Management of Pulmonary Hypertension: Physiological and Pharmacological Considerations for Anesthesiologists

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in understanding pulmonary vascular physiology and pathophysiology. This review discusses basic physiology, clinical concepts, and treatment options for pulmonary hypertension and the related right ventricular heart failure focusing on secondary pulmonary hypertension in patients during anesthetic procedures. Physiology of Pulmonary Circulation The pulmonary vascular bed is a high-flow, low-pressure circulation system. Pulmonary vessels have less resistance in comparison to the systemic circulation under normal conditions because of higher compliance of pulmonary precapillary arterioles with a thinner media and less smooth muscle cells (SMCs) compared with the corresponding systemic arterioles. In addition, the cross-sectional area of the pulmonary vascular bed is large and highly distensible with recruitable vessels available to accommodate increase in flow resulting in low pressure and low resistance. In contrast to the systemic arteries, pulmonary vessels constrict with hypoxia (Euler-Liljestrand reflex) and relax in the presence of hyperoxia. Furthermore, changes in cardiac output (CO), airway pressure, and gravity affect the pulmonary more than the systemic circulation. Increases in CO distend open vessels and recruit previously closed vessels. Therefore, the cross-sectional area of pulmonary circulation enlarges and results in a decrease in pulmonary vascular resistance (PVR). An increase in CO has very little effect on pulmonary arterial pressure (PAP) because of the recruitment and distension of pulmonary vessels. An increased PAP or left atrial pressure (LAP) may also distend and recruit pulmonary vessels. Clinically, this means that enhanced CO caused by the administration of inotropic drugs or enlarged blood volume will passively decrease PVR. The contribution of intra- and extraalveolar vessels accounts for the unique U-shaped relationship between lung volume and PVR, which is minimal at functional residual capacity and increased at large and small lung volumes (Fig. 1). Clinically, this may be observed when hyperinflation of the lungs greatly increases PVR.Figure 1: Relationship between lung volume and pulmonary vascular resistance (PVR) (123). RV = residual volume, FRC = functional residual capacity, TLC = total lung capacity.Gravity influences the distribution of blood flow in the pulmonary circulation. Blood flow as well as ventilation increases in the dependent areas of the lung. The relationship between alveolar and hydrostatic pressure implies important clinical consequences. Patients with unilateral lung disease should be positioned with the diseased side up as was already shown by Remolina et al. (1). Lying with the sick lung dependent resulted in the worst gas exchange and the lowest arterial oxygen pressure (1). Application of high levels of positive end-expiratory pressure (PEEP) will narrow the capillaries in the well-ventilated lung areas and divert flow to less well-ventilated or nonventilated areas. Therefore, a decrease in PaO2 is the consequence. Constantly changing hemodynamics, mechanical forces, and hormonal environment influence the vascular endothelium and the underlying SMCs. Under normal circumstances, the interaction between endothelium and SMCs results in a low vascular resistance in the pulmonary circulation. An increasing number of molecules seem to be involved in these biochemical transductions: L-arginine-nitric oxide (NO)-cyclic-3′-5′guanosine monophosphate (cGMP) pathway seems to have a predominant role (2). Physiological agonists such as bradykinin and acetylcholine as well as mechanical stress derived from pulmonary blood flow can activate endothelial cells. This results in oxidation of the guanidino-nitrogen atom of the amino acid L-arginine by the constitutive NO synthase to form and release NO. NO diffuses from endothelial cells to the SMCs, and produces relaxation by activating guanylate cyclase with increasing intracellular cGMP (2). Pulmonary endothelial cells (surface area of 200 m2 in the adult) have a very strategic location: they are exposed to the entire CO, link the pulmonary and systemic circulation, and also regulate SMC tone by signaling to the vascular wall. Endothelial cells both seem to sense local shear stress and to initiate a response (e.g., production of NO) in order to accommodate rapid changes of blood flow. NO and prostacyclin (PGI2) support oxygenation and lung inflation in dilating the pulmonary vasculature after birth, keeping a key regulatory role in the lung because of its prompt, local powerful action compared with a brief half-life time (3). Pathophysiology of Pulmonary Hypertension It is now understood that the balance between vasoconstrictors and vasodilators and mitogenic and antimitogenic factors derived from the endothelium is disturbed in situations with an increase in PAP (4, 5). Endothelial dysfunction is promoted by hypoxia, acidosis, free radicals (6), inflammatory mediators, shear stress caused by increased pulmonary blood flow from left-to-right intracardiac shunt (7), and fibrin from thromboembolism (8). There is no widely accepted range for normal PAP. However, mean PAP >25 mm Hg (normal 15 mm Hg) at rest or >30 mm Hg with exercise is generally accepted as indicative for pulmonary hypertension (9). The enhanced pressure in the pulmonary circulation is associated with an increase in PVR and results in a progressive inability of the right ventricle (RV) to sustain its output leading to RV hypertrophy and RV failure depending from acute or chronic changes (4). In a study by Vizza et al. (10), prevalence of RV dysfunction (defined as RV ejection fraction RVEF 300 dynes · s · cm−5 is indicative of pulmonary hypertension. Pulmonary blood flow and volume are not always equal to or correlated with CO, because of intracardiac or other shunts. Vascular Remodeling Chronic pulmonary hypertension leads to structural alterations of the pulmonary vasculature and to a progression of histological changes known as “vascular remodeling” (11). Under physiological conditions, pulmonary arterioles are thin-walled vessels with the media occupying only 7% of the vessel thickness. The major finding in remodeled vessels caused by a chronic stimulus like hypoxia is the increase in SMCs in already muscularized arteries and extension of SMCs into vessels that are normally thin and nonmuscular (12) and thickening of the adventitial layer (13). Thickening of the adventitial layer is the result of marked proliferation of the fibroblasts, which has been shown to be modulated by protein kinase C and mitogen-activated protein kinase (14). After the proliferative response, there is an increase in adventitial connective tissue including a switch in SMC phenotype to a more synthetic cell that is responsible for deposition of increased connective tissue (12). This deposition of most notably collagen is probably a protective mechanism strengthening the vascular wall against the increase in intravascular pressure (15). Additionally, damage to intimal endothelium as well as intimal hyperplasia and fibrosis can be detected (5). The central regulatory function of the pulmonary endothelium is underlined by the fact that a dysfunctional endothelium can influence the development of pulmonary hypertension at the levels of coagulation control, vasomotor and pulmonary vascular The major stimulus for is hypoxia The increase in PVR is caused by the pulmonary which to arteries and to the capillaries and in resistance arterioles in Pulmonary SMC seem to have an important role for of these by and The of is alveolar to approximately of the response is by such as atrial by such as and by increased LAP, by increased alveolar pressure, and by be observed with acidosis, by and by of or NO synthase increases in PAP are caused by vascular as well as secondary and of and cells to SMCs are a of chronic to hypoxia by and collagen and deposition In addition, vasomotor function may be in these remodeled vessels the of biochemical of pulmonary hypertension are oxygen and an in factors Remodeling also in secondary to and in patients with chronic lung disease and The and increased blood flow to vascular by endothelial cells and the balance of pulmonary Under physiological conditions, these cells factors that initiate SMC proliferation such as and endothelial cells may to which normally decrease SMC of the stimulus can to of structural of Pulmonary Hypertension Pulmonary hypertension is caused by a of acute and chronic pulmonary diseases with an increase in PAP 1). 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