Inspired oxygen: present, past, and future.

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 Po2 in the atmosphere was near zero, and it remained so for millions of years. But about 2 billion years ago, the Po2 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.

Alexander von Humboldt (1769-1859): early high-altitude explorer and renowned plant naturalist.

Alexander von Humboldt (1769-1859) was one of the most distinguished German scientists of the late 18th and early 19th centuries. His fame came chiefly from his extensive explorations in South America and his eminence as a plant naturalist. He attempted to climb the inactive volcano Chimborazo in Ecuador, which was thought to be the highest mountain in the world at the time, and he reached an altitude of about 5,543 m, which was a record height for humans. During the climb, he had typical symptoms of acute mountain sickness, which he correctly attributed to the low level of oxygen, and he was apparently the first person to make this connection. His ability as a naturalist enabled him to recognize the effect of high altitude on the distribution of plants, and by comparing his observations on Chimborazo with those in the European Alps and elsewhere, he inferred that the deleterious effects of high altitude were universal. During his return trip to Europe, he called on President Thomas Jefferson in Washington, where he was given a warm reception, and discussed conservation issues. He then returned to Paris, where he produced 29 volumes over a period of 31 years describing his travels. Here the effects of high altitude on the distribution of plants compared with animals are briefly reviewed. Following Humboldt's death in 1859, there was extensive coverage of his contributions, but curiously, his fame has diminished over the years, and inexplicably, he now has a lower profile in North America.

Oxygen deficit is a sensitive measure of mild gas exchange impairment at inspired O2 between 12.5% and 21.

The oxygen deficit (OD) is the difference between the end-tidal alveolar Po2 and the calculated Po2 of arterial blood based on measured oxygen saturation that acts as a proxy for the alveolar-arterial Po2 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% O2. The present study measured how the OD varied at different values of inspired O2. Healthy subjects were split by age (young 22-31; n = 23; older 42-90; n = 13). Across all inspired O2 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 O2 levels (all P < 0.0001). The OD difference between age groups and its variance was greater at higher O2 values (age × O2 interaction; P = 0.002). The decrease in OD with lower values of inspired O2 in both cohorts is consistent with the increased accuracy of the calculated arterial Po2 based on the O2-Hb dissociation curve and with the expected decrease in the alveolar-arterial Po2 difference due to a lower arterial saturation. The persisting higher OD seen in older subjects, irrespective of the inspired O2, shows that the measurement of OD remains sensitive to mild gas exchange impairment, even when breathing 21% O2.

Measuring the efficiency of pulmonary gas exchange using expired gas instead of arterial blood: comparing the "ideal" Po2 of Riley with end-tidal Po2.

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 Po2 and the calculated arterial Po2. The end-tidal Po2 is measured using a rapid gas analyzer, and the arterial Po2 is derived from pulse oximetry after allowing for the effect of the Pco2 on the oxygen affinity of hemoglobin. In the present report we show that the values of end-tidal Po2 and Pco2 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 Po2 difference (A-aDO2) 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 Pco2 as arterial blood, and the same respiratory exchange ratio as the whole lung. It transpires that, in normal subjects, the end-tidal Po2 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 Po2, but that it is easier to obtain.

Fritz Rohrer (1888-1926), a pioneer in pulmonary mechanics whose work was inexplicably ignored for about 30 years.

Fritz Rohrer (1888-1926) has a special place in the history of respiratory physiology for two reasons. The first is that he laid the foundations of modern pulmonary mechanics in the early 1900s. For example, his seminal paper on pulmonary dynamics, that is, the pressure-flow relationships in the airways, was published in 1915 in one of the top journals in the field. It included extensive measurements of airway dimensions in postmortem human lungs and a sophisticated analysis of the modes of airflow. This was closely followed by a very original analysis of lung statics, which included studies of airway pressures at normal, maximal, and minimal lung volumes in relaxed normal volunteers, and was published in 1916. Remarkably, both papers were essentially ignored at the time. Fortunately, in 1925 he was able to summarize his major findings in a chapter in an important handbook of physiology. However, he tragically died from pulmonary tuberculosis in the following year at the early age of 37. The second reason for his importance in the history of pulmonary mechanics is that inexplicably his very innovative research was essentially ignored for about 30 years. It was not until the 1940s that his work was rediscovered, although not in time to save investigators from duplicating his very original studies. Possible reasons why his work was ignored for so long are discussed. Even today it is not easy to recover some important features of his career, and some aspects of his very original research are still almost unknown.

Three classical papers in respiratory physiology by Christian Bohr (1855-1911) whose work is frequently cited but seldom read.

History has been kind to Christian Bohr (1855-1911). His name is attached eponymously to three different areas of respiratory physiology. The first is the Bohr dead space, which refers to the portion of the tidal volume that does not undergo gas exchange. The second is the increase in oxygen affinity of hemoglobin caused by the addition of carbon dioxide to the blood. This is known as the Bohr effect and is a very important feature of gas exchange, both in the lung and in peripheral tissues. Both of these contributions by Bohr are familiar to most students. Bohr's third contribution refers to the calculation of the changes in the Po2 of blood as oxygen is loaded in the pulmonary capillary, the so-called Bohr integration. This contribution is less well known now, partly because of the advent of digital computing, but it was important in its day. The analysis is challenging because the very nonlinear shape of the oxygen dissociation curve means that the Po2 difference between the alveolar gas and the capillary blood, which is the driving pressure for diffusion, changes in a complicated way. All three papers are in German, and two of them are long and tedious to read. English translations are available, but few people read the papers, despite the fact that the first two articles are very frequently cited. In the present article, Bohr's contributions are reviewed, and some parts of the articles that are particularly difficult to understand are clarified.

Noninvasive measurement of pulmonary gas exchange: comparison with data from arterial blood gases.

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 Po2 difference (AaDO2) calculated from arterial blood gases. The end-tidal Po2 was measured from the expired gas during steady-state breathing, the arterial Po2 was derived from a pulse oximeter if the SpO2 was 95% or less, which was the case for 23 patients. The difference between the end-tidal and the calculated Po2 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 AaDO2 ( R2 0.72). The arterial Po2 that was calculated from the noninvasive technique was correlated with the results from the arterial blood gases ( R2 0.76) and with a mean bias of +2.7 mmHg. The Pco2 was correlated with the results from the arterial blood gases (R2 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.

Measurements of pulmonary gas exchange efficiency using expired gas and oximetry: results in normal subjects.

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 Po2 is then calculated from the oximeter reading and the oxygen dissociation curve, using the end-tidal Pco2 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 Po2 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 Po2 minus the measured arterial Po2. 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.

Oxygen Conditioning: A New Technique for Improving Living and Working at High Altitude.

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.

The beginnings of cardiac catheterization and the resulting impact on pulmonary medicine.

The early history of cardiac catheterization has many interesting features. First, although it would be natural to assume that the procedure was initiated by cardiologists, two of the three people who shared the Nobel Prize for the discovery were pulmonologists, while the third was a urologist. The primary objective of the pulmonologists André Cournand and Dickinson Richards was to obtain mixed venous blood from the right heart so that they could use the Fick principle to calculate total pulmonary blood flow. Cournand's initial catheterization studies were prompted by his reading of an account by Werner Forssmann, who catheterized himself 12 years before. His bold experiment was one of the most bizarre in medical history. In the earliest studies that followed, Cournand and colleagues first passed catheters into the right atrium, and then into the right ventricle, and finally, the pulmonary artery. At the time, the investigators did not appreciate the significance of the low vascular pressures, nor that what they had done would revolutionize interventional cardiology. Within a year, William Dock predicted that there would be a very low blood flow at the top of the upright lung, and he proposed that this was the cause of the apical localization of pulmonary tuberculosis. The fact that the pulmonary vascular pressures are very low has many implications in lung disease. Cardiac catheterization changed the face of investigative cardiology, and its instigators were awarded the Nobel Prize in 1956.

Leonardo da Vinci: engineer, bioengineer, anatomist, and artist.

Leonardo da Vinci (1452-1519) enjoys a reputation as one of the most talented people of all time in the history of science and the arts. However, little attention has been given to his contributions to physiology. One of his main interests was engineering, and he was fascinated by structural problems and the flow patterns of liquids. He also produced a large number of ingenious designs for warfare and a variety of highly original flying machines. But of particular interest to us are his contributions to bioengineering and how he used his knowledge of basic physical principles to throw light on physiological function. For example, he produced new insights into the mechanics of breathing including the action of the ribs and diaphragm. He was the first person to understand the different roles of the internal and external intercostal muscles. He had novel ideas about the airways including the mode of airflow in them. He also worked on the cardiovascular system and had a special interest in the pulmonary circulation. But, interestingly, he was not able to completely divorce his views from those of Galen, in that although he could not see pores in the interventricular septum of the heart, one of his drawings included them. Leonardo was a talented anatomist who made many striking drawings of the human body. Finally, his reputation for many people is based on his paintings including the Mona Lisa that apparently attracts more viewers than any other painting in the world.

Carbon Dioxide Exposure Resulting From Hood Protective Equipment Used in Joint Arthroplasty Surgery.

BACKGROUND: To protect both the surgeon and patient during procedures, hooded protection shields are used during joint arthroplasty procedures. Headache, malaise, and dizziness, consistent with increased carbon dioxide (CO2) exposure, have been anecdotally reported by surgeons using hoods. We hypothesized that increased CO2 concentrations were causing reported symptoms. METHODS: Six healthy subjects (4 men) donned hooded protection, fan at the highest setting. Arm cycle ergometry at workloads of 12 and 25 watts (W) simulated workloads encountered during arthroplasty. Inspired O2 and CO2 concentrations at the nares were continuously measured at rest, 12 W, and 25 W. At each activity level, the fan was deactivated and the times for CO2 to reach 0.5% and 1.0% were measured. RESULTS: At rest, inspired CO2 was 0.14% ± 0.04%. Exercise had significant effect on CO2 compared with rest (0.26% ± 0.08% at 12 W, P = .04; 0.31% ± 0.05% at 25 W, P = .003). Inspired CO2 concentration increased rapidly with fan deactivation, with the time for CO2 to increase to 0.5% and 1.0% after fan deactivation being rapid but variable (0.5%, 12 ± 9 seconds; 1%, 26 ± 15 seconds). Time for CO2 to return below 0.5% after fan reactivation was 20 ± 37 seconds. CONCLUSION: During simulated joint arthroplasty, CO2 remained within Occupational Safety and Health Administration (OSHA) standards with the fan at the highest setting. With fan deactivation, CO2 concentration rapidly exceeds OSHA standards.

Barcroft's bold assertion: All dwellers at high altitudes are persons of impaired physical and mental powers.

Barcroft's bold assertion that everyone at high altitude has physical and mental impairment compared with sea level was very provocative. It was a result of the expedition that he led to Cerro de Pasco in Peru, altitude 4300 m. Although it is clear that newcomers to high altitude have reduced physical powers, some people believe that this does not apply to permanent residents who have been at high altitude for generations. The best evidence supports Barcroft's contention, although permanent residents often perform better than acclimatized lowlanders. Turning to neuropsychological function, newcomers to high altitude certainly have some impairment, and there is evidence that the same applies to highlanders. However the notion that permanent residents are impaired is anathema to many people. For example the eminent Peruvian physician Carlos Monge took great exception to Barcroft's remark and even attributed it to the fact that Barcroft was suffering from acute mountain sickness when he made it! Monge referred to 'climatic aggression', by which he meant the negative consequences of the inevitable hypoxia of high altitude. Recent technological advances such as oxygen enrichment of room air can overcome this 'aggression'. This might be useful in some settings at high altitude such as a nursery where newborn babies are cared for, and possibly operating rooms where the surgeon's dexterity may be enhanced. Other situations might be dormitories, conference rooms, and perhaps some school rooms. These constitute possible ways by which the effects of Barcroft's assertion might be countered.

Frank Low and the first images of the ultrastructure of the pulmonary blood-gas barrier.

Frank N. Low (1911-1998) has the distinction of publishing the first electron micrographs showing the ultrastructure of the pulmonary capillary and particularly the blood-gas barrier. This work in 1952 and 1953 was enabled by the progress in fixation and staining of tissue made by George Palade and was part of the very rapid advance in electron microscopy during the previous 25 years. Low's micrographs clearly showed the three layers of the blood-gas barrier: capillary endothelium, extracellular matrix, and alveolar epithelium. The images immediately resolved the debate about the composition of the blood-gas barrier that had been raging for 100 years. The first published micrographs were rather poor, but the quality rapidly improved and a major event was the first electron micrograph of the human blood-gas barrier published in 1953. These images had an enormous influence on the development of pulmonary physiology and biology. For example, for the first time it became clear that the barrier separating the blood from the alveolar gas was vanishingly thin. The discovery of the extracellular matrix layer ultimately clarified how this barrier, despite its extraordinary thinness, was sufficiently strong to avoid mechanical failure. Despite the major advances made by Low, his name is almost unknown in pulmonary physiology and biology, and perhaps this tribute will help to give him his due.

Everest Physiology Pre-2008.

When Edmund Hillary and Tenzing Norgay reached the summit of Mt. Everest in 1953, it was the culmination of many attempts beginning in 1921. Alexander Kellas had actually predicted as early as 1920 that the mountain could be climbed, but the extreme altitude of 8848 m with the consequent oxygen deprivation had foiled previous attempts. One reason for the success of the 1953 expedition was the work done by the British physiologist Griffith Pugh in 1952 when he studied many of the physiological factors at high altitude including the oxygen requirements. Seven years later, Pugh and Hillary teamed up again for the Silver Hut Expedition in 1960-1961 that elucidated many of the problems of very high altitude. A group of physiologists spent several months at an altitude of 5800 m in a prefabricated hut and studied many aspects of exercise, pulmonary gas exchange, control of ventilation, and blood changes. Maximal exercise was measured as high as 7440 m and raised anew the question of whether Everest could ever be climbed without supplementary oxygen. The answer was shown to be yes in 1978 by Messner and Habeler, and 3 years later the American Medical Research Expedition to Everest clarified the physiological adaptations that allow humans to reach the highest point on earth. Five people reached the summit, the barometric pressure there was measured for the first time, and alveolar gas samples from the summit showed the critical importance of the extreme hyperventilation. However, the maximal oxygen consumption for the summit inspired PO2 of 43 mmHg was shown to be only about 1 l min(-1). In other words, the highest point on earth is very close to the limit of human tolerance to oxygen deprivation. As we celebrate the anniversary of Charles Darwin, it would be nice to have an evolutionary explanation for this, but in fact it is a cosmic coincidence.

Robert Hooke: early respiratory physiologist, polymath, and mechanical genius.

Robert Hooke (1635-1703) was a polymath who made important contributions to respiratory physiology and many other scientific areas. With Robert Boyle, he constructed the first air pump that allowed measurements on small animals at a reduced atmospheric pressure, and this started the discipline of high-altitude physiology. He also built the first human low-pressure chamber and described his experiences when the pressure was reduced to the equivalent of an altitude of ∼2,400 m. Using artificial ventilation in an animal preparation, he demonstrated that movement of the lung was not essential for life. His book Micrographia describing early studies with a microscope remains a classic. He produced an exquisite drawing of the head of a fly, showing the elaborate compound eye. There is also a detailed drawing of a flea, and Hooke noted how the long, many-jointed legs enable the insect to jump so high. For 40 years, he was the curator of experiments for the newly founded Royal Society in London and contributed greatly to its intellectual ferment. His mechanical inventions covered an enormous range, including the watch spring, the wheel barometer, and the universal joint. Following the Great Fire of London in 1666, he designed many of the new buildings in conjunction with Christopher Wren. Unfortunately, Hooke had an abrasive personality, which was partly responsible for a lack of recognition of his work for many years. However, during the last 25 years, there has been renewed interest, and he is now recognized as a brilliant scientist and innovator.

Torricelli and the ocean of air: the first measurement of barometric pressure.

The recognition of barometric pressure was a critical step in the development of environmental physiology. In 1644, Evangelista Torricelli described the first mercury barometer in a remarkable letter that contained the phrase, "We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight." This extraordinary insight seems to have come right out of the blue. Less than 10 years before, the great Galileo had given an erroneous explanation for the related problem of pumping water from a deep well. Previously, Gasparo Berti had filled a very long lead vertical tube with water and showed that a vacuum formed at the top. However, Torricelli was the first to make a mercury barometer and understand that the mercury was supported by the pressure of the air. Aristotle stated that the air has weight, although this was controversial for some time. Galileo described a method of measuring the weight of the air in detail, but for reasons that are not clear his result was in error by a factor of about two. Torricelli surmised that the pressure of the air might be less on mountains, but the first demonstration of this was by Blaise Pascal. The first air pump was built by Otto von Guericke, and this influenced Robert Boyle to carry out his classical experiments of the physiological effects of reduced barometric pressure. These were turning points in the early history of high-altitude physiology.

Henry Cavendish (1731-1810): hydrogen, carbon dioxide, water, and weighing the world.

Henry Cavendish (1731-1810) was an outstanding chemist and physicist. Although he was not a major figure in the history of respiratory physiology he made important discoveries concerning hydrogen, carbon dioxide, atmospheric air, and water. Hydrogen had been prepared earlier by Boyle but its properties had not been recognized; Cavendish described these in detail, including the density of the gas. Carbon dioxide had also previously been studied by Black, but Cavendish clarified its properties and measured its density. He was the first person to accurately analyze atmospheric air and reported an oxygen concentration very close to the currently accepted value. When he removed all the oxygen and nitrogen from an air sample, he found that there was a residual portion of about 0.8% that he could not characterize. Later this was shown to be argon. He produced large amounts of water by burning hydrogen in oxygen and recognized that these were its only constituents. Cavendish also worked on electricity and heat. However, his main contribution outside chemistry was an audacious experiment to measure the density of the earth, which he referred to as "weighing the world." This involved determining the gravitational attraction between lead spheres in a specially constructed building. Although this was a simple experiment in principle, there were numerous complexities that he overcame with meticulous attention to experimental details. His result was very close to the modern accepted value. The Cavendish Experiment, as it is called, assures his place in the history of science.