Oxygen Transport

Oxygen transport refers to the delivery of fully oxygenated blood to peripheral tissues, cellular uptake of oxygen, use of oxygen within the tissue, and the return of partially desaturated blood to the lungs. The oxygen transport pathway consists of multiple steps ranging from the ambient air to the perfusion of peripheral tissues with oxygenated arterial blood (Figure 2-1). Oxygen transport has become the basis for conceptualizing cardiovascular and pulmonary function and diagnosing and managing cardiovascular and pulmonary dysfunction.^2–8

Oxygen transport variables include oxygen delivery (DO₂), oxygen consumption (), and the oxygen extraction ratio (OER), the utilization coefficient. Oxygen demand is the amount of oxygen required by the cells for aerobic metabolism. Oxygen demand is usually reflected by ; however, in cases of severe cardiovascular and pulmonary dysfunction and compromise to oxygen transport, can fall short of the demand for oxygen. Oxygen transport variables, including the components of DO₂, , and OER, are shown in Figure 2-2. DO₂ is determined by arterial oxygen content and cardiac output, by the arteriovenous oxygen content difference and cardiac output, and oxygen extraction by the ratio of DO₂ to .

Measures and indexes of oxygen transport that reflect the function of the component steps of the oxygen transport pathway are shown in Table 2-1.

Inspired Gas Pulmonary Variables Pulmonary Hemodynamic Variables Systemic Hemodynamic Variables Diffusion Gas Exchange Oxygen Extraction and Use Adequacy of Tissue Perfusion and Oxygen Transport

Energy Transfer and Cellular Oxidation

Cellular metabolism and survival depend on the continuous synthesis and degradation of adenosine triphosphate (ATP), the major source of energy for biological work. Work is performed in biological systems for contraction of skeletal, cardiac, and smooth muscle (e.g., exercise, digestion, glandular secretion, and thermoregulation) and for nerve impulse transmission (Box 2-1). These processes require a continuous supply of ATP, which is made available primarily by aerobic (oxygen-requiring) processes. In the event that oxygen delivery is inadequate, nonaerobic (anaerobic, or non–oxygen-requiring) energy-transferring processes can also supply ATP. Supplying energy anaerobically, however, is more costly metabolically; that is, it is not efficient, is limited, and cannot be sustained because of the disruptive effects of lactate (a cellular byproduct of anaerobic metabolism) on physiological processes. Metabolic acidosis is a consequence of lactate accumulation. In patients who are critically ill, the presence of metabolic acidosis secondary to anaerobic metabolism can be life threatening. Prolonged anaerobic metabolism is lethal in two respects. First, the patient is increasingly dependent on anaerobic metabolism because of inadequate DO₂ to peripheral tissues; second, acidosis interferes with normal cellular processes and homeostasis, which require an optimal pH of 7.40.

The ATP molecule consists of an adenine and a ribose molecule with three phosphates attached. The splitting of the terminal phosphate bond or the two terminal phosphate bonds generates a considerable amount of energy. This energy is used to power various chemical reactions associated with metabolism. These metabolic processes take place in specialized organelles in the cells called mitochondria. The primary pathways that are responsible for the formation of ATP are the Krebs cycle and the electron transfer chain.

The Krebs cycle and the electron transfer chain are the biochemical pathways in the mitochondria of the cell responsible for harnessing oxygen for aerobic metabolism and ensuring a continuous supply of oxygen for this process. Initially, glucose is phosphorylated to produce two molecules of ATP (glycolysis). Glucose is oxidized to produce two molecules of pyruvic acid, yielding a net gain of two molecules of ATP per molecule of glucose. The two pyruvate molecules enter the Krebs cycle, where they are oxidized to CO₂ and water. This process yields 30 ATP molecules. Hydrogen ions released in the process are transferred to the electron transfer chain, yielding 4 ATP molecules for cellular metabolism. Electrons are removed from hydrogen and funneled down the electron transport chain by specialized electron carrier molecules, cytochromes 1 to 5. Only the last of these cytochromes, cytochrome oxidase, can reduce molecular oxygen to water. This process is driven by a gradient of high-to-low potential energy. This energy, transferred as electrons, is passed from H₂ to O₂ and is trapped and conserved as high-energy phosphate bonds. Oxygen is involved in these metabolic pathways only at the end of the electron transfer chain, where oxygen is the final electron acceptor and combines with H₂ to form H₂O. More than 90% of ATP synthesis takes place through the electron transfer chain by means of the oxidative reactions associated with oxidative phosphorylation. An individual’s peak aerobic capacity is determined by the availability of oxygen at the end of the electron transport chain.

For each molecule of glucose that is metabolized, 36 molecules of ATP are produced: 4 molecules by substrate phosphorylation (anaerobic) and 32 by oxidative phosphorylation (aerobic). The low ATP yield from anaerobic metabolism explains why anaerobic metabolism can serve only as a short-term energy source.

The complex, enzymatically controlled chemical reactions of metabolism are designed to form and conserve energy through the Krebs cycle and the electron transfer chain and then use this energy for biological work.9,10 Carbohydrates, fats, and proteins ingested from foodstuffs in the diet are oxidized to provide the energy for phosphorylation of adenosine diphosphate (ADP) (i.e., the formation of ATP by combining ADP with phosphate). These substances are broken down, and they access the Krebs cycle at the pyruvic acid or acetyl coenzyme A (CoA) levels (Fig. 2-3). Some amino acids can enter the Krebs cycle directly.

The Krebs cycle degrades acetyl CoA to carbon dioxide (CO₂) and hydrogen (H₂) atoms. The primary purpose of this cycle is to generate hydrogen ions for the electron transfer chain by two principal electron acceptors, nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). Many acids catalyze the numerous reactions of the Krebs cycle.

Cellular oxidation, or respiration, refers to the function of the electron transfer chain to release energy in small amounts and to conserve energy in the formation of high-energy bonds. It is this process that ensures a continual energy supply to meet the needs of metabolism (Fig. 2-4).

Three major systems of energy transfer exist to supply energy during all-out exercise over varying durations.¹⁰ Although these systems are discrete, they overlap. Cellular ATP and creatine phosphate (CP) are immediate energy sources for the first 10 seconds of exercise. From 30 to 60 seconds, glycolysis provides a short-term energy source. The ATP-CP system and the glycolytic system are anaerobic processes. As exercise persists for several minutes, the long-term aerobic system predominates. Thus, for sustained physical activity and exercise, energy is provided primarily by aerobic metabolism. For this process, oxygen is provided by the oxygen transport pathway. Carbon compounds that enter the body in the form of carbohydrate, fat, and protein undergo oxidative metabolism in the form of aerobic glycolysis in the mitochondria in the cytoplasm of cells.

Muscle Contraction and Metabolism

The basic mechanism for muscle contraction is excitation contraction coupling.11,12 Action potentials mediated centrally or through the spinal cord depolarize the muscle cell membrane (the sarcolemma) and stimulate the release of calcium from the lateral sacs of the sarcoplasmic reticulum. The sarcoplasmic reticulum is an extensive network of invaginations and tubular channels encasing the muscle fibers (myofibrils). The calcium floods over the myofilaments of the myofibrils within the sarcomere. Myofilaments consist of thin actin fiber and thick myosin fiber protein, which interdigitate with each other, giving the typical striated appearance to skeletal muscle (Fig. 2-5). Actin is a helical molecule with tropomyosin intertwined along its length. Tropomyosin normally inhibits the interaction of actin and myosin. Calcium causes a conformational change of the tropomyosin molecule that enables troponin, also distributed along the actin molecule, to combine with calcium. The combining of calcium and troponin triggers the interdigitation of actin and myosin (the sliding-filament theory of muscle contraction). Contraction involves myosin heads (cross bridges) attaching to and detaching from actin in a cyclical manner that causes the actin and myosin filaments to slide past each other. In this way, the muscle is shortened without shortening of the myofilaments.

The energy for muscle contraction in the form of adenosine triphosphate (ATP) is generated within the mitochondria of the myofibrils. Myosin ATPase splits ATP so that the transfer of this energy can be used for muscle contraction. Specifically, the enzyme ATPase is activated when actin and myosin are joined. ATP is then available to bind with the cross bridge, causing it to detach from actin. Relaxation occurs with the cessation of electrical excitation and the rapid removal or sequestration of calcium into the lateral sacs of the sarcoplasmic reticulum.

The specific metabolic properties of muscle depend on the constituent muscle fiber types.¹³ The three primary muscle fiber types are fast-twitch fibers, slow-twitch fibers, and intermediate fibers, which have the properties of both fast-twitch and slow-twitch fibers. The fast-twitch fibers (fast glycolytic fibers) are recruited during short-term, sprint-type exercise that relies mainly on anaerobic metabolism. These fibers are well adapted for rapid, forceful contractions because they have large amounts of myosin ATPase, rapid calcium release and uptake, and a high rate of cross-bridge cycling. Slow-twitch fibers (slow oxidative fibers) are recruited during prolonged aerobic exercise. These fibers have large amounts of myoglobin, mitochondria, and oxidative enzymes. Compared with the fast-twitch fibers, slow-twitch fibers are fatigue resistant. The intermediate fibers have both anaerobic and aerobic metabolic enzymes, which makes these fibers capable of both types of muscle work. Although the characteristics of the fiber types are distinct, activity and exercise recruit both types of fibers. Depending on the particular activity or exercise, one fiber type may be preferentially recruited over the others.

Principles of Oxygen Transport

Individuals need a continuous supply of oxygen to meet moment-to-moment demands for oxygen commensurate with changing metabolic demands for energy at the cellular level as well as basal metabolic demands.14,15 Oxygen transport occurs by convection or diffusion. Convection of oxygen refers to the movement of oxygen from the alveoli to the tissue capillaries and is determined primarily by hemoglobin concentration, oxygen saturation, and cardiac output. The diffusion of oxygen refers to the movement of oxygen from the capillaries to the mitochondria and is determined by metabolic rate, vascular resistance, capillary recruitment, and tissue oxygen consumption and extraction.

Normally, DO₂ is regulated by tissue metabolism and the overall demand for oxygen. At rest, DO₂ is three to four times greater than oxygen demand, and is not directly dependent on DO₂. In a healthy individual, the increased metabolic demands of exercise constitute the greatest challenge to the oxygen transport system; can increase 20 times. In response to increased muscle metabolism, blood flow increases to the peripheral muscles through vasodilation and capillary recruitment, thereby increasing the availability of oxygen to working tissues and its extraction from the arterial blood. As DO₂ and increase, venous return, stroke volume, and heart rate also increase, thereby increasing cardiac output (CO). CO can increase by more than five times during strenuous exercise. The capacity to increase CO reflects a person’s overall aerobic power.

At rest, regional differences in the proportion of CO normally delivered to the body organs reflect differences in organ functions and are not necessarily matched to the metabolic rate.¹⁶ For example, the distribution of CO to the kidneys is 20%; to the mesenteric, splenic, and portal tissues, 20% to 30%. Comparatively, muscle at rest receives 10% and the brain and myocardium receive less than 5% each.

Oxygen Content of the Blood

The majority of oxygen is transported in arterial blood to the tissues. Oxygen is largely combined with hemoglobin (98%) compared with a relatively minimal amount that is dissolved in the blood (2%). The oxyhemoglobin dissociation curve represents the relationship between the affinity of hemoglobin for oxygen and the arterial oxygen tension. The affinity of hemoglobin for oxygen depends on the tissues’ oxygen demand. In a healthy individual, exercising muscle increases the demand for oxygen. The heat of the working muscles and the acidic environment during exercise result in reduced oxyhemoglobin affinity and increased oxygen release. This is reflected by a shift to the right of the oxyhemoglobin dissociation curve (see Chapter 4). The affinity of hemoglobin and oxygen is increased with the cessation of exercise, which is reflected by a leftward shift of the curve.

Oxygen Delivery to the Tissues

The final steps in oxygen transport involve the dissociation of oxygen from hemoglobin and the diffusion of oxygen from the capillaries to the cells.¹⁷ Diffusion depends on the quantity and rate of blood flow, the difference in capillary and tissue oxygen pressures, the capillary surface area, capillary permeability, and diffusion distance.¹⁸ With increased metabolic demand by the tissues, capillary dilation and recruitment increase capillary surface area and reduce vascular resistance to flow, diffusion distance is decreased, the movement of oxygen into the cell is facilitated, and the tissue oxygen tension is increased.

Two diffusion gradients determine effective oxygen transport: one occurs between the pulmonary capillaries and the alveoli; the other occurs between the peripheral capillaries and the tissue cells. Diffusion of oxygen occurs as the blood moves from the aorta to the arterioles. The mean oxygen tension in the aorta is about 95 mm Hg and in the arterioles is 70 to 80 mm Hg. The oxygen gradient between the arterioles and the cells is the steepest. The mean oxygen pressure is less than 50 mm Hg in the capillaries. The oxygen tension in the capillaries determines the rate of diffusion to the cells. An optimal diffusion gradient maintains the oxygen tension in the cell at between 1 and 10 mm Hg; oxygen tension is less than 0.5 mm Hg in the mitochondria.¹⁶ This decremental PaO₂ profile down the oxygen transport pathway, from the airways to the tissues, is termed the oxygen cascade (Figure 2-6).

Cardiac Output

In addition to arterial oxygen content, CO is a primary determinant of DO₂.¹⁴ The transport of oxyhemoglobin to the tissues is dependent on convective blood flow by way of CO. CO is the volume of blood pumped from the right or left ventricle per minute. The components of CO are stroke volume (SV) and heart rate (HR) (i.e., CO = SV × HR). SV is the amount of blood ejected from the left ventricle during each ventricular systole or heartbeat and is determined by the preload, myocardial distensibility, myocardial contractility, and afterload. DO₂ is optimized in patients by increasing CO through the therapeutic manipulation of preload, myocardial contractility, afterload, and heart rate.

Preload

Preload is the end-diastolic muscle fiber length of the ventricles before systolic ejection. On the left side it reflects the left ventricular end-diastolic volume (LVEDV). The LVEDV is dependent on venous return, blood volume, and left atrial contraction. An increase in ventricular volume stretches the myocardial fibers and increases the force of myocardial contraction (the Starling effect) and stroke volume. This effect is limited by the physiological limits of distension of the myocardium. Excessive stretching, as in fluid overload of the heart, leads to suboptimal overlap of the actin and myosin filaments, thus impairing rather than enhancing contractility.

Afterload

Afterload is the resistance to the ejection of blood during ventricular systole. Afterload of the left ventricle is determined primarily by four factors: the distensibility of the aorta, the vascular resistance, the patency of the aortic valve, and the viscosity of the blood.

Myocardial Contractility

Myocardial contractility reflects actin-myosin coupling during contraction and is assessed by the ejection fraction, the rate of circumferential muscle fiber shortening, the pressure-volume relationships, and the rate of change of ventricular pressure over time.

Oxygen Debt

Tissue oxygen debt, or recovery oxygen consumption, is the difference between oxygen demand and oxygen consumption. In healthy individuals, oxygen debt can be sustained for short periods during intense exercise. Anaerobic metabolism is stimulated to produce ATP under these conditions. In patients who are critically ill, the degree of oxygen debt is correlated with survival.¹⁹

Oxygen Extraction Ratio or Utilization Coefficient

The oxygen extraction ratio, or utilization coefficient, reflects the proportion of oxygen delivered to that consumed. OER is calculated by dividing by DO₂. Normally, OER is 23% at rest.

Supply-Dependent Oxygen Consumption

Normally, a decrease in DO₂ does not reduce .²⁰ With a decrement in DO₂, the tissues extract a commensurate amount of oxygen from the blood. In patients who are critically ill, DO₂ may be limited to the point where basic metabolic needs for oxygen (300 mL/min/M²) are not met.^20–23 The critical level at which falls is associated with tissue anaerobic metabolism and the development of lactic acidosis and decreased pH (Fig. 2-7).^19,24 Serum lactates correspondingly increase and provide a valid index of anaerobic metabolism in patients with multiorgan system failure. When oxygen transport data are analyzed, the effect of sedation may suggest a dependency between DO₂ and , so the impact of medication in this relationship must be considered.²⁵

Oxygen Transport Pathway

Oxygen transport is dependent on several interconnecting steps, ranging from inhalation of oxygen-containing air through the nares to oxygen extraction at the cellular level in response to metabolic demand (see Fig. 2-1). These steps provide the mechanism for ventilatory, cardiovascular, and metabolic coupling. In addition, blood is responsible for transporting oxygen within the body; thus its constituents and consistency directly affect this process.

Quality and Quantity of Blood

Although not considered a discrete step in the oxygen transport pathway, blood is the essential medium for transporting oxygen. To fulfill this function, blood must be delivered in an adequate yet varying amount, proportional to metabolic demands, and must have the appropriate constituents and consistency. Thus consideration of the characteristics of the circulating blood volume is essential to any discussion of oxygen transport.

Blood volume is compartmentalized within the intravascular compartment such that 70% is contained within the venous compartment, 10% in the systemic arteries, 15% in the pulmonary circulation, and 5% in the capillaries.²⁶ The large volume of blood contained within the venous circulation permits adjustments to be made as CO demand changes. The veins constrict, for example, when CO needs to be increased. When blood volume is normal and body fluids are appropriately distributed between the intravascular and extravascular compartments, fluid balance is considered normal. When they are disrupted, a fluid balance problem exists. In addition, fluid imbalance affects the concentration of electrolytes, particularly sodium, which is present in the highest concentration in the extracellular fluid. Four primary fluid problems that have implications for oxygen transport are water deficit, water excess, sodium deficit, and sodium excess (see Chapter 16). Other ions that are affected often in fluid and electrolyte imbalance deficits include potassium, chloride, calcium, and magnesium. These electrolyte disturbances also contribute to impaired oxygen transport by affecting the electrical and mechanical behavior of the heart and blood vessels, thereby also affecting CO and the distribution of oxygenated arterial blood to the periphery.

Blood is a viscous fluid composed of cells and plasma. Because 99% of blood consists of red blood cells, the white blood cells play almost no role in determining the physical characteristics of blood.

Hematocrit refers to the proportion of red blood cells in the plasma. The normal hematocrit is 38% for women and 42% for men. Blood is several times more viscous than water, which increases the difficulty with which blood is pumped through the heart and flows through vessels; the greater the number of cells, the greater the friction between the layers of blood, which results in increased viscosity. Thus the viscosity of the blood increases significantly with increases in hematocrit. An increase in hematocrit, as in polycythemia, increases blood viscosity several times. The concentration and types of protein in the plasma can also affect viscosity, but to a lesser extent.

In adults, red blood cells are produced in the marrow of the membranous bones, such as the vertebrae, sternum, ribs, and pelvis. The production of red blood cells at these sites diminishes with age. Tissue oxygenation is the basic regulator of red blood cell production. Hypoxemia stimulates red blood cell production through erythropoietin production in bone.²⁶

Viscosity of the blood has its greatest effect in the small vessels. Blood flow is considerably reduced in small vessels, which results in aggregates of red blood cells adhering to the vessel walls. This effect is not offset by the tendency of the blood to become less viscous in small vessels (a result of the alignment of the blood cells flowing through these vessels, which minimizes the frictional forces between layers of flowing blood cells). In small capillaries, blood cells can become stuck, particularly where the nuclei of endothelial cells protrude and momentarily obstruct blood flow.

The major function of the red blood cells is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues. Red blood cells also contain a large quantity of carbonic anhydrase, which catalyzes the reaction between CO₂ and H₂O. The rapidity of this reaction makes it possible for blood to react with large quantities of CO₂ to transport it from the tissues to the lungs for elimination.

Hemoglobin is contained within red blood cells in a concentration of up to 34 g/dL of cells. Each gram of hemoglobin is capable of combining with 1.34 mL of oxygen (see Figure 2-2). In healthy women, 19 mL of oxygen can be carried in the blood (given that the whole blood of women contains an average of 14 g/100 mL of blood); in healthy men, the blood can carry 21 mL of oxygen (assuming the average concentration in the whole blood of men is 16 g/dL).

The clotting factors of the blood are normally in a proportion that does not promote clotting. Factors that promote coagulation (procoagulants) and factors that inhibit coagulation (anticoagulants) circulate in the blood. In the event of a ruptured blood vessel, prothrombin is converted to thrombin, which catalyzes the transformation of fibrinogen to fibrin threads. This fibrin mesh captures platelets, blood cells, and plasma to form a blood clot.

The extreme example of abnormal clotting is disseminated intravascular coagulation (DIC), when both hemorrhage and coagulation occur simultaneously. The acute form of this syndrome occurs in patients who are critically ill and undergoing multiorgan system failure. The mechanism appears to involve tissue factors, factors that damage the blood vessel walls, and factors that increase platelet aggregation. The chronic form of DIC occurs in chronic conditions such as neoplastic disease.

Plasma is the extracellular fluid of the blood and contains 7% proteins—namely, albumin, globulin, and fibrinogen. The primary function of albumin and, to a lesser extent, globulin and fibrinogen, is to create osmotic pressure at the capillary membrane and to prevent fluid leaking into the interstitial spaces. Globulins transport substances in the blood and provide immunity as the antibodies that fight infection and toxicity. Fibrinogen is fundamental to blood clotting. Most blood proteins, including hemoglobins, are also excellent acid-base buffers and are responsible for 70% of all the buffering power of whole blood.

Blood flow (Q) depends on a pressure gradient (P) and vascular resistance (R) (i.e., Q = P/R). Thus blood flow equals the pressure gradient divided by resistance. The length of a given blood vessel and the viscosity of the blood are also determinants of blood flow.

The average blood volume is 5000 mL. Approximately 3000 mL of this is plasma and 2000 mL is red blood cells. These values vary according to gender, weight, and other factors. Normally, changes in blood volume reflect fluid imbalances (deficits and excesses) created by losses through the skin and respiratory tract, as well as through urinary, sweat, and fecal losses. Exercise and hot weather are major challenges to fluid balance in health.

Plasma contains large quantities of sodium and chloride ions and small amounts of potassium, calcium, magnesium, phosphate, sulfate, and organic acid ions. Plasma also contains a large amount of protein. The large ionic constituents of plasma are responsible for regulating intracellular and extracellular fluid volumes, as well as the osmotic factors that cause shifts of fluid between the intracellular and extracellular compartments.

Oxyhemoglobin Dissociation

Demand for oxygen at the cellular level changes from moment to moment. The properties of oxyhemoglobin dissociation ensure that there is a continuous supply of oxygen at the cellular level. Oxygen combines with hemoglobin molecules in the pulmonary circulation and then is released in the tissue capillaries in response to a reduced arterial oxygen tension. The S-shaped oxyhemoglobin dissociation curve (see Chapter 4) shifts to the right in response to reduced tissue pH, increased CO₂, increased temperature, and increased diphosphoglycerate (DPG), a constituent of normal blood cells.

Blood delivery and its ability to transport oxygen effectively are central to all steps in the oxygen transport pathway and must be considered at each stage in clinical problem solving and decision making.

Steps in the Oxygen Transport Pathway

Step One: Inspired Oxygen and Quality of the Ambient Air

In healthy individuals, the concentration of inspired oxygen is relatively constant at 21%. If an individual is at a high altitude, the fraction of inspired oxygen is reduced as elevation increases.

Atmospheric air consists of 79% nitrogen, 20.97% oxygen, and 0.03% CO₂. Because nitrogen is an inert gas and is not absorbed in the lungs, it has a crucial role in keeping the alveoli open. The constituents of the air have become an increasingly important social, environmental, and health issue because of environmental hazards, pollution, and the thinning of the ozone layer, which result in deterioration of air quality, an increase in toxic oxygen-free radicals, and a reduction in atmospheric oxygen pressure.

Many factors influence air quality: geographical region, season, urban versus rural area, high versus low elevation, home environment, work environment, indoor versus outdoor ambience, level of ventilation, presence of air conditioning, buildings that are closed, areas with high levels of particulate matter, areas with gaseous vapors and toxic materials that can be inhaled, and smoke-filled versus smoke-free environments. Poor air quality may overwhelm the filtering ability of the upper respiratory tract and the sensitivity of the airways, causing lung damage, both acutely and over time. Chronic irritation of the lungs by poor air quality can lead to allergies, chronic inflammatory reactions, fibrosis, and alveolar capillary membrane thickening. At the alveolar level, the inspired air is saturated with water vapor. In dry environments, however, the upper respiratory tract may become dehydrated, lose its protective mucous covering, become eroded, and provide a portal for infection even though the air is adequately humidified by the time it reaches the lower airways and alveoli.

Step Two: Airways

The structures of the airways throughout the respiratory tract differ according to their functions. The main airway, the trachea, consists of cartilaginous rings, connective tissue, and small amounts of smooth muscle. This structure is essential to provide a firm and relatively inflexible conduit for air to pass from the nares through the head and neck to the lungs while avoiding airway collapse. As the airways become smaller and branch throughout the lung tissue, they consist primarily of smooth muscle. Airway narrowing, or obstruction, and the resulting increased resistance to airflow can be caused by a variety of factors, including edema, mucus, foreign objects, calcification, particulate matter, and space-occupying lesions, as well as by hyperreactivity of bronchial smooth muscle. The airways are lined with cilia, which are fine, microscopic, hair-like projections responsible for wafting debris, cells, and microorganisms away from the lungs into larger airways to be removed and evacuated. The airways are also lined with mucus, which consists of two layers, the upper gel layer and the lower sol layer, with which the cilia communicate.

Step Three: Lungs and Chest Wall

Air entry into the lungs depends on the integrity of the respiratory muscles, in particular the diaphragm, the lung parenchyma, and the chest wall. The contraction and descent of the diaphragm generate a negative intrapleural pressure that inflates the lungs. The distribution of ventilation is determined primarily by the negative intrapleural pressure gradient down the lungs. The negative intrapleural pressure gradient results in uneven ventilation down the lungs and in interregional differences (see Chapter 4). There are, however, other factors that contribute to uneven ventilation within regions of the lung. These intraregional differences reflect regional differences in lung compliance and airway resistance.²⁷ In patients with partially obstructed airways, reduced lung compliance and increased airway resistance increase the time needed for alveolar filling. Gas exchange is compromised if there is inadequate time for alveolar filling or emptying (i.e., increased time constants).¹⁸ Different time constants across lung units contribute to uneven patterns of ventilation during inspiration. A lung unit with a long time constant is slow to fill and empty, and it may continue filling when surrounding units are emptying. Another factor that contributes to uneven ventilation is altered diffusion distance. In diseases in which diffusion distance is increased, ventilation among lung units is uneven.

The lungs and the parietal pleura are richly supplied with thin-walled lymphatic vessels.¹⁶ Lymphatic vessels have some smooth muscle and thus can actively contract to propel lymph fluid forward. This forward motion is augmented by valves along the lymphatic channels. The rise and fall of the pleural pressure during respiration compress lymphatic vessels with each breath, which promotes a continuous flow of lymph. During expiration and increased intrapleural pressure, fluid is forced into the lymphatic vessels. The visceral pleura continuously drains fluid from the lungs. This creates a negative pressure in the pleural space, which keeps the lungs expanded. This pressure exceeds the elastic recoil pressure of the lung parenchyma, which counters the tendency of elastic recoil to collapse the lungs.

The peritoneal cavity of the abdomen consists of a visceral peritoneum containing the viscera and a parietal peritoneum lining the abdominal cavity. Numerous lymphatic channels interconnect the peritoneal cavity and the thoracic duct; some arise from the diaphragm. With cycles of inspiration and expiration, large amounts of lymph are moved from the peritoneal cavity to the thoracic duct of the venous drainage system. High venous pressures and vascular resistance through the liver can interfere with normal fluid balance in the peritoneal cavity. This leads to the transudation of fluid with high protein content into the abdominal cavity. Such an accumulation of fluid is referred to as ascites. Large volumes of fluid can accumulate in the abdominal cavity and compromise cardiovascular and pulmonary function secondary to increased intraabdominal pressure on the underside of the diaphragm.

Optimal diaphragmatic excursion requires a balance between thoracic and intraabdominal pressures. Increases in abdominal pressure secondary to factors such as fluid accumulation can impair diaphragmatic descent and chest wall expansion. Other factors include gas entrapment, gastrointestinal obstruction, space-occupying lesions, and paralytic ileus.

Step Four: Diffusion

Diffusion of oxygen from the alveolar sacs to the pulmonary arterial circulation depends on four factors: the area of the alveolar capillary membrane, the diffusing capacity of the alveolar capillary membrane, the pulmonary capillary blood volume, and the ventilation and perfusion ratio.⁹ The transit time of blood at the alveolar capillary membrane is also an important factor that determines diffusion. The blood remains in the pulmonary capillaries for 0.75 second at rest. Within 0.25 second, one-third of that time, the blood is completely saturated. This provides a safety margin during exercise or other conditions in which CO is increased and pulmonary capillary transit time is reduced. The blood can normally be fully oxygenated even with reduced transit time.

Step Five: Perfusion

The distribution of blood perfusing the lungs is primarily gravity dependent, so the dependent lung fields are perfused to a greater extent than are the nondependent lung fields. In upright lungs, the bases are better perfused than the apices (see Chapter 4). Ventilation and perfusion matching is optimal in the midzones of upright lungs.¹⁸ In healthy individuals, the ventilation-to-perfusion ratio is a primary determinant of arterial oxygenation. In upright lungs, this ratio is 0.8 in the midzone.

Step Six: Myocardial Function

Optimal myocardial function and CO depend on the synchronized coupling of electrical excitation of the heart and its mechanical contraction. The sinoatrial node, located in the right atrium, is the normal pacemaker for the heart and elicits the normal sinus rhythm with its multiple-component P-QRS-T configuration (see Chapter 12). This wave of electrical excitation spreads throughout the specialized neural conduction system of the atria, the interventricular septum, and the ventricles and is followed by the contraction of the atria and then of the ventricles. The contraction of the right and left ventricles ejects blood into the pulmonary and systemic circulations, respectively.

CO depends on several factors in addition to the integrity of the conduction system and the adequacy of myocardial depolarization (dromotropic effect). The amount of blood returned to the heart (preload) determines the amount ejected (the Starling effect). The distensibility of the ventricles to accommodate this blood volume must be optimal—neither too stiff nor too compliant. The force and contractility of the myocardial muscle must be sufficient to eject the blood (inotropic effect and chronotropic effect, respectively). CO is determined by the aortic pressure needed to overcome peripheral vascular resistance and the capacity of the ventricles to eject blood into the pulmonary and systemic circulations (afterload).

The pericardial cavity, like the pleural and peritoneal cavities, is a potential space containing a thin layer of fluid. The space normally has a negative pressure. During expiration, pericardial pressure is increased and fluid is forced out of the space into the mediastinal lymphatic channels. This process is normally facilitated by increased volumes of blood in the heart and each ventricular systole.

Step Seven: Peripheral Circulation

When oxygenated blood is ejected from the heart, the peripheral circulation provides a conduit to supply this blood to metabolically active tissue. Blood vessels throughout the body are arranged both in series and in parallel. The arteries and capillaries are designed to advance blood and thus perfuse the tissues with oxygenated blood. The architecture of the vasculature is such that the proximal large arteries have a higher proportion of connective tissue and elastic elements than do the distal medium and small arteries, which have a progressively higher proportion of smooth muscle. This structure enables the large proximal arteries to withstand high pressure when blood is ejected during ventricular systole. Considerable potential energy is stored within the elastic walls of these blood vessels as the heart contracts. During diastole the forward propulsion of blood is facilitated by the elastic recoil of these large vessels. The thin-walled muscular arterioles serve as the stopcocks of the circulation and regulate blood flow through regional vascular beds (e.g., of the skin, gut, muscle, and organs) and maintain peripheral vascular resistance to regulate systemic blood pressure. Blood flow through these regional vascular beds is determined by neural and humoral stimulation (exogenous) and by local tissue factors (endogenous). Blood pressure control is regulated primarily by neural stimulation of the peripheral circulation and regional vascular beds.

The microcirculation consists of the precapillary arterioles, capillaries, and venules. The Starling effect governs the balance of hydrostatic and oncotic pressures within the capillaries and surrounding tissues. The balance of these pressures is 0.3 mm Hg; its net effect is a small outward filtration of fluid from the microvasculature into the interstitial spaces (see Chapter 4). Any excess fluid or loss of plasma protein is drained into the surrounding lymphatic vessels, which usually have a small negative pressure, as does the interstitium. Integrity of the microcirculation is essential to regulate the diffusion of oxygen across the tissue capillary membrane and removing CO₂ and waste products.

The greater the muscular component of blood vessels, the greater their responsiveness to both exogenous neural stimulation and endogenous stimulation via circulating humoral neurotransmitters, such as catecholamines and local tissue factors. This responsiveness is essential for the moment-to-moment regulation of the peripheral circulation with respect to tissue perfusion and oxygenation, commensurate with tissue metabolic demands and control of total peripheral resistance and systemic blood pressure.

Step Eight: Tissue Extraction and Use of Oxygen

Perfusion of the tissues with oxygenated blood commensurate with metabolic demand is the principal goal of the oxygen transport system.³ Oxygen is continuously being used by all cells in the body; thus it diffuses rapidly out of the circulation and through cell membranes to meet varying metabolic needs. Diffusion occurs down a gradient from areas of high to low oxygen pressure. The distances between capillaries and cells are variable, so a significant safety factor is required to ensure adequate arterial oxygen tensions. Intracellular PO₂ ranges from 5 to 60 mm Hg, with an average of 23 mm Hg.¹⁶ Given that only 3 mm Hg of oxygen pressure is needed to support metabolism, 23 mm Hg of oxygen pressure provides an adequate safety margin. These mechanisms ensure an optimal oxygen supply over a wide range of oxygen demands during healthy functioning and in the event of impaired oxygen delivery because of illness. Normally, the rate of oxygen extraction by the cells is regulated by the oxygen demand of cells (i.e., the rate at which ADP is formed from ATP) rather than by the availability of oxygen.

Adequate quality and quantity of mitochondrial enzymes required for the Krebs cycle and electron transfer chain, along with the availability of myoglobin, may be limiting factors in the oxygen transport pathway secondary to nutritional deficits and muscle enzyme deficiencies. Myoglobin is a protein comparable to hemoglobin and is localized within muscle mitochondria. Myoglobin combines reversibly with oxygen to provide an immediate source of oxygen when there are increased metabolic demands and to facilitate oxygen transfer within the mitochondria.

Normally the amount of oxygen extracted by the tissues at rest is 23% (i.e., the ratio of oxygen consumed to oxygen delivered). This ratio ensures that greater amounts of oxygen can be extracted during periods of increased metabolic demand.

To detect tissue hypoxia, particularly in patients who are critically ill, regional assessments such as gastric mucosal PCO₂ and pH have been proposed as being superior to global assessment of and DO₂.²⁸ Regional measures of oxygenation could help to enhance the specificity of treatment based on tissue indicators.²⁹

Step Nine: Return of Partially Desaturated Blood and CO₂ to the Lungs

Partially desaturated blood and CO₂ are removed from cells via the venous circulation to the right side of the heart and lungs. CO₂ diffuses across the alveolar capillary membrane and is eliminated from the body through the respiratory system, and deoxygenated venous blood is reoxygenated. The oxygen transport cycle is sensitively tuned to adjust to changes in the metabolic demand of the various organ systems, such as digestion in the gastrointestinal system and cardiac and skeletal muscle work during exercise.

Factors that interfere with tissue oxygenation and the capacity of the tissue to use oxygen include abnormal oxygen demands, reduced hemoglobin and myoglobin levels, edema, and poisoning of the cellular enzymes.³⁰

Factors that Normally Perturb Oxygen Transport

Basal metabolic rate (BMR) reflects the rate of metabolism for an individual in a completely rested state: no food intake within several hours, a good night’s sleep, no arousing or distressing emotional stimulation, and a comfortable ambient temperature. Normally, the BMR is constant within and among individuals if measured under standardized conditions. BMR reflects the energy expended by the body’s cells to maintain resting function and includes the work of breathing; heart, renal, and brain function; and thermoregulation.

Normally, over the course of the day, the human body is exposed to fluctuations in ambient temperature and humidity, ingestion states, activity and exercise levels (exercise stress), body positions and body position changes (gravitational stress), emotional states (emotional stress), and states of arousal. These factors significantly influence and energy expenditure from moment-to-moment and thus increase rate of metabolism.

Several factors related to disease can significantly increase oxygen consumption and metabolic rate over and above the BMR. Such factors include fever, the disease process itself, the process of healing and recovery from injury or disease, thermoregulatory disturbance, reduced arousal, increased arousal resulting from anxiety or pain, sleep loss, medical and surgical interventions, fluid imbalance, and medications.⁵ These factors may contribute to a systemic increase in the BMR or may reflect local changes in tissue metabolism. Autoregulation of the regional vascular beds promotes increased regional blood flow in accordance with their local tissue metabolic demand.

Because gravitational stress and exercise stress are fundamental to normal cardiovascular and pulmonary function and oxygen transport, the effects of gravity and exercise are highlighted. These two factors augment arousal through stimulation of the reticular activating system in the brainstem and the autonomic nervous system (ANS), which, when depressed, significantly compromises oxygen transport. Emotional stress also has a marked effect on the stimulation of the ANS (the fight-or-flight response) and hence on oxygen transport. These concepts and their clinical implications are described in detail in Chapters 18 and 19.

Gravitational Stress

Humans are designed to function in a 1-g gravitational field. Given that 60% of the body weight is fluid contained within the intravascular and extravascular compartments and that this fluid has considerable mass, changes in body position result in significant instantaneous fluid shifts that can threaten hemodynamic stability.6,31 To maintain consciousness and normal body function during changes in body position, the heart and peripheral vasculature are designed to detect these fluid shifts and accommodate quickly to avoid deleterious functional consequences (e.g., reduced SV, CO, circulating blood volume, and cerebral perfusion). Preservation of the fluid-regulating mechanisms is essential to counter the hemodynamic effects of changing body position. This capacity is impaired with recumbency, which has long been associated with bed rest deconditioning in patients and older populations.^32,33 Restoration of adaptation to gravitational stress by upright positioning of a patient is the only means by which these fluid-regulating mechanisms can be maintained and orthostatic intolerance and its short- and long-term sequelae averted.

Exercise Stress

Exercise constitutes the greatest perturbation to homeostasis and oxygen transport in humans. CO can increase by five times to adjust to the metabolic demands of exercise stress. All steps in the oxygen transport pathway are affected by exercise stress. Ventilation is increased, and ventilation and perfusion matching is optimized to maximize oxygenation of blood. Heart rate and stroke volume are increased to effect greater CO of oxygenated blood to the tissues. At the tissue level, oxygen extraction is enhanced.

Emotional Stress

The body responds to emotional stress much as it does to exercise stress—by undergoing the sympathetic stress reaction (the fright-fight-flight reaction). Perceived threat, the basis of emotional stress, can also trigger the fright-fight-flight reaction and a series of sympathetically mediated physiological responses. This reaction, which prepares the body for fight or for flight, includes an increase in circulating stress hormones, heart rate, blood pressure, CO, blood glucose, muscle strength, mental alertness, cellular metabolism, and local blood flow to specific muscle groups, as well as inhibition of involuntary function.

Summary

This chapter describes the oxygen transport system, a system that is essential to life, activity, and social participation. Its component steps and their interdependence are highlighted. This framework provides a conceptual basis for the practice of cardiovascular and pulmonary physical therapy.

The oxygen transport system is designed to deliver oxygen from the ambient air to every cell in the body to support cellular respiration (i.e., metabolic use of oxygen at the cellular level). Blood is the essential medium in which cellular and noncellular components transport oxygen from the cardiovascular and pulmonary unit to the peripheral tissues. The fundamental components in the oxygen transport pathway are described. These components include the quality of the ambient air, the airways, lungs, chest wall, pulmonary circulation, lymphatic circulation, heart, peripheral circulation, and peripheral tissues of the organs of the body.

In healthy individuals, the most significant factors that perturb oxygen transport are changes in gravitational stress secondary to changes in body position, exercise stress secondary to the increased oxygen demand of working muscles, and arousal and emotional stress. A thorough understanding of the normal effects of gravitational and exercise stress and arousal is essential to understanding deficits in oxygen transport. Numerous factors can impair and threaten oxygen transport, including underlying pathophysiology, restricted mobility, recumbency, factors related to the patient’s care, and factors related to the individual (see Chapters 2 and 17). The physical therapist needs a detailed understanding of these concepts to diagnose such threats and deficits, to understand their impact on activity and participation, and to prescribe effective treatments.