505CHAPTER 45 Ventilation/Perfusion Inequality arterial (PPA), alveolar (PA), and pulmonary venous (PV) pressures PBF within the lung zones depends on the relative magnitudes of these pressures within[.]
CHAPTER 45 Ventilation/Perfusion Inequality Fractal Model of Pulmonary Blood Flow and Ventilation PBF possesses greater heterogeneity than described in the gravitational model alone.6–8 Isogravitational PBF was shown to be nearly as heterogeneous as that of the entire lung (Fig 45.3) Rather than being randomly distributed, PBF was similar within neighboring regions.8 High-flow regions bordered other highflow regions while low-flow regions abutted other low-flow regions The distribution of PBF was shown to be independent of the scale of measurement, suggesting a fractal nature of PBF A fractal structure has a characteristic form that remains constant over a magnitude of scales (Fig 45.4).8 Both the bronchial tree and pulmonary vascular beds have a fractal design.9,10 In animal models and in humans under conditions of microgravity, the contribution of gravity to overall perfusion heterogeneity was of secondary importance Blood flow in the lung shows a gradient from the hilum to the periphery, with increased flow to the dorsal compared to ventral region regardless of position.9–11 The asymmetry of flow at pulmonary artery branches accounts for the heterogeneity of flow within isogravitational planes In other words, regions that share a parent or grandparent branch have more similar flows than branches that are separated by a greater distance This fractal pattern extends to the subacinar level.12 The close correlation between regional ventilation and perfusion suggests that ventilation has spatial characteristics similar to Left Flow/mean flow 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 Cephalad Dorsal Ventral Right arterial (PPA), alveolar (PA), and pulmonary venous (PV) pressures PBF within the lung zones depends on the relative magnitudes of these pressures within each zone In the upright subject, zone is the most cephalad and zone the most caudad In zone 1, PA PPA Pv, and the region has negligible blood flow, as high alveolar pressure is believed to compress collapsible capillaries This region is one of high VA/Q ratios or dead space ventilation Zone conditions are rare except in cases of diminished PBF (e.g., hypotension or cardiac failure) or increased PA encountered during positive-pressure ventilation Zone is found in the middle of the lung, where PPA PA PV PBF is determined by the difference between PPA and PA Venous pressure does not influence the flow rate Blood flow progressively increases with descent through this zone as PPA increases, whereas PA remains relatively constant The VA/Q ratio decreases when moving from the rostral to caudal lung The most caudal lung region is zone 3, where PPA PV PA Here, the arteriovenous pressure gradient (PPA – PV) determines PBF.3 VA/Q ratios are the lowest in this region, where perfusion is generally greater than ventilation The lung can be considered to have a zone region in the most dependent areas of lung when transudated pulmonary interstitial fluid increases interstitial pressures, thereby reducing blood flow Zone can be considered a Starling resistor, where PPA Pinterstitial PV PA and blood flow is determined by the difference between pulmonary artery and interstitial pressures This effect is exaggerated as lung volume diminishes from total lung capacity to residual volume PBF in immature animals differs in several important ways from that of adult animals The immature pulmonary vascular bed appears to be fully recruited, with no contribution of Starling resistors in the pulmonary circulation during exposure to acute or chronic hypoxia.4,5 Furthermore, neonatal piglets show a relative hypoxemia with an increased dispersion of PBF 505 Dorsal Caudad Transverse section Upright posture (isogravitational plane) Sagittal section Upright posture • Fig 45.3 Isogravitational heterogeneity of pulmonary blood flow Recon- struction of transverse and sagittal plane from a single baboon animal during upright posture Each square depicts location and relative blood flow to a piece of lung in a given plane Heterogeneity of blood flow is present in isogravitational planes Flow is not random; rather, neighboring pieces tend to have similar magnitudes of flow Cephalad-caudad (gravitational) gradient is apparent in the sagittal section perfusion.13–16 Fractals possess a large area-to-volume ratio, ensuring that all alveoli are serviced by capillaries efficiently and that gas and substrate exchange irrespective of an organism’s size The innate structure of the lung itself appears to underlie the precision of VA/Q matching.17 There is a close association of the developing bronchial tree and pulmonary arterial tree during organogenesis.18 Basal pulmonary vascular tone is minimal, suggesting that vasoregulation is of minor importance for maintaining close VA/Q matching normally.19–21 Passive matching of perfusion and ventilation by pulmonary structure suggests an optimally engineered system because it requires no active feedback mechanism function normally (Fig 45.5).22 A fractal design has several additional advantages in addition to VA/Q matching on a structural level.22 Fractals ensure minimal energy expenditure to deliver substrate due to lower hydrodynamic resistance.22 There is conservation of biological material to construct the vascular and bronchial trees.22 A fractal design uses a smaller amount of genetic code for pulmonary construction by using a recursive construction mechanism that requires only a handful of proteins.22 VA/Q Abnormalities in Pulmonary Disease Hypoxemia The primary causes of hypoxemia in children are intrapulmonary shunt and VA/Q mismatch, specifically, areas of VA/Q ratios less than When patients have VA/Q mismatch, areas of low and high VA/Q are often both present VA/Q mismatch results in hypoxemia because the low O2 content in the areas with VA/Q less than cannot be corrected by the areas of high VA/Q ratios because of the predominance of hemoglobin in the O2 content 506 S E C T I O N V Pediatric Critical Care: Pulmonary A B • Fig 45.4 Fractal structures (A) This curve is produced by a simple iterative transformation beginning with a straight line At each step, the middle third of all lines is replaced with two segments, one-third length of the line, forming part of an equilateral triangle An infinite number of iterations can be performed Thus, as increasing magnification reveals more detail, the overall appearance of the new segment remains similar to that of the previous segment (B) The pulmonary vascular (and bronchial) tree is a repetitive pattern of dichotomous branches that become progressively smaller and fill a predetermined area calculation VA/Q mismatch has less effect on CO2, as high VA/Q areas can more effectively correct regions of low VA/Q Shunt has been distinguished from VA/Q mismatch, as it does not correct well with the administration of higher Fio2 Oxygen content of arterial blood represents a weighted average of the O2 content of shunted blood (Qs/Qt) and the remaining fraction (1– Qs/Qt): Lung volume Vital capacity Infant Functional residual capacity Pressure • Fig 45.5 Relative Eq 45.7 where Qs and Qt represent shunt and total lung blood flow, respectively, and CaO2, CvO2, and CcO2 are the arterial, venous, and pulmonary capillary oxygen contents, respectively This equation can then be rearranged to solve for shunt fraction: Adult CaO2 Qs/Qt CvO2 (1 – Qs/Qt) CcO2 ventilation and perfusion maps Regional ventilation and perfusion scaled to the measured minute ventilation and cardiac output in the pig Both regional ventilation and perfusion show clustering in which adjacent units have similar flows There is a strong correlation in which areas of high ventilation receive high perfusion and areas of low ventilation receive low perfusion (These pig lungs were examined in cubes of 1.5 to 2.0 cm3 volume.) Q s /Q t C C O2 C a O2 C c O2 C v O2 Eq 45.8 Regional alveolar hypoxia causes precapillary pulmonary vasoconstriction, restricting blood flow to the area, improving VA/Q matching.23,24 A similar, though less robust, response occurs with decreased mixed venous oxygenation (Pvo2) This compensatory response, termed hypoxic pulmonary vasoconstriction (HPV), is most effective when hypoxia is localized and when the Pao2 is between 60 and 90 mm Hg24 but is of minimal importance in the normal lung.24–26 In humans, HPV can reduce flow to atelectatic regions by approximately 50%.27 The degree of HPV varies across CHAPTER 45 Ventilation/Perfusion Inequality the lung and is affected by lung disease, sepsis, vasodilators, anesthetics, and changes in the Fio2 Inspiration of 100% O2 worsens VA/Q mismatch by opposing HPV.28 Additionally, 100% may destabilize small alveoli, causing them to collapse, thus adding to shunt Pediatric Acute Respiratory Distress Syndrome Pediatric acute respiratory distress syndrome (PARDS) is marked by profound hypoxemia refractory to high Fio2, suggesting shunt as the primary mechanism.29 Hypoxemia and intrapulmonary shunt in PARDS is proportional to cardiac output.29 Intrapulmonary shunt results from alveolar flooding, atelectasis, and right-to-left shunt through a patent foramen ovale Some patients also have units with very low VA/Q ratios The low VA/Q units explain the increase in venous admixture with decreasing Fio2 and may represent transient events that occur when alveoli are in the process of collapsing or reexpanding.30 Units with low VA/Q ratio deteriorate to shunt as a result of absorption atelectasis, especially when exposed to high Fio2 Pneumonia Hypoxemia found in patients with pneumonia is multifactorial Animal models of pneumococcal lobar pneumonia showed intrapulmonary shunt early in the course that evolved to regions with low VA/Q ratios.31 Patients receiving mechanical ventilation for bacterial pneumonia had a combination of intrapulmonary shunt and increased perfusion to low VA/Q units.32 High Fio2 did not increase intrapulmonary shunt but did oppose HPV in pneumonia patients Similar less severe findings were observed in spontaneously breathing patients with pneumonia.33 Pleural Effusion The accumulation of fluid between the chest wall and lung leads to atelectasis, resulting in dyspnea and hypoxemia A small study of nine adults without chronic lung disease and acute pleural effusion, mainly from tuberculosis, showed that intrapulmonary shunt was the primary cause of hypoxemia.34 Thoracentesis can alleviate dyspnea but may be associated with improved, worsening, or unchanged hypoxemia shortly after drainage.34–39 Improvement may be associated with lung reexpansion and improved VA/Q matching; worsening or no change in hypoxemia is hypothesized to be due to slow lung reexpansion, or ex vacuo, pulmonary edema.34 Asthma Ventilation/perfusion abnormalities have been found across the spectrum of patients with asthma These patients usually have a bimodal distribution of blood flow with normal units and large areas of low VA/Q with little intrapulmonary shunt.40 However, no correlation exists between measurements of airway obstruction and gas exchange.41 Thus, maximum airflow rates and VA/Q inequalities appear to be unrelated, suggesting that spirometric changes reflect bronchoconstriction in larger and medium-sized airways, whereas VA/Q abnormalities are mainly related to edema and/or mucus formation occurring in the distal small airways.41 High Fio2 may oppose HPV, placing low VA/Q regions at risk for 507 absorption atelectasis Bronchodilators may enhance the perfusion of low VA/Q areas, exacerbating hypoxemia However, the beneficial effects of bronchodilators on airway resistance outweigh any worsening in VA/Q mismatch Pulmonary Embolism Pulmonary emboli tend to travel to high-flow regions of the lung, producing a shift of PBF toward regions that previously had seen low flow, resulting in VA/Q mismatch as the predominate mechanism of hypoxemia.21 Postembolism, blood flows preferentially to nondependent areas because they have a greater capacity for capillary recruitment.21 Before embolization, regions with high blood flow had good VA/Q matching After embolization, regional ventilation is preserved or slightly increased but blood flow to embolized lung tissue falls, increasing VA/Q ratios.42 The shifts in blood flow to nonembolized regions results in increased VA/Q heterogeneity, and the new areas of higher blood flow (lower VA/Q) result in hypoxemia Nonperfused or poorly perfused areas contribute to dead space, but hypercapnia is uncommon due to compensatory increases in minute ventilation.43 In patients who present with shock, inadequate blood flow means less blood can be diverted to create low VA/Q regions; thus, the degree of arterial hypoxemia may be better than expected In contrast, increases in total PBF result in lower arterial oxygenation due to increases in VA/Q mismatch despite increases in Do2 Primary Pulmonary Hypertension VA/Q inequalities tend to be moderate even in late stages of pulmonary hypertension.44 Much of the cardiac output is distributed to lung units with almost normal VA/Q ratios, while less than 10% perfused underventilated or unventilated areas.44 When PBF is reduced, hypoxemia often occurs because of low mixed venous Po2 Oxygen, sodium nitroprusside, isoproterenol, and nifedipine worsen VA/Q matching, but patients not usually experience hypoxemia due to increased flow, resulting in an increase in Svo2 that raises end capillary Po2 Therapeutic Considerations Positive End-Expiratory Pressure The application of positive end-expiratory pressure (PEEP) can improve oxygenation but may either decrease or increase dead space PEEP decreases the proportion of shunt units by recruiting atelectactic units, thereby improving FRC, closing capacity and the surface area for gas exchange By decreasing cardiac output (Q), PEEP also decreases intrapulmonary shunt However, even when Q is preserved, PEEP improves VA/Q inequity because of increased flow to recruited units.30 With constant Q, PEEP decreases venous admixture and increases Pvo2 PEEP also affects dead space Low levels of PEEP decrease dead space by reductions in atelectasis, but high levels of PEEP increase dead space from the overinflation of some lung units, leading to compression of neighboring capillaries and zone conditions The percent of recruitable lung has been shown to be proportional to the severity of acute respiratory distress syndrome (ARDS) Higher levels of PEEP in patients with a lower proportion of recruitable lung provides small benefit and may be harmful.45 508 S E C T I O N V Pediatric Critical Care: Pulmonary Prone Positioning The prone position has multiple benefits for patients with lung disease Studies have shown that prone positioning, especially when employed early in the course of ARDS, improves survival This benefit remains undemonstrated in children, however.46–48 Prone positioning improves oxygenation by producing more evenly distributed ventilation (especially to dorsal regions) and improved VA/Q correlation.30,49–51 In ARDS and other lung injury models, nonaerated or poorly aerated portions of the lung are found mainly in the dependent areas The majority of perfusion goes through dorsal lung regions, whether in the prone or supine position.4 A larger gradient of ventilation is found in the supine when compared to the prone position Prone positioning produces a more uniform distribution of stress and strain of lung tissue and redistributes ventilation to the dorsal lung regions Positive-pressure ventilation, especially PEEP, redistributes perfusion toward the dependent portion of the lungs.4,32 This redistribution may increase the vertical perfusion gradient in the supine position but may reduce it in the prone position Nitric Oxide Nitric oxide (NO) improves gas exchange by preferentially increasing blood flow to well-ventilated regions of the lung NO reaches the well-ventilated units, producing local vasodilation and reducing shunt fraction.52 Beneficial effects appear over a wide range of doses A randomized trial in children with PARDS showed a significantly greater extracorporeal membrane oxygenation-free survival in the inhaled NO group compared with controls.53 NO does not appear to be beneficial in persons with chronic lung diseases, possibly because the structural damage precludes rapid vascular changes or because shunt usually is not found in such diseases Measuring Pulmonary Ventilation/Perfusion Lung ventilation/perfusion scintigraphy, commonly called V/Q scan, is the nuclear medicine study used most commonly in the clinical setting to assess PBF and ventilation Research studies may use V/Q scans for adjunctive data but typically measure VA/Q ratios with a multiple inert gas technique V/Q scans use radiolabeled albumin and inert gases or aerosols to assess pulmonary gas and blood flow This study can show regional mismatch where perfusion is more compromised than ventilation and may be used to diagnose pulmonary embolism54 or plan for lung resection.55 A pattern of reverse mismatch where ventilation is more abnormal than perfusion may also be seen in the setting of obstructive lung disease on V/Q scan.55 Electrical impedance tomography (EIT) may evolve into a bedside tool for repeated measurement of regional ventilation and perfusion in the future This technology applies an electrical current to the thorax and measures the resultant modified current as it passes through tissues of varying resistance.56 Most research has been performed to evaluate changes in ventilation with modification of respiratory support.57–60 Lung perfusion may also be quantified but fewer investigations have considered this aspect of analysis.56 The advantages of EIT include the ability to perform repeated measurements at the bedside without transport out of the intensive care unit.56,57 It is unclear in the current literature whether targeting regional ventilation or VA/Q ratios will result in improved patient-centered outcomes Key References Altemeier WA, McKinney S, Glenny RW Fractal nature of regional ventilation distribution J Appl Physiol (1985) 2000;88:1551-1557 Altemeier WA, Robertson HT, McKinney S, et al Pulmonary embolization causes hypoxemia by redistribution regional blood flow without changing ventilation J Appl Physiol (1985) 1998;85:2337-2343 Gattinoni L, Caironi P, Cressoni M, et al Lung recruitment in patients with the acute respiratory distress syndrome N Engl J Med 2006;354: 1775-1786 Glenny RW, Robertson HT Fractal properties of pulmonary blood flow: characterization of spatial heterogeneity J Appl Physiol (1985) 1990; 69:532-545 Guerin C, Reignier J, Richard J-C, et al Prone positioning in severe acute respiratory distress syndrome N Engl J Med 2013;368: 2159-2168 Hakim TS, Dean GW, Lisbona R Gravity independent inequality in pulmonary blood flow in humans J Appl Physiol (1985) 1987;63: 1114-1121 Hughes JMB, Grant BJB, Greene RE, et al Inspiratory flow rate and ventilation distribution in normal subjects and in patients with simple bronchitis Clin Sci 1972;43:583-595 West GB, Brown JH, Enquist BJ A general model for the origin of allometric scaling laws in biology Science 1997;276:122-126 West JB Regional differences in gas exchange in the lung of erect man J Appl Physiol 1962;17:893-898 The full reference list for this chapter is available at ExpertConsult.com e1 References West JB Regional differences in gas exchange in the lung of erect man J Appl Physiol 1962;17:893-898 Hughes JMB, Grant BJB, Greene RE, et al Inspiratory flow rate and ventilation distribution in normal subjects and in patients with simple bronchitis Clin Sci 1972;43:583-595 West JB, Dollery CT, Naimark A Distributions of blood flow in isolated lung: relation to vascular and alveolar pressures J Appl Physiol 1964;19:713-724 Gibson RL, Truog WE, Redding GJ Hypoxic pulmonary vasoconstriction during and after infusion of group B Streptococcus in neonatal piglets: vascular pressure-flow analysis Am Rev Respir Dis 1988;137:774-778 Redding GJ, Gibson RL, Standaert TA, et al Regional pulmonary blood flow in piglets during group B streptococcal bacteremia Am Rev Respir Dis 1990;141:1209-1213 Reed JH, Wood EH Effect of body position on vertical distribution of pulmonary blood flow J Appl Physiol 1970;28:303-311 Hakim TS, Dean GW, Lisbona R Gravity independent inequality in pulmonary blood flow in humans J Appl Physiol (1985) 1987;63:1114-1121 Glenny RW, Robertson HT Fractal properties of pulmonary blood flow: characterization of spatial heterogeneity J Appl Physiol (1985) 1990;69:532-545 Glenny RW, Lamm WJ, Albert RK, et al Gravity is a minor determinant of pulmonary blood flow distribution J Appl Physiol (1985) 1991;71:620-629 10 Glenny RW, Bernard S, Robertson HT, et al Gravity is an important but secondary determinant of regional pulmonary blood flow in upright primates J Appl Physiol (1985) 1999;86:623-632 11 Prisk GK, Guy HJ, Elliot AR, et al Ventilatory inhomogeneity determined from multiple-breath washouts during sustained microgravity on Spacelab SLS-1 J Appl Physiol (1985) 1995;78): 597-607 12 Glenny RW, Bernard S, Robertson HT Pulmonary blood flow remains fractal down to the level of gas exchange J Appl Physiol (1985) 2000;89:742-748 13 Altemeier WA, McKinney S, Glenny RW Fractal nature of regional ventilation distribution J Appl Physiol (1985) 2000;88:1551-1557 14 Harris RS, Schuster DP Visualizing lung function with positron emission tomography J Appl Physiol (1985) 2007;102:448-458 15 Hopkins SR, Levin DL, Emami K, et al Advances in magnetic resonance imaging of lung physiology J Appl Physiol (1985) 2007; 102:1244-1254 16 Petersson J, Sanchez-Crespo A, Larsson SA, et al Physiological imaging of the lung: single-photon-emission computed tomography (SPECT) J Appl Physiol (1985) 2004;102:468-476 17 Melsom MN, Kramer-Johansen J, Flatebo T, et al Distribution of pulmonary ventilation and perfusions measured simultaneously in awake goats Acta Physiol Scand 1997;159:199-208 18 Weibel ER Fractal geometry: a design principle for living organisms Am J Physiol Lung Cell Mol Physiol 1991;261:L361-L369 19 Celermajer DS, Dollery C, Burch M, et al Role of the endothelium in the maintenance of low pulmonary vascular tone in normal children Circulation 1994;89:2041-2044 20 Vaughan DJ, Brogan TV, Kerr ME, et al Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs Am J Physiol Lung Cell Mol Physiol 2003;284(5):L834-L843 21 Altemeier WA, Robertson HT, McKinney S, et al Pulmonary embolization causes hypoxemia by redistribution regional blood flow without changing ventilation J Appl Physiol (1985) 1998;85: 2337-2343 22 West GB, Brown JH, Enquist BJ A general model for the origin of allometric scaling laws in biology Science 1997;276:122-126 23 Duke HN The site of action of anoxia on the pulmonary blood vessels of the cat J Physiol (Lond) 1954;125:373-382 24 Grant BJB, Davies EE, Jones HA, et al Local regulation of pulmonary blood flow and ventilation-perfusion ratios in the coatimundi J Appl Physiol 1976;40:216-228 25 Mougdi R, Michelakis ED, Archer SL Hypoxic pulmonary vasoconstriction J Appl Physiol 2005;98:390-403 26 Arai TJ, Henderson AC, Dubowitz DJ, et al Hypoxic pulmonary vasoconstriction does not contribute to pulmonary blood flow heterogeneity in normoxia in normal supine humans J Appl Physiol 2009;106:1057-1064 27 Morrell NW, Nijran KS, Biggs T, Seed WA Magnitude and time course of hypoxic pulmonary vasoconstriction in man Respir Physiol 1995;100:271-281 28 Dantzker DR, Wagner PD, West JB Proceedings: Instability of poorly ventilated lung units during oxygen breathing J Physiol 1974;242:72P 29 Dantzker DR, Lynch JP, Weg JG Depression of cardiac output is a mechanism of shunt reduction in the therapy of acute respiratory failure Chest 1980;77:636-642 30 Walther SM, Domino KB, Glenny RW, et al Positive endexpiratory pressure redistributes perfusion to dependent regions in supine but not prone lambs Crit Care Med 1999;27:37-45 31 Wagner PD, Laravuso RB, Goldzimmer E, et al Distribution of ventilation-perfusion in dogs with normal and abnormal lungs J Appl Physiol 1975;38:1099-1109 32 Gea J, Roca J, Torres A, et al Mechanism of abnormal gas exchange in patients with pneumonia Anesthesiology 1991;75:782-789 33 Lampron N, Lemaire F, Teisseire B, et al Mechanical ventilation with 100% oxygen does not increase intrapulmonary shunt in patients with severe bacterial pneumonia Am Rev Respir Dis 1985; 131:409-413 34 Agusti AGN, Cardus J, Roca J, Grau JM, Xaubet A, RodriguezRoisin R Ventilation-perfusion mismatch in patients with pleural effusion: effects of thoracentesis Am J Respir Crit Care Med 1997;156:1205-1209 35 Brown NE, Zamel N, Aberman A Changes in pulmonary mechanics and gas exchange following thoracentesis Chest 1978;540-542 36 Perpina M, Benlloch E, Marco V, Abad F, Nauffal D Effects of thoracentesis on pulmonary gas exchange Thorax 1983;38:747-750 37 Karetzy MS, Kothari GA, Fourre JA, Khan AU Effect of thoracentesis on arterial oxygen tension Respiration 1978;96-103 38 Trapnell DH, Thurston JGB Unilateral pulmonary oedema after pleural aspiration Lancet 1970;1(7661):1367-1369 39 Brandstetter RD, Cohen RP Hypoxemia after thoracentesis: a predictable and treatable condition JAMA 1979;242:1060-1061 40 Wagner PD, Dantzker DR, Iacovoni VE, et al Ventilationperfusion inequality in asymptomatic asthma Am Rev Respir Dis 1978;118:605-612 41 Roca J, Ramis L, Rodriguez-Roisin R, et al Serial relationships between ventilation-perfusion inequality and spirometry in acute severe asthma requiring hospitalization Am Rev Respir Dis 1988; 137:579-584 42 Turetz M, Sideris AT, Friedman OA, et al Epidemiology, pathophysiology, and natural history of pulmonary embolism Semin Intervent Radiol 2018;35:92-98 43 Santolicandro A, Rediletto R, Fornai E, et al Mechanisms of hypoxemia and hypocapnia in pulmonary embolism Am J Respir Crit Care Med 1995;152:336-347 44 Dantzker DR, Bower JS Pulmonary vascular tone improves VA/Q matching in obliterative pulmonary hypertension J Appl Physiol Respir Environ Exerc Physiol 1981;51:607-613 45 Gattinoni L, Caironi P, Cressoni M, et al Lung recruitment in patients with the acute respiratory distress syndrome N Engl J Med 2006;354:1775-1786 46 Guerin C, Reignier J, Richard J-C, et al Prone positioning in severe acute respiratory distress syndrome N Engl J Med 2013; 368:2159-2168 47 Pelosi P, Brazzi L, Gattinoni L Prone position in acute respiratory distress syndrome Eur Respir J 2002;20:1017-1028 ... structures (A) This curve is produced by a simple iterative transformation beginning with a straight line At each step, the middle third of all lines is replaced with two segments, one-third length... CvO2, and CcO2 are the arterial, venous, and pulmonary capillary oxygen contents, respectively This equation can then be rearranged to solve for shunt fraction: Adult CaO2 Qs/Qt CvO2 (1 – Qs/Qt)... matching.23,24 A similar, though less robust, response occurs with decreased mixed venous oxygenation (Pvo2) This compensatory response, termed hypoxic pulmonary vasoconstriction (HPV), is most effective when