Action Potential in Cardiac Muscle Cells

Cardiac myocytes are electrically coupled to surrounding myocytes by gap junctions, allowing action potentials to spread through the heart in a coordinated manner. When an activation wavefront (wave of depolarization) approaches a myocyte, the membrane potential, initially at resting potential, becomes less negative. At a potential of about −70 mV (the “threshold”), fast sodium channels open, resulting in the rapid influx of sodium ions into the cell (depolarizing current), causing a sudden increase in the membrane potential to about +30 mV. This represents phase 0, or the depolarization phase, of the action potential. Phase 1 represents a slight repolarization in which the fast sodium channels close and potassium diffuses out of the cell. Phase 2 is the plateau phase of the action potential during which calcium channels open, allowing an inward (depolarizing) calcium current to balance the outward (repolarizing) potassium current. Both sets of channels slowly close during the plateau phase, and the inward and outward currents remain in approximate balance. Phase 3 is the repolarization phase of the action potential, in which potassium permeability increases, and the outward going potassium current repolarizes the membrane. Phase 4 commences with the restoration of the resting potential and finishes with the next activation wave front.

During phase 2 and the early part of phase 3 the membrane is completely resistant to further depolarization (the absolute refractory period). During the later part of phase 3, the membrane can undergo depolarization only in response to a supranormal stimulus (the relative refractory period).

A cardiac action potential is transmitted deep within the myocyte by invaginations of the cell membrane known as T tubules. The entry of calcium into the cell during an action potential leads to the release of calcium from the sarcoplasmic reticulum into the cytoplasm of the myocyte, precipitating muscular contraction.

Action Potentials within Pacemaker Cells

Cells of the SA and AV nodes have slow action potentials that undergo spontaneous depolarization and are therefore known as pacemaker cells. Under normal circumstances, the rate of spontaneous depolarization of the AV node cells is less than that of the SA node. Thus, the SA node is the dominant pacemaker, and it inhibits the slower pacemakers. This process is known as overdrive suppression.

The action potential within pacemaker cells of the SA and AV nodes is different from that within normal myocytes. Pacemaker cells have a higher resting membrane potential (−60 mV), lack fast sodium channels, and undergo slow, stable depolarization during phase 4 to threshold. This spontaneous depolarization occurs as a consequence of decreased potassium diffusion out of the cell and increased diffusion of calcium and sodium into the cell. Once the membrane reaches threshold (−40 mV), calcium channels open, resulting in a “slow” phase 0 depolarization. Repolarization (phase 3) occurs as a consequence of reduced diffusion of calcium and increased diffusion of potassium. The slope of phase 4 determines the speed with which the membrane reaches threshold and another action potential is initiated. Therefore, the slope of phase 4 determines heart rate.

In addition to the SA and AV nodes, spontaneous depolarization can also occur within myocytes of the conducting system (latent pacemakers). These pacemakers are typically slower than the atrial ones. In the presence of complete AV block, slow ventricular escape rhythms originating from these ventricular pacemakers usually occur. In other conditions (e.g., epicardial pacing or after myocardial infarction) nonspecialized cardiac myocytes can take over the pacemaker function of the heart.

Relationship between the Action Potential and the Electrocardiogram

The electrocardiogram (ECG) is the surface recording of the electrical activity of the heart. (Its interpretation is described in Chapter 8.) The relationship between the action potential and the ECG is shown in Figure 1-1. The P wave corresponds to depolarization of the atria during late ventricular diastole. The PR interval is the time from the onset of atrial activation to the onset of ventricular activation—a significant portion of which is taken up by the delay through the AV node. The QRS complex corresponds to ventricular depolarization. The ST segment spans the time when the ventricular myocytes are in phase 2 (plateau) of their action potentials, and the T wave corresponds to ventricular repolarization.

Control of Heart Rate and Cardiac Conduction

The electric activity in the heart is controlled by the autonomic nervous system and circulating epinephrine. Parasympathetic stimulation via the vagus nerve causes the release of acetylcholine that binds to muscarinic receptors on cells within the SA and AV nodes, leading to an increase in potassium permeability within these cells. Increased potassium permeability hyperpolarizes the cell membrane (meaning the membrane potential becomes more negative) and reduces the slope of phase 4 of the action potential (see Fig. 1-2), thus reducing heart rate and prolonging conduction through the AV node (↑PR interval). Intense vagal stimulation (e.g., during laryngoscopy) can lead to asystole (SA block) or complete heart block (AV block).

Sympathetic stimulation causes the release of norepinephrine, which activates β₁ receptors on the cellular membrane. This leads to decreased potassium permeability and increased calcium and sodium permeability, which reduces the extent of repolarization and increases the slope of phase 4 in pacemaker cells (see Fig. 1-2), thus increasing heart rate and shortening the PR interval. Sympathetic nervous system activation also causes increased excitability throughout the entire conducting system.

A completely denervated heart has a resting rate of about 100 beats/min, this being the intrinsic rate of discharge of the SA node. The normal resting heart rate is 60 to 70 beats/min, indicating that parasympathetic tone dominates in the normal heart at rest. Abnormalities of impulse generation and conduction are discussed in Chapter 21.

Systole

Ventricular systole commences with the closure of the mitral and tricuspid valves once ventricular pressure exceeds atrial pressure. The closure of these valves causes the first heart sound. During this early contraction, ventricular pressure rises but there is no change in ventricular volume (isovolumetric contraction). Once the pressure in the left and right ventricles exceeds the pressure in the aorta and pulmonary artery, the aortic and pulmonary valves open and the ejection phase of systole begins. Ejection is initially rapid and then decreases. When the pressure in the ventricles falls below the pressure in the aorta and pulmonary artery, blood flow reverses briefly, causing the aortic and pulmonary valves to close, which in turn results in the second heart sound, at which time systole is complete. (Abnormalities of systole are discussed later in Myocardial Dysfunction.)

Diastole

Diastole commences with the closure of the aortic and pulmonary valves. Intraventricular pressure falls but there is very little increase in ventricular volume (isovolumetric relaxation). Once ventricular pressure falls below atrial pressure, the mitral and tricuspid valves open and ventricular filling begins. Initially, the pressure gradient between the atria and the ventricles is high and ventricular filling is rapid (the phase of rapid early filling). Under normal circumstances about 70% of ventricular filling occurs during this phase. As diastole progresses, ventricular pressure rises and the rate of filling slows (the phase of diastasis). The final 25% of filling during ventricular diastole results from atrial contraction (the phase of atrial systole). When the pressure in the ventricles rises above the pressure in the atria the mitral and tricuspid valves close and diastole is complete. Isovolumetric relaxation and the first part of rapid early filling are active, energy-requiring processes.

In various disease states diastolic filling is abnormal. For instance, with mitral stenosis a high proportion of ventricular filling occurs late in diastole. In this circumstance, shortening of diastole due to tachycardia or loss of atrial systole due to the development of atrial fibrillation can cause marked hemodynamic compromise. A similar situation exists when active relaxation is prolonged (e.g., due to myocardial ischemia or left ventricular hypertrophy). Conversely, in some circumstances (e.g., restrictive cardiomyopathy) a greater proportion of diastolic filling occurs early in diastole. In this circumstance, cardiac output may be improved with modest tachycardia. Diastolic dysfunction is discussed in Chapter 20.

Preload

The functional contractile unit of the myocyte is the sarcomere, which is composed of overlapping thick and thin filaments. The thick filaments contain the protein myosin; the thin filaments contain the proteins actin, tropomyosin, and the troponin complex. Activation of the troponin complex by calcium leads to binding between actin and myosin and contraction of the sarcomere. The force of contraction is partly dependent on the degree of overlap of the thick and thin filaments. In the resting state the sarcomere is 1.8 to 2.0 μm long. Maximum overlap of the filaments occurs at a sarcomere length of about 2.3 μm—that is, when the sarcomere is prestretched above its resting length. This property of the sarcomere underlies the Starling law of the heart, which states that the degree of fiber stretch at end-diastole (preload) determines the force of contraction. In the intact heart, this is represented by the relationship between end-diastolic volume and stroke volume and can be displayed as a ventricular function curve (Fig. 1-8). Over the physiologic range, the relationship is relatively linear; thus, the ejection fraction, which is the slope of the ventricular function curve (SV/EDV), is relatively preload independent. In the ICU, left ventricular end-diastolic volume (or its surrogate, end-diastolic area) may be estimated by echocardiography. The effect of increasing preload on the pressure-volume loop is shown in Figure 1-4.

Figure 1.8 Ventricular function curves. At constant contractility, an increase in left ventricular end-diastolic volume (EDV) results in an increase in stroke volume (SV). This is a clinical application of the Starling law of the heart. The slope of the curve (SV/EDV) is ejection fraction, and over the physiologic range of end-diastolic volumes, it is relatively constant. An increase in contractility shifts the curve upward and to the left such that stroke volume is increased for a given end-diastolic volume. A decrease in contractility shifts the curve downward and to the right such that stroke volume is reduced for a given end-diastolic volume. At very high ventricular volumes, increases in end-diastolic volume may cause a fall in stroke volume.

Left Ventricular Compliance

Because end-diastolic pressure is related to end-diastolic volume through the passive pressure-volume relationship (see Fig. 1-6), end-diastolic pressure is used as a surrogate for end-diastolic volume as a measure of preload. Clinically, left ventricular end-diastolic pressure is usually inferred from the pulmonary artery wedge pressure (PAWP; Chapter 8), which is obtained by means of a pulmonary artery catheter. Unfortunately, the relationship between end-diastolic volume and end-diastolic pressure (ventricular compliance) is not linear. At high ventricular volumes, a small increase in end-diastolic volume is associated with a big increase in end-diastolic pressure (see Fig. 1-6). Furthermore, left ventricular compliance may be altered by disease. For example, compliance is decreased in aortic stenosis and increased in aortic regurgitation (see Fig. 1-7). In some situations, an increase in filling pressure may actually be associated with a reduction in preload (e.g., pericardial tamponade). Thus, the estimation of preload from the PAWP may be misleading (see Chapter 8).^1,2

Ventricular Interactions

The term preload generally refers to left ventricular end-diastolic fiber stretch because it is easier to model mathematically and also because left ventricular preload determines systemic stroke volume. However, when intravenous fluid is administered, right ventricular preload is augmented. Because the left and right ventricles are in series (series interdependence), a change in the loading conditions (preload or afterload) of one ventricle is, within a few cardiac cycles, transmitted to the other ventricle. Thus, increased right ventricular preload leads to an increase in right ventricular output, thereby increasing left ventricular preload.

If the left and right ventricles have normal systolic and diastolic function, and if tricuspid valve function is normal, right ventricular end-diastolic pressure (central venous pressure; CVP) may be used as a surrogate for left ventricular preload. However, when using CVP to estimate preload, the following points should be borne in mind:

Figure 1.9 Output of the left and right ventricles at different atrial filling pressures.

(Redrawn from Guyton AC, Hall JE: Textbook of Medical Physiology, ed 10. Fig. 9.10, p. 104. Philadelphia, WB Saunders, 2000.)

A further effect that must be considered is the fact that the left and right ventricles have a shared septum (parallel interdependence). Severe right ventricular volume overload (e.g., due to tricuspid regurgitation or right ventricular infarction) leads to leftward displacement of the ventricular septum, impairing left ventricular diastolic function. In this situation, administration of fluid to augment left ventricular preload will cause further leftward displacement of the ventricular septum and worsen left ventricular filling. Similarly, severe left ventricular dilatation can impair right ventricular diastolic filling.

Afterload

Afterload can be defined as ventricular wall stress during systole. It is determined by the impedance to ejection and ventricular geometry. Wall stress can be calculated by using the Laplace law:

(1-3)

where r = the radius of the ventricle, ΔP = the pressure gradient across the ventricular wall, and w = wall thickness. Thus, left ventricular afterload is increased by left ventricular dilatation and reduced by left ventricular hypertrophy. The transmural left ventricular pressure gradient, and therefore afterload, is increased by high systemic vascular resistance, high arterial blood pressure, and a noncompliant aorta. Transmural ventricular pressure is reduced by high intrathoracic pressure such as that which occurs with mechanical ventilation and positive end-expiratory pressure (PEEP).

A sudden increase in afterload is associated with an immediate fall in stroke volume. Over the next few beats, stoke volume gradually recovers due to increased diastolic ventricular volume (see Fig. 1-5). However, patients with congestive cardiac failure who are operating on the plateau part of their ventricular function curve (see Fig. 1-8) are unable to increase stroke volume by increasing preload—that is, they have reduced preload reserve. Thus, in patients with congestive cardiac failure, increased afterload (e.g., due to phenylephrine) can cause a precipitous fall in cardiac output. Indeed, afterload reduction is a fundamental principle of the treatment of left ventricular failure.

A sudden fall in afterload is associated with an immediate increase in stroke volume. If venous return is also increased, a sustained increase in stroke volume occurs. This is the mechanism by which cardiac output is increased to supranormal levels in patients with septic shock and also the mechanism by which vasodilating drugs preserve cardiac output in patients with congestive cardiac failure.

Clinically, ventricular wall stress is difficult to measure, and systemic vascular resistance (see later material) derived from a pulmonary artery catheter is commonly used as a surrogate. However, systemic vascular resistance reflects only the nonpulsatile components of afterload and does not take into account ventricular dimensions and the compliance of the arterial tree. This is important clinically. For instance, with severe aortic regurgitation, marked left ventricular dilatation occurs, increasing left ventricular wall stress and afterload. However, measured systemic vascular resistance may be normal or low. Systemic vascular resistance is a particularly unhelpful surrogate of left ventricular afterload in mechanically ventilated cardiac surgery patients who have stiff aortas and dilated ventricles.

Contractility

Contractility is the intrinsic contractile function of the ventricle, independent of preload and afterload. Alterations in contractility are shown on the ventricular function curve in Figure 1-8. An increase in contractility shifts the curve upward and to the left, resulting in an increased stroke volume for a given end-diastolic volume; a decrease in contractility shifts the curve downward and to the right, resulting in reduced stoke volume for the same end-diastolic volume.

Experimentally, contractility may be evaluated by pressure-volume loops. If a number of loops are obtained by varying preload, the coordinates at end-systole form a straight line, known as the end-systolic pressure/volume relationship. The slope of this line is a reasonably load-independent measure of contractility (see Figs. 1-4 and 1-6). Unfortunately, there is no simple method of assessing contractility clinically. Ejection fraction and cardiac output, the commonly used clinical parameters of cardiac performance, are influenced by loading conditions, as explained subsequently.

The force of contraction of a given degree of myocyte overlap is determined by the cytoplasmic concentration of calcium, and this is the basis of alterations in contractility. The intracellular calcium concentration is regulated mainly by the activity of the sympathetic nervous system and circulating epinephrine. Physiologic and pharmacologic control of contractility is discussed in Chapter 3.

Ischemia, Stunning, and Hibernation

Myocardial ischemia results from an imbalance between myocardial oxygen supply and demand (as outlined subsequently in Oxygen Supply and Demand in the Coronary Circulation). If oxygen supply is inadequate to replenish the ATP consumed during the repetitive coupling and uncoupling of actin and myosin molecules, systolic and diastolic dysfunction occurs. Brief periods (<10 min) of total oxygen deprivation or longer periods of reduced oxygen delivery produce dysfunction that is potentially reversible with restoration of the blood supply. More prolonged periods of ischemia result in irreversible myocardial infarction.

Relief of ischemia does not always result in an immediate return of contractile function. Myocardial stunning is temporary myocardial dysfunction that persists following the resolution of an ischemic episode (postischemic dysfunction). This dysfunction occurs in the presence of normal, or near normal, coronary blood flow and in the absence of irreversible cellular damage. Return of contractile function occurs over a period of hours to days. Myocardial stunning arises primarily from reperfusion injury. The mechanisms of reperfusion injury and myocardial stunning are incompletely understood, but they involve the generation of oxygen-derived free radicals (e.g., superoxide, peroxynitrite), altered concentration and sensitivity to intracellular calcium, and endothelial dysfunction.^3,4 Myocardial stunning is encountered in a number of clinical situations, such as after cardiopulmonary bypass and subsequent to reperfusion therapy for an acute coronary syndrome.

Hibernating myocardium is a state of chronic ischemic dysfunction. Hibernating myocardium was initially thought to be caused by low baseline blood flow. However, it is now recognized that baseline blood flow may be near normal and that the primary problem is reduced vasodilator reserve. Small increases in oxygen demand can then provoke acute ischemia that is typically painless.⁵ As with stunning, hibernating myocardium is not associated with permanent disruption of cellular integrity. However, there is some loss of the contractile elements, along with disorganization of the cytoskeletal proteins and interstitial inflammation.⁶ The downregulation of cellular function that occurs with myocardial hibernation serves to reduce myocardial oxygen requirements, helping to minimize cellular damage. Once blood supply has been restored, recovery of normal function is slower than with myocardial stunning, taking some days. If hibernating myocardium is not revascularized, myocardial fibrosis and irreversible dysfunction eventually occur. Hibernating myocardium is a significant cause of congestive cardiac failure in patients with coronary artery disease; the other two causes are infarction and remodeling (see subsequent material).

Collectively, ischemic, hibernating, and stunned myocardium are referred to as viable myocardium. The distinctions among normal, viable, and infarcted myocardium are of tremendous importance in terms of prognosis and treatment options for patients with coronary artery disease, and are discussed in Chapter 5.

Remodeling

Remodeling⁷ is an alteration in ventricular structure that occurs as part of normal growth or due to a pathologic process such as hypertension, valvular heart disease, myocardial infarction, or a cardiomyopathy. The primary feature of remodeling is hypertrophy. Ventricular hypertrophy is an adaptive response to a change in loading conditions that helps to attenuate ventricular dilatation, reduce wall stress (see Equation 1-3), and stabilize contractile function. Ventricular hypertrophy is initiated by myocardial stretch and various neuroendocrine processes.

Chronic pressure overload such as that which occurs with hypertension and aortic stenosis typically results in concentric hypertrophy, in which ventricular wall thickness is increased out of proportion to the increase in chamber size. Chronic volume overload such as that which occurs with aortic and mitral regurgitation typically results in eccentric hypertrophy, in which wall thickness is increased in proportion to chamber size.

Following a myocardial infarction, ventricular remodeling (hypertrophy, dilation, impaired contractility) can occur in sites adjacent to or remote from the zone of infarction, that is, within normal myocardium. The signal for remodeling within this normal myocardium is complex; it involves alterations in ventricular loading conditions, activation of neuroendocrine pathways (including the sympathetic nervous system, the renin-angiotensin-aldosterone system [RAAS], and natriuretic peptides; see subsequent material), and inflammation within infarcted and noninfarcted myocardium.

Unchecked, ventricular remodeling can eventually result in irreversible cardiac dysfunction due to myocardial fibrosis. However, if appropriate therapy is introduced early enough, remodeling can be interrupted or reversed. If possible, treatment should be directed to the underlying cause: for valvular heart disease, this involves valve repair or replacement; and for hypertension, it involves effective control of blood pressure. Following myocardial infarction, pharmacologic antagonists (angiotensin-converting enzyme [ACE] inhibitors, β blockers, aldosterone antagonists) to the neuroendocrine pathways involved in the remodeling process have proven to be partially effective (see Chapter 19).

Determinants of Vascular Resistance

For laminar flow, resistance is determined by the radius (r) of the vessel, the length of the vessel (l), and the viscosity (η) of the blood:

(1-7)

On the basis of this equation it is seen that resistance is inversely proportional to the 4th power of the radius of the vessel; that is, a fourfold reduction in diameter increases resistance 256 times! The muscular arterioles, by virtue of their ability to alter their caliber dramatically in response to various physiologic signals, are the main sites at which systemic vascular resistance is determined. Another contributor to systemic vascular resistance is blood viscosity, which is largely determined by hematocrit. Doubling of the hematocrit from 0.3 to 0.6 increases blood viscosity fivefold to tenfold. Elevated hematocrit, such as that which occurs in patients with cyanotic heart disease or chronic hypoxemia, can cause clinically important increases in systemic vascular resistance. For turbulent flow through atherosclerotic arteries or stenotic valves, flow is not directly proportional to the pressure gradient as shown in Equation 1-4; it is proportional to the square root of the pressure gradient. Thus, for a given perfusion pressure, flow is reduced in a system with turbulent flow.

Blood Pressure

Blood is ejected into the aorta in a pulsatile fashion. The pulse pressure is the difference between the systolic and diastolic arterial pressures and is normally in the range of 30 to 60 mmHg. Pulse pressure is determined mainly by stroke volume and the compliance of the arterial tree, particularly the aorta. An increase in stroke volume is associated with an increase in pulse pressure. The aorta is a compliant structure that expands during systole to accommodate the stroke volume and recoils during diastole as the stroke volume leaves the aorta. In this way, the aorta damps down the magnitude of the pulse pressure. With increasing age, the compliance of the aorta decreases and the damping effect on the arterial waveform is diminished. This leads to an increase in pulse pressure, which is caused mainly by an increase in the systolic component of blood pressure. Pulse pressure diminishes progressively as blood moves distally within the arterial system so that flow is essentially pulseless at the level of the capillary. Alterations in the arterial pressure waveform at different sites within the arterial tree and in various disease states are discussed in Chapter 8.

The pulse pressure wave is transmitted rapidly through the arterial tree to the periphery, increasing in velocity from about 3 m/sec in the proximal aorta to more than 20 m/sec in the small arteries. In contrast, the velocity of the blood itself is much slower, as discussed further on.

MAP is the area under the pressure wave (∫P.dt) divided by the cardiac period, or the average pressure throughout the cardiac cycle. MAP can be empirically estimated from the diastolic arterial pressure (DAP) and the pulse pressure (PP):

(1-8)

MAP is the driving pressure for all organs in the body except the lungs and is the subject of tight homeostatic control (see Control of Blood Pressure). The normal value for MAP in an adult at rest is 70 to 90 mmHg, but it changes with activity, age, and disease. Between the aorta and the arterioles, mean pressure changes very little. Consistent with their role as resistance vessels, the pressure drop across the arterioles is substantial (>40 mmHg). At the arteriolar end of the capillary the pressure is about 30 mmHg, dropping to 15 mmHg at the venous end of the capillary, and to about 5 mmHg within the right atrium.

Bernoulli Principle

It is usual to refer to the pressure gradient between two points as the driving force of blood flow, but more accurately, the driving force is the total energy gradient (ΔE). Bernoulli’s principle states that, apart from frictional losses, this energy is constant and is made up of pressure energy (due to the pumping of the heart), gravitational energy, and the kinetic energy of the moving blood:

(1-9)

where E is the energy per unit volume, P is pressure, ρ is the density of the fluid, v is the velocity of the fluid, and h is the height of the fluid column from the point of measurement to some reference point. Energy may be swapped between these forms. For instance, when velocity and hence kinetic energy in a flowing fluid increase, pressure must decrease (assuming h remains constant). In most parts of the circulation, flow velocity is relatively small, hence most energy is in the form of pressure. However, in some situations—for instance, when blood flows at increased velocity through a stenotic aortic valve (see subsequent discussion)—there is a drop in pressure. The clinical significance of this is explained in Coronary Circulation.

Blood Velocity

For a given flow (Q), the velocity (v) of blood is proportional to the cross-sectional area (CSA) of the blood vessels:

(1-10)

Because the flow (cardiac output) is the same throughout the circulation, and because the total cross-sectional area of the blood vessels is greatest in the microcirculation, the velocity of blood flow is slowest in the capillaries and greatest in the large blood vessels such as the aorta. Average blood flow velocity at rest is 0.3 m/sec in the aorta and just 1 mm/sec in the capillaries. Blood flow is pulsatile in the arteries, so flow velocity can vary markedly. At rest, the peak velocity in the aorta is about 1 m/sec and this may increase to more than 3 m/sec during exercise, when cardiac output is increased. Similarly, blood velocity increases at a site of pathologic narrowing (e.g., aortic coarctation, aortic valve stenosis). For instance, if the aortic valve cross-sectional area falls from 3 cm² to 0.5 cm² but cardiac output remains unchanged, peak aortic velocity increases sixfold, typically from about 1 m/sec to 6 m/sec. This is discussed further in Chapter 7.

Wall Stress and Aneurysm Growth

The Laplace relationship (see Equation 1-3) in the heart is also an important principle when considering arterial aneurysms. Untreated, arterial aneurysms progressively dilate and eventually rupture. An increase in the diameter of the vessel wall leads to an increase wall stress, which in turn leads to further damage to and dilatation of the vessel wall and further increases in wall stress. Also, based on the Bernoulli relationship described earlier, as blood flow velocity decreases in the dilated vessel, pressure energy increases, causing further increases in wall stress. This cycle of increasing wall stress and progressive dilatation continues in a self-reinforcing cycle until the vessel finally ruptures.

Coronary Circulation

Myocardial oxygen requirements are very high; even in the resting state, myocardial oxygen consumption is 8 ml/100 g/min, which is 20 times greater than in resting skeletal muscle. Adequate oxygen supply is achieved through a combination of high blood flow (about 80 ml/100 g/min at rest) and a high oxygen extraction. Coronary sinus oxygen saturation is about 35% at rest, the lowest venous saturation of any organ in the body.

During systole, high pressures develop within the wall of the left ventricle such that the pressure within the subendocardium is close to the pressure within the chamber (the pressure within the epicardium is much lower). Coronary flow to the right ventricle and atria occurs during both systole and diastole, but there is very little blood flow to the left ventricle during systole, especially to the subendocardium. Diastole is shorter at high heart rates, so tachycardia can further compromise left ventricular subendocardial blood flow.

Autoregulation in the coronary circulation is well developed. Under normal circumstances, the lower limit of autoregulation occurs at a coronary perfusion pressure of about 50 mmHg. Left ventricular coronary perfusion pressure (CPP) may be defined as:

(1-11)

where DAP is diastolic arterial pressure and LVEDP is left ventricular end-diastolic pressure. Coronary perfusion pressure may fall below the lower autoregulatory limit in the settings of diastolic hypotension (e.g., due to excessive arteriolar vasodilation or aortic regurgitation) and raised left ventricular end-diastolic pressure (e.g., due to congestive cardiac failure). With aortic stenosis, left ventricular end-diastolic pressure may be elevated, but the pressures in the aortic root may be low because of the Bernoulli principle explained earlier, thus compromising coronary perfusion pressure.

Coronary atherosclerosis is an important limiting factor for coronary blood flow. In the presence of fixed coronary artery stenoses and maximal arteriolar dilatation (such as occurs during exercise or stress), coronary flow is dependent on the extent of the coronary narrowing and perfusion pressure, not on arteriolar tone. Thus, autoregulation is lost, and coronary flow is pressure dependent. Furthermore, in regions of coronary stenoses, blood flow may be turbulent, increasing frictional losses that further reduce perfusion pressure and coronary flow. The determinants of myocardial oxygen supply and demand are discussed later in this chapter.

Pulmonary Circulation

The pulmonary vascular bed is a low-pressure, low-resistance circulation. The normal resistance in the pulmonary circulation is one tenth that of the systemic circulation, and it requires a transpulmonary perfusion gradient of just 5 to 10 mmHg to drive blood through the lungs. The transpulmonary gradient is the difference between the mean pulmonary artery pressure and the left atrial pressure. A value greater than 10 mmHg suggests increased pulmonary vascular resistance. In keeping with the low pressure, the walls of the pulmonary artery and its branches are normally thin and contain little smooth muscle. The pulmonary capillaries are surrounded by gas-filled spaces, the alveoli. Because the pulmonary capillaries are thin walled, a change in alveolar pressure can cause the capillaries to collapse or distend. In a spontaneously breathing erect subject, the alveolar pressure at the apex of the lung may be greater than the capillary pressure, causing collapse of the capillaries and a region of no-flow (Fig. 1-11). This zone of no-flow is increased by factors that reduce capillary hydrostatic pressure (e.g., hypovolemia) and raise intrathoracic pressure (e.g., positive pressure ventilation and PEEP). As explained later in Alveolar Dead Space, these regions of no blood flow constitute alveolar dead space and can contribute to hypercarbia.

Figure 1.11 Distribution of blood flow to the lungs. The lung is divided into three West zones (after the physiologist John B. West), based on the relative differences in the pulmonary arterial, pulmonary venous, and alveolar pressures. In West zone 3, pulmonary arterial and venous pressures exceed alveolar pressure, and blood flow is determined by the arterial-venous pressure difference. In West zone 2, pulmonary arterial pressure, but not pulmonary venous pressure, exceeds alveolar pressure, and blood flow is determined by the arterial-alveolar pressure difference. In West zone 1, alveolar pressure exceeds pulmonary arterial and pulmonary venous pressure, and no flow occurs. In spontaneously breathing healthy subjects, West zone 1 does not normally exist but with positive pressure ventilation (alveolar) or hypovolemia (arterial), it may be substantial.

(Redrawn from JB West et al: J Appl Physiol 19:713, 1964.)

The response of the pulmonary vascular bed to an increase in pulmonary arterial pressure is a reduction in pulmonary vascular resistance. This is achieved by a combination of capillary recruitment (particularly in the poorly perfused apical regions of the lungs) and capillary distension. In this way, a dramatic increase in pulmonary flow can be achieved with minimal increase in pulmonary arterial pressure. Because myocardial pressure work consumes more energy than volume work, the increased workload of the right ventricle during exercise is minimized.

Another important determinant of pulmonary vascular resistance is alveolar oxygen tension (Pao₂). Within individual lung units, a fall in the Pao₂ results in pulmonary arteriolar vasoconstriction. This process is known as hypoxic pulmonary vasoconstriction, and it has a very important role in matching ventilation and perfusion within the lung and maintaining systemic arterial oxygen tension (Pao₂) (see Matching Ventilation and Perfusion later in this chapter). Hypoxic vasoconstriction becomes significant when the alveolar oxygen tension falls below about 9 kPa (70 mmHg). Pulmonary vascular resistance is also influenced by pH: acidosis (and therefore hypercarbia) leads to increased resistance. The causes and treatment of elevated pulmonary vascular resistance are discussed in Chapter 24.

Cerebral Circulation

The brain has a high blood flow (about 50 ml/100 g/min) that is tightly autoregulated. Cerebral blood flow is strongly influenced by arterial carbon dioxide tension (Paco₂): a decrease in Paco₂ is associated with cerebral vasoconstriction and a fall in cerebral blood flow; a rise in Paco₂ is associated with cerebral vasodilation and an increase in cerebral blood flow. Severe hypoxia (Pao₂ <8 kPa or 60 mmHg) is associated with cerebral vasodilation and an increase in cerebral blood flow. Cerebral perfusion pressure is the difference between MAP and CVP or intracranial pressure—whichever is the highest. Raised intracranial pressure (e.g., due to an intracerebral bleed) will potentially reduce CPP below the lower autoregulatory limit, thereby compromising cerebral blood flow. In this situation, augmentation of MAP to preserve cerebral perfusion pressure is indicated. Hyperventilation has been used in the past for the treatment of elevated intracranial pressure, but the resultant fall in cerebral blood flow is the reason this strategy is no longer recommended.

Splanchnic Circulation

Under normal circumstances blood flow to the gut is determined by local metabolic activity; for instance, blood flow to the small bowel may double after a meal. The exact mechanism of splanchnic blood flow autoregulation is not known but probably involves vasodilatory substances released from the gut mucosa, such as cholecystokinin and vasoactive intestinal peptide.

In contrast to the cerebral and coronary circulations, the gastrointestinal tract is under a high level of sympathetic nervous system control. Under conditions of circulatory shock, intense splanchnic vasoconstriction releases blood from venous reservoirs into the central circulation but may also induce gut and hepatic ischemia. This ischemia, with or without subsequent reperfusion injury, can contribute to systemic inflammation (see Chapter 2).

Autonomic Nervous System

The acute control of blood pressure in response to changes in metabolic activity or circulating volume is determined primarily by the autonomic nervous system and the baroreceptor reflex. Baroreceptors are stretch receptors located in the carotid sinus and the aortic arch. They alter their rate of discharge according to the arterial blood pressure: as blood pressure rises, the rate of discharge increases; as blood pressure falls, the rate of discharge decreases. In addition to the baroreceptors, the walls of the atria contain stretch receptors that respond to changes in atrial pressure. Afferent pathways (i.e., to the brain) from the baroreceptors and atrial stretch receptors pass via the glossopharyngeal and vagus nerves to the vasomotor center in the medulla. The efferent pathways (i.e., from the brain) are primarily noradrenergic sympathetic fibers to α₁ receptors in the peripheral circulation and to β₁ receptors in the heart. Stimulation of α₁ receptors within the vasculature leads to arteriolar and venous constriction, which increases afterload and preload, respectively. Stimulation of β₁ receptors on the heart results in tachycardia and increased contractility, which increases cardiac output and MAP. Tachycardia is further augmented by a reduction in parasympathetic tone.

Epinephrine and, to a lesser extent, norepinephrine are released into the blood from the adrenal medulla under the influence of the sympathetic nervous system. Epinephrine has actions similar to those of norepinephrine at α₁ and β₁ receptors, but it also stimulates vasodilatory β₂ receptors, particularly in the arterioles of skeletal muscle, the heart, and the liver. Pharmacologic manipulations of the sympathetic nervous system are discussed in Chapter 3.

Renin-Angiotensin-Aldosterone System

The RAAS is involved primarily in the long-term control of blood pressure by the renal regulation of extracellular fluid and vascular volume, as described in renal function below. However, the RAAS also plays an important role in the short-term control of blood pressure during pathologic states.

Renin is secreted by the kidney in response to: (1) sympathetic stimulation; (2) reduced sodium load in the renal tubule (see Glomerular Function and Renal Blood Flow); (3) a fall in pressure within the glomerulus. Renin causes the formation of angiotensin I from circulating angiotensinogen. Angiotensin I is converted to angiotensin II in the lungs under the action of ACE. Angiotensin II is a potent vasoconstrictor and also stimulates release of aldosterone from the adrenal cortex. Aldosterone causes sodium retention and potassium loss within the distal nephron. Circulating levels of angiotensin II and aldosterone are elevated in hemorrhagic shock, cardiac failure, and essential hypertension.

The RAAS is modified therapeutically by ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists (see Chapter 3).

Vasopressin

Vasopressin (antidiuretic hormone; ADH) is a peptide released from the posterior pituitary in response to an increase in serum osmolarity and hypovolemia. The main actions of vasopressin are antidiuresis and vasoconstriction. An increase in serum osmolarity to above 285 mOsm/l (e.g., due to water loss or as a consequence of aldosterone-mediated renal sodium retention) leads to increased vasopressin secretion, resulting in water retention within the distal tubule of the kidney (see Tubular Function). This process ensures that water is always retained with sodium and that serum osmolarity is tightly controlled.

Nonosmotic release of vasopressin occurs in response to hypovolemia (mediated by atrial stretch receptors) and hypotension (mediated by arterial baroreceptors). In addition to antidiuresis, high concentrations of vasopressin cause intense vasoconstriction in most vascular beds except the cerebral and coronary circulations. Thus, in the presence of hypovolemia, vasopressin helps maintain blood pressure and facilitates the redistribution of flow to essential organs. Vasopressin secretion in response to hypovolemia occurs even if osmolarity is normal. Thus, circulating volume is defended at the expense of tonicity. The therapeutic use of vasopressin is described in Chapter 3.

Natriuretic Peptides

Three natriuretic peptides are recognized: atrial natriuretic peptide; brain natriuretic peptide (also called B-type natriuretic peptide); and C-type natriuretic peptide. Atrial natriuretic peptide is secreted from the atria under the influence of atrial stretch and various hormones, including catecholamines, vasopressin, and the endothelins. Brain natriuretic peptide, despite its name, is secreted mainly from the left and right ventricles in response to altered wall stress. C-type natriuretic peptide is found within the central nervous system, kidney, and vascular endothelium.

The natriuretic peptides have a role as counterregulatory hormones to angiotensin II, norepinephrine, and the endothelins. The natriuretic peptides reduce blood pressure and circulating volume by a range of actions, including suppression of aldosterone production and sympathetic nervous system activity, arteriolar and venous vasodilation, and renal natriuresis (sodium loss) and diuresis.

Plasma levels of brain natriuretic peptide are elevated in a range of cardiac conditions, including congestive heart failure,¹¹ aortic stenosis,¹² pulmonary embolus,¹³ and shock¹⁴ and following cardiac surgery.¹⁵ Plasma levels of brain natriuretic peptide are useful in distinguishing cardiac from noncardiac causes of acute dyspnea¹⁶ and in predicting the outcome of congestive cardiac failure.¹¹ Brain natriuretic peptide is available in a human recombinant form (nesiritide) for the treatment of acute heart failure (see Chapter 3).

Nitric Oxide

Nitric oxide is a small, unstable (half-time of 6 sec), vasodilatory molecule that is synthesized from the amino acid L-arginine and released from vascular endothelium. Low levels (picomolar) of nitric oxide are produced under the influence of the enzyme constitutive nitric oxide synthetase (cNOS) as part of normal homeostasis. The main stimulus for cNOS-mediated nitric oxide production is vascular shear stress. This is thought to be the mechanism of flow-induced vasodilation, in which large arteries dilate in response to distal arteriolar dilatation. Nitric oxide also has antiplatelet, antiinflammatory, and antiatherosclerotic functions.¹⁷ Reduced production of nitric oxide has been linked to a range of cardiovascular disease, including essential hypertension¹⁸ and coronary atherosclerosis.¹⁹ Conversely, in systemic inflammatory states (see Chapter 2), high quantities (nanomolar) of nitric oxide are synthesized under the influence of the enzyme inducible nitric oxide synthetase (iNOS) and contribute to pathologic vasodilation and cellular injury.²⁰

Inhaled nitric oxide is used as a vasodilator of pulmonary arterioles to reduce pulmonary vascular resistance and improve the matching of ventilation and perfusion (and therefore Pao₂) within the lung. The drugs nitroglycerin and nitroprusside function as vasodilators by acting as donors of nitric oxide (see Chapter 3).

Endothelins

Endothelins²¹ (endothelin 1, 2, and 3) are vasoconstrictor peptides synthesized by endothelium. As with nitric oxide, endothelins are produced and act locally (paracrine effect). Plasma levels increase rapidly in response to a reduction in blood pressure (e.g., due to adopting the upright position). The synthesis and release of endothelins occur mainly in response to direct mechanical effects on the endothelium. However, their levels are augmented by norepinephrine, vasopressin, and angiotensin and are inhibited by nitric oxide, atrial natriuretic peptides, and prostacyclin. Endothelin levels are increased in all forms of shock but particularly in septic shock. A nonselective endothelin antagonist, bosentan, is used in the treatment of pulmonary hypertension (see Chapter 24).

Other Substances

A range of other substances modulate vascular tone in normal and pathologic states, including prostaglandins, thromboxanes, leukotrienes, cytokines, and the products of the kinin, coagulation, and complement cascades.

Tissue Edema

Fluid that is lost from the capillary is normally returned to the circulation via the lymphatics. However, if fluid losses overwhelm the lymphatic system, tissue edema develops. This can occur in the following circumstances:

Hypovolemia and Prerenal Azotemia

Under the influence of high levels of vasopressin and aldosterone, modest hypovolemia results in the production of a small volume of highly concentrated urine (>500 mOsm/l) that has a low sodium concentration (<20 mmol/l). However, within the autoregulatory range of blood pressure, renal blood flow and GFR remain relatively normal.

Below the autoregulatory range, renal blood flow and GFR decrease. A reduction in GFR leads to a decrease in the excretion of nitrogenous wastes such as urea and creatinine, resulting in increased serum levels of these compounds. This is known as prerenal azotemia. At this stage tubular function remains intact and hypertonic urine can still be generated. Prerenal azotemia may be reversed by restoration of renal blood flow, but if it persists it can lead to acute tubular necrosis.

Renal autoregulation is influenced by a number of factors. Chronic hypertension may reset the renal autoregulation range to a higher level. Autoregulation may be lost in certain disease states such as sepsis—in which case renal blood flow and GFR become pressure dependent. Inhibition of renal vasodilatory prostaglandin production by nonsteroidal antiinflammatory drugs can reduce renal blood flow, particularly in the settings of atherosclerotic renovascular disease, congestive cardiac failure, and hypovolemia. Thus, prerenal azotemia and secondary acute tubular necrosis can occur despite a MAP above the lower limit of renal autoregulation.

Acute Tubular Necrosis

As noted, the renal medulla is particularly sensitive to hypoxic injury, especially the metabolically active epithelial cells of the proximal convoluted tubule and the thick ascending limb of the loop of Henle. Damage to the tubular epithelial cells results in loss of the hypertonic medullary interstitium and the inability to generate concentrated urine. Injured tubular cells may slough from their basement membrane and, along with other inflammatory debris, cause tubular obstruction. Tubular obstruction causes increased pressure within the Bowman capsule, further reducing GFR. An inflammatory response within the medulla can result in leukocyte adhesion and microaggregate formation within the vasa recta, further reducing medullary oxygen delivery.

Urine output is low or may cease entirely due to the greatly reduced GFR and tubular obstruction. Loss of the hypertonic medulla causes urinary osmolarity to fall and urinary sodium to rise (>40 mmol/l). In addition to prerenal tubular ischemia, tubular dysfunction can also occur as the result of toxicity to drugs, particularly radiographic contrast agents and antibiotics (gentamicin, amphotericin).

Depending on the severity of the renal insult and on other factors, such as the presence of preexisting chronic renal dysfunction, the restoration of renal blood flow may result in a partial or complete return of renal function. Typically, during the recovery phase urine-concentrating ability remains impaired, and patients produce large volumes of diluted urine. Azotemia may persist or even worsen during this phase.

Mixed Venous Oxygen Saturation

In Equation 1-15 it is seen that mixed venous oxygen saturation (Svo₂) depends on: (1) O₂ (2) Sao₂; (3) hemoglobin concentration; (4) cardiac output. If Sao₂ and hemoglobin concentration are within normal limits, the Svo₂ provides a guide to whether cardiac output is appropriate for metabolic requirements. For example, if cardiac output is low (e.g., 2 l/min/m²) but Svo₂ is normal (e.g., 70%), global oxygen delivery is adequate. Conversely, if cardiac output is high (5 l/min/m²) but Svo₂ is low (e.g., 50%), global oxygen delivery is inadequate. However, the situation is complicated by the fact that Svo₂ does not provide a measure of the adequacy of tissue oxygenation. For instance, the widespread vasodilation that occurs with systemic inflammation may result in the opening of cutaneous arteriovenous shunts, while at the same time blood flow through the microcirculation may be greatly reduced (see Chapter 2). In this situation, oxygenated blood bypasses the tissues, resulting in a normal or elevated Svo₂ despite severe tissue hypoxemia.

Oxygen Supply and Demand in the Coronary Circulation

In the absence of hypoxia or severe anemia, myocardial oxygen delivery is determined by the factors that control myocardial blood flow described earlier. Myocardial oxygen consumption is determined by preload, afterload, contractility, and heart rate. Therefore, myocardial oxygen consumption is increased by left ventricular dilatation, (e.g., heart failure) and by the requirement for high intraventricular pressure (e.g., aortic stenosis, arterial hypertension).

In most tissues, an increase in oxygen demand is met by increased oxygen extraction and increased oxygen delivery. However, in the coronary circulation this may not be possible for two reasons. First, even under normal circumstances oxygen extraction in the coronary circulation is very high (about 65%; see earlier discussion). Second, in the presence of fixed coronary stenoses, it may not be possible to increase oxygen delivery by metabolically mediated vasodilation.

In diverse clinical situations it is often difficult to tell how manipulations of the overall hemodynamic state affect the balance of myocardial oxygen supply and demand, particularly in patients with heart failure or coronary artery disease. For instance, the administration of a vasopressor such as norepinephrine will increase left ventricular afterload and therefore increase myocardial oxygen consumption. However, by increasing perfusion pressure, oxygen delivery may be augmented. Whether the net effect is beneficial or harmful depends on the clinical situation. In a septic hypotensive patient with fixed coronary stenoses, the overall effect of norepinephrine is likely to be beneficial, but in a normotensive patient with borderline perfusion of the subendocardium, norepinephrine may worsen myocardial ischemia. A particular dilemma is the combination of low cardiac output (manifesting as a low Svo₂) and coronary artery disease, for instance, a patient who suffers cardiogenic shock following a large anterior myocardial infarction. In this situation, most manipulations to increase global oxygen delivery will increase myocardial oxygen demands and potentially exacerbate myocardial ischemia. However, four interventions that do make physiologic sense in this situation are: (1) reducing oxygen consumption with sedation, neuromuscular blockade, and the avoidance of hyperthermia; (2) insertion of an intraaortic balloon pump (see Chapter 40); (3) treating anemia; (4) insulin therapy (see Chapter 36). The administration of insulin increases the uptake of glucose and reduces the utilization of free fatty acids by the heart, which has an oxygen-sparing effect.²³

Dead-space Ventilation

The lungs can be divided into the conducting airways (trachea, bronchi, bronchioles) and the respiratory zone (respiratory bronchioles and alveoli). Gas exchange takes place only in the respiratory zone. Minute ventilation _E) is the total (expired) ventilation that occurs in 1 minute and is composed of alveolar ventilation _A) and dead space ventilation _D).

(1-16)

At rest in the adult, minute ventilation is about 7.5 l, of which alveolar ventilation constitutes 5 l and dead space ventilation 2.5 l. Dead-space ventilation is wasted ventilation that does not contribute to gas exchange. It is composed of: (1) anatomic dead space; (2) apparatus dead space; and (3) alveolar dead space (or physiologic dead space). Anatomic dead space is the volume of the conducting airways and, in health, it constitutes the majority of total dead space. Apparatus dead space is the volume of the rebreathing components of the ventilator circuit (mainly the endotracheal tube and filter) and does not normally contribute significantly to total dead space. Alveolar dead space is that part of the respiratory zone that is ventilated but not perfused. Alveolar dead space is normally insignificant but can increase dramatically in the presence of lung disease (see subsequent section V/Q Mismatch and Intrapulmonary Shunting) and with hypovolemia and mechanical ventilation (see previous section Pulmonary Circulation). Clearly, if minute ventilation is unchanged but dead space ventilation increases, alveolar ventilation must fall.

Alveolar Ventilation and Paco₂

Paco₂ is inversely proportional to alveolar ventilation and directly proportional to the rate of production of carbon dioxide co₂):

(1-17)

By examining Equations 1-16 and 1-17, all of the causes of hypercarbia can be understood:

Lung Compliance

A plot of lung volume against pressure throughout the respiratory cycle yields a loop such as that shown in Figure 1-15. The slope of the curve (ΔV/ΔP) represents the compliance of the lung and chest wall. Compliance changes throughout the respiratory cycle depending on the lung volume. Compliance is reduced at very low and very high lung volumes; that is, a greater distending pressure is required to achieve the same volume change. Compliance is determined mainly by the elastic properties of the lungs and chest wall and by the surface tension of the liquid film lining the alveoli.

Figure 1.15 Static pressure-volume curve for the respiratory system during expiration from total lung capacity (TLC) to residual volume (RV). The volume at the end of a quiet expiration is functional residual capacity (FRC). The slope of the curve (ΔV/ΔP) is compliance. Compliance is reduced at very low and very high lung volumes. The curves for the lung and chest wall are also shown. The total compliance of the respiratory system is the sum of the reciprocals of the lung and chest wall compliances (1/Ctotal = 1/Clungs + 1/Cchest). A static compliance curve is obtained by having a subject slowly expire through a spirometer. A tap is then closed and the subject relaxes the respiratory muscles; after a few seconds the pressure is recorded. The process is repeated at multiple lung volumes. This static curve is quite different from the dynamic pressure-volume loops that are recorded during mechanical ventilation (see Chapter 29).

(Modified from Rahn H et al: Am J Physiol 146:161, 1946.)

The volume in the lungs at the end of quiet expiration is the functional residual capacity (FRC). FRC is determined by the balance between the elastic forces of the lungs (which tend to collapse the lungs) and the elastic forces of the chest wall (which tend to expand the lungs).

Compliance is reduced in many disease states, including pulmonary edema, acute respiratory distress syndrome, pneumonia, atelectasis, empyema, fibrotic lung disease, and restricted chest wall or diaphragmatic movement (e.g., obesity, chest binders, intraabdominal sepsis). Reduced compliance results in:

Airway Resistance

Airway resistance is the pressure difference between mouth and alveoli, divided by airflow. The chief sites of airway resistance are the medium-sized bronchi. Airway resistance is increased at low lung volumes due to reduced airway diameter and at high gas-flow rates due to turbulent flow (e.g., during forced expiration). Diseases in which airway narrowing occurs, such as chronic obstructive pulmonary disease and asthma, increase airway resistance.

Increased airway resistance can result in the following:

Work of Breathing

Inspiration is an active process in which energy is expended to overcome the elastic recoil of the lungs and the resistance to gas flow through the air passages. Expiration is normally passive; the potential energy stored in the deformed elastic tissues is used to overcome airway resistance. If airway resistance is greatly increased, expiration may become active.

At rest, the work of breathing is very low, consuming only about 5% of total oxygen consumption, but in the presence of lung disease in which lung compliance is reduced or airways resistance is increased, the work of breathing increases substantially. Within certain limits, increased work of breathing can be compensated for by increased effort, but with progressively increasing work of breathing, exhaustion develops, minute ventilation falls, and hypercarbia develops.

Pao₂ and Hypoxemia

The normal value of Pao₂ for an adult at rest, breathing air at sea level, is 11 to 14.5 kPa (82 to 102 mmHg). Values below this level constitute hypoxemia. There are five potential causes of hypoxemia: (1) low inspired partial pressure of oxygen (e.g., breathing air at altitude); (2) hypoventilation; (3) impaired diffusion of oxygen across the alveolar-capillary membrane; (4) intracardiac shunting; and (5) impaired ventilation/perfusion (V/Q) matching within the lung (including intrapulmonary shunting). Of these, only hypoventilation, impaired V/Q matching, and intracardiac shunting are important clinically—at least in hospitals close to sea level.

When breathing air at sea level with normal lungs, Po₂ progressively falls from the inspired gas (Pio₂ ≈ 20 kPa or 150 mmHg) to the alveolus (Pao₂ ≈ 14 kPa or 105 mmHg) to the arterial blood (Pao₂ ≈ 12 kPa or 90 mmHg). The main cause of the drop in Po₂ between the gas inspired and the lungs is the displacement of oxygen from the alveoli by carbon dioxide and the consumption of oxygen. The main cause of the drop between the alveoli and arterial blood is V/Q mismatch in the lungs.

Hypoventilation

Hypoventilation causes hypoxemia by reducing Pao₂, mainly by displacing oxygen with carbon dioxide. This can be quantified by the alveolar air equation:

(1-18)

where RQ is the respiratory quotient, the ratio of carbon dioxide production to oxygen consumption:

(1-19)

RQ varies between 0.7 and 1, depending on which energy substrate is being utilized; on a normal diet it is about 0.8. The alveolar air equation has important clinical implications. For example, if a patient breathing room air hypoventilates sufficiently to double her or his Paco₂ from 5 to 10 kPa (38 to 75 mmHg), the Pao₂ will fall from 13.75 to 7.5 kPa (103 to 56 mmHg)—a substantial reduction. However, if the patient then breathes supplemental oxygen to increase the fraction of inspired oxygen to 33% (P_Io₂ = 33 kPa or 248 mmHg), Pao₂ increases to 20 kPa (150 mmHg) which, in the absence of major V/Q mismatch, results in a Pao₂ of about 18 kPa (135 mmHg). This example illustrates the fact that hypoxemia due to pure hypoventilation can be corrected easily by supplemental oxygen.

V/Q Mismatch and Intrapulmonary Shunting

Matching of Ventilation and Perfusion.

For efficient gas exchange to take place there must be a match between ventilation and perfusion throughout the lung. The lung can be thought of as being composed of multiple units, each with its own V/Q ratio (Fig. 1-16). Ideally, each unit would have a V/Q ratio of 1. In practice, V/Q ratios vary throughout the lung due to regional differences in ventilation and blood flow.

Figure 1.16 Schematic to illustrate the causes of ventilation-perfusion mismatch within the lung. See text for details.

Lung units with a V/Q ratio less than 1 have inadequate ventilation relative to perfusion. In the extreme form, no ventilation occurs (V/Q = 0), and intrapulmonary shunting exists; this is the situation in consolidated or atelectatic lung tissue. Conversely, lung units with a V/Q ratio greater than 1 have inadequate perfusion relative to ventilation. In the extreme form, no perfusion occurs (V/Q = ∞), and alveolar dead space exists; this is the situation that occurs within West zone 1 (see Fig. 1-11 and Pulmonary Circulation, discussed previously) and downstream from a pulmonary embolus.

Most forms of acute and chronic lung disease are characterized by increased heterogeneity of V/Q ratios, with regions of relative shunt and regions of relative dead space. The main way in which the impact of V/Q mismatch on Pao₂ and Paco₂ is minimized is by means of hypoxic pulmonary vasoconstriction, described earlier in Pulmonary Circulation.

Consequences of Hypoxemia and Hypercarbia