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InternalMed_Harrison. N. meningitidis LPS has also been found in many isolates from patients with chronic meningococcemia. In contrast, gram-negative bacteria that make lipid A with fewer than six acyl chains (Yersinia pestis, Francisella tularensis, Vibrio vulnificus, Pseudomonas aeruginosa, and Burkholderia pseudomallei, among others) are poorly recognized by MD-2–TLR4. When these bacteria enter the body, they may initially induce relatively little inflammation. When they do trigger severe sepsis, it is often after they have multiplied to high density in tissues and blood. The importance of LPS recognition in disease pathogenesis was demonstrated by engineering of a virulent strain of Y. pestis that makes tetraacyl LPS at 37°C to produce hexaacyl LPS; unlike its virulent parent, the mutant strain stimulated local inflammation and was rapidly cleared from tissues. These findings were subsequently replicated in F. tularensis. For at least one large class of microbes—gram-negative aerobic bacteria—the


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InternalMed_Harrison. local inflammation and was rapidly cleared from tissues. These findings were subsequently replicated in F. tularensis. For at least one large class of microbes—gram-negative aerobic bacteria—the pathogenesis of sepsis thus depends, at least in part, on whether the bacterium’s major signal molecule, LPS, can be sensed by the host.


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InternalMed_Harrison. Local and Systemic Host Responses to Invading Microbes Recognition of microbial molecules by tissue phagocytes triggers the production and/or release of numerous host molecules (cytokines, chemokines, prostanoids, leukotrienes, and others) that increase blood flow to the infected tissue (rubor), enhance the permeability of local blood vessels (tumor), recruit neutrophils and other cells to the site of infection (calor), and elicit pain (dolor). These reactions are familiar elements of local inflammation, the body’s frontline innate immune mechanism for eliminating microbial invaders. Systemic responses are activated by neural and/or humoral communication with the hypothalamus and brainstem; these responses enhance local defenses by increasing blood flow to the infected area, augmenting the number of circulating neutrophils, and elevating blood levels of numerous molecules (such as the microbial recognition proteins discussed above) that have anti-infective functions.


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InternalMed_Harrison. cytokines and other mediators Cytokines can exert endocrine, paracrine, and autocrine effects (Chap. 372e). TNF-α stimulates leukocytes and vascular endothelial cells to release other cytokines (as well as additional TNF-α), to express cell-surface molecules that enhance neutrophil endothelial adhesion at sites of infection, and to increase prostaglandin and leukotriene production. Whereas blood levels of TNF-α are not elevated in individuals with localized infections, they increase in most patients with severe sepsis or septic shock. Moreover, IV infusion of TNF-α can elicit fever, tachycardia, hypotension, and other responses. In animals, larger doses of TNF-α induce shock and death.


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InternalMed_Harrison. Although TNF-α is a central mediator, it is only one of many proinflammatory molecules that contribute to innate host defense. Chemokines, most prominently IL-8 and IL-17, attract circulating neutrophils to the infection site. IL-1β exhibits many of the same activities as TNF-α. TNF-α, IL-1β, interferon γ, IL-12, IL-17, and other proinflammatory cytokines probably interact synergistically with one another and with additional mediators. The nonlinearity and multiplicity of these interactions have made it difficult to interpret the roles played by individual mediators in both tissues and blood.


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InternalMed_Harrison. coagulation factors Intravascular thrombosis, a hallmark of the local inflammatory response, may help wall off invading microbes and prevent infection and inflammation from spreading to other tissues. IL-6 and other mediators promote intravascular coagulation initially by inducing blood monocytes and vascular endothelial cells to express tissue factor (Chap. 78). When tissue factor is expressed on cell surfaces, it binds to factor VIIa to form an active complex that can convert factors X and IX to their enzymatically active forms. The result is activation of both extrinsic and intrinsic clotting pathways, culminating in the generation of fibrin. Clotting is also favored by impaired function of the protein C–protein S inhibitory pathway and depletion of antithrombin and proteins C and S, whereas fibrinolysis is reduced by increases in plasma levels of plasminogen activator inhibitor 1. Thus, there may be a striking propensity toward intravascular fibrin deposition, thrombosis, and


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InternalMed_Harrison. S, whereas fibrinolysis is reduced by increases in plasma levels of plasminogen activator inhibitor 1. Thus, there may be a striking propensity toward intravascular fibrin deposition, thrombosis, and bleeding; this propensity has been most apparent in patients with intravascular endothelial infections such as meningococcemia (Chap. 180). Evidence points to tissue factor–expressing microparticles derived from leukocytes as a potential trigger for intra-vascular coagulation. The contact system is activated during sepsis but contributes more to the development of hypotension than to that of disseminated intravascular coagulation (DIC).


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InternalMed_Harrison. Neutrophil extracellular traps (NETs) are produced when neutrophils, stimulated by microbial agonists or IL-8, release granule proteins and chromatin to form an extracellular fibrillar matrix. NETs kill bacteria and fungi with antimicrobial granule proteins (e.g., elastase) and histones. It has been reported that NETs can form within hepatic sinusoids in animals injected with large amounts of LPS, and platelets can induce NET formation without killing neutrophils. A role played by NETs in organ hypofunction during sepsis has been proposed but not established. control mechanisms Elaborate control mechanisms operate within 1753 both local sites of inflammation and the systemic compartment.


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InternalMed_Harrison. Local control mechanisms Host recognition of invading microbes within subepithelial tissues typically ignites immune responses that rapidly kill the invaders and then subside to allow tissue recovery. The forces that put out the fire and clean up the battleground include molecules that neutralize or inactivate microbial signals. Among these molecules are intracellular factors (e.g., suppressor of cytokine signaling 3 and IL-1 receptor–associated kinase 3) that diminish the production of proinflammatory mediators by neutrophils and macrophages; anti-inflammatory cytokines (IL-10, IL-4); and molecules derived from essential polyunsaturated fatty acids (lipoxins, resolvins, and protectins) that promote tissue restoration. Enzymatic inactivation of microbial signal molecules (e.g., LPS) may be required to restore homeostasis; a leukocyte enzyme, acyloxyacyl hydrolase, has been shown to prevent prolonged inflammation in mice by inactivating LPS.


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InternalMed_Harrison. Systemic control mechanisms The signaling apparatus that links microbial recognition to cellular responses in tissues is less active in the blood. For example, whereas LPS-binding protein plays a role in recognizing LPS, in plasma it also prevents LPS signaling by transferring LPS molecules into plasma lipoprotein particles that sequester the lipid A moiety so that it cannot interact with cells. At the high concentrations found in blood, LPS-binding protein also inhibits monocyte responses to LPS, and the soluble (circulating) form of CD14 strips off LPS that has bound to monocyte surfaces.


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InternalMed_Harrison. Systemic responses to infection also diminish cellular responses to microbial molecules. Circulating levels of cortisol and anti-inflammatory cytokines (e.g., IL-6 and IL-10) increase even in patients with minor infections. Glucocorticoids inhibit cytokine synthesis by monocytes in vitro; the increase in blood cortisol levels that occurs early in the systemic response presumably plays a similarly inhibitory role. Epinephrine inhibits the TNF-α response to endotoxin infusion in humans while augmenting and accelerating the release of IL-10; prostaglandin E2 has a similar “reprogramming” effect on the responses of circulating monocytes to LPS and other bacterial agonists. Cortisol, epinephrine, IL-10, and C-reactive protein reduce the ability of neutrophils to attach to vascular endothelium, favoring their demargination and thus contributing to leukocytosis while preventing neutrophilendothelial adhesion in uninflamed organs. Studies in rodents have found that macrophage cytokine


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InternalMed_Harrison. favoring their demargination and thus contributing to leukocytosis while preventing neutrophilendothelial adhesion in uninflamed organs. Studies in rodents have found that macrophage cytokine synthesis is inhibited by acetylcholine that is produced by choline acetyltransferase–secreting CD4+ T cells in response to stimulation by norepinephrine, whereas acetylcholineproducing B cells reduce neutrophil infiltration into tissues. Several lines of evidence thus suggest that the body’s neuroendocrine responses to injury and infection normally prevent inflammation within organs distant from a site of infection. There is also evidence that these responses may be immunosuppressive.


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InternalMed_Harrison. IL-6 plays important roles in the systemic compartment. Released by many different cell types, IL-6 is an important stimulus to the hypothalamic-pituitary-adrenal axis, is the major procoagulant cytokine, and is a principal inducer of the acute-phase response, which increases the blood concentrations of numerous molecules that have anti-infective, procoagulant, or anti-inflammatory actions. Blood levels of IL-1 receptor antagonist often greatly exceed those of circulating IL-1β, for example, and this excess may inhibit the binding of IL-1β to its receptors. High levels of soluble TNF receptors neutralize TNF-α that enters the circulation. Other acute-phase proteins are protease inhibitors or antioxidants; these may neutralize potentially harmful molecules released from neutrophils and other inflammatory cells. Increased hepatic production of hepcidin (stimulated largely by IL-6) promotes the sequestration of iron in hepatocytes, intestinal epithelial cells, and erythrocytes; this


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InternalMed_Harrison. other inflammatory cells. Increased hepatic production of hepcidin (stimulated largely by IL-6) promotes the sequestration of iron in hepatocytes, intestinal epithelial cells, and erythrocytes; this effect reduces iron acquisition by invading microbes while contributing to the normocytic, normochromic anemia associated with inflammation.


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InternalMed_Harrison. It may thus be said that both local and systemic responses to infectious agents benefit the host in important ways. Most of these responses and the molecules responsible for them have been highly conserved during animal evolution and therefore may be adaptive. 1754 Elucidating how they become maladaptive and contribute to lethality remains a major challenge for sepsis research.


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InternalMed_Harrison. Organ Dysfunction and Shock As the body’s responses to infection intensify, the mixture of circulating cytokines and other molecules becomes very complex: elevated blood levels of more than 60 molecules have been found in patients with septic shock. Although high concentrations of both proand anti-inflammatory molecules are found, the net mediator balance in the plasma of these extremely sick patients seems to be anti-inflammatory. For example, blood leukocytes from patients with severe sepsis are often hyporesponsive to agonists such as LPS. In patients with severe sepsis, persistence of leukocyte hyporesponsiveness has been associated with an increased risk of dying; at this time, the most predictive biomarker is a decrease in the expression of HLA-DR (class II) molecules on the surfaces of circulating monocytes, a response that seems to be induced by cortisol and/or IL-10. Apoptotic death of B cells, follicular dendritic cells, and CD4+ T lymphocytes also may contribute


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InternalMed_Harrison. the surfaces of circulating monocytes, a response that seems to be induced by cortisol and/or IL-10. Apoptotic death of B cells, follicular dendritic cells, and CD4+ T lymphocytes also may contribute significantly to the immunosuppressive state.


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InternalMed_Harrison. endothelial injury Given the vascular endothelium’s important roles in regulating vascular tone, vascular permeability, and coagulation, many investigators have favored widespread vascular endothelial injury as the major mechanism for multiorgan dysfunction. In keeping with this idea, one study found high numbers of vascular endothelial cells in the peripheral blood of septic patients. Leukocyte-derived mediators and platelet-leukocyte-fibrin thrombi may contribute to vascular injury, but the vascular endothelium also seems to play an active role. Stimuli such as TNF-α induce vascular endothelial cells to produce and release cytokines, procoagulant molecules, platelet-activating factor, nitric oxide, and other mediators. In addition, regulated cell-adhesion molecules promote the adherence of neutrophils to endothelial cells. Although these responses can attract phagocytes to infected sites and activate their antimicrobial arsenals, endothelial cell activation can also promote


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InternalMed_Harrison. of neutrophils to endothelial cells. Although these responses can attract phagocytes to infected sites and activate their antimicrobial arsenals, endothelial cell activation can also promote increased vascular permeability, microvascular thrombosis, DIC, and hypotension.


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InternalMed_Harrison. Tissue oxygenation may decrease as the number of functional capillaries is reduced by luminal obstruction due to swollen endothelial cells, decreased deformability of circulating erythrocytes, leukocyte-platelet-fibrin thrombi, or compression by edema fluid. On the other hand, studies using orthogonal polarization spectral imaging of the microcirculation in the tongue found that sepsis-associated derangements in capillary flow could be reversed by applying acetylcholine to the surface of the tongue or by giving nitroprusside intravenously; these observations suggest a neuroendocrine basis for the loss of capillary filling. Oxygen utilization by tissues may also be impaired by changes (possibly induced by nitric oxide) that decrease oxidative phosphorylation and ATP production while increasing glycolysis. The local accumulation of lactic acid, a consequence of increased glycolysis, may decrease extracellular pH and contribute to the slowdown in cellular metabolism that occurs within


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InternalMed_Harrison. glycolysis. The local accumulation of lactic acid, a consequence of increased glycolysis, may decrease extracellular pH and contribute to the slowdown in cellular metabolism that occurs within affected tissues.


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InternalMed_Harrison. Remarkably, poorly functioning “septic” organs usually appear normal at autopsy. There is typically very little necrosis or thrombosis, and apoptosis is largely confined to lymphoid organs and the gastrointestinal tract. Moreover, organ function usually returns to normal if patients recover. These points suggest that organ dysfunction during severe sepsis has a basis that is principally biochemical, not structural.


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InternalMed_Harrison. sePtic shock The hallmark of septic shock is a decrease in peripheral vascular resistance that occurs despite increased levels of vasopressor catecholamines. Before this vasodilatory phase, many patients experience a period during which oxygen delivery to tissues is compromised by myocardial depression, hypovolemia, and other factors. During this “hypodynamic” period, the blood lactate concentration is elevated and central venous oxygen saturation is low. Fluid administration is usually followed by the hyperdynamic vasodilatory phase, during which cardiac output is normal (or even high) and oxygen consumption declines despite adequate oxygen delivery. The blood lactate level may be normal or increased, and normalization of central venous oxygen saturation may reflect improved oxygen delivery, decreased oxygen uptake by tissues, or left-to-right shunting.


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InternalMed_Harrison. Prominent hypotensive molecules include nitric oxide, β-endorphin, bradykinin, platelet-activating factor, and prostacyclin. Agents that inhibit the synthesis or action of each of these mediators can prevent or reverse endotoxic shock in animals. However, in clinical trials, neither a platelet-activating factor receptor antagonist nor a bradykinin antagonist improved survival rates among patients with septic shock, and a nitric oxide synthase inhibitor, L-NG-methylarginine HCl, actually increased the mortality rate.


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InternalMed_Harrison. Severe Sepsis: A Single Pathogenesis? In some cases, circulating bacteria and their products almost certainly elicit multiorgan dysfunction and hypotension by directly stimulating inflammatory responses within the vasculature. In patients with fulminant meningococcemia, for example, mortality rates have correlated directly with blood levels of endotoxin and bacterial DNA and with the occurrence of DIC (Chap. 180). In most patients infected with other gram-negative bacteria, in contrast, circulating bacteria or bacterial molecules may reflect uncontrolled infection at a local tissue site and have little or no direct impact on distant organs; in these patients, inflammatory mediators or neural signals arising from the local site seem to be the key triggers for severe sepsis and septic shock. In a large series of patients with positive blood cultures, the risk of developing severe sepsis was strongly related to the site of primary infection: bacteremia arising from a pulmonary or


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InternalMed_Harrison. shock. In a large series of patients with positive blood cultures, the risk of developing severe sepsis was strongly related to the site of primary infection: bacteremia arising from a pulmonary or abdominal source was eightfold more likely to be associated with severe sepsis than was bacteremic urinary tract infection, even after the investigators controlled for age, the kind of bacteria isolated from the blood, and other factors. A third pathogenesis may be represented by severe sepsis due to superantigen-producing S. aureus or Streptococcus pyogenes; the T cell activation induced by these toxins produces a cytokine profile that differs substantially from that elicited by gram-negative bacterial infection. Further evidence for different pathogenetic pathways has come from observations that the pattern of mRNA expression in peripheral-blood leukocytes from children with sepsis is different for gram-positive, gram-negative, and viral pathogens.


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InternalMed_Harrison. The pathogenesis of severe sepsis thus may differ according to the infecting microbe, the ability of the host’s innate defense mechanisms to sense and respond to it, the site of the primary infection, the presence or absence of immune defects, and the prior physiologic status of the host. Genetic factors are probably important as well, yet despite much study very few allelic polymorphisms have been associated with sepsis severity in more than one or two analyses. Further studies in this area are needed. The manifestations of the septic response are superimposed on the symptoms and signs of the patient’s underlying illness and primary infection. The rate at which severe sepsis develops may differ from patient to patient, and there are striking individual variations in presentation. For example, some patients with sepsis are normoor hypothermic; the absence of fever is most common in neonates, in elderly patients, and in persons with uremia or alcoholism.


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InternalMed_Harrison. Hyperventilation, producing respiratory alkalosis, is often an early sign of the septic response. Disorientation, confusion, and other manifestations of encephalopathy may also develop early on, particularly in the elderly and in individuals with preexisting neurologic impairment. Focal neurologic signs are uncommon, although preexisting focal deficits may become more prominent.


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InternalMed_Harrison. Hypotension and DIC predispose to acrocyanosis and ischemic necrosis of peripheral tissues, most commonly the digits. Cellulitis, pustules, bullae, or hemorrhagic lesions may develop when hematogenous bacteria or fungi seed the skin or underlying soft tissue. Bacterial toxins may also be distributed hematogenously and elicit diffuse cutaneous reactions. On occasion, skin lesions may suggest specific pathogens. When sepsis is accompanied by cutaneous petechiae or purpura, infection with N. meningitidis (or, less commonly, H. influenzae) should be suspected (see Fig. 25e-42); in a patient who has been bitten by a tick while in an endemic area, petechial lesions also suggest Rocky Mountain spotted fever (see Fig. 211-1). A cutaneous lesion seen almost exclusively in neutropenic patients is ecthyma gangrenosum, often caused by P. aeruginosa. This bullous lesion surrounded by edema undergoes central hemorrhage and necrosis (see Fig. 189-1).


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InternalMed_Harrison. Histopathologic examination shows bacteria in and around the wall of a small vessel, with little or no neutrophilic response. Hemorrhagic or bullous lesions in a septic patient who has recently eaten raw oysters suggest V. vulnificus bacteremia, whereas such lesions in a patient who has recently sustained a dog bite may indicate bloodstream infection due to Capnocytophaga canimorsus or Capnocytophaga cynodegmi. Generalized erythroderma in a septic patient suggests the toxic shock syndrome due to S. aureus or S. pyogenes.


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InternalMed_Harrison. Gastrointestinal manifestations such as nausea, vomiting, diarrhea, and ileus may suggest acute gastroenteritis. Stress ulceration can lead to upper gastrointestinal bleeding. Cholestatic jaundice, with elevated levels of serum bilirubin (mostly conjugated) and alkaline phosphatase, may precede other signs of sepsis. Hepatocellular or canalicular dysfunction appears to underlie most cases, and the results of hepatic function tests return to normal with resolution of the infection. Prolonged or severe hypotension may induce acute hepatic injury or ischemic bowel necrosis.


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InternalMed_Harrison. Many tissues may be unable to extract oxygen normally from the blood, so that anaerobic metabolism occurs despite near-normal mixed venous oxygen saturation. Blood lactate levels rise early because of increased glycolysis as well as impaired clearance of the resulting lactate and pyruvate by the liver and kidneys. The blood glucose concentration often increases, particularly in patients with diabetes, although impaired gluconeogenesis and excessive insulin release on occasion produce hypoglycemia. The cytokine-driven acute-phase response inhibits the synthesis of transthyretin while enhancing the production of C-reactive protein, fibrinogen, and complement components. Protein catabolism is often markedly accelerated. Serum albumin levels decline as a result of decreased hepatic synthesis and the movement of albumin into interstitial spaces.


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InternalMed_Harrison. MAJOR COMPLICATIONS Cardiopulmonary Complications Ventilation-perfusion mismatching produces a fall in arterial Po2 early in the course. Increasing alveolar epithelial injury and capillary permeability result in increased pulmonary water content, which decreases pulmonary compliance and interferes with oxygen exchange. In the absence of pneumonia or heart failure, progressive diffuse pulmonary infiltrates and arterial hypoxemia occurring within 1 week of a known insult indicate the development of mild acute respiratory distress syndrome (ARDS) (200 mmHg < Pao2/Fio2 ≤ 300 mmHg), moderate ARDS (100 mmHg < Pao2/Fio2 ≤ 200 mmHg), or severe ARDS (Pao2/Fio2 ≤100 mmHg). Acute lung injury or ARDS develops in ~50% of patients with severe sepsis or septic shock. Respiratory muscle fatigue can exacerbate hypoxemia and hypercapnia. An elevated pulmonary capillary wedge pressure (>18 mmHg) suggests fluid volume overload or cardiac failure rather than ARDS. Pneumonia caused by viruses or by


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InternalMed_Harrison. exacerbate hypoxemia and hypercapnia. An elevated pulmonary capillary wedge pressure (>18 mmHg) suggests fluid volume overload or cardiac failure rather than ARDS. Pneumonia caused by viruses or by Pneumocystis may be clinically indistinguishable from ARDS.


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InternalMed_Harrison. Sepsis-induced hypotension (see “Septic Shock,” above) usually results initially from a generalized maldistribution of blood flow and blood volume and from hypovolemia that is due, at least in part, to diffuse capillary leakage of intravascular fluid. Other factors that may decrease effective intravascular volume include dehydration from antecedent disease or insensible fluid losses, vomiting or diarrhea, and polyuria. During early septic shock, systemic vascular resistance is usually elevated and cardiac output may be low. After fluid repletion, in contrast, cardiac output typically increases and systemic vascular resistance falls. Indeed, normal or increased cardiac output and decreased systemic vascular resistance distinguish septic shock from cardiogenic, extracardiac obstructive, and hypovolemic shock; other processes that can produce this combination include anaphylaxis, beriberi, cirrhosis, and overdoses of nitroprusside or narcotics.


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InternalMed_Harrison. Depression of myocardial function, manifested as increased end-diastolic and systolic ventricular volumes with a decreased ejection fraction, develops within 24 h in most patients with severe sepsis. Cardiac output is maintained despite the low ejection fraction because ventricular dilation permits a normal stroke volume. In survivors, myocardial function returns to normal over several days. Although myocardial dysfunction may contribute to hypotension, refractory hypotension is usually due to low systemic vascular resistance, and 1755 death most often results from refractory shock or the failure of multiple organs rather than from cardiac dysfunction per se.


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InternalMed_Harrison. Adrenal Insufficiency The diagnosis of adrenal insufficiency may be very difficult in critically ill patients. Whereas a plasma cortisol level of ≤15 μg/mL (≤10 μg/mL if the serum albumin concentration is <2.5 mg/dL) indicates adrenal insufficiency (inadequate production of cortisol), many experts now feel that the adrenocorticotropic hormone (CoSyntropin®) stimulation test is not useful for detecting less profound degrees of corticosteroid deficiency in patients who are critically ill.


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InternalMed_Harrison. The concept of critical illness–related corticosteroid insufficiency (CIRCI) was proposed to encompass the different mechanisms that may produce corticosteroid activity that is inadequate for the severity of a patient’s illness. Although CIRCI may result from structural damage to the adrenal gland, it is more commonly due to reversible dysfunction of the hypothalamic-pituitary axis or to tissue corticosteroid resistance resulting from abnormalities of the glucocorticoid receptor or increased conversion of cortisol to cortisone. The major clinical manifestation of CIRCI is hypotension that is refractory to fluid replacement and requires pressor therapy. Some classic features of adrenal insufficiency, such as hyponatremia and hyperkalemia, are usually absent; others, such as eosinophilia and modest hypoglycemia, may sometimes be found. Specific etiologies include fulminant N.


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InternalMed_Harrison. N. meningitidis bacteremia, disseminated tuberculosis, AIDS (with cytomegalovirus, Mycobacterium avium-intracellulare, or Histoplasma capsulatum disease), or the prior use of drugs that diminish glucocor ticoid production, such as glucocorticoids, megestrol, etomidate, or ketoconazole. Renal Complications Oliguria, azotemia, proteinuria, and nonspecific urinary casts are frequently found. Many patients are inappropriately polyuric; hyperglycemia may exacerbate this tendency. Most renal failure is due to acute tubular necrosis induced by hypovolemia, arterial hypotension, or toxic drugs, although some patients also have glomerulonephritis, renal cortical necrosis, or interstitial nephritis. Drug-induced renal damage may greatly complicate therapy, particu larly when hypotensive patients are given aminoglycoside antibiotics. Nosocomial sepsis following acute renal injury is associated with a high mortality rate.


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InternalMed_Harrison. Coagulopathy Although thrombocytopenia occurs in 10–30% of patients, the underlying mechanisms are not understood. Platelet counts are usually very low (<50,000/μL) in patients with DIC; these low counts may reflect diffuse endothelial injury or microvascular thrombosis, yet thrombi have only infrequently been found on biopsy of septic organs. Neurologic Complications Delirium (acute encephalopathy) is often an early manifestation of sepsis. Depending on the diagnostic criteria used, it occurs in 10–70% of septic patients at some point during the hospital course. When the septic illness lasts for weeks or months, “critical illness” polyneuropathy may prevent weaning from ventilatory support and produce distal motor weakness. Electrophysiologic studies are diagnostic. Guillain-Barré syndrome, metabolic disturbances, and toxin activity must be ruled out. Recent studies have documented long-term cognitive loss in survivors of severe sepsis.


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InternalMed_Harrison. Immunosuppression Patients with severe sepsis often become profoundly immunosuppressed. Manifestations include loss of delayed-type hypersensitivity reactions to common antigens, failure to control the primary infection, and increased risk for secondary infections (e.g., by opportunists such as Stenotrophomonas maltophilia, Acinetobacter calcoaceticus-baumannii, and Candida albicans). Approximately one-third of patients experience reactivation of herpes simplex virus, varicellazoster virus, or cytomegalovirus infections; the latter are thought to contribute to adverse outcomes in some instances.


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InternalMed_Harrison. Abnormalities that occur early in the septic response may include leukocytosis with a left shift, thrombocytopenia, hyperbilirubinemia, and 1756 proteinuria. Leukopenia may develop. The neutrophils may contain toxic granulations, Döhle bodies, or cytoplasmic vacuoles. As the septic response becomes more severe, thrombocytopenia worsens (often with prolonged thrombin time, decreased fibrinogen, and the presence of d-dimers, suggesting DIC), azotemia and hyperbilirubinemia become more prominent, and levels of aminotransferases rise. Active hemolysis suggests clostridial bacteremia, malaria, a drug reaction, or DIC; in the case of DIC, microangiopathic changes may be seen on a blood smear. During early sepsis, hyperventilation induces respiratory alkalosis. With respiratory muscle fatigue and the accumulation of lactate, metabolic acidosis (with increased anion gap) typically supervenes. Evaluation of arterial blood gases reveals hypoxemia that is initially correctable with supplemental


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InternalMed_Harrison. the accumulation of lactate, metabolic acidosis (with increased anion gap) typically supervenes. Evaluation of arterial blood gases reveals hypoxemia that is initially correctable with supplemental oxygen but whose later refractoriness to 100% oxygen inhalation indicates right-to-left shunting. The chest radiograph may be normal or may show evidence of underlying pneumonia, volume overload, or the diffuse infiltrates of ARDS. The electrocardiogram may show only sinus tachycardia or nonspecific ST–T wave abnormalities. Most diabetic patients with sepsis develop hyperglycemia. Severe infection may precipitate diabetic ketoacidosis that may exacerbate hypotension (Chap. 417). Hypoglycemia occurs rarely and may indicate adrenal insufficiency. The serum albumin level declines as sepsis continues. Hypocalcemia is rare.


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InternalMed_Harrison. There is no specific diagnostic test for sepsis. Diagnostically sensitive findings in a patient with suspected or proven infection include fever or hypothermia, tachypnea, tachycardia, and leukocytosis or leukopenia (Table 325-1); acutely altered mental status, thrombocytopenia, an elevated blood lactate level, respiratory alkalosis, or hypotension also should suggest the diagnosis. The systemic response can be quite variable, however. In one study, 36% of patients with severe sepsis had a normal temperature, 40% had a normal respiratory rate, 10% had a normal pulse rate, and 33% had normal white blood cell counts. Moreover, the systemic responses of uninfected patients with other conditions may be similar to those characteristic of sepsis. Examples include pancreatitis, burns, trauma, adrenal insufficiency, pulmonary embolism, dissecting or ruptured aortic aneurysm, myocardial infarction, occult hemorrhage, cardiac tamponade, postcardiopulmonary bypass syndrome, anaphylaxis,


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InternalMed_Harrison. adrenal insufficiency, pulmonary embolism, dissecting or ruptured aortic aneurysm, myocardial infarction, occult hemorrhage, cardiac tamponade, postcardiopulmonary bypass syndrome, anaphylaxis, tumor-associated lactic acidosis, and drug overdose.


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InternalMed_Harrison. Definitive etiologic diagnosis requires identification of the causative microorganism from blood or a local site of infection. At least two blood samples should be obtained (from two different venipuncture sites) for culture; in a patient with an indwelling catheter, one sample should be collected from each lumen of the catheter and another via venipuncture. In many cases, blood cultures are negative; this result can reflect prior antibiotic administration, the presence of slow-growing or fastidious organisms, or the absence of microbial invasion of the bloodstream. In these cases, Gram’s staining and culture of material from the primary site of infection or from infected cutaneous lesions may help establish the microbial etiology. Identification of microbial DNA in peripheral blood or tissue samples by polymerase chain reaction may also be definitive. The skin and mucosae should be examined carefully and repeatedly for lesions that might yield diagnostic information. With


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InternalMed_Harrison. blood or tissue samples by polymerase chain reaction may also be definitive. The skin and mucosae should be examined carefully and repeatedly for lesions that might yield diagnostic information. With overwhelming bacteremia (e.g., pneumococcal sepsis in splenectomized individuals; fulminant meningococcemia; or infection with V. vulnificus, B. pseudomallei, or Y. pestis), microorganisms are sometimes visible on buffy coat smears of peripheral blood.


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InternalMed_Harrison. Patients in whom sepsis is suspected must be managed expeditiously. This task is best accomplished by personnel who are experienced in the care of the critically ill. Successful management requires urgent measures to treat the infection, to provide hemodynamic and respiratory support, and to remove or drain infected tissues. These measures should be initiated within 1 h of the patient’s presentation with severe sepsis or septic shock. Rapid assessment and diagnosis are therefore essential.


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InternalMed_Harrison. Antimicrobial chemotherapy should be started as soon as samples of blood and other relevant sites have been obtained for culture. A large retrospective review of patients who developed septic shock found that the interval between the onset of hypotension and the administration of appropriate antimicrobial chemotherapy was the major determinant of outcome; a delay of as little as 1 h was associated with lower survival rates. Use of “inappropriate” antibiotics, defined on the basis of local microbial susceptibilities and published guidelines for empirical therapy (see below), was associated with fivefold lower survival rates, even among patients with negative cultures.


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InternalMed_Harrison. It is therefore very important to promptly initiate empirical antimicrobial therapy that is effective against both gram-positive and gram-negative bacteria (Table 325-3). Maximal recommended doses of antimicrobial drugs should be given intravenously, with adjustment for impaired renal function when necessary. Available information about patterns of antimicrobial susceptibility among bacterial isolates from the community, the hospital, and the patient should be taken into account. When culture results become available, the regimen can often be simplified because a single antimicrobial agent is usually adequate for the treatment of a known pathogen. Meta-analyses have concluded that, with one exception, combination antimicrobial therapy is not superior to monotherapy for treating gram-negative bacteremia; the exception is that aminoglycoside monotherapy for P. aeruginosa bacteremia is less effective than the combination of an aminoglycoside with an antipseudomonal β-lactam agent.


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InternalMed_Harrison. bacteremia; the exception is that aminoglycoside monotherapy for P. aeruginosa bacteremia is less effective than the combination of an aminoglycoside with an antipseudomonal β-lactam agent. Empirical antifungal therapy should be strongly considered if the septic patient is already receiving broad-spectrum antibiotics or parenteral nutrition, has been neutropenic for ≥5 days, has had a long-term central venous catheter in place, or has been hospitalized in an ICU for a prolonged period. The chosen antimicrobial regimen should be reconsidered daily in order to provide maximal efficacy with minimal resistance, toxicity, and cost.


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InternalMed_Harrison. Most patients require antimicrobial therapy for at least 1 week. The duration of treatment is typically influenced by factors such as the site of tissue infection, the adequacy of surgical drainage, the patient’s underlying disease, and the antimicrobial susceptibility of the microbial isolate(s). The absence of an identified microbial pathogen is not necessarily an indication for discontinuing antimicrobial therapy because “appropriate” antimicrobial regimens seem to be beneficial in both culture-negative and culture-positive cases.


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InternalMed_Harrison. Removal or drainage of a focal source of infection is essential. In one series, a focus of ongoing infection was found in ~80% of surgical ICU patients who died of severe sepsis or septic shock. Sites of occult infection should be sought carefully, particularly in the lungs, abdomen, and urinary tract. Indwelling IV or arterial catheters should be removed and the tip rolled over a blood agar plate for quantitative culture; after antibiotic therapy has been initiated, a new catheter should be inserted at a different site. Foley and drainage catheters should be replaced. The possibility of paranasal sinusitis (often caused by gram-negative bacteria) should be considered if the patient has undergone nasal intubation or has an indwelling nasogastric or feeding tube. Even in patients without abnormalities on chest radiographs, computed tomography (CT) of the chest may identify unsuspected parenchymal, mediastinal, or pleural disease. In the neutropenic patient, cutaneous sites of


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InternalMed_Harrison. without abnormalities on chest radiographs, computed tomography (CT) of the chest may identify unsuspected parenchymal, mediastinal, or pleural disease. In the neutropenic patient, cutaneous sites of tenderness and erythema, particularly in the perianal region, must be carefully sought. In patients with sacral or ischial decubitus ulcers, it is important to exclude pelvic or other soft tissue pus collections with CT or magnetic resonance imaging (MRI). In patients with severe sepsis arising from the urinary tract, sonography or CT should be used to rule out ureteral obstruction, perinephric abscess, and renal abscess. Sonographic or CT imaging of the upper abdomen may disclose


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InternalMed_Harrison. Immunocompetent adult The many acceptable regimens include (1) piperacillin-tazobactam (3.375 g q4–6h); (2) imipenem-cilastatin (0.5 g q6h), ertapenem (1 g q24h), or meropenem (1 g q8h); or (3) cefepime (2 g q12h). If the patient is allergic to β-lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin (500–750 mg q12h) plus clindamycin (600 mg q8h). Vancomycin (15 mg/kg q12h) should be added to each of the above regimens.


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InternalMed_Harrison. Neutropenia (<500 neutrophils/μL) Regimens include (1) imipenemcilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q8h) or (2) piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h). Vancomycin (15 mg/kg q12h) should be added if the patient has an indwelling vascular catheter, has received quinolone prophylaxis, or has received intensive chemotherapy that produces mucosal damage; if staphylococci are suspected; if the institution has a high incidence of MRSA infections; or if there is a high prevalence of MRSA isolates in the community. Empirical antifungal therapy with an echinocandin (for caspofungin: a 70-mg loading dose, then 50 mg daily), voriconazole (6 mg/kg q12h for 2 doses, then 3 mg/ kg q12h), or a lipid formulation of amphotericin B should be added if the patient is hypotensive, has been receiving broad-spectrum antibacterial drugs, or remains febrile 5 days after initiation of empirical antibacterial therapy.


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InternalMed_Harrison. Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporinresistant pneumococci is high, add vancomycin. If the patient is allergic to β-lactam drugs, vancomycin (15 mg/kg q12h) plus either moxifloxacin (400 mg q24h) or levofloxacin (750 mg q24h) should be used. IV drug user Vancomycin (15 mg/kg q12h) is essential. AIDS Cefepime alone (2 g q8h) or piperacillintazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) should be used. If the patient is allergic to β-lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used. Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus. Source: Adapted in part from DN Gilbert et al: The Sanford Guide to Antimicrobial Therapy, 43rd ed, 2013. evidence of cholecystitis, bile duct dilation, and pus collections in the liver, subphrenic space, or spleen. HEMODYNAMIC, RESPIRATORY, AND METABOLIC SUPPORT


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InternalMed_Harrison. The primary goals are to restore adequate oxygen and substrate delivery to the tissues as quickly as possible and to improve tissue oxygen utilization and cellular metabolism. Adequate organ perfusion is thus essential. Circulatory adequacy is assessed by measurement 1757 of arterial blood pressure and monitoring of parameters such as mentation, urine output, and skin perfusion. Indirect indices of oxygen delivery and consumption, such as central venous oxygen saturation, may also be useful. Initial management of hypotension should include the administration of IV fluids, typically beginning with 1–2 L of normal saline over 1–2 h. To avoid pulmonary edema, the central venous pressure should be maintained at 8–12 cmH2O. The urine output rate should be kept at >0.5 mL/kg per hour by continuing fluid administration; a diuretic such as furosemide may be used if needed. In about one-third of patients, hypotension and organ hypoperfusion respond to fluid resuscitation; a reasonable goal is


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InternalMed_Harrison. fluid administration; a diuretic such as furosemide may be used if needed. In about one-third of patients, hypotension and organ hypoperfusion respond to fluid resuscitation; a reasonable goal is to maintain a mean arterial blood pressure of >65 mmHg (systolic pressure >90 mmHg). If these guidelines cannot be met by volume infusion, vasopressor therapy is indicated (Chap. 326). Titrated doses of norepinephrine should be administered through a central catheter. If myocardial dysfunction produces elevated cardiac filling pressures and low cardiac output, inotropic therapy with dobutamine is recommended. Dopamine is rarely used.


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InternalMed_Harrison. In patients with septic shock, plasma vasopressin levels increase transiently but then decrease dramatically. Early studies found that vasopressin infusion can reverse septic shock in some patients, reducing or eliminating the need for catecholamine pressors. Although vasopressin may benefit patients who require less nor-epinephrine, its role in the treatment of septic shock seems to be a minor one overall. CIRCI (see “Adrenal Insufficiency,” above) should be strongly con sidered in patients who develop hypotension that does not respond to fluid replacement therapy. Hydrocortisone (50 mg IV every 6 h) should be given; if clinical improvement occurs over 24–48 h, most experts would continue hydrocortisone therapy for 5–7 days before slowly tapering and discontinuing it. Meta-analyses of recent clinical trials have concluded that hydrocortisone therapy hastens recovery from sepsis-induced hypotension without increasing long-term survival.


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InternalMed_Harrison. Ventilator therapy is indicated for progressive hypoxemia, hyper capnia, neurologic deterioration, or respiratory muscle failure. Sustained tachypnea (respiratory rate, >30 breaths/min) is frequently a harbinger of impending respiratory collapse; mechanical ventilation is often initiated to ensure adequate oxygenation, to divert blood from the muscles of respiration, to prevent aspiration of oropharyngeal contents, and to reduce the cardiac afterload. The results of recent studies favor the use of low tidal volumes (6 mL/kg of ideal body weight, or as low as 4 mL/kg if the plateau pressure exceeds 30 cmH2O). Patients undergoing mechanical ventilation require careful sedation, with daily interruptions; elevation of the head of the bed helps to prevent nosocomial pneumonia. Stress-ulcer prophylaxis with a histamine H2-receptor antagonist may decrease the risk of gastrointestinal hemorrhage in ventilated patients.


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InternalMed_Harrison. Erythrocyte transfusion is generally recommended when the blood hemoglobin level decreases to ≤7 g/dL, with a target level of 9 g/dL in adults. Erythropoietin is not used to treat sepsis-related anemia. Bicarbonate is sometimes administered for severe metabolic acidosis (arterial pH <7.2), but there is little evidence that it improves either hemodynamics or the response to vasopressor hormones. DIC, if complicated by major bleeding, should be treated with transfusion of fresh-frozen plasma and platelets. Successful treatment of the underlying infection is essential to reverse both acidosis and DIC. Patients who are hypercatabolic and have acute renal failure may benefit greatly from intermittent hemodialysis or continuous veno-venous hemofiltration.


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InternalMed_Harrison. In patients with prolonged severe sepsis (i.e., that lasting more than 2 or 3 days), nutritional supplementation may reduce the impact of protein hypercatabolism; the available evidence favors the enteral delivery route. Prophylactic heparinization to prevent deep venous thrombosis is indicated for patients who do not have active bleeding or coagulopathy; when heparin is contraindicated, compression 1758 stockings or an intermittent compression device should be used. Recovery is also assisted by prevention of skin breakdown, nosocomial infections, and stress ulcers. The role of tight control of the blood glucose concentration in recovery from critical illness has been addressed in numerous controlled trials. Meta-analyses of these trials have concluded that use of insulin to lower blood glucose levels to 100–120 mg/dL is potentially harmful and does not improve survival rates. Most experts now recommend using insulin only if it is needed to maintain the blood glucose concentration


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InternalMed_Harrison. glucose levels to 100–120 mg/dL is potentially harmful and does not improve survival rates. Most experts now recommend using insulin only if it is needed to maintain the blood glucose concentration below ~180 mg/dL. Patients receiving intravenous insulin must be monitored frequently (every 1–2 h) for hypoglycemia.


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InternalMed_Harrison. Despite aggressive management, many patients with severe sepsis or septic shock die. Numerous interventions have been tested for their ability to improve survival rates among patients with severe sepsis. The list includes endotoxin-neutralizing proteins, inhibitors of cyclooxygenase or nitric oxide synthase, anticoagulants, polyclonal immunoglobulins, glucocorticoids, a phospholipid emulsion, and antagonists to TNF-α, IL-1, platelet-activating factor, and bradykinin. Unfortunately, none of these agents has improved rates of survival among patients with severe sepsis/septic shock in more than one large-scale, randomized, placebo-controlled clinical trial. Many factors have contributed to this lack of reproducibility, including (1) heterogeneity of the patient populations studied, the primary infection sites, the preexisting illnesses, and the inciting microbes; and (2) the nature of the “standard” therapy also used. A dramatic example of this problem was seen in a trial of tissue


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InternalMed_Harrison. primary infection sites, the preexisting illnesses, and the inciting microbes; and (2) the nature of the “standard” therapy also used. A dramatic example of this problem was seen in a trial of tissue factor pathway inhibitor. Whereas the drug appeared to improve survival rates after 722 patients had been studied ( p = .006), it did not do so in the next 1032 patients, and the overall result was negative. This inconsistency argues that the results of a clinical trial may not apply to individual patients, even within a carefully selected patient population. It also suggests that, at a minimum, a sepsis intervention should show a significant survival benefit in more than one placebo-controlled, randomized clinical trial before it is accepted as routine clinical practice. In one attempt to reduce patient heterogeneity in clinical trials, experts have called for changes that would restrict these trials to patients who have similar underlying diseases (e.g., major trauma) and inciting


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InternalMed_Harrison. to reduce patient heterogeneity in clinical trials, experts have called for changes that would restrict these trials to patients who have similar underlying diseases (e.g., major trauma) and inciting infections (e.g., pneumonia). Other investigators have proposed using specific biobe harmful to patients whose adaptive defense mechanisms are working well. This analysis suggests that if more aggressive early resuscitation improves survival rates among sicker patients, it will become more difficult to obtain additional benefit from other therapies; that is, if an intervention improves patients’ risk status, moving them into a “less severe illness” category, it will be harder to show that adding another agent to the therapeutic regimen is beneficial.


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InternalMed_Harrison. An international consortium has advocated “bundling” of multiple therapeutic maneuvers into a unified algorithmic approach that will become the standard of care for severe sepsis. In theory, such a strategy would improve care by mandating measures that seem to bring maximal benefit, such as the rapid administration of appropriate antimicrobial therapy, fluids, and blood pressure support. Caution may be engendered by the fact that three of the key elements of the initial algorithm were eventually withdrawn for lack of evidence; moreover, the benefit of the current sepsis bundles has not been established in randomized controlled clinical trials.


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InternalMed_Harrison. Approximately 20–35% of patients with severe sepsis and 40–60% of patients with septic shock die within 30 days. Others die within the ensuing 6 months. Late deaths often result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple organs, or the patient’s underlying disease. Case–fatality rates are similar for culture-positive and culture-negative severe sepsis. Prognostic stratification systems such as APACHE II indicate that factoring in the patient’s age, underlying condition, and various physiologic variables can yield useful estimates of the risk of dying of severe sepsis. Age and prior health status are probably the most important risk factors (Fig. 325-1). In patients with no known preexisting morbidity, the case–fatality rate remains <10% until the fourth decade of life, after which it gradually increases to >35% in the very elderly. Death is significantly more likely in severely septic patients with preexisting illness.


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InternalMed_Harrison. remains <10% until the fourth decade of life, after which it gradually increases to >35% in the very elderly. Death is significantly more likely in severely septic patients with preexisting illness. Septic shock is also a strong predictor of markers, such as IL-6 levels in blood or the expression of HLA-DR on peripheral-blood monocytes, to identify the patients most likely to benefit from certain interventions.


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InternalMed_Harrison. Recombinant activated protein C (aPC) was the first immunomodulatory drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with severe sepsis or septic shock. Approval was based on the results of a single randomized controlled trial in which the drug was given within 24 h of the patient’s first sepsis-related organ dysfunction; the 28-day survival rate was significantly higher among aPC recipients


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InternalMed_Harrison. Case-fatality rate, % who were very sick (APACHE II score, ≥25) before infusion of the protein than among placebo-treated controls. Subsequent trials failed to show a benefit of aPC treatment in patients who were less sick (APACHE II score, <25) or in children, and, a decade after its licensure by the FDA, the drug was withdrawn from the market when a European trial failed to confirm its efficacy in adults with sepsis. Agents in ongoing or planned clinical trials include intravenous immunoglobulin, a polymyxin B hemofiltration column, and FIGURE 325-1 Age, years Influence of age and prior health status on outcome granulocyte-macrophage colony-stimulating factor, which has been reported to restore monocyte immunocompetence in patients with sepsis-associated immunosuppression.


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InternalMed_Harrison. A careful retrospective analysis found that the apparent efficacy of all sepsis therapeutics studied to date has been greatest among the patients at greatest risk of dying before treatment; conversely, use of many of these drugs has been associated with increased mortality rates among patients who are less ill. It is possible that neutralizing one of many different mediators may help patients who are very sick, whereas disrupting the mediator balance may of severe sepsis. With modern therapy, fewer than 10% of previously healthy young individuals (below 35 years of age) die with severe sepsis; the case–fatality rate then increases slowly through middle and old age. The most commonly identified etiologic agents in patients who die are Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Neisseria meningitidis. Individuals with preexisting comorbidities are at greater risk of dying of severe sepsis at any age. The etiologic agents in these cases are likely to be


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InternalMed_Harrison. pneumoniae, and Neisseria meningitidis. Individuals with preexisting comorbidities are at greater risk of dying of severe sepsis at any age. The etiologic agents in these cases are likely to be S. aureus, Pseudomonas aeruginosa, various Enterobacteriaceae, enterococci, or fungi. (Adapted from DC Angus et al: Crit Care Med 29:1303, 2001.) both short-and long-term mortality. Cognitive impairment may be significant in survivors, particularly those who are elderly.


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InternalMed_Harrison. Prevention offers the best opportunity to reduce morbidity and mortality from severe sepsis. In developed countries, most episodes of severe sepsis and septic shock are complications of nosocomial infections. These cases might be prevented by reducing the number of invasive procedures undertaken, by limiting the use (and duration of use) of indwelling vascular and bladder catheters, by reducing the incidence and duration of profound neutropenia (<500 neutrophils/ μL), and by more aggressively treating localized nosocomial infections. Indiscriminate use of antimicrobial agents and glucocorticoids should be avoided, and optimal infection-control measures (Chap. 168) should be used. Studies indicate that 50–70% of patients who develop nosocomial severe sepsis or septic shock have experienced a less severe stage of the septic response on at least one previous day in the hospital. Research is needed to identify patients at increased risk and to develop adjunctive agents that can modulate


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InternalMed_Harrison. a less severe stage of the septic response on at least one previous day in the hospital. Research is needed to identify patients at increased risk and to develop adjunctive agents that can modulate the septic response before organ dysfunction or hypotension occurs. Cardiogenic Shock and Pulmonary Edema Judith S. Hochman, David H. Ingbar Cardiogenic shock and pulmonary edema are life-threatening condi-tions that should be treated as medical emergencies. The most com-mon joint etiology is severe left ventricular (LV) dysfunction that leads 326 to pulmonary congestion and/or systemic hypoperfusion (Fig. 326-1). The pathophysiology of pulmonary edema and shock is discussed in Chaps. 47e and 324, respectively.


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InternalMed_Harrison. Cardiogenic shock (CS) is characterized by systemic hypoperfusion due to severe depression of the cardiac index (<2.2 [L/min]/m2) and sustained systolic arterial hypotension (<90 mmHg) despite an elevated filling pressure (pulmonary capillary wedge pressure [PCWP] >18 mmHg). It is associated with in-hospital mortality rates >50%. The major causes of CS are listed in Table 326-1. Circulatory failure based on cardiac dysfunction may be caused by primary myocardial failure, most commonly secondary to acute myocardial infarction (MI) (Chap. 295), and less frequently by cardiomyopathy or myocarditis (Chap. 287), cardiac tamponade (Chap. 288), or critical valvular heart disease (Chap. 283).


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InternalMed_Harrison. Incidence The rate of CS complicating acute MI was 20% in the 1960s, stayed at ~8% for >20 years, but decreased to 5–7% in the first decade of this millennium largely due to increasing use of early reperfusion therapy for acute MI. Shock is more common with ST elevation MI (STEMI) than with non-ST elevation MI (Chap. 295). LV failure accounts for ~80% of cases of CS complicating acute MI. Acute severe mitral regurgitation (MR), ventricular septal rupture (VSR), predominant right ventricular (RV) failure, and free wall rupture or tamponade account for the remainder.


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InternalMed_Harrison. Pathophysiology CS is characterized by a vicious circle in which depression of myocardial contractility, usually due to ischemia, results in reduced cardiac output and arterial blood pressure (BP), which result in hypoperfusion of the myocardium and further ischemia and depression of cardiac output (Fig. 326-1). Systolic myocardial dysfunction reduces stroke volume and, together with diastolic dysfunction, leads to elevated LV end-diastolic pressure and PCWP as well as to pulmonary congestion. Reduced coronary perfusion leads to worsening ischemia and progressive myocardial dysfunction and a rapid


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InternalMed_Harrison. FIGURE 326-1 Pathophysiology of cardiogenic shock. Systolic and diastolic myocardial dysfunction results in a reduction in cardiac output and often pulmonary congestion. Systemic and coronary hypo-perfusion occur, resulting in progressive ischemia. Although a number of compensatory mechanisms are activated in an attempt to support the circulation, these compensatory mechanisms may become maladaptive and produce a worsening of hemodynamics. *Release of inflammatory cytokines after myocardial infarction may lead to inducible nitric oxide expression, excess nitric oxide, and inappropriate vasodilation. This causes further reduction in systemic and coronary perfusion. A vicious spiral of progressive myocardial dysfunction occurs that ultimately results in death if it is not interrupted. LVEDP, left ventricular end-diastolic pressure. (From SM Hollenberg et al: Ann Intern Med 131:47, 1999.) downward spiral, which, if uninterrupted, is often fatal. A systemic inflammatory response syndrome


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InternalMed_Harrison. left ventricular end-diastolic pressure. (From SM Hollenberg et al: Ann Intern Med 131:47, 1999.) downward spiral, which, if uninterrupted, is often fatal. A systemic inflammatory response syndrome may accompany large infarctions and shock. Inflammatory cytokines, inducible nitric oxide synthase, and excess nitric oxide and peroxynitrite may contribute to the genesis of CS as they do to that of other forms of shock (Chap. 324). Lactic acidosis and hypoxemia from CS contribute to the vicious circle by worsening myocardial ischemia and hypotension. Severe acidosis reduces the efficacy of endogenous and exogenously administered catecholamines. Refractory sustained ventricular or atrial tachyarrhythmias can cause or exacerbate CS.


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InternalMed_Harrison. Patient Profile Older age, female sex, prior MI, diabetes, anterior MI location, and extensive coronary artery stenoses are associated with an increased risk of CS complicating MI. Shock associated with a first inferior MI should prompt a search for a mechanical cause. CS may rarely occur in the absence of significant stenosis, as seen in LV apical ballooning/Takotsubo’s cardiomyopathy. Timing Shock is present on admission in only one-quarter of patients who develop CS complicating MI; one-quarter develop it rapidly thereafter, within 6 h of MI onset. Another quarter develop shock later on the first day. Subsequent onset of CS may be due to reinfarction, marked infarct expansion, or a mechanical complication.


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InternalMed_Harrison. Diagnosis Due to the unstable condition of these patients, supportive therapy must be initiated simultaneously with diagnostic evaluation (Fig. 326-2). A focused history and physical examination should be performed, blood specimens sent to the laboratory, and an electrocardiogram (ECG) and chest x-ray obtained. Etiologies of Cardiogenic Shock or Pulmonary Edema Acute myocardial infarction/ischemia LV failure Ventricular septal rupture Papillary muscle/chordal rupture–severe MR Ventricular free wall rupture with subacute tamponade Other conditions complicating large MIs Post-cardiac arrest Post-cardiotomy Refractory sustained tachyarrhythmias Acute fulminant myocarditis End-stage cardiomyopathy LV apical ballooning Takotsubo’s cardiomyopathy Hypertrophic cardiomyopathy with severe outflow obstruction Aortic dissection with aortic insufficiency or tamponade Severe valvular heart disease Other Etiologies of Cardiogenic Shockb RV failure due to:


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InternalMed_Harrison. Other Etiologies of Cardiogenic Shockb RV failure due to: Severe acidosis, severe hypoxemia aThe etiologies of CS are listed. Most of these can cause pulmonary edema instead of shock or pulmonary edema with CS. bThese cause CS but not pulmonary edema. Abbreviations: LV, left ventricular; MI, myocardial infarction; MR, mitral regurgitation; RV, right ventricular; VSR, ventricular septal rupture. Echocardiography is an invaluable diagnostic tool in patients with suspected CS.


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InternalMed_Harrison. Echocardiography is an invaluable diagnostic tool in patients with suspected CS. clinical findings Most patients have dyspnea and appear pale, apprehensive, and diaphoretic, and mental status may be altered. The pulse is typically weak and rapid, often in the range of 90–110 beats/min, or severe bradycardia due to high-grade heart block may be present. Systolic BP is reduced (<90 mmHg or ≥30 mmHg below baseline) with a narrow pulse pressure (<30 mmHg), but occasionally BP may be maintained by very high systemic vascular resistance. Tachypnea, Cheyne-Stokes respirations, and jugular venous distention may be present. There is typically a weak apical pulse and soft S1, and an S3 gallop may be audible. Acute, severe MR and VSR usually are associated with characteristic systolic murmurs (Chap. 295). Rales are audible in most patients with LV failure. Oliguria is common.


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InternalMed_Harrison. laboratory findings The white blood cell count is typically elevated with a left shift. Renal function is initially unchanged, but blood urea nitrogen and creatinine rise progressively. Hepatic transaminases may be markedly elevated due to liver hypoperfusion. The lactic acid level is elevated. Arterial blood gases usually demonstrate hypoxemia and anion gap metabolic acidosis, which may be compensated by respiratory alkalosis. Cardiac markers, creatine phosphokinase and its MB fraction, and troponins I and T are typically markedly elevated. electrocardiogram In CS due to acute MI with LV failure, Q waves and/or >2-mm ST elevation in multiple leads or left bundle branch block are usually present. More than one-half of all infarcts associated with shock are anterior. Global ischemia due to severe left main stenosis usually is accompanied by severe (e.g., >3 mm) ST depressions in multiple leads.


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InternalMed_Harrison. chest roentgenogram The chest x-ray typically shows pulmonary vascular congestion and often pulmonary edema, but these findings may be absent in up to a third of patients. The heart size is usually normal when CS results from a first MI but is enlarged when it occurs in a patient with a previous MI. echocardiogram A two-dimensional echocardiogram with color-flow Doppler (Chap. 270e) should be obtained promptly in patients with suspected CS to help define its etiology. Doppler mapping demonstrates a left-to-right shunt in patients with VSR and the severity of MR when the latter is present. Proximal aortic dissection with aortic regurgitation or tamponade may be visualized, or evidence for pulmonary embolism may be obtained (Chap. 300).


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InternalMed_Harrison. Pulmonary artery catheterization The use of pulmonary artery (Swan-Ganz) catheters in patients with established or suspected CS is controversial (Chaps. 272 and 321). Their use is generally recommended for measurement of filling pressures and cardiac output to confirm the diagnosis and to optimize the use of IV fluids, inotropic agents, and vasopressors in persistent shock (Table 326-2). O2 saturation measurement from right atrial, RV, and pulmonary arterial blood samples can rule out a left-to-right shunt. In CS, low mixed venous O2 saturations and elevated arteriovenous (AV) O2 differences reflect low cardiac index and high fractional O2 extraction. However, when sepsis accompanies CS, AV O2 differences may not be elevated (Chap. 324). The PCWP is elevated. Use of sympathomimetic amines may return these measurements and the systemic BP to normal. Systemic vascular resistance may be low, normal, or elevated in CS. Equalization of rightand left-sided filling pressures (right atrial


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InternalMed_Harrison. may return these measurements and the systemic BP to normal. Systemic vascular resistance may be low, normal, or elevated in CS. Equalization of rightand left-sided filling pressures (right atrial and PCWP) suggests cardiac tamponade as the cause of CS (Chap. 288).


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InternalMed_Harrison. left heart catheterization and coronary angiograPhy Measurement of LV pressure and definition of the coronary anatomy provide useful information and are indicated in most patients with CS complicating MI. Cardiac catheterization should be performed when there is a plan and capability for immediate coronary intervention (see below) or when a definitive diagnosis has not been made by other tests.


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InternalMed_Harrison. (Fig. 326-2) In addition to the usual treatment of acute MI (Chap. 295), initial therapy is aimed at maintaining adequate systemic and coronary perfusion by raising systemic BP with vasopressors and adjusting volume status to a level that ensures optimum LV filling pressure. There is interpatient variability, but the values that generally are associated with adequate perfusion are systolic BP ~90 mmHg or mean BP >60 mmHg and PCWP >20 mmHg. Hypoxemia and acidosis must be corrected; most patients require ventilatory support (see “Pulmonary Edema,” below). Negative inotropic agents should be discontinued and the doses of renally cleared medications adjusted. Hyperglycemia should be controlled with insulin. Bradyarrhythmias may require transvenous pacing. Recurrent ventricular tachycardia or rapid atrial fibrillation may require immediate treatment (Chap. 276).


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InternalMed_Harrison. Various IV drugs may be used to augment BP and cardiac output in patients with CS. All have important disadvantages, and none has been shown to change the outcome in patients with established shock. Norepinephrine is a potent vasoconstrictor and inotropic stimulant that is useful for patients with CS. As first line of therapy norepinephrine was associated with fewer adverse events, including arrhythmias, compared to a dopamine randomized trial of patients Third line of action


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InternalMed_Harrison. Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema Most likely major underlying disturbance? Acute pulmonary edema Check blood pressure Systolic BP Greater than 100 mmHg and not less than 30 mmHg below baseline ACE Inhibitors Short-acting agent such as captopril (1 to 6.25 mg) Low output-cardiogenic shock Check blood pressure Section 9.5 – 2013 American College of Cardiology Foundation /American Heart Association Guidelines for Management of ST-Elevation Myocardial Infarction andFigures 3 and 4 – 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: Adult Advanced Cardiovascular Life Support Hypovolemia BradycardiaTachycardiaAdminister • Fluids• Blood transfusions• Cause-specific interventionsConsider vasopressorsArrhythmia Systolic BP Greater than 100 mmHgDopamine, 5 to 15 ˜g/kg per minute IV Nitroglycerin 10to 20 ˜g/min IVDobutamine Systolic BP 70 to 100 mmHgSystolic BP NO


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InternalMed_Harrison. interventionsConsider vasopressorsArrhythmia Systolic BP Greater than 100 mmHgDopamine, 5 to 15 ˜g/kg per minute IV Nitroglycerin 10to 20 ˜g/min IVDobutamine Systolic BP 70 to 100 mmHgSystolic BP NO signs/symptoms of shocksigns/symptoms of shock* 2 to 20 ˜g/kg per minute IVless than 100 mmHg *Norepinephrine 0.5 to 30 ˜g/min IV or Administer • Furosemide IV 0.5 to 1.0 mg/kg• Morphine IV 2 to 4 mg• Oxygen/intubation as needed• Nitroglycerin SL, then 10to 20 ˜g/min IV if SBP greater than 100 mmHg• *Norepinephrine, 0.5 to 30 ˜g/min IV or Dopamine, 5 to 15 ˜g/kg per minute IV if SBP <100 mmHg and signs/symptoms of shock present • Dobutamine 2 to 20 ˜g/kg per minute IV if SBP 70to 100 mmHg and no signs/symptoms of shockFirst line of actionSecond line of actionFurther diagnostic/therapeutic considerations (should be consideredin nonhypovolemic shock)Therapeutic • Intraaortic balloon pump or othercirculatory assist device• Reperfusion/revascularization


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InternalMed_Harrison. FIGURE 326-2 The emergency management of patients with cardiogenic shock, acute pulmonary edema, or both is outlined.


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InternalMed_Harrison. *Furosemide: <0.5 mg/kg for new-onset acute pulmonary edema without hypervolemia; 1 mg/kg for acute on chronic volume overload, renal insufficiency. †For management of bradycardia and tachycardia, see Chaps. 274 and 276. Additional information can also be found in Section 9.5 of the 2013 American College of Cardiology Foundation/American Heart Association Guidelines for Management of ST-Elevation Myocardial Infarction and Figures 3 and 4 of the 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: Adult Advanced Cardiovascular Life Support. *Indicates modification from published guidelines. ACE, angiotensinconverting enzyme; BP, blood pressure; MI, myocardial infarction. (Modified from Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 7: The era of reperfusion: Section 1: Acute coronary syndromes [acute myocardial infarction]. The American Heart Association in collaboration with


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InternalMed_Harrison. and Emergency Cardiovascular Care. Part 7: The era of reperfusion: Section 1: Acute coronary syndromes [acute myocardial infarction]. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 102:I172, 2000.) with several etiologies of circulatory shock. Although it did not significantly improve survival compared to dopamine, its relative safety suggests that norepinephrine is reasonable as initial vasopressor therapy. Norepinephrine should be started at a dose of 2 to 4 μg/ min and titrated upward as necessary. If systemic perfusion or systolic pressure cannot be maintained at >90 mmHg with a dose of 15 μg/min, it is unlikely that a further increase will be beneficial.


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InternalMed_Harrison. Dopamine has varying hemodynamic effects based on the dose; at low doses (≤ 2 μg/kg per min), it dilates the renal vascular bed, although its outcome benefits at this low dose have not been demonstrated conclusively; at moderate doses (2–10 μg/kg per min), it has positive chronotropic and inotropic effects as a consequence of β-adrenergic receptor stimulation. At higher doses, a vasoconstrictor effect results from α-receptor stimulation. It is started at an infusion rate of 2–5 μg/kg per min, and the dose is increased every 2–5 min to a maximum of 20–50 μg/kg per min. Dobutamine is a synthetic sympathomimetic amine with positive inotropic action and minimal positive chronotropic activity at low doses (2.5 μg/kg per min) but moderate chronotropic activity at higher doses. Although the usual dose is up to 10 μg/kg per min, its vasodilating activity precludes its use when a vasoconstrictor effect is required.


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InternalMed_Harrison. Circulatory assist devices can be placed percutaneously or surgically and can be used to support the left, right, or both ventricles. Venoarterial extracorporeal membrane oxygenation (VA ECMO, a pump in combination with an oxygenator) may be used when respiratory failure accompanies biventricular failure. Temporary percutaneous devices can be used as a bridge to surgically implanted devices in community hospital settings or when neurologic status is uncertain. The most commonly used device is an intraaortic balloon pump (IABP), which is inserted into the aorta via the femoral artery and provides temporary hemodynamic support. However, routine IABP use in conjunction with early revascularization (predominantly with percutaneous coronary intervention [PCI]) did not reduce 30-day mortality in the IABP-SHOCK II trial. Although other percutaneous devices, including VA ECMO, result in better hemodynamic support compared to IABP, the effects on clinical outcomes are unknown. Surgically


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InternalMed_Harrison. in the IABP-SHOCK II trial. Although other percutaneous devices, including VA ECMO, result in better hemodynamic support compared to IABP, the effects on clinical outcomes are unknown. Surgically implanted devices can support the circulation as bridging therapy for cardiac transplant candidates or as destination therapy (Chap. 281). Assist devices should be used selectively in suitable patients in consultation with advanced heart failure specialists.


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InternalMed_Harrison. SVR, (dyn · s)/ RA, mmHg RVS, mmHg RVD, mmHg PAS, mmHg PAD, mmHg PCW, mmHg CI, (L/min)/m2 cm5 Normal values <6 <25 0–12 <25 0–12 <6–12 ≥2.5 (800–1600) MI without pul-– – – – – ~13 (5–18) ~2.7 (2.2–4.3) – monary edemab Pulmonary ↔↑↔↑↔↑↑ ↑ ↑ ↔↓↑ Septic shock ↓↔↓↔↓↓ ↓↓↑↓ aThere is significant patient-to-patient variation. Pressure may be normalized if cardiac output is low. bForrester et al classified nonreperfused MI patients into four hemodynamic subsets. (From JS Forrester et al: N Engl J Med 295:1356, 1976.) PCW pressure and CI in clinically stable subset 1 patients are shown. Values in parentheses represent range. c”Isolated” or predominant RV failure. dPCW and pulmonary artery pressures may rise in RV failure after volume loading due to RV dilation and right-to-left shift of the interventricular septum, resulting in impaired LV filling. When biventricular failure is present, the patterns are similar to those shown for LV failure.


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InternalMed_Harrison. Abbreviations: CI, cardiac index; MI, myocardial infarction; P/SBF, pulmonary/systemic blood flow; PAS/D, pulmonary artery systolic/diastolic; PCW, pulmonary capillary wedge; RA, right atrium; RVS/D, right ventricular systolic/diastolic; SVR, systemic vascular resistance. Source: Table prepared with the assistance of Krishnan Ramanathan, MD. The rapid establishment of blood flow in the infarct-related artery is essential in the management of CS and forms the centerpiece of management. The randomized SHOCK Trial demonstrated that 132 lives were saved per 1000 patients treated with early revascularization with PCI or coronary artery bypass graft (CABG) compared with initial medical therapy including IABP with fibrinolytics followed by delayed revascularization. The benefit is seen across the risk strata and is sustained up to 11 years after an MI. Early revascularization with PCI or CABG is recommended in candidates suitable for aggressive care.


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InternalMed_Harrison. Prognosis Within this high-risk condition, there is a wide range of expected death rates based on age, severity of hemodynamic abnormalities, severity of the clinical manifestations of hypoperfusion, and the performance of early revascularization.


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InternalMed_Harrison. Although transient hypotension is common in patients with RV infarction and inferior MI (Chap. 295), persistent CS due to RV failure accounts for only 3% of CS complicating MI. The salient features of RV shock are absence of pulmonary congestion, high right atrial pressure (which may be seen only after volume loading), RV dilation and dysfunction, only mildly or moderately depressed LV function, and predominance of single-vessel proximal right coronary artery occlusion. Management includes IV fluid administration to optimize right atrial pressure (10–15 mmHg); avoidance of excess fluids, which cause a shift of the interventricular septum into the LV; sympathomimetic amines; the early reestablishment of infarct-artery flow; and assist devices.


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InternalMed_Harrison. (See also Chap. 295) Acute severe MR due to papillary muscle dysfunction and/or rupture may complicate MI and result in CS and/or pulmonary edema. This complication most often occurs on the first day, with a second peak several days later. The diagnosis is confirmed by echo-Doppler. Rapid stabilization with IABP is recommended, with administration of dobutamine as needed to raise cardiac output. Reducing the load against which the LV pumps (afterload) reduces the volume of regurgitant flow of blood into the left atrium. Mitral valve surgery is the definitive therapy and should be performed early in the course in suitable candidates. (See also Chap. 295) Echo-Doppler demonstrates shunting of blood from the left to the right ventricle and may visualize the opening in the interventricular septum. Timing and management are similar to those for MR with IABP support and surgical correction for suitable candidates.


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InternalMed_Harrison. Myocardial rupture is a dramatic complication of STEMI that is most likely to occur during the first week after the onset of symptoms; its frequency increases with the age of the patient. The clinical presentation typically is a sudden loss of pulse, blood pressure, and consciousness but sinus rhythm on ECG (pulseless electrical activity) due to cardiac tamponade (Chap. 288). Free wall rupture may also result in CS due to subacute tamponade when the pericardium temporarily seals the rupture sites. Definitive surgical repair is required.


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InternalMed_Harrison. (See also Chap. 287) Myocarditis can mimic acute MI with ST deviation or bundle branch block on the ECG and marked elevation of cardiac markers. Acute myocarditis causes CS in a small proportion of cases. These patients are typically younger than those with CS due to acute MI and often do not have typical ischemic chest pain. Echocardiography usually shows global LV dysfunction. Initial management is the same as for CS complicating acute MI (Fig. 326-2) but does not involve coronary revascularization. Endomyocardial biopsy is recommended to determine the diagnosis and need for immunosuppressives for entities such as giant cell myocarditis. Refractory CS can be managed with assist devices with or without ECMO. The etiologies and pathophysiology of pulmonary edema are discussed in Chap. 47e.


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InternalMed_Harrison. The etiologies and pathophysiology of pulmonary edema are discussed in Chap. 47e. Diagnosis Acute pulmonary edema usually presents with the rapid onset of dyspnea at rest, tachypnea, tachycardia, and severe hypoxemia. Crackles and wheezing due to alveolar flooding and airway compression from peribronchial cuffing may be audible. Release of endogenous catecholamines often causes hypertension. It is often difficult to distinguish between cardiogenic and noncardiogenic causes of acute pulmonary edema. Echocardiography may identify systolic and diastolic ventricular dysfunction and valvular lesions. Electrocardiographic ST elevation and evolving Q waves are usually diagnostic of acute MI and should prompt immediate institution of MI protocols and coronary artery reperfusion therapy (Chap. 295). Brain natriuretic peptide levels, when substantially elevated, support heart failure as the etiology of acute dyspnea with pulmonary edema (Chap. 279).


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InternalMed_Harrison. The use of a Swan-Ganz catheter permits measurement of PCWP and helps differentiate high-pressure (cardiogenic) from normal-pressure (noncardiogenic) causes of pulmonary edema. Pulmonary artery catheterization is indicated when the etiology of the pulmonary edema is uncertain, when edema is refractory to therapy, or when it is accompanied by hypotension. Data derived from use of a catheter often alter the treatment plan, but no impact on mortality rates has been demonstrated. The treatment of pulmonary edema depends on the specific etiology. As an acute, life-threatening condition, a number of measures must be applied immediately to support the circulation, gas exchange, and lung mechanics. Simultaneously, conditions that frequently complicate pulmonary edema, such as infection, acidemia, anemia, and acute kidney dysfunction, must be corrected.


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InternalMed_Harrison. Patients with acute cardiogenic pulmonary edema generally have an identifiable cause of acute LV failure—such as arrhythmia, ischemia/infarction, or myocardial decompensation (Chap. 279)— that may be rapidly treated, with improvement in gas exchange. In contrast, noncardiogenic edema usually resolves much less quickly, and most patients require mechanical ventilation. Oxygen Therapy Support of oxygenation is essential to ensure adequate O2 delivery to peripheral tissues, including the heart.


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InternalMed_Harrison. Positive-Pressure Ventilation Pulmonary edema increases the work of breathing and the O2 requirements of this work, imposing a significant physiologic stress on the heart. When oxygenation or ventilation is not adequate in spite of supplemental O2, positive-pressure ventilation by face or nasal mask or by endotracheal intubation should be initiated. Noninvasive ventilation (Chap. 323) can rest the respiratory muscles, improve oxygenation and cardiac function, and reduce the need for intubation. In refractory cases, mechanical ventilation can relieve the work of breathing more completely than can noninvasive ventilation. Mechanical ventilation with positive end-expiratory pressure can have multiple beneficial effects on pulmonary edema: (1) decreases both preload and afterload, thereby improving cardiac function; (2) redistributes lung water from the intraalveolar to the extraalveolar space, where the fluid interferes less with gas exchange; and (3) increases lung volume to avoid


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InternalMed_Harrison. improving cardiac function; (2) redistributes lung water from the intraalveolar to the extraalveolar space, where the fluid interferes less with gas exchange; and (3) increases lung volume to avoid atelectasis.


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InternalMed_Harrison. In most forms of pulmonary edema, the quantity of extravascular lung water is determined by both the PCWP and the intravascular volume status. Diuretics The “loop diuretics” furosemide, bumetanide, and torsemide are effective in most forms of pulmonary edema, even in the presence of hypoalbuminemia, hyponatremia, or hypochloremia. Furosemide is also a venodilator that rapidly reduces preload before any diuresis, and is the diuretic of choice. The initial dose of furosemide should be ≤0.5 mg/kg, but a higher dose (1 mg/kg) is required in patients with renal insufficiency, chronic diuretic use, or hypervol-1763 emia or after failure of a lower dose.


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InternalMed_Harrison. Nitrates Nitroglycerin and isosorbide dinitrate act predominantly as venodilators but have coronary vasodilating properties as well. They are rapid in onset and effective when administered by a variety of routes. Sublingual nitroglycerin (0.4 mg × 3 every 5 min) is first-line therapy for acute cardiogenic pulmonary edema. If pulmonary edema persists in the absence of hypotension, sublingual may be followed by IV nitroglycerin, commencing at 5–10 μg/min. IV nitroprusside (0.1–5 μg/kg per min) is a potent venous and arterial vasodilator. It is useful for patients with pulmonary edema and hypertension but is not recommended in states of reduced coronary artery perfusion. It requires close monitoring and titration using an arterial catheter for continuous BP measurement.


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InternalMed_Harrison. Morphine Given in 2to 4-mg IV boluses, morphine is a transient venodilator that reduces preload while relieving dyspnea and anxiety. These effects can diminish stress, catecholamine levels, tachycardia, and ventricular afterload in patients with pulmonary edema and systemic hypertension. Angiotensin-Converting Enzyme (ACE) Inhibitors ACE inhibitors reduce both afterload and preload and are recommended for hypertensive patients. A low dose of a short-acting agent may be initiated and followed by increasing oral doses. In acute MI with heart failure, ACE inhibitors reduce shortand long-term mortality rates. tide (nesiritide) is a potent vasodilator with diuretic properties and is effective in the treatment of cardiogenic pulmonary edema. It should be reserved for refractory patients and is not recommended in the setting of ischemia or MI.


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InternalMed_Harrison. Physical Methods In nonhypotensive patients, venous return can be reduced by use of the sitting position with the legs dangling along the side of the bed. Inotropic and Inodilator Drugs The sympathomimetic amines dopa mine and dobutamine (see above) are potent inotropic agents. The bipyridine phosphodiesterase-3 inhibitors (inodilators), such as milrinone (50 μg/kg followed by 0.25–0.75 μg/kg per min), stimulate myocardial contractility while promoting peripheral and pulmonary vasodilation. Such agents are indicated in patients with cardiogenic pulmonary edema and severe LV dysfunction.


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InternalMed_Harrison. Digitalis Glycosides Once a mainstay of treatment because of their positive inotropic action (Chap. 279), digitalis glycosides are rarely used at present. However, they may be useful for control of ventricular rate in patients with rapid atrial fibrillation or flutter and LV dysfunction, because they do not have the negative inotropic effects of other drugs that inhibit atrioventricular nodal conduction. Intraaortic Balloon Counterpulsation IABP or other LV-assist devices (Chap. 281) may help relieve cardiogenic pulmonary edema and are indicated when refractory pulmonary edema results from the etiologies discussed in the CS section, especially in preparation for surgical repair.


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InternalMed_Harrison. Treatment of Tachyarrhythmias and Atrial-Ventricular Resynchronization (See also Chap. 277) Sinus tachycardia or atrial fibrillation can result from elevated left atrial pressure and sympathetic stimulation. Tachycardia itself can limit LV filling time and raise left atrial pressure further. Although relief of pulmonary congestion will slow the sinus rate or ventricular response in atrial fibrillation, a primary tachyarrhythmia may require cardioversion. In patients with reduced LV function and without atrial contraction or with lack of synchronized atrioventricular contraction, placement of an atrioventricular sequential pacemaker should be considered (Chap. 274). Stimulation of Alveolar Fluid Clearance A variety of drugs can stimulate alveolar epithelial ion transport and upregulate the clearance of alveolar solute and water, but this strategy has not been proven beneficial in clinical trials thus far.


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InternalMed_Harrison. Critical Care Medicine Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac death Robert J. Myerburg, Agustin Castellanos OVERVIEW AND DEFINITIONS Sudden cardiac death (SCD) is defined as natural death due to cardiac 327 1764 SPECIAL CONSIDERATIONS Risk of Iatrogenic Cardiogenic Shock In the treatment of pulmonary edema, vasodilators lower BP, and their use, particularly in combination, may lead to hypotension, coronary artery hypoperfusion, and shock (Fig. 326-1). In general, patients with a hypertensive response to pulmonary edema tolerate and benefit from these medications. In normotensive patients, low doses of single agents should be instituted sequentially, as needed. Acute Coronary Syndromes (See also Chap. 295) Acute STEMI complicated by pulmonary edema is associated with in-hospital mortality rates of 20–40%. After immediate stabilization, coronary artery blood flow must be reestablished rapidly. When available, primary PCI is preferable; alternatively, a fibrinolytic


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InternalMed_Harrison. mortality rates of 20–40%. After immediate stabilization, coronary artery blood flow must be reestablished rapidly. When available, primary PCI is preferable; alternatively, a fibrinolytic agent should be administered. Early coronary angiography and revascularization by PCI or CABG also are indicated for patients with non-ST elevation acute coronary syndrome. Assist devices may be used selectively as noted for refractory pulmonary edema.


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InternalMed_Harrison. Extracorporeal Membrane Oxygenation For patients with acute, severe noncardiogenic edema with a potential rapidly reversible cause, ECMO may be considered as a temporizing supportive measure to achieve adequate gas exchange. Usually venovenous ECMO is used in this setting. Unusual Types of Edema Specific etiologies of pulmonary edema may require particular therapy. Reexpansion pulmonary edema can develop after removal of longstanding pleural space air or fluid. These patients may develop hypotension or oliguria resulting from rapid fluid shifts into the lung. Diuretics and preload reduction are contraindicated, and intravascular volume repletion often is needed while supporting oxygenation and gas exchange.


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InternalMed_Harrison. High-altitude pulmonary edema often can be prevented by use of dexamethasone, calcium channel–blocking drugs, or long-acting inhaled β2-adrenergic agonists. Treatment includes descent from altitude, bed rest, oxygen, and, if feasible, inhaled nitric oxide; nifedipine may also be effective. For pulmonary edema resulting from upper airway obstruction, recognition of the obstructing cause is key, because treatment then is to relieve or bypass the obstruction. causes in a person who may or may not have previously recognized heart disease but in whom the time and mode of death are unexpected. The term “sudden,” in the context of SCD, is defined for most clinical and epidemiologic purposes as 1 h or less between a change in clinical status heralding the onset of the terminal clinical event and the cardiac arrest itself. One exception is unwitnessed deaths, in which pathologists may expand the temporal definition to 24 h after the victim was last seen to be alive and stable.


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InternalMed_Harrison. Another exception is the variable interval between cardiac arrest and biological death that results from community-based interventions, following which victims may remain biologically alive for days or even weeks after a cardiac arrest that has resulted in irreversible central nervous system damage. Confusion in terms can be avoided by adhering strictly to definitions of cardiovascular collapse, cardiac arrest, and death (Table 327-1). Although cardiac arrest is often potentially reversible by appropriate and timely interventions, death is biologically, legally, and literally an absolute and irreversible event. Biological death may be delayed by interventions, but the relevant pathophysiologic event remains the sudden and unexpected cardiac arrest. Accordingly, for statistical purposes, deaths that occur during hospitalization or within 30 days after resuscitated cardiac arrest are counted as sudden deaths.


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InternalMed_Harrison. The majority of natural deaths are caused by cardiac disorders. However, it is common for underlying heart diseases—often far advanced—to go unrecognized before the fatal event. As a result, up to two-thirds of all SCDs occur as the first clinical expression of previously undiagnosed disease or in patients with known heart disease, the extent of which suggests low individual risk. The magnitude of sudden cardiac death as a public health problem is highlighted by the estimate that ~50% of all cardiac deaths are sudden and unexpected, accounting for a total SCD burden estimated to range from <200,000 to >450,000 deaths each year in the United States. SCD is a direct consequence of cardiac arrest, which may be reversible if addressed promptly. Because resuscitation techniques and emergency rescue systems are available to respond to victims of out-of-hospital cardiac arrest, which was uniformly fatal in the past, understanding the SCD problem has practical clinical importance.


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InternalMed_Harrison. Cardiovascular collapse is a general term connoting loss of sufficient cerebral blood flow to maintain consciousness due to acute dysfunction of the heart and/or peripheral vasculature. It may be caused by vasodepressor syncope (vasovagal syncope, postural hypotension with syncope, neurocardiogenic syncope; Chap. 27), a transient severe bradycardia, or cardiac arrest. The latter is distinguished from the transient forms of cardiovascular collapse in that it usually requires an active intervention to restore spontaneous blood flow. In contrast, vasodepressor syncope and other primary bradyarrhythmic syncopal events are transient and non-life-threatening, with spontaneous return of consciousness.


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InternalMed_Harrison. In the past, the most common electrical mechanism for cardiac arrest was ventricular fibrillation (VF) or pulseless sustained ventricular tachycardia (PVT). These were the initial rhythms recorded in 60–80% of cardiac arrests, with VF being the far more common of the two. Severe persistent bradyarrhythmias, asystole, and pulseless electrical activity (PEA; organized electrical activity, unusually slow, without mechanical response, formerly called electromechanical dissociation [EMD]) caused another 20–30%. Currently, asystole has emerged as the most common mechanism recorded at initial contact (45–50% of cases). PEA accounts for 20–25%, and VF is now present on initial contact in 25–35%. Undoubtedly, a significant proportion of the asystole cases began as VF and deteriorated to asystole because of long response times, but there are data suggesting an absolute reduction in VF as well. Acute low cardiac output states, having a precipitous onset, also may present clinically as a cardiac


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InternalMed_Harrison. of long response times, but there are data suggesting an absolute reduction in VF as well. Acute low cardiac output states, having a precipitous onset, also may present clinically as a cardiac arrest. These hemodynamic causes include massive acute pulmonary emboli, internal blood loss from a ruptured aortic aneurysm, intense anaphylaxis, and cardiac rupture with tamponade after myocardial infarction (MI).