key: cord-342150-dadc8whz authors: Lindahl, Sten G. E. title: Using the prone position could help to combat the development of fast hypoxia in some patients with COVID‐19 date: 2020-06-17 journal: Acta Paediatr DOI: 10.1111/apa.15382 sha: doc_id: 342150 cord_uid: dadc8whz The world is facing an explosive COVID‐19 pandemic. Some cases rapidly develop deteriorating lung function, which causes deep hypoxaemia and requires urgent treatment. Many centres have started treating patients in the prone position, and oxygenation has improved considerably in some cases. Questions have been raised regarding the mechanisms behind this. The mini review provides some insights into the role of supine and prone body positions and summarises the latest understanding of the responsible mechanisms. The scope for discussion is outside the neonatal period and entirely based on experimental and clinical experiences related to adults. The human respiratory system is a complex interplay of many different variables. Therefore, this mini review has prioritised previous and ongoing research to find explanations based on three scientific areas: gravity, lung structure and fractal geometry and vascular regulation. It concludes that gravity is one of the variables responsible for ventilation/perfusion matching but in concert with lung structure and fractal geometry, ventilation and regulation of lung vascular tone. Since ventilation distribution does not change between supine and prone positions, the higher expression of nitric oxide in dorsal lung vessels than in ventral vessels is likely to be the most important mechanism behind enhanced oxygenation in the prone position. Hence, the prone position in infants younger than 6 months is not recommended. However, it may be discussed with regard to toddlers, pre-school and school children who suffer from acute lung insufficiency with deep hypoxaemia to such an extent that it threatens their life. But these age groups are not so well studied. The subject is highly interesting, and it will be a challenge in the future to design investigations that are able to evaluate prone and supine positions in a developing respiratory system. This paper reviews the use of supine and prone positions in adult patients with severe respiratory insufficiency. It aims to reach a conclusion about the mechanisms that explain the sometimes dramatic improvements in oxygenation when these patients are turned prone. But it has been difficult to demonstrate that the prone position used for these sick patients also improves mortality rates. Such studies are difficult to perform and interpret, as the nature of the disease and the extremely complex intensive care they receive are hard to control. This makes it hard to evaluate comparable patient groups and collect reliable outcome data. This point was well made in a 2019 paper by Gattinoni et al which also highlighted the impact of protective ventilator settings to avoid ventilator-induced lung injuries. 1 Guérin et al examined a well-controlled and carefully selected patient population that received intensive care and assessed the mortality rates related to supine and prone positions. The authors concluded that mortality was lower in the group treated prone. 2 The world is currently experiencing an explosive pandemic caused by a new coronavirus, with a clinical presentation of a somewhat different kind. In some cases, patients experience rapidly deteriorating The function of the human respiratory system is a complex interplay of different variables, such as the rib cage, the diaphragm, abdominal distension, pleural pressure, body fluids, heart function, pulmonary and systemic circulation, lung parenchyma, the tracheobronchial tree, alveoli and central and peripheral innervation. All of these act in concert to achieve adequate gas exchange for the maintenance of life. Each of them is a theoretical area in its own right, with regard to detailed mechanistic functions. It would not be possible for a review like this to provide a comprehensive overarching presentation of them all. Therefore, it was necessary to prioritise key scientific areas for this mini review. That is why the finding on mechanisms and explanations will focus on three scientific areas: gravity, lung structure and fractal geometry and vascular regulation. For many years, pulmonary circulation was defined according to gravity and based on advanced investigations in upright humans. [3] [4] [5] According to these studies, pulmonary circulation was described in three zones. This was due to relationships between pulmonary artery pressure, alveolar pressure and pulmonary venous pressure from apical to basal lung regions with increasing pulmonary perfusion down the lung. In addition, a fourth zone was added for basal lung regions, where conditions allow pulmonary interstitial pressure to exceed pulmonary venous and alveolar pressures. These investigations and physiological interpretations have played an important role in developing our understanding of lung function today. This platform created new knowledge which has, step-by-step, resulted in advanced treatment of the insufficient lung. • Gravity is only one variable responsible for ventilation/ perfusion matching and is executed in concert with lung structure and fractal geometry, gas distribution and regulation of lung vascular tone. • The most important mechanism is the higher expression of nitric oxide in dorsal lung vessels than in ventral vessels. Chest in 1988. 10 Certainly, gravity is of interest for pulmonary circulation and ventilation and influences V/Q matching along the vertical axis and, more so, at the longer distances down the lung. To extrapolate the importance of gravity for pulmonary circulation, a study was performed using single photon emission tomography in volunteers subjected to hypergravity of three times normal gravity (3 G). A human centrifuge was used with the subjects in the supine position. Interestingly, a paradoxical result was reached, with a shift of dominant perfusion from dependent to independent lung regions when the normal gravitational force (0 G) was changed to 3 G. 16 This paradoxical finding invited to thoughts on lung structure and to the experimental study by Beck and Rehder 8 using microspheres in isolated perfused dog lungs. They concluded that: The distribution of regional vascular conductances were related to the anatomic location and were not related to gravity, nor were they caused by nonuniformities in regional lung expan- Like all organs, the anatomy and structure of lungs are genetically determined and are important pre-requisite conditions for function. Embryologic development of the lungs is characterised by dichotomous branching of both the airways and vessels. The branching follows a genetically determined geometric pattern, such as angles related to the common stem from which the dichotomous branching originates. Also, the development of airways and vessels are in parallel and happens synchronously. This structural arrangement will ensure laminar transport of both gas and blood to, and from, alveoli. Altered angulations of the fractal geometry often cause turbulence and increased resistance, which reduces oxygenation and gas exchange ( Figure 1 ). Fractal geometry of the airways and vessels has, to a large extent, been clarified by findings from the Washington School of Medicine in Seattle. 23, 24 Investigations using microspheres found that small 29 Single photon emission computed tomography image of pulmonary perfusion in one supine volunteer before (A) and after (B) NOS inhibition using L-NMMA intravenously. R indicates the right lung The finding that vascular conductance in dogs was greater in dorsal than in ventral lung vasculature clearly indicated that there ought to be vasoactive mechanisms in the lungs that were counteracting gravity. 8 Another important observation was in 1996, when Hlastala et al, found that lung perfusion in standing horses was not dominantly governed by gravity. 27 This was a valuable step as it narrowed down several possibilities that might constitute the most responsible mechanism for improved V/Q matching in the prone position. A next step was to explore whether NO production in human lung vasculature could be responsible for improved V/Q matching in the prone position. An investigation was designed to challenge the hypothesis that NO plays an important role in the regulation of regional lung perfusion. Nitric oxide synthase (NOS) messenger ribonucleic acid (mRNA) and NOS activity using citrulline assay were analysed in ventral and dorsal lung tissue samples from patients subjected to lung surgery. 29 In addition, the study also assessed regional lung perfusion in volunteers by single photon emission computed tomography before and after NOS inhibition. The hypothesis was supported, and it was found that mRNA expression of endothelial NOS was higher in dorsal than in ventral lung regions. Moreover, it was found that calcium-dependent NOS activity in citrulline units was higher in dorsal than ventral lung whereas calcium-independent NOS activity was similar in ventral and dorsal regions (Figure 2A Based on this review, it is concluded that gravity is one of the variables responsible for V/Q matching, but in concert with lung structure and fractal geometry, gas distribution and regulation of lung vascular tone. This conclusion is based on a long series of investigations published in leading journals and illustrates the essence of science, where brick is laid on brick in a process of continued development. In view of the unchanged ventilation distribution of prone and supine, it currently seems that the most important mechanism is different regulation of lung vascularity in dorsal and ventral lung regions, due to expression of the potent vasodilator NO. This mechanism is also present in horses and in pigs making it likely that the enhanced NO production in dorsal lung regions is an evolutionary trait preserved from the time when we walked on four legs. It is very likely that there is more to know, and understand, about the complex lung function which will be further elucidated in future investigations. Based on the above findings, it appears that using the prone position to combat the fast development of deep hypoxia in some patients with COVID-19 is a useful tool. This could even be used in spontaneously breathing patients with deep hypoxaemia prior to initiation of mechanical ventilation and extra corporeal oxygenation. The author has no conflicts of interest to declare. 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Regulation of regional lung perfusion by nitric oxide Using the prone position could help to combat the development of fast hypoxia in some patients with COVID-19