Respiratory Physiology and Pathophysiology

Key Points

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Removal of carbon dioxide (CO ₂ ) is determined by alveolar ventilation, not by total (minute) ventilation.
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Dead space ventilation can be dramatically increased in patients with chronic obstructive pulmonary disease and pulmonary embolism to more than 80% of minute ventilation.
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Breathing at small lung volumes increases airway resistance and promotes closure of airways.
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Hypoxemia can be caused by alveolar hypoventilation, diffusion impairment, ventilation-perfusion mismatch, and right-to-left shunt.
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Almost all anesthetics reduce skeletal muscle tone, which decreases functional residual capacity (FRC) to levels close to the awake residual volume.
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Atelectasis during anesthesia is caused by decreased FRC and the use of high inspired oxygen concentrations (FiO ₂ ), including breathing oxygen before induction of anesthesia.
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General anesthesia causes ventilation-perfusion mismatch (airway closure) and shunts (atelectasis).
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Venous admixture is due to ${\dot{V}}_{A} / \dot{Q}$ ${\dot{V}}_{A} / \dot{Q}$ mismatch (response to increased FiO ₂ ) and shunts (unresponsive to increased FiO ₂ ).
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Hypoxic pulmonary vasoconstriction is blunted by most anesthetics, and this results in increased ventilation-perfusion mismatching.
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Respiratory work is increased during anesthesia as a consequence of reduced respiratory compliance and increased airway resistance.

Respiratory Physiology Is Central to the Practice of Anesthesia

Respiratory function is inextricably linked to the practice of anesthesia. Adverse respiratory effects can occur during anesthesia, and the most serious cases involve hypoxemia. These events range from intractable hypoxemia caused by loss of airway patency to postoperative respiratory depression from opioids or regional anesthesia. In the absence of adverse outcomes, general anesthesia still has significant effects on respiratory function and lung physiology, documented by observations made in the operating and recovery rooms. Improved appreciation of anesthesia-induced physiologic alterations (e.g., mechanisms of bronchospasm, impact of mechanical ventilation), as well as pioneering developments in monitoring (e.g., pulse oximetry and capnography), together are associated with the specialty of anesthesiology’s emergence as a leader in patient safety. Finally, integrative measures of respiratory function, ranging from exercise capacity, spirometry to tissue oxygenation, to global O ₂ consumption, may help predict outcomes following anesthesia and surgery.

Pulmonary Physiology in Health

The mechanisms by which anesthesia-associated respiratory dysfunction is caused can be determined with an examination of normal functions and mechanisms of respiration in health. We briefly review cellular respiration, whereby O ₂ is consumed and CO ₂ is produced, the transport of O ₂ and CO ₂ in the blood, and the principles by which the lung oxygenates blood and eliminates CO ₂ .

Respiration in the Cell

The partial pressure of oxygen (PaO ₂ ) in normal arterial blood is approximately 100 mm Hg, and decreases to 4 to 22 mm Hg in the mitochondrion, where it is consumed. Glucose (C ₆ H ₁₂ O ₆ ) is converted into pyruvate (CH ₃ COCOO ⁻ ) and H ⁺ by glycolysis in the cytoplasm, and the pyruvate diffuses into the mitochondria and forms the initial substrate for Krebs cycle, which in turn produces nicotinamide adenine dinucleotide (NADH), as well as adenosine triphosphate (ATP), CO ₂ , and H ₂ O. The NADH is a key electron (and H ⁺ ) donor in the process of oxidative phosphorylation, wherein O ₂ and adenosine diphosphate are consumed and ATP and H ₂ O are produced. Thus the net effect is oxidation of glucose to produce energy (ultimately as ATP), H ₂ O, and CO ₂ .

Transport of O ₂ in the Blood

O ₂ reaches the cells following transport by arterial blood, and the overall delivery of O ₂ ( ${\dot{D} O}_{2}$ ${\dot{D} O}_{2}$ ) is the product of the arterial blood O ₂ content (CaO ₂ ) and blood flow (cardiac output, $\dot{Q}$ $\dot{Q}$ ) as

\dot{D} O_{2} = C a O_{2} \times \dot{Q}

$\dot{D} O_{2} = C a O_{2} \times \dot{Q}$

Oxygen is carried in the blood in two forms: O ₂ bound to hemoglobin (the vast bulk), and O ₂ dissolved in the plasma, and the content is expressed as the sum of these components:

C a O_{2} = [\begin{matrix} (S a O_{2} \times H b \times O_{2} c o m b i n i n g c a p a c i t y o f H b) \\ + (O_{2} s o l u b i l i t y \times P a O_{2}) \end{matrix}]

$C a O_{2} = [\begin{matrix} (S a O_{2} \times H b \times O_{2} c o m b i n i n g c a p a c i t y o f H b) \\ + (O_{2} s o l u b i l i t y \times P a O_{2}) \end{matrix}]$

where CaO ₂ (O ₂ content) is the milliliters of O ₂ per 100 mL of blood, SaO ₂ is the fraction of hemoglobin (Hb) that is saturated with O ₂ , O ₂ -combining capacity of Hb is 1.34 mL of O ₂ per gram of Hb, Hb is grams of Hb per 100 mL of blood, Pa o ₂ is the O ₂ tension (i.e., dissolved O ₂ ), and solubility of O ₂ in plasma is 0.003 mL of O ₂ per 100 mL plasma for each mm Hg Pa o ₂

The binding of O ₂ to hemoglobin is a complex, allosteric mechanism. Important insights can be gained by understanding how characteristic abnormalities of blood O ₂ carriage (e.g., carbon monoxide [CO] poisoning, methemoglobinemia) affect O ₂ tension, content, and delivery.

Methemoglobin (MetHb), formed by the oxidation to Fe ³⁺ (ferric) instead of the usual Fe ²⁺ (ferrous) iron, is less able to bind O ₂ , resulting in diminished O ₂ content and less O ₂ delivery. Here, the Pa o ₂ (in the absence of lung disease) will be normal: if the O ₂ content is calculated from the Pa o ₂ , it will appear normal, but if directly measured, it will be low. In contrast, MetHb level will be elevated. In severe cases, lactic acidosis develops because of impaired O ₂ delivery. In addition, because MetHb has a blue-brown color, the patient will appear blue, even if the fraction of MetHb is modest; specialized oximetry can separately measure MetHb levels. The apparent cyanosis is not responsive to supplemental O ₂ , and therapy involves converting (i.e., reducing) the MetHb to Hb (e.g., by using methylene blue). Important medical causes of MetHb include benzocaine, dapsone, or in susceptible patients, inhaled nitric oxide (NO).

In CO poisoning, the CO binds to Hb, with far greater (over 200-fold) avidity than molecular O ₂ , tightly forming CO-Hb and resulting in two main effects. First, formation of CO-Hb results in fewer sites available for O ₂ binding, and this reduces the blood O ₂ content. Second, the formation of CO-Hb causes conformational changes in the Hb molecule such that the tendency to release bound O ₂ is reduced. This effect corresponds to a leftward shift of the Hb-O ₂ dissociation curve, and although this aspect of CO binding does not reduce the O ₂ content or “global” delivery of O ₂ , it does reduce the release of O ₂ and its local delivery to the cells. Because the color of CO-Hb closely resembles that of O ₂ -Hb, the color of the blood (and the patient) is bright red; however, as with MetHb, the PaO ₂ will be normal (assuming no pulmonary disease) as will be the calculated CaO ₂ ; however, the measured CaO ₂ will be low and if severe, a lactic acidosis will be present. Modern pulse oximeters can distinguish between Hb-O ₂ and CO-Hb.

Finally, the Bohr effect refers to a shift of the Hb-O ₂ dissociation curve caused by changes in CO ₂ or pH. In the systemic capillaries, the P co ₂ is higher than in the arterial blood (and the pH correspondingly lower) because of local CO ₂ production. These circumstances shift the Hb-O ₂ dissociation curve to the right, which increases the offloading of O ₂ to the tissues. The opposite occurs in the pulmonary capillaries; here, the P co ₂ is lower (and the pH correspondingly higher) because of CO ₂ elimination, and the dissociation curve is shifted to the left to facilitate O ₂ binding to Hb.

Transport of Co ₂ in the Blood

CO ₂ is produced by metabolism in the mitochondria, where the CO ₂ levels are highest. The transport path (involving progressively decreasing pressure gradients) is from mitochondria through cytoplasm, into venules, and finally, in mixed venous blood from where it is eliminated through the alveoli. In the blood, CO ₂ is transported in three main forms: dissolved (reflected as Pa co ₂ , partial pressure; accounts for approximately 5% of transported CO ₂ ), bicarbonate ion (HCO ₃ –; almost 90%), and carbamino CO ₂ (CO ₂ bound to terminal amino groups in Hb molecules; approximately 5%). The usual quantities of CO ₂ in the arterial and (mixed) venous blood are approximately 21.5 and 23.3 mmol of CO ₂ per liter of blood, respectively.

Breathing O ₂ can sometimes induce hypercapnia, as occurs in patients with severe chronic lung disease who are breathing supplemental O ₂ . Although traditionally thought to occur because increased Pa o ₂ reduces ventilatory drive, this is now thought not to be the case, resulting instead from the Haldane effect, as well as from impairment of hypoxic pulmonary vasoconstriction (HPV). The Haldane effect is the difference in the amount of CO ₂ carried in oxygenated versus deoxygenated blood, and two mechanisms explain this. First, increased Pa o ₂ decreases the ability to form carbamino compounds—reducing the amount of CO ₂ bound to Hb—thereby raising the amount of dissolved CO ₂ (i.e., elevated P co ₂ ). Second, the amino acid histidine, which has an imidazole group that is an effective H ⁺ buffer at physiologic pH, is an important linking molecule between heme groups and the Hb chains. Increasing the partial pressure of oxygen (PO ₂ ) increases the amount of O ₂ bound to Hb; this changes the conformation of the Hb molecule, which in turn alters the heme-linked histidine and reduces its H ⁺ buffering capacity. Therefore, more H ⁺ is free (not buffered) and binds to HCO ₃ –, releasing stored CO ₂ . Impairment of HPV by elevated O ₂ allows increased perfusion to poorly ventilated regions; this has the effect of decreasing perfusion (and delivery of CO ₂ ) to better ventilated regions, diminishing the efficiency of CO ₂ exhalation. Patients with impaired ability to increase alveolar ventilation ( ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ ) cannot compensate for the increased CO ₂ availability, and therefore, in these patients, adding supplemental O ₂ can result in elevated Pa co ₂ .

Oxygenation in the Pulmonary Artery

Systemic venous blood (central venous blood) enters the right ventricle via the right atrium. The O ₂ saturation (SO ₂ ) differs among the major veins: higher venous SO ₂ reflects greater blood flow, less tissue oxygen uptake, or both. SO ₂ is usually higher in the inferior vena cava (IVC) than in the superior vena cava (SVC), possibly because of the high renal and hepatic flow relative to O ₂ consumption. In the right ventricle, the central venous blood ( $S_{cv} O_{2}$ $S_{cv} O_{2}$ ) from the SVC and IVC is joined by additional venous blood from the coronary circulation (via the coronary sinuses). In the right ventricle, an additional small amount of venous drainage from the myocardium enters through the thebesian veins, and as all this venous blood enters the pulmonary artery, it is well mixed and is termed mixed-venous blood ( $S_{v} O_{2}$ $S_{v} O_{2}$ ); thus $S_{v} O_{2} < S_{cv} O_{2}$ $S_{v} O_{2} < S_{cv} O_{2}$ , although the trends of each usually run in parallel.

Ventilation

Ventilation refers to the movement of inspired gas into and exhaled gas out of the lungs.

Alveolar Ventilation

Fresh gas enters the lung by cyclic breathing at a rate and depth (tidal volume, V _T ) determined by metabolic demand, usually 7 to 8 L/min. While most inspired gas reaches the alveoli, some (100-150 mL) of each V _T remains in the airways and cannot participate in gas exchange. Such dead space (V _D ) constitutes approximately one third of each V _T . Anatomic V _D is the fraction of the V _T that remains in the “conducting” airways, and physiologic V _D is any part of a V _T that does not participate in gas exchange ( Fig. 13.1 ).

For a single tidal volume (V _T , mL), the following is true:

V_{T} = V_{A} + V_{D}

$V_{T} = V_{A} + V_{D}$

The product of V _T (mL) times the respiratory rate (per minute) is the minute ventilation ( ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ ). Aggregated over time, minute ventilation ( ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ , mL/min) is:

{\dot{V}}_{E} = {\dot{V}}_{A} + f \times V_{D}

${\dot{V}}_{E} = {\dot{V}}_{A} + f \times V_{D}$

The portion of the ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ that reaches the alveoli and respiratory bronchioles each minute and participates in gas exchange is called the alveolar ventilation ( ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ ), and it is approximately 5 L/min. Because this is similar to the blood flow through the lungs (i.e., the cardiac output, also 5 L/min), the overall alveolar ventilation-perfusion ratio is approximately 1.

Dead Space Ventilation

Maintenance of Pa co ₂ is a balance between CO ₂ production ( ${\dot{V} CO}_{2}$ ${\dot{V} CO}_{2}$ , reflecting metabolic activity) and alveolar ventilation ( ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ ). If ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ is constant but V _D is increased, ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ will naturally be reduced, and the Pa co ₂ will therefore rise. Therefore, if V _D is increased, ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ must also increase to prevent a rise in Pa co ₂ . Such elevations in V _D occur when a mouthpiece or facemask is used, and in such cases, the additional V _D is termed “apparatus deadspace” (which can be up to 300 mL; anatomic V _D of the airways is 100-150 mL).

Increases in the volume of the conducting airways (e.g., bronchiectasis) increase the overall V _D only slightly. Far more significant increases in V _D occur when perfusion to a large number of ventilated alveoli is interrupted, as occurs in a pulmonary embolus (see Fig. 13.1 ). Indeed, with multiple pulmonary emboli, V _D /V _T can exceed 0.8 (2.7-fold normal). In such a case, to maintain a normal ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ (5 L/min), the ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ would have to increase (also 2.7-fold) to almost 20 L/min. This effort would cause considerable dyspnea, in addition to the dyspnea induced by the lowered PaO ₂ .

Obstructive lung disease can result in diversion of inspired air into (nonobstructed) ventilated, but poorly perfused, regions of the lung. This results in local excesses of ventilation versus perfusion (high ${\dot{V}}_{A} / \dot{Q}$ ${\dot{V}}_{A} / \dot{Q}$ ratio) in such regions, which is equivalent to an increase in V _D /V _T (see Fig. 13.1 ). Patients with severe chronic obstructive pulmonary disease (COPD) may have a V _D /V _T ratio of up to 0.9, and would have to hyperventilate massively (30-50 L/min) to maintain normal Pa co ₂ , which is not possible where ventilator reserve is diminished. Such patients demonstrate reduced ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ but often have an elevated ${\dot{V}}_{E}$ ${\dot{V}}_{E}$ . An important compensatory mechanism is that a lower level of ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ will maintain stable CO ₂ excretion where the Pa co ₂ is increased ( Box 13.1 ).

BOX 13.1

Alveolar Gas Equations

Alveolar Oxygen Tension (P _A o ₂ )

P_{A O_{2}} = P I O_{2} - \frac{P_{AC O_{2}}}{R} + [P_{AC O_{2}} \times Fi O_{2} \times \frac{1 - R}{R}]

$P_{A O_{2}} = P I O_{2} - \frac{P_{AC O_{2}}}{R} + [P_{AC O_{2}} \times Fi O_{2} \times \frac{1 - R}{R}]$

where P io ₂ is inspired oxygen tension, P aco ₂ is alveolar CO ₂ tension (assumed to equal arterial Pc o ₂ ), R is the respiratory exchange ratio (normally in the range of 0.8-1.0), and FiO ₂ is the inspired oxygen fraction. The term within brackets compensates for the larger O ₂ uptake than CO ₂ elimination over the alveolar capillary membranes.

A simplified equation can be written without the compensation term:

P_{A O_{2}} = P I O_{2} - \frac{P_{A C O_{2}}}{R}

$P_{A O_{2}} = P I O_{2} - \frac{P_{A C O_{2}}}{R}$

Alveolar Ventilation

Alveolar ventilation ( ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ ) can be expressed as

{\dot{V}}_{A} = f \times (V_{T} - V_{DS})

${\dot{V}}_{A} = f \times (V_{T} - V_{DS})$

where f is breaths/min, V _T is tidal volume, and V _DS is physiologic dead space.

Alveolar ventilation can also be derived from:

{\dot{V}}_{C O_{2}} = c \times {\dot{V}}_{A} \times F_{A C O_{2}}

${\dot{V}}_{C O_{2}} = c \times {\dot{V}}_{A} \times F_{A C O_{2}}$

where ${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ is CO ₂ elimination, c is a conversion constant, and F aco ₂ is the alveolar CO ₂ concentration.

If ${\dot{V}}_{A}$ ${\dot{V}}_{A}$ is expressed in L/min, ${\dot{V}}_{{CO}_{2}}$ ${\dot{V}}_{{CO}_{2}}$ in mL/min, and F aco ₂ is replaced by P aco ₂ in mm Hg, c = 0.863. By rearranging:

{\dot{V}}_{A} = \frac{{\dot{V}}_{C O_{2}} \times 0.863}{P_{A C O_{2}}}

${\dot{V}}_{A} = \frac{{\dot{V}}_{C O_{2}} \times 0.863}{P_{A C O_{2}}}$

Static Lung Volumes—Functional Residual Capacity

The amount of air in the lungs after an ordinary expiration is called functional residual capacity (FRC; Fig. 13.2 ); it is usually 3 to 4 L and occurs because of the balance of inward (lung) forces and outward (chest wall) forces. The inward force is the “elastic recoil” of the lung and emanates from the elastic lung tissue fibers, contractile airway smooth muscle, and alveolar surface tension. The outward force is developed by passive recoil from the ribs, joints, and muscles of the chest wall. FRC is greater with increased height and age (loss of elastic lung tissue), and smaller in women and in obesity.

Fig. 13.2, (A) Ventilation and lung volumes in a healthy subject with normal lungs. (B) A patient with restrictive lung disease. (C) A patient with chronic obstructive pulmonary disease (COPD). In restrictive disease, the vital capacity (VC) is decreased and expiratory flow rate is increased (i.e., steeper than the normal slope of the forced expiratory curve). In COPD, the residual volume (RV) is increased, the VC is reduced, and forced expiration is slowed. ERV, Expiratory reserve volume; TLC, total lung capacity.

There are two reasons why maintenance of gas in the lung at end-expiration (i.e., FRC) is important. First, inflating an already opened (inflated) lung is easier than when the lung is deflated. This is because complete collapse results in liquid-only surfaces interfacing in alveoli (high surface tension), whereas alveoli in partially inflated lung have air-liquid interfaces (lower surface tension). Second, although perfusion in the lung is phasic, the frequency is rapid and the oscillations in flow are low, resulting in nearly continuous flow. Ventilation is different: the frequency is far slower and the size of the oscillations far larger. If the lung (or large parts of it) completely deflate between breaths, the blood flowing from closed alveoli (that contain zero O ₂ ) would have very low SO ₂ (the same as mixed venous blood); this would mix into the overall blood flow from the lungs and cause a major O ₂ desaturation after every exhalation.

Respiratory Mechanics

The study of respiratory mechanics tells us how inspired air is distributed within the lung and permits quantitation of the severity of lung disease. The components of overall impedance to breathing results from elastance (the reciprocal of compliance), resistance, and inertia.

Compliance of the Respiratory System

The lung is like a rubber balloon that can be distended by positive pressure (inside) or negative pressure (outside). Under normal circumstances, inflation of the lung is maintained because although the pressure inside (alveolar pressure) is zero, the outside pressure (i.e., the pleural pressure) is sufficiently negative. The net distending pressure, which is the difference of the (positive) airway pressure (P _AW ) and the (negative) pleural pressure (P _PL ) is termed the transpulmonary pressure (P _TP ). Thus:

P_{T P} = P_{A W} - P_{P L}

$P_{T P} = P_{A W} - P_{P L}$

Clearly, increasing the P _AW increases the P _TP . In addition, lowering the P _PL (which is usually negative and making it more negative) also increases the P _TP .

Compliance —the reciprocal of elastance—is the term that expresses how much distention (volume in liters) occurs for a given level of P _TP (pressure, cm H ₂ O); it is usually 0.2 to 0.3 L/cm H ₂ O. However, although higher values of P _TP maintain greater levels of lung opening, the relationship—as with most elastic structures—between applied pressure and resultant volume is curvilinear ( Fig. 13.3 ). Lung compliance depends on the lung volume; it is lowest at an extremely low or high FRC (see Fig. 13.3 ). In lung diseases characterized by reduced compliance (e.g., ARDS, pulmonary fibrosis, or edema), the pressure-volume (PV) curve is flatter and shifted to the right ( Fig. 13.4 ). In contrast, although emphysema involves the loss of elastic tissue, the overall loss of lung tissue (as seen on computed tomography [CT] scanning) means that the compliance is increased; the PV curve is therefore shifted to the left and is steeper (see Fig. 13.4 ).

Fig. 13.3, The pressure-volume relationships of the lung. The relationship is curvilinear (typical for an elastic structure). The pleural pressure is lower (more subatmospheric) in the upper regions. In the upright subject, the transpulmonary pressure (P TP = P AW –P PL ) is higher in apical than in basal regions. This results in different positions on the pressure volume curve of the upper (flatter, less compliant) versus lower (steeper, more compliant) lung regions. Thus lower lung regions expand more (i.e., receive more ventilation) for a given increase in transpulmonary pressure than upper units. TLC, Total lung capacity.

Fig. 13.4, Pressure-volume curves of the lung in healthy and lung-diseased patients. In fibrosis, the slope of the curve is flatter, reflecting considerable increases in pressure variation and in respiratory work. In asthma or bronchitis, there is a parallel (upward) shift of the pressure-volume curve, indicating an increase in lung volume but no change in compliance. In emphysema, the slope of the curve is steeper, reflecting tissue loss and possible increased compliance. However, in emphysema, asthma, or bronchitis, the airway resistance is increased; this increases work of breathing and overrides any benefit from increased compliance.

Chest wall impedance is not noticed during spontaneous breathing because the respiratory “pump” includes the chest wall. Chest wall mechanics can be measured only if complete relaxation of the respiratory muscles can be achieved ; however, during mechanical ventilation, the respiratory muscles can be completely relaxed. As the lung is inflated by P _AW , the properties of the chest wall will determine the resulting change in P _PL . Under these circumstances, the increase in lung volume per unit increase in P _PL is the chest wall compliance. Values of chest wall compliance are about the same as that of the lung and are reduced with obesity, chest wall edema, pleural effusions, and diseases of the costovertebral joints.

Resistance of the Respiratory System

Airways

Resistance impedes airflow into (and out of) the lung. The major component of resistance is the resistance exerted by the airways (large and small), and a minor component is the sliding of lung and the chest wall tissue elements during inspiration (and expiration). Resistance is overcome by (driving) pressure. In spontaneous breathing, driving pressure will be the P _PL ; in positive pressure ventilation, the driving pressure will be the difference between the pressures applied to the endotracheal tube (P _AW ; “source”) and the alveolus (P _ALV ; “destination”). Resistance (R) is calculated as driving pressure (ΔP) divided by the resultant gas flow (F):

R = \frac{Δ P}{F}

$R = \frac{Δ P}{F}$

The value of airway resistance is approximately 1 cm H ₂ O/L/sec, and is higher in obstructive lung disease (e.g., COPD, asthma); in severe asthma, it is elevated approximately tenfold. The presence of an endotracheal tube adds a resistance of 5 (or 8) cm H ₂ O/L/min for a tube with internal diameter of size 8 (or 7) cm. For any tube for which the airflow is laminar (smooth, streamlined), the resistance increases in direct proportion to the tube length and increases dramatically (to the fourth power) as the diameter of the tube is reduced.

Two factors explain why most (approximately 80%) of the impedance to gas flow occurs in the large airways. First, as bronchi progressively branch, the resistances are arranged in parallel and the total cross-sectional area at the level of the terminal bronchioles adds up to almost tenfold that at the trachea. Second, in tubes that are large, irregular or branched, the flow is often turbulent, not laminar. When flow is laminar:

F_{(l a m)} = \frac{Δ P}{R}

$F_{(l a m)} = \frac{Δ P}{R}$

In contrast, when flow is turbulent:

F_{(t u r b)} = \frac{Δ P}{R^{2}}

$F_{(t u r b)} = \frac{Δ P}{R^{2}}$

Therefore, for a given radius, far more pressure is required to achieve comparable flow where flow is turbulent; thus the effort required is greater and if prolonged or severe, respiratory failure is more likely.

Several factors can alter airflow resistance. First, resistance lessens as lung volume increases; this is intuitive, as increasing volume (positive pressure or spontaneous breathing) stretches the diameter of the airways. Because this is the key determinant of resistance, the resistance falls to a small extent. The opposite occurs with exhalation ( Fig. 13.5 ). However, as lung volume approaches residual volume (RV)—as can happen during anesthesia—the airways are narrowed in parallel with the compressing lung tissue and the resistance rises exponentially. These effects are apparent with active or passive ventilation. Second, active ventilation has additional effects. Forced expiration can compress small airways (i.e., that do not contain cartilage). In addition, forced expiration can cause turbulent flow in small airways in patients with COPD, precipitously dropping pressure in the lumen and thereby narrowing the bronchioles and resulting in expiratory flow limitation and, after multiple breaths, eventual “dynamic hyperinflation.” Expiring against resistance (or pursed-lips breathing) is sometimes used by those with COPD to make breathing easier. This works by increasing expiratory resistance and slowing expiration. The slowed expiration reduces the pressure gradient driving expiration (i.e., pressure highest in the alveolus, lower toward the mouth). Therefore, the point along the airway tree at which pressure inside the airway has decreased to less than that outside the airway (equal to pleural pressure) is moved from smaller collapsible airways toward the mouth to noncollapsible, cartilaginous airways ( Fig. 13.6 ); this prevents collapse of the smaller airways, which are vital for proper gas exchange.

Fig. 13.5, Schematic drawing of airflow resistance against lung volume at different flow rates. As lung volume falls, the resistance to flow increases; the steepness of this increase is far greater at lung volumes below functional residual capacity (FRC) . In addition, higher airflow rates are associated with greater resistance. At extremely low lung volume, the resistance is comparable to values seen in moderate to severe asthma (6-8 cm H 2 O × l– 1 × s). RV, Residual volume; TLC, total lung capacity.

Fig. 13.6, Schematic drawings of the equal pressure point (EPP) concept and dynamic compression of airways. (A) Slightly forced expiration during otherwise normal conditions. With the application of some expiratory muscle effort, pleural pressure (P PL ) is positive, 4 cm H 2 O (0.4 kPa). The elastic recoil pressure (P ST ) of the alveoli (6 cm H 2 O) and the pleural pressure add together to yield intraalveolar pressure (P ALV ) (10 cm H 2 O). This causes expiratory flow. At some point downstream toward the airway opening, airway pressure (P AW ) has dropped by 6 cm H 2 O, so intraluminal pressure and pleural, extraluminal pressure are the same. This is the EPP. From this point to the mouth, intraluminal airway pressure is lower than the surrounding, extraluminal pressure and the airway may be compressed. (B) An attempt to stabilize the airway by so-called “pursed-lip” breathing. The increased resistance to expiratory flow requires increased expiratory effort to maintain gas flow. Thus pleural pressure is increased in comparison to the normal conditions (P pl = 20 cm H 2 O). Alveolar elastic recoil pressure (P ST ) is the same as in the earlier condition, provided that lung volume is the same. If expiratory flow is of the same magnitude as during normal breathing, pressure along the airway falls to the same extent as during normal breathing. Thus the EPP will have the same location as during normal breathing, and no stabilization of the airway has been achieved. The two ways of moving the EPP toward the mouth and to less collapsible airways is by raising alveolar recoil pressure (P st ) by an increase in lung volume or by lowering the expiratory flow rate so that the pressure drop along the airway tree is slowed down.

The large airways (i.e., pharynx, larynx, and trachea) are outside the chest wall. During inspiration, the intrathoracic airways are exposed to extraluminal pressure (i.e., P _PL ) that is less than the lumen pressure; in contrast, the extrathoracic airways are exposed to lumen pressure that is less than the extraluminal (i.e., atmospheric) pressure. This feature, coupled with downward stretch induced by inspiration, narrows the large extrathoracic airways; in the presence of preexisting narrowing (e.g., thyroid enlargement or tumor, paralyzed vocal cord, epiglottitis), this can critically reduce the cross-sectional area.

Tissue

Although not intuitively obvious, resistance of the lung tissue is the applied pressure on tissue divided by the resulting velocity of tissue movement. There are various approaches to determining this in humans, including separately considering the PV characteristics using plethysmography (where the area of the PV curve corresponds to work against total pulmonary resistance) and esophageal pressure (where the area of the PV curve corresponds to work against “tissue” resistance). Alternative approaches mathematically model the lung responses to varying respiratory frequencies. Lung tissue resistance amounts to 20% of the total resistance to breathing; it can be increased threefold or fourfold in chronic lung disease and is reduced by panting respirations. Finally, in adult respiratory distress syndrome (ARDS) the chest wall resistance is increased.

Inertia or Acceleration of Gas and Tissue

A final component of the total impedance to breathing is inertance, or the pressure required to accelerate air and tissue during inspiration and expiration. This component is minor, however, and can hardly be measured under normal breathing, regardless of whether the lungs are healthy. Nonetheless, tissue inertia is large during rapid ventilation, and it could be important during the rapid, shallow breathing characteristic of weaning failure or during high-frequency oscillation.

Distribution of Inspired Gas

Inspired gas is not evenly distributed throughout the lung; naturally, more gas enters those lung units that expand most during inspiration. In the resting lung, the basal (dependent) regions are less aerated than the apical (nondependent) regions; therefore, they have the capacity to undergo greater expansion. During inspiration, most gas goes to the basal units (dorsal, when supine; lower right lung when in the right lateral position). This distribution is because of the compliance properties of the lung and the effects of position on the distribution of the distending pleural pressure (i.e., the P _PL gradient). These changes are not related to the properties of the inspired gas.

In the upright position, the P _PL is less negative at the base of the lung than at the apex. Because the alveolus pressure (P _A ) is uniform throughout the lung, the distending P _TP is greater at the apex; therefore, before inspiration commences, the apical lung is more open (and is less compliant) than the basal lung ( Figs. 13.3 and 13.7 ). With inspiration, the contracting diaphragm lowers the P _PL by a comparable amount in all areas of the pleural surface (because of the fluid-like behavior of normal lung ) and distends the basal more than the apical regions (see Figs. 13.3 and 13.7 ). Because the pleural pressure gradient is oriented according to gravity, the distribution of ventilation changes with body position.

The P _PL gradient exists because lung density, gravity, and conformation of the lung to the shape of the thorax result in crowding of the basal lung tissue, making the local P _PL less negative in the basal regions. Because the density of normal lung is approximately 0.3, P _PL will become more positive by 0.3 cm H ₂ O for each downward vertical centimeter, and more so with injured or edematous lungs. Indeed, experimentally induced weightlessness decreases inhomogeneity in the distribution of ventilation, but does not eliminate it; therefore, nongravitational (e.g., tissue, airway) factors also play a role.

Although the vertical height of the lung is the same in the prone and supine positions, the vertical gradient P _PL is less when prone, perhaps because the mediastinum compresses the dependent lung when supine but rests on the sternum when prone. A more even distribution of inspired gas—with improved oxygenation—in the prone position was predicted by Bryan in 1974 ⁴⁴ ; this has been confirmed experimentally.

During low-flow states (e.g., at rest), distribution is determined by differences in compliance and not by airway resistance. Because compliance at the start of inflation is less in the (already more aerated) apex, ventilation is preferentially directed to the base. In contrast, at high airflow, resistance (not compliance) is the key determinant of distribution; because the resistance is lower in upper, more expanded lung regions, increasing flow rate equalizes the distribution of ventilation, as shown by distribution of ¹³³ Xe gas in humans ( Fig. 13.8 ). This is important during exercise or stress because greater amounts of the alveolar-capillary surface area will be used.

Fig. 13.8, Distribution of ventilation to upper versus lower lung regions as inspiratory flow is altered. At low flow, the bulk of the airflow goes to the lower regions. At higher flow rates (e.g., during exercise) the distribution is more even, ensuring more efficient use of all alveolar-capillary membranes for gas transfer (provided that pulmonary blood flow shows a similar distribution pattern).

Airway Closure

Expiration causes the airways to narrow, and deep expiration can cause them to close. The volume remaining above RV where expiration below FRC closes some airways is termed closing volume (CV), and this volume added to the RV is termed the closing capacity (CC; i.e., the total capacity of the lung at which closing can occur). Closure of airways during expiration is normal and is potentiated by increasing P _PL , especially with active expiration. When P _PL exceeds the P _AW , the airway—if collapsible—will tend to close, and this usually commences at the bases because the basal P _PL is greatest (see Fig. 13.7 ).

Fig. 13.7, Schematic of regional alveolar and airway volume at an upper (A) and a lower (B) lung level (left panel) . There is a vertical pleural pressure (P PL ) gradient between the uppermost and lowermost regions (–6.5 to 1 = –7.5 cm H 2 O). Airway pressure (P AW ) is atmospheric, or 0 cm H 2 O throughout; thus, in the upper regions, P AW > P PL maintains airways open. In contrast, in the lower regions, P PL > P AW causes airway closure—potentially exacerbated by subsequent alveolar gas absorption behind the occluded airway. The right panel shows the distribution of ventilation and perfusion ratios from the multiple inert gas elimination technique. A “normal” mode of ventilation and blood flow (A) can be seen corresponding to the open and ventilated alveoli in the upper parts of the lung. In addition, there is a range of low V˙A/Q˙ V˙A/Q˙ ratios with more perfusion than ventilation (B) . This pattern is compatible with intermittent airway closure during breathing.

Three applications of this important principle are of key relevance to anesthesia. First, airway closure depends on age: in youth, the closure does not occur until expiration is at or near RV, whereas with older age, it occurs earlier in expiration (i.e., at higher lung volumes). This occurs because P _PL is on average more “positive” (i.e., atmospheric, equal to P _AW ) as age increases. Closing can occur at or above FRC in individuals aged 65 to 70 years, such that dependent regions will undergo closure during normal expiration. This may be the major reason why oxygenation decreases with age. Second, in the supine position, FRC is less than when upright, but CC is unchanged; therefore, exhalation of a usual V _T (from FRC) encroaches on CC in a supine 45-year-old, and closure may be continuous in a supine 70-year-old ( Fig. 13.9 ). Finally, COPD increases the lung volume at which closure occurs, possibly exacerbated by airway edema and increased bronchial tone.

Fig. 13.9, Resting functional residual capacity (FRC) and closing capacity (CC) . FRC increases with age (because of loss of elastic tissue), and superimposed upon this is a step decrease in FRC with supine position (because of diaphragm elevation by abdominal contents), and a further decrease with anesthesia in the supine position. The CC is also increased with age, but far more steeply, causing airway closure above FRC in upright subjects (>65 yr) and in supine subjects (>45 yr). This relationship between CC and FRC explains decreasing oxygenation with age.

Diffusion of Gas

Gas moves in the large and medium-sized airways by bulk flow (i.e., convection), meaning that the gas molecules travel together at a given mean velocity according to a driving pressure gradient. Flow is through multiple generations of bronchi, and the net resistance falls with each division. After the 14th generation, airways merge with alveoli and participate in gas exchange (respiratory bronchioles). The cross-sectional area expands massively (trachea, 2.5 cm ² ; 23rd generation bronchi, 0.8 m ² ; alveolar surface, 140 m ² ), resulting in a sharp drop in overall resistance. Because the number of gas molecules is constant, the velocity falls rapidly, which by the time the gas enters the alveoli is miniscule (0.001 mm/s); it is zero when it reaches the alveolar membrane. The velocity of the gas entering the alveolus is slower than the diffusion rates of O ₂ and CO ₂ ; therefore, diffusion—not convection—is necessary for transport in the distal airways and alveoli. Indeed, CO ₂ is detectable at the mouth after just seconds of breath-holding, because of rapid diffusion and because of cardiac oscillations (i.e., mixing).

Gas mixing is complete in the alveoli of a normal lung during normal breathing. However, if the alveolus expands (e.g., emphysema), the diffusion distance may be too great to allow complete mixing, potentially leaving a layer of CO ₂ -rich gas lining the alveolar membrane and a core of O ₂ -rich gas in the alveolus. This represents a “micro” version of inhomogeneous distribution of ventilation.

Perfusion

The pulmonary circulation differs from the systemic circulation: it operates at a five to tenfold lower pressure, and the vessels are shorter and wider. There are two important consequences of the particularly low vascular resistance. First, the downstream blood flow in the pulmonary capillaries is pulsatile, in contrast to the more constant systemic capillary flow. Second, the capillary and alveolar walls are protected from exposure to high hydrostatic pressures; therefore, they can be sufficiently thin to optimize diffusion (i.e., exchange) of gas but not permit leakage of plasma or blood into the airspace. Whereas an abrupt increase in the pulmonary arterial (or venous) pressure can cause breaks in the capillaries, slower increases (i.e., months to years) stimulate vascular remodeling. This remodeling might protect against pulmonary edema (and possibly against lung injury ), but diffusion will be impaired.

Distribution of Lung Blood Flow

Pulmonary blood flow depends on driving pressure and vascular resistance; these factors (and flow) are not homogenous throughout the lung. The traditional thinking about lung perfusion emphasized the importance of gravity; however, factors other than gravity are also important.

Distribution of Blood Flow in the Lung: the Effect of Gravity

Blood has weight and therefore blood pressure is affected by gravity. The height (base to apex) of an adult lung is approximately 25 cm; therefore, when a person is standing, the hydrostatic pressure at the base is 25 cm H ₂ O (i.e., approximately 18 mm Hg) higher than at the apex. The mean pulmonary arterial pressure is approximately 12 mm Hg at the level of the heart, and the pulmonary artery pressure at the lung apex can therefore approach zero. Thus less blood flow will occur at the apex (versus the base), and in the setting of positive pressure ventilation, the apical alveoli can compress the surrounding capillaries and prevent any local blood flow.

Based on such gravitational distribution of pulmonary artery pressure, as well as the effect of alveolar expansion, West and colleagues divided the lung into zones I to III ( Fig. 13.10 ). This system is based on the principle that perfusion to an alveolus depends on the pressures in the pulmonary artery (P _PA ), pulmonary vein (P _PV ), and alveolus (P _ALV ). In the apex (zone I), the key issue is that pulmonary arterial pressure is less than alveolar pressure; therefore, no perfusion occurs. Zone I conditions can exist during mechanical ventilation and be exacerbated by low P _PA . Whenever zone I conditions exist, the nonperfused alveoli constitute additional dead space (V _D ). Below the apex in zone II, P _PV is less than alveolar pressure, and the veins are collapsed except during flow, as in a “vascular waterfall.” Although P _ALV is always greater than P _PV , perfusion occurs when P _PA exceeds P _ALV (i.e., intermittently, during systole). Below this zone is zone III, in which there are two important differences: P _PA and P _PV both always exceed P _ALV . As a result, there is perfusion throughout systole and diastole (and inspiration and expiration). Gravity results in equal increases in both P _PA and P _PV toward the lung base; therefore, gravity cannot affect flow throughout zone III by increasing the P _PA to P _PV pressure gradient alone. Nonetheless, it is possible that the greater weight of the blood nearer the base results in vessel dilatation, thereby lowering vascular resistance and increasing flow. It was subsequently recognized that there is also a decrease in perfusion in the lung base, or zone IV, that is thought to occur because of the effects of gravity compressing the lung at the bases—and the blood vessels therein—and thereby increasing vascular resistance.

Fig. 13.10, Vertical distribution of lung blood flow. The so-called zones I, II, III, and IV are indicated. In zone I there is no perfusion, only ventilation. In zone II, pulmonary artery pressure exceeds alveolar pressure which in turn exceeds venous pressure; the driving pressure is PPA−P alv . In zone III, arterial and venous pressures both exceed alveolar pressure, and here the driving pressure is P PA −P PV . In the lung base, blood flow is decreased possibly because of increased interstitial pressure that compresses extra alveolar vessels. P ALV , intraalveolar pressure; P PV , pulmonary vein pressure; P PA , pulmonary artery pressure; Q T , cardiac output.

Finally, additional evidence for the effect of gravity comes from volunteer experiments in which gravity was increased or abolished by altering the flight pattern of a jet aircraft. In these experiments, zero gravity decreased cardiac oscillations of O ₂ and CO ₂ during a breath-hold, indicating development of more homogeneous perfusion. In contrast, more recent experiments of exhaled gas analysis (on the Mir space station) reported that the heterogeneity of lung perfusion was reduced, but not eliminated, in the presence of microgravity, indicating that gravity contributes to the heterogeneity of blood flow distribution but does not explain it entirely. While the precise role of gravity is disputed, it is likely to play a smaller role when supine versus when upright.

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Key Points

Respiratory Physiology Is Central to the Practice of Anesthesia

Pulmonary Physiology in Health

Respiration in the Cell

Transport of O 2 in the Blood

Transport of Co 2 in the Blood

Oxygenation in the Pulmonary Artery

Ventilation

Alveolar Ventilation

Dead Space Ventilation

Alveolar Oxygen Tension (P A o 2 )

Alveolar Ventilation

Static Lung Volumes—Functional Residual Capacity

Respiratory Mechanics

Compliance of the Respiratory System

Resistance of the Respiratory System

Airways

Tissue

Inertia or Acceleration of Gas and Tissue

Distribution of Inspired Gas

Airway Closure

Diffusion of Gas

Perfusion

Distribution of Lung Blood Flow

Distribution of Blood Flow in the Lung: the Effect of Gravity

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Transport of O ₂ in the Blood

Transport of Co ₂ in the Blood

Alveolar Oxygen Tension (P _A o ₂ )