Patho Exam 2

Blood consists of various cells that circulate suspended in a solution of protein and inorganic materials (plasma), which is approximately 92% water and 8% dissolved substances (solutes). The blood volume amounts to about 6 quarts (5.5 L) in adults.

• Plasma differs from serum in that serum is plasma that has been allowed to clot in the laboratory in order to remove fibrinogen and other clotting factors that may interfere with some diagnostic tests.
• The plasma contains a large number of proteins (plasma proteins). These vary in structure and function and can be classified into two major groups, albumin and globulins. Most plasma proteins are produced by the liver.

Immature erythrocyte

Erythrocytes (red blood cells) are the most abundant cells of the blood, occupying approximately 48% of the blood volume in men and about 42% in women. Erythrocytes are primarily responsible for tissue oxygenation. Hemoglobin (Hb) carries the gases, and electrolytes regulate gas diffusion through the cell's plasma membrane. The mature erythrocyte lacks a nucleus and cytoplasmic organelles (e.g., mitochondria), so it cannot synthesize protein or carry out oxidative reactions. Because it cannot undergo mitotic division, the erythrocyte has a limited life span (approximately 120 days).

• Leukocytes (white blood cells) defend the body against organisms that cause infection and also remove debris, including dead or injured host cells of all kinds (Figure 19-2). The leukocytes act primarily in the tissues but are transported in the circulation. The average adult has approximately 5000 to 10,000 leukocytes/mm3 of blood.
• Leukocytes are classified according to structure as either granulocytes or agranulocytes and according to function as either phagocytes or immunocytes. The granulocytes, which include neutrophils, basophils, and eosinophils, are all phagocytes. (Phagocytic action is described in Chapter 5.) Of the agranulocytes, the monocytes and macrophages are phagocytes, whereas the lymphocytes are immunocytes (cells that create immunity

• The neutrophil (polymorphonuclear neutrophil [PMN]) is the most numerous and best understood of the granulocytes (Figure 19-3) Neutrophils constitute about 55% of the total leukocyte count in adults.
• Neutrophils are the chief phagocytes of early inflammation.

• Platelets (thrombocytes) are not true cells but disk-shaped cytoplasmic fragments that are essential for blood coagulation and control of bleeding. They lack a nucleus, have no deoxyribonucleic acid (DNA), and are incapable of mitotic division. They do, however, contain cytoplasmic granules capable of releasing proinflammatory biochemical mediators when stimulated by injury to a blood vessel (Figure 19-4) (see Chapter 5).
• The normal platelet concentration is 150,000 to 400,000 platelets/mm3 of circulating blood, although the normal ranges may vary slightly from laboratory to laboratory. An additional one third of the body's available platelets are in a reserve pool in the spleen. A platelet circulates for approximately 10 days, ages, and is removed by macrophages of the MPS, mostly in the spleen. Thrombopoietin (TPO), a hormone growth factor, is the main regulator of the circulating platelet mass. TPO is primarily produced by the liver and induces platelet production in the bone marrow.6 Platelets express receptors for TPO, and when circulating platelet levels are normal, TPO is adsorbed onto the platelet surface and prevented from accessing the bone marrow and initiating further platelet production. When platelet levels are low, however, the amount of TPO exceeds the number of available platelet TPO receptors, and free TPO can enter the bone marrow.

The hematologic system arises from the proliferation and differentiation of hematopoietic stem cells. All humans originate from a single cell (the fertilized egg) that has the capacity to proliferate and eventually differentiate into the huge diversity of cells of the human body.

Several cytokines participate in hematopoiesis, particularly colony-stimulating factors (CSFs or hematopoietic growth factors), which stimulate the proliferation of progenitor cells and their progeny and initiate the maturation events necessary to produce fully mature cells. Multiple cell types, including endothelial cells, fibroblasts, and lymphocytes, produce CSFs.

Under certain conditions, the levels of circulating hematologic cells need to be rapidly replenished. Medullary hematopoiesis can be accelerated by any or all of three mechanisms: (1) conversion of yellow bone marrow, which does not produce blood cells, to red marrow, which does, by the actions of erythropoietin (a hormone that stimulates erythrocyte production); (2) faster differentiation of daughter cells; and presumably (3) faster proliferation of stem cells

Hemostasis means arrest of bleeding. As a result of hemostasis, damaged blood vessels may maintain a relatively steady state of blood volume, pressure, and flow. Three equally important components of the control of hemostasis are platelets, blood proteins (clotting factors), and the vasculature (endothelial cells and subendothelial matrix)

A blood clot is a meshwork of protein strands that stabilizes the platelet plug and traps other cells, such as erythrocytes, phagocytes, and microorganisms (Figure 19-18). The strands are made of fibrin, which is produced by the clotting (coagulation) system.

• The macrocytic (megaloblastic) anemias are characterized by unusually large stem cells (megaloblasts) in the marrow that mature into erythrocytes that are unusually large in size (macrocytic), thickness, and volume.2 The hemoglobin content is normal, thus allowing them to be classified as normochromic.
• These anemias are the result of ineffective erythrocyte deoxyribonucleic acid (DNA) synthesis, commonly caused by deficiencies of vitamin B12 (cobalamin) or folate (folic acid). These defective erythrocytes die prematurely, which decreases their numbers in the circulation, causing anemia.
• Defective DNA synthesis in megaloblastic anemias causes red cell growth and development to proceed at unequal rates. DNA synthesis and cell division is blocked or delayed. However, ribonucleic acid (RNA) replication and protein (hemoglobin) synthesis proceed normally. Asynchronous development leads to an overproduction of hemoglobin during prolonged cellular division, creating a larger than normal erythrocyte with a disproportionately small nucleus. With each cell division, the disproportion between RNA and DNA becomes more apparent.

• The microcytic-hypochromic anemias are characterized by abnormally small erythrocytes that contain abnormally reduced amounts of hemoglobin (see Figure 20-2, B). Hypochromia occurs even in cells of normal size.
• Microcytic-hypochromic anemia can result from (1) disorders of iron metabolism, (2) disorders of porphyrin and heme synthesis, or (3) disorders of globin synthesis. Specific conditions include iron deficiency anemia, sideroblastic anemia, and thalassemia.

• excessive production of red cell
• Polycythemia exists in two forms: relative and absolute. Relative polycythemia results from hemoconcentration of the blood associated with dehydration. It is of minor consequence and resolves with fluid administration or treatment of underlying conditions.

• an increase in granulocytes (neutrophils, eosinophils, or basophils)—begins when stored blood cells are released. Neutrophilia is another term that may be used to describe granulocytosis because neutrophils are the most numerous of the granulocytes
• When the demand for circulating mature neutrophils exceeds the supply, immature neutrophils (and other leukocytes) are released from the bone marrow. Premature release of the immature cells is responsible for the phenomenon known as a shift-to-the-left or leukemoid reaction.

Neutropenia is a condition associated with a reduction in circulating neutrophils and exists clinically when the neutrophil count is less than 2000/mm3. Reduction in neutrophils occurs in severe prolonged infections when production of granulocytes cannot keep up with demand.

• Leukemia is a clonal malignant disorder of the blood and blood-forming organs.13 The common pathologic feature of all forms of leukemia is an uncontrolled proliferation of malignant leukocytes, causing an overcrowding of bone marrow and decreased production and function of normal hematopoietic cells.
• The classification of leukemia is based on (1) the predominant cell of origin (either myeloid or lymphoid) and (2) the degree of differentiation that took place before the cell became malignant (acute, with a rapid growth of immature blood cells, or chronic, with a slow growth of more differentiated cells) (Figure 20-6). Thus there are four types of leukemia: acute lymphocytic (ALL) or myelogenous (AML) and chronic lymphocytic (CLL) or myelogenous (CML).13–15 Further classification of acute leukemias is based on characteristics that may provide significant therapeutic prognostic information, such as structure, number of cells, genetics, identification of surface markers, and histochemical staining

Lymphomas consist of a diverse group of neoplasms that develop from the proliferation of malignant lymphocytes in the lymphatic system. The most recent classification of lymphomas was published by the World Health Organization (WHO) and is derived from the Revised European-American Lymphoma (REAL) Classification. This classification is based on the cell type from which the lymphoma probably originated. The groups include Hodgkin lymphoma and two that were previously classified as non-Hodgkin lymphoma (B cell neoplasms, T cell and NK cell neoplasms). With the new classification, multiple myeloma, which was previously classified independently, is included as a B cell lymphoma.

In the past, splenomegaly (enlargement of the spleen) has been associated with various disease states. It is now recognized that splenomegaly is not necessarily pathologic; an enlarged spleen may be present in certain individuals without any evidence of disease. Splenomegaly may be, however, one of the first physical signs of underlying conditions, and its presence should not be ignored. In conditions where splenomegaly is present, the normal functions of the spleen may become overactive, producing a condition known as hypersplenism.

• defined as a platelet count below 150,000/mm3 of blood, although most individuals do not consider the decrease significant unless it falls below 100,000/mm3, and the risk for hemorrhage associated with minor trauma does not appreciably increase until the count falls below 50,000/mm3. Spontaneous bleeding without trauma can occur with counts ranging from 10,000/mm3 to 15,000/mm3. When this happens, skin manifestations (i.e., petechiae, ecchymoses, and larger purpuric spots) are observed or frank bleeding from mucous membranes occurs. Severe bleeding results if the count falls below 10,000/mm3 and can be fatal if it occurs in the gastrointestinal tract, respiratory tract, or central nervous system.
• Before thrombocytopenia is diagnosed, the presence of a pseudothrombocytopenia must be ruled out. This phenomenon is seen in approximately 1 in 1000 to 10,000 samples and results from an error in platelet counting when a blood sample is analyzed by an automated cell counter. Platelets in the blood can become nonspecifically agglutinated by immunoglobulins in the presence of ethylenediaminetetraacetic acid (EDTA) and are not counted, thus giving an apparent, but false, thrombocytopenia. Thrombocytopenia also may be falsely diagnosed because of a dilutional effect observed after massive transfusion of platelet-poor packed cells to treat a hemorrhage. This is observed when more than 10 units of blood have been transfused within a 24-hour period. The precipitating hemorrhage also depletes platelets, contributing to the pseudothrombocytopenic state. Splenic sequestering of platelets in hypersplenism also stimulates thrombocytopenia. Hypothermia (<25° C) also predisposes to a thrombocytopenic state, which is reversed when temperatures return to normal, suggesting sequestering and release.

• Thrombocythemia (also called thrombocytosis) is defined as a platelet count greater than 400,000/mm3 of blood.28 Thrombocythemia may be primary or secondary (reactive) and is usually asymptomatic until the count exceeds 1 million/mm3. Then intravascular clot formation (thrombosis), hemorrhage, or other abnormalities can occur.
• Pathophysiology
• Essential (primary) thrombocythemia (ET) is a myeloproliferative disorder in which platelet production increases, resulting in platelet counts in excess of 600,000/mm3. It can occur in individuals at most any age. Manifestations include increased numbers of bone marrow megakaryocytes, splenomegaly, and periodic episodes of hemorrhage or thrombosis, or both. The thrombocythemia is secondary to increased plasma thrombopoietin levels resulting from defects in the thrombopoietin receptor. The defective receptor cannot adequately bind and remove thrombopoietin from the blood; thus circulating levels remain high. Along with increased platelets, there may be a concomitant increase in the number of red cells, indicating a myeloproliferative disorder; however, the increase in red cells is not to the extent seen in polycythemia vera.
• Secondary thrombocythemia may occur after splenectomy because platelets that normally would be stored in the spleen remain in circulating blood. The increase in platelets may be gradual, with thrombocythemia not occurring for up to 3 weeks after splenectomy. Reactive thrombocythemia may occur during some inflammatory conditions, such as rheumatoid arthritis and cancers. In these conditions, excessive production of some cytokines (e.g., IL-6, IL-11) may induce increased production of thrombopoietin in the liver, resulting in increased megakaryocyte proliferation. Reactive thrombocythemia may also occur during a variety of physiologic conditions, such as after exercise.

is the condition in which an individual is at risk for thrombosis, but by itself it is a rare cause of thrombosis. Hypercoagulability is differentiated according to whether it results from primary (hereditary) or secondary (acquired) causes.

The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the newborn (HDN), also termed erythroblastosis fetalis. HDN is an alloimmunity (isoimmunity) disease in which maternal blood and fetal blood are antigenically incompatible, causing the mother's immune system to produce antibodies against fetal erythrocytes.

• Iron deficiency anemia is the most common blood disorder of infancy and childhood, with the highest incidence occurring between 6 months and 2 years of age. Incidence is not related to gender or race, but socioeconomic factors are important because they affect nutrition.1 Iron deficiency anemia is common in children because they need an extremely high amount of iron for normal growth to occur.
• Between 4 years of age and the onset of puberty, dietary iron deficiency is uncommon. During adolescence, however, it is relatively common, especially in menstruating females. Rapid growth, together with the average teenager's dietary habits, causes iron depletion.

• The most common cause of hemolytic anemia in newborns is alloimmune disease (HDN). HDN can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. Maternal-fetal incompatibility exists if mother and fetus differ in ABO blood type or if the fetus is Rh-positive and the mother is Rh-negative. Some minor blood antigens also may be involved.
• ABO incompatibility occurs in about 20% to 25% of all pregnancies, but only 1 in 10 cases of ABO incompatibility results in HDN. Rh incompatibility occurs in fewer than 10% of pregnancies and rarely causes HDN in the first incompatible fetus. Even after five or more pregnancies, only 5% of women have babies with hemolytic disease. Usually erythrocytes from the first incompatible fetus cause the mother's immune system to produce antibodies that affect the fetuses of subsequent incompatible pregnancies.
• The key to treatment of HDN resulting from Rh incompatibility lies in prevention (immunoprophylaxis). One of the success stories of immunology has been the result obtained with Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D. If an Rh-negative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce antibody against the D antigen, and the next Rh-positive baby she conceives will be protected.

• Sickle cell disease is a group of disorders characterized by the production of abnormal hemoglobin S (Hb S) within the erythrocytes. Hb S is formed by a genetic mutation in which one amino acid (valine) replaces another (glutamic acid) (Figure 21-2). Hb S, the so-called sickle hemoglobin, reacts to deoxygenation and dehydration by solidifying and stretching the erythrocyte into an elongated sickle shape, producing hemolytic anemia (Figure 21-3).
• Sickle cell disease is an inherited, autosomal recessive disorder expressed as sickle cell anemia
• Hemoglobin S is soluble and usually causes no problem when properly oxygenated. When oxygen tension decreases, the single amino acid substitution in the beta-globin chain of Hb S polymerizes, forming abnormal fluid polymers. As these polymers realign, they cause the red cell to deform into the sickle shape. Sickling depends on the degree of oxygenation, pH, and dehydration of the individual. A decrease in oxygenation (hypoxemia) and pH, as well as dehydration, increases sickling. Deoxygenation is probably the most important variable in determining the occurrence of sickling
• When sickling occurs, the general manifestations of hemolytic anemia—pallor, fatigue, jaundice, and irritability—sometimes are accompanied by acute manifestations called crises

Leukemia, cancer of the blood-forming tissues, is the most common malignancy of childhood, representing approximately 33% of all childhood cancers. Childhood lymphoma, or cancer of the lymphoid system (primarily lymph nodes), is the third most common malignant neoplasm of children in the United States, representing approximately 11% of all childhood cancers. (See Chapter 20 for a discussion of leukemia in adults.) Table 21-6 defines the major classifications of leukemia.

• Approximately 80% to 85% of leukemias in children are acute lymphoblastic leukemia (ALL). The remaining 15% to 20% are acute nonlymphocytic leukemias (ANLLs) (which include myeloblastic, promyelocytic, monocytic, and myelomonoblastic) and erythroleukemia, the rare red blood cell leukemia. Because the vast majority of ANLL cases involve the myeloblastic cell, many experts refer to the disease as acute myelogenous leukemia (AML). Both a juvenile form and an adult form of chronic myelocytic leukemia (CML) develop in children but are uncommon and account for only 2% of all leukemias in childhood. Chronic lymphocytic leukemia (CLL) is virtually nonexistent in children.
• ALL is the most common malignancy in children, representing nearly one third of all pediatric cancers. The annual incidence of ALL is about 30 cases per million people, with a peak incidence in children 2 to 5 years of age, and affects almost twice as many white children as nonwhite children (4.2:100,000 versus 2.4:100,000, respectively). Childhood ALL also is more common in boys than in girls (1.3:1.0).
• The onset of leukemia may be abrupt or insidious, but the most common symptoms reflect the consequence of bone marrow failure: decreased levels of both red blood cells and platelets and changes in white blood cells. Pallor, fatigue, petechiae, purpura, bleeding, and fever generally are present. Approximately 45% of children have a hemoglobin level below 7 g/dl. If acute blood loss occurs, characteristic symptoms of tachycardia, air hunger, restlessness, and thirst may be present. Epistaxis often occurs in children with severe thrombocytopenia.
• Fever is usually present as a result of (1) infection associated with the decrease in functional neutrophils

Arterial blood pressure is determined by the cardiac output times the peripheral resistance (see Figure 22-30). The systolic blood pressure is the arterial blood pressure during ventricular contraction or systole. The diastolic blood pressure is the arterial blood pressure during ventricular filling or diastole. The mean arterial pressure (MAP), which is the average pressure in the arteries throughout the cardiac cycle, depends on the elastic properties of the arterial walls and the mean volume of blood in the arterial system.

The cardiac output (minute volume) of the heart can be changed by alterations in heart rate, stroke volume (volume of blood ejected during each ventricular contraction), or both.

Antidiuretic hormone (ADH) is released by the posterior pituitary and causes reabsorption of water by the kidney. With reabsorption, the blood plasma volume will increase, increasing blood pressure. Antidiuretic hormone, also known as arginine vasopressin, is also a potent vasoconstrictor, thus increasing peripheral resistance

Renin is an enzyme synthesized and secreted by the juxtaglomerular cells of the kidney. It also has been found in the adrenal cortex, salivary gland, brain, pituitary gland, arterial smooth muscle cells in the vascular endothelium, and myocardium. Renin is an essential factor that interacts with many other systems to control vascular tone and renal sodium excretion.13 The primary factor that stimulates renin release is a drop in renal perfusion as detected by the juxtaglomerular cells. Other factors that stimulate renin release include a decrease in the amount of sodium chloride delivered to the kidney, β-adrenergic stimuli, and low potassium concentrations in plasma. Once in the circulation, renin splits off a polypeptide from angiotensinogen to generate angiotensin I (Ang I). This is converted by an enzyme, angiotensin-converting enzyme (ACE), to angiotensin II (Ang II), a powerful vasoconstrictor that stimulates the secretion of aldosterone from the adrenal gland (see Figure 22-33, A, and 17-18). This kidney-based renin-angiotensin system serves as an important regulatory loop. For example, decreases in blood pressure or renal blood flow (as might occur after hemorrhage or dehydration) stimulate secretion of renin. This causes the formation of Ang I, which is then converted to Ang II. Ang II causes vasoconstriction and aldosterone secretion. The resultant increase in TPR and sodium retention restores blood pressure. Overall, the renin-angiotensin system is activated after volume depletion or hypotension, and is suppressed after volume repletion.

Atrial natriuretic peptide (ANP) is a hormone secreted from cells in the right atrium when right atrial blood pressure increases. ANP increases urine sodium loss, leading to the formation of a large volume of dilute urine that decreases blood volume and blood pressure

Angiotensins and Their Receptors, AT1 and AT2. Blocking the angiotensin-converting enzyme (ACE) with ACE inhibitors decreases the amount of angiotensin II. Blocking the receptor AT1 with drugs (AT1 antagonists) blocks the attachment of angiotensin II to the cell, preventing the cellular effects and decreasing the vascular, cardiac, and renal effects.

A varicose vein is a vein in which blood has pooled, producing distended, tortuous, and palpable vessels

A thrombus is a blood clot that remains attached to a vessel wall (see Figure 20-17). A detached thrombus is a thromboembolus. Venous thrombi are more common than arterial thrombi because flow and pressure are lower in the veins than in the arteries. Deep venous thrombosis (DVT) occurs primarily in the lower extremity. Three factors (triad of Virchow) promote venous thrombosis: (1) venous stasis (e.g., immobility, age, congestive heart failure), (2) venous endothelial damage (e.g., trauma, intravenous medications), and (3) hypercoagulable states (e.g., inherited disorders, malignancy, pregnancy, use of oral contraceptives or hormone replacement therapy). Orthopedic trauma or surgery, spinal cord injury, and obstetric/gynecologicconditions can be associated with up to a 100% likelihood of DVT.

Hypertension is consistent elevation of systemic arterial blood pressure. Hypertension (HTN) is the most common primary diagnosis in the United States. One in three Americans has hypertension, and more than two thirds of those older than age 60 are affected.8 The chance of developing primary hypertension increases with age. Although hypertension is usually considered an adult health problem, it is important to remember that hypertension does occur in children and is being diagnosed with increasing frequency (see Chapter 24). The prevalence of HTN is higher in blacks and in those with diabetes. Hypertension is defined by the Seventh Joint National Committee Report as a sustained systolic blood pressure of 140 mm Hg or greater or a diastolic pressure of 90 mm Hg or greater (Table 23-1).9 Normal blood pressure is associated with the lowest cardiovascular risk, whereas those who fall into the prehypertension category (which includes between 25% and 37% of the U.S. population) are at risk for developing hypertension and many associated cardiovascular complications unless lifestyle modification and treatment are instituted.8,10 All stages of hypertension are associated with increased risk for target organ disease events, such as myocardial infarction, kidney disease, and stroke; thus both stage I and stage II hypertension need effective long-term therapy.

A specific cause for primary hypertension has not been identified, and a combination of genetic and environmental factors is thought to be responsible for its development.12 Genetic predisposition to hypertension is believed to be polygenic. The inherited defects are associated with renal sodium excretion, insulin and insulin sensitivity, activity of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), and cell membrane sodium or calcium transport.13 Factors associated with primary hypertension include (1) family history of hypertension; (2) advancing age; (3) gender (men younger than age 55 and women after age 70); (4) black race; (5) high dietary sodium intake; (6) glucose intolerance (insulin resistance and diabetes mellitus); (7) cigarette smoking; (8) obesity; (9) heavy alcohol consumption; and (10) low dietary intake of potassium, calcium, and magnesium (see Risk Factors: Primary Hypertension). Many of these factors are also risk factors for other cardiovascular disorders. In fact, obesity, hypertension, dyslipidemia, and glucose intolerance often are found together in a condition called the metabolic syndrome

• The sympathetic nervous system has been implicated in both the development and the maintenance of elevated blood pressure and plays a role in hypertensive end-organ damage
• In hypertensive individuals, overactivity of the RAAS contributes to salt and water retention and increased vascular resistance

• Inflammation plays a role in the pathogenesis of hypertension.21 Endothelial injury and tissue ischemia result in the release of vasoactive inflammatory cytokines. Although many of these cytokines (e.g., histamine, prostaglandins) have vasodilatory actions in acute inflammatory injury, chronic inflammation contributes to vascular remodeling and smooth muscle contraction. Endothelial injury and dysfunction in primary hypertension is further characterized by a decreased production of vasodilators, such as nitric oxide, and an increased production of vasoconstrictors, such as endothelin.22
• Obesity is recognized as an important risk factor for hypertension in both adults and children and contributes to many of the neurohumoral, metabolic, renal, and cardiovascular processes that cause hypertension.23 Obesity causes changes in the adipokines (i.e., leptin and adiponectin) and also is associated with increased activity of the SNS and the RAAS. Obesity is linked to inflammation, endothelial dysfunction, and insulin resistance and an increased risk for cardiovascular complications from hypertension24 (see Health Alert: Obesity and Hypertension).
• Finally, insulin resistance is common in hypertension, even in individuals without clinical diabetes.25 Insulin resistance is associated with decreased endothelial release of nitric oxide and other vasodilators. It also affects renal function and causes renal salt and water retention. Insulin resistance is associated with overactivity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. It is interesting to note that in many individuals with diabetes treated with drugs that increase insulin sensitivity, blood pressure often declines, even in the absence of antihypertensive drugs. The interactions between obesity, hypertension, insulin resistance, and lipid disorders in the metabolic syndrome result in a high risk of cardiovascular disease

• The term orthostatic (postural) hypotension refers to a decrease in systolic blood pressure of at least 20 mm Hg or a decrease in diastolic blood pressure of at least 10 mm Hg within 3 minutes of moving to a standing position. The term idiopathic, or primary, orthostatic hypotension implies no known initial cause. Some define the disorder as a separate entity, whereas others suggest it is a part of a generalized degenerative central nervous system disease. It affects men more often than women and usually occurs between the ages of 40 and 70 years. Up to 18% of older adults may be affected by primary orthostatic hypotension, and it is a significant risk factor for falls and associated injury
• Normally when an individual stands, the gravitational changes on the circulation are compensated by such mechanisms as reflex arteriolar and venous constriction and increased heart rate. Other compensatory mechanisms include mechanical factors, such as the closure of valves in the venous system, contraction of the leg muscles, and a decrease in intrathoracic pressure. The normally increased sympathetic activity during upright posture is mediated through a stretch receptor (baroreceptor) reflex that responds to shifts in volume caused by postural changes.

• An aneurysm is a localized dilation or outpouching of a vessel wall or cardiac chamber (Figure 23-5). The law of Laplace (discussed in detail in Chapter 22) can provide an understanding of the hemodynamics of an aneurysm. True aneurysms involve all three layers of the arterial wall and are best described as a weakening of the vessel wall
• The aorta is particularly susceptible to aneurysm formation because of constant stress on the vessel wall and the absence of penetrating vasa vasorum in the media layer.

Embolism is the obstruction of a vessel by an embolus—a bolus of matter circulating in the bloodstream. The embolus may consist of a dislodged thrombus; an air bubble; an aggregate of amniotic fluid; an aggregate of fat, bacteria, or cancer cells; or a foreign substance. An embolus travels in the bloodstream until it reaches a vessel through which it cannot fit. No matter how tiny it is, an embolus will eventually lodge in a systemic or pulmonary vessel determined by its source. Pulmonary emboli originate on the venous side (mostly from the deep veins of the legs)

Both Raynaud phenomenon and Raynaud disease are characterized by attacks of vasospasm in the small arteries and arterioles of the fingers and, less commonly, the toes. Although the clinical manifestations of the phenomenon and the disease are the same, their causes differ.

• Atherosclerosis is a form of arteriosclerosis characterized by thickening and hardening of the vessel wall. It is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called a plaque. 
• Atherosclerosis begins with injury to the endothelial cells that line artery walls. Pathologically, the lesions progress from endothelial injury and dysfunction to fatty streak to fibrotic plaque to complicated lesion (Figures 23-7 and 23-8). Possible causes of endothelial injury include the common risk factors for atherosclerosis, such as smoking, hypertension, diabetes, increased levels of low-density lipoprotein (LDL), decreased levels of high-density lipoprotein (HDL), and autoimmunity. Other “nontraditional” risk factors include elevated levels of highly-sensitive C-reactive protein (hs-CRP), increased serum fibrinogen level, insulin resistance, oxidative stress, infection, and periodontal disease.

• Low-Density Lipoprotein Oxidation. Low-density lipoprotein (LDL) enters the arterial intima through an intact endothelium. In hypercholesterolemia, the influx of LDL exceeds the eliminating capacity and an extracellular pool of LDL is formed. This is enhanced by association of LDL with the extracellular matrix. Intimal LDL is oxidized through the action of free oxygen radicals formed by enzymatic or nonenzymatic reactions. This generates proinflammatory lipids that induce endothelial expression of the adhesion molecule (i.e., vascular cell adhesion molecule-1), activate complement, and stimulate chemokine secretion. All of these factors cause adhesion and entry of mononuclear leukocytes, particularly monocytes and T lymphocytes. Monocytes differentiate into macrophages. Macrophages up-regulate and internalize oxidized LDL and transform into foam cells. Macrophage uptake of oxidized LDL also leads to presentation of its fragments to antigen-specific T cells. This induces an autoimmune reaction that leads to production of proinflammatory cytokines. Such cytokines include interferon-γ, tumor necrosis factor-alpha, and interleukin-1, which act on endothelial cells to stimulate expression of adhesion molecules and procoagulant activity; on macrophages to activate proteases, endocytosis, nitric oxide (NO), and cytokines; and on smooth muscle cells (SMCs) to induce NO production and inhibit growth and collagen and actin expression. LDL, Low-density lipoprotein.
• An increased serum concentration of LDL is a strong indicator of coronary risk

Peripheral artery disease (PAD) refers to atherosclerotic disease of arteries that perfuse the limbs, especially the lower extremities. PAD affects up to 20% of Americans ages 65 or older.8 The risk factors for PAD are the same as those previously described for atherosclerosis, and it is especially prevalent in individuals with diabetes.

Coronary artery disease, myocardial ischemia, and myocardial infarction form a pathophysiologic continuum that impairs the pumping ability of the heart by depriving the heart muscle of blood-borne oxygen and nutrients. The earliest lesions of the continuum are those of coronary artery disease (CAD), which is usually caused by atherosclerosis (see Figure 23-10). CAD can diminish the myocardial blood supply until deprivation impairs myocardial metabolism enough to cause ischemia, a local state in which the cells are temporarily deprived of  blood supply. They remain alive but cannot function normally. Persistent ischemia or the complete occlusion of a coronary artery causes the acute coronary syndromes including infarction, or irreversible myocardial damage. Infarction constitutes the often-fatal event known as a heart attack.

Low levels of HDL cholesterol also are a strong indicator of coronary risk, and high levels of HDL may be more protective for the development of atherosclerosis than low levels of LDL

Hypertension is responsible for a twofold to threefold increased risk of atherosclerotic cardiovascular disease. It contributes to endothelial injury, a key step in atherogenesis (see p. 594). It also can cause myocardial hypertrophy, which increases myocardial demand for coronary flow. Overactivity of the SNS and RAAS commonly found in hypertension also contributes to the genesis of CAD.

Both direct and passive (environmental) smoking increase the risk of CAD. Nicotine stimulates the release of catecholamines (epinephrine and norepinephrine), which increase heart rate and peripheral vascular constriction. As a result, blood pressure increases, as do cardiac workload and oxygen demand. Cigarette smoking is associated with an increase in LDL level, a decrease in HDL level, and generation of toxic oxygen radicals, which contribute to vessel inflammation and thrombosis. The risk of CAD increases with heavy smoking and decreases when smoking is stopped.

Diabetes mellitus is an extremely important risk factor for CAD. Insulin resistance and diabetes have multiple effects on the cardiovascular system including endothelial damage, thickening of the vessel wall, increased inflammation, increased thrombosis, glycation of vascular proteins, and decreased production of endothelial-derived vasodilators such as nitric oxide (see Chapter 18). Diabetes is also associated with dyslipidemia.

It is estimated that 65% of the adult population in the United States is overweight or obese, and an estimated 47 million U.S. residents have a combination of obesity, dyslipidemia, hypertension, and insulin resistance, called the metabolic syndrome, which is associated with an even higher risk for CAD events.8 Abdominal obesity has the strongest link with increased CAD risk and is related to inflammation, insulin resistance, decreased HDL level, increased blood pressure, and fewer changes in hormones called adipokines (leptin and adiponectin).68,69 A sedentary lifestyle not only increases the risk of obesity but also has an independent effect on increasing CAD risk. Physical activity and weight loss offer substantial reductions in risk factors for CAD.

• Many individuals with reversible myocardial ischemia will have a normal physical examination between events. Physical examination of those experiencing myocardial ischemia may disclose rapid pulse rate or extra heart sounds (gallops or murmurs), and pulmonary congestion indicating impaired left ventricular function. The presence of xanthelasmas (small fat deposits) around the eyelids or arcus senilis of the eyes (a yellow lipid ring around the cornea) suggests dyslipidemia and possible atherosclerosis. The presence of peripheral or carotid artery bruits suggests probable atherosclerotic disease and increases the likelihood that CAD is present.
• Electrocardiography is a critical tool for the diagnosis of myocardial ischemia. Because many individuals have normal electrocardiograms when there is no pain, diagnosis requires that electrocardiography be performed during an attack of angina or during exercise stress testing. The ST segment and the T wave segments of the electrocardiogram correlate with ventricular contraction and relaxation (see Figure 22-10). Transient ST segment depression and T wave inversion are characteristic signs of subendocardial ischemia. ST elevation, indicative of transmural ischemia, is seen in individuals with Prinzmetal angina, but is more common in transmural myocardial infarction (Figure 23-15). The electrocardiogram also can identify the coronary artery that is involved.
• Exercise stress testing is indicated to detect ischemic changes in asymptomatic individuals with multiple risk factors for coronary disease, such as diabetes and dyslipidemia, and for older individuals who plan to start a vigorous exercise regimen. Stress testing is made more sensitive when radioisotope imaging is added to the ECG as an indicator of myocardial ischemia. Currently, the diagnostic modality of choice for the diagnosis of myocardial ischemia is single photon emission computerized tomography (SPECT), which is effective at identifying ischemia and estimating coronary risk. Radioisotope imaging with thallium-201 and stress echocardiography are other techniques used to diagnose CAD. Unfortunately, although all of these tests are helpful in documenting coronary obstruction, they cannot detect the presence of vulnerable plaques, which are the cause of the majority of acute coronary syndromes. Noninvasive tests for evaluating coronary atherosclerotic lesions include measurement of coronary artery calcium concentration by computed tomography (CT), noninvasive coronary angiography using electron beam CT, protein-weighted magnetic resonance imaging, and intravascular ultrasound; however, the sensitivity and specificity of these tests vary widely and are not recommended for routine evaluation of CAD

• When coronary blood flow is interrupted for an extended period of time, myocyte necrosis occurs. This results in myocardial infarction (MI). Plaque progression, disruption, and subsequent clot formation are the same for myocardial infarction as they are for unstable angina (see Figures 23-16, 23-17, and 23-18). In this case, however, the thrombus is less labile and occludes the vessel for a prolonged period, such that myocardial ischemia progresses to myocyte necrosis and death. Pathologically, there are two major types of myocardial infarction: subendocardial infarction and transmural infarction. Clinically, however, myocardial infarction is categorized as non-ST segment elevation myocardial infarction (non-STEMI) or ST segment elevation MI (STEMI).
• If the thrombus disintegrates before complete distal tissue necrosis has occurred, the infarction will involve only the myocardium directly beneath the endocardium (subendocardial MI). This infarction will usually present with ST segment depression and T wave inversion without Q waves; therefore it is termed non-STEMI. It is especially important to recognize this form of acute coronary syndrome because recurrent clot formation on the disrupted atherosclerotic plaque is likely. If the thrombus lodges permanently in the vessel, the infarction will extend through the myocardium all the way from endocardium to epicardium, resulting in severe cardiac dysfunction (transmural MI). Transmural myocardial infarction will usually result in marked elevations in the ST segments on ECG and these individuals are categorized as having ST segment elevation MI, or STEMI. Clinically, it is important to identify those individuals with STEMI because they are at highest risk for serious complications and should receive definitive intervention without delay.

The number and severity of postinfarction complications depend on the location and extent of necrosis, the individual's physiologic condition before the infarction, and the availability of swift therapeutic intervention. Sudden cardiac death can occur in individuals with myocardial ischemia even if infarction is absent or minimal and is a multifactorial problem. Risk factors for sudden death are related to three factors: ischemia, left ventricular dysfunction, and electrical instability.

Acute pericarditis is acute inflammation of the pericardium. The etiology of acute pericarditis is most often idiopathic or caused by viral infection by coxsackie, influenza, hepatitis, measles, mumps, or varicella viruses. It also is the most common cardiovascular complication of human immunodeficiency virus (HIV) infection. Other causes include myocardial infarction, trauma, neoplasm, surgery, uremia, bacterial infection (especially tuberculosis), connective tissue disease (especially systemic lupus erythematosus and rheumatoid arthritis), or radiation therapy.97 The pericardial membranes become inflamed and roughened, and a pericardial effusion may develop that can be serous, purulent, or fibrinous

• Pericardial effusion is the accumulation of fluid in the pericardial cavity and can occur in all forms of pericarditis. The fluid may be a transudate, such as the serous effusion that develops with left heart failure, overhydration, or hypoproteinemia. More often, however, the fluid is an exudate, which reflects pericardial inflammation like that seen with acute pericarditis, heart surgery, some chemotherapeutic agents, infections, and autoimmune disorders such as systemic lupus erythematosus. (Types of exudate are described in Chapter 5.) If the fluid is serosanguineous, the underlying cause is likely to be tuberculosis, neoplasm, uremia, or radiation. Idiopathic serosanguineous (cause unknown) effusion is possible, however. Effusions of frank blood are generally related to aneurysms, trauma, or coagulation defects (Figure 23-23). If chyle leaks from the thoracic duct, it may enter the pericardium and lead to cholesterol pericarditis.
• Pericardial effusion, even in large amounts, is not necessarily clinically significant, except that it indicates an underlying disorder. If an effusion develops gradually, the pericardium can stretch to accommodate large quantities of fluid without compressing the heart. If the fluid accumulates rapidly, however, even a small amount (50 to 100 ml) may create sufficient pressure to cause cardiac compression, a serious condition known as tamponade. The danger is that pressure exerted by the pericardial fluid eventually will equal diastolic pressure within the heart chambers, which will interfere with right atrial filling during diastole. This causes increased venous pressure, systemic venous congestion, and signs and symptoms of right heart failure (distention of the jugular veins, edema, hepatomegaly). Decreased atrial filling leads to decreased ventricular filling, decreased stroke volume, and reduced cardiac output. Life-threatening circulatory collapse may occur.

The cardiomyopathies are a diverse group of diseases that primarily affect the myocardium itself. Most are the result of remodeling caused by the effect of the neurohumoral responses to ischemic heart disease or hypertension on the heart muscle. They may, however, be secondary to infectious disease, exposure to toxins, systemic connective tissue disease, infiltrative and proliferative disorders, or nutritional deficiencies. Many cases are idiopathic—that is, their cause is unknown. The cardiomyopathies are categorized as dilated (formerly, congestive), hypertrophic, or restrictive, depending on their physiologic effects on the heart

Dilated cardiomyopathy is usually the result of ischemic heart disease, valvular disease, diabetes, renal failure, alcohol or drug toxicity, peripartum complications, genetic disorder, or infection.101 It is characterized by impaired systolic function leading to increases in intracardiac volume, ventricular dilation, and systolic heart failure (Figure 23-26) (see p. 622). Individuals complain of dyspnea, fatigue, and pedal edema. Findings on examination include a displaced apical pulse, S3 gallop, peripheral edema, jugular venous distention, and pulmonary congestion. Diagnosis is confirmed by chest x-ray and echocardiogram, and management is focused on reducing blood volume, increasing contractility, and reversing the underlying disorder if possible.101 Heart transplant is required in severe cases.

• Disorders of the endocardium (the innermost lining of the heart wall) damage the heart valves, which are composed of endocardial tissue. Endocardial damage can be either congenital or acquired. The acquired forms result from inflammatory, ischemic, traumatic, degenerative, or infectious alterations of valvular structure and function. One of the most common causes of acquired valvular dysfunction is degeneration or inflammation of the endocardium secondary to rheumatic heart disease (Table 23-6). Structural alterations of the heart valves are caused by remodeling changes in the valvular extracellular matrix and lead to stenosis, incompetence, or both.
• In valvular stenosis, the valve orifice is constricted and narrowed, so blood cannot flow forward and the workload of the cardiac chamber proximal to the diseased valve increases (Figure 23-28). Pressure (intraventricular or atrial) rises in the chamber to overcome resistance to flow through the valve, necessitating greater exertion by the myocardium and producing myocardial hypertrophy.
• Although all four heart valves may be affected, in adults those of the left heart (mitral and aortic valves) are far more commonly affected than those of the right heart (tricuspid and pulmonic valves). In valvular regurgitation (also called insufficiency or incompetence), the valve leaflets, or cusps, fail to shut completely, permitting blood flow to continue even when the valve is presumably closed

Aortic stenosis is the most common valvular abnormality, affecting nearly 2% of adults older than 65 years of age.8 It has three common causes: (1) congenital bicuspid valve, (2) degeneration with aging, and (3) inflammatory damage caused by rheumatic heart disease. Numerous gene abnormalities have been associated with aortic stenosis. Aortic stenosis is also associated with many risk factors for coronary artery disease.8 Aortic valve degeneration with aging is associated with chronic inflammation, lipoprotein deposition in the tissue, and leaflet calcification. The orifice of the aortic valve narrows, causing resistance to blood flow from the left ventricle into the aorta (Figure 23-29). Outflow obstruction increases pressure within the left ventricle as it tries to eject blood through the narrowed opening. Left ventricular hypertrophy develops to compensate for the increased workload. Eventually, hypertrophy increases myocardial oxygen demand, which the coronary arteries may not be able to supply. If this occurs, ischemia may cause attacks of angina. In addition, aortic stenosis is frequently accompanied by atherosclerotic coronary disease, further contributing to inadequate coronary perfusion. Untreated aortic stenosis can lead to hypertrophic cardiomyopathy, dysrhythmias, myocardial infarction, and heart failure

Mitral regurgitation has many possible causes, including mitral valve prolapse, rheumatic heart disease, infective endocarditis, MI, connective tissue diseases (Marfan syndrome), and dilated cardiomyopathy. Mitral regurgitation permits backflow of blood from the left ventricle into the left atrium during ventricular systole, producing a holosystolic (throughout systole) murmur heard best at the apex, which radiates into the back and axilla. Because of increased volume from the left atrium, the left ventricle becomes dilated and hypertrophied to maintain adequate cardiac output. The volume of backflow reentering the left atrium gradually increases, causing atrial dilation and associated atrial fibrillation. As the left atrium enlarges, the valve structures stretch and become deformed, leading to further backflow. As mitral valve regurgitation progresses, left ventricular function may become impaired to the point of failure. Eventually, increased atrial pressure leads to pulmonary hypertension and failure of the right ventricle.105 Mitral incompetence is usually well tolerated—often for years—until ventricular failure occurs. Most clinical manifestations are caused by heart failure. The severity of regurgitation can be estimated by echocardiography, and surgical repair or valve replacement may become necessary. In acute mitral regurgitation due to MI, surgical repair must be done emergently.

Mitral valve prolapse is the most common valve disorder in the United States, with a prevalence of 2.4% of adults

Rheumatic fever is a systemic, inflammatory disease caused by a delayed exaggerated immune response to infection by the group A β-hemolytic streptococcus in genetically predisposed individuals. In its acute form, rheumatic fever is a febrile illness characterized by inflammation of the joints, skin, nervous system, and heart.108 If untreated, rheumatic fever can cause scarring and deformity of cardiac structures, resulting in rheumatic heart disease (RHD).

Infective endocarditis is a general term used to describe infection and inflammation of the endocardium—especially the cardiac valves. There are approximately 15,000 new cases of infective endocarditis per year in the United States and it accounts for approximately 1 in 1000 admissions to the hospital.112 Bacteria are the most common cause of infective endocarditis, especially streptococci, staphylococci, and enterococci. Other causes include viruses, fungi, rickettsia, and parasites. Infective endocarditis was once a lethal disease, but morbidity and mortality diminished significantly with the advent of antibiotics and improved diagnostic techniques

A dysrhythmia, or arrhythmia, is a disturbance of heart rhythm. Normal heart rhythms are generated by the sinoatrial (SA) node and travel through the heart's conduction system, causing the atrial and ventricular myocardium to contract and relax at a regular rate that is appropriate to maintain circulation at various levels of physical activity (see Chapter 22). Dysrhythmias range in severity from occasional “missed” or rapid beats to serious disturbances that impair the pumping ability of the heart, contributing to heart failure and death. Dysrhythmias can be caused either by an abnormal rate of impulse generation (Table 23-8) from the SA node or other pacemaker or by the abnormal conduction of impulses (Table 23-9) through the heart's conduction system, including the myocardial cells themselves.

p rate 60 or less

p rate 100-150

• Early beats with P waves
• QRS occasionally opposite in deflection from usual QRS

Heart failure is when the heart is unable to generate an adequate cardiac output, causing inadequate perfusion of tissues or increased diastolic filling pressure of the left ventricle, or both, so that pulmonary capillary pressures are increased. It affects nearly 10% of individuals older than age 65 and is the most common reason for admission to the hospital in that age group. Ischemic heart disease and hypertension are the most important predisposing risk factors.8 Other risk factors include age, obesity, diabetes, renal failure, valvular heart disease, cardiomyopathies, myocarditis, congenital heart disease, and excessive alcohol use. Numerous genetic polymorphisms have been linked to an increased risk for heart failure, including genes for cardiomyopathies, myocyte contractility, and neurohumoral receptors. Recently, genetic changes in kinases, phosphatases, and cellular calcium cycling are being explored.117 Most causes of heart failure result from dysfunction of the left ventricle (systolic and diastolic heart failure). The right ventricle also may be dysfunctional, especially in pulmonary disease (right ventricular failure). Finally, some conditions cause inadequate perfusion despite normal or elevated cardiac output (high-output failure).

• Left heart failure is commonly called congestive heart failure and can be further categorized as systolic heart failure or diastolic heart failure. It is possible for these two types of heart failure to occur simultaneously in one individual.
• Systolic heart failure is defined as an inability of the heart to generate an adequate cardiac output to perfuse vital tissues. Cardiac output depends on the heart rate and stroke volume. Stroke volume is influenced by three major determinants: contractility, preload, and after load
• The clinical manifestations of left heart failure are the result of pulmonary vascular congestion and inadequate perfusion of the systemic circulation. Individuals experience dyspnea, orthopnea, cough of frothy sputum, fatigue, decreased urine output, and edema. Physical examination often reveals pulmonary edema (cyanosis, inspiratory crackles, pleural effusions), hypotension or hypertension, an S3 gallop, and evidence of underlying CAD or hypertension. The diagnosis can be further confirmed with echocardiography showing decreased cardiac output and cardiomegaly. The level of serum brain natriuretic peptide (BNP) can also help make the diagnosis of heart failure and give some insight into its severity

Diastolic heart failure is also known as heart failure with preserved systolic function or heart failure with normal ejection fraction (HFNEF). Diastolic heart failure can occur singly or along with systolic heart failure. Isolated diastolic heart failure is defined as pulmonary congestion despite a normal stroke volume and cardiac output. It is the cause of 40% to 50% of all cases of left heart failure and is more common in women. It results from decreased compliance of the left ventricle and abnormal diastolic relaxation such that a normal left ventricular end-diastolic volume (LVEDV) results in an increased left ventricular end-diastolic pressure (LVEDP). This pressure is reflected back into the pulmonary circulation and results in pulmonary edema.

Right heart failure is defined as the inability of the right ventricle to provide adequate blood flow into the pulmonary circulation at a normal central venous pressure. It can result from left heart failure when an increase in left ventricular filling pressure is reflected back into the pulmonary circulation. As pressure in the pulmonary circulation rises, the resistance to right ventricular emptying increases (Figure 23-39). The right ventricle is poorly prepared to compensate for this increased afterload and will dilate and fail. When this happens, pressure will rise in the systemic venous circulation, resulting in peripheral edema and hepatosplenomegaly. Treatment relies on management of the left ventricular dysfunction as just outlined. When right heart failure occurs in the absence of left heart failure, it is typically attributable to diffuse hypoxic pulmonary disease such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and acute respiratory distress syndrome (ARDS). These disorders result in an increase in right ventricular afterload. The mechanisms for this type of right ventricular failure (cor pulmonale) are discussed in Chapter 26. Finally, myocardial infarction, cardiomyopathies, and pulmonic valvular disease interfere with right ventricular contractility and can lead to right heart failure.

• In shock the cardiovascular system fails to perfuse the tissues adequately, resulting in widespread impairment of cellular metabolism. Because tissue perfusion can be disrupted by any factor that alters heart function, blood volume, or blood pressure, shock has many causes and various clinical manifestations. Ultimately, however, shock progresses to organ failure and death, unless compensatory mechanisms reverse the process or clinical intervention succeeds. Untreated severe shock overwhelms the body's compensatory mechanisms through positive feedback loops that initiate and maintain a downward physiologic spiral.
• The term multiple organ dysfunction syndrome (MODS) describes the failure of two or more organ systems after severe illness and injury and is a frequent complication of severe shock. The disease process is initiated and perpetuated by uncontrolled inflammatory and stress responses. It is progressive and is associated with significant mortality.

Shock is classified by cause as cardiogenic (caused by heart failure), hypovolemic (caused by insufficient intravascular fluid volume), neurogenic (caused by neural alterations of vascular smooth muscle tone), anaphylactic (caused by immunologic processes), or septic (caused by infection). As described previously, each of these share similar effects on tissues and cells but can vary in their clinical manifestations and severity.

• All
• tissues depend on a blood supply and the blood supply depends on endothelial cells,
• which form the lining, or endothelium, of the blood vessel (Figure 22-23).
• Endothelial cells are really quite remarkable in that they can adjust their
• number and arrangement to accommodate local requirements. They are a
• life-support tissue extending and remodeling the network of blood vessels to
• enable tissue growth, motion, and repair. Vascular endothelial cells produce a
• number of essential chemicals including vasodilators, vasoconstrictors,
• anticoagulants, and growth factors. The endothelium performs these vital
• functions through synthesis and release of vasoactive chemicals.

• A, Capillaries have a wall
• composed of only a single layer of flattened cells, whereas the walls of the
• larger vessels also have smooth muscle. B, Capillary with red blood
• cells in single file (× 500).

• Contraction
• narrows the vessel lumen (the internal cavity of the vessel), which
• diminishes flow through the vessel (vasoconstriction). When the smooth
• muscle layer relaxes, more blood flows through the vessel lumen (vasodilation).

• Stroke
• volume, or the volume of
• blood ejected per beat during systole, also depends on the force of
• contraction, which depends on myocardial contractility or the degree of
• myocardial fiber shortening. Three major factors determine the force of
• contraction

• 1.      Changes in the stretching of the
• ventricular myocardium caused by changes in VEDV (preload). As discussed
• previously, increased blood flow from the veins into the heart distends the
• ventricle by increasing preload, which increases the stroke volume and,
• subsequently, cardiac output, up to a certain point. However, an excessive
• increase in preload leads to decreased stroke volume.

• 2.      Alterations in the inotropic stimuli of
• the ventricles. Chemicals affecting contractility are called inotropic agents.
• The most important positive inotropic agents are epinephrine and norepinephrine
• released from the sympathetic nervous system. Other positive inotropes include
• thyroid hormone and dopamine. The most important negative inotropic agent is
• acetylcholine released from the vagus nerve. Many drugs have positive or
• negative inotropic properties that can have profound effects on cardiac
• function.

• 3.      Adequacy of myocardial oxygen supply.
• Myocardial contractility also is affected by oxygen and carbon dioxide levels
• (tensions) in the coronary blood. With severe hypoxemia (arterial oxygen
• saturation less than 50%), contractility is decreased. With less severe
• hypoxemia (saturation more than 50%), contractility is stimulated. Moderate
• degrees of hypoxemia may increase contractility by enhancing the myocardial
• response to circulating catecholamines

• Left
• ventricular afterload
• is the resistance to ejection of blood from the left ventricle. It is the load
• the muscle must move after it starts to contract. Aortic systolic pressure is a
• good index of afterload. Pressure in the ventricle must exceed aortic pressure
• before blood can be pumped out during systole. Low aortic pressures (decreased
• afterload) enable the heart to contract more effectively, whereas high aortic
• pressures (increased afterload) slow contraction and cause higher workloads
• against which the heart must function so it can eject less blood. Increased
• aortic pressure is usually the result of increased peripheral vascular
• resistance (PVR), also called total peripheral resistance (TPR). In
• individuals with hypertension, increased PVR means that afterload is
• chronically elevated, resulting in increased ventricular workload and
• hypertrophy of the myocardium. In some individuals, changes in afterload are
• the result of aortic valvular disease

• Preload is the volume and associated pressure
• generated in the ventricle at the end of diastole (ventricular end-diastolic
• volume [VEDV] and pressure [VEDP]). Preload is determined by two
• primary factors: (1) the amount of venous return entering the ventricle during
• diastole, and (2) the blood left in the ventricle after systole (end-systolic
• volume). Venous return is dependent on blood volume and flow through the venous
• system and the atrioventricular valves. End-systolic volume is dependent on the
• strength of ventricular contraction and the resistance to ventricular emptying.

• The
• ventricle does not eject all the blood it contains, and the amount ejected per
• beat is called the ejection fraction. The ejection fraction can be
• estimated by echocardiography and is the stroke volume divided by the
• end-diastolic volume. The end-diastolic volume of the normal ventricle is about
• 70 to 80 ml/m2, and the stroke volume is about 40 to 60 ml/beat;
• thus the normal ejection fraction of the resting heart is about 60% to 75%. The
• ejection fraction is increased by factors that increase contractility (e.g.,
• sympathetic nervous system activity). A decrease in ejection fraction is a
• hallmark of ventricular failure. The effects of aging on cardiovascular function
• are summarized in Table
• 22-3.

• The
• factors that determine cardiac output are (1) preload, (2) afterload, (3)
• myocardial contractility, and (4) heart rate. Preload, afterload, and
• contractility affect stroke volume.

• Rhythmicity is the regular generation of an action
• potential by the heart's conduction system. The SA node sets the pace because
• normally it has the fastest rate. The SA node depolarizes spontaneously 60 to
• 100 times per minute. If the SA node is damaged, the AV node will become the
• heart's pacemaker at a rate of about 40 to 60 spontaneous depolarizations per
• minute. Eventually, however, conduction cells in the atria usually take over
• from the AV node. Purkinje fibers are capable of spontaneous depolarization but
• at a rate of only 30 to 40 beats/min

• Automaticity, or the property of generating
• spontaneous depolarization to threshold, enables the SA and AV nodes to
• generate cardiac action potentials without any stimulus. Cells capable of
• spontaneous depolarization are called automatic cells. Those of the
• cardiac conduction system can stimulate the heart to beat even when it is
• removed from the body.

• The
• normal electrocardiogram is recorded from electrical activity transmitted by
• skin electrodes and reflects the sum of all the cardiac action potentials (Figure 22-10).
• The P wave represents atrial depolarization. The PR interval is a
• measure of time from the onset of atrial activation to the onset of ventricular
• activation (normally 0.12 to 0.20 second). The PR interval represents the time
• necessary for electrical activity to travel from the sinus node through the
• atrium, AV node, and His-Purkinje system to activate ventricular myocardial
• cells. The QRS complex represents the sum of all ventricular muscle cell
• depolarizations. The configuration and amplitude of the QRS complex vary
• considerably among individuals. The duration is normally between 0.06 and 0.10
• second. During the ST interval, the entire ventricular myocardium is
• depolarized. The QT interval is sometimes called the “electrical
• systole” of the ventricles. It lasts about 0.4 second but varies inversely with
• the heart rate. The T wave represents ventricular repolarization.

• Normally,
• electrical impulses arise in the sinoatrial node (SA node, sinus node),
• which is often called the pacemaker of the heart. The SA node is located at the
• junction of the right atrium and superior vena cava, just superior to the
• tricuspid valve. The SA node is heavily innervated by both sympathetic and parasympathetic
• nerve fibers.4
• In the resting adult the SA node generates about 75 action potentials per
• minute.

• The branch of the systemic circulation that supplies the heart is termed the coronary
• circulation and consists of coronary arteries,

• The heart pumps blood through two separate circulatory systems: one to the lungs and one
• to all other parts of the body. Structures on the right side of the heart, or right heart, pump blood through the lungs. This system is termed the pulmonary
• circulation. The left side of the heart, or left heart, sends blood
• throughout the systemic circulation, which supplies all of the body
• except the lungs (Figure
• 22-1). These two systems are serially connected; thus the output of
• one becomes the input of the other.

Abnormal movement from one side of the heart to the other is termed a shunt. Shunting of blood flow from the left heart into the right heart is called a left-to-right shunt and occurs in conditions such as atrial septal defect and ventricular septal defect

• Incidence of congenital heart disease 50% 
• Common defects AVSD, VSD

• Upper respiratory tract mucosa:
• Maintains constant temperature and humidification of gas entering lungs; traps and removes foreign particles, some bacteria, and noxious gases from inspired air
• Nasal hairs and turbinates:
• Trap and remove foreign particles, some bacteria, and noxious gases from inspired air
• Mucous blanket:
• Protects trachea and bronchi from injury; traps most foreign particles and bacteria that reach lower airways
• Cilia:
• Propel mucous blanket and entrapped particles toward oropharynx, where they can be swallowed or expectorated
• Alveolar macrophages:
• Ingest and remove bacteria and other foreign material from alveoli by phagocytosis
• Irritant receptors in nares (nostrils):
• Stimulation by chemical or mechanical irritants triggers sneeze reflex, which results in rapid removal of irritants from nasal passages
• Irritant receptors in trachea and large airways
• Stimulation by chemical or mechanical irritants triggers cough reflex, which results in removal of irritants from lower airways

The membrane covering the lungs is the visceral pleura; that lining the thoracic cavity is the parietal pleura. The area between the two pleurae is called the pleural space, or pleural cavity. Normally, only a thin layer of fluid secreted by the pleura (pleural fluid) fills the pleural space, lubricating the pleural surfaces and allowing the two layers to slide over each other without separating. Pressure in the pleural space is usually negative or subatmospheric

Ventilation is the mechanical movement of gas or air into and out of the lungs. It is often misnamed respiration, which is actually the exchange of oxygen and carbon dioxide during cellular metabolism.

Breathing is usually involuntary, because homeostatic changes in ventilatory rate and volume are adjusted automatically by the nervous system to maintain normal gas exchange. Voluntary breathing is necessary for talking, singing, laughing, and deliberately holding one's breath. The mechanisms that control respiration are complex

• The major muscles of inspiration are the diaphragm and the external intercostal muscles (muscles between the ribs) (Figure 25-10). The diaphragm is a dome-shaped muscle that separates the abdominal and thoracic cavities. When it contracts and flattens downward, it increases the volume of the thoracic cavity, creating a negative pressure that draws gas into the lungs through the upper airways and trachea. Contraction of external intercostal muscles elevates the anterior portion of the ribs and increases the volume of the thoracic cavity by increasing its front-to-back (anterior-posterior [AP]) diameter. Although the external intercostals may contract during quiet breathing, inspiration at rest is usually assisted by the diaphragm only.
• The accessory muscles of inspiration are the sternocleidomastoid and scalene muscles. Like the external intercostals, these muscles enlarge the thorax by increasing its AP diameter. The accessory muscles assist inspiration when minute volume (volume of air inspired and expired per minute) is high, as during strenuous exercise, or when the work of breathing is increased because of disease. The accessory muscles do not increase the volume of the thorax as efficiently as the diaphragm does.
• There are no major muscles of expiration because normal, relaxed expiration is passive and requires no muscular effort. The accessory muscles of expiration, the abdominal and internal intercostal muscles, assist expiration when minute volume is high, during coughing, or when airway obstruction is present. When the abdominal muscles contract, intra-abdominal pressure increases, pushing up the diaphragm and decreasing the volume of the thorax. The internal intercostal muscles pull down the anterior ribs, decreasing the AP diameter of the thorax.

Alveolar ventilation, or distention, is made possible by surfactant, which lowers surface tension by coating the air-liquid interface in the alveoli. Surfactant, a lipoprotein produced by type II alveolar cells, includes two groups of surfactant proteins. One group consists of small hydrophobic molecules that have a detergent-like effect that separates the liquid molecules, thereby decreasing alveolar surface tension.2,9 As the radius of a surfactant-lined sphere (alveolus) shrinks the surface tension decreases, and as the radius expands the surface tension increases. This occurs because the smaller radius causes surfactant molecules to crowd together and then repel one another strongly. A larger radius spreads them apart, decreasing their mutual repellence. Therefore normal alveoli are much easier to inflate at low lung volumes (i.e., after expiration) than at high volumes (i.e., after inspiration). The decrease in surface tension caused by surfactant also is responsible for keeping the alveoli free of fluid. If surfactant is not produced in adequate quantities, alveolar surface tension increases, causing alveolar collapse, decreased lung expansion, increased work of breathing, and severe gas-exchange abnormalities. The second group of surfactant proteins consists of large hydrophilic molecules called collectins that are capable of inhibiting foreign pathogens

The work of breathing is determined by the muscular effort (and therefore oxygen and energy) required for ventilation. Normally very low, the work of breathing may increase considerably in diseases that disrupt the equilibrium between forces exerted by the lung and chest wall. More muscular effort is required when lung compliance decreases (e.g., in pulmonary edema), chest wall compliance decreases (e.g., in spinal deformity or obesity), or airways are obstructed by bronchospasm or mucous plugging (e.g., in asthma or bronchitis). Pulmonary function tests (PFTs) measure lung volumes and flow rates and can be used to diagnose lung disease

• PaO2 Partial pressure of oxygen in arterial blood
• PaCO2 Partial pressure of carbon dioxide in arterial blood
• PvO2 Partial pressure of oxygen in mixed venous or pulmonary artery blood
• V/Q Ratio of ventilation to perfusion

Approximately 1000 ml (1 L) of oxygen is transported to the cells of the body each minute. Oxygen is transported in the blood in two forms: a small amount dissolves in plasma, and the remainder binds to hemoglobin molecules. Without hemoglobin, oxygen would not reach the cells in amounts sufficient to maintain normal metabolic function.

• The alveolocapillary membrane is ideal for oxygen diffusion because it has a large total surface area (70 to 100 m2) and is very thin (0.5 micrometer [μm]). In addition, the partial pressure of oxygen molecules in alveolar gas (PAo2) is much greater than that in capillary blood, a condition that promotes rapid diffusion down the concentration gradient from the alveolus into the capillary. The partial pressure of oxygen (oxygen tension) in mixed venous or pulmonary artery blood (Pvo2) is approximately 40 mm Hg as it enters the capillary, and alveolar oxygen tension (PAo2) is approximately 100 mm Hg at sea level. Therefore, a pressure gradient of 60 mm Hg facilitates the diffusion of oxygen from the alveolus into the capillary (Figure 25-16).
• Blood remains in the pulmonary capillary for about 0.75 second, but only 0.25 second is required for oxygen concentration to equilibrate (equalize) across the alveolocapillary membrane. Therefore oxygen has ample time to diffuse into the blood, even during increased cardiac output, which speeds blood flow and shortens the time the blood remains in the capillary.

The oxyhemoglobin dissociation curve is shifted to the right by acidosis (low pH) and hypercapnia (increased Paco2). In the tissues, the increased levels of carbon dioxide and hydrogen ions produced by metabolic activity decrease the affinity of hemoglobin for oxygen. The curve is shifted to the left by alkalosis (high pH) and hypocapnia (decreased Paco2). In the lungs, as carbon dioxide diffuses from the blood into the alveoli, the blood carbon dioxide level is reduced and the affinity of hemoglobin for oxygen is increased. The shift in the oxyhemoglobin dissociation curve caused by changes in carbon dioxide and hydrogen ion concentrations in the blood is called the Bohr effect.

• Dyspnea is defined as “a subjective experience of breathing discomfort that is comprised of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and it may induce secondary physiological and behavioral responses.”1 It is often described as breathlessness, air hunger, shortness of breath, labored breathing, and preoccupation with breathing. Dyspnea may be the result of pulmonary disease, or many other conditions such as pain, heart disease, trauma, and anxiety.2
• In pulmonary conditions, the severity of the experience of dyspnea may not directly correlate with the severity of underlying disease. Either diffuse or focal disturbances of ventilation, gas exchange, or ventilation-perfusion relationships can cause dyspnea, as can increased work of breathing or any disease that damages lung tissue (lung parenchyma). One proposed mechanism for dyspnea involves an impaired sense of effort where the perceived work of breathing is greater than the actual motor response that is generated. Stimulation of many receptors can contribute to the sensation of dyspnea, including mechanoreceptors in the chest wall, upper airway receptors, and central and peripheral chemoreceptors.3
• The signs of dyspnea include flaring of the nostrils, use of accessory muscles of respiration, and retraction (pulling back) of the intercostal spaces. In dyspnea caused by parenchymal disease (e.g., pneumonia), retractions of tissue between the ribs (subcostal and intercostal retractions) may be observed, more commonly in children. In upper airway  obstruction, supercostal retractions (retractions of tissues above the ribs) predominate. Dyspnea can be quantified by the use of both ordinal rating scales and visual analog scales and is frequently associated with significant anxiety.
• Dyspnea may occur transiently or can become chronic. Often the first episode occurs with exercise and is called dyspnea on exertion. This type of dyspnea is common to many pulmonary disorders. Orthopnea is dyspnea that occurs when an individual lies flat and is common in individuals with heart failure. The recumbent position redistributes body water, causes the abdominal contents to exert pressure on the diaphragm, and decreases the efficiency of the respiratory muscles. Sitting in a forward-leaning posture or supporting the upper body on several pillows generally relieves orthopnea. Some individuals with pulmonary or cardiac disease awake at night gasping for air and have to sit or stand to relieve the dyspnea (paroxysmal nocturnal dyspnea [PND]).

Cough is a protective reflex that helps clear the airways by an explosive expiration. Inhaled particles, accumulated mucus, inflammation, or the presence of a foreign body initiates the cough reflex by stimulating the irritant receptors in the airway. There are few such receptors in the most distal bronchi and the alveoli; thus it is possible for significant amounts of secretions to accumulate in the distal respiratory tree without cough being initiated. The cough reflex consists of inspiration, closure of the glottis and vocal cords, contraction of the expiratory muscles, and reopening of the glottis, causing a sudden, forceful expiration that removes the offending matter. The effectiveness of the cough depends on the depth of the inspiration and the degree to which the airways narrow, increasing the velocity of expiratory gas flow. Cough occurs frequently in healthy individuals; however, those with an inability to cough effectively are at greater risk for pneumonia.

Acute cough is cough that resolves within 2 to 3 weeks of the onset of illness or resolves with treatment of the underlying condition. It is most commonly the result of upper respiratory tract infections, allergic rhinitis, acute bronchitis, pneumonia, congestive heart failure, pulmonary embolus, or aspiration. Chronic cough is defined as cough that has persisted for more than 3 weeks, although 7 or 8 weeks may be a more appropriate timeframe because acute cough and bronchial hyperreactivity can be prolonged in some cases of viral infection. In individuals who do not smoke, chronic cough is commonly caused by postnasal drainage syndrome, nonasthmatic eosinophilic bronchitis, asthma, or gastroesophageal reflux disease. In persons who smoke, chronic bronchitis is the most common cause of chronic cough, although lung cancer must always be considered. Up to 33% of individuals taking angiotensin-converting enzyme inhibitors for cardiovascular disease develop chronic cough that resolves with discontinuation of the drug.

• Hemoptysis is the expectoration of blood or bloody secretions. This is sometimes confused with hematemesis, which is the vomiting of blood. Blood produced with coughing is usually bright red, has an alkaline pH, and is mixed with frothy sputum. Blood that is vomited is dark, has an acidic pH, and is mixed with food particles.
• Hemoptysis usually indicates infection or inflammation that damages the bronchi (bronchitis, bronchiectasis) or the lung parenchyma (pneumonia, tuberculosis, lung abscess). Other causes include cancer and pulmonary infarction. The amount and duration of bleeding provide important clues about its source. Bronchoscopy, combined with chest computed tomography (CT), is used to confirm the site of bleeding.

Hypoventilation is inadequate alveolar ventilation in relation to metabolic demands. Hypoventilation occurs when minute volume (tidal volume times respiratory rate) is reduced. It is caused by alterations in pulmonary mechanics or in the neurologic control of breathing.4 When alveolar ventilation is normal, carbon dioxide (CO2) is removed from the lungs at the same rate as it is produced by cellular metabolism; therefore arterial and alveolar Pco2 values remain at normal levels (40 mm Hg). With hypoventilation, CO2 removal is slower than CO2 production and the level of CO2 in the arterial blood (Paco2) increases, causing hypercapnia (Paco2 greater than 44 mm Hg) (see Table 25-2 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.3 Pronounced hypoventilation can cause somnolence or disorientation.

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. Increased respiratory rate or tidal volume can occur with severe anxiety, acute head injury, pain, and in response to conditions that cause insufficient oxygenation of the blood.

• Cyanosis is a bluish discoloration of the skin and mucous membranes caused by increasing amounts of desaturated or reduced hemoglobin (which is bluish) in the blood. It generally develops when 5 g of hemoglobin is desaturated, regardless of hemoglobin concentration.
• Peripheral cyanosis (slow blood circulation in fingers and toes) is most often caused by poor circulation resulting from intense peripheral vasoconstriction, such as that observed in persons who have Raynaud disease, are in cold environments, or are severely stressed. Peripheral cyanosis is best observed in the nail beds. Central cyanosis is caused by decreased arterial oxygenation (low Pao2) from pulmonary diseases or pulmonary or cardiac right-to-left shunts. Central cyanosis is best detected in buccal mucous membranes and lips.
• Lack of cyanosis does not necessarily indicate that oxygenation is normal. In adults, cyanosis is not evident until severe hypoxemia is present and, therefore, is an insensitive indication of respiratory failure. Severe anemia (inadequate hemoglobin concentration) and carbon monoxide poisoning (in which hemoglobin binds to carbon monoxide instead of to oxygen) can cause inadequate oxygenation of tissues without causing cyanosis. Individuals with polycythemia (an abnormal increase in numbers of red blood cells), however, may have cyanosis when oxygenation is adequate. Therefore, cyanosis must be interpreted in relation to the underlying pathophysiologic condition. If cyanosis is suggested, the Pao2 should be measured.

Clubbing is the selective bulbous enlargement of the end (distal segment) of a digit (finger or toe) (Figure 26-1); its severity can be graded from 1 to 5 based on the extent of nail bed hypertrophy and the amount of changes in the nails themselves or as early, moderate or severe. It is usually painless. Clubbing is commonly associated with diseases that cause chronic hypoxemia, such as bronchiectasis, cystic fibrosis, pulmonary fibrosis, lung abscess, and congenital heart disease. It can sometimes be seen in individuals with lung cancer even without hypoxemia because of the effects of inflammatory cytokines and growth factors (hypertrophic osteoarthropathy)

Hypercapnia, or increased carbon dioxide concentration in the arterial blood (increased Paco2), is caused by hypoventilation of the alveoli. As discussed in Chapter 25, carbon dioxide is easily diffused from the blood into the alveolar space; thus, minute volume (respiratory rate times tidal volume) determines not only alveolar ventilation but also Paco2. Hypoventilation is often overlooked because the breathing pattern and ventilatory rate may appear to be normal; therefore it is important to obtain blood gas analysis to determine the severity of hypercapnia and resultant respiratory acidosis

Hypoxemia, or reduced oxygenation of arterial blood (reduced Pao2), is caused by respiratory alterations, whereas hypoxia, or reduced oxygenation of cells in tissues, may be caused by alterations of other systems as well. 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.

• Respiratory failure is defined as inadequate gas exchange such that Pao2 ≤50 mm Hg or Paco2 ≥50 mm Hg with pH ≤7.25. Respiratory failure can result from direct injury to the lungs, airways, or chest wall or indirectly because of injury to another body system, such as the brain or spinal cord. 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 or mechanical ventilator. 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.
• 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, chronic renal failure, chronic hepatic disease, and infection also increase the tendency to develop postoperative respiratory failure.
• Prevention of postoperative respiratory failure includes frequent 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 for a time.

Pneumothorax is the presence of air or gas in the pleural space caused by a rupture in the visceral pleura (which surrounds the lungs) or the parietal pleura and chest wall. As air separates the visceral and parietal pleurae, it destroys the negative pressure of the pleural space and disrupts the equilibrium between elastic recoil forces of the lung and chest wall. The lung then tends to recoil by collapsing toward the hilum

Primary (spontaneous) pneumothorax, which occurs unexpectedly in healthy individuals (usually men) between 20 and 40 years of age, is caused by the spontaneous rupture of blebs (blister-like formations) on the visceral pleura. Bleb rupture can occur during sleep, rest, or exercise. The ruptured blebs are usually located in the apices of the lungs. The cause of bleb formation is not known, although more than 80% of these individuals have been found to have emphysema-like changes in their lungs even if they have no history of smoking or no known genetic disorder. Approximately 10% of affected individuals have a significant family history of primary pneumothorax that has been linked to mutations in the folliculin gene

• Pleural effusion is the presence of fluid in the pleural space. The most common mechanism of pleural effusion is migration of fluids and other blood components through the walls of intact capillaries bordering the pleura. Pleural effusions that enter the pleural space from intact blood vessels can be transudative (watery) or exudative (high concentrations of white blood cells and plasma proteins). Other types of pleural effusion are characterized by the presence of microorganisms (empyema), blood (hemothorax), or chyle (chylothorax). Mechanisms of pleural effusion are summarized in Table 26-1.
• Small collections of fluid may not affect lung function and may remain undetected. Most will be removed by the lymphatic system once the underlying condition is resolved. Dyspnea, compression atelectasis with impaired ventilation, and pleural pain are common. Mediastinal shift and cardiovascular manifestations occur in a large, rapidly developing effusion. Physical examination shows decreased breath sounds and dullness to percussion on the affected side. A pleural friction rub can be heard over areas of inflamed pleura.
• Diagnosis is confirmed by chest x-ray and thoracentesis (needle aspiration), which can determine the type of effusion and provide symptomatic relief. If the effusion is large, drainage usually requires the placement of a chest tube and surgical interventions may be needed to prevent recurrence of the effusion

• Empyema (infected pleural effusion) is the presence of microorganisms and cellular debris (pus) in the pleural space. Empyema occurs most commonly in older adults and children and usually develops as a complication of pneumonia, surgery, trauma, or bronchial obstruction from a tumor. Commonly documented infectious organisms include Staphylococcus aureus, Escherichia coli, anaerobic bacteria, and Klebsiella pneumoniae.
• Individuals with empyema present clinically with cyanosis, fever, tachycardia (rapid heart rate), cough, and pleural pain. Breath sounds are decreased directly over the empyema. Diagnosis is made by chest radiographs, thoracentesis, and sputum culture. The treatment for empyema includes the administration of appropriate antimicrobials and drainage of the pleural space with a chest tube. In severe cases, ultrasound-guided pleural drainage, instillation of fibrinolytic agents, or introduction of deoxyribonuclease (DNase) into the pleural space is needed for adequate drainage

Restrictive lung diseases are characterized by decreased compliance of the lung tissue. This means that it takes more effort to expand the lungs during inspiration, which increases the work of breathing. Individuals with lung restriction complain of dyspnea and have an increased respiratory rate and decreased tidal volume. Pulmonary function testing discloses a decrease in forced vital capacity (FVC). Restrictive lung diseases commonly cause mismatch and affect the alveolocapillary membrane, which reduces the diffusion of oxygen from the alveoli into the blood and leads to hypoxemia. Some of the most common restrictive lung diseases in adults are aspiration, atelectasis, bronchiectasis, bronchiolitis, pulmonary fibrosis, inhalational disorders, pneumoconiosis, allergic alveolitis, pulmonary edema, and acute respiratory distress syndrome.

• Aspiration is the passage of fluid and solid particles into the lung. It tends to occur in individuals whose normal swallowing mechanism and cough reflex are impaired by central or peripheral nervous system abnormalities. Predisposing factors include an altered level of consciousness caused by substance abuse, sedation, or anesthesia; seizure disorders; cerebrovascular accident; and neuromuscular disorders that cause dysphagia. Elderly individuals also are at increased risk for aspiration.12 The right lung, particularly the right lower lobe, is more susceptible to aspiration than the left lung because the branching angle of the right main stem bronchus is straighter than the branching angle of the left main stem bronchus.
• The aspiration of large food particles or foreign bodies can obstruct a bronchus, resulting in bronchial inflammation and collapse of airways distal to the obstruction. Clinical manifestations include the sudden onset of choking, coughing, vomiting, dyspnea, and wheezing. If the aspirated solid is not identified and removed by bronchoscopy, a chronic, local inflammation develops that may lead to recurrent infection and bronchiectasis (permanent dilation of the bronchus). Once the pathologic process has progressed to bronchiectasis, surgical resection of the affected area is usually required.
• Aspiration of acidic gastric fluid (pH <2.5) may cause severe pneumonitis (lung inflammation). Bronchial damage includes inflammation, loss of ciliary function, and bronchospasm. In the alveoli, acidic fluid damages the alveolocapillary membrane, allowing plasma and blood cells to move from capillaries into the alveoli, resulting in hemorrhagic pneumonitis. The lung becomes stiff and noncompliant as surfactant production is disrupted, leading to further edema and collapse.

• Pulmonary fibrosis is an excessive amount of fibrous or connective tissue in the lung. The most common form has no known cause and therefore is called idiopathic pulmonary fibrosis. Pulmonary fibrosis also can be caused by formation of scar tissue after active pulmonary disease (e.g., acute respiratory distress syndrome, tuberculosis), in association with a variety of autoimmune disorders (e.g., rheumatoid arthritis, progressive systemic sclerosis, sarcoidosis), or by inhalation of harmful substances (e.g., coal dust, asbestos).
• Fibrosis causes a marked loss of lung compliance. The lung becomes stiff and difficult to ventilate, and the diffusing capacity of the alveolocapillary membrane may decrease, causing hypoxemia. Diffuse pulmonary fibrosis has a poor prognosis.

Pneumoconiosis represents any change in the lung caused by inhalation of inorganic dust particles, usually in the workplace. As in all cases of environmentally acquired lung disease, the individual's history of exposure is important in determining the diagnosis. Pneumoconiosis often occurs after years of exposure to the offending dust, with progressive fibrosis of lung tissue.

• The most common cause of pulmonary edema is left-sided heart disease. When the left ventricle fails, filling pressures on the left side of the heart increase. Vascular volume redistributes into the lungs, causing an increase in pulmonary capillary hydrostatic pressure. When the hydrostatic pressure exceeds oncotic pressure (which holds fluid in the capillary), fluid moves out into the interstitial space (the space within the alveolar septum between alveolus and capillary). When the flow of fluid out of the capillaries exceeds the lymphatic system's ability to remove it, pulmonary edema develops.
• Another cause of pulmonary edema is capillary injury that increases capillary permeability, as in cases of acute respiratory distress syndrome or inhalation of toxic gases, such as ammonia. Capillary injury and inflammation causes water and plasma proteins to leak out of the capillary and move into the interstitial space, increasing the interstitial oncotic pressure (which is usually very low). As the interstitial oncotic pressure begins to exceed capillary oncotic pressure, water moves out of the capillary and into the lung. (This phenomenon is discussed in Chapter 4, Figures 4-1 and 4-2.) Pulmonary edema also can result from obstruction of the lymphatic system. Drainage can be blocked by compression of lymphatic vessels by edema, tumors, and fibrotic tissue and by increased systemic venous pressure.

Acute respiratory distress syndrome (ARDS) is characterized by acute lung inflammation and diffuse alveolocapillary injury. Acute lung injury (ALI) is a less severe form of lung inflammation. Both ARDS and ALI are defined as (1) the acute onset of bilateral infiltrates on chest radiograph, (2) a low ratio of partial pressure of arterial oxygen to the fraction of inhaled oxygen, and (3) the absence of clinical evidence of left atrial hypertension.22 In the United States more than 30% of intensive care unit (ICU) admissions are complicated by ARDS. Advances in therapy have decreased overall mortality in people younger than 60 years to approximately 40%, although mortality in older adults and those with severe infections remains much higher. The most common predisposing factors are sepsis and multiple trauma; however, there are many other causes, including pneumonia, burns, aspiration, cardiopulmonary bypass surgery, pancreatitis, blood transfusions, drug overdose, inhalation of smoke or noxious gases, fat emboli, high concentrations of supplemental oxygen, radiation therapy, and disseminated intravascular coagulation.

Obstructive lung disease is characterized by airway obstruction that is worse with expiration. More force (i.e., use of accessory muscles of expiration) is required to expire a given volume of air and emptying of the lungs is slowed. In adults the major obstructive lung diseases are asthma, chronic bronchitis, and emphysema. Asthma is one of the most common lung disorders in the United States. Because many individuals have both chronic bronchitis and emphysema, these diseases together are often called chronic obstructive pulmonary disease (COPD). Asthma is more acute and intermittent than COPD, even though it can be chronic (Figure 26-8). The unifying symptom of obstructive lung diseases is dyspnea, and the unifying sign is wheezing. Individuals have an increased work of breathing, ventilation-perfusion mismatching, and a decreased forced expiratory volume in 1 second (FEV1).

• Asthma is a chronic inflammatory disorder of the bronchial mucosa that causes hyperresponsiveness and constriction of the airways.28 Asthma occurs at all ages, with approximately half of all cases developing during childhood (see Chapter 27) and another third before age 40. In the United States asthma has been diagnosed in more than 34 million persons.29 Death rates have declined since 1995 in the United States but the incidence of asthma has increased, especially in urban areas.
• Asthma is a familial disorder, and more than 100 genes have been identified that may play a role in the susceptibility and pathogenesis of asthma, including those that influence the production of interleukin-4 (IL-4) and interleukin-5 (IL-5), immunoglobulin E (IgE), eosinophils, mast cells, and β-adrenergic receptors as well as those that increase bronchial hyperresponsiveness.30 The expression of these genetic factors is influenced by other risk factors including age at onset of disease; levels of allergen exposure; urban residence; exposure to air pollution, tobacco smoke, and environmental tobacco smoke; recurrent respiratory tract viral infections; gastroesophageal reflux disease; and obesity.28,31,32 There is considerable evidence that exposure to high levels of certain allergens during childhood increases the risk for asthma. Furthermore, decreased exposure to certain infectious organisms appears to create an immunologic imbalance that favors the development of allergy and asthma. This complex relationship has been called the hygiene hypothesis.33 Urban exposure to pollution and cockroaches, decreased exercise, and increased obesity play a role in the increasing prevalence of asthma, particularly in children.
• Pathophysiology
• Many cells and cellular elements contribute to the persistent inflammation of the bronchial mucosa and hyperresponsiveness of the airways, including mast cells, eosinophils, basophils, macrophages (dendritic cells), neutrophils, and lymphocytes. Inflammatory mediators released by these cells increase capillary permeability and stimulate smooth muscle contraction and increased secretion of mucus. Airway epithelial exposure to antigen initiates both an innate and an adaptive immune response (type I hypersensitivity) in sensitized individuals (see Chapter 7).34,35 There is both an immediate (acute asthmatic response) and a late (delayed) response.
• During the early asthmatic response antigen exposure to the bronchial mucosa activates B cells (plasma cells) to produce antigen-specific IgE. Cross-linking of IgE molecules with the antigen on the surface of mast cells causes mast cell degranulation with the release of inflammatory mediators including histamine, bradykinins, leukotrienes and prostaglandins, platelet activating factor, and interleukins (see Figures 5-8 and 7-9 for additional details).35 These mediators cause vasodilation, increased capillary permeability, mucosal edema, bronchial smooth muscle contraction (bronchospasm), and mucus secretion from mucosal goblet cells with narrowing of the airways and obstruction to airflow (see Figures 26-8 and 27-7, A).36 Other inflammatory cytokines, such as TNF and IL-1, have been found to alter muscarinic receptor function and lead to increased levels of acetylcholine, which cause bronchial smooth muscle contraction and mucus secretion. The late asthmatic response begins 4 to 8 hours after the early response (see Figure 27-7, B). Chemotactic recruitment of neutrophils, eosinophils, and lymphocytes during the acute response causes a latent release of inflammatory mediators, again inciting bronchospasm, edema, and mucus secretion with obstruction to airflow. Synthesis of leukotrienes contributes to prolonged smooth muscle contraction. Eosinophils cause direct tissue injury with fibroblast proliferation and airway scarring. Release of toxic neuropeptides contributes to increased bronchial hyperresponsiveness. Damage to ciliated epithelial cells contributes to impaired mucociliary function, with the accumulation of mucus and cellular debris forming plugs in the airways (see Figures 26-9 and 27-7 for additional details).35,37 Untreated inflammation can lead to long-term airway damage that is irreversible, known as airway remodeling (subepithelial fibrosis, smooth muscle hypertrophy).38
• Airway obstruction increases resistance to airflow and decreases flow rates, especially expiratory flow. Impaired expiration causes air trapping, hyperinflation distal to obstructions, and increased work of breathing. Changes in resistance to airflow are not uniform throughout the lungs and the distribution of inspired air is uneven, with more air flowing to the less resistant portions. Continued air trapping increases intrapleural and alveolar gas pressures and causes decreased perfusion of the alveoli. Increased alveolar gas pressure, decreased ventilation, and decreased perfusion lead to variable and uneven ventilation-perfusion relationships within different lung segments. Hyperventilation is triggered by lung receptors responding to increased lung volume and obstruction. The result is early hypoxemia without CO2 retention. Hypoxemia further increases hyperventilation through stimulation of the respiratory center, causing Paco2 to decrease and pH to increase (respiratory alkalosis). With progressive obstruction of expiratory airflow, air trapping becomes more severe and the lungs and thorax become hyperexpanded, positioning the respiratory muscles at a mechanical disadvantage. This leads to a fall in tidal volume with increasing CO2 retention and respiratory acidosis. Respiratory acidosis signals respiratory failure, especially when left ventricular filling, and thus cardiac output, becomes compromised because of severe hyperinflation.

If bronchospasm is not reversed by usual measures, the individual is considered to have severe bronchospasm or status asthmaticus. If status asthmaticus continues, hypoxemia worsens, expiratory flows and volumes decrease further, and effective ventilation decreases. Acidosis develops as Paco2 level begins to rise. Asthma becomes life-threatening at this point if treatment does not reverse this process quickly. A silent chest (no audible air movement) and a Paco2 >70 mm Hg are ominous signs of impending death.

• The diagnosis of asthma is supported by a history of allergies and recurrent episodes of wheezing, dyspnea, and cough or exercise intolerance. Further evaluation includes spirometry, which may document reversible decreases in FEV1 during an induced attack.
• The evaluation of an acute asthma attack requires the rapid assessment of arterial blood gases and expiratory flow rates (using a peak flow meter) and a search for underlying triggers, such as infection. Hypoxemia and respiratory alkalosis are expected early in the course of an acute attack. The development of hypercapnia with respiratory acidosis signals the need for mechanical ventilation. Management of the acute asthma attack requires immediate administration of oxygen and inhaled beta-agonist bronchodilators. In addition, oral corticosteroids should be administered early in the course of management. Careful monitoring of gas exchange and airway obstruction in response to therapy provides information necessary to determine whether hospitalization is necessary. Antibiotics are not indicated for acute asthma unless there is a documented bacterial infection.39
• Management of asthma begins with avoidance of allergens and irritants. Individuals with asthma tend to underestimate the severity of their asthma and extensive education is important, including use of a peak flow meter and adherence to an action plan should symptoms worsen. In the mildest form of asthma (intermittent), short-acting beta-agonist inhalers are prescribed. For all categories of persistent asthma, anti-inflammatory medications are essential and inhaled corticosteroids are the mainstay of therapy. In individuals who are not adequately controlled with inhaled corticosteroids, leukotriene antagonists can be considered. In more severe asthma, long-acting beta agonists can be used to control persistent bronchospasm; however, these agonists can actually worsen asthma in some individuals with certain genetic polymorphisms (see Health Alert: Pharmacogenetics and Beta Agonists in the Treatment of Asthma). Immunotherapy has been shown to be an important tool in reducing asthma exacerbations and can now be given sublingually.40 Monoclonal antibodies to IgE (omalizumab) have been found to be helpful in selected individuals. The National Asthma Education and Prevention Program offers stepwise guidelines for the diagnosis and management of chronic asthma based on clinical severity and they may be reviewed at www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.

Chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.

Long-acting beta agonists (LABAs) (salmeterol and formoterol) are recommended by the National Asthma Education and Prevention Program (NAEPP) to be used in conjunction with inhaled corticosteroids as step 3 therapy for asthma. LABAs have been found to improve symptoms in many individuals and exert both a bronchodilatory and an anti-inflammatory effect on the airways. However, the safety of LABAs has been questioned because of increased mortality in some populations using these drugs. Recent evidence suggests that the reason for this increased mortality is that those individuals who exhibited worsening symptoms while taking LABAs used these medications alone, instead of in conjunction with inhaled steroids as recommended. Thus they were simply masking ongoing inflammation and airway damage. There also is some evidence to suggest that persons who have a polymorphism of the beta-adrenergic receptor gene (ADRβ2) are at risk for complications if they use LABAs. This polymorphism is known as the Arg16Arg genotype and is associated with an increased risk for worsening bronchospasm, increased hospitalizations, and increased mortality when using LABAs. This genotype occurs more frequently in blacks and may explain some of the differences in asthma mortality among these individuals. Studies continue to evaluate other genes and their relationship to medication response, a field of study now known as pharmacogenetics.

• Pneumonia is infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa, or parasites. It is the sixth leading cause of death in the United States. The incidence and mortality of pneumonia are highest in the elderly. Risk factors for pneumonia include advanced age, compromised immunity, underlying lung disease, alcoholism, altered consciousness, impaired swallowing, smoking, endotracheal intubation, malnutrition, immobilization, underlying cardiac or liver disease, and residence in a nursing home. Individuals who live in poverty also are at significantly increased risk for pneumonia.49 The causative microorganism influences how the individual presents clinically, how the pneumonia should be treated, and the prognosis. Community-acquired pneumonia (CAP) tends to be caused by different microorganisms as compared with those infections acquired in the hospital (nosocomial). In addition, the characteristics of the individual are important in determining which etiologic microorganism is likely; for example, immunocompromised individuals tend to be susceptible to opportunistic infections that are uncommon in normal adults. In general, nosocomial infections and those affecting immunocompromised individuals have a higher mortality than CAPs. Some of the most common causal microorganisms are included in the list at the top of p. 695.
• The most common community-acquired pneumonia is caused by Streptococcus pneumoniae (also known as pneumococcus), which results in hospitalization in more than half of affected individuals and an overall hospital mortality of 10%.50 Mycoplasma pneumoniae is a common cause of pneumonia in young people, especially those living in group housing such as dormitories and army barracks. Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is becoming more common.51,52 Influenza and respiratory syncytial virus are the most common causes of viral community-acquired pneumonia in adults.53 Nosocomial pneumonia is a frequent complication in the intensive care unit, most often in persons placed on mechanical ventilation (ventilator-associated pneumonia [VAP]) (see Health Alert: Ventilator-Associated Pneumonia [VAP]). Pseudomonas aeruginosa, other gram-negative microorganisms, and Staphylococcus aureus (including MRSA) are the most common etiologic agents in nosocomial pneumonia. Immunocompromised individuals (e.g., those with human immunodeficiency virus [HIV] or those undergoing organ transplantation) are especially susceptible to Pneumocystis jiroveci (formerly called P. carinii), mycobacterial infections, and fungal infections of the respiratory tract. These infections can be difficult to treat and have a high mortality.

• Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, an acid-fast bacillus that usually affects the lungs but may invade other body systems. Tuberculosis is the leading cause of death from a curable infectious disease in the world. TB cases increased greatly during the mid-1990s as a result of acquired immunodeficiency syndrome (AIDS). Emigration of infected individuals from high-prevalence countries, transmission in crowded institutional settings, homelessness, substance abuse, and lack of access to medical care also have contributed to the spread of TB.
• Tuberculosis is highly contagious and is transmitted from person to person in airborne droplets.59 In immunocompetent individuals, the microorganism is usually contained by the inflammatory and immune response systems. This results in latent TB infection (LTBI) and is associated with no clinical evidence of disease. Microorganisms lodge in the lung periphery, usually in the upper lobe. Some bacilli migrate through the lymphatics and become lodged in the lymph nodes, where they encounter lymphocytes and initiate the immune response.
• Once the bacilli are inspired into the lung, they multiply and cause localized nonspecific pneumonitis (lung inflammation). Inflammation in the lung causes activation of alveolar macrophages and neutrophils. These phagocytes engulf the bacilli and begin the process by which the body's defense mechanisms isolate the bacilli, preventing them from spreading. The neutrophils and macrophages seal off the colonies of bacilli, forming a granulomatous lesion called a tubercle (see Chapter 5). Infected tissues within the tubercle die, forming cheeselike material called caseation necrosis. Collagenous scar tissue then grows around the tubercle, completing isolation of the bacilli. The immune response is complete after about 10 days, preventing further multiplication of the bacilli.
• Once the bacilli are isolated in tubercles and immunity develops, tuberculosis may remain dormant for life. If the immune system is impaired, reactivation with progressive disease occurs and may spread through the blood and lymphatics to other organs. Infection with human immunodeficiency virus (HIV) is the single greatest risk factor for reactivation of tuberculosis infection. Cancer, immunosuppressive medications (e.g., corticosteroids), poor nutritional status, and renal failure can also reactivate disease

LTBI is asymptomatic. Symptoms of active disease often develop so gradually that they are not noticed until the disease is advanced. Common clinical manifestations include fatigue, weight loss, lethargy, anorexia (loss of appetite), and a low-grade fever that usually occurs in the afternoon. A cough that produces purulent sputum develops slowly and becomes more frequent over several weeks or months. Night sweats and general anxiety are often present. Dyspnea, chest pain, and hemoptysis may occur as the disease progresses. Extrapulmonary TB disease is common in HIV-infected individuals and may cause neurologic deficits, meningitis symptoms, bone pain, and urinary symptoms.

• Tuberculosis is diagnosed by a positive tuberculin skin test (TST; purified protein derivative [PPD]), sputum culture, immunoassays, and chest radiographs.60 A positive skin test indicates the need for yearly chest radiographs to detect active disease. When active pulmonary disease is present, the tubercle bacillus can be cultured from the sputum and may be seen with an acid-fast stain. However, sputum culture can take up to 6 weeks to become positive.
• Treatment consists of antibiotic therapy to control active disease or prevent reactivation of LTBI. Recommended treatment includes a combination of as many as four different drugs to which the organism is susceptible. Side effects are common and new drugs are being explored.61 Two worrisome treatment categories of TB have become more prevalent in recent years. “Multidrug-resistant TB” now accounts for approximately 5% of cases worldwide. Even more concerning is the emergence of “extensively drug-resistant TB” for which finding effective treatment is even more difficult

Acute bronchitis is acute infection or inflammation of the airways or bronchi and is usually self-limiting. In the vast majority of cases, acute bronchitis is caused by viruses. Bacterial bronchitis is rare in healthy adults but is common in individuals with COPD. Although many of the clinical manifestations are similar to those of pneumonia (i.e., fever, cough, chills, malaise), chest radiographs show no infiltrates. Individuals with viral bronchitis present with a nonproductive cough that often occurs in paroxysms and is aggravated by cold, dry, or dusty air. In some cases, purulent sputum is produced. Chest pain often develops from the effort of coughing. Treatment consists of rest, aspirin, humidity, and a cough suppressant, such as codeine. Bacterial bronchitis is treated with rest, antipyretics, humidity, and antibiotics.

• 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 23). Other less common emboli include tissue fragments, lipids (fats), a foreign body, or an air bubble. Risk factors for PE include conditions and disorders that promote blood clotting 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, 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 impact or 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 occur as 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

• In most cases, the clinical manifestations of PE are nonspecific, so 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.
• 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.

• Routine chest radiographs and pulmonary function tests are not definitive for pulmonary embolism. 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 in combination with scanning using spiral computed tomography (CT). Serum brain natriuretic peptide levels are increased in PE and levels are correlated with the severity of associated hemodynamic complications.64
• Prevention of PE depends on 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 usually with low-molecular-weight heparin or warfarin. Newer medications such as the antithrombotics fondaparinux, idraparinux, and ximelagatran are superior to standard prevention in high-risk individuals undergoing orthopedic surgery.
• Anticoagulant therapy is the primary treatment for pulmonary embolism. Initial anticoagulant therapy usually includes low-molecular-weight heparins (e.g., enoxaparin), fondaparinux, or unfractionated heparin.64,65 If a massive life-threatening embolism occurs, a fibrinolytic agent, such as streptokinase, is sometimes used, and some individuals will require surgical thrombectomy. After stabilization, coumadin or low-molecular-weight heparin is continued for several months.

• Pulmonary hypertension is defined as a mean pulmonary artery pressure >25 mm Hg. Pulmonary hypertension is classified into several categories66:
• 1. Pulmonary arterial hypertension (PAH) that is idiopathic, heritable, drug or toxin induced (weight loss medications, amphetamines, cocaine), or associated with other conditions, such as HIV infection and collagen vascular diseases
• 2. Pulmonary hypertension associated with left heart diseases (discussed in Chapters 23 and 24)
• 3. Pulmonary hypertension associated with lung respiratory disease or hypoxia, or both
• 4. Chronic thromboembolic pulmonary hypertension
• 5. Pulmonary hypertension with unclear and/or multifactorial mechanisms

Cancer of the larynx represents approximately 2% to 3% of all cancers in the United States, with more than 12,000 new cases diagnosed in 2010.68 The primary risk factor for laryngeal cancer is tobacco smoking; risk is further heightened with the combination of smoking and alcohol consumption. The human papillomavirus (HPV) also has been linked to both benign and malignant disease of the larynx.69 The highest incidence is in men between 50 and 75 years of age.

• Lung cancers (bronchogenic carcinomas) arise from the epithelium of the respiratory tract. Therefore the term lung cancer excludes other pulmonary tumors, including sarcomas, lymphomas, blastomas, hematomas, and mesotheliomas. There were an estimated 222,000 new cases of lung cancer in the United States in 2010.68 It is the most common cause of cancer death in the United States and is responsible for 31% of all cancer deaths in men and 26% of all cancer deaths in women. Overall 5-year survival remains low at 20%.
• The most common cause of lung cancer is tobacco smoking. Smokers with obstructive lung disease (low FEV1 measurements) are at even greater risk. Other risk factors for lung cancer include secondhand (environmental) smoke, occupational exposures to certain workplace toxins, radiation, and air pollution. Genetic risks include polymorphisms of the genes responsible for growth factor receptors, DNA repair, and detoxification of inhaled smoke

Primary lung cancers arise from cells that line the bronchi within the lungs and are therefore called bronchogenic carcinomas. It is now believed that most of these cancers arise from mutated epithelial stem cells.72 Although there are many types of lung cancer, they can be divided into two major categories: non–small cell lung carcinoma (NSCLC) and neuroendocrine tumors of the lung. The category of non–small cell lung carcinoma accounts for 75% to 85% of all lung cancers and can be subdivided into three types of lung cancer: squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma. Neuroendocrine tumors of the lung arise from the bronchial mucosa and include: small cell carcinoma, large cell neuroendocrine carcinoma, typical carcinoid and atypical carcinoid tumors.73 Small cell carcinoma is the most common of these neuroendocrine tumors, accounting for 15% to 20% of all lung cancers. Characteristics of these tumors, including clinical manifestations, are listed in Table 26-3. Many cancers that arise in other organs of the body metastasize to the lungs; however, these are not considered lung cancers and are categorized by their primary site of origin.

Squamous cell carcinoma accounts for about 30% of bronchogenic carcinomas. These tumors are typically located near the hila and project into bronchi (Figure 26-18, A). Because of this central location, symptoms of nonproductive cough or hemoptysis are common. Pneumonia and atelectasis are often associated with squamous cell carcinoma (see Figure 26-18, A). Chest pain is a late symptom associated with large tumors. These tumors are often fairly well localized and tend not to metastasize until late in the course of the disease.

Large cell carcinomas constitute 10% to 15% of bronchogenic carcinomas. This cell type has lost all evidence of differentiation and is therefore sometimes referred to as undifferentiated large cell anaplastic  cancer. The cells are large and contain darkly stained nuclei. These tumors commonly arise centrally and can grow to distort the trachea and cause widening of the carina.

Small cell carcinomas are the most common type of neuroendocrine lung tumors. Most of these tumors are central in origin (Figure 26-18, C). Cell sizes range from 6 to 8 μm. Because these tumors show a rapid rate of growth and tend to metastasize early and widely, small cell carcinomas have the worst prognosis.

Diagnostic tests for the evaluation of lung cancer include chest x-ray, sputum cytologic studies, chest computed tomography, fiberoptic bronchoscopy, and biopsy. Low-dose helical computed tomography is emerging as a sensitive and specific diagnostic test. Biopsy determines the cell type, and the evaluation of lymph nodes and other organ systems is used to determine the stage of the cancer. The histologic cell type and the stage of the disease are the 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)

Although new chemotherapeutic agents have improved outcomes slightly in the management of lung cancer, overall survival rates remain poor and the toxicities of these regimens limit their use. New understandings of the genetic and immunologic features of lung cancer cells have led to new treatment options. Gene therapy is emerging as a way of restoring normal tumor-suppressor gene function (e.g., p53) and increasing tumor responsiveness to chemoradiation through gene transfer, restoring normal DNA methylation patterns, and altering microRNA function. Immunologic therapies include antibodies to epidermoid growth factor receptors (erlotinib, gefitinib, and cetuximab) and antiangiogenesis drugs. The effectiveness of these strategies is still being evaluated, but new knowledge is leading to opportunities for innovative treatment.

Disorders of the upper airways can cause significant obstruction to airflow. Common causes of upper airway obstruction in children are infections, foreign body aspiration, and obstructive sleep apnea.

Croup is an acute laryngotracheobronchitis and almost always occurs in children between 6 months and 5 years of age with a peak incidence at 2 years of age. In 85% of cases, croup is caused by a virus, most commonly parainfluenza and in other instances by influenza A, rhinovirus, or respiratory syncytial virus.2,3 The incidence of croup is higher in males and is most common during the winter months. Approximately 15% of affected children have a strong family history of croup.2 Spasmodic croup usually occurs in older children. The etiology is unknown although association with viruses, allergies, asthma, and gastroesophageal reflux disease (GERD) is being investigated.2,3 Bacterial laryngotracheitis is the most common potentially life-threatening upper airway infection in children. It is most often caused by Staphylococcus aureus (S. aureus) (including methicillin-resistant S. aureus [MRSA] strains), Haemophilus influenzae (H. influenzae), or group A beta-hemolytic Streptococcus (GABHS)

Typically, the child experiences rhinorrhea, sore throat, and low-grade fever for a few days, and then develops a harsh (seal-like) barking cough, inspiratory stridor, and hoarse voice. The quality of voice, cough, and stridor may suggest the location of the obstruction (Figure 27-3). Most cases resolve spontaneously within 24 to 48 hours and do not warrant hospital admission. A child with severe croup usually displays deep retractions (Figure 27-4), stridor, agitation, tachycardia, and sometimes pallor or cyanosis.

• Historically, acute epiglottitis was caused by H. influenzae type B. Since the advent of H. influenzae vaccine, the overall incidence of acute epiglottitis has been reduced by 80% to 90%; however, up to 25% of epiglottitis cases are still caused by nontypeable strains of H. influenzae.9 Current cases in children usually are related to vaccine failure or are caused by other pathogens, such as GABHS, Streptococcus pneumoniae, Candida species, S. aureus, MRSA, or viral pathogens.
• Pathophysiology
• The epiglottis arises from the posterior tongue base and covers the laryngeal inlet during swallowing. Bacterial invasion of the mucosa with associated inflammation leads to the rapid development of edema causing severe, life-threatening obstruction of the upper airway

Aspiration of foreign bodies (FBs) into the airways usually occurs in children 1 to 3 years of age. More than 100,000 cases occur each year.13 Most objects are expelled by the cough reflex, but some objects may lodge in the larynx, trachea, or bronchi. Large objects (e.g., a bite of hot dog, nuts, popcorn, grapes, beans, toy pieces, fragments of popped balloons, or coins) may occlude the airway and become life-threatening. Items of particular concern would be batteries and magnets. The aspiration event commonly is not witnessed or is not  recognized when it happens because the coughing, choking, or gagging symptoms may resolve quickly. Foreign bodies lodged in the larynx or upper trachea cause cough, stridor, hoarseness or inability to speak, respiratory distress, and agitation or panic; the presentation is often dramatic and frightening. If the child is acutely hypoxic and unable to move air, immediate action such as sweeping the oral airway or performing abdominal thrusts (formerly called the Heimlich maneuver) may be required to prevent tragedy. Otherwise, bronchoscopic removal should be performed urgently. If an aspirated foreign body is small enough, it will be transferred to a bronchus before becoming lodged. If the foreign body is lodged in the airway for a notable period of time, local irritation, granulation, obstruction, and infection will ensue. Thus children may present with cough or wheezing, atelectasis, pneumonia, lung abscess, or blood-streaked sputum. These children are treated by prompt bronchoscopic removal of the object and administration of antibiotics as necessary

• Obstructive sleep apnea syndrome (OSAS) is defined by partial or intermittent complete upper airway obstruction during sleep with disruption of normal ventilation and sleep patterns. Childhood OSAS is quite common, with an estimated prevalence of 2% to 3% of children 12 to 14 years of age and up to 13% of children between 3 and 6 years of age.15,16 Prevalence is estimated to be two to four times higher in vulnerable populations (blacks, Hispanics, and preterm infants).17 In children, unlike adults, OSAS occurs equally among girls and boys. Possible influences early in life may include passive smoke inhalation, socioeconomic status, and snoring together with genetic modifiers that promote airway inflammation. OSAS also is more likely to occur in children who have a history of a clinically significant episode of respiratory syncytial virus (RSV) bronchiolitis in infancy; this is believed to change the neuroimmunomodulatory pathways in the upper airway.18
• Pathophysiology
• By far the most common predisposing factor to OSAS in children is adenotonsillar hypertrophy, which causes physical impingement on the nasopharyngeal airway. OSAS also may occur in children who are overweight or obese, and in those with craniofacial anomalies (with structurally small nasopharyngeal airways) or reduced motor tone of the upper airways (as may be seen in neurologic disorders, cerebral palsy, and Down syndrome). Allergy and asthma also may contribute to this condition.
•  If obstructive sleep apnea is documented or strongly suspected clinically, children are most often referred for tonsillectomy and adenoidectomy (T & A) on the basis of described symptoms and physical findings, such as enlarged tonsils, adenoidal facies, and mouth breathing

Respiratory distress syndrome (RDS) of the newborn (previously also called hyaline membrane disease [HMD]) is a significant cause of neonatal morbidity and mortality.23 It occurs almost exclusively in premature infants and the incidence has increased in the United States over the past 2 decades.24 RDS occurs in 50% to 60% of infants born at 29 weeks’ gestation and decreases significantly by 36 weeks. Infants of diabetic mothers and those with cesarean delivery (especially elective C-section) also are more likely to develop RDS. It is more common in boys than girls and more common in whites than non-whites. Death rates have declined significantly since the introduction of antenatal steroid therapy and postnatal surfactant therapy. Risk factors are summarized in Risk Factors: Respiratory Distress Syndrome of the Newborn.