Aortic stenosis

Aortic stenosis is now the most common valvular abnormality, affecting nearly 2% of adults older than 65 years of age. It has three common causes:

FIGURE 23-45 Aortic stenosis.

A Normal aortic valve. B Congenital bicuspid aortic stenosis. C Rheumatic aortic stenosis. D Calcified degenerative aortic stenosis.

Source: A & D Manabe H, Yutani C (eds). Atlas of valvular heart disease. Singapore: Churchill Livingstone; 1998. B & C Courtesy of William C Roberts, MD.

Aortic valve degeneration with ageing is associated with lipoprotein deposition in the tissue with chronic inflammation and leaflet calcification.⁸⁰ The orifice of the aortic semilunar valve narrows, causing diminished blood flow from the left ventricle into the aorta. Outflow obstruction increases pressure within the left ventricle as it tries to eject blood through the narrowed opening.

Aortic stenosis tends to develop gradually. Clinical manifestations include decreased stroke volume, reduced systolic blood pressure and narrowed pulse pressure (the difference between systolic and diastolic pressure). Heart rate is often slow and pulses are faint. Left ventricular hypertrophy develops to compensate for the increased workload. Eventually, hypertrophy increases myocardial oxygen demand, which the coronary arteries may be unable to meet. In addition, aortic stenosis is frequently accompanied by atherosclerotic coronary disease, further contributing to inadequate coronary perfusion.⁸⁰

Untreated aortic stenosis can lead to arrhythmias, myocardial infarction and heart failure. Echocardiography can be used to assess the severity of valvular obstruction before the onset of symptoms, and management almost always includes valve replacement with a prosthetic valve (see Figure 23-46), followed by long-term anticoagulation and prophylaxis for endocarditis, as needed.

FIGURE 23-46 Various valve replacements.

A A porcine bioprosthesis. B A mechanical valve prosthesis of the tilting disc variety replacing the native mitral valve. C A mechanical valve prosthesis of the older ball-and-cage variety.

Source: Klatt EC. Robbins and Cotran atlas of pathology. 2nd edn. Philadelphia: Saunders; 2010.

Mitral stenosis

Mitral stenosis impairs the flow of blood from the left atrium to the left ventricle. Mitral stenosis is most commonly caused by rheumatic heart disease. In fact, when stenosed mitral valves are examined after removal for mitral valve replacement, almost all have evidence of rheumatic changes.⁸¹ In addition, mitral stenosis is two to three times more common in women than in men.⁸² Autoimmunity in response to group A β-haemolytic streptococcal protein antigens leads to inflammation and scarring of the valvular leaflets. Scarring causes the leaflets to become fibrous and fused and the chordae tendineae become shortened.

Impedance to blood flow results in incomplete emptying of the left atrium and elevated atrial pressure as the chamber tries to force blood through the stenotic valve. Continued increases in left atrial volume and pressure cause atrial dilation and hypertrophy. The risk of developing atrial arrhythmias (especially fibrillation) and arrhythmia-induced thrombi is high. As mitral stenosis progresses, symptoms of decreased cardiac output occur, especially during exertion. Continued elevation of left atrial pressure and volume causes pressure to rise in the pulmonary circulation. If untreated, chronic mitral stenosis develops into pulmonary hypertension, pulmonary oedema and right ventricular failure.

Management includes anticoagulation and endocarditis prophylaxis along with β-blockers or calcium channel blockers to slow the heart rate. Mitral stenosis can often be repaired surgically but may require valve replacement (usually porcine; see Figure 23-46A) in advanced cases.

Aortic regurgitation

Aortic regurgitation results from an inability of the aortic valve leaflets to close properly during diastole resulting from abnormalities of the leaflets or the aortic root and annulus, or both.⁸³ It can be congenital (bicuspid valve abnormalities) or acquired. Acquired aortic regurgitation can be caused by rheumatic heart disease, bacterial endocarditis, syphilis, hypertension, connective tissue disorders (e.g. Marfan’s syndrome), appetite-suppressing medications, trauma or atherosclerosis. In more than one-third of cases of aortic regurgitation there is no known cause.

The haemodynamic abnormalities depend on the size of the ‘leak’. During systole, blood is ejected from the left ventricle into the aorta. During diastole, some of the ejected blood flows back into the left ventricle. Volume overload occurs in the ventricle because it receives blood from both the left atrium and the aorta during diastole. Over time, the end-diastolic volume of the left ventricle increases and myocardial fibres stretch to accommodate the extra fluid. Compensatory dilation permits the left ventricle to increase its stroke volume and maintain cardiac output. Ventricular hypertrophy also occurs as an adaptation to the increased volume and because of increased afterload created by the high stroke volume and resultant systolic hypertension. Ventricular dilation and hypertrophy eventually cannot compensate for aortic incompetence and heart failure develops.

Clinical manifestations include widened pulse pressure resulting from increased stroke volume and diastolic backflow. Other symptoms are usually associated with heart failure, which occurs when the ventricle can no longer pump adequately. Arrhythmias and endocarditis are common complications of aortic regurgitation. The severity of regurgitation can be estimated by echocardiography, and surgical management (valve replacement; see Figure 23-46) may be delayed for many years through careful use of vasodilators and inotropic agents.

Mitral regurgitation

Mitral regurgitation has many possible causes, including mitral valve prolapse (see below), rheumatic heart disease, infective endocarditis, acute myocardial infarction, connective tissue diseases (such as Marfan’s syndrome) and congestive cardiomyopathy (myocardial disease). Mitral regurgitation permits backflow of blood from the left ventricle into the left atrium during ventricular systole. Eventually, the left ventricular volume increases, causing it to become dilated and hypertrophied to maintain adequate cardiac output. The volume of backflow re-entering 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 also causes pulmonary hypertension and failure of the right ventricle. 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 (see Figure 23-46).

Tricuspid regurgitation

Tricuspid regurgitation is more common than tricuspid stenosis (narrowing) and is usually associated with failure and dilation of the right ventricle secondary to pulmonary hypertension. Tricuspid valve incompetence leads to volume overload in the right ventricle, increased systemic venous blood pressure and right heart failure. Pulmonary semilunar valve dysfunction can have the same consequences as tricuspid valve dysfunction.

PATHOPHYSIOLOGY

Acute rheumatic fever can develop only as a sequel to pharyngeal infection by group A β-haemolytic streptococcus. Streptococcal skin infections do not progress to acute rheumatic fever, although both skin and pharyngeal infections can cause acute glomerulonephritis. This is because the strains of the microorganism that affect the skin do not have the same antigenic molecules in their cell membranes as those that cause pharyngitis and therefore do not elicit the same kind of immune response. Acute rheumatic fever is the result of an abnormal humoral and cell-mediated immune response to group A streptococcal cell membrane antigens called M proteins (see Figure 23-47).

FIGURE 23-47 The pathogenesis and structural changes of rheumatic heart disease.

Beginning usually with a sore throat, rheumatic fever can develop only as a sequel to pharyngeal infection by group A β-haemolytic streptococcus. Suspected as a hypersensitivity reaction, it is proposed that antibodies directed against the M proteins of certain strains of streptococci cross-react with tissue glycoproteins in the heart, joints and other tissues. The exact nature of cross-reacting antigens has been difficult to define, but it appears that the streptococcal infection causes an autoimmune response against self-antigens. Inflammatory lesions are found in various sites; the most distinctive within the heart are called Aschoff bodies. The chronic sequelae result from progressive fibrosis because of healing of the inflammatory lesions and the changes induced by valvular deformities.

Source: Damjanov I. Pathology for the health professions. 3rd edn. St Louis: Saunders; 2006.

Diffuse, proliferative and exudative inflammatory lesions develop in the connective tissues, especially in the heart. The inflammation may subside before treatment, leaving behind damage to the heart valves and increasing the individual’s susceptibility to recurrent acute rheumatic fever after any subsequent streptococcal infections. Repeated attacks of acute rheumatic fever cause chronic proliferative changes (scarring) in the affected regions.

Approximately 10% of individuals with rheumatic fever develop rheumatic heart disease. The primary lesion usually involves the endocardium. Endocardial inflammation causes swelling of the valve leaflets, with secondary erosion along the lines of leaflet contact. Small beadlike clumps of vegetation containing platelets and fibrin are deposited on eroded valvular tissue and on the chordae tendineae (see Figure 23-48).

FIGURE 23-48 Mitral stenosis with vegetation.

Mitral stenosis and clumps of vegetation (V) containing platelets and fibrin are shown in this micrograph. The mitral leaflets are thickened and fused.

Source: Stevens A, Lowe J. Pathology. Edinburgh: Mosby; 2000.

Myocarditis (inflammation of the myocardium) may occur. Cardiomegaly and left heart failure may occur during episodes of untreated acute or recurrent rheumatic fever. Conduction defects and atrial fibrillation are often associated with rheumatic heart disease.

CLINICAL MANIFESTATIONS

Many common clinical manifestations of acute rheumatic fever — fever, lymphadenopathy, arthralgia (painful joints), nausea, vomiting, epistaxis (nose bleeds), abdominal pain and tachycardia — are also associated with other disorders and are therefore not diagnostic of the disease. The major clinical manifestations of acute rheumatic fever are carditis, acute migratory polyarthritis (inflammation of more than one joint), chorea (a central nervous system disorder — see Chapter 9) and erythema marginatum (truncal rash), which may occur singly or in combination 1–5 weeks after streptococcal infection of the pharynx.

EVALUATION AND TREATMENT

When combined with physical assessment findings, laboratory values lend significant support to the diagnosis of acute rheumatic fever. A positive throat culture for group A β-haemolytic streptococci can be an important finding when associated with certain physical signs. Elevated white blood cell count, erythrocyte sedimentation rate and C-reactive protein indicate inflammation. All three are usually increased at the time cardiac or joint symptoms begin to appear. They are more useful in identifying an acute inflammatory process and suggesting prognosis than in diagnosing acute rheumatic fever. These test results return towards normal levels as the inflammatory process resolves.

Therapy for acute rheumatic fever is aimed at eradicating the streptococcal infection and involves a 10-day regimen of oral penicillin or erythromycin administration. Non-steroidal anti-inflammatory drugs (NSAIDs) are used as anti-inflammatory agents for both rheumatic carditis and arthritis. Serious carditis may require adding cardiac glycosides, corticosteroids, diuretics and bed rest to the regimen. Surgical repair of damaged valves may be needed in chronic recurrent rheumatic fever and carditis leading to rheumatic heart disease.

Research suggests that a rheumatic recurrence will develop in 50–65% of children with known rheumatic fever if they have another group A streptococcal infection. To prevent a recurrence of acute rheumatic fever, continuous prophylactic antibiotic therapy may be necessary for as long as 5 years.⁸⁵ Appropriate antibiotic therapy given within the first 9 days of infection usually prevents rheumatic fever.

Impairment of oxygen use

In all types of shock, the cell either is not receiving an adequate amount of oxygen or is unable to use oxygen. Without oxygen, the cell shifts from aerobic to anaerobic metabolism. Anaerobic metabolism is a less efficient method of extracting energy from carbon bonds and the cell begins to use its stores of ATP faster than stores can be replaced. Without ATP, the cell cannot maintain an electrochemical gradient across its selectively permeable membrane. Specifically, the cell cannot operate the sodium–potassium pump. Sodium and chloride accumulate inside the cell and potassium exits. Cells of the nervous system and myocardium are profoundly and immediately affected. The resting potentials of these cells are reduced and action potentials decrease in amplitude. Various clinical manifestations of impaired central nervous system and myocardial function result (see Figure 23-59).

As sodium moves into the cell, water follows. Throughout the body, the water drawn from the interstitium (the fluid compartment between the cells) into the cells is ‘replaced’ by water that is, in turn, drawn out of the vascular space. This decreases circulatory volume. Within the cells, water causes cellular oedema, which disrupts intracellular organelle membranes, leading to leakage of lysosomal contents. These enzymes injure the cells internally and can then leak into the interstitium.

Three positive feedback loops further impair oxygen use: (1) activation of the coagulation cascade; (2) decreased circulatory volume; and (3) toxin (lysosomal enzyme) release. The coagulation cascade activates the inflammatory response and causes clotting in the peripheral venous circulation leading to a decrease in venous return. Decreased blood volume causes the second positive feedback loop and magnifies decreased tissue perfusion in all types of shock. Toxin release, the third positive feedback loop, not only injures the cell that released it but also injures adjacent cells. By damaging the mechanisms of the surrounding cells, the lysosomal enzymes that leak from the cells extend the areas of impaired metabolism and cellular injury.

In addition to decreasing ATP stores, anaerobic metabolism affects the pH of the cell and metabolic acidosis develops. A compensatory mechanism enables the cardiac and skeletal muscles to use lactic acid as a fuel source, but only for a limited time. The decreasing pH (more acidic conditions) of the cell that is functioning anaerobically has serious consequences. Enzymes necessary for cellular function dissociate under acid conditions. Enzyme dissociation stops cell function, repair and division. As lactic acid is released systemically, blood pH drops, reducing the oxygen-carrying capacity of the blood. Therefore, less oxygen is delivered to the cells. Further acidosis triggers the release of more lysosomal enzymes because the low pH disrupts lysosomal membrane integrity — and the vicious cycle continues.

Impairment of glucose use

Impaired glucose use can be caused by either impaired glucose delivery or impaired glucose uptake by the cells (see Figure 23-59). The reasons for inadequate glucose delivery are the same as those outlined for inadequate oxygen delivery.

Some compensatory mechanisms activated by shock contribute to decreased glucose uptake by the cells. High serum levels of cortisol, thyroid hormone and catecholamines account for hyperglycaemia and insulin resistance, tachycardia, increased peripheral resistance and increased cardiac contractility. Cells shift to alternative processes (namely glycogenolysis, gluconeogenesis and lipolysis) to generate fuel for survival. Except in the liver, kidneys and muscles, body cells have extremely limited stores of glycogen. In fact, total body stores can fuel the metabolism for only about 10 hours. The depletion of fat and glycogen stores is not itself a cause of organ failure, but the energy costs of glycogenolysis and lipolysis are considerable and contribute to cellular failure.

The depletion of protein is a cause of organ failure. When gluconeogenesis causes proteins to be used for fuel, these proteins are no longer available to maintain cellular structure, function, repair and replication. As proteins are broken down, ammonia and urea are produced. Ammonia is toxic to living cells. Uraemia (high urea levels) develops and uric acid further disrupts cellular metabolism. Serum albumin and other plasma proteins are consumed for fuel first. Serum protein consumption decreases capillary osmotic pressure and contributes to the development of interstitial oedema, creating another positive feedback loop that decreases circulatory volume.

A final outcome of impaired cellular metabolism is the build-up of metabolic end products in the cell and interstitial spaces. Waste products are toxic to the cells and further disrupt cellular function and membrane integrity. Once a sufficiently large number of cells from vital organs have damage to their cellular membranes, leakage of lysosomal enzymes and ATP depletion, shock can be irreversible.

Cardiogenic shock

Cardiogenic shock is defined as ‘decreased cardiac output and evidence of tissue hypoxia in the presence of adequate intravascular volume’.⁹⁸ Most cases of cardiogenic shock follow acute myocardial infarction, because the myocardium is damaged and therefore contractions are inadequate. Cardiogenic shock is often unresponsive to treatment, with a mortality of more than 70% reported. The pathophysiology of cardiogenic shock is outlined as a concept map in Figure 23-60.

FIGURE 23-60 Cardiogenic shock.

Shock becomes life-threatening when compensatory mechanisms (in blue) cause increased myocardial oxygen requirements. Renal and hypothalamic adaptive responses (i.e. renin-angiotensin-aldosterone and antidiuretic hormone) maintain or increase blood volume. The adrenal gland releases catecholamines (e.g. mostly adrenaline, some noradrenaline), causing vasoconstriction and increases in contractility and heart rate. These adaptive mechanisms, however, increase myocardial demands for oxygen and nutrients. These demands further strain the heart, which can no longer pump an adequate volume, resulting in shock and impaired metabolism. SVR = systemic vascular resistance.

The clinical manifestations of cardiogenic shock are caused by widespread impairment of cellular metabolism. They include impaired mentation, elevated preload in the systemic and pulmonary vasculature, systemic and pulmonary oedema, dusky skin colour, hypotension, oliguria (low urine output) and dyspnoea.⁹⁸ Management of cardiogenic shock includes careful fluid and catecholamine administration.

Hypovolaemic shock

Hypovolaemic shock is caused by loss of fluid volume: either whole blood (haemorrhage), plasma (burns) or interstitial fluid (diaphoresis, diabetes mellitus, emesis, diarrhoea or diuresis) in large amounts.⁹⁹ Hypovolaemic shock begins to develop when intravascular volume has decreased by about 15% (see Figure 23-61 for details of haemorrhage).

FIGURE 23-61 The effects of haemorrhage on cardiac output and arterial pressure.

Controlled bleeding over 30 minutes demonstrates the changes in arterial pressure and cardiac output, which compensate until about 15% of blood is lost.

Source: Guyton AC, Hall JE. Textbook of medical physiology. 11th edn. Philadelphia: Saunders; 2006.

Hypovolaemia is offset initially by compensatory mechanisms (see Figure 23-62). Heart rate and peripheral vascular resistance increase, boosting both cardiac output and tissue perfusion pressures. Interstitial fluid moves into the vascular compartment. The liver and spleen add to blood volume by releasing stored red blood cells and plasma. In the kidneys, renin stimulates aldosterone release and the retention of sodium (and hence water), and antidiuretic hormone from the posterior pituitary gland also increases water retention. However, if the initial fluid or blood loss is great or if loss continues, compensation fails, resulting in decreased tissue perfusion. As in cardiogenic shock, oxygen and nutrient delivery to the cells is impaired and cellular metabolism fails. Anaerobic metabolism and lactate production result in lactic acidosis and serum and cellular electrolyte abnormalities.

FIGURE 23-62 Hypovolaemic shock.

This type of shock becomes life-threatening when compensatory mechanisms (in purple) are overwhelmed by continued loss of intravascular volume.

The clinical manifestations of hypovolaemic shock include poor skin turgor, thirst, oliguria, low preload, tachycardia, thready pulse, high peripheral vascular resistance and deterioration of mental status. The differences between the signs and symptoms of hypovolaemic shock and those of cardiogenic shock are mainly caused by differences in fluid volume and cardiac muscle health. Management begins with rapid fluid replacement with crystalloids and blood products.⁹⁹ If adequate tissue perfusion cannot be restored promptly, systemic inflammation and multiple organ dysfunction are likely.

Neurogenic shock

Neurogenic shock (sometimes called vasogenic shock) is the result of widespread and massive vasodilation that results from parasympathetic overstimulation and sympathetic understimulation (see Figure 23-63). This type of shock can be caused by any factor that stimulates parasympathetic stimulation or inhibits sympathetic stimulation of vascular smooth muscle. Trauma to the spinal cord or medulla and conditions that interrupt the supply of oxygen or glucose to the medulla can cause neurogenic shock by interrupting sympathetic activity. Depressive drugs, anaesthetic agents and severe emotional stress and pain are other causes. The loss of vascular tone results in ‘relative hypovolaemia’. Blood volume has not changed, but because of widespread vasodilation, the amount of space containing the blood has increased, so that peripheral vascular resistance decreases drastically, meaning that pressure in the vessels is inadequate to drive nutrients across the capillary membranes to the cells. In addition, bradycardia can occur with a decrease in cardiac output, which further contributes to hypotension and tissue hypoperfusion.¹⁰⁰ As with other types of shock, this leads to impaired cellular metabolism. Management includes the careful use of fluids and vasopressors until blood pressure stabilises.¹⁰¹

FIGURE 23-63 Neurogenic shock.

Anaphylactic shock

Anaphylactic shock results from a widespread hypersensitivity reaction known as anaphylaxis. The basic physiological alteration is the same as that of neurogenic shock: vasodilation, peripheral pooling and relative hypovolaemia, leading to decreased tissue perfusion and impaired cellular metabolism (see Figure 23-64). Anaphylactic shock is often more severe than other types of shock because the hypersensitivity reaction that triggers vasodilation has other pathophysiological effects that rapidly involve the entire body.

FIGURE 23-64 Anaphylactic shock.

IgE = immunoglobulin E.

Anaphylactic shock begins as an allergic reaction to an allergen. Common allergens known to cause reactions are insect venoms, shellfish, peanuts, latex and medications such as penicillin. In genetically predisposed individuals, allergens initiate a vigorous humoral immune response (type I hypersensitivity), which results in the production of large quantities of immunoglobulin E (IgE) antibody (refer to Chapter 15). Mast cells degranulate and release a large number of vasoactive and inflammatory cytokines. This provokes an extensive immune and inflammatory response, including vasodilation and increased vascular permeability, resulting in peripheral pooling and tissue oedema.^102,103 Respiratory difficulty occurs due to constriction of the smooth muscle layers in airway walls.

The onset of anaphylactic shock is usually sudden and progression to death can occur within minutes unless emergency treatment is given. The first manifestations may be anxiety, difficulty breathing, gastrointestinal cramps, oedema, hives (urticaria) and sensations of burning or itching of the skin.¹⁰² A precipitous fall in blood pressure occurs, followed by impaired mentation. Treatment begins with removal of the antigen (if possible). Adrenaline is administered intramuscularly to cause vasoconstriction and reverse airway constriction. Fluids are given intravenously to reverse the relative hypovolaemia, and antihistamines and corticosteroids are given to stop the inflammatory reaction.

Septic shock

Septic shock is one component of a continuum of progressive dysfunctions called the systemic inflammatory response syndrome (SIRS). The syndrome begins with an infection that progresses to bacteraemia, then sepsis, severe sepsis, septic shock and finally multiple organ dysfunction syndrome. Consensus about definitions of each component was achieved in 1992 and revised in 2001; these definitions are presented in Table 23-16.^104,105

Table 23-16 CAUSES AND DEFINITIONS OF SEPTIC SHOCK

Source: Adapted from American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Crit Care Med 1992; 20(6):864–874; Levy MM et al. SCCM/ES/CM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31(4):1250–1256.

Septic shock, a common cause of death of individuals in intensive care units, has a high mortality rate and can be caused by any class of microorganism. While it is mainly caused by bacteria, fungi and viruses, in almost one-third of cases the infectious organism is never identified.

Most septic shock begins when bacteria enter the bloodstream to produce bacteraemia. These bacteria may directly stimulate an inflammatory response or they may release toxic substances into the bloodstream. Gram-negative microorganisms release endotoxins and gram-positive microorganisms release exotoxins (see Chapter 14). These substances trigger the septic syndrome by interacting with macrophages and activate the complement system, the coagulation cascade, kinins and inflammatory cells (see Figure 23-65).¹⁰⁶

FIGURE 23-65 Septic shock.

The release of inflammatory mediators triggers intense cellular responses and the subsequent release of secondary mediators, including cytokines, prostaglandins, platelet-activating factor, oxygen-free radicals, nitric oxide and proteolytic enzymes. Chemotaxis, activation of granulocytes and reactivation of the phagocytic cells and inflammatory cascades result. This systemic inflammation, especially through the action of nitric oxide, leads to widespread vasodilation with compensatory tachycardia and increased cardiac output in the early stages of septic shock. As the disease progresses, inflammatory mediators, such as complement and interleukins, depress myocardial contractility such that cardiac output falls and tissue perfusion decreases.¹⁰⁷ Tissue perfusion and cellular oxygen extraction are also affected by activation of the coagulation cascade through the action of platelet-activating factor and depletion of the endogenous anticoagulant protein C.

The inflammatory response can become overwhelming, leading to the systemic inflammatory response syndrome, which can progress to widespread tissue hypoxia and necrosis, leading to the multiple organ dysfunction syndrome.¹⁰⁴ It has been determined that there is a parallel release of anti-inflammatory mediators and a depression in the immune response that accompanies the systemic inflammatory response syndrome, which contributes to the overall shock syndrome (see the box ‘Risk factors: inflammatory and anti-inflammatory mediators contributing to septic shock’).^{108–110 4 6}

Clinical manifestations of septic shock are low arterial pressure, low peripheral vascular resistance from vasodilation, systemic oedema and an alteration in oxygen extraction by all cells. Tachycardia causes cardiac output to remain normal or become elevated, although myocardial contractility is reduced. Temperature instability is present, ranging from hyperthermia to hypothermia. Effects on other organ systems may result in deranged renal function, gastrointestinal mucosa changes that lead to the release of bacteria from the gut into the bloodstream, jaundice, clotting abnormalities, deterioration of mental status and adult respiratory distress syndrome. Treatment includes multiple drug antibacterial therapy, removal of the source of infection if one is found, fluid resuscitation and inotropic drugs to improve haemodynamic parameters. Many experimental treatments are under study; however, because the septic syndrome is incompletely understood, recommended treatment continues to evolve.

CLINICAL MANIFESTATIONS OF SHOCK

The clinical manifestations of shock are variable depending on the type of shock, and observable and measurable signs and symptoms are often conflicting in nature. Subjective complaints in shock are usually nonspecific. The individual may report feeling sick, weak, cold, hot, nauseated, dizzy, confused, afraid, thirsty and short of breath. Hypotension, characterised by a mean arterial pressure below 60 mmHg, is common to almost all shock states; however, it is a late sign of decreased tissue perfusion. Cardiac output and urinary output are usually variable early in shock states but generally become decreased as the shock syndrome progresses. Moreover, the feedback loops of intravascular clotting, decreased venous return and toxin release all contribute to a deterioration of cardiac output (see Figure 23-66).

FIGURE 23-66 The progression of shock when positive feedback loops lead to further reductions in cardiac output.

Red-coloured boxes represent feedback responses.

Source: Modified from Guyton AC, Hall JE. Textbook of medical physiology. 11th edn. Philadelphia: Saunders; 2006.

TREATMENT FOR SHOCK

The first treatment for shock is to discover and correct the underlying cause. General supportive treatment includes intravenous fluid administered to expand intravascular volume, inotrope drugs and supplemental oxygen. Further treatment depends on the cause and severity of the shock syndrome, which was discussed above with each type of shock. Once positive feedback loops are established, intervention in shock is difficult. Prevention and very early treatment offer the best prognosis.

PATHOPHYSIOLOGY

As a result of the initiating insult (sepsis, injury or disease), the neuroendocrine system is activated with the release of the stress hormones cortisol, adrenaline and noradrenaline into the bloodstream. The sympathetic nervous system is stimulated to compensate for complications resulting from the injury, such as fluid loss and hypotension. Vascular endothelial damage occurs as a direct result of injury or from damage by bacterial toxins and inflammatory mediators released into the circulation. The vascular endothelium becomes permeable, allowing fluid and protein to leak into the interstitial spaces, contributing to hypotension and hypoperfusion. When the endothelium is damaged, platelets and tissue thromboplastin are activated, resulting in systemic microvascular coagulation.

A massive systemic immune/inflammatory response then develops involving neutrophils, macrophages and mast cells (see Table 23-17). The pathways by which neutrophils and macrophages are activated vary and involve multiple events rather than individual triggers.

Table 23-17 CELLS OF INFLAMMATION AND MULTIPLE ORGAN DYSFUNCTION

Source: Danesh J et al. C reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387–1397; Fichtlscherer S, Heeschen C, Zeiher AM. Inflammatory markers and coronary artery disease. Curr Opin Pharmacol 2004; 4:124–131; Karaduman M et al. Leptin, soluble interleukin-6 receptor, C-reactive protein and soluble vascular cell adhesion molecule-1 levels in human coronary atherosclerotic plaque. Clin Experim Immunol 2006; 143(3):452–457; Tomai F et al. Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease. Eur Heart J 2005; 26(20):2099–2105.

The numerous inflammatory and clotting processes operating in the multiple organ dysfunction syndrome cause maldistribution of blood flow and hypermetabolism. Oxygen delivery to the tissues decreases despite the increased systemic blood flow. Hypermetabolism with accompanying alterations in carbohydrate, fat and lipid metabolism is initially a compensatory measure to meet the body’s increased demands for energy. The alterations in metabolism affect all aspects of fuel utilisation. The net result of hypermetabolism is depletion of oxygen and fuel supplies.

Decreased oxygen delivery to the cells caused by the maldistribution of blood flow, coagulation, myocardial depression and the hypermetabolic state combine to create an imbalance in oxygen supply and demand. Tissue hypoxia ensues with cellular acidosis and impaired cellular function and results in the multiple organ failure.

CLINICAL MANIFESTATIONS

There is often a predictable clinical pattern in the development of multiple organ dysfunction syndrome.¹¹¹ After the initial event and aggressive resuscitation for approximately 24 hours, the individual develops a low-grade fever, tachycardia, dyspnoea, altered mental status and hyperdynamic and hypermetabolic states. The lung is often the first organ to fail, resulting in acute respiratory distress syndrome. Between 7 and 10 days, the hypermetabolic and hyperdynamic states intensify, bacteraemia is common, and signs of liver and kidney failure appear. During days 14 to 24, renal and liver failure becomes more severe and the gastrointestinal system shows evidence of dysfunction. Haematological failure and myocardial failure are usually later manifestations. Death may occur as early as 14 days or after a period of several weeks.

The clinical manifestations of individual organ failure within this syndrome are the result of inflammation and tissue hypoxia. Respiratory failure is characterised by tachypnoea, pulmonary oedema, use of accessory muscles and hypoxaemia. Liver failure, although developing early, is not clinically detectable until later stages of the syndrome, at which time jaundice, abdominal distension, liver tenderness, muscle wasting and hepatic encephalopathy (see Chapter 27) appear.

Progressive oliguria and oedema mark the development of renal failure. Anuria (no urine), hyperkalaemia and metabolic acidosis may occur if renal shutdown is severe. The gastrointestinal system is sensitive to ischaemic and inflammatory injury; clinical manifestations of bowel involvement are haemorrhage, ileus (impaired gut motility), malabsorption, diarrhoea or constipation, vomiting, anorexia and abdominal pain.

The signs and symptoms of cardiac failure in the hypermetabolic, hyperdynamic phase of the syndrome are similar to those of septic shock: tachycardia, bounding pulse, increased cardiac output, decreased peripheral vascular resistance and hypotension. In the terminal stages, hypodynamic circulation with bradycardia, profound hypotension and ventricular arrhythmias may develop. Ischaemia and inflammation are responsible for the central nervous system manifestations, which include apprehension, confusion, disorientation, restlessness, agitation, headache, decreased cognitive ability and memory, and decreased level of consciousness. When ischaemia is severe, seizures and coma can occur.

EVALUATION AND TREATMENT

Because presently there is no specific therapy for multiple organ dysfunction syndrome, early detection is extremely important so that supportive measures can be initiated immediately. Frequent assessment of the clinical status of individuals at known risk is essential. Once organ failure develops, monitoring of laboratory values and haemodynamic parameters can also be used to assess the degree of impairment. Therapeutic management consists of prevention and support.

CHAPTER SUMMARY

Alterations of blood flow and pressure

Hypertension is the elevation of systemic arterial blood pressure resulting from increases in cardiac output or total peripheral resistance, or both.

Hypertension can be primary, without a known cause, or secondary, caused by an underlying disease.

The risk factors for hypertension include a family history; being male; advancing age; obesity; high sodium intake; diabetes mellitus; cigarette smoking; and heavy alcohol consumption.

The exact cause of primary hypertension is unknown, although several hypotheses have been proposed, including overactivity of the sympathetic nervous system; overactivity of the renin-angiotensin-aldosterone system; sodium and water retention by the kidneys; hormonal inhibition of sodium–potassium transport across cell walls; and complex interactions involving insulin resistance, inflammation and endothelial function.

Clinical manifestations of hypertension result from damage of organs and tissues outside the vascular system. These include heart disease, renal disease, central nervous system problems and musculoskeletal dysfunction.

Hypertension is managed with both pharmacological and non-pharmacological methods.

Systemic hypertension in children differs from adults in aetiology and presentation.

Orthostatic hypotension is a drop in blood pressure that occurs on standing. The compensatory vasoconstriction response to standing is replaced by a marked vasodilation and blood pooling in the muscle vasculature.

Orthostatic hypotension may be acute or chronic. The acute form is caused by a delay in the normal regulatory mechanisms. The chronic forms are secondary to a specific disease or are idiopathic in nature.

The clinical manifestations of orthostatic hypotension include fainting and may involve cardiovascular symptoms, as well as impotence and bowel and bladder dysfunction.

Arteriosclerosis is a thickening and hardening of the arteries, involving the intimal layer and leading to hypertension. It seems to be a part of the normal ageing process, but it is a disease state when it occurs to the point of symptom development.

Arteriosclerosis raises the systolic pressure by decreasing arterial distensibility and lumen diameter.

Atherosclerosis is a form of arteriosclerosis and is the leading contributor to coronary heart disease and cerebrovascular disease.

Atherosclerosis is an inflammatory disease that begins with endothelial injury (smoking, hypertension, diabetes mellitus [insulin resistance], dyslipidaemia) and progresses through several stages to become a fibrotic plaque.

Once a plaque has formed, it can rupture, resulting in clot formation and instability and vasoconstriction, leading to obstruction of the lumen and inadequate oxygen delivery to tissues.

Coronary heart disease is almost always the result of atherosclerosis that gradually narrows the coronary arteries or that ruptures and causes sudden thrombus formation and myocardial ischaemia and even infarction. Many risk factors contribute to the onset and escalation of coronary heart disease, including dyslipidaemia, smoking, hypertension, diabetes mellitus (insulin resistance), advancing age, obesity, sedentary lifestyle, psychosocial factors and heavy consumption of alcohol.

The three risk factors most predictive of coronary heart disease are hypercholesterolaemia, cigarette smoking and hypertension.

Coronary heart disease is most commonly the result of atherosclerosis to the coronary arteries and the resultant decrease in myocardial blood supply.

Angina pectoris is chest pain caused by myocardial ischaemia.

Therapeutic interventions for coronary heart disease include the use of vasodilators and medications to reduce cardiac workload (e.g. β-blockers), as well as surgical procedures.

Atherosclerotic plaque progression can be gradual, but sudden coronary obstruction due to thrombus formation causes the acute coronary syndromes. These include unstable angina and myocardial infarction.

Unstable angina results in reversible myocardial ischaemia.

Myocardial infarction is caused by prolonged, unrelieved ischaemia that interrupts blood supply to the myocardium. After about 20 minutes of myocardial ischaemia, irreversible hypoxic injury causes cellular death and tissue necrosis.

Myocardial infarction is clinically classified as non-ST elevation myocardial infarction (non STEMI) and ST elevation myocardial infarction (STEMI), based on ECG findings that suggest the extent of the myocardial damage (subendocardial versus transmural).

An increase in plasma enzyme levels is used to diagnose the occurrence of myocardial infarction and indicate its severity. Elevations of the creatine kinase-myocardial band (CK-MB), troponins and lactic dehydrogenase (LDH) are most predictive of a myocardial infarction.

Treatment of a myocardial infarction includes revascularisation (thrombolytics or percutaneous coronary intervention), antithrombotics, ACE inhibitors and β-blockers. Pain relief and fluid management are also key components of care. Arrhythmias and cardiac failure are the most common complications of acute myocardial infarction.

An aneurysm is a localised dilation of a vessel wall, to which the aorta is particularly susceptible.

A thrombus is a clot that remains attached to a vascular wall. Arteriosclerosis can generate thrombus formation through roughening of the intima that activates the coagulation cascade. Thrombus formation may be discrete or diffuse.

An embolus is a mobile aggregate of a variety of substances that occludes the vasculature. Sources of emboli include clots, air, amniotic fluid, bacteria, fat and foreign matter. These emboli cause ischaemia and necrosis when a vessel is totally blocked.

Emboli to the central organs cause tissue death in lungs, kidneys and mesentery.

Deep venous thrombosis results from stasis of blood flow, endothelial damage or hypercoagulability. The most serious complication of deep venous thrombosis is pulmonary embolism.

Varicosities are areas of veins in which blood has pooled, usually in the saphenous veins.

Varicosities may be caused by damaged valves as a result of trauma to the valve or by chronic venous distention involving gravity and venous constriction.

Chronic venous insufficiency is inadequate venous return over a long period of time that causes pathological ischaemic changes in the vasculature, skin and supporting tissues.

Venous stasis ulcers follow the development of chronic venous insufficiency and probably develop as a result of the borderline metabolic state of the cells in the affected extremities.

Alterations of cardiac function

Most congenital heart defects have begun to develop by the eighth week of gestation and some have associated causes, both environmental and genetic.

Environmental risk factors associated with the incidence of congenital heart defects typically are maternal conditions. Maternal conditions include viral infections, diabetes, drug intake and advanced maternal age.

Classification of congenital heart defects is based on whether they cause: (a) blood flow to the lungs to increase, decrease or remain normal; (b) cyanosis; and (c) obstruction to flow.

Cyanosis, a bluish discolouration of the skin, indicates that the tissues are not receiving normal amounts of oxygenated blood. Cyanosis can be caused by defects that: (a) restrict blood flow into the pulmonary circulation; (b) overload the pulmonary circulation, causing pulmonary hypertension, pulmonary oedema and respiratory difficulty; or (c) cause large amounts of deoxygenated blood to shunt from the pulmonary circulation to the systemic circulation.

Congenital defects that maintain or create direct communication between the pulmonary and systemic circulatory systems cause blood to shunt from one system to another, mixing oxygenated and deoxygenated blood and increasing blood volume and, occasionally, pressure on the receiving side of the shunt.

The direction of shunting through an abnormal communication depends on differences in pressure and resistance between the two systems. Flow is always from an area of high pressure to an area of low pressure.

Acyanotic congenital defects that increase pulmonary blood flow consist of abnormal openings (atrial septal defect, ventricular septal defect, patent ductus arteriosus or atrioventricular septal defect) that permit blood to shunt from left (systemic circulation) to right (pulmonary circulation). Cyanosis does not occur because the left-to-right shunt does not interfere with the flow of oxygenated blood through the systemic circulation.

If the abnormal communication between the left and right circuits is large, volume and pressure overload in the pulmonary circulation lead to left heart failure.

Cyanotic congenital defects in which saturated and desaturated blood mix within the heart or great arteries include truncus arteriosus, tetralogy of Fallot and transposition of the great vessels.

In cyanotic heart defects that decrease pulmonary blood flow (tetralogy of Fallot), myocardial hypertrophy cannot compensate for restricted right ventricular outflow. Flow to the lungs decreases and cyanosis is caused by an insufficient volume of oxygenated blood.

Initial treatment for congenital heart disease, depending on the defect, is aimed at controlling the level of congestive heart failure or cyanosis. Interventional procedures in the cardiac catheterisation laboratory and surgical palliation or repair are performed to restore circulation to as normal as possible.

Alterations of the heart wall

Inflammation of the pericardium, or pericarditis, may result from several sources (infection, drug therapy, tumours). Pericarditis presents with symptoms that are physically troublesome, but in and of themselves they are not life-threatening.

Fluid may collect within the pericardial sac (pericardial effusion). Cardiac function may be severely impaired if the accumulation of fluid occurs rapidly and involves a large volume.

The cardiomyopathies are a diverse group of primary myocardial disorders that are usually the result of remodelling, neurohumoral responses and hypertension. The cardiomyopathies are categorised as dilated, hypertrophic and restrictive. The size of the cardiac muscle walls and chambers may increase or decrease depending on the type of cardiomyopathy, thereby altering contractile activity.

The haemodynamic integrity of the cardiovascular system depends to a great extent on properly functioning cardiac valves. Congenital or acquired disorders that result in stenosis, incompetence or both can structurally alter the valves.

Characteristic heart sounds, cardiac murmurs and systemic complaints assist in determining which valve is abnormal. If severely compromised function exists, a prosthetic heart valve may be surgically implanted to replace the faulty one.

Mitral valve prolapse is a common finding, especially in young women. Although not grossly abnormal, the mitral valve leaflets do not position themselves properly during systole. Mitral valve prolapse may be a completely asymptomatic condition or can result in unpredictable symptoms. Afflicted valves are at greater risk for developing infective endocarditis.

Rheumatic fever is an inflammatory disease that results from a delayed immune response to a streptococcal infection in genetically predisposed individuals. The disorder usually resolves without sequelae if treated early.

Severe or untreated cases of rheumatic fever may progress to rheumatic heart disease, a potentially disabling cardiovascular disorder.

Infective endocarditis is a general term for infection and inflammation of the endocardium, especially the cardiac valves. The most common cause of infective endocarditis is Staphylococcus aureus, followed by Streptococcus viridans. In the mildest cases, valvular function may be slightly impaired by vegetations that collect on the valve leaflets. If left unchecked, severe valve abnormalities, chronic bacteraemia and systemic emboli may occur as vegetations break off the valve surface and travel through the bloodstream. Antibiotic therapy can limit the extension of this disease.

Alterations of cardiac conduction

Arrhythmias are disturbances of heart rhythm. Arrhythmias range in severity from occasional missed beats or rapid beats to disturbances that impair myocardial contractility and are life-threatening.

Arrhythmias can occur because of an abnormal rate of impulse generation or the abnormal conduction of impulses.

Atrial fibrillation is the most common arrhythmia and is most prevalent in the elderly.

Heart failure

Heart failure is an inability of the heart to supply the metabolism with adequate circulatory volume and pressure.

Left heart failure (congestive heart failure) can be divided into systolic and diastolic heart failure.

Systolic heart failure is caused by increased preload, decreased contractility or increased afterload.

The most common causes of systolic heart failure are myocardial infarction, fluid overload, hypertension or valvular disease.

In addition to the haemodynamic changes of systolic heart failure, there is a neuroendocrine response that tends to exacerbate and perpetuate the condition.

The neuroendocrine mediators include the sympathetic nervous system and the renin-angiotensin-aldosterone system; thus, diuretics, β-blockers and ACE inhibitors are important components of the pharmacological therapy.

Diastolic heart failure is a clinical syndrome characterised by the symptoms and signs of heart failure, a preserved ejection fraction and abnormal diastolic function.

Diastolic dysfunction means that the left ventricular end-diastolic pressure is increased, even if volume and cardiac output are normal.

Right heart failure is usually the result of chronic pulmonary hypertension caused by left heart failure or chronic hypoxic lung disease.

Shock

Shock is a widespread impairment of cellular metabolism involving positive feedback loops that places the individual on a downward physiological spiral leading to the multiple organ dysfunction syndrome.

Types of shock are cardiogenic, hypovolaemic, neurogenic, anaphylactic and septic. The multiple organ dysfunction syndrome can develop from all types of shock.

The final common pathway in all types of shock is impaired cellular metabolism — cells switch from aerobic to anaerobic metabolism. Energy stores drop and cellular mechanisms relative to membrane permeability, action potentials and lysosyme release fail.

Anaerobic metabolism results in activation of the inflammatory response, decreased circulatory volume and decreasing pH.

Impaired cellular metabolism results in cellular inability to use glucose because of impaired glucose delivery or impaired glucose intake, resulting in a shift to glycogenolysis, gluconeogenesis and lipolysis for fuel generation.

Glycogenolysis is effective for about 10 hours. Gluconeogenesis results in the use of proteins necessary for structure, function, repair and replication, which leads to more impaired cellular metabolism.

Gluconeogenesis contributes to lactic acid, uric acid and ammonia build-up, interstitial oedema and impairment of the immune system, as well as general muscle weakness leading to decreased respiratory function and cardiac output.

Cardiogenic shock is decreased cardiac output, tissue hypoxia and the presence of adequate intravascular volume.

Hypovolaemic shock is caused by loss of blood or fluid in large amounts. The use of compensatory mechanisms may be vigorous, but tissue perfusion ultimately decreases and results in impaired cellular metabolism.

Neurogenic shock results from massive vasodilation, causing a relative hypovolaemia, even though cardiac output may be high, and results in impaired cellular metabolism.

Anaphylactic shock is caused by physiological recognition of a foreign substance. The inflammatory response is triggered and a massive vasodilation with fluid shift into the interstitium follows. The relative hypovolaemia leads to impaired cellular metabolism.

Septic shock begins with impaired cellular metabolism caused by uncontrolled septicaemia. The infecting agent triggers the inflammatory and immune responses. This inflammatory response is accompanied by widespread changes in tissue and cellular function.

Multiple organ dysfunction syndrome is the progressive failure of two or more organ systems after a severe illness or injury. It can be triggered by chronic inflammation, necrotic tissue, severe trauma, burns, adult respiratory distress syndrome, acute pancreatitis and other severe injuries.

Multiple organ dysfunction syndrome involves the stress response; changes in the vascular endothelium resulting in microvascular coagulation; release of complement, coagulation and kinin proteins; and numerous inflammatory processes. The consequences of all these mediators are an altered blood flow distribution, hypermetabolism, hypoxic injury and myocardial depression.

Clinical manifestations of the multiple organ dysfunction syndrome include inflammation, tissue hypoxia and hypermetabolism. All organs can be affected, including the kidneys, lungs, liver, gastrointestinal tract and central nervous system.