16.15 The pulmonary circulation 3691 16.15.1 Struc

16.15 The pulmonary circulation 3691 16.15.1 Structure and function of the pulmonary circulation 3691 Nicholas W. Morrell

16.15 The pulmonary circulation CONTENTS 16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell 16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.15.1  Structure and function of
the pulmonary circulation Nicholas W. Morrell ESSENTIALS The normal pulmonary circulation distributes deoxygenated blood at low pressure and high flow to the pulmonary capillaries for the purposes of gas exchange. The structure of pulmonary blood ves- sels varies with their function—​from large elastic conductance ar- teries, to small muscular arteries, to thin-​walled vessels involved in gas exchange. Pulmonary vascular resistance is about one-​tenth of systemic vascular resistance, with the small muscular and partially muscular arteries of 50–​150 µm diameter being the site of the greatest con- tribution to resistance. The gas-​exchanging capillary surface area (c.125 m2) contains a blood volume of about 150 ml at any one time, with the blood–​gas barrier being only 0.2–​0.3 µm thick at its thin- nest part. In the normal pulmonary circulation, a large increase in cardiac output causes only a small rise in mean pulmonary arterial pressure because pulmonary vascular resistance falls on exercise: this is accomplished by a combination of vascular distensibility and re- cruitment. Pulmonary blood flow is heterogeneous: gravity causes increased blood flow in the more dependent parts of the lung; within a horizontal region—​or within an acinus—​blood-​flow heterogeneity is imposed by the branching pattern of the vessels. Many neural and humoral mediators can influence pulmonary vascular tone, including nitric oxide and prostacyclin. Alveolar hyp- oxia causes constriction of the small pulmonary arteries, whereas systemic arteries dilate when hypoxic: this hypoxic pulmonary vaso- constriction can reduce venous admixture and improve arterial oxy- genation in the presence of bronchial obstruction. Despite large regional differences in the matching of ventilation and perfusion within the normal lung, the overall lung ventilation–​perfusion ratio is maintained remarkably steady at around 0.85. Introduction The main function of the pulmonary circulation is respiratory gas exchange, a vital function that the lungs take over from the pla- centa at birth. The structure of the pulmonary circulation is highly adapted to fulfil this role. It receives the entire cardiac output from the right ventricle during each cardiac cycle, and this mixed venous blood is delivered at high flow but low pressure to the delicate al- veolar structures where gas exchange occurs. Blood flow is matched closely to the regional ventilation within the lung to optimize and maintain systemic arterial oxygenation. This chapter discusses the anatomy and physiology of the pulmonary circulation. Structure of the pulmonary circulation The pulmonary arteries and bronchi, together with lymphatics, run in a single connective tissue sheath in the centre of pulmonary segments and lobules, the so-​called bronchovascular bundle. The ‘conventional’ pulmonary arteries branch dichotomously and symmetrically, along with the airways, and they also give off extra branches between the conventional branching points, called ‘super- numerary’ or short branches. The intrapulmonary veins pursue a different course along the edges of lobules and segments, in the interlobular septa. The branching pattern of veins is similar to that of the pulmonary arteries. The branching pattern of the pulmonary arteries can be de- scribed by a ‘divergent’ approach, where the main pulmonary artery is called generation 1, with each division giving rise to generation 2, 3, and so on. An alternative is the ‘convergent’ ap- proach where the most peripheral branch is numbered ‘order 1’, and the orders increase until the main pulmonary artery (order 17) is reached. Fig. 16.15.1.1 shows this arrangement going from the precapillary arteriole of order 1, whose diameter is about 13

section 16  Cardiovascular disorders 3692 μm, to the main pulmonary artery (order 17) with a diameter of 30 000 μm. Note the ninefold expansion in cross-​sectional area of the pulmonary vascular bed from order 2 to order 1: it is these precapillary vessels that are often involved in disease processes that affect the pulmonary circulation. In the normal lung, the site of the greatest pulmonary vascular resistance (PVR) is in the small partially muscular and muscular pulmonary arteries (orders 4 to 6; 50–​150 μm diameter). The wall structure of the pulmonary arteries changes along their length depending on the function of the vessel (Fig. 16.15.1.2). All preacinar arteries have a complete muscular coat, but the muscle layer may be incomplete or absent in smaller intra-​acinar vessels. • Elastic arteries (orders 17–​13)—​these larger arteries have adven- titial, muscular, and intimal layers. The media, or muscular layer, is bounded by internal and external elastic laminae, with three or more elastic laminae within the muscle coat. Medial thickness is about 1 to 2% of external diameter. • Muscular arteries (orders 13–​3)—​these small arteries have a thicker muscle layer in relation to their external diameter (2–​5%), and they possess only internal and external elastic laminae; in the smallest arteries, the internal elastic lamina disappears. • Partially muscular arteries (orders 5–​3)—​the smooth muscle fibres investing the smallest pulmonary arteries taper off in a spiral, leading to an incomplete muscular coat (Fig. 16.15.1.2). Most ar- teries of 50–​100 μm external diameter are partially muscular. • Non​muscular arteries (orders 5–​1)—​these arteries have no elastic laminae. The smooth muscle cell is replaced by pericytes whose basement membrane fuses with that of the endothelial cell lining the vascular lumen. • Supernumerary arteries—​these are small, relatively thin-​walled arteries that branch sharply from the parent vessel between bifurcations of the conventional branching system, starting from orders 11 to 12. They provide a short cut for blood supplying the alveoli adjacent to the conduit arteries and bronchi, which would otherwise require a long and circuitous supply by the axial route. • Pulmonary veins—​the branching pattern and organization of the pulmonary veins is similar to that of the arteries, but with only 15 orders, because the four pulmonary veins converge on the left atrium without joining up to form an additional two orders. Veins do not have an internal elastic lamina. Their walls contain more elastic tissue and less muscle than arteries of the same size. There are supernumerary veins like the supernumerary arteries. • Capillary network—​the 300 million precapillary vessels lead into a network of alveolar septal capillaries with a blood volume (150 ml) equal to that in the pulmonary arterial or venous systems. The capillary surface area is about 125 m2 (c.86% of the alveolar sur- face area). Individual capillaries are not much wider than a single erythrocyte, hence the microvascular bed at normal vascular pres- sures is essentially a sheet of blood one red cell thick, exposed to alveolar gas on both sides. Alveolar capillaries have a thick side and a thin side. The thin side consists of the cytoplasmic exten- sions of the luminal endothelial cell and the alveolar epithelial cell with their fused basement membrane (0.2–​0.3 μm across). The thick side, up to 2 μm across, contains collagen, elastin, and fibro- blast processes to give structural support to the alveolus. Pulmonary vascular resistance The pulmonary circulation is a high-​flow, low-​pressure system whose vascular resistance is one-​tenth of systemic vascular resist- ance. PVR is the ratio of the mean pulmonary arterial–​venous pres- sure difference (Ppa − Ppv) to mean pulmonary blood flow (Qp): ( pa pv) p PVR(mmHg/litrepermin). P P Q −

/ Vascular volume (ml) Architecture of pulmonary arterial trees Main pulmonary artery 80 17 15 13 11 9 7 3 5 1 60 14.8 8.0 Diameter (mm) 5.8 3.65 2.1 1.3 0.8 0.5 Elastic Muscular Partially muscular Intra−acinar Terminal bronchioles Respiratory bronchioles Alveolar ducts Pre-capillary (300 × 106) Non muscular 0.2 0.14 0.08 0.05 0 Vascular cross-sectional area (cm2) 200 300 400 Arterial branch order Cross-sectional area 20 0 30 Vascular volume 0.35 40 100 Fig. 16.15.1.1  Map of the pulmonary arterial tree showing how vascular volumes, cross-​sectional areas, diameters, and wall structure vary with branch order number. Intermediate cell Pericyte Smooth muscle cell Arterial lumen Muscular Partially muscular Anatomy of peripheral pulmonary arteries Nonmuscular Fig. 16.15.1.2  The changing structure of pulmonary arteries.

16.15.1  Structure and function of the pulmonary circulation 3693 The normal PVR is less than 2 mm Hg/​litre per min at rest. The main determinants of PVR are captured in the equation for Poiseuille flow (steady flow of a Newtonian fluid through long, straight, unbranched tubes): PVR

~ / , 8 4 µ π l D where L is vascular path length, µ is the viscosity of blood, and D is vessel diameter. L/​D 4 is known as the geometric factor, the import- ance of which can be seen by considering that a 16% decrease in D leads to a twofold increase in PVR. In reality, the situation is more complicated because blood flow in the lungs is not of uniform vel- ocity, but is, of course, pulsatile. PVR normally falls on exercise despite the increase in cardiac output, hence Ppa rises only modestly, perhaps from 15 mm Hg at rest to 23 mm Hg. The fall in PVR during exercise is accomplished by a combination of vascular ‘distensibility’ (vascular compliance) and ‘recruitment’ (number of parallel pathways with flow). Vascular recruitment means that a vessel goes from a state of zero flow to one of finite flow. An increase in pulmonary arterial pressure during ex- ercise can distend pulmonary arteries. The total compliance of the pulmonary circulation is about 20 ml/​mm Hg, hence on heavy exer- cise, if all vascular pressures rose by 10 mm Hg, pulmonary vascular volume would increase by 200 ml, provided vessels had not reached their limiting size. The distribution of PVR can be partitioned into a three-​segment model, which can be described as having (1) arterial, (2) ‘middle’, and (3) venous segments. In isolated lungs, about 20% of the total PVR lies in the distensible ‘middle’ segment (capillaries and small arteries and veins), with 40% each in the arterial and venous seg- ments. This distribution can be altered by factors (e.g. hypoxia), that increase resistance predominantly in the ‘middle’ segment. Blood viscosity is a further factor that affects PVR (e.g. when polycy- thaemia increases PVR). Distribution of pulmonary blood flow Blood flow within the lung is heterogeneous in distribution. For example, between lung regions of secondary lobule size (c.10 cm3) there is a modest amount of gravity-​dependent heterogeneity, with flow increasing with vertical distance (more to the lower zones than the upper zones). Within these lung regions and within the respira- tory acinus there is a greater degree of heterogeneity, which is inde- pendent of gravity. Gravity-​dependent flow The effects of gravity are best illustrated by considering that, in the human erect posture at rest, mean pulmonary artery pressure (Ppa) at the level of the hilum is about 18 cmH2O, whereas the apex of the lung is 20 cmH2O above the hilum. Consequently, the apex of the lung will be perfused only during the systolic pressure peak. In the supine position, the apical blood flow increases, with the re- sult that the distribution from apex to base becomes more uniform. During exercise, with the increase in cardiac output, both upper and lower zone blood flow increases, but the upper increases more than the lower, so that flow becomes more even. The role of gravity in determining pulmonary blood flow was extended by West and encompassed in the three-​zone model of pulmonary circulation (Fig. 16.15.1.3). This model relies on the assumption that the site of major flow resistance is in the small vessels whose extravascular pressure is the alveolar pressure (Palv). There is no flow in zone I because Palv is greater than Ppa. Flow increases down zone II be- cause the driving pressure increases by 1 cm of H2O for each 1 cm distance down the lung. Flow increases with distance down zone III, although ΔP (Ppa − Ppv) remains constant, because local PVR decreases due to capillary distension and recruitment. The driving pressure for blood flow is determined by the relationship between Palv, Ppa, and pulmonary venous pressure (Ppv) down the up- right lung. A further zone (zone IV) is found at the lung base: in this zone, blood flow is observed to decrease with distance down the lung due to increased perivascular pressure in extra-​alveolar vessels. Gravity-​independent flow The branching pattern of pulmonary arteries imposes changes in perfusion that are independent of gravity. Within any given hori- zontal level of the upright lung, there is a decrease in blood flow in peripheral lung regions compared to central hilar regions. This is thought to be due to the reduction in Ppa in small acinar arteries with increasing distance from the hilum. This pattern is also seen at the level of the secondary lobule (the group of acini supplied by one terminal bronchiole), with a decreasing gradient of blood flow from the centre to the periphery. Regulation of pulmonary vasomotor tone The pulmonary circulation differs from the systemic in that it is under minimal resting tone and is almost fully dilated under normal conditions. Circulating and local production of vasodilators and vasoconstrictors contribute to the resting tone, with the balance tipped in favour of vasodilators. Nitric oxide, produced locally by endothelial cells, and the arachidonic acid metabolite prostacyclin are important vasodilators that contribute to this low pulmonary vascular tone. The autonomic nervous system interacts with humoral me- diators and haemodynamic forces in the control of pulmonary vascular tone, autonomic innervation of the lung being via parasympathetic (cholinergic:  predominantly vasodilator) and Ppa Ppv Palv Blood flow Zone I Palv>Ppa>Ppv Zone II Ppa>Palv>Ppv Zone III Ppa>Ppv>Palv Distance Fig. 16.15.1.3  The three-​zone model of pulmonary blood flow distribution.

section 16  Cardiovascular disorders 3694 sympathetic (adrenergic: predominantly vasoconstrictor) nerves in the periarterial plexus. Hypoxic pulmonary vasoconstriction The pulmonary circulation responds to a reduction in the partial pressure of alveolar oxygen by vasoconstriction. This is opposite to the response to hypoxia in the systemic circulation, where tissue hypoxia leads to vasodilatation, hence improving tissue oxygen delivery. Hypoxic pulmonary vasoconstriction (HPV) probably plays little role in the normal distribution of pulmonary blood flow or regulation of ventilation–​perfusion relationships in hu- mans. However, in diseases characterized by airway obstruction, such as acute asthma or chronic obstructive lung disease, HPV can divert blood flow away from poorly ventilated lung regions, redu- cing venous admixture (shunt through poorly ventilated lung re- gions) and preserving arterial oxygenation. The magnitude of the response varies widely between individuals and is, at best, 50% effi- cient. It is noteworthy that populations indigenous to high-​altitude regions (e.g. Tibetans), lack HPV with no obviously detrimental effect. At high altitude, with low atmospheric partial pressures of oxygen, HPV would lead to generalized vasoconstriction and pul- monary hypertension, which is presumably more detrimental than the lack of HPV. Ventilation–​perfusion relationships In the normal lung, it is remarkable that pulmonary blood flow and ventilation are, in general, well matched given the heterogen- eity of blood flow described earlier. Of course, regional ventila- tion is also under similar constraints and forces as the blood flow. In terms of the structure and function of the airways and alveoli in brief, the airways run with the arteries in the bronchovascular bundle and the branching patterns are similar. Regional ventila- tion is under the influence of gravity: the lung sits in the thorax under its own weight, which leads to a gradient of intrapleural pressure, with more negative pressures at the top of the lung than at the bottom in the upright position. This means that the lung is more expanded at the apex than at the base at the end of a normal breath (functional residual capacity). Thus, the upper and lower parts of the lung are operating on different portions of their pressure–​volume curves. The result is that, during normal breathing, greater ventilation is delivered to the bottom than to the top of the lung. This gradient of regional ventilation down the lung is reminiscent of the gradient of blood flow just described. In fact, with increasing distance up the lung, the rate of change of ventilation per unit of alveolar volume is somewhat less than the rate of change of perfusion (about one-​third). This leads to large regional differences in the ventilation–​perfusion ratio up the lung (Fig. 16.15.1.4): alveoli at the bottom of the lung are rela- tively overperfused, leading to a low ventilation–​perfusion ratio (c.0.6); by contrast, alveoli at the apex of the lung are relatively underperfused, leading to ventilation–​perfusion ratios over 3.0. Nevertheless, the overall ventilation–​perfusion ratio for the whole lung is approximately 0.85. The regional ventilation–​perfusion ratio will determine the partial pressures of oxygen and CO2 found in the alveoli at a given level of the lung, and this will be reflected in the gas tensions found in pulmonary venous blood draining those alveoli. The result is that the Po2 is higher, and the Pco2 lower, in blood draining from the top of the lung, compared with the bottom. The matching of ventilation and perfusion in the normal lung ensures that the overall ventilation–​perfusion ratio remains fairly constant with changes in posture or exercise. Acknowledgement Much of the chapter written for the third edition of the Oxford Textbook of Medicine by the late J. S. Prichard has been retained here. Fig. 16.15.1.4  (a) O2–​CO2 diagram showing how the change in ventilation–​perfusion ratio up the lung determines the regional composition of alveolar gas. Dashed lines show the composition of mixed venous (pulmonary arterial) blood and inspired (tracheal) gas. (b) Effects of change in ventilation–​perfusion ratio up the lung on the regional composition of alveolar gas, with volumes of lung slices, ventilations, and blood flows also shown.