a Cardiac Output

The pulmonary vascular bed is a high-flow, low-pressure system in health. As increases, pulmonary vascular pressures increase minimally.¹⁸ However, increases in distend open vessels and recruit previously closed vessels. Accordingly, pulmonary vascular resistance (PVR) drops because the normal pulmonary vasculature is quite distensible (and partly because of the addition of previously unused vessels to the pulmonary circulation). As a result of the distensibility of the normal pulmonary circulation, an increase in Ppa increases the radius of the pulmonary vessels, which causes PVR to decrease (Fig. 5-7). Conversely, the opposite effect occurs within the pulmonary vessels during a decrease in . As decreases, pulmonary vascular pressures decrease, the radii of the pulmonary vessels are reduced, and PVR consequently increases. The pulmonary vessels of patients with significant pulmonary hypertension are less distensible and act more like rigid pipes. In this setting, Ppa increases much more sharply with any increase in because PVR in these stiff vessels does not decrease significantly due to minimal expansion of their radii.

Figure 5-7 Passive changes in pulmonary vascular resistance (PVR) as a function of pulmonary artery pressure (Ppa) and pulmonary blood flow (): PVR = Ppa/. As increases, Ppa also increases, but to a lesser extent, and PVR decreases. As decreases, Ppa also decreases, but to a lesser extent, and PVR increases.

(Redrawn with modification from Fishman AP: Dynamics of the pulmonary circulation. In Hamilton WF, editor: Handbook of physiology. Section 2: Circulation, vol 2, Baltimore, 1963, Williams & Wilkins, p 1667.)

Understanding the relationships among Ppa, PVR, and during passive events is a prerequisite to recognition of active vasomotion in the pulmonary circulation (see Lung Volume). Active vasoconstriction occurs whenever decreases and Ppa either remains constant or increases. Increased Ppa and PVR have been found to be “a universal feature of acute respiratory failure.”¹⁹

Active pulmonary vasoconstriction can increase Ppa and Ppv, contributing to the formation of pulmonary edema, and in that way it has a role in the pathophysiology of adult respiratory distress syndrome (ARDS). Active vasodilation occurs whenever increases and Ppa either remains constant or decreases. When deliberate hypotension is achieved with sodium nitroprusside, often remains constant or increases, but Ppa decreases, and therefore so does PVR.

b Lung Volume

Lung volume and PVR have an asymmetric, U-shaped relationship because of the varying effect of lung volume on small intra-alveolar and large extra-alveolar vessels, which in both cases is minimal at functional residual capacity (FRC). FRC is defined as the amount of volume (gas) in the lungs at end-exhalation during normal tidal breathing. Ideally, this means that the patient is inspiring a normal VT, with minimal or no muscle activity or pressure difference between the alveoli and atmosphere at end-exhalation. Total PVR is increased when lung volume is either increased or decreased from FRC (Fig. 5-8).^20–22 The increase in total PVR above FRC results from alveolar compression of small intra-alveolar vessels, which results in an increase in small-vessel PVR (i.e., creation of zone 1 or zone 2).²³ As a relatively small mitigating or counterbalancing effect to the compression of small vessels, the large extra-alveolar vessels can be expanded by the increased tethering of interstitial connective tissue at high lung volumes (and with spontaneous ventilation only—the negativity of perivascular pressure at high lung volumes). The increase in total PVR below FRC results from an increase in the PVR of large extra-alveolar vessels (passive effect). The increase in large-vessel PVR is partly due to mechanical tortuosity or kinking of these vessels (passive effect). In addition, small or grossly atelectatic lungs become hypoxic, and it has been shown that the increased large-vessel PVR in these lungs is also caused by an active vasoconstrictive mechanism known as hypoxic pulmonary vasoconstriction (HPV).²⁴ The effect of HPV (discussed in greater detail in “Alveolar Gases”) is significant whether the chest is open or closed and whether ventilation is by positive pressure or spontaneous.²⁵

Figure 5-8 Total pulmonary vascular resistance (PVR) relates to lung volume as an asymmetric, U-shaped curve. The trough of the curve occurs when lung volume equals functional residual capacity (FRC). Total PVR is the sum of the resistance in small vessels (increased by increasing lung volume [LV] and the resistance in large vessels (increased by decreasing LV). The end point for increasing LV toward total lung capacity (TLC) is the creation of zone 1 conditions, and the end point for decreasing LV toward residual volume (RV) is the creation of low ventilation-perfusion () and atelectatic (atel) areas that demonstrate hypoxic pulmonary vasoconstriction (HPV).

(Data fromr Bhavani-Shankar K, Hart NS, Mushlin PS: Negative pressure induced airway and pulmonary injury. Can J Anaesth 44:78, 1997; Berggren SM: The oxygen deficit of arterial blood caused by non-ventilating parts of the lung. Acta Physiol Scand Suppl 4:11, 1942; and Benumof JL: One lung ventilation: Which lung should be PEEPed? Anesthesiology 56:161, 1982.)

a Tissue (Endothelial- and Smooth Muscle–derived) Products

The pulmonary vascular endothelium synthesizes, metabolizes, and converts a multitude of vasoactive mediators and plays a central role in the regulation of PVR. However, the main effecter site of pulmonary vascular tone is the pulmonary vascular smooth muscle cell (which both senses and produces multiple pulmonary vasoactive compounds).²⁷ The autocrine/paracrine molecules listed in Table 5-1 are all actively involved in the regulation of pulmonary vascular tone during various conditions. Numerous additional compounds bind to receptors on the endothelial or smooth muscle cell membranes and modulate the levels (and effects) of these vasoactive molecules.

Nitric oxide (NO) is the predominant endogenous vasodilatory compound. Its discovery by Palmer and colleagues 25 years ago ended the long search for the so-called endothelium-derived relaxant factor (EDRF).²⁸ Since then, a massive amount of laboratory and clinical research has demonstrated the ubiquitous nature of NO and its predominant role in vasodilation of both pulmonary and systemic blood vessels.²⁹ In the pulmonary endothelial cell, L-arginine is converted to L-citrulline by means of nitric oxide synthase (NOS) to produce the small, yet highly reactive NO molecule.³⁰ Because of its small size, NO can diffuse freely across membranes into the smooth muscle cell, where it binds to the heme moiety of guanylate cyclase (which converts guanosine triphosphate to cyclic guanosine monophosphate [cGMP]).³¹ cGMP activates protein kinase G, which dephosphorylates the myosin light chains of pulmonary vascular smooth muscle cells and thereby causes vasodilation.³¹ NOS exists in two forms: constitutive (cNOS) and inducible (iNOS). cNOS is permanently expressed in some cells, including pulmonary vascular endothelial cells, and produces short bursts of NO in response to changing levels of calcium and calmodulin and shear stress. The cNOS enzyme is also stimulated by linked membrane-based receptors that bind numerous molecules in the blood (e.g., acetylcholine, bradykinin).³¹ In contrast, iNOS is usually produced only as a result of inflammatory mediators and cytokines and, when stimulated, produces large quantities of NO for an extended duration.³¹ It is well known that NO is constitutively produced in normal lungs and contributes to the maintenance of low PVR.^32,33

Endothelin-1 (ET-1) is a pulmonary vasoconstrictor.³⁴ The endothelins are 21-amino-acid peptides that are produced by a variety of cells. ET-1 is the only family member produced in pulmonary endothelial cells, and it is also produced in vascular smooth muscle cells.³⁴ ET-1 exerts its major vascular effects through activation of two distinct G protein–coupled receptors (ETA and ETB). ETA receptors are found in the medial smooth muscle layers of the pulmonary (and systemic) blood vessels and in atrial and ventricular myocardium.³⁴ When stimulated, ETA receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.³⁵ ETB receptors are localized on endothelial cells and some smooth muscle cells.³⁶ Activation of ETB receptors stimulates the release of NO and prostacyclin, thereby promoting pulmonary vasodilation and inhibiting apoptosis.³⁰ Bosentan, an ET-1 receptor antagonist, has produced modest improvement in the treatment of pulmonary hypertension.³⁷ The more selective ETA receptor antagonist, sitaxsentan, showed additional benefit in improving pulmonary hypertension.³⁸ However, both of these ET-1 receptor antagonists are associated with an increased risk of liver toxicity.³⁹ In summary, it appears that there is a normal balance between NO and ET-1, with a slight predominance toward NO production and vasodilation in health.

Similarly, various eicosanoids are elaborated by the pulmonary vascular endothelium, with a balance toward the vasodilatory compounds in health. Prostaglandin I₂ (PGI₂), now known as epoprostenol (previously known as prostacyclin), causes vasodilation and is continuously elaborated in small amounts in healthy endothelium. In contrast, thromboxane A₂ and leukotriene B₄ are elaborated under pathologic conditions and are thought to be involved in the pathophysiology of pulmonary artery hypertension (PAH) associated with sepsis and reperfusion injury.²⁶

Therapeutically, epoprostenol has been used successfully to decrease PVR in patients with chronic PAH when infused or inhaled.^40,41 Currently, the synthetic PGI₂ (iloprost) is the most commonly used inhaled eicosanoid for reduction of PVR in patients with PAH.⁴¹Although most patients with chronic PAH are unresponsive to an acute vasodilator challenge with short-acting agents such as epoprostenol, adenosine, or NO,⁴² long-term administration of epoprostenol has been shown to decrease PVR in these patients.⁴³ Furthermore, some patients with previously severe PAH have been weaned from epoprostenol after long-term administration, with dramatically decreased PVR and improved exercise tolerance.⁴² The vascular remodeling required to provide such a dramatic reduction in PVR is probably the result of mechanisms besides simple local vasodilation, as predicted by Fishman in an editorial in 1998.⁴⁴ One such mechanism that appears to be important is the increased clearance of ET-1 (a potent vasoconstrictor and mitogen) with long-term epoprostenol administration.⁴⁵

b Alveolar Gases

Hypoxia-induced vasoconstriction constitutes a fundamental difference between pulmonary vessels and all other systemic blood vessels (which vasodilate in the presence of hypoxia). Alveolar hypoxia of in vivo and in vitro whole lung, unilateral lung, lobe, or lobule of lung results in localized pulmonary vasoconstriction. This phenomenon is widely referred to as HPV and was first described more than 65 years ago by Von Euler and Liljestrand.⁴⁶ The HPV response is present in all mammalian species and serves as an adaptive mechanism for diverting blood flow away from poorly ventilated to better ventilated regions of the lung and thereby improving ratios.⁴⁷ The HPV response is also critical for fetal development because it minimizes perfusion of the unventilated lung.

The HPV response occurs primarily in pulmonary arterioles of about 200 µm internal diameter (ID) in humans (60 to 700 µm ID in other species).⁴⁸ These vessels are advantageously situated anatomically in close relation to small bronchioles and alveoli, which permits rapid and direct detection of alveolar hypoxia. Indeed, blood may actually become oxygenated in small pulmonary arteries because of the ability of O₂ to diffuse directly across the small distance between the contiguous air spaces and vessels.⁴⁹ This direct access that gas in the airways has to small arteries makes possible a rapid and localized vascular response to changes in gas composition.

The O₂ tension at the HPV stimulus site (PsO₂) is a function of both PAO₂ and mixed venous O₂ pressure ().⁵⁰ The PsO₂-HPV response is sigmoid, with a 50% response when PAO₂, , and PsO₂ are approximately 30 mm Hg. Usually, PAO₂ has a much greater effect than does because O₂ uptake is from the alveolar space to the blood in the small pulmonary arteries.⁵⁰

Numerous theories have been developed to explain the mechanism of HPV.^46,51–53 Many vasoactive substances have been proposed as mediators of HPV, including leukotrienes, prostaglandins, catecholamines, serotonin, histamine, angiotensin, bradykinin, and ET-1, but none has been identified as the primary mediator. In 1992, Xuan proposed that NO has a pivotal role in modulating PVR.⁵⁴ NO is involved, but not precisely in the way that Xuan first proposed. There are multiple sites of O₂ sensing with variable contributions from the NO, ET-1, and eicosanoid systems (described earlier). In vivo, HPV is currently thought to result from the synergistic action of molecules produced in both endothelial cells and smooth muscle cells.⁵⁵ However, HPV can proceed in the absence of intact endothelium, suggesting that the primary O₂ sensor is in the smooth muscle cell and that endothelium-derived molecules modulate only the primary HPV response.

The precise mechanism of HPV is still under investigation. However, current data support a mechanism involving the smooth muscle mitochondrial electron transport chain as the HPV sensor (Fig. 5-9).⁵⁶ In addition, reactive oxygen species (possibly H₂O₂ or superoxide) are released from complex III of the electron transport chain and probably serve as second messengers to increase calcium in pulmonary artery smooth muscle cells during acute hypoxia.⁵⁷ However, alternative (less likely) mechanisms are still being investigated.⁵⁸ One alternative hypothesis suggests that smooth muscle microsomal reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductase or sarcolemmal NADPH oxidase is the sensing mechanism.⁵⁸ Another, previously popular theory posited that voltage-sensitive potassium (K_V) channels were required for the HPV response. However, K_V channels are no longer believed to be obligate but instead are thought to be attenuators, because a study demonstrated that inhibition of K_V channels failed to inhibit the HPV response.⁵⁸

Figure 5-9 Schematic model of the mitochondrial O₂-sensing and effector mechanism probably responsible for hypoxic pulmonary vasoconstriction (HPV). In this model, reactive O₂ species (ROS) are released from electron transport chain complex III and act as second messengers in the hypoxia-induced calcium (Ca²⁺) increase and resultant HPV. The solid arrows represent electron transfer steps; solid bars show sites of electron chain inhibition. Normal mitochondrial electron transport involves the movement of reducing equivalents generated in the Krebs cycle through complex I or II and then through complex III (ubiquinone) and complex IV (cytochrome oxidase). The Q cycle converts the dual electron transfer in complex I and II into a single electron transfer step used in complex IV. The ubisemiquinone (a free radical) created in this process can generate superoxide, which in the presence of superoxide dismutase (SOD) produces H₂O₂, the probable mediator of the hypoxia-induced increased Ca²⁺ and HPV. This process is amplified during hypoxia. Diphenyleneiodonium (DPI), rotenone, and myxothiazol (not shown in figure) are inhibitors of the proximal portion of the electron transport chain.

(From Waypa GB, Marks JD, Mack MM, et al: Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary artery myocytes. Circ Res 91:719, 2002.)

In summary, HPV probably results from a direct action of alveolar hypoxia on pulmonary smooth muscle cells, sensed by the mitochondrial electron transport chain, with reactive O₂ species (probably H₂O₂ or superoxide) serving as second messengers to increase calcium and smooth muscle vasoconstriction. The endothelium-derived products serve to both potentiate (ET-1) and attenuate (NO, PGI₂) the HPV response. Additional mechanisms (humoral and neurogenic influences) may also modulate the baseline pulmonary vascular tone and affect the magnitude of the HPV response.

Elevated PaCO₂ has a pulmonary vasoconstrictor effect. Both respiratory acidosis and metabolic acidosis augment HPV, whereas respiratory and metabolic alkalosis cause pulmonary vasodilation and serve to reduce HPV.

The clinical effects of HPV in humans can be classified under three basic mechanisms. First, life at high altitude or whole-lung respiration of a low inspired concentration of O₂ (FIO₂) increases Ppa. This is true for newcomers to high altitude, for the acclimatized, and for natives.⁵³ The vasoconstriction is considerable; in healthy people breathing 10% O₂, Ppa doubles whereas pulmonary wedge pressure remains constant.⁵⁹ The increased Ppa increases perfusion of the apices of the lung (through recruitment of previously unused vessels), which results in gas exchange in a region of lung not normally used (i.e., zone 1). Therefore, with a low FIO₂, PAO₂ is greater and the alveolar-arterial O₂ tension difference and the ratio between dead space and tidal volume (VD/VT) are less than would be expected or predicted on the basis of a normal (sea level) distribution of ventilation and blood flow. High-altitude pulmonary hypertension is an important component in the development of mountain sickness subacutely (hours to days) and cor pulmonale chronically (weeks to years).⁶⁰ There is now good evidence that in both patients with chronic obstructive pulmonary disease (COPD) and those with obstructive sleep apnea (OSA), nocturnal episodes of arterial O₂ desaturation (caused by episodic hypoventilation) are accompanied by elevations in Ppa that can eventually lead to sustained pulmonary hypertension and cor pulmonale.⁶¹

Second, hypoventilation (low ratio), atelectasis, or nitrogen ventilation of any region of the lung usually causes a diversion of blood flow away from the hypoxic to the nonhypoxic lung (40% to 50% in one lung, 50% to 60% in one lobe, 60% to 70% in one lobule) (Fig. 5-10).⁶² The regional vasoconstriction and blood flow diversion are of great importance in minimizing transpulmonary shunting and normalizing regional ratios during disease of one lung, one-lung anesthesia (see Chapter 26), inadvertent intubation of a main stem bronchus, and lobar collapse.

Figure 5-10 Schematic drawing of regional hypoxic pulmonary vasoconstriction (HPV); one-lung ventilation is a common clinical example of regional HPV. HPV in the hypoxic atelectatic lung causes redistribution of blood flow away from the hypoxic lung to the normoxic lung, thereby diminishing the amount of shunt flow () that can occur through the hypoxic lung. Inhibition of hypoxic lung HPV causes an increase in the amount of shunt flow through the hypoxic lung, thereby decreasing the alveolar oxygen tension (PAO₂).

Third, in patients who have COPD, asthma, pneumonia, or mitral stenosis but not bronchospasm, administration of pulmonary vasodilator drugs such as isoproterenol, sodium nitroprusside, or nitroglycerin inhibits HPV and causes a decrease in PaO₂ and PVR and an increase in right-to-left transpulmonary shunting.⁶³ The mechanism for these changes is thought to be deleterious inhibition of preexisting and, in some lesions, geographically widespread HPV without concomitant and beneficial bronchodilation.⁶³ In accordance with the latter two lines of evidence (one-lung or regional hypoxia and vasodilator drug effects on whole-lung or generalized disease), HPV is thought to divert blood flow away from hypoxic regions of the lung, thereby serving as an autoregulatory mechanism that protects PaO₂ by favorably adjusting regional ratios. Factors that inhibit regional HPV are extensively discussed elsewhere.^64,65

c Neural Influences on Pulmonary Vascular Tone

The three systems used to innervate the pulmonary circulation are the same ones that innervate the airways: the sympathetic, parasympathetic, and nonadrenergic noncholinergic (NANC) systems.²⁶ Sympathetic (adrenergic) fibers originate from the first five thoracic nerves and enter the pulmonary vessels as branches from the cervical ganglia, as well as from a plexus of nerves arising from the trachea and main stem bronchi. These nerves act mainly on pulmonary arteries down to a diameter of 60 µm.²⁶ Sympathetic fibers cause pulmonary vasoconstriction through α₁-receptors. However, the pulmonary arteries also contain vasodilatory α₂-receptors and β₂-receptors. The α₁-adrenergic response predominates during sympathetic stimulation, such as occurs with pain, fear, and anxiety.²⁶ The parasympathetic (cholinergic) nerve fibers originate from the vagus nerve and cause pulmonary vasodilation through an NO-dependent process.²⁶ Binding of acetylcholine to a muscarinic (M₃) receptor on the endothelial cell increases intracellular calcium and stimulates cNOS.²⁶ NANC nerves cause pulmonary vasodilation through NO-mediated systems by using vasoactive intestinal peptide as the neurotransmitter. The functional significance of this system is still under investigation.²⁶

d Humoral Influences on Pulmonary Vascular Tone

Numerous molecules are released into the circulation that either affect pulmonary vascular tone (by binding to pulmonary endothelial receptors) or are acted on by the pulmonary endothelium and subsequently become activated or inactivated (Table 5-2). The entire topic of nonrespiratory function of the lung is fascinating but beyond the scope of this chapter. Here, we highlight the effects that circulating molecules have on pulmonary vascular tone.

Although we understand the basic effect that various circulating factors have on pulmonary vascular tone, it is unlikely that these compounds are modulators of pulmonary vascular tone in normal circumstances. However, they have marked effects during disease (e.g., ARDS, sepsis).

Endogenous catecholamines (epinephrine and norepinephrine) bind to both α_1- (vasoconstrictor) and β₂-(vasodilator) receptors on the pulmonary endothelium, but when elaborated in high concentration, they have a predominant α₁ (vasoconstrictor) effect. The same is true for exogenously administered catecholamines. Other amines (e.g., histamine, serotonin) are elaborated systemically or locally after various challenges and have variable effects on PVR. Histamine can be released from mast cells, basophils, and elsewhere. When histamine binds directly to H₁ receptors on endothelium, NO-mediated vasodilation occurs (as seen after epinephrine-induced pulmonary vasoconstriction). Direct stimulation of H₂ receptors on smooth muscle cell membranes also causes vasodilation. In contrast, stimulation of H₁ receptors on the smooth muscle membrane results in vasoconstriction. Serotonin (5-hydroxytryptamine) is a potent vasoconstrictor that can be elaborated from activated platelets (e.g., after pulmonary embolism) and can lead to acute severe pulmonary hypertension.⁶⁶

Numerous peptides circulate and cause either pulmonary vasodilation (e.g., substance P, bradykinin, vasopressin [a systemic vasoconstrictor]) or vasoconstriction (e.g., neurokinin A, angiotensin). These peptides produce clinically detectable effects on PVR only when administered in high concentration, such as with exogenous administration or in disease.

Two other classes of molecules must be mentioned for completeness: eicosanoids (whose vasoactive effects were discussed earlier) and purine nucleosides (which are similarly highly vasoactive).²⁶ Adenosine is a pulmonary vasodilator in normal subjects, whereas adenosine triphosphate (ATP) has a variable normalizing effect, depending on baseline pulmonary vascular tone.⁶⁷

a Lung Volumes and Functional Residual Capacity

FRC is defined as the volume of gas in the lung at the end of a normal expiration when there is no airflow and P_A equals ambient pressure. Under these conditions, expansive chest wall elastic forces are exactly balanced by retractive lung tissue elastic forces (Fig. 5-15).⁷⁹

Figure 5-15 A, The resting state of normal lungs when they are removed from the chest cavity; that is, elastic recoil causes total collapse. B, The resting state of a normal chest wall and diaphragm when the thoracic apex is open to the atmosphere and the thoracic contents are removed. C, The lung volume that exists at the end of expiration is the functional residual capacity (FRC). At FRC, the elastic forces of the lung and chest walls are equal and in opposite directions. The pleural surfaces link these two opposing forces.

(Redrawn with modification from Shapiro BA, Harrison RA, Trout CA: The mechanics of ventilation. In Shapiro BA, Harrison RA, Trout CA, editors: Clinical application of respiratory care, ed 3, Chicago, 1985, Year Book, p 57.)

The expiratory reserve volume is part of FRC; it is the additional gas beyond the end-tidal volume that can be consciously exhaled, resulting in the minimum volume of lung possible, known as residual volume. Therefore, FRC equals residual volume plus expiratory reserve volume (Fig. 5-16). With regard to the other lung volumes shown in Figure 5-16, V_T, vital capacity, inspiratory capacity, inspiratory reserve volume, and expiratory reserve volume can be measured by simple spirometry. Total lung capacity (TLC), FRC, and residual volume contain a fraction (residual volume) that cannot be measured by simple spirometry. However, if one of these three volumes is measured, the others can easily be derived, because the other lung volumes, which relate these three volumes to one another, can be measured by simple spirometry.

Figure 5-16 The dynamic lung volumes that can be measured by simple spirometry are tidal volume, inspiratory reserve volume, expiratory reserve volume, inspiratory capacity, and vital capacity. The static lung volumes are residual volume, functional residual capacity, and total lung capacity. Static lung volumes cannot be measured by simple spirometry and require separate methods of measurement (e.g., inert gas dilution, nitrogen washout, total-body plethysmography).

Residual volume, FRC, and TLC can be measured by any of three techniques: (1) nitrogen washout, (2) inert gas dilution (e.g., helium washin), and (3) total-body plethysmography. The first method, the nitrogen washout technique, is based on measuring expired nitrogen concentrations before and after the patient breathes pure O₂ for several minutes; the difference is the total quantity of nitrogen eliminated. If, for example, 2 L of N₂ is eliminated and the initial alveolar N₂ concentration was 80%, the initial volume of the lung was 2.5 L. The second method, the inert gas dilution technique, uses the washin of an inert tracer gas such as helium. If 50 mL of helium is introduced into the lungs and, after equilibration, the helium concentration is found to be 1%, the volume of the lung is 5 L. The third method, the total-body plethysmography technique, uses Boyle’s law (P₁V₁ = P₂V₂, where P₁= initial pressure, V₁ = initial volume). The subject is confined within a gas-tight box (plethysmograph) so that changes in the volume of the body during respiration may be readily determined as a change in pressure within the sealed box. Although each technique has technical limitations, all are based on sound physical and physiologic principles and provide accurate results in normal patients. Disparity between FRC as measured in the body plethysmograph and as determined by the helium dilution method is often used as a way of detecting large, nonventilating air-trapped blebs.⁸⁰ Obviously, there are difficulties in applying the body plethysmograph to anesthetized patients.

b Airway Closure and Closing Capacity

As discussed earlier (see “Distribution of Ventilation”), Ppl increases from the top to the bottom of the lung and determines regional alveolar size, compliance, and ventilation. Of even greater importance to the anesthesiologist is the recognition that these gradients in Ppl may lead to airway closure and collapse of alveoli.

Patient with Normal Lungs

Figure 5-17A illustrates the normal resting end-expiratory (FRC) position of the lung–chest wall combination. The distending transpulmonary ΔP and the intrathoracic air passage transmural ΔP are 5 cm H₂O, and the airways remain patent. During the middle of a normal inspiration (see Fig. 5-17B), there is an increase in transmural ΔP (to 6.8 cm H₂O) that encourages distention of the intrathoracic air passages. During the middle of a normal expiration (see Fig. 5-17C), expiration is passive; PA is attributable only to the elastic recoil of the lung (2 cm H₂O), and there is a decrease (to 5.2 cm H₂O) but still a favorable (distending) intraluminal transmural ΔP. During the middle of a severe forced expiration (see Fig. 5-17D), Ppl increases far higher than atmospheric pressure and is communicated to the alveoli, which have a pressure that is still higher because of the elastic recoil of the alveolar septa (an additional 2 cm H₂O).

Figure 5-17 Pressure gradients across the airways. The airways consist of a thin-walled intrathoracic portion (near the alveoli) and a more rigid (cartilaginous) intrathoracic and extrathoracic portion. During expiration, the pressure from elastic recoil is assumed to be +2 cm H₂O in normal lungs (A through D) and +1 cm H₂O in abnormal lungs (E and F). The total pressure inside the alveolus is pleural pressure plus elastic recoil. The arrows indicate the direction of airflow. EPP, Equal pressure point. See text for explanation.

(Redrawn with modification from Benumof JL: Anesthesia for thoracic surgery, ed 2, Philadelphia, 1995, Saunders, Chapter 8.)

At high gas flow rates, the pressure drop down the air passage is increased, and there is a point at which intraluminal pressure equals either the surrounding parenchymal pressure or Ppl; that point is termed the equal pressure point (EPP). If the EPP occurs in small intrathoracic air passages (distal to the 11th generation, the airways have no cartilage and are called bronchioles), they may be held open at that particular point by the tethering effect of the elastic recoil of the immediately adjacent or surrounding lung parenchyma. If the EPP occurs in large extrathoracic air passages (proximal to the 11th generation, the airways have cartilage and are called bronchi), they may be held open at that particular point by their cartilage. Downstream of the EPP (in either small or large airways), transmural ΔP is reversed (−6 cm H₂O), and airway closure occurs. Thus, the patency of airways distal to the 11th generation is a function of lung volume, and the patency of airways proximal to the 11th generation is a function of intrathoracic (pleural) pressure. In extrathoracic bronchi with cartilage, the posterior membranous sheath appears to give first by invaginating into the lumen.⁸¹ If lung volume were abnormally decreased (e.g., because of splinting) and expiration were still forced, the caliber of the airways would be relatively reduced at all times, which would cause the EPP and point of collapse to move progressively from larger to smaller air passages (closer to the alveolus).

In adults with normal lungs, airway closure can still occur even if exhalation is not forced, provided that residual volume is approached closely enough. Even in patients with normal lungs, as lung volume decreases toward residual volume during expiration, small airways (0.5 to 0.9 mm in diameter) show a progressive tendency to close, whereas larger airways remain patent.^82,83 Airway closure occurs first in the dependent lung regions (as directly observed by computed tomography) because the distending transpulmonary pressure is less and the volume change during expiration is greater.³² Airway closure is most likely to occur in the dependent regions of the lung whether the patient is in the supine or the lateral decubitus position and whether ventilation is spontaneous or positive-pressure ventilation.^32,84,85

Measurement of Closing Capacity

CC is a sensitive test of early small-airways disease and is performed by having the patient exhale to residual volume (Fig. 5-18).⁸⁹ As inhalation from residual volume toward TLC is begun, a bolus of tracer gas (e.g., xenon 133, helium) is injected into the inspired gas. During the initial part of this inhalation from residual volume, the first gas to enter the alveolus is the VD gas and the tracer bolus. The tracer gas enters only alveoli that are already open (presumably the apices of the lung) and does not enter alveoli that are already closed (presumably the bases of the lung). As the inhalation continues, the apical alveoli complete filling and the basilar alveoli begin to open and fill, but with gas that does not contain any tracer gas.

Figure 5-18 Measurement of closing capacity (CC) with the use of a tracer gas such as xenon 133 (¹³³Xe). The bolus of tracer gas is inhaled near residual volume (RV) and, because of airway closure in the dependent lung, is distributed only to nondependent alveoli whose air passages are still open. During expiration, the concentration of tracer gas becomes constant after the dead space is washed out. This plateau (phase III) gives way to a rising concentration of tracer gas (phase IV), when there is once again closure of the dependent airways because the only contribution made to expired gas is by the nondependent alveoli with a high ¹³³Xe concentration. FRC, Functional residual capacity; TLC, total lung capacity.

(Redrawn with modification from Lumb AB: Respiratory system resistance: Measurement of closing capacity. In Lumb AB, editor: Nunn’s applied respiratory physiology, ed 5, London, 2000, Butterworths, p 79.)

A differential tracer gas concentration is thus established, with the gas in the apices having a higher tracer concentration than that in the bases (see Fig. 5-18). As the subject exhales and the diaphragm ascends, a point is reached at which the small airways just above the diaphragm start to close and thereby limit airflow from these areas. The airflow now comes more from the upper lung fields, where the alveolar gas has a much higher tracer concentration, which results in a sudden increase in the tracer gas concentration toward the end of exhalation (phase IV of Fig. 5-18).

Closing volume (CV) is the difference between the onset of phase IV and residual volume; because it represents part of a vital capacity maneuver, it is expressed as a percentage of vital lung capacity. CV plus residual volume is known as CC and is expressed as a percentage of TLC. Smoking, obesity, aging, and the supine position increase CC.⁹⁰ In healthy individuals at a mean age of 44 years, CC = FRC in the supine position, and at a mean age of 66 years, CC = FRC in the upright position.⁹¹

Relationship Between Functional Residual Capacity and Closing Capacity

The relationship between FRC and CC is far more important than consideration of FRC or CC alone, because it is this relationship that determines whether a given respiratory unit is normal or atelectatic or has a low ratio. The relationship between FRC and CC is as follows. When the volume of the lung at which some airways close is greater than the whole of VT, lung volume never increases enough during tidal inspiration to open any of these airways. As a result, these airways stay closed during the entire tidal respiration. Airways that are closed all the time are equivalent to atelectasis (Fig. 5-19). If the CV of some airways lies within VT, as lung volume increases during inspiration, some previously closed airways open for a short time until lung volume recedes once again below the CV of these airways. Because these opening and closing airways are open for a shorter time than normal airways are, they have less chance or time to participate in fresh gas exchange, a circumstance equivalent to a low- region. If the CC of the lung is below the whole of tidal respiration, no airways are closed at any time during tidal respiration; this is a normal circumstance. Anything that decreases FRC relative to CC or increases CC relative to FRC converts normal areas to low- and atelectatic areas,⁸³ which causes hypoxemia.

Figure 5-19 Relationship between functional residual capacity (FRC) and closing capacity (CC). FRC is the amount of gas in the lungs at end-exhalation during normal tidal breathing, shown by the level of each trough of the sine wave tidal volume. CC is the amount of gas that must be in the lungs to keep the small conducting airways open. This figure shows three different CCs, as indicated by the three different straight lines. See the text for an explanation of why the three different FRC-CC relationships depicted result in normal or low ventilation-perfusion () relationships or atelectasis. The abscissa is time.

(Redrawn from Benumof JL: Anesthesia for thoracic surgery, ed 2, Philadelphia, 1995, Saunders, Chapter 8.)

Mechanical intermittent positive-pressure breathing (IPPB) may be efficacious because it can take a previously spontaneously breathing patient with a low- relationship (in which CC is greater than FRC but still within VT, as depicted in Figure 5-20, right panel) and increase the amount of inspiratory time that some previously closed (at end-exhalation) airways spend in fresh gas exchange, thereby increasing (see Fig. 5-20, middle panel). However, if PEEP is added to IPPB, PEEP increases FRC to a lung volume equal to or greater than CC, thereby restoring a normal FRC-to-CC relationship so that no airways are closed at any time during the tidal respiration depicted in Figure 5-20 (left panel) (IPPB + PEEP). Thus, anesthesia-induced atelectasis (identified by crescent-shaped densities on computed tomography) in the dependent regions of patients’ lungs has not been reversed with IPPB alone but has been reversed with IPPB plus PEEP (5 to 10 cm H₂O).³²

Figure 5-20 Relationship of functional residual capacity (FRC) to closing capacity (CC) during spontaneous ventilation, intermittent positive-pressure breathing (IPPB), and IPPB with positive end-expiratory pressure (IPPB + PEEP). See the text for an explanation of the effect of the two ventilatory maneuvers (IPPB and PEEP) on the relationship of FRC to CC. The abscissa is time.

a Overview

The principal function of the heart and lungs is supporting O₂ delivery to and CO₂ removal from the tissues in accordance with metabolic requirements while maintaining arterial blood O₂ and CO₂ partial pressures within a narrow range. The respiratory and cardiovascular systems are linked in series to accomplish this function over a wide range of metabolic requirements, which may increase 30-fold from rest to heavy exercise. The functional links in the O₂ transport chain are as follows: (1) ventilation and distribution of ventilation with respect to perfusion, (2) diffusion of O₂ into blood, (3) chemical reaction of O₂ with Hb, (4) total cardiac output of arterial blood, and (5) distribution of blood to tissues and release of O₂ (Table 5-3). The system is seldom stressed except at exercise, and the earliest symptoms of cardiac or respiratory diseases are often seen only during exercise.

TABLE 5-3 Functional Capacities and Potential Maximum O₂ Transport of Each Link in the O₂ Transport Chain in Normal Humans* at Sea Level

Link in Chain	Functional Capacity in Normal Humans	Theoretical Maximum O2 Transport Capacity
Ventilation	200 L/min (MVV)	0.030 × MVV = 6.0 L O2/min
Diffusion and chemical reaction		DLO2 = 6.1 L O2/min
Cardiac output	20 L/min
O2 extraction	75%	0.16 × Cardiac output = 3.2 L O2/min
(CaO2 − difference)	(16 mL O2/100 mL or 0.16)

CaO₂ − , Arteriovenous O₂ content difference; DLO₂, diffusing capacity of lung for oxygen; MVV, maximum voluntary ventilation.

^* Hemoglobin = 15 g/dL; physiologic dead space in percentage of tidal volume = 0.25; partial alveolar pressure of oxygen >110 mm Hg.

From Cassidy SS: Heart-lung interactions in health and disease. Am J Med Sci 30:451–461, 1987.

The maximum functional capacity of each link can be determined independently. Table 5-3 lists these measured functional capacities for healthy, young men. Because theoretical maximal O₂ transport at the ventilatory step or at the diffusion and chemical reaction step (approximately 6 L/min in healthy humans at sea level) exceeds the O₂ transportable by the maximum cardiac output and distribution steps, the limit to O₂ transport is the cardiovascular system. Respiratory diseases would not be expected to limit maximum O₂ transport until functional capacities are reduced by 40% to 50%.

b Oxygen-Hemoglobin Dissociation Curve

As a red blood cell (RBC) passes by the alveolus, O₂ diffuses into plasma and increases PAO₂. As PAO₂ increases, O₂ diffuses into the RBC and combines with Hb. Each Hb molecule consists of four heme molecules attached to a globin molecule. Each heme molecule consists of glycine, α-ketoglutaric acid, and iron in the ferrous (Fe²⁺) form. Each ferrous ion has the capacity to bind with one O₂ molecule in a loose, reversible combination. As the ferrous ions bind to O₂, the Hb molecule begins to become saturated.

The oxy-Hb dissociation curve relates the saturation of Hb (rightmost y-axis in Fig. 5-25) to PAO₂. Hb is fully saturated (100%) by a PO₂ of approximately 700 mm Hg. The saturation at normal arterial pressure (point a on upper, flat part of the oxy-Hb curve in Figure 5-25) is 95% to 98%, achieved by a PaO₂ of about 90 to 100 mm Hg. When PO₂ is less than 60 mm Hg (90% saturation), saturation falls steeply, and the amount of Hb uncombined with O₂ increases greatly for a given decrease in PO₂. Mixed venous blood has a PO₂ () of about 40 mm Hg and is approximately 75% saturated, as indicated by the middle of the three points () on the oxy-Hb curve in Figure 5-25.

Figure 5-25 Oxygen-hemoglobin dissociation curve. Four different ordinates are shown as a function of oxygen partial pressure (the abscissa). In order from right to left, they are arterial O₂ saturation (%), O₂ content (mL of O₂/dL of blood), O₂ supply to peripheral tissues (mL/min), and O₂ available to peripheral tissues (mL/min), which is O₂ supply minus the approximately 200 mL/min that cannot be extracted below a partial pressure of 20 mm Hg. Three points are shown on the curve: a, normal arterial pressure; , normal mixed venous pressure; P₅₀, the partial pressure (27 mm Hg) at which hemoglobin is 50% saturated.

The oxy-Hb curve can also relate the O₂ content (CO₂) (vol%, or mL of O₂ per dL of blood; see Fig. 5-25) to PO₂. Oxygen is carried both in solution in plasma (0.003 mL of O₂/mm Hg PO₂ per dL) and combined with Hb (1.39 mL of O₂/g of Hb), to the extent (percentage) that Hb is saturated. Therefore,

For a patient with an Hb content of 15 g/dL, a PAO₂ of 100 mm Hg, and a of 40 mm Hg, the arterial O₂ content (CaO₂) = (1.39)(15)(1) + (0.003)(100) = 20.9 + 0.3 = 21.2 mL/dL; the mixed venous O₂ content () = (1.39)(15)(0.75) + (0.003)(40) = 15.6 + 0.1 = 15.7 mL/dL. Therefore, the normal arteriovenous O₂ content difference is approximately 5.5 mL/dL of blood.

Note that equation (13) uses the constant 1.39, which means that 1 g of Hb can carry 1.39 mL of O₂. Controversy exists over the magnitude of this number. Originally, 1.34 had been used,⁹² but with determination of the molecular weight of Hb (64,458), the theoretical value of 1.39 became popular.⁹³ After extensive human studies, Gregory observed in 1974 that the applicable value was 1.31 mL O₂/g of Hb in human adults.⁹⁴ That the clinically measured CO₂ is lower than the theoretical 1.39 is probably due to the small amount of methemoglobin (MetHb) and carboxyhemoglobin (COHb) normally present in blood.

The oxy-Hb curve can also relate O₂ transport (L/min) to the peripheral tissues (see Fig. 5-25) to PO₂. The term O₂ transport is synonymous with the term O₂ delivery. This value is obtained by multiplying the O₂ content by (O₂ transport = × CaO₂). To do this multiplication, one must convert the content unit of mL/dL to mL/L by multiplying by 10; subsequent multiplication of mL/L against in L/min yields mL/min. Thus, if = 5 L/min and CaO₂ = 20 mL of O₂/dL, the arterial point corresponds to 1000 mL O₂/min going to the periphery, and the venous point corresponds to 750 mL O₂/min returning to the lungs, with = 250 mL/min.

The oxy-Hb curve can also relate the O₂ actually available to the tissues (leftmost y axis in Fig. 5-25) as a function of PO₂. Of the 1000 mL/min of O₂ normally going to the periphery, 200 mL/min of O₂ cannot be extracted because it would lower PO₂ below the level at which organs such as the brain can survive (rectangular dashed line in Fig. 5-25); the O₂ available to tissues is therefore 800 mL/min. This amount is approximately three to four times the normal resting . When = 5 L/min and arterial saturation is less than 40%, the total flow of O₂ to the periphery is reduced to 400 mL/min; the available O₂ is then 200 mL/min, and O₂ supply just equals O₂ demand. Consequently, with low arterial saturation, tissue demand can be met only by an increase in or, in the longer term, by an increase in Hb concentration.

The affinity of Hb for O₂ is best described by the PO₂ level at which Hb is 50% saturated (P₅₀) on the oxy-Hb curve. The normal adult P₅₀ is 26.7 mm Hg (see Fig. 5-25).

The effect of a change in PO₂ on Hb saturation is related to both P₅₀ and the portion of the oxy-Hb curve at which the change occurs.⁹⁵ In the region of normal PaO₂ (75 to 100 mm Hg), the curve is relatively horizontal, and shifts of the curve have little effect on saturation. In the region of mixed venous PO₂, where the curve is relatively steep, a shift of the curve leads to a much greater difference in saturation. A P₅₀ lower than 27 mm Hg describes a left-shifted oxy-Hb curve, which means that at any given PO₂, Hb has a higher affinity for O₂ and is therefore more saturated than normal. This lower P₅₀ may require higher than normal tissue perfusion to produce the normal amount of O₂ unloading. Causes of a left-shifted oxy-Hb curve are alkalosis (metabolic and respiratory—the Bohr effect), hypothermia, abnormal fetal Hb, carboxyhemoglobin, methemoglobin, and decreased RBC 2,3-diphosphoglycerate (2,3-DPG) content. (The last condition may occur with the transfusion of old acid citrate-dextrose–stored blood; storage of blood in citrate-phosphate-dextrose minimizes changes in 2,3-DPG with time.⁹⁵) A P₅₀ higher than 27 mm Hg describes a right-shifted oxy-Hb curve, which means that at any given PO₂, Hb has a low affinity for O₂ and is less saturated than normal. This higher P₅₀ may allow a lower tissue perfusion than normal to produce the normal amount of O₂ unloading. Causes of a right-shifted oxy-Hb curve are acidosis (metabolic and respiratory—the Bohr effect), hyperthermia, abnormal Hb, increased RBC 2,3-DPG content, and inhaled anesthetics (see later discussion).⁹⁵ Abnormalities in acid-base balance result in alteration of 2,3-DPG metabolism to shift the oxy-Hb curve to its normal position. This compensatory change in 2,3-DPG requires between 24 and 48 hours. Therefore, with acute acid-base abnormalities, O₂ affinity and the position of the oxy-Hb curve change. However, with more prolonged acid-base changes, the reciprocal changes in 2,3-DPG levels shift the oxy-Hb curve and O₂ affinity back toward normal.⁹⁵

Many inhaled anesthetics have been shown to shift the oxy-Hb dissociation curve to the right.⁹⁶ Isoflurane shifts P₅₀ to the right by 2.6 ± 0.07 mm Hg at a vapor pressure of approximately 1 minimum alveolar concentration (MAC) (1.25%).⁹⁷ On the other hand, high-dose fentanyl, morphine, and meperidine do not alter the position of the curve.

c Effect of on Alveolar Oxygen Tension

PAO₂ is directly related to FIO₂ in normal patients. PAO₂ and FIO₂ also correspond to PaO₂ when there is little to no right-to-left transpulmonary shunt (). Figure 5-26 shows the relationship between FIO₂ and PaO₂ for a family of right-to-left transpulmonary shunts; the calculations assume a constant and normal and PaCO₂. With no , a linear increase in FIO₂ results in a linear increase in PAO₂ (solid straight line). As the shunt is increased, the lines relating FIO₂ to PaO₂ become progressively flatter.⁹⁸ With a shunt of 50% of , an increase in FIO₂ results in almost no increase in PaO₂. The solution to the problem of hypoxemia secondary to a large shunt is not increasing the FIO₂ but rather causing a reduction in the shunt (e.g., PEEP, patient positioning, suctioning, fiberoptic bronchoscopy, diuretics, antibiotics).

Figure 5-26 Effect of changes in inspired oxygen concentration on arterial oxygen tension (PaO₂) for various right-to-left transpulmonary shunts. Cardiac output (), hemoglobin (Hb), oxygen consumption (), and arteriovenous oxygen content differences [C(a − )O₂] are assumed to be normal. PCO₂, partial pressure of carbon dioxide; PO₂, partial pressure of oxygen.

d Effect of and on Arterial Oxygen Content

In addition to an increased , CaO₂ is decreased by decreased (for a constant ) and by increased (for a constant ). In either case, along with a constant right-to-left shunt, the tissues must extract more O₂ from blood per unit blood volume, and therefore, must primarily decrease (Fig. 5-27). When blood with lower passes through whatever shunt exists in the lung and remains unchanged in its , it must inevitably mix with oxygenated end-pulmonary capillary blood (c′ flow) and secondarily decrease CaO₂. The amount of O₂ flowing per minute through any particular lung channel, as depicted in Figure 5-27, is a product of blood flow times the O₂ content of that blood. Thus, . With and further algebraic manipulation,⁹⁹

Figure 5-27 Effect of a decrease in cardiac output () or an increase in oxygen consumption () on mixed venous and arterial oxygen content. Mixed venous blood () either perfuses ventilated alveolar capillaries (ALV) and becomes oxygenated end-pulmonary capillary blood (c′), or it perfuses whatever true shunt pathways exist and remains the same in composition (i.e., desaturated). These two pathways must ultimately join together to form mixed arterial (a) blood. If decreases or increases, or both, the tissues must extract more oxygen per unit volume of blood than under normal conditions. Thus, the primary effect of a decrease in or an increase in is a decrease in mixed venous oxygen content. The mixed venous blood with a decreased oxygen content must flow through the shunt pathway as before (which may remain constant in size) and lower the arterial content of oxygen. Thus, the secondary effect of a decrease in or an increase in is a decrease in arterial oxygen content.

The larger the intrapulmonary shunt, the greater is the decrease in CaO_2, because more venous blood with lower can admix with end-pulmonary capillary blood (c′) (see Fig. 5-37).^100,101 Therefore, the alveolar-arterial oxygen difference P(A − a)O₂ is a function both of the size of the and of what is flowing through the —namely, —and is a primary function of and . Figure 5-28 shows the equivalent circuit of the pulmonary circulation in a patient with a 50% shunt, a normal of 15 mL/dL, and a moderately low CaO₂ of 17.5 mL/dL. Decreasing or increasing , or both, causes a larger primary decrease in to 10 mL/dL and a smaller but still significant secondary decrease in CaO₂ to 15 mL/dL; the ratio of change in to change in CaO₂ in this example of 50% is 2 : 1.

Figure 5-28 The equivalent circuit of the pulmonary circulation in a patient with a 50% right-to-left shunt. Oxygen content is in mL/dL of blood. A decrease in cardiac output () or an increase in O₂ consumption () can cause a decrease in mixed venous oxygen content, from 15 to 10 mL/dL in this example, which in turn causes a decrease in the arterial content of oxygen, from 17.5 to 15.0 mL/dL). In this 50% shunt example, the decrease in mixed venous oxygen content was twice the decrease in arterial oxygen content.

If a decrease in or an increase in is accompanied by a decrease in , there may be no change in PaO₂ (i.e., a decreasing effect on PaO₂ is offset by an increasing effect on PaO₂) (Table 5-4). These changes sometimes occur in diffuse lung disease. However, if a decrease in or an increase in is accompanied by an increase in , PaO₂ may be greatly decreased (i.e., a decreasing effect on PaO₂ is compounded by another decreasing effect on PaO₂). These changes sometimes occur in regional ARDS and atelectasis.¹⁰²

TABLE 5-4 Relationship Between Cardiac Output (), Shunt (), and Venous () and Arterial (PaO₂) Oxygenation

Changes	Clinical Situation
If ↓ → ↓ and = 0 → PaO2↓	Decreased cardiac output, stable shunt
If ↓ → ↓ and ↓ → PaO2 = 0	Application of PEEP in ARDS
If ↓ → ↓ and ↑ → PaO2 ↓↓	Shock combined with ARDS or atelectasis

ARDS, Adult respiratory distress syndrome; 0, no change; PEEP, positive end-expiratory pressure; ↓, decrease; ↑, increase.

e Fick Principle

The Fick principle allows calculation of and states that the amount of O₂ consumed by the body () is equal to the amount of O₂ leaving the lungs ()(CaO₂) minus the amount of O₂ returning to the lungs ()():

Condensing the content symbols yields the usual expression of the Fick equation:

This equation states that O₂ consumption is equal to times the arteriovenous O₂ content difference [C(a − ) O₂]. Normally, (5 L/min)(5.5 mL)/dL = 0.27 L/min (see “Oxygen-Hemoglobin Dissociation Curve”).

Similarly, the amount of O₂ consumed by the body () is equal to the amount of O₂ brought into the lungs by ventilation ()(FIO₂) minus the amount of O₂ leaving the lungs by ventilation ()(FEO₂), where is expired minute ventilation and FEO₂ is the mixed expired O₂ fraction: . Because the difference between and is due to the difference between (normally 250 mL/min) and (normally 200 mL/min) and is only 50 mL/min (see later discussion), essentially equals .

Normally, = 5.0 L/min(0.21 − 0.16) = 0.25 L/min. In determining in this way, can be measured with a spirometer, FIO₂ can be measured with an O₂ analyzer or from known fresh gas flows, and FEO₂ can be measured by collecting expired gas in a bag for a few minutes. A sample of the mixed expired gas is used to measure PEO₂. To convert PEO₂ to FEO₂, one simply divides PEO₂ by dry atmospheric pressure: PEO₂/713 = FEO₂.

In addition, the Fick equation is useful in understanding the impact of changes in on PaO₂ and . If remains constant (K) and decreases (↓), the arteriovenous O₂ content difference has to increase (↑):

The C(a − )O₂ difference increases because a decrease in causes a much larger and primary decrease in versus a smaller and secondary decrease in CaO₂, as follows¹⁰¹:

Thus, and are much more sensitive indicators of because they change more with changes in than CaO₂ (or PaO₂) does (see Figs. 5-27 and 5-37).