health in the literature using Medline, as well as reference lists of articles and handbooks. Articles were assessed from the perspective of working conditions in fire-protected rooms. Results: Oxygen reduced to 15% and 13% in normobaric atmospheres is equivalent to the hypobaric atmospheres found at 2,700 and 3,850-m altitudes. When acutely exposed, a healthy person responds within minutes to hours with increased ventilation, stimulation of the sympathetic system, increased heart rate, increased pulmonary-circulation resistance,reduced plasma volume, and stimulation of erythropoesis. Acute mountain sickness occurs frequently at these oxygen partial pressures, but the full syndrome is rare if continuous exposure is limited to 6 h. Mood, cognitive, and psychomotor functions may be mildly impaired in these conditions, but data are inconclusive. Persons suffering from cardiac, pulmonary, or hematological diseases should consult a specialist in order for their individual risk to be assessed, and medical screening for any of these diseases is strongly recommended prior to exposure. Conclusion: Preliminary evidence suggests that working environments with low oxygen concentrations to a minimum of 13% and normal barometric pressure do not impose a health hazard, provided that precautions are observed, comprising medical examinations and limitation of exposure time. However, evidence is limited, particularly with P. Angerer (&) Æ D. Nowak Institute and Outpatient Clinic for Occupational and Environmental Medicine, Ludwig-Maximilians-University, Ziemssenstrasse 1, 80336, Munich, Germany peter.angerer@arbeits.med.uni-muenchen.de Tel.: Fax: regard to workers performing strenuous tasks or having various diseases. Therefore, close monitoring of the health problems of people working in low oxygen atmospheres is necessary. Keywords Fire protection Æ Normobaric hypoxia Æ Acute mountain sickness Æ Brain function Æ Coronary artery disease Introduction Reduction of oxygen in the air by replacement with nitrogen effectively extinguishes fire. Permanently low oxygen (LO), i.e., at a concentration of 15 to 13% of the room air even prevents many materials from being ignited by fire. This effect is due to a changed mixing ratio of oxygen and nitrogen, with fewer oxygen molecules available for the combustion process. Although this method of fire prevention was recognized years ago, recent technological and economic developments have promoted its rapidly increasing use. In Germany, the first system was installed in In 2002, it is estimated that 20 systems are in operation and several hundred people will be exposed to LO environments. Avoidance of the destruction caused by the fire itself and its extinction may be economically vital for companies that depend on electronic data processing and storage, on the trading of unique and irreplaceable merchandise (e.g., a seasonal fashion collection), or on the storage of highly explosive chemicals. There are now commercial technical systems available that maintain a permanently LO concentration by continuously adding nitrogen that is produced on site. These systems also continuously monitor the oxygen fraction. Jobs in fire-protected rooms may be permanent (full shift) or temporary (to finish a time-limited task). The job may require complex intellectual abilities or strenuous physical work. Eventually, a person working in LO may develop an acute or a chronic disease. These

2 88 possibilities raise numerous questions concerning occupational medicine and safety. Although the use of LO atmospheres for fire protection will soon affect a significant number of people, empirical studies about its medical sequelae are sparse. Yet, LO caused by low barometric pressure (hypobaric hypoxia) is an environment that people have been exposed to at high altitudes for centuries, e.g., in mountains, or more recently in aviation. The aim of this paper is to review the scientific knowledge on the effect of LO in all types of environments and to draw conclusions for the well being, performance and health of people that must work in a LO atmosphere at normal barometric pressure (normobaric hypoxia). The review will focus on the following questions: 1. What are the physiological effects on healthy persons of entering, staying in and working in a room with an oxygen concentration of 15% 13%? 2. How does LO content affect mood and intellectual and physical performance? 3. Is working in LO a health risk for healthy persons? 4. Which pre-existing diseases endanger a person working in LO? Methods Search for publications We used three sources for the search of literature: Medline (National Library of Medicine, PubMed as retrieval system); leading international standard textbooks of medical specialties that deal with LO atmospheres (in particular, aviation, sport, high-altitude climbing, military activity) and leading international standard textbooks covering the relevant diseases (in particular, cardiac/ circulatory, pulmonary, hematological, neurological); guidelines of medical associations concerning exposure to LO atmospheres. Furthermore, the bibliographies of all articles selected by the initial screening were searched. In order to obtain comprehensive information on all issues that are relevant for human health when individuals are exposed to LO, as a first step we used broad search terms without restriction of the time period (last search March 2002, updated August 2002), but limited the search to studies in humans. The terms high altitude, hypobaric hypoxia, normobaric hypoxia and acute mountain sickness returned a total of 3,115 articles. These were then screened according to the following criteria: (1) exposure to LO concentrations within the range relevant to the workplace (i.e., corresponding to normobaric hypoxia oxygen between 15% and 13%, with a wide safety margin: taking into account lower arterial oxygen partial pressures in elderly or chronically ill persons we reviewed exposures corresponding to approximately 10% oxygen in normobaric atmospheres, or 6,000-m altitude); (2) objectives of the studies relevant to our research questions; (3) comparability with respect to co-exposure (i.e., temperature); (4) published in English, German or French. Screening resulted in 256 articles for review. Criteria for inclusion in the review In answering our first question ( physiological effects ) articles selected from textbooks were accepted provided that, by comparison with other textbooks and with the original research, the findings were indisputable. For questions 2 4, we independently selected original studies that fulfilled the following criteria: (1) focused on relevant questions of performance or health; (2) appropriate methods; (3) valid measurement and description of the major exposure (oxygen concentration); (4) measurement, description and control of co-exposures (e.g., strenuous physical work); (5) well-defined outcome measures, accurate assessment, appropriate time for follow-up; (6) validity of interpretation. In cases of disagreement between the reviewers the decision was made after discussion. Eventually, 72 original papers were included in the review. Synthesis The heterogeneity of the included research with respect to subjects, methods, and situations studied, did not allow a systematic review. We thus performed a critical review by weighting the evidence according to the validity of the results of the original research, the relevance for the situation at the workplace, and the heterogeneity of the conclusions among studies. All articles pertaining to this review s central questions (see above) are reported and discussed. Physical and physiological background The ambient air is composed of 20.9% oxygen, 78.1% nitrogen, 0.03% carbon dioxide and less than 2% other gases. In a mixture of gases, according to Dalton s law, the partial pressure of a gas equals the product of its fractional concentration and the absolute pressure. At sea level, with a normal barometric pressure of 760 mmhg (=101.3 kpa) and a dry atmosphere, oxygen has a partial pressure of 160 mmhg (=21.2 kpa). At an altitude of approximately 2,700 m, with a mean barometric pressure of 72.8 kpa, the partial pressure of oxygen is 15.2 kpa. Oxygen also has this partial pressure when the oxygen fraction is 15% and the barometric pressure is kpa. Further examples of corresponding oxygen partial pressures under normobaric hypoxic and hypobaric normoxic conditions are listed in Table 1. The oxygen partial pressure resulting from LO concentration combined with low barometric pressure can be easily calculated according to Dalton s law, e.g., at 1,000 m, where the barometric pressure is 89.9 kpa, an oxygen concentration of 13% equals an oxygen partial pressure of 11.7 kpa, which corresponds to the oxygen partial pressure at an altitude of 4,750 m, where the oxygen concentration is 20.9%. Table 1 Examples of corresponding oxygen partial pressures under normobaric hypoxic and hypobaric normoxic conditions Concentration of oxygen at kpa barometric pressure (%) Corresponding partial pressure of oxygen (kpa) , , , , , , ,450 Approximate altitude corresponding to the partial pressure of oxygen (m)

3 89 The partial pressure of oxygen but not its mixing ratio (the critical measure for fire extinction) with other gases is critical for pulmonary gas exchange. During passage through the airways, air is saturated with steam, which contributes another 47 mmhg (6.27 kpa) partial pressure and thus reduces the partial pressure of oxygen to 150 mmhg (19.87 kpa). In the alveoli, the inhaled air mixes with the expiratory air, which has an oxygen partial pressure that is reduced to 40 mmhg (5.33 kpa), thus resulting in an oxygen partial pressure of approximately 100 mmhg (13.33 kpa). In a healthy young person, the oxygen partial pressures in the alveoli and blood are almost identical. Yet, since pulmonary shunts (parts of the pulmonary circulation that have no contact with ventilated alveoli) contribute venous blood to the arterial circulation, the resulting oxygen partial pressure in arterial blood is approximately 95 mmhg (=12.64 kpa). In the blood, oxygen is bound and carried by hemoglobin, which is found almost entirely in erythrocytes. Blood transport of oxygen to the tissues depends on the circulation. Gas exchange in the tissues depends on differences in partial pressures: oxygen is released from hemoglobin when its partial pressure in the blood is lowered due to oxygen consumption in the tissues. The complex system of oxygen supply can be disturbed by many disorders of the respiratory system, the circulation, and the blood. They will be discussed in detail later. Physiological response to acute and prolonged hypoxia A fall in oxygen partial pressure stimulates an immediate increase in ventilation and in heart rate. The peripheral chemoreceptors, i.e., carotid and aortic bodies, are primarily sensitive to hypoxia but also respond to changes in carbon dioxide and ph. Although ventilation increases within the first minutes, it increases further during the first days of hypoxia, due to stimulation of the hypoxic ventilatory response (HVR) and the hypercapnic ventilatory response (HCVR). The HVR is defined as increase in ventilatory rate in response to a lower partial pressure of arterial oxygen (PaO 2 ). It becomes even stronger after several days at a high altitude. The relationship between ventilatory rate and partial pressure of oxygen can be described by a hyperbolic curve : the ventilatory rate per decrease in arterial oxygen partial pressure changes minimally up to an altitude of 3,000 m, above which it increases rapidly. There are considerable individual differences in HVR [88]. Parallel to HVR, the HCVR also increases during the initial exposure to LO (days to weeks) resulting in very low arterial carbon dioxide partial pressures (PaCO 2 ) at extreme altitudes [88]. Similarly, several changes in the cardiovascular system also occur within minutes, mediated by a stimulation of the carotid body and subsequent sympathetic activation. Epinephrine increases transiently, whereas the increase in norepinephrine is more sustained. With acute hypoxia, heart rate and, thereby, cardiac output, increase for a given workload, but return to normal values after full acclimatization. Stroke volume is initially unchanged and later reduced, possibly due to a decrease in plasma volume. Myocardial contractility is preserved. Initially, blood pressure is slightly decreased, due to hypoxemia-induced vasodilatation but soon returns to normal or slightly elevated levels [88]. Low alveolar oxygen partial pressure promotes pulmonary vasoconstriction, which increases pulmonary vascular resistance and leads to pulmonary hypertension. Although this is usually well tolerated, high-altitude pulmonary edema (HAPE) may develop in some healthy individuals, and right heart failure may occur in patients with pulmonary disease [88]. Conversely, blood flow increases in the coronary arteries [34, 46]. In the cerebral circulation, hypoxia promotes vasodilatation and thus increases cerebral blood flow [76], especially in the hypothalamic region [8]. However, this effect may be mitigated by the vasoconstrictory influence of hypocapnia [76]. Several hormones are affected by hypobaric hypoxia: corticosteroids increase, the adrenosympathetic system is stimulated in the first days, and thyroid function is enhanced. These hormones result in an increased metabolism. Furthermore, plasma endothelin levels are raised by hypoxia, which may be detrimental to patients with heart failure [88]. A lower alveolar oxygen partial pressure diminishes the difference to the venous oxygen partial pressure and hence the driving force for oxygen diffusion. In addition, shorter capillary transit time due to increased cardiac output and exaggerated ventilation/perfusion mismatch also impair oxygen diffusion. Thus, overall, impaired oxygen diffusion is the factor that limits performance [77]. In healthy persons, this applies equally to normobaric hypoxia and hypobaric hypoxia [39]. Maximum heart rate and oxygen uptake with exercise are lower than at normal oxygen concentrations. Another early response to acute hypoxia is reduction of plasma volume. Thus, the number of red cells per unit volume is rapidly increased. This process continues for several weeks. Erythropoietin is also released almost immediately, but weeks to months pass until a new steady state of red cell production by the bone marrow is reached. The concentration of 2,3-diphosphoglycerate starts to increase in the red blood cells within the first hours of hypoxia and reduces the binding of oxygen to hemoglobin [88]. However, this effect is overridden by increased binding due to a low PaCO 2, with subsequent alkalosis. The net effect is a shift of the oxygen dissociation curve to the left, i.e., increased oxygen affinity [88]. The hematological effects of intermittent normobaric hypoxia are comparable to those occurring with hypobaric hypoxia as described above [66]. High-altitude illness After rapid accent to high altitude, i.e., ascent without acclimatization, an individual can develop acute

4 90 high-altitude illness (HAI). This includes acute mountain sickness (AMS), a frequently occurring syndrome of transitory symptoms, high-altitude cerebral edema and high-altitude pulmonary edema, two infrequent but potentially life-threatening conditions. AMS is characterized by a typical combination of unspecific symptoms in a specific setting. According to the Lake Louise Consensus Group it is defined as the presence of headache in an unacclimatized person who has recently arrived at an altitude of (usually) more than 2,500 m, plus the presence of one or more of the following symptoms: gastrointestinal symptoms (anorexia, nausea, or vomiting), insomnia, dizziness, and lassitude or fatigue [38, 68]. The Lake Louise Score grades the intensity of each symptom on a scale ranging from 0 (absent) to 3 (most severe). The score has been used in a variety of situations and proven to be valid in both field and experimental settings [75]. Complications: although AMS is usually self-limited, it may progress to high-altitude cerebral edema. This is an advanced state of AMS that is diagnosed if ataxia and/or impaired consciousness is present in a person suffering from AMS or acute high-altitude pulmonary edema [38]. High-altitude cerebral edema may lead to death within hours if untreated, i.e., if the person is not treated with a higher oxygen partial pressure. High-altitude pulmonary edema is closely related to the two cerebral syndromes but may also occur by itself, presenting as dry cough, dyspnea, tachypnea, and decreased performance. As for cerebral edema, a rapid increase in oxygen pressure is life saving [38]. Pathophysiologically, hypoxia leads to neurohumoral and hemodynamic responses that result in excess microvascular perfusion, elevated hydrostatic capillary pressure, capillary leakage, and edema. However, the exact mechanisms have been only partly elucidated [38]. Working in LO conditions raises the following questions: does normobaric hypoxia provoke HAI to the same extent as hypobaric hypoxia? What reduction in the partial pressure of oxygen leads to complaints, and with what frequency? How soon after exposure might symptoms be expected? What preventive measures can be taken? Incidence, risk factors, time course, prevention: to examine the relative contribution of prolonged hypoxia and low barometric pressure at high altitude to the symptoms of AMS, researchers exposed a group of nine men to simulated altitude, normobaric hypoxia, and normoxic hypobaria in a blind experiment. All subjects completed three different 9-h exposures: a simulated altitude of 4,564 m (barometric pressure 57.6 kpa, resulting in an oxygen partial pressure of 10.7 kpa); normobaric hypoxia (10.7-kPa oxygen partial pressure) achieved by adding nitrogen; and normoxic hypobaria (57.6 kpa barometric pressure) achieved by adding oxygen. Lake Louise AMS score (mean of rating at 6-h and 9-h exposure) were 3.7±0.8, 2.0±0.8, and 0.4±0.2 for hypobaric hypoxia, normobaric hypoxia and hypobaric normoxia, respectively. After 6 h of exposure five, two, and none of the subjects, respectively, developed AMS in the three settings. This indicates a lower risk for AMS in normobaric hypoxia than in hypobaric hypoxia [70]. However, in an experiment simulating the normobaric hypoxia as found in submarines, using 13% oxygen (but not 17%), provoked AMS in five of 12 young men; however, not all complaints occurred during the first hours but during the first day of exposure [49]. Larger field studies investigated AMS incidence in people who rapidly ascended to altitudes, providing barometric pressures comparable to those found in fireprevention settings. Even at altitudes as low as 2,000 m, 25% of participants in seminars had at least mild forms of AMS, compared with 5% at sea level [59]. In conferences held in various resorts in the Rocky Mountains at altitudes between 1,920 and 2,956 m, 25% of participants reported at least three symptoms of AMS; 56% of participants reported impaired physical activity and 58% took pain medication, with headache being the most frequent symptom [42]. In another meeting in the same region, at almost 3,000 m, the incidence of AMS was 41% [16]. Above 4,000 m the incidence may increase to well over 50% [23, 25, 37]. Factors that increase the risk of AMS are residence at a low altitude, a previous episode of AMS, age below 60 years, a self-reported moderate or bad state of health, and pulmonary diseases [42]. Moderate exercise also considerably increases the risk [71]. High-altitude cerebral and pulmonary edema were not observed in these studies. At an altitude of 3,750 m, the incidence of pulmonary edema after rapid ascent was calculated to be 0.6% per ascent, from the summation of 1,157 ascents made by 79 persons [44]. Personnel at an observatory at 4,200 m, who commuted daily or weekly from sea level, developed cerebral and pulmonary edema with an incidence of 0.03% and 0.03%, respectively. Whether people exposed to normobaric hypoxia are at a similar risk has not been studied. The onset of symptoms after a rapid ascent or instant exposure in a chamber is typically expected within 6 10 h, but may occur after just 1 h [16, 25, 38]. Other studies with different main endpoints have also reported that some symptoms developed within the first hours [87]. Most reports agree that the first symptom occurs during the first 12 ( 24) h [42, 49, 59] and the maximum intensity is usually reached within h [24]. For example, one of the largest studies investigating AMS in work-related exposure compared commuters who drove every day from sea level to 4,200 m in order to work in an astronomical observatory with shift workers who stayed on the summit for 5 days. After 5 h on the mountain only 40% were free of symptoms, 35% experienced breathlessness, and 25% suffered from headaches. Shiftworkers suffered from similar symptoms on their 1st day, but from significantly fewer symptoms on their 5th day at altitude. Cerebral symptoms such as poor concentration, lethargy, and confusion, were reported by 10% [23]. No commuter had symptoms severe enough to require immediate descent [23]. Compared

5 91 with hypobaric hypoxia, the time course for AMS due to normobaric hypoxia seems to be similar. When exposed to 13% oxygen, 42% of the persons had AMS during the first day [49]. After 6 h of exposure to approximately 10.5% oxygen, 22% of the subjects fulfilled the criteria of AMS [70]. The most effective measure to prevent HAI is acclimatization, which means slow ascent to high altitudes. The avoidance of exertion is also recommended [38]. Oxygen, acetazolamide, and dexamethasone effectively prevent and treat AMS. Aspirin (three 320-mg tablets, one every 4 h, starting 1 h before rapid ascent to high altitudes) was effective in preventing headaches at 3,480 m [10]. In a fire-prevention setting, people are exposed only intermittently to LO concentrations, either during a full working day or part of it. Data on the association between intermittent hypoxia and HAI are sparse. As described above, commuting from sea level to an altitude of 4,200 m for 6 h per day does not provide enough acclimatization to prevent AMS [23, 24]. In conclusion, normobaric hypoxia in fire prevention (15 13% oxygen as defined above) may cause AMS in a considerable proportion of exposed people, the number being dependent on the oxygen concentration. Limitation of the time spent continuously in LO, to 6 h or fewer, seems to be the most effective preventative measure. As a time limit, 6 h is justified mainly by the abovecited experience with commuters whose working time at altitude (4,200 m) was limited to 6 h and who never had an experience of severe AMS [23]. For people suffering from headache during this general time frame, shorter exposure times are appropriate, which must be individually determined. There are no conclusive data on the incidence of AMS or the occurrence of isolated symptoms within the first 6 h of exposure. Furthermore, the timing of work breaks to avoid symptoms has not been assessed. Severe forms of HAI (cerebral or pulmonary edema) are expected to be extremely rare, even without the limiting of working time, and are easily prevented if the person leaves the room if severe symptoms arise. The most important individual predictor for AMS in a healthy person is AMS during previous exposure to LO partial pressures. Acclimatization is probably not feasible. General pharmacological prophylaxis, although effective, carries a high risk of side effects and therefore conflicts with ethical principles applicable to these circumstances. Brain function (mood, cognition, psychomotor function) and brain structure The effects of hypobaric and normobaric hypoxia, in natural or in experimental settings, on various functions of the central nervous system such as mood, mental performance, or neurological functioning, will be reviewed here briefly. Study populations, exposure conditions, study designs, and most importantly, outcome measures, vary highly between studies. Thus, it is difficult for a uniform conclusion to be drawn. For this reason, investigations must be discussed separately, in some detail. Altitudes of 4,000 m or below, or equivalent normobaric oxygen concentrations Cognitive and psychomotor performance: the effects of oxygen partial pressure at altitudes up to 4,000 m are mostly studied because of practical problems in commercial and military air traffic. In a comprehensive review, Ernsting [21] concluded in 1978 that the most clear-cut effect of mild hypoxia (i.e., altitudes of 1,500 4,000 m) on psychomotor and mental performance was a prolongation of the time necessary to learn a new task. He recommended that the hypoxia due to breathing air at an altitude of 8,000 ft (2,440 m) should not be accepted for aircrew engaged in air operations because of the very significant impairment of ability to respond to novel complex situations which it induces. Instead, he advocated an altitude of 1,829 m, leading to an alveolar oxygen partial pressure of 70 mmhg, as the maximum which should be accepted for operating aircrew during routine flight [21]. This conclusion was partly based on experiments performed by Denison et al. [17]. Subjects breathing air with an oxygen partial pressure of 17.7 kpa (or less), equivalent to an altitude of approximately 1,500 m, had a prolonged reaction time in a complex orientation task which they learned in hypoxia. In comparison, the group that learned the task in normoxia did not exhibit this impairment [17]. These results were corroborated by the findings of Crow and Kelman [13] and by two other groups. Since then several studies have attempted to replicate these findings. One experiment examined 150 men and women at various altitudes to investigate the hypothesis that mild hypoxia can impair performance of a novel task. Subjects 19 to 52 years of age were studied in groups at ground level and in simulated altitudes of 305, 2,440, 3,050, or 3,660 m, immediately after exposure and during the following 7 min. A logical reasoning task was performed by naive (untrained) subjects, and their ability to learn the task was measured. All groups improved as an effect of learning but there was no significant difference in the learning rate between any of the groups at higher altitudes compared with those at ground level. The only effect attributable to altitude was an increased overall error rate in the group tested at 3,660 m. Subjects at this altitude did not slow their work rate although they made more mistakes, which suggests that they did not realize that they were performing badly [33]. Other studies also failed to reproduce the results of Denison and his coworkers and demonstrated no effect of hypoxia on short-term memory [14], or spatial orientation [26]. In order to clear up these discrepancies, another large study also assessed the ability of naive subjects to learn new tasks when exposed to a range of mild acute hypoxic

6 92 conditions in an altitude chamber. It was investigated whether or not light exercise (27 W) that decreases arterial oxygen saturation also impairs performance [65]. The 144 subjects, years old, were randomized to 16 groups that were evenly divided among four simulated altitudes (1,525, 2,440, 3,050, and 3,660 m) to which the subjects were blind. At each altitude, two groups were studied while exercising, and while at rest. One group was examined first at ground level then at a higher altitude, and the other in the opposite order. There was no measurable decrement in the ability of naive subjects to learn the Manikin test (the spatial orientation task used by Denison et al. [17]), a logical reasoning task, and a serial choice reaction task at all altitudes tested [65]. Thus, in summary, more recent studies with a sophisticated design and larger numbers of subjects failed to reproduce the early findings that learning of new tasks is impaired at moderate altitudes. In a more global assessment, two experiments assessed the effect of prolonged normobaric hypoxia, simulating conditions found in a submarine. A group of men resided continuously for 15 days in a normobaric chamber containing successive oxygen concentrations of 21%, 17%, and 13%. Their performance of a mental arithmetic test at rest and while exercising at low and high workloads did not change when oxygen was reduced [50]. In similar field experiments, young male soldiers were exposed to different degrees of normobaric hypoxia (resulting in oxygen partial pressures of 13, 14, and 15 kpa) for several days with intermittent periods of normoxia. Performance in tests of spatial orientation, visual reaction time, parallel processing and motor skills, mostly improved as a result of learning, and in no test was performance or learning reduced [35]. However, there are several psychological experiments suggesting that hypoxia indeed impairs mood and certain cognitive and psychomotor functions at moderate altitudes. At a simulated altitude equivalent to 3,048 m, seven male and female subjects were observed for 6.5 h and tested immediately after the barometric pressure had been changed and every 2nd hour thereafter (4 time points in total). Performance decreased by 10 to 20% at one or more time points for arithmetic, reasoning, longand short-term memory, perceptual speed, and visual reaction time, when compared with performance at ground level. However, except for short-term memory, which deteriorated progressively, no relationship with the duration of hypoxia was detected. Some tests revealed large individual differences in the reaction to hypoxia [87]. As described above, at 3,660 m, the error rate but not the speed of work was affected in a logical reasoning task [33]. In a randomized, double-blind trial, a group of male subjects (18 31 years old) was exposed to rapid change in simulated altitudes of sea level, 2,135, and 3,660 m, each for approximately 100 min. Response times for a task that required rapid judgment concerning the orientation of visual stimuli were slower at both altitudes, and accuracy was lower at 3,660 m. Decrements in performance were independent of the test order, i.e., whether the test was learned initially at sea level or at a higher altitude [58]. In a parallel group design, 72 young male and female volunteers were evenly distributed to simulated altitudes of 610 and 3,800 m (and 4,575 m), where they remained for 90 min. Vigilance and recall of low memory load (two pieces of information) were not impaired but recall of high memory load (i.e., four pieces of information) deteriorated at both altitudes. It was concluded that at higher altitudes short-term memory concerning the recall of larger amounts of information is impaired [7]. Mood: the concept live high train low of training athletes was assessed in subjects exposed to intermittent normobaric hypoxia corresponding to altitudes of 2,000 or 2,700 m for 12 h per day. No effect on the profile of mood states was observed [66]. In a field experiment, 35 healthy male and female volunteers were transported to an initial altitude of 1,600 m and continued to 4,300 m. They were tested immediately after ascent and then twice daily (morning and evening), by the Clyde Mood Scale. At 1,600 m subjects were more sleepy on the day of arrival. At 4,300 m, marked changes in four of six mood factors occurred (for details see below) [5, 81]. Above 4000-m altitude or equivalent normobaric oxygen concentrations There is a consensus that at extreme altitudes such as those reached by mountaineers, brain function may be impaired to an extent that can be detected even without a psychological test battery. This impairment has been summarized as thought processes are slowed, but accurate procedures can be carried out if one concentrates hard enough (p.194 [88]). Some of the more recent evidence on the effect of hypoxia on cerebral function as induced by oxygen partial pressures far below those required for fire protection will be reviewed briefly for the following reasons: (1) most of the studies at altitudes below 4,000 m involved young healthy subjects. Gas exchange decreases physiologically with age and may decrease rapidly with any pulmonary disease, even if only a few symptoms are present. Thus, people working in fire-protected rooms (usually between years of age) may have much lower Pa0 2 values, corresponding to higher or highest altitudes. (2) As mentioned above, at lower partial pressures of alveolar oxygen, arterial oxygen partial pressure may further decrease with exercise. Since most studies involved either no exercise or only mild exercise, an oxygen partial pressure equivalent to extreme altitudes may be present if strenuous work is performed. Extensive practical experience originates from the individual s assessment of problems associated with working in observatories. In the above-mentioned observatory at 4,200 m on Mouna Kea, Hawaii, some employees commute daily by vehicle from sea level. These employees must perform complex mental tasks. During 44 day visits, 19 commuters (men and women,

7 93 mean age 35.5 years) were assessed by psychometric tests. Whereas the Wechsler digit span forwards test was unaffected, the digit span backwards test (numerate memory) and the digit symbol substitution test (combination of motor speed and recoding of information) were mildly impaired at altitude [23]. In another study, army volunteers were flown from sea level to a laboratory at 4,300 m for a stay of 6 days. Two of five measures of cognitive performance deteriorated at this altitude: computer interaction and mental addition, but not coding, pattern comparison, or tower of Hanoi (the latter requiring spatial skills and logical reasoning). An increase in depression and anxiety as measured on the Clyde Mood Scale and the Multiple Affect Adjective Check List was noticed on their first day at 4,300 m [45]. Healthy male army volunteers were tested for the immediate and prolonged effects of a simulated altitude of 4,300 m for 2.5 days on a comprehensive cognitive assessment battery. During the first 8 h at the higher altitude, subjects performed worse on three of nine cognitive tasks representing aspects of memory, grammatical reasoning, and susceptibility to interference (Stroop test). However, subjects not afflicted by AMS showed little cognitive impairment [15]. Unexpectedly, in a group of 17 non-acclimatized mountaineers who ascended to 4,559 m within 24 h, short-term memory deteriorated but performance in conceptual tasks improved when AMS developed. In healthy subjects, memory improved but cognitive flexibility did not change [67]. It was demonstrated that a relatively small increase in hypoxia had a marked effect on symptoms and performance of male subjects who underwent testing in simulated altitudes of 500 (control), 4,200, and 4,700 m during 4.5-h exposures. An environmentalsymptom questionnaire especially assessing symptoms of AMS, the Profile of Mood states, the Clyde Mood Scale, and the Multiple Affect Adjective Checklist to assess moods, and ten additional tasks measuring a variety of cognitive and motor functions, were administered within 60 to 265 min after the onset of exposure. At 4,200 m, 11% of symptom factors, 25% of mood factors and 40% of performance measures deteriorated. At 4,700 m, deterioration occurred in 78% of symptom factors, 75% of mood factors and 70% of performance measures. If tests were repeated during the 4.5 h, no difference was found between the time points [82]. The nature of poorer performance in a visual serial choice response time task was examined in an experimental study. LO concentration simulating the oxygen partial pressure at 4,700 m resulted in a disruption of the task s components reaction time and movement time [27]. An 8-h experiment exposed subjects to a simulated altitude of 4,500 m to examine the processes occurring when a person begins a visual task (early visual process) slowed by hypoxia. Neither an effect of acute (1 h) nor of prolonged (7 h) hypoxia was observed on the parallel/ pre-attentional processes. In contrast, slowed search rates in prolonged hypoxia were observed, indicating impairment of serial/attentional processes [85]. Few research projects have systematically investigated the effect of altitudes above 5,000 m on brain function and structure: A group of trekkers was examined before, during, and after an actual ascent to 5,100 m in Nepal. Upper-limb psychomotor function, as tested by a nine-hole pegboard test, deteriorated (i.e., became slower) at this altitude but recovered after return to sea level. The change was most pronounced in subjects older than 50 years, within the first 24 h after arrival, and in subjects that experienced symptoms of AMS [84]. Professional divers were familiarized to hypoxia by breathing normobaric gas mixtures with LO and high nitrogen concentrations, i.e., 7.85 to 6.2% oxygen. Under these extreme conditions, performance on a twodimensional tracking task decreased [74]. Several studies indicate that acclimatization by continuous exposure to LO for several days or weeks prevents many of the brain function changes observed in unacclimatized persons: A small group of 21 to 31-yearold healthy volunteers lived in a decompression chamber for 40 days, during which time a simulated altitude of 8,845 m was gradually reached. Cognitive function was tested up to 7,630 m, usually 0.5 to 2.5 days after a new altitude had been simulated. This slow acclimatization process resulted in impairment, but only at relatively high altitudes: short-term memory scan rate at or above 7,020 m, pattern-recognition form at or above 5,490 m, and grammatical reasoning at or above 7,020 m. Code substitution and manual dexterity were never impaired. Interestingly, pattern comparison was impaired in all eight subjects at 7,625 m [47]. In a similarly comprehensive, more recent experiment ( Everest-Comex 97 ), eight climbers were acclimatized at actual altitudes and then decompressed in a chamber over 30 days to the altitude of 8,848 m. Psychological testing was performed in climbers at different stages of ascent and in controls at the same time at sea level but under similar conditions. Psychomotor ability (pegboard test) and mental efficiency (number ordination = Rey s test) became worse in climbers above 5,500 and 6,500 m, respectively. Reaction time did not differ between groups. Surprisingly, neither the presence of AMS symptoms nor the individual oxygen saturation correlated with the scores in psychological tests [1]. Direct comparison of acclimatized mountaineers with unacclimatized volunteers at rapidly simulated altitude levels of 450, 2,000, 4,000, and 6,000 m revealed neurobehavioral impairment. The ability to subtract a given number from 1,000 as many times as possible was impaired in volunteers at 6,000 m, but not in mountaineers [51]. No effect was observed in a small group of mountaineers acclimatized by intermittent simulation of 5,000 m of altitude that was rapidly increased within 5 days to 7,000 m. Apart from a transient increase of error rate at 6,500 m, no impairment was observed in a choice reaction time task (Manikin test) [54]. Only a few studies have used appropriate methodology to examine whether exposure to extremely low environmental oxygen pressures causes permanent

8 94 neurological impairment. In a series of studies, mountaineers who ascended to altitudes of between 5,488 and 8,848 m and subjects who participated in a simulated ascent to 8,848 m over 40 days were examined before and after the exposure. Visual long-term memory, verbal long-term memory and performance in an aphasia test deteriorated [43]. In a group of climbers, clinical history, neurological examination, and magnetic resonance imaging (MRI) of the brain were done before and after an ascent to above 7,500 m. Although no neurological dysfunction could be detected, two climbers who had experienced severe neurological symptoms during the climb (due to AMS), showed new lesions on MRI [30]. This confirmed earlier observations that 46% of 26 climbers had MRI abnormalities after ascending to over 7,000 m without oxygen compared to no abnormalities in 21 controls [29]. In contrast, a more recent study observed no changes in brain MRI and neuropsychological tests in climbers after they had ascended to over 6,000 m compared with before the ascent [4]. At least three studies detected an impaired postural stability by a sensitive measuring system in altitudes between 2,438 and 5,486 m. These changes were small, no falls occurred, and subjects did not experience vertigo [28, 41, 64]. In conclusion, with oxygen partial pressures at real or simulated altitudes of more than 4,000 m or with corresponding oxygen partial pressures if oxygen concentrations are less than 13% at sea level, several cognitive and neurophysiological functions are impaired and mood is altered. The severity of impairment increases with decreasing partial pressure. Intermittent hypoxia does not seem to provide protective acclimatization, whereas acclimatization by continuous hypoxia evidently prevents or delays dysfunction. Healthy persons working in LO for fire prevention are exposed to higher oxygen concentrations, and these extreme conditions do usually not apply unless strenuous physical work is performed. However, persons with hypoxemia due to one of the diseases discussed below may be exposed to a situation where brain oxygen supply is decreased to levels comparable to those in healthy persons at extreme altitudes. Exposure to extremely low oxygen partial pressures may cause structural brain damage, but the findings are somewhat conflicting. Below 4,000 m, and thus at oxygen concentrations of 15 13%, the situation is less clear. Some investigators found mild or transitory impairment of cognitive functions while others demonstrated no effect. However, reaction time may be slowed, and, subsequently, accuracy may be decreased. Demanding memory functions and performance of any complex cognitive task may also be impaired. Discrepancies within and between studies suggest a high individual variability. Some cognitive decline seems to occur only in persons who experience symptoms of AMS, suggesting that such persons need special care if high performance is required. However, the practical significance of the described changes in performance remains unclear. Overall, severe, overt malfunctioning is very unlikely. Pilots are allowed to fly airplanes despite mild hypoxia. Thus, in fire-protection environments, the oxygen level (15, 14, 13%?) and the risk emerging from a less-than-optimal performance of a task (e.g., driving a vehicle in a hypoxic environment) determine whether an appropriate screening test to detect a deficiency relevant to a specific work situation should be performed. For standard working operations, the monitoring of AMS symptoms is probably sufficient. Individuals with pre-existing diseases Oxygen delivery to the cell involves a cascade of physiological systems mainly involving the respiratory system, heart, circulation, and red blood cells. Any condition that impairs oxygen transport or delivery to target tissues may have an enhanced effect if the oxygen concentration in the ambient air is low. This may potentially decrease blood oxygen partial pressure to below a critical level. Conversely, hypoxia elicits compensatory mechanisms that may aggravate a pre-existing disease. Thus, in chronic heart failure, hypoxia further increases sympathetic activation. All relevant medical conditions that do not interfere with normal work but that might cause problems while an individual is working in LO are discussed below. Cardiovascular diseases Coronary artery disease (CAD): In stable CAD, blood flow, and thus oxygen supply, is usually sufficient for the resting myocardium but may be insufficient if the demand is increased by exercise, high blood pressure, emotional arousal, or hypoxemia. Irrespective of whether insufficient oxygenation is due to narrowed arteries, deficiency of oxygen in the blood, or both, the result may be decreased myocardial contractility, arrhythmia, or angina. Several small studies investigated the effect of acute, short-term exposure to LO in CAD patients. To our knowledge, no epidemiological or clinical studies with optimal methodology exist that address the question as to whether patients with CAD exposed to LO are at risk for acute coronary events, such as myocardial infarction. However, several observational studies described below allow an estimation to be made of the risk. Nine men with CAD were evaluated by symptomlimited treadmill tests on two separate occasions in a laboratory at 1,600 and 3,100 m. Heart rate and systolic pressure at sub-maximal workloads were increased at 3,100 m. Angina and/or ST-segment depression occurred at the same product of heart rate and systolic pressure, but at lower workloads. From this study it was

9 95 concluded that a heart rate ranging between 70 85% of the rate that would result in ischemia at a lower altitude best predicts a tolerable exercise level at higher altitudes [60]. Thus, higher altitude seems to impose a similar strain on physical performance, but at lower workloads. This is supported by a more recent study in which younger subjects were tested at sea level and after ascent to 2,700 and 3,700 m. Whereas resting heart rate and mean blood pressure did not differ, the product of heart rate and blood pressure was increased by exercise more at higher altitudes than at sea level (up to double at 3,700 m) [63]. Another experimental study examined 20 elderly persons (68±3 years) at sea level and at a simulated altitude of 2,500 m. Seven subjects had CAD and ten were at high risk for CAD. During exercise testing at 2,500 m, the ischemic threshold decreased by 5% and additional signs of exercise-induced ischemia were observed in three persons. No subject was symptomatic, and no additional high-grade arrhythmias arose; however, single premature ventricular complexes increased by 63% [55]. Similarly, in 17 men with documented CAD, exercise time until ischemia developed was acutely reduced by 11% in normobaric hypoxia (16% oxygen) corresponding to approximately 2,100-m altitude; however, there was no resting angina [48]. In a recent study, patients with CAD and a low ejection fraction (mean 39%) exercised at 1,000 and 2,500 m actual altitude in parallel with a group of healthy controls. Most patients were on state-of-the-art medication. Exercise capacity decreased significantly in both groups but oxygen saturation at rest and during exercise remained unchanged. There were no complications or signs of ischemia [20]. Chronic heart failure: is characterized by high circulating catecholamine levels, high endothelin levels, increased transcapillary permeability in the lung, poor skeletal muscle metabolism, high oxygen extraction in the periphery, and poor pulmonary function [56, 78]. Altitude may adversely influence any of these factors and thus provoke deterioration of the disease [53]. Yet, one study exposed patients who had stable heart failure due to primary cardiomyopathy or ischemic heart disease, and normal to markedly diminished workload, to reduced oxygen concentrations corresponding to the oxygen partial pressures at altitudes of 92, 1,000, 1,500, 2,000, and 3,000 m. The peak work rate decreased with decreasing oxygen concentrations, and the relative decrease was most marked among those subjects with the lowest performance at baseline. However, no exerciseinduced severe arrhythmia, angina, or any other adverse coronary event occurred [2]. In the above-described study of patients with CAD and moderately impaired left ventricular function, acute hypoxia was also well tolerated [20]. Other heart diseases: patients with congenital heart disease and pulmonary hypertension may decompensate if pulmonary artery pressure further increases in response to hypoxia. Nevertheless, simulated and actual altitudes up to 2,438 m were well tolerated by a small group of patients with cyanotic congenital heart disease and preserved ventricular function [40]. For patients with pacemakers, an early study reported a transient mild increase in pacemaker threshold. In a more recent investigation, simulated altitudes between 450 and 4,000 m did not change stimulation threshold [89]. Acute coronary syndromes: indirect evidence for the risk of myocardial infarction, sudden cardiac death, or other acute complications of CAD comes from epidemiological studies. One study examined 97 elderly persons, of whom 20% had CAD, during a 5-day sojourn at 2,500-m altitude. Approximately one-fifth experienced some palpitations and one-tenth unspecific chest pain. No significant ECG changes were observed, and no therapy was required [69]. A retrospective study of all helicopter evacuations and deaths among trekkers reviewed a total of 148,000 persons with trekking permits in Nepal between 1 Jan 1984, and 30 June Of these trekking tourists, 20% were over 50 years old. Cardiac illness accounted for 5% of 111 helicopter rescues, and no deaths [80]. Conversely, in Austria, mountain hiking was associated with a 4.1-fold risk, and skiing with a 2.1-fold risk, of sudden cardiac death, as compared with the overall risk [9]. Finally, of the observatory personnel at 4,200 m on Mauna Kea in Hawaii, only one smoker experienced a myocardial infarction over a 10-year period, compared with an average of 60 employees per day [24]. In conclusion, from a pathophysiological point of view, patients with heart disease would be expected to be at markedly increased risk when exposed to hypoxia, but experimental studies indicate that this risk is surprisingly low. Yet, physical performance deteriorates with altitude, especially in those persons with the most severe heart dysfunctions. However, these studies are limited by small subject numbers, patient selection, experimental design lacking real-life stress, and, especially, by the short duration of exposure. To our knowledge, prospective epidemiological studies of people with heart disease or people at risk have not been conducted. Thus, in hypoxic conditions, the risk for deterioration of the disease, such as acute coronary syndrome, life-threatening arrhythmia, or cardiac decompensation, cannot be completely excluded; however, published data do not support such a risk. Certainly, the strain on the cardiocirculatory system is greatest within the first hours of exposure, since most adaptive mechanisms return to baseline as acclimatization progresses. Special precautions must therefore be taken for people entering an LO atmosphere for the first time. Occupational safety and health require that persons with known or suspected heart disease, who have symptoms during their usual daily activities, undergo exercise testing by an experienced physician and receive optimal treatment. If typical signs of the disease still occur in spite of treatment (e.g., signs of ischemia, cardiac decompensation, arrhythmia) this person should not be exposed to LO. The American Heart Association and the American College of Physicians recommend air travel only 2 to 3 weeks after a myocardial infarction, and thus this is the earliest time at which an LO atmosphere should be entered [73].

10 96 Pulmonary diseases Hypoxemia is a hallmark of many pulmonary disorders. Severe hypoxemia adversely influences the outcome of pulmonary disease, whereas permanent supplementation of oxygen improves survival. Therefore, the American Thoracic Society and the European Respiratory Society recommend long-term oxygen therapy if oxygen partial pressure at rest is equal to or below 55 mmhg [3, 83]. As noted above, arterial oxygen partial pressure decreases with decreasing ambient oxygen partial pressure. In healthy individuals at high altitudes, maintenance of sufficient blood oxygen is limited by maximum air flow, respiratory muscle fatigue, energy expenditure of the respiratory muscles, and diffusion limitation [77]. These factors aggravate hypoxemia during exercise at high altitudes [77]. Most pulmonary diseases are expected to deteriorate in hypoxic conditions. Short-term hypoxemia results in dyspnea, decrease in physical performance, and impaired organ function, with the brain being most sensitive to hypoxia. Long-term hypoxemia may worsen the prognosis of patients with pulmonary disorders [11]. Several small short-term studies have examined the effects of normobaric hypoxia, hypobaric hypoxia (simulated altitude), and actual altitude, on hypoxemia and symptoms of pulmonary diseases. The following are examples of changes in arterial oxygen partial pressure, all in patients with chronic obstructive pulmonary disease (COPD). In an airplane, mean PaO 2 decreased from 68 mmhg at ground level to 51 mmhg at 1,650 m and to 45 mmhg at 2,250 m [79]; after ascent to 1,950 m, mean PaO 2 decreased from 66 to 52 mmhg [32]. At a simulated altitude of 2,500 m, mean PaO 2 dropped from 68 to 53 mmhg [57], whereas at a simulated altitude of 2,450 m, mean PaO 2 dropped from 72 to 47 mmhg [19]. Normobaric and hypobaric hypoxia reduced PaO 2 in patients with COPD from 75.8 mmhg (at sea level) to 49.5 mmhg at 2,440 m while at rest, but to 38.6 mmhg during light exercise equal to walking through an airplane aisle at 2,440 m [61]. Similarly, in patients with cystic fibrosis, PaO 2 decreased from 79.5 mmhg at ground level to 60 mmhg at 2,000 m and 45.5 mmhg at 3,000-m simulated altitude [72]. As is obvious from these examples, PaO 2 during hypoxia can be estimated from PaO 2 during normoxia. A regression formula has been developed that allows estimation to be made of PaO 2 at altitudes between 1,520 and 3,050 m in patients with chronic obstructive lung disease (COLD): predicted PaO 2 = x y (x = expected altitude in thousands of feet; y = sea level PaO 2 in millimeters of mercury)[31]. A refined formula which includes simple lung-function values has been developed, and was tested for normobaric and hypobaric conditions: predicted PaO 2 =0.238 (PaO 2 at sea level, mmhg) (FEV 1 /FVC) [18]. This formula was reliable in both conditions and for healthy people and patients with COLD alike [18]. No severe complications were observed during the above-mentioned studies. In some cases dyspnea, headache and fatigue were reported [31]. In commercial long-distance flights, the median cabin pressure was found to be equivalent to 1,894-m altitude with transient drops in pressure equivalent to 2,717 m [12]. In order to avoid complications for patients traveling by plane, the American Thoracic Society and the European Respiratory Society recommend the provision of oxygen during the flight if the arterial oxygen tension at rest is expected to fall below 50 and 55 mmhg, respectively [3, 83]. An additional aspect of lung disease which has not been fully elucidated is the decline of mental function with severe hypoxemia. As described earlier, at altitudes above 4,000 m, marked impairment of brain function has been observed. However, patients with lung disease may become as hypoxemic at moderate altitudes as healthy people become only at extreme altitudes. This may be practically relevant if demanding work must be performed, such as driving a vehicle or making complex decisions. In conclusion, the same safety measures as recommended for travel should be applied for people who plan to work in a room with LO concentrations. In patients with known or suspected lung disease, especially COPD, we recommend the measuring of forced expiratory volume in 1 second (FEV 1 ), vital capacity, and blood gases at rest or with physical exercise as required at the work site, in order for arterial oxygenation at the workplace to be calculated. Patients expected to have a PaO 2 below 55 mm Hg should not work in LO atmospheres. Hematological disease Oxygen transport and delivery to the tissues critically depends on hemoglobin. Any disease that affects its quality or quantity will increase the hypoxemia resulting from hypoxia. Oxygen delivery can be calculated as follows: DO 2 =CO [(hb SaO )+( PaO 2 )] where DO 2 is delivery of oxygen, CO is cardiac output, hb is hemoglobin, SaO 2 is arterial oxygen saturation, and PaO 2 is arterial oxygen partial pressure. If red cell mass is decreased (anemia) and blood is exchanged for isovolumic fluid, normovolemic anemia results. In this situation the DO 2 below which the oxygen supply to the tissues becomes critical lies between 4.9 and 9.8 ml oxygen [36]. This formula helps one to estimate the oxygen delivery to the tissues for an anemic individual exposed to hypoxia. From a practical point of view, anemia should be treated to ensure that a person does not suffer from an increased strain when exposed to hypoxia. A special situation is sickle cell disease in which the abnormal hemoglobin changes its structure in hypoxemia and may lead to a sickle cell crisis [52, 86]. In conclusion, we recommend that patients with a disease that afflicts red blood cells see a physician who is competent in hematology in order for the potential risk

11 97 to be estimated and possibilities to lower or avoid it be determined. Discussion Sufficient evidence indicates that working in a confined space with normal barometric pressure, and 15% or 13% oxygen in the air will elicit physiological reactions similar to those of acute exposure to altitudes of 2,700 3,850 m. Up to half of the persons exposed to 13% oxygen may be at risk of AMS unless continuous exposure is limited, with 6 h being a reasonable threshold because AMS typically occurs beyond this time: This has been demonstrated in commuters who travel daily from sea level to a telescope at 4,200 m altitude [22]. Nevertheless, even within 6 h, the probability of isolated symptoms of AMS (especially headache) is high. People who suffer from headache within the first 6 h may need an individualized work schedule. We estimate the risk for severe complications of AMS, such as pulmonary and cerebral edema, as minimal, provided that people working in LO are properly informed and instructed to leave the environment when symptoms appear. Mild impairment of complex cerebral functions should be considered when one assesses occupational safety. Although numerous studies have been conducted, the question remains unsettled as to whether LO within the range discussed here results in a deterioration of mental performance that is relevant to the quality and safety of work. Individual factors such as age and impaired health, additional strain such as physical work, and the task itself, may critically influence the performance. Thus, a psychological or psychomotor test which imitates the real work situation with regard to oxygen concentration, task and further factors, may help to clarify whether an individual worker will be able to perform an intended task safely. Since most research was done in non-industrial environments there are no studies that address the effect of common exposure to LO and toxic inhalable chemicals. In the respective situations, techniques such as lung function monitoring may provide the necessary information. Cardiac, circulatory, and pulmonary diseases have been studied in LO environments and are discussed in the scientific literature. The recommendations of the respective medical associations with regard to air travel and stay at high altitude appear to have been safe in practice for a long time. However, the quality of the epidemiological studies is poor overall, and the available data do, at best, suggest that acute complications of these diseases do not occur more often at altitude than at sea level. Therefore, we recommend a restrictive selection of people who plan to enter LO environments despite having one of the above-mentioned diseases (see Appendix). Virtually, there are no data concerning the impact of LO on people with hyperthyroidism, diabetes, or neurological diseases such as epilepsy. The fact that meticulous search hardly leads to one case report may be interpreted as non-existence of the problem or conversely that it has been overlooked. We tend to the first interpretation, since millions of people have traveled and lived at high altitude for centuries, so that aggravation of the above-mentioned frequent diseases can be expected to have attracted attention. Nevertheless, we believe that close observation of these and similar diseases is imperative until we have more data available. In this review, we have not addressed the issue of pregnancy. Whereas studies in populations living at high altitude indicate no danger for mother and fetus, the data on the effect of short-term exposure to LO are limited. Commercial airlines permit air travel until the 30th gestation week and beyond. Cabin pressure may drop to an equivalent of 2,717 m [12], corresponding to 15% oxygen at sea level. The exposure to LO per se has been assessed to be safe down to this level [6, 62]. In summary, we strongly recommend that all people planning to enter a room with LO, independent of the exposure time, should undergo a medical examination before being exposed. Recommendations for a specific medical examination are given in the Appendix. People with heart, lung, or special hematological disorders, should contact a specialist, since the decision to work in LO atmospheres must be based on individual risk. Based on the available evidence with regard to occupational health and safety, fire protection by a permanently lowered oxygen concentration appears to be a safe technique if the precautions mentioned above are taken. The extra expenses due to the necessary medical surveillance may be worthwhile if the outbreak of fire and the risk of severe personal injury can thus be prevented. However, it must be noted that the evidence is limited, in particular with regard to workers performing strenuous mental or physical tasks, those co-exposed to noxious influences, and those with various diseases. Therefore, close monitoring of the health problems of people working in LO atmospheres is necessary. Further research is required that examines the effects of LO on health over the whole spectrum of persons exposed to normobaric hypoxia and in various work situations. Acknowledgements This work was partly supported by an unrestricted grant provided by Wagner Alarm- und Sicherheitssysteme GmbH, Langenhagen, Germany. Appendix: Preliminary guidelines for an occupational health screening and surveillance examination for persons working in atmospheres with reduced oxygen concentrations for the purpose of fire prevention Area of applicability Every individual who enters a room in which the oxygen concentration is reduced to 17% to 13% volume

12 98 should be medically examined so that pre-existing diseases which would lead to health risks with hypoxia can be ruled out. Types of examinations Initial examination Prior to working in an atmosphere with reduced oxygen concentration. Follow-up examinations While working in an atmosphere with reduced oxygen concentration. Post-exposure examinations Not applicable. Initial examination Screening Medical history General medical history, occupational history, and present medical complaints, should be determined. The history should then be taken in a structured format according to the questionnaire shown below. If one of the questions is answered with a yes, a supplementary examination should be performed. History (medical questions directed at the patient): Is there a family history of benign blood disease, inherited blood disease, low blood count, anemia, or sickle-cell disease? Did you experience any pains (with the exception of headaches), such as abdominal, chest, or joint pains during previous stays at high altitude (mountains) or during airplane flights? Have you ever felt sick with headaches, nausea, vomiting, shortness of breath or fatigue during previous stays at high altitudes (mountains) or during airplane flights? Do you have any known heart disease? Do you have any known lung or airway disease? Do you have anemia? Do you have sickle-cell disease? Have you ever had a stroke or a stroke that improved (transient ischemic attack), or are you aware of any narrowing of the blood vessels in the neck? Have you ever been treated for rhythm problems of the heart? Have you had any episodes of dizziness within the last 3 months which have prevented you from pursuing your normal daily activities? Have you ever been unconscious within the past year? Do you have to pause during your daily activities at work or at home because of shortness of breath? Do you have to pause to catch your breath while climbing a flight of stairs? Has your physical performance decreased within the past 3 months? Have you ever had any pain or pressure in your chest while under physical or mental stress? Have you had any chest pain within the past month while at rest? Have you woken up in the past 3 months because of shortness of breath? Examination taking into account the actual working conditions The physical examination should include at least the items described below; if a finding is not within the normal range, a supplementary examination should be performed. Physical examination (questions directed at the physician): Are there any pathological findings on examination of the respiratory tract or lungs, especially regarding: Breathing pattern. Respiratory frequency. Inspection/percussion/auscultation of the lungs. Are there any pathological findings on examination of the heart, circulation or arteries, especially regarding: Jugular venous pressure? Peripheral edema? Frequency and rhythm of the heart? Point of maximum impulse? Auscultation of the heart? Bruits in the carotid arteries? Blood pressure (greater than 200/110 or below 100/ 60 mmhg)? Special examination for the screening Resting EKG: pathological changes should lead to additional investigations. Complete blood count and peripheral blood smear: if erythrocyte indices reveal pathological changes supplementary investigations should be performed. Laboratory: Is the hemoglobin above or below the reference range of the specific laboratory? Is the erythrocyte morphology pathological?

13 99 Supplementary examination If the criteria of the screening are fulfilled (the examined individual answers the questions with a yes, or there is a pathological finding on physical examination or in the ECG or blood test) then a supplementary examination should be performed. This can be done by any physician who has the experience and technical equipment. At least one of the following must be performed if the examination indicates a cardiac, circulatory or pulmonary disorder, or if anemia is present. The suspected disease determines which of the following investigations should be performed: Exercise-ECG to determine cardiocirculatory performance and possibly to induce cardiac ischemia. Spirometry to determine the FEV 1. Arterial or capillary blood-gas analysis to calculate the expected PaO 2 in environments with reduced oxygen concentration (for formula for this calculation see Supplement 2). Duplex ultrasonography if stenosis of an artery that supplies the brain is suspected. Hemoglobin electrophoresis if sickle-cell disease is suspected. Occupational health criteria Ongoing medical concerns For individuals with: Coronary heart disease, hypertensive heart disease, cardiac valve disease with exercise-induced ischemia (e.g., stress- or exercise-induced angina pectoris, hypotension, typical EKG changes). Chronic heart failure that leads to dyspnea or physical limitations with daily or work-related tasks. A further indication is a workload of less than 75 W in total or 1.5 W per kg bodyweight. Respiratory tract and lung disease, chronic heart failure or anemia, who will have a PaO 2 of <55 mmhg under hypoxic conditions as calculated from their PaO 2 (see Supplement 2). Signs of high-altitude illness, especially AMS, when previously exposed to hypoxia (Lake Louise Score including the question regarding sleeping disturbance 3, see Supplement 1). Such individuals should have a trial exposure. If the real working conditions lead to AMS (Lake Louise Score without the question regarding sleeping disturbance 3), then there are ongoing medical concerns. Dizziness in the past 3 months that has affected daily activities. High-grade (>70%) stenosis of the common or internal carotid arteries. A stroke or a documented transient ischemic attack in the past. Such people should have a trial exposure. If symptoms such as dizziness, problems with concentration or confusion (or other neuropsychiatric symptoms) occur under these trial working conditions there should be ongoing medical concerns. Sickle-cell disease. If there has been no sickle-cell crisis in the past, then a trial exposure is possible for a heterozygous individual. Further health risks are present only if this leads to signs of a sickle-cell crisis or hemolysis. Temporary health concerns Persons with the diseases listed in the section Ongoing medical concerns, above, as long as improvements are expected either spontaneously or with adequate treatment. No health concerns if specific precautions are met Individuals with the diseases listed in the section Ongoing medical concerns, above, if a medical examination is performed directly after a trial exposure to the specific working conditions and no negative medical effects can be determined. No health concerns All other persons. Follow-up examinations Time intervals for follow-up examinations Initial follow-up examination Within the first 3 years if oxygen concentrations are 15 13% vol. Within the first 5 years if oxygen concentrations are >15 17% vol. Further follow-up examinations Within the first 3 years if oxygen concentrations are 15 13% vol. Within the first 5 years if oxygen concentrations are >15 17% vol. Earlier follow-up examinations Are at the physician s discretion and may be scheduled if they allow more precise assessment of the risk due to the exposure. If the initial supplementary examination revealed an illness that would be relevant when the person was exposed to hypoxia (especially cardiac or pulmonary disease and anemia) then follow-up examinations should be performed within 3 months. Scope of the follow-up examination In general, only a medical history which especially considers complaints arising during exposure, and a screening physical examination are required (similar to the initial screening). Further examinations to clarify possible complaints related to the working environment are at the physician s discretion. If the supplementary examination reveals a disease that could lead to occupational medicine problems, then follow-up examinations are required according to the conditions listed in

14 100 the Occupational health criteria section above. Occupational medicine criteria See Occupational health criteria above. Post-exposure examinations Not applicable. Supplement 1 Lake Louise consensus: scoring of AMS AMS self-assessment: the sum of the responses is the AMS self-report score. Headache and at least one other symptom must be present for the diagnosis of AMS. A score of 3 or more is taken as AMS. The question relating to sleep will not always be relevant, e.g., for assessing the effect of low oxygen concentration during a work shift. see [88]. Supplement 2 Estimation of arterial oxygen tension during work in environments with reduced oxygen concentration A regression formula has been developed to allow estimation of PaO 2 at altitudes between 1,520 and 3,050 m in patients with COLD: Predicted PaO 2 ¼ 22:8 2:74x þ 0:68y where x = expected altitude in thousands of feet; y = sea level PaO 2 in mmhg). Meter-to-feet conversion: m/ = feet [31]. Symptom Headache Gastrointestinal symptoms Fatigue and/or weakness Dizziness/light-headedness Difficulty sleeping Scoring 0 None at all 1 Mild headache 2 Moderate headache 3 Severe headache, incapacitating 0 Good appetite 1 Poor appetite or nausea 2 Moderate nausea or vomiting 3 Severe, incapacitating nausea and vomiting 0 None 1 Mild fatigue/weakness 2 Moderate fatigue/weakness 3 Severe fatigue/weakness 0 None 1 Mild 2 Moderate 3 Severe, incapacitating 0 Slept as well as usual 1 Did not sleep as well as usual 2 Woke many times, poor night s sleep 3 Could not sleep at all References 1. Abraini JH, Bouquet C, Joulia F, et al. (1998) Cognitive performance during a simulated climb of Mount Everest: implications for brain function and central adaptive processes under chronic hypoxic stress. Pflugers Arch 436: Agostoni P, Cattadori G, Guazzi M, et al. (2000) Effects of simulated altitude-induced hypoxia on exercise capacity in patients with chronic heart failure. Am J Med 109: American Thoracic Society (1995) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:S Anooshiravani M, Dumont L, Mardirosoff C, et al. (1999) Brain magnetic resonance imaging (MRI) and neurological changes after a single high altitude climb. Med Sci Sports Exerc 31: Banderet LE (1977) Self-rated moods of humans at 4300 m pretreated with placebo or acetazolamide plus staging. Aviat Space Environ Med 48: Barry M, Bia F (1989) Pregnancy and travel. JAMA 261: Bartholomew CJ, Jensen W, Petros TV, et al. (1999) The effect of moderate levels of simulated altitude on sustained cognitive performance. Int J Aviat Psychol 9: Buck A, Schirlo C, Jasinksy V, et al. (1998) Changes of cerebral blood flow during short-term exposure to normobaric hypoxia. J Cereb Blood Flow Metab 18: Burtscher M, Philadelphy M, Likar R (1993) Sudden cardiac death during mountain hiking and downhill skiing. N Engl J Med 329: Burtscher M, Likar R, Nachbauer W, et al. (1998) Aspirin for prophylaxis against headache at high altitudes: randomised, double blind, placebo controlled trial. BMJ 316: Cote TR, Stroup DF, Dwyer DM, et al. (1993) Chronic obstructive pulmonary disease mortality. A role for altitude. Chest 103: Cottrell JJ (1988) Altitude exposures during aircraft flight. Flying higher. Chest 93: Crow TJ, Kelman GG (1969) Psychological effects of mild hypoxia. J Physiol 204: Crow TJ, Kelman GR (1971) Effect of mild acute hypoxia on human short-term memory. Br J Anaesth 43: Crowley JS, Wesensten N, Kamimori G, et al. (1992) Effect of high terrestrial altitude and supplemental oxygen on human performance and mood. Aviat Space Environ Med 63: Dean AG, Yip R, Hoffmann RE (1990) High incidence of mild acute mountain sickness in conference attendees at 10,000 foot altitude. J Wilderness Med 1: Denison DM, Ledwith F, Poulton EC (1966) Complex reaction times at simulated cabin altitudes of 5,000 feet and 8,000 feet. Aerosp Med 37: Dillard TA, Moores LK, Bilello KL, et al. (1995) The preflight evaluation. A comparison of the hypoxia inhalation test with hypobaric exposure. Chest 107: Dillard TA, Rajagopal KR, Slivka WA, et al. (1998) Lung function during moderate hypobaric hypoxia in normal subjects and patients with chronic obstructive pulmonary disease. Aviat Space Environ Med 69: Erdmann J, Sun KT, Masar P, et al. (1998) Effects of exposure to altitude on men with coronary artery disease and impaired left ventricular function. Am J Cardiol 81: Ernsting J (1978) Prevention of hypoxia acceptable compromises. Aviat Space Environ Med 49: Forster P (1984) Reproducibility of individual response to exposure to high altitude. BMJ 289: Forster PJ (1985) Effect of different ascent profiles on performance at 4,200 m elevation. Aviat Space Environ Med 56: Forster PJG (2000) Working at high altitude. In: Baxter PJ, Adams PH, Aw T-C, Cockroft A, Harrington M (eds)

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