alterations of pulmonary function

hyperventilation

Hyperventilation is alveolar ventilation exceeding metabolic demands. The lungs remove CO2 faster than it is produced by cellular metabolism, resulting in decreased PaCO2, or hypocapnia (PaCO2 less than 36 mm Hg). Hypocapnia results in a respiratory alkalosis that also can interfere with tissue function. Like hypoventilation, hyperventilation can be determined by arterial blood gas analysis. Hyperventilation commonly occurs with severe anxiety, acute head injury, pain, and in response to conditions that cause hypoxemia.

hypoventilation

Hypoventilation is inadequate alveolar ventilation in relation to metabolic demands. Hypoventilation occurs when minute volume (tidal volume × respiratory rate) is reduced. It is caused by alterations in pulmonary mechanics or in the neurologic control of breathing.6 When alveolar ventilation is normal, carbon dioxide (CO2) is removed from the lungs at the same rate as it is produced by cellular metabolism and arterial and alveolar PCO2 values remain at normal levels (40 mm Hg). With hypoventilation, CO2 removal does not keep up with CO2 production and PaCO2 increases, causing hypercapnia (PaCO2 greater than 44 mm Hg) (see Table 26-2 for a definition of gas partial pressures and other pulmonary abbreviations). This results in respiratory acidosis that can affect the function of many tissues throughout the body. Hypoventilation is often overlooked until it is severe because breathing pattern and ventilatory rate may appear to be normal and changes in tidal volume can be difficult to detect clinically. Blood gas analysis (i.e., measurement of the PaCO2 of arterial blood) reveals the hypoventilation. Pronounced hypoventilation can cause secondary hypoxemia, somnolence, or disorientation.

hypoxemia

Hypoxemia, or reduced oxygenation of arterial blood (reduced PaO2), is caused by respiratory alterations. Hypoxemia results from problems with one or more of the major mechanisms of oxygenation: 1. Oxygen delivery to the alveoli a. Oxygen content of the inspired air (FiO2) b. Ventilation of alveoli 690 2. Diffusion of oxygen from the alveoli into the blood a. Balance between alveolar ventilation and perfusion (image match) b. Diffusion of oxygen across the alveolar capillary barrier 3. Perfusion of pulmonary capillaries The amount of oxygen in the alveoli is called the PAO2 and is dependent on two factors. The first factor is the presence of adequate oxygen content of the inspired air. The amount of oxygen in inspired air is expressed as the percentage or fraction of air that is composed of oxygen, called the FiO2. The FiO2 of air at sea level is approximately 21% or 0.21. Anything that decreases the FiO2 (such as high altitude) decreases the PAO2. A second factor is the amount of alveolar minute volume (tidal volume × respiratory rate). Hypoventilation results in an increase in PACO2 and a decrease in PAO2 such that there is less oxygen available in the alveoli for diffusion into the blood. This type of hypoxemia can be completely corrected if alveolar ventilation is improved by increases in the rate and depth of breathing. Hypoventilation causes hypoxemia in unconscious persons; in persons with neurologic, muscular, or bone diseases that restrict chest expansion; and in individuals who have chronic obstructive pulmonary disease.Hypoxemia is most often associated with a compensatory hyperventilation and the resultant respiratory alkalosis (i.e., decreased PaCO2 and increased pH). However, in individuals with associated ventilatory difficulties, hypoxemia may be complicated by hypercapnia and respiratory acidosis. Hypoxemia results in widespread tissue dysfunction and, when severe, can lead to organ infarction. In addition, hypoxic pulmonary vasoconstriction can contribute to increased pressures in the pulmonary artery (pulmonary artery hypertension) and lead to right heart failure or cor pulmonale. Clinical manifestations of acute hypoxemia may include cyanosis, confusion, tachycardia, edema, and decreased renal output.

pulmonary malignancies

Laryngeal cancer occurs primarily in men and represents 2% to 3% of all cancers. Squamous cell carcinoma of the true vocal cords is most common and presents with a clinical symptom of progressive hoarseness. Lung cancer, the most common cause of cancer death in the United States, is commonly caused by tobacco smoking. Lung cancer (bronchogenic carcinomas) cell types include non-small cell carcinoma (squamous cell, adenocarcinoma, and large cell) and, less commonly, neuroendocrine tumors (small cell carcinoma, large cell neuroendocrine carcinoma, and typical carcinoid and atypical carcinoid tumors). Each type arises in a characteristic site or type of tissue, causes distinctive clinical manifestations, and differs in likelihood of metastasis and prognosis. Tobacco smoke contains more than 30 carcinogens and is responsible for causing 80% to 90% of lung cancers. These carcinogens, along with inherited genetic predisposition to cancers, result in tumor development. Once lung cancer is initiated by these carcinogen-induced mutations, further tumor development is promoted by growth factors that alter cell growth and differentiation, such as epidermal growth factor, and by production of inflammatory mediators, such as toxic oxygen free radicals. The bronchial mucosa suffers multiple carcinogenic "hits" because of repetitive exposure to tobacco smoke and, eventually, epithelial cell changes begin to be visible on biopsy. These changes progress from metaplasia to carcinoma in situ and finally to invasive carcinoma. Further tumor progression includes invasion of surrounding tissues and finally metastasis to distant sites including the brain, bone marrow, and liver (see Chapter 10 for details of cancer biology). Clinical manifestations Table 27-3 summarizes the characteristic clinical manifestations according to tumor type. Symptoms are 711often attributed to side effects of smoking; and when they are severe enough to motivate the individual to seek medical advice, the disease is usually advanced. Evaluation and treatment Screening for lung cancer remains controversial but low-dose spiral CT scans decrease the risk of dying from lung cancer by 20% in heavy smokers.96 Diagnostic tests for the evaluation of lung cancer include sputum cytologic studies, chest imaging, virtual bronchoscopy, radial probe endobronchial ultrasound, electromagnetic navigational bronchoscopy, and biopsy. Biopsy determines the cell type, and the evaluation of lymph nodes and other organ systems is used to determine the stage of the cancer.97 The histologic cell type, the genotype, and the stage of the disease are major factors that influence choice of therapy. The current accepted system for the staging of non-small cell cancer is the TNM classification (T denotes the extent of the primary tumor, N indicates the nodal involvement, M describes the extent of metastasis) (see Chapter 10). In contrast, small cell lung cancers are only staged as either limited (confined to the area of origin in the lung) or extensive. The only proven way of reducing the risk for lung cancer is the cessation of smoking and avoidance of environmental toxins.98 For all types of early-stage lung carcinoma, the preferred treatment is surgical resection. Once metastasis has occurred, total surgical resection is more difficult and survival rates dramatically decrease. For individuals with non-small cell carcinoma with metastasis at diagnosis, adjunctive radiation and chemotherapy and treatment based on molecular markers may improve outcomes.99 Treatment modalities, including dose-intensified radiation, radiofrequency ablation, microwave ablation, cryotherapy, and brachytherapy, may be available as primary or palliative treatment for those for whom surgical removal is not an option.

Pulmonary hypertension

Pulmonary artery hypertension (PAH) is defined as a mean pulmonary artery pressure greater than 25 mm Hg at rest. PAH is classified into several groups82: 1. No known cause or associated with inheritance, drugs or toxins, connective tissue disease or infection 2. Pulmonary hypertension attributable to left heart disease (see Chapter 24) 3. Pulmonary hypertension caused by chronic lung disease or hypoxia, or both 4. Chronic thromboembolic pulmonary hypertension 5. Pulmonary hypertension caused by other multifactorial mechanisms including blood, metabolic and systemic disorders. COPD is the most common lung disease associated with PAH, but any condition that causes chronic hypoxemia can result in pulmonary hypertension. 708 Pathophysiology Idiopathic pulmonary arterial hypertension (IPAH) (also called pulmonary hypertension caused by unclear multifactorial mechanisms) is characterized by endothelial dysfunction with overproduction of vasoconstrictors, such as thromboxane and endothelin, and decreased production of vasodilators, such as prostacyclin and nitric oxide. Vascular growth factors are released, causing fibrosis and thickening of vessel walls (called remodeling) with luminal narrowing and abnormal vasoconstriction.83 These changes cause resistance to pulmonary artery blood flow, thus increasing the pressure in the pulmonary arteries and right ventricle. Gas exchange is reduced with restriction in lung volumes. As resistance and pressure increase, the workload of the right ventricle increases and subsequent right ventricular hypertrophy, followed by failure, may occur (cor pulmonale). The pathogenesis of PAH and cor pulmonale resulting from disease of the respiratory system or hypoxia is shown in Figure 27-17.Pulmonary hypertension associated with lung respiratory disease or hypoxia, or both, is a serious complication of many acute and chronic pulmonary disorders, such as COPD and hypoventilation associated with obesity. These conditions are complicated by hypoxic pulmonary vasoconstriction, which further increases pulmonary artery pressure. Clinical manifestations Pulmonary hypertension may not be detected until it is quite severe. The symptoms are often masked by other forms of pulmonary or cardiovascular disease. The first indication of PAH may be an abnormality seen on a chest radiograph (enlarged right heart border) or an electrocardiogram that shows right ventricular hypertrophy. Manifestations of fatigue, chest discomfort, tachypnea, and dyspnea (particularly with exercise) are common. Examination may reveal peripheral edema, jugular venous distention, a precordial heave, and accentuation of the pulmonary component of the second heart sound. Evaluation and treatment Definitive diagnosis of PAH can be made only with right heart catheterization. Common diagnostic modalities used to determine the cause include chest x-ray, echocardiography, and computed tomography. The diagnosis of IPAH is made when all other causes of pulmonary hypertension have been ruled out. General therapies for PAH include administration of oxygen, diuretics, and anticoagulants and avoidance of contributing factors, such as air travel, decongestant medications, nonsteroidal anti-inflammatory medications, pregnancy, and tobacco use. Medications used in the treatment of PAH include prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and a soluble guanylate cyclase activator. None of these drugs are curative but there is improved morbidity and mortality.84 Percutaneous catheter-based therapies are under development.85 Individuals who do not achieve adequate clinical remission may require lung transplantation. The most effective treatment for pulmonary hypertension associated with lung respiratory disease or hypoxia, or both, is treatment of the primary disorder. Supplemental oxygen may be indicated to reverse hypoxic vasoconstriction.

pulmonary thromboembolism

Pulmonary embolism (PE) is occlusion of a portion of the pulmonary vascular bed by an embolus. PE most commonly results from embolization of a clot from deep venous thrombosis involving the lower leg (see Chapter 24). Other less common emboli include tissue fragments, lipids (fats), a foreign body, an air bubble, or amniotic fluid. Risk factors for PE include conditions and disorders that promote blood 707clotting as a result of venous stasis (immobilization, heart failure), hypercoagulability (inherited coagulation disorders, malignancy, hormone replacement therapy, oral contraceptives), and injuries to the endothelial cells that line the vessels (trauma, infection, caustic intravenous infusions). Genetic risks include factor V Leiden, antithrombin II, protein S, protein C, and prothrombin gene mutations. No matter its source, a blood clot becomes an embolus when all or part of it detaches from the site of formation and begins to travel in the bloodstream. Pathophysiology The effect of the embolus depends on the extent of pulmonary blood flow obstruction, the size of the affected vessels, the nature of the embolus, and the secondary effects. Pulmonary emboli can result in any of the following: 1. Embolus with infarction: an embolus that causes infarction (death) of a portion of lung tissue 2. Embolus without infarction: an embolus that does not cause permanent lung injury (perfusion of the affected lung segment is maintained by the bronchial circulation) 3. Massive occlusion: an embolus that occludes a major portion of the pulmonary circulation (i.e., main pulmonary artery embolus) 4. Multiple pulmonary emboli: multiple emboli may be chronic or recurrent Significant obstruction of the pulmonary vasculature leads to increased pulmonary artery vasoconstriction, pulmonary hypertension and right ventricular dilation and afterload.79 The pathogenesis of pulmonary embolism caused by a thrombus is summarized in Figure 27-16If the embolus does not cause infarction, the clot is dissolved by the fibrinolytic system and pulmonary function returns to normal. If pulmonary infarction occurs, shrinking and scarring develop in the affected area of the lung. Clinical manifestations In most cases, the clinical manifestations of PE are nonspecific; therefore, evaluation of risk factors and predisposing factors is an important aspect of diagnosis. Although most emboli originate from clots in the lower extremities, deep vein thrombosis is often asymptomatic, and clinical examination has low sensitivity for the presence of clot, especially in the thigh and pelvis. An individual with PE usually presents with the sudden onset of pleuritic chest pain, dyspnea, tachypnea, tachycardia, and unexplained anxiety. Occasionally syncope (fainting) or hemoptysis occurs. With large emboli, a pleural friction rub, pleural effusion, fever, and leukocytosis may be noted. Recurrent small emboli may not be detected until progressive incapacitation, precordial pain, anxiety, dyspnea, and right ventricular enlargement are exhibited. Massive occlusion causes severe pulmonary hypertension and shock. Evaluation and treatment Routine chest radiographs and pulmonary function tests are not definitive for pulmonary embolism in the first 24 hours. Arterial blood gas analyses usually demonstrate hypoxemia and hyperventilation (respiratory alkalosis). The diagnosis is made by measuring elevated levels of d-dimer in the blood (a product of thrombus degradation) in combination with CT scanning or MRI. Measurement of the levels of brain natriuretic peptide and troponin is useful in PE associated with right ventricular dysfunction.80 Prevention of PE includes elimination of predisposing factors for individuals at risk. Venous stasis in hospitalized persons is minimized by leg elevation, bed exercises, position changes, early postoperative ambulation, and pneumatic calf compression. Clot formation is also prevented by prophylactic low-dose anticoagulant therapy. Anticoagulant therapy is the primary treatment for pulmonary embolism. Initial anticoagulant therapy usually includes low-molecular-weight heparins (e.g., enoxaparin) and factor Xa inhibitors. If a massive life-threatening embolism occurs, a fibrinolytic agent, such as streptokinase, is sometimes used, and some individuals will require catheter directed therapies or surgical thrombectomy. A filter in the inferior vena cava can prevent emboli from reaching the lungs. After stabilization, anticoagulation is continued for several months.81

ARF (Acute Respiratory Failure)

Respiratory failure is defined as inadequate gas exchange such that PaO2 ≤60 mm Hg or PaCO2 ≥50 mm Hg, with pH ≤7.25.10 Respiratory failure can result from direct injury to the lungs, airways, or chest wall or indirectly because of disease or injury involving another body system, such as the brain, spinal cord, or heart. It can occur in individuals who have an otherwise normal respiratory system or in those with underlying chronic pulmonary disease. Most pulmonary diseases can cause episodes of acute respiratory failure. If the respiratory failure is primarily hypercapnic, it is the result of inadequate alveolar ventilation and the individual must receive ventilatory support, such as with a bag-valve mask, noninvasive positive pressure ventilation, or intubation and placement on mechanical ventilation. If the respiratory failure is primarily hypoxemic, it is the result of inadequate exchange of oxygen between the alveoli and the capillaries and the individual must receive supplemental oxygen therapy. Many people will have combined hypercapnic and hypoxemic respiratory failure and will require both kinds of support. 691 Respiratory failure is an important potential complication of any major surgical procedure, especially those that involve the central nervous system, thorax, or upper abdomen. The most common postoperative pulmonary problems are atelectasis, pneumonia, pulmonary edema, and pulmonary emboli. People who smoke are at risk, particularly if they have preexisting lung disease. Limited cardiac reserve, neurologic disease, chronic renal failure, chronic hepatic disease, and infection also increase the tendency to develop postoperative respiratory failure. Prevention of postoperative respiratory failure includes frequent turning and position changes, deep-breathing exercises, and early ambulation to prevent atelectasis and accumulation of secretions. Humidification of inspired air can help loosen secretions. Incentive spirometry gives individuals immediate feedback about tidal volumes, which encourages them to breathe deeply. Supplemental oxygen is given for hypoxemia, and antibiotics are given as appropriate to treat infection. If respiratory failure develops, the individual may require mechanical ventilation or extracorporeal membrane oxygenation. Vasoconstriction is caused by alveolar and pulmonary venous hypoxia, often termed hypoxic pulmonary vasoconstriction, and results from an increase in intracellular calcium levels in vascular smooth muscle cells in response to low oxygen concentration and the presence of charged oxygen molecules called oxygen radicals.7 It can affect only one portion of the lung (i.e., one lobe that is obstructed, decreasing its PAO2) or the entire lung. If only one segment of the lung is involved, the arterioles to that segment constrict, shunting blood to other, well-ventilated portions of the lung. This reflex improves the lung's efficiency by better matching ventilation and perfusion. If all segments of the lung are affected, however, vasoconstriction occurs throughout the pulmonary vasculature and pulmonary hypertension (elevated pulmonary artery pressure) can result. The pulmonary vasoconstriction caused by low alveolar PO2 is reversible if the alveolar PO2 is corrected. Chronic alveolar hypoxia can result in structural changes in pulmonary arterioles causing permanent pulmonary artery hypertension, which eventually leads to right heart failure (cor pulmonale).7 Acidemia also causes pulmonary artery constriction. If the acidemia is corrected, the vasoconstriction is reversed. (Respiratory acidosis and metabolic acidosis are described in Chapter 5.) An elevated PaCO2 value without a drop in pH does not cause pulmonary artery constriction. Other biochemical factors that affect the caliber of vessels in pulmonary circulation are histamine, prostaglandins, serotonin, nitric oxide, an

hypoxia

hypoxia (or ischemia) is reduced oxygenation of cells in tissues. Although hypoxemia can lead to tissue hypoxia, tissue hypoxia can result from other abnormalities unrelated to alterations of pulmonary function, such as low cardiac output or cyanide poisoning. contribute to gasping respirations that consist of irregular, quick inspirations with an expiratory pause. Anxiety can cause sighing respirations, which consist of irregular breathing characterized by frequent, deep sighing inspirations. Cheyne-Stokes respirations are characterized by alternating periods of deep and shallow breathing. Apnea lasting from 15 to 60 seconds is followed by ventilations that increase in volume until a peak is reached; then ventilation (tidal volume) decreases again to apnea. Cheyne-Stokes respirations result from any condition that reduces blood flow to the brainstem, which in turn slows impulses sending information to the respiratory centers of the brainstem. Hypoxia, or lack of sufficient oxygen within cells, is the single most common cause of cellular injury (Figure 4-9). Hypoxia can result from 79a reduced amount of oxygen in the air, loss of hemoglobin or decreased efficacy of hemoglobin, decreased production of red blood cells, diseases of the respiratory and cardiovascular systems, and poisoning of the oxidative enzymes (cytochromes) within the cells. Hypoxia plays a role in physiologic processes including cell differentiation, angiogenesis, proliferation, erythropoiesis, and overall cell viability.15 The main consumers of oxygen are mitochondria and the cellular responses to hypoxia are reported to be mediated by the production of reactive oxygen species (ROS) at the mitochondrial complex III.15 Investigators are studying the role of ROS as hypoxia signaling molecules. More commonly, hypoxia is associated with the pathophysiologic conditions such as inflammation, ischemia, and cancer. Hypoxia can induce inflammation and inflamed lesions can become hypoxic (Figure 4-10).16 The cellular mechanisms involved in hypoxia and inflammation are emerging and include activation of immune responses and oxygen-sensing compounds called prolyl hydroxylases (PHDs) and hypoxia-inducible transcription factor (HIF). The hypoxia-inducible factor (HIF) is a family of transcription regulators that coordinate the expression of many genes in response to oxygen deprivation. Mammalian development occurs in a hypoxic environment.17 Hypoxia-induced signaling involves complicated crosstalk between hypoxia and inflammation, linking hypoxia and inflammation to inflammatory bowel disease, certain cancers, and infections.16 Research is ongoing to understand the mechanisms of how tumors adapt to low oxygen levels by inducing angiogenesis, increasing glucose consumption, and promoting the metabolic state of glycolysis.18The most common cause of hypoxia is ischemia (reduced blood supply). Ischemic injury often is caused by the gradual narrowing of 80arteries (arteriosclerosis) or complete blockage by blood clots (thrombosis), or both. Progressive hypoxia caused by gradual arterial obstruction is better tolerated than the acute anoxia (total lack of oxygen) caused by a sudden obstruction, as with an embolus (a blood clot or other blockage in the circulation). An acute obstruction in a coronary artery can cause myocardial cell death (infarction) within minutes if the blood supply is not restored, whereas the gradual onset of ischemia usually results in myocardial adaptation. Myocardial infarction and stroke, which are common causes of death in the United States, generally result from atherosclerosis (a type of arteriosclerosis) and consequent ischemic injury. (Vascular obstruction is discussed in Chapter 24.) Cellular responses to hypoxic injury caused by ischemia have been demonstrated in studies of the heart muscle. Within 1 minute after blood supply to the myocardium is interrupted, the heart becomes pale and has difficulty contracting normally. Within 3 to 5 minutes, the ischemic portion of the myocardium ceases to contract because of a rapid decrease in mitochondrial phosphorylation, causing insufficient ATP production. Lack of ATP leads to increased anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen. When glycogen stores are depleted, even anaerobic metabolism ceases. A reduction in ATP levels causes the plasma membrane's sodium-potassium (Na+-K+) pump and sodium-calcium exchange mechanism to fail, which leads to an intracellular accumulation of sodium and calcium and diffusion of potassium out of the cell. Sodium and water then can enter the cell freely, and cellular swelling, as well as early dilation of the endoplasmic reticulum (ER), results. Dilation causes the ribosomes to detach from the rough ER, reducing protein synthesis. With continued hypoxia, the entire cell becomes markedly swollen, with increased concentrations of sodium, water, and chloride and decreased concentrations of potassium. These disruptions are 81reversible if oxygen is restored. If oxygen is not restored, however, vacuolation (formation of vacuoles) occurs within the cytoplasm and swelling of lysosomes and marked mitochondrial swelling result from damage to the outer membrane. Continued hypoxic injury with accumulation of calcium subsequently activates multiple enzyme systems resulting in membrane damage, cytoskeleton disruption, DNA and chromatin degradation, ATP depletion, and eventual cell death (see Figures 4-9, C, and 4-27). Structurally, with plasma membrane damage, extracellular calcium readily moves into the cell and intracellular calcium stores are released. Increased intracellular calcium levels activate cell enzymes (caspases) that promote cell death by apoptosis (see Figures 4-29 and 4-33). Persistent ischemia is associated with irreversible injury and necrosis. Irreversible injury is associated structurally with severe swelling of the mitochondria, severe damage to plasma membranes, and swelling of lysosomes. Overall, death is mainly by necrosis but apoptosis also contributes.1 Restoration of blood flow and oxygen, however, can cause additional injury called ischemia-reperfusion injury (Figure 4-11). Ischemia-reperfusion injury is very important clinically because it is associated with tissue damage during myocardial and cerebral infarction. Several mechanisms are now proposed for ischemia-reperfusion injury and include: • Oxidative stress—Reoxygenation causes the increased generation of reactive oxygen species (ROS) and nitrogen species.1 Highly reactive oxygen intermediates (oxidative stress) generated include hydroxyl radical (OH−), superoxide radical (image), and hydrogen peroxide (H2O2) (see pp. 82-83). The nitrogen species include nitric oxide (NO) generated by endothelial cells, macrophages, neurons, and other cells. These radicals can all cause further membrane damage and mitochondrial calcium overload. The white blood cells (neutrophils) are especially affected with reperfusion injury, including neutrophil adhesion to the endothelium. Antioxidant treatment not only reverses neutrophil adhesion but also can reverse neutrophil-mediated heart injury. In one study of individuals undergoing elective percutaneous coronary intervention (PCI), pretreatment with vitamin C was associated with less myocardial injury.19 The PREVEC Trial (Prevention of reperfusion damage associated with percutaneous coronary angioplasty following acute myocardial infarction) seeks to evaluate whether vitamins C and E reduce infarct size in patients subjected to percutaneous coronary angioplasty after acute myocardial infarction.20 • Increased intracellular calcium concentration—Intracellular and mitochondrial calcium overload the cell; this process begins during acute ischemia. Reperfusion causes even more calcium influx because of cell membrane damage and ROS-induced injury to the sarcoplasmic reticulum. The increased calcium increases mitochondrial permeability, eventually leading to depletion of ATP and further cell injury. • Inflammation—Ischemic injury increases inflammation because danger signals (from cytokines) are released by resident immune cells when cells die and this signaling initiates inflammation. • Complement activation—The activation of complement may increase the tissue damage from reperfusion-ischemia injury.1

alterations in pulmonary vasculature

pulmonary hypertension, pulmonary thromboembolism, pulmonary malignancies