CELLULAR RESPIRATION - Aerobic Metabolism

Cellular Respiration

The principal function of the lungs is to allow gas exchange between blood and inspired air. This need arises as a direct result of cellular aerobic metabolism, which creates a constant demand for uptake of oxygen (O₂) and elimination of carbon dioxide (CO₂).

Aerobic Metabolism

Normally, nearly all human cells derive energy aerobically (ie, by using O₂). Carbohydrates, fats, and proteins are metabolized to two-carbon fragments (acetylcoenzyme A [acetyl-CoA]) that enter the citric acid cycle within mitochondria (see Chapter 34). As the acetyl-CoA is metabolized to CO₂, energy is derived and stored in nicotine adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD), and guanosine triphosphate (GTP). That energy is subsequently transferred to adenosine triphosphate (ATP) through a process called oxidative phosphorylation. Oxidative phosphorylation accounts for more than 90% of total body O₂ consumption and involves a series of enzyme-mediated (cytochrome) electron transfers that are coupled to ATP formation. In the last step, molecular O₂ is reduced to water.

For glucose, an important cellular fuel, the overall reaction is as follows:

The energy generated (approximately 1200 kJ/mol of glucose) is actually stored in the third phosphate bond on ATP:

For every molecule of glucose oxidized, up to a total of 38 molecules of ATP can be produced. Once formed, the energy stored in ATP can be used for ion pumps, muscle contraction, protein synthesis, or cellular secretion; in the process, the adenosine diphosphate (ADP) is regenerated:

Cells maintain a ratio of ATP to ADP of 10:1.

Note: ATP cannot be stored but must be continually formed requiring a constant supply of metabolic substrates and O₂.

The ratio of total CO₂ production (CO ) to O₂ consumption (O ) is referred to as the respiratory quotient (RQ) and is generally indicative of the primary type of fuel being utilized. The respiratory quotients for carbohydrates, lipids, and proteins are 1.0, 0.7, and 0.8, respectively. CO is normally about 200 mL/min, whereas O is approximately 250 mL/min. Because proteins are generally not used as a primary fuel source, the normal respiratory quotient of 0.8 probably reflects utilization of a combination of both fats and carbohydrates. An RQ of > 1 is seen with lipogenesis (overfeeding), and an RQ of 0.7 implies lipolysis (fasting or starvation). Oxygen consumption can also be estimated based on a patient's weight in kilograms (see

Anaerobic Metabolism

Compared with aerobic metabolism, anaerobic metabolism produces a very limited amount of ATP. In the absence of O₂, ATP can be produced only from the conversion of glucose to pyruvate to lactic acid. The anaerobic metabolism of each molecule of glucose yields a net of only two ATP molecules (61 kJ) (compared with 38 ATP molecules formed aerobically). Moreover, the progressive lactic acidosis that develops severely limits the activity of the enzymes involved. When O₂ tension is restored to normal, lactate is reconverted to pyruvate and aerobic metabolism is resumed.

Effects of Anesthesia on Cell Metabolism

General anesthesia typically reduces both O and CO by about 15%. Additional reductions are often seen as a result of hypothermia (see Chapter 21). The greatest reductions are in cerebral and cardiac O₂ consumption.

Rib Cage & Muscles of Respiration

The rib cage contains the two lungs, each surrounded by its own pleura. The apex of the chest is small, allowing only for entry of the trachea, esophagus, and blood vessels, whereas the base is formed by the diaphragm. Contraction of the diaphragmthe principal pulmonary musclecauses the base of the thoracic cavity to descend 1.57 cm and its contents (the lungs) to expand. Diaphragmatic movement normally accounts for 75% of the change in chest volume. Accessory pulmonary muscles also increase chest volume (and lung expansion) by their action on the ribs. Each rib (except for the last two) articulates posteriorly with a vertebra and is angulated downward as it attaches anteriorly to the sternum. Upward and outward rib movement expands the chest.

During normal breathing, the diaphragm and, to a lesser extent, the external intercostal muscles are responsible for inspiration; expiration is generally passive. With increasing effort, the sternocleidomastoid, scalene, and pectoralis muscles can be recruited during inspiration. The sternocleidomastoids assist in elevating the rib cage, whereas the scalene muscles prevent inward displacement of the upper ribs during inspiration. The pectoralis muscles can assist chest expansion when the arms are placed on a fixed support. Expiration is normally passive in the supine position but becomes active in the upright position and with increased effort. Exhalation is facilitated by musclesincluding the abdominal muscles (rectus abdominis, external and internal oblique, and transversus) and perhaps the internal intercostalsaiding the downward movement of the ribs.

Although not usually considered pulmonary muscles, some pharyngeal muscles are important in maintaining the patency of the airway (see Chapter 5). Tonic and reflex inspiratory activity in the genioglossus keeps the tongue away from the posterior pharyngeal wall. Tonic activity in the levator palati, tensor palati, palatopharyngeus, and palatoglossus prevents the soft palate from falling back against the posterior pharynx, particularly in the supine position.

Tracheobronchial Tree

Humidification and filtering of inspired air are functions of the upper airway (nose, mouth, and pharynx). The function of the tracheobronchial tree is to conduct gas flow to and from the alveoli. Dichotomous division (each branch dividing into two smaller branches), starting with the trachea and ending in alveolar sacs, is estimated to involve 23 divisions, or generations (Figure 221). With each generation, the number of airways is approximately doubled. Each alveolar sac contains, on average, 17 alveoli. An estimated 300 million alveoli provide an enormous membrane (50100 m²) for gas exchange in the average adult.

With each successive division, the mucosal epithelium and supporting structures of the airways gradually change. The mucosa makes a gradual transition from ciliated columnar to cuboidal and finally to flat alveolar epithelium. Gas exchange can occur only across the flat epithelium, which begins to appear on pulmonary bronchioles (generations 1719). The wall of the airway gradually loses its cartilaginous support (at the bronchioles) and then its smooth muscle. Loss of cartilaginous support causes the patency of smaller airways to become dependent on radial traction by the elastic recoil of the surrounding tissue; as a corollary, airway diameter becomes dependent on total lung volume (see below).

Cilia on the columnar and cuboidal epithelium normally beat in a synchronized fashion such that the mucus produced by the secretory glands lining the airway (and any associated bacteria or debris) moves up toward the mouth.

Alveoli

Alveolar size is a function of both gravity and lung volume. The average diameter of an alveolus is thought to be 0.050.33 mm. In the upright position, the largest alveoli are at the pulmonary apex, whereas the smallest tend to be at the base. With inspiration, discrepancies in alveolar size diminish.

Each alveolus is in close contact with a network of pulmonary capillaries. The walls of each alveolus are asymmetrically arranged (Figure 222). On the thin side, where gas exchange occurs, the alveolar epithelium and capillary endothelium are separated only by their respective cellular and basement membranes; on the thick side, where fluid and solute exchange occurs, the pulmonary interstitial space separates alveolar epithelium from capillary endothelium. The pulmonary interstitial space contains mainly elastin, collagen, and perhaps nerve fibers. Gas exchange occurs primarily on the thin side of the alveolocapillary membrane, which is less than 0.4 m thick. The thick side (12 m) provides structural support for the alveolus.

The pulmonary epithelium contains at least two cell types. Type I pneumocytes are flat and form tight (1-nm) junctions with one another. These tight junctions are important in preventing the passage of large oncotically active molecules such as albumin into the alveolus. Type II pneumocytes, which are more numerous than type I pneumocytes (but because of their shape occupy less than 10% of the alveolar space), are round cells that contain prominent cytoplasmic inclusions (lamellar bodies). These inclusions contain surfactant, an important substance necessary for normal pulmonary mechanics (see below). Unlike type I cells, type II pneumocytes are capable of cell division and can produce type I pneumocytes if the latter are destroyed. They are also resistant to O₂ toxicity.

Other cell types present in the lower airways include pulmonary alveolar macrophages, mast cells, lymphocytes, and APUD (amino precursor uptake and decarboxylation) cells. Neutrophils are also typically present in smokers and in patients with acute lung injury.

Pulmonary Circulation & Lymphatics

The lungs are supplied by two circulations, pulmonary and bronchial. The bronchial circulation arises from the left heart and sustains the metabolic needs of the tracheobronchial tree down to the level of the pulmonary bronchioles. Below that level, lung tissue is supported by a combination of the alveolar gas and the pulmonary circulation.

The pulmonary circulation normally receives the total output of the right heart via the pulmonary artery, which divides into right and left branches to supply each lung. Deoxygenated blood passes through the pulmonary capillaries, where O₂ is taken up and CO₂ is eliminated. The oxygenated blood is then returned to the left heart by four main pulmonary veins (two from each lung). Although flows through the systemic and pulmonary circulations are equal, the lower pulmonary vascular resistance results in pulmonary vascular pressures one-sixth as great as those in the systemic circulation; as a result, both pulmonary arteries and veins normally have thinner walls with less smooth muscle.

There are connections between the bronchial and the pulmonary circulations. Direct pulmonary arteriovenous communications, bypassing the pulmonary capillaries, are normally insignificant but may become important in certain pathological states. The importance of the bronchial circulation in contributing to the normal venous admixture is discussed below.

Pulmonary Capillaries

Pulmonary capillaries are incorporated into the walls of alveoli. The average diameter of these capillaries (about 10 m) is barely enough to allow passage of a single red cell. Because each capillary network supplies more than one alveolus, blood may pass through several alveoli before reaching the pulmonary veins. Because of the relatively low pressure in the pulmonary circulation, the amount of blood flowing through a given capillary network is affected by both gravity and alveolar size. Large alveoli have a smaller capillary cross-sectional area and consequently increased resistance to blood flow. In the upright position, apical capillaries tend to have reduced flows, whereas basal capillaries have higher flows.

The pulmonary capillary endothelium has relatively large junctions, 5 nm wide, allowing the passage of large molecules such as albumin. As a result, pulmonary interstitial fluid is relatively rich in albumin. Circulating macrophages and neutrophils are able to pass through the endothelium as well as the smaller alveolar epithelial junctions with relative ease. Pulmonary macrophages are commonly seen in the interstitial space and inside alveoli; they serve to prevent bacterial infection and to scavenge foreign particles.

Pulmonary Lymphatics

Lymphatic channels in the lung originate in the interstitial spaces of large septa. Because of the large endothelial junctions, pulmonary lymph has a relatively high protein content, and total pulmonary lymph flow is normally as much as 20 mL/h. Large lymphatic vessels travel upward alongside the airways, forming the tracheobronchial chain of lymph nodes. Lymphatic drainage channels from both lungs communicate along the trachea. Fluid from the left lung drains primarily into the thoracic duct, whereas fluid from the right lung empties into the right lymphatic duct.

Innervation

The diaphragm is innervated by the phrenic nerves, which arise from the C3C5 nerve roots. Unilateral phrenic nerve block or palsy only modestly reduces most indices of pulmonary function (about 25%). Although bilateral phrenic nerve palsies produce more severe impairment, accessory muscle activity may maintain adequate ventilation in some patients. Intercostal muscles are innervated by their respective thoracic nerve roots. Cervical cord injuries above C5 are incompatible with spontaneous ventilation because both phrenic and intercostal nerves are affected.

The vagus nerves provide sensory innervation to the tracheobronchial tree. Both sympathetic and parasympathetic autonomic innervation of bronchial smooth muscle and secretory glands is present. Vagal activity mediates bronchoconstriction and increases bronchial secretions via muscarinic receptors. Sympathetic activity (T1T4) mediates bronchodilation and also decreases secretions via ₂-receptors. ₁-Adrenergic receptor stimulation decreases secretions but may cause bronchoconstriction. A nonadrenergic, noncholinergic bronchodilator system is also present; vasoactive intestinal peptide is its putative neurotransmitter. The nerve supply of the larynx is reviewed in Chapter 5.

Both - and -adrenergic receptors are present in the pulmonary vasculature but the sympathetic system normally has little effect on pulmonary vascular tone. ₁-Activity causes vasoconstriction; ₂-activity mediates vasodilation. Parasympathetic vasodilatory activity appears to be mediated via the release of nitric oxide.

Basic Mechanism of Breathing

The periodic exchange of alveolar gas with the fresh gas from the upper airway reoxygenates desaturated blood and eliminates CO₂. This exchange is brought about by small cyclic pressure gradients established within the airways. During spontaneous ventilation, these gradients are secondary to variations in intrathoracic pressure; during mechanical ventilation they are produced by intermittent positive pressure in the upper airway.

Spontaneous Ventilation

Normal pressure variations during spontaneous breathing are shown in Figure 223. The pressure within alveoli is always greater than the surrounding (intrathoracic) pressure unless the alveoli are collapsed. Alveolar pressure is normally atmospheric (zero for reference) at end-inspiration and end-expiration. By convention in pulmonary physiology, pleural pressure is used as a measure of intrathoracic pressure. Although it may not be entirely correct to refer to the pressure in a potential space, the concept allows the calculation of transpulmonary pressure. Transpulmonary pressure, or P_{transpulmonary}, is then defined as follows:

At end-expiration, intrapleural pressure normally averages about 5 cm H₂O and because alveolar pressure is 0 (no flow), transpulmonary pressure is +5 cm H₂O.

Diaphragmatic and intercostal muscle activation during inspiration expands the chest and decreases intrapleural pressure from 5 cm H₂O to 8 or 9 cm H₂O. As a result, alveolar pressure also decreases (between 3 and 4 cm H₂O), and an alveolar-upper airway gradient is established; gas flows from the upper airway into alveoli. At end-inspiration (when gas inflow has ceased), alveolar pressure returns to zero, but intrapleural pressure remains decreased; the new transpulmonary pressure (5 cm H₂O) sustains lung expansion.

During expiration, diaphragmatic relaxation returns intrapleural pressure to 5 cm H₂O. Now the transpulmonary pressure does not support the new lung volume, and the elastic recoil of the lung causes a reversal of the previous alveolarupper airway gradient; gas flows out of alveoli, and original lung volume is restored.

Mechanical Ventilation

Most forms of mechanical ventilation intermittently apply positive airway pressure at the upper airway. During inspiration, gas flows into alveoli until alveolar pressure reaches that in the upper airway. During the expiratory phase of the ventilator, the positive airway pressure is removed or decreased; the gradient reverses, allowing gas flow out of alveoli.

Effects of Anesthesia on Respiratory Pattern

The effects of anesthesia on breathing are complex and relate to both changes in position and anesthetic agents. When a patient is placed supine from an upright or sitting position, the proportion of breathing from rib cage excursion decreases; abdominal breathing predominates. The diaphragm's higher position in the chest (about 4 cm) allows it to contract more effectively than when the patient is upright. Similarly, in the lateral decubitus position, ventilation favors the dependent lung because the dependent hemidiaphragm takes a higher position in the chest (see Chapter 24).

Regardless of the agent used, light anesthesia often results in irregular breathing patterns; breath holding is common. Breaths become regular with deeper levels of anesthesia. Inhalation agents generally produce rapid, shallow breaths, whereas nitrousopioid techniques result in slow, deep breaths.

Interestingly, induction of anesthesia often activates expiratory muscles; expiration becomes active. The latter regularly necessitates paralysis during abdominal surgery. At 1.2 minimum alveolar concentration (MAC), inhalation agents increase respiratory rate and decrease tidal volume (VT). The absolute volumes displaced by both the thorax and diaphragm both decrease under anesthesia, but the ratio remains the same (ie, the thoracic and diaphragmatic contributions to VT remain the same). At deeper levels of anesthesia, muscle activity is depressed, but if there is any rebreathing of CO₂, muscle activity in all muscle groups is increased.