What is the term for alveolar ventilation without pulmonary capillary perfusion

Alveolar ventilation-perfusion ratios and pulmonary gas exchange: 100 years since recognition

A debate about physiological measurement provides insight into a practical problem

Features

CC Michel
Department of Bioengineering, Imperial College London, UK

https://doi.org/10.36866/pn.110.28

Large differences in the ratio of alveolar ventilation to alveolar capillary blood flow, VA/QC, in different regions of the lungs have been recognised as a principal cause of hypoxaemia in respiratory disease since the 1950s. The concept was first suggested in a paper published in the 1918/1919 volume of The Journal of Physiology to account for the crippling breathlessness suffered by the soldiers who had survived gas attacks in the First World War. The importance of the ratio, VA/QC, in pulmonary gas exchange did not appear in this paper de novo but emerged in two papers, published by physiologists in 1915 and 1917, concerned with the volume of the respiratory dead space.

The author of the 1915 paper was John Scott Haldane (Fig. 1A) and he was also senior author with JC Meakins and JG Priestley of the 1918/1919 paper. At the time, Haldane was a Fellow of New College, Oxford, and was well-known, not only for developing new methods of gas and blood analysis and for his researches in respiratory physiology but also for his success in solving a range of practical problems arising in clinical medicine, in coal mines and from the Royal Navy’s concerns for the survival of submariners and divers.

The Danish authors of the 1917 paper were August Krogh and Johannes Lindhard (Fig. 1B). Lindhard was a lecturer in the Theory of Gymnastics at the University of Copenhagen where Krogh had recently been promoted to be Professor of Zoophysiology. Krogh had earlier worked with Christian Bohr, Professor of Physiology in Copenhagen, and carried out most of the experimental work for Bohr’s most famous paper on the O2 dissociation curve. In 1910, he had published seven papers, some with his wife Marie Krogh, providing the strongest evidence for believing that the uptake of O2 in the lungs occurred by diffusion alone. For this and his later work on O2 exchange in muscle capillaries, he was awarded the Nobel Prize in 1920.

First suggestion that non-uniformity of VA/Q might be important

The 1915 and the 1917 papers were part of a series, published in The Journal of Physiology and The American Journal of Physiology between 1912 and 1917, debating whether the volume of the airways where no gas exchange occurs, the respiratory dead space, VD, increased significantly with increased tidal volume (VT) and total ventilation: Haldane and his colleagues believed that it did; Krogh and Lindhard, that it did not. Both groups agreed that expired air was a mixture of gas from the alveoli (which, at the outset of the debate was believed to have a uniform composition) and a smaller volume of inspired air from the conducting tubes of the lungs and pharynx, the respiratory dead space, which had not been involved in gas exchange. The tidal volume, the composition of the alveolar air, the expired air and the inspired air could all be measured. The dead space volume was calculated as that volume of inspired air that was necessary to dilute the alveolar gas so that the concentrations of CO2 and/or O2 would equal those in the expired air. Earlier, Haldane and Priestley had shown that in healthy resting subjects, the fractional concentrations of CO2, O2 and N2 in alveolar air could be measured in samples taken at the end of a forced expiration. The technique was widely accepted but Krogh and Lindhard (quite correctly) questioned its use in exercising subjects when gas exchange rates were greatly increased with metabolic rate.

Haldane’s 1915 paper reported experiments on himself sitting at rest. He had breathed in time to a metronome at different frequencies and allowed his tidal volume to find its most comfortable value. He found not only that VD increased with VT but that when VD was calculated from the O2 concentrations in the alveolar and expired air, it had a larger value than when calculated from CO2 concentrations. To account for this, Haldane argued that VD was a functional as well as an anatomical volume. He cited descriptions of the terminal airway by Miller (1893) who had reported that the walls of the terminal conducting components, the atria, which led into the alveoli, had a similar fine structure to the alveoli. Haldane believed the atria were sites of gas exchange and that they would be better ventilated than the alveoli. Therefore, he argued, that just as the respiratory exchange ratio, R, was raised for both lungs during voluntary hyperventilation, hyperventilation of the atria would ‘extract much extra CO2 from the blood but cannot impart O2 to it’ and have a permanently high R. The overall value of R for the lungs, however, had to reflect R of the body’s metabolism and, to compensate for the hyperventilated atria, some alveoli would be hypoventilated. Without being explicit, Haldane concluded that the larger VD for O2 than for CO2 resulted from the smaller volume of O2 that the air ‘can impart’ to the blood. Despite the lack of clarity, this paper is the first suggesting that the composition of the alveolar gas might vary in different parts of the lungs.

Krogh and Lindhard (1917) acknowledged that they had previously assumed that alveolar PO2 and PCO2 were the same in all alveoli. They pointed out that, if different parts of the lungs were less well-ventilated than others, differences in composition would occur in both O2 and CO2 and ‘other gases in special mixing operations’ adding ‘unless indeed the circulation through each lobe should be in proportion to the ventilation’. As West (2004) has pointed out, this proviso suggests that they really understood the general consequence of averaging flows of different composition upon the alveolar-arterial (A-a) PO2 and PCO2 differences. Krogh and Lindhard recognised that the mean fractional concentration of gas derived from many alveoli with different ventilations should be calculated as the sum of the product of ventilation and the fractional concentration of the gas in each alveolus divided by the sum of ventilations of each alveolus.

This correct average revealed that over-ventilated alveoli made a greater contribution to the composition of the alveolar gas than their numbers in the alveolar population. Similarly, the over-perfused, under-ventilated alveoli made a greater than average contribution to the composition of the mixed arterial blood. When calculated correctly, non-uniformity of VA/QC affects the overall alveolar-arterial difference for all gases.

Haldane did not see this general consequence of VA/Q variation. He did, however, recognise a second effect, which arises from the curvature of the oxygen dissociation curve and increases the A-a difference for PO2. This effect was explained clearly in his 1918/1919 paper with Meakins and Priestley where the authors identified large variations in VA/QC as a cause of systemic hypoxia.

Hypoxaemia in survivors of gas warfare

After poisonous gas was first used as a weapon in World War 1, Haldane was asked by the British government how the Allied troops might be protected in gas warfare. Subsequently, he designed the first effective gas mask but its introduction was delayed largely because in 1915, Haldane was removed from all official committees. This occurred immediately after his politician brother, Lord Richard Haldane, had been forced to resign from the Cabinet after the Daily Mail had accused him of German sympathies. It seems that several years before the war, Richard Haldane had written praising German Universities (he had studied at Göttingen in the 1880s).

John Haldane’s restoration as an advisor started informally (Goodman, 2007). In 1917, a Canadian medical officer, JC Meakins, who was caring for survivors of gas warfare, sought advice from fellow-Canadian, Sir William Osler, then Regius Professor of Medicine in Oxford. Osler arranged for Haldane to visit Meakins at the Canadian Military Hospital at Taplow, outside Reading. Very soon, Haldane and Meakins were collaborating on an experimental programme and were joined by Haldane’s former colleague, JG Priestley, who was a medical officer in the Royal Army Medical Corps. Meakins’ patients were breathless and their rapid shallow breathing limited their exercise capacity so severely that their condition was described as ‘effort syndrome’. They had raised numbers of circulating red cells and their symptoms were relieved by breathing oxygen, indicating they were hypoxic although their alveolar PO2’s were often in the normal range. Suspecting that exposure to toxic gases had scarred the lungs, reducing their distensibility and so limiting the tidal volume (VT) of these patients, Haldane speculated that a reduced VT increased the A-a PO2 difference and hence the arterial PO2.

Haldane and his colleagues now investigated (on themselves) the effects of limiting VT while they could adjust their frequency of breathing. Using the apparatus shown in Fig. 2, they breathed through respiratory valves, inspiring from a concertina-
like reservoir, whose volume could be adjusted. The recordings of inspired volume and frequency were supplemented by measurements of alveolar and expired gases at the start and end of each experiment. They found that as inspired volume was reduced, respiratory frequency rose with the subject feeling increasingly uncomfortable until, with tidal volumes of less than 150 ml and frequencies of 100 per minute or more, the experiment had to be stopped.

Haldane argued that if different parts of the lung opened sequentially during inspiration, then some areas of the lungs would be ventilated better than others during each respiratory cycle and these differences would be accentuated when VT was restricted. If a volume of gas from a well-ventilated area were mixed with an equal volume of gas from a poorly ventilated area, the mean PO2 of the mixture would equal the mean of the PO2’s in the two regions of the lungs. For equal volumes of blood leaving the two regions of the lungs and mixing in the pulmonary veins, the situation was different. The mixture would have an O2 content equal to the mean oxygen content of its components, but its PO2 would be determined by the oxygen dissociation curve of blood. Haldane explained that because the slope of the oxygen dissociation curve becomes less steep as PO2 rises between its value in mixed venous blood and its value in the inspired air, the mean arterial PO2 is disproportionately weighted by the blood passing through the under-ventilated alveoli. In this way, the mean PO2 of the arterial blood could be considerably below that in the mean alveolar air (see Fig. 3). Haldane argued that the resulting A-a PO2 difference would be greatly increased in soldiers suffering from the chronic effects of gas poisoning and this accounted for their hypoxaemia.

Haldane’s explanation for the chronic breathlessness of the surviving soldiers did not lead to a cure for them but their symptoms could be relieved by breathing oxygen. Haldane had earlier recommended the use of O2 in the management of patients with pneumonia and designed a simple apparatus for delivering a mixture of O2 and room air to these patients. He was also one of the first to recognise the complications of breathing pure O2 for any prolonged period.

Haldane’s conclusion that uneven ventilation of the lungs could lead to severe hypoxia followed directly from his thinking in his 1915 paper on the respiratory dead space. Here he suggested that differences in ventilation of different areas of the lungs accounted for the difference in VD for O2 and CO2. Although not explicit, his statement that increased ventilation could ‘extract much extra CO2 from the blood but cannot impart O2 to it’ indicates he was thinking about the differences in the O2 and CO2 dissociation curves which were the basis of his explanation of how uneven ventilation led to hypoxia in surviving gassed soldiers. The academic debate about VD measurement had sharpened Haldane’s insight when
he faced a clinical problem. Also, Haldane believed his conclusions were of general importance, giving a full account of his paper with Meakins and Priestley in the chapter on ‘The causes of anoxaemia’ in both editions of his monograph on ‘Respiration’. Only after the Second World War and 10 years after Haldane’s death, however, was the importance of VA/QC generally recognised. This story and later investigations on pulmonary gas exchange have been well reviewed by West (2004).

Acknowledgements

I thank R Maynard, R Michel, G Clough and FE Curry for their helpful comments on earlier drafts of this article.

Glossary

VA – Alveolar ventilation: volume of inspired gas entering (or exchanging with) the alveolar gas per unit time.

QC -Alveolar capillary blood flow.

VD –Volume of respiratory dead space: volume of inspired gas filling the conducting tubes of the lungs at the end of inspiration, remaining unchanged in composition (apart from water vapour) since it is not involved in pulmonary gas exchange.

R – Respiratory exchange ratio: the ratio of the mass of CO2 eliminated divided by the mass of O2 taken up by the inspired air over one or more respiratory cycles.

PO2, PCO2 etc. – gas partial pressures. In the gas phase this is the fraction of the total gas pressure of a gas mixture exerted by one of its components and is the product of total pressure of the mixture and the fractional concentration of the gas in
the mixture (Dalton’s Law). In the blood phase, partial pressure of a gas in a liquid is a measure of its potential energy and it is defined as the partial pressure of the gas in equilibrium with the liquid.

Gas content of blood – should really be the gas content per unit volume of blood. It is the total volume of a gas that can be released from a unit volume of blood (often 100ml when it is expressed as volumes per cent).

A-a gradient – the difference in partial pressure between the mixed alveolar gas and the arterial blood.

References

Goodman M (2007). Suffer and survive. Gas attacks, Miners’ Canaries, Space suits and the Bends: The Extreme Life of Dr J.S. Haldane. Simon and Schuster. London.

Haldane JS (1915). The variations in the effective dead space in breathing. American Journal of Physiology 38, 20–28.

Haldane JS, Meakins JC & Priestley JG (1918–1919). The effects of shallow breathing. The Journal of Physiology 52, 433–453.

Krogh A & Lindhard J (1917). The volume of the dead space in breathing and the mixing of gases in the lungs of man. The Journal of Physiology 51, 59–90.

West JB (2004). A century of pulmonary gas exchange. Am J Resp and Crit Care Med 169(8), 897–902.

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