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Many of us think a lot about oxygen. This includes how the normal body handles oxygen in health, but particularly how this is complicated by lung disease. Few of us are aware that as human inhabitants of the earth, we have a unique privilege. This is that as air breathers, we and most other animals on Earth, are the only living creatures in the known universe that have unlimited supply of oxygen. This situation came about through one of the greatest miracles of nature, that is photosynthesis, the ability to release oxygen from water using the energy of sunlight. One consequence of this was that the first atmospheric oxygen came from the metabolism of microorganisms, the cyanobacteria, that used photosynthesis, but for which oxygen was an unwanted by-product. In fact, the oxygen had to be discarded for the organisms to thrive. When a major increase of oxygen concentration in the atmosphere occurred some 2 billion years ago, and the partial pressure of oxygen in the air rose to perhaps 200 mmHg, this Great Oxidation Event as it was called, was a death sentence for the large population of anaerobic animals for whom oxygen was toxic. Today much of the oxygen in the atmosphere comes from photosynthesis in microorganisms, including the cyanobacteria, and the recently discovered Prochlorococcus, that discard this unwanted by-product. The result is that the PO2 in our atmosphere at sea level remains nearly constant at about 150 mm Hg, although the factors responsible for this are not understood., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

As earthlings, we take the oxygen in the air that we breathe for granted. Few people realize that this easy access to oxygen makes us unique in the whole universe. Nowhere else in our planetary system or in distant stars has stable oxygen ever been detected. However, the present plentiful supply of oxygen in our atmosphere was not always there. Long after the Earth was formed some 4.5 billion years ago, the Po 2 in the atmosphere was near zero, and it remained so for millions of years. But about 2 billion years ago, the Po 2 dramatically increased to as high as 200 mmHg during the Great Oxygen Event, due to the activity of microorganisms, the cyanobacteria. Subsequently, the oxygen level fell to the intermediate values that we have today. Here, we also look to the future, for example, the next 50 years. This period will be special because it will include the beginnings of human space exploration, initially to the Moon and Mars. Neither of these has atmospheric oxygen. Nevertheless, plans to visit and live on both of these are developing rapidly. We consider the fascinating problems of how to ensure that sufficient oxygen will be available for the groups of people. Although it is interesting to discuss these issues now, we can expect that major advances will be made in the next few years.

When using a new noninvasive method for measuring the efficiency of pulmonary gas exchange, a key measurement is the oxygen deficit, defined as the difference between the end-tidal alveolar Po 2 and the calculated arterial Po 2 . The end-tidal Po 2 is measured using a rapid gas analyzer, and the arterial Po 2 is derived from pulse oximetry after allowing for the effect of the Pco 2 on the oxygen affinity of hemoglobin. In the present report we show that the values of end-tidal Po 2 and Pco 2 are highly reproducible, providing a solid foundation for the measurement of the oxygen deficit. We compare the oxygen deficit with the classical ideal alveolar-arterial Po 2 difference (A-aDO 2 ) as originally proposed by Riley, and now extensively used in clinical practice. This assumes Riley's criteria for ideal alveolar gas, namely no ventilation-perfusion inequality, the same Pco 2 as arterial blood, and the same respiratory exchange ratio as the whole lung. It transpires that, in normal subjects, the end-tidal Po 2 is essentially the same as the ideal value. This conclusion is consistent with the very small oxygen deficit that we have reported in young normal subjects, the significantly higher values seen in older normal subjects, and the much larger values in patients with lung disease. We conclude that this noninvasive measurement of the efficiency of pulmonary exchange is identical in many respects to that based on the ideal alveolar Po 2 , but that it is easier to obtain.

The oxygen deficit (OD) is the difference between the end-tidal alveolar Po 2 and the calculated Po 2 of arterial blood based on measured oxygen saturation that acts as a proxy for the alveolar-arterial Po 2 difference. Previous work has shown that the alveolar gas meter (AGM100) can measure pulmonary gas exchange, via the OD, in patients with a history of lung disease and in normal subjects breathing 12.5% O 2 . The present study measured how the OD varied at different values of inspired O 2 . Healthy subjects were split by age (young 22-31; n = 23; older 42-90; n = 13). Across all inspired O 2 levels (12.5, 15, 17.5, and 21%), the OD was higher in the older cohort 10.6 ± 1.0 mmHg compared with the young -0.4 ± 0.6 mmHg ( P < 0.0001, using repeated measures ANOVA), the difference being significant at all O 2 levels (all P < 0.0001). The OD difference between age groups and its variance was greater at higher O 2 values (age × O 2 interaction; P = 0.002). The decrease in OD with lower values of inspired O 2 in both cohorts is consistent with the increased accuracy of the calculated arterial Po 2 based on the O 2 -Hb dissociation curve and with the expected decrease in the alveolar-arterial Po 2 difference due to a lower arterial saturation. The persisting higher OD seen in older subjects, irrespective of the inspired O 2 , shows that the measurement of OD remains sensitive to mild gas exchange impairment, even when breathing 21% O 2 .

The efficiency of pulmonary gas exchange is often assessed by the ideal alveolar-arterial partial pressure difference (A-aDO 2 ). Through a combination of pulse oximetry and rapidly responding gas analyzers to measure the partial pressures of O 2 and CO 2 in expired gas, one can measure the oxygen deficit. Defined as the difference between the measured alveolar Po 2 and the arterial Po 2 calculated from S p O 2 , the oxygen deficit is a substitute for the alveolar-arterial Po 2 difference. The oxygen deficit is physiologically reasonable in that it increases with age in healthy subjects and is well correlated with the A-aDO 2 . To calculate arterial Po 2 from saturation, the saturation should be below the very flat upper part of the O 2 -Hb dissociation curve; good estimates can be made provided the arterial O 2 saturation is below ~95%. Since saturations at or above 95% imply reasonably well-maintained gas exchange efficiency, this limitation is of only minor concern. Calculations show that it is necessary to take into account the change in Po 2 at a saturation of 50% of the O 2 -Hb dissociation curve based on the measured alveolar Pco 2 . As the measurement is designed to be noninvasive, determination of any base excess is not practical, but calculations show that the effect of assuming a zero base excess is modest, with a similar small effect from an abnormal body temperature. Taken together, these results show that a noninvasive assessment of pulmonary gas exchange efficiency can be obtained from subjects with below-normal arterial O 2 saturations through a combination of expired O 2 and CO 2 measurements and S p O 2 made during quiet breathing. NEW & NOTEWORTHY The details and limitations of a noninvasive measurement of pulmonary gas exchange efficiency, the oxygen deficit, are described. The oxygen deficit, calculated from expired gas measurements made during quiet breathing coupled with pulse oximetry, is a good surrogate measurement of the ideal alveolar-arterial Po 2 difference and does not require arterial blood gas sampling.

A new noninvasive method was used to measure the impairment of pulmonary gas exchange in 34 patients with lung disease, and the results were compared with the traditional ideal alveolar-arterial Po 2 difference (AaDO 2 ) calculated from arterial blood gases. The end-tidal Po 2 was measured from the expired gas during steady-state breathing, the arterial Po 2 was derived from a pulse oximeter if the S p O 2 was 95% or less, which was the case for 23 patients. The difference between the end-tidal and the calculated Po 2 was defined as the oxygen deficit. Oxygen deficit was 42.7 mmHg (SE 4.0) in this group of patients, much higher than the means previously found in 20 young normal subjects measured under hypoxic conditions (2.0 mmHg, SE 0.8) and 11 older normal subjects (7.5 mmHg, SE 1.6) and emphasizes the sensitivity of the new method for detecting the presence of abnormal gas exchange. The oxygen deficit was correlated with AaDO 2 ( R 2 0.72). The arterial Po 2 that was calculated from the noninvasive technique was correlated with the results from the arterial blood gases ( R 2 0.76) and with a mean bias of +2.7 mmHg. The Pco 2 was correlated with the results from the arterial blood gases (R 2 0.67) with a mean bias of -3.6 mmHg. We conclude that the oxygen deficit as obtained from the noninvasive method is a very sensitive indicator of impaired pulmonary gas exchange. It has the advantage that it can be obtained within a few minutes by having the patient simply breathe through a tube.

We are developing a novel, noninvasive method for measuring the efficiency of pulmonary gas exchange in patients with lung disease. The patient wears an oximeter, and we measure the partial pressures of oxygen and carbon dioxide in inspired and expired gas using miniature analyzers. The arterial Po 2 is then calculated from the oximeter reading and the oxygen dissociation curve, using the end-tidal Pco 2 to allow for the Bohr effect. This calculation is only accurate when the oxygen saturation is <94%, and therefore, these normal subjects breathed 12.5% oxygen. When the procedure is used in patients with hypoxemia, they breathe air. The Po 2 difference between the end-tidal and arterial values is called the "oxygen deficit." Preliminary data show that this index increases substantially in patients with lung disease. Here we report measurements of the oxygen deficit in 20 young normal subjects (age 19 to 31 yr) and 11 older normal subjects (47 to 88 yr). The mean value of the oxygen deficit in the young subjects was 2.02 ± 3.56 mmHg (means ± SD). This mean is remarkably small. The corresponding value in the older group was 7.53 ± 5.16 mmHg (means ± SD). The results are consistent with the age-related trend of the traditional alveolar-arterial difference, which is calculated from the calculated ideal alveolar Po 2 minus the measured arterial Po 2 . That measurement requires an arterial blood sample. The present study suggests that this noninvasive procedure will be valuable in assessing the degree of impaired gas exchange in patients with lung disease.

Large numbers of people visit, work, or reside at high altitude. The inevitable hypoxia reduces physical performance and, in many instances, impairs neuropsychological function. The new technique of oxygen conditioning raises the oxygen concentration in the air of buildings such as homes, schools, and hospitals. The result is to decrease the equivalent altitude and improve both physical and cognitive performance., (©2016 Int. Union Physiol. Sci./Am. Physiol. Soc.)

Large numbers of people live or work at high altitude, and many visit to trek or ski. The inevitable hypoxia impairs physical working capacity, and at higher altitudes there is also cognitive impairment. Twenty years ago oxygen enrichment of room air was introduced to reduce the hypoxia, and this is now used in dormitories, hotels, mines, and telescopes. However, recent advances in technology now allow large amounts of oxygen to be obtained from air or cryogenic oxygen sources. As a result it is now feasible to oxygenate large buildings and even institutions such as hospitals. An analogy can be drawn between air conditioning that has improved the living and working conditions of millions of people who live in hot climates and oxygen conditioning that can do the same at high altitude. Oxygen conditioning is similar to air conditioning except that instead of cooling the air, the oxygen concentration is raised, thus reducing the equivalent altitude. Oxygen conditioning on a large scale could transform living and working conditions at high altitude, where it could be valuable in homes, hospitals, schools, dormitories, company headquarters, banks, and legislative settings., (Copyright © 2015 the American Physiological Society.)

Carl Wilhelm Scheele (1742-1786) has an important place in the history of the discovery of respiratory gases because he was undoubtedly the first person to prepare oxygen and describe some of its properties. Despite this, his contributions have often been overshadowed by those of Joseph Priestley and Antoine Lavoisier, who also played critical roles in preparing the gas and understanding its nature. Sadly, Scheele was slow to publish his discovery and therefore Priestley is rightly recognized as the first person to report the preparation of oxygen. This being said, the thinking of both Scheele and Priestley was dominated by the phlogiston theory, and it was left to Lavoisier to elucidate the true nature of oxygen. In addition to his work on oxygen, Scheele was enormously productive in other areas of chemistry. Arguably he discovered seven new elements and many other compounds. However, he kept a low profile during his life as a pharmacist, and he did not have strong links with contemporary prestigious institutions such as the Royal Society in England or the French Académie des Sciences. He was elected to the Royal Swedish Academy of Science but only attended one meeting. Partly as a result, he remains a somewhat nebulous figure despite the critical contribution he made to the history of respiratory gases and his extensive researches in other areas of chemistry. His death at the age of 43 may have been hastened by his habit of tasting the chemicals that he worked on., (Copyright © 2014 the American Physiological Society.)

Joseph Priestley (1733–1804) was the first person to report the discovery of oxygen and describe some of its extraordinary properties. As such he merits a special place in the history of respiratory physiology. In addition his descriptions in elegant 18th-century English were particularly arresting, and rereading them never fails to give a special pleasure. The gas was actually first prepared by Scheele (1742–1786) but his report was delayed. Lavoisier (1743–1794) repeated Priestley's initial experiment and went on to describe the true nature of oxygen that had eluded Priestley, who never abandoned the erroneous phlogiston theory. In addition to oxygen, Priestley isolated and characterized seven other gases. However, most of his writings were in theology because he was a conscientious clergyman all his life. Priestley was a product of the Enlightenment and argued that all beliefs should be able to stand the scientific scrutiny of experimental investigations. As a result his extreme liberal views were severely criticized by the established Church of England. In addition he was a supporter of both the French and American Revolutions. Ultimately his political and religious attitudes provoked a riot during which his home and his scientific equipment were destroyed. He therefore emigrated to America in 1794 where his friends included Thomas Jefferson and Benjamin Franklin. He settled in Northumberland, Pennsylvania although his scientific work never recovered from his forced departure. But the descriptions of his experiments with oxygen will always remain a high point in the history of respiratory physiology.

Joseph Barcroft (1872-1947) was an eminent British physiologist who made contributions to many areas. Some of his studies at high altitude and related topics are reviewed here. In a remarkable experiment he spent 6 days in a small sealed room while the oxygen concentration of the air gradually fell, simulating an ascent to an altitude of nearly 5,500 m. The study was prompted by earlier reports by J. S. Haldane that the lung secreted oxygen at high altitude. Barcroft tested this by having blood removed from an exposed radial artery during both rest and exercise. No evidence for oxygen secretion was found, and the combination of 6 days incarceration and the loss of an artery was heroic. To obtain more data, Barcroft organized an expedition to Cerro de Pasco, Peru, altitude 4,300 m, that included investigators from both Cambridge, UK and Harvard. Again oxygen secretion was ruled out. The protocol included neuropsychometric measurements, and Barcroft famously concluded that all dwellers at high altitude are persons of impaired physical and mental powers, an assertion that has been hotly debated. Another colorful experiment in a low-pressure chamber involved reducing the pressure below that at the summit of Mt. Everest but giving the subjects 100% oxygen to breathe while exercising as a climber would on Everest. The conclusion was that it would be possible to reach the summit while breathing 100% oxygen. Barcroft was exceptional for his self-experimentation under hazardous conditions.

When lowlanders go to high altitude, the resulting oxygen deprivation impairs mental and physical performance, quality of sleep, and general well-being. This paper compares the effects of ventilatory acclimatization and oxygen enrichment of room air on the improvement of oxygenation as judged by the increase in the alveolar P(O2) and the reduction in equivalent altitude. The results show that, on the average, complete ventilatory acclimatization at an altitude of 5000 m increases the alveolar P(O2) by nearly 8 torr, which corresponds to a reduction in equivalent altitude of about 1000 m, although there is considerable individual variability. By comparison, oxygen enrichment to 27% at 5000 m can easily reduce the equivalent altitude to 3200 m, which is generally well tolerated. Because full ventilatory acclimatization at altitudes up to about 3600 m reduces the equivalent altitude to about 3000 m, oxygen enrichment is not justified for well-acclimatized persons. At an altitude of 4200 m, where several telescopes are located on the summit of Mauna Kea, full acclimatization reduces the equivalent altitude to about 3400 m, but the pattern of commuting probably would not allow this. Therefore, at this altitude, oxygen enrichment would be beneficial but is not essential. At higher altitudes such as 5050 m, where other telescopes are located or planned, the gain in oxygenation from acclimatization is insufficient to produce an adequate mental or physical performance for most work, and oxygen enrichment is highly desirable. Full ventilatory acclimatization requires at least a week of continuous exposure, although much of the improvement is seen in the first 2 days.

The Swiss expedition to Everest (altitude 8,848 m) in the spring of 1952 very nearly attained the summit with two of the climbers reaching 8,595 m. This would have been the first ascent of Everest. One main reason for failure was the inadequate oxygen equipment which was modified from sets designed for mine rescue using potassium peroxide generators. Oxygen could not be inhaled while the mountaineers were climbing because of the rigid mouthpiece assembly and the high breathing resistance of the equipment. It was argued that breathing oxygen during rest periods would suffice, but this was a fallacy as had been demonstrated by Kellas 30 years before.

Increasingly, lowlanders are commuting to high altitude for commercial, scientific, or defense reasons. Oxygen enrichment of room air at high altitude is a simple but highly effective way of improving sleep quality, mental performance, work efficiency, and general well-being. This review summarizes some of the practical aspects of providing oxygen enrichment including room construction, oxygen concentrators, ventilation levels, costs, use of liquid oxygen, fire hazard, and safe upper limits for oxygen enrichment. The physiological and medical effects of oxygen enrichment are discussed under the headings of sleep, neuropsychological function, and general well-being, productivity, and fatigue. Oxygen enrichment of room air can play a major role in improving living and working conditions for commuters to high altitude.

Oxygen enrichment of room air has proved to be valuable for people who need to work at altitudes of 4000 m and above. In the present study the feasibility of using the same technique in ski and other mountain resorts at the lower altitudes of 2500 to 4000 m is considered. Although many people find these altitudes invigorating, some are distressed by the hypoxia, especially at night. The analysis shows that all resorts up to an altitude of 3250 m (10,600 ft) can have the equivalent altitude reduced to 1000 m (3280 ft) by oxygen enrichment without incurring a fire hazard. (The equivalent altitude is that which provides the same inspired P(O2) during air breathing.) Even resorts or laboratories as high as 4250 m can have the equivalent altitude safely reduced to 1500 m, that is, lower than the altitude of Denver, Colorado. This application of oxygen enrichment is likely to be most valuable for improving sleep and assisting in the initial acclimatization process.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

The efficiency of pulmonary gas exchange has long been assessed using the alveolar-arterial difference in PO2, the A-aDO2, a construct developed by Richard Riley ~70years ago. However, this measurement is invasive (requiring an arterial blood sample), time consuming, expensive, uncomfortable for the patients, and as such not ideal for serial measurements. Recent advances in the technology now provide for portable and rapidly responding measurement of the PO2 and PCO2 in expired gas, which combined with the well-established measurement of arterial oxygen saturation via pulse oximetry (SpO2) make practical a non-invasive surrogate measurement of the A-aDO2, the oxygen deficit. The oxygen deficit is the difference between the end-tidal PO2 and the calculated arterial PO2 derived from the SpO2 and taking into account the PCO2, also measured from end-tidal gas. The oxygen deficit shares the underlying basis of the measurement of gas exchange efficiency that the A-aDO2 uses, and thus the two measurements are well-correlated (r 2~0.72). Studies have shown that the new approach is sensitive and can detect the age-related decline in gas exchange efficiency associated with healthy aging. In patients with lung disease the oxygen deficit is greatly elevated compared to normal subjects. The portable and non-invasive nature of the approach suggests potential uses in first responders, in military applications, and in underserved areas. Further, the completely non-invasive and rapid nature of the measurement makes it ideally suited to serial measurements of acutely ill patients including those with COVID-19, allowing patients to be closely monitored if required. [ABSTRACT FROM AUTHOR]

The efficiency of pulmonary gas exchange is often assessed by the ideal alveolar-arterial partial pressure difference (A-aDO2). Through a combination of pulse oximetry and rapidly responding gas analyzers to measure the partial pressures of O2 and CO2 in expired gas, one can measure the oxygen deficit. Defined as the difference between the measured alveolar PO2 and the arterial PO2 calculated from SpO2, the oxygen deficit is a substitute for the alveolar-arterial PO2 difference. The oxygen deficit is physiologically reasonable in that it increases with age in healthy subjects and is well correlated with the A-aDO2. To calculate arterial PO2 from saturation, the saturation should be below the very flat upper part of the O2-Hb dissociation curve; good estimates can be made provided the arterial O2 saturation is below ~95%. Since saturations at or above 95% imply reasonably well-maintained gas exchange efficiency, this limitation is of only minor concern. Calculations show that it is necessary to take into account the change in PO2 at a saturation of 50% of the O2-Hb dissociation curve based on the measured alveolar PCO2. As the measurement is designed to be noninvasive, determination of any base excess is not practical, but calculations show that the effect of assuming a zero base excess is modest, with a similar small effect from an abnormal body temperature. Taken together, these results show that a noninvasive assessment of pulmonary gas exchange efficiency can be obtained from subjects with below-normal arterial O2 saturations through a combination of expired O2 and CO2 measurements and SpO2 made during quiet breathing. NEW & NOTEWORTHY The details and limitations of a noninvasive measurement of pulmonary gas exchange efficiency, the oxygen deficit, are described. The oxygen deficit, calculated from expired gas measurements made during quiet breathing coupled with pulse oximetry, is a good surrogate measurement of the ideal alveolar-arterial PO2 difference and does not require arterial blood gas sampling. [ABSTRACT FROM AUTHOR]

High-altitude physiology can be said to have begun in 1644 when Torricelli described the first mercury barometer and wrote the immortal words 'We live submerged at the bottom of an ocean of the element air.' Interestingly, the notion of atmospheric pressure had eluded his teacher, the great Galileo. Blaise Pascal was responsible for describing the fall in pressure with increasing altitude, and Otto von Guericke gave a dramatic demonstration of the enormous force that could be developed by atmospheric pressure. Robert Boyle learned of Guericke's experiment and, with Robert Hooke, constructed the first air pump that allowed small animals to be exposed to a low pressure. Hooke also constructed a small low-pressure chamber and exposed himself to a simulated altitude of about 2400 meters. With the advent of ballooning, humans were rapidly exposed to very low pressures, sometimes with tragic results. For example, the French balloon, Zénith, rose to over 8000 m, and two of the three aeronauts succumbed to the hypoxia. Paul Bert was the first person to clearly state that the deleterious effects of high altitude were caused by the low partial pressure of oxygen ( [ABSTRACT FROM AUTHOR]

The article sheds light on physiologic basis of high-altitude diseases. Many physicians are surprised to learn how many people live, work, and play at high altitude. Some 140 million persons reside at altitudes over 2500 m, mainly in North, Central, and South America, Asia, and eastern Africa. Increasingly, people are moving to work at high altitude. For example, there are telescopes at altitudes over 5000 m and mines at over 4500 m, and the Golmud-Lhasa railroad being constructed in Tibet will have 30 000 to 50 000 workers at high altitudes, including many who work at more than 4000 m. In addition, the physiology of hypoxia, which is at the basis of high-altitude medicine, plays an important role in many lung and heart diseases. High altitude affects the human body because of oxygen deprivation. Other factors, such as severe cold, high winds, and intense solar radiation, may be present but can be nullified by appropriate protection.

Discusses the history of George Ingle Finch's first use of supplementary oxygen for climbing at extreme altitudes. Expedition of Finch and Geoffrey Bruce in Mount Everest in 1922; Finch's development of the oxygen equipment; Low-pressure chamber experiment.