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DEFINITIONS  

Animals mount both local and systemic responses to microbes that traverse epithelial barriers and invade underlying tissues. Fever or hypothermia, leukocytosis or leukopenia, tachypnea, and tachycardia are the cardinal signs of the systemic response often called the systemic inflammatory response syndrome (SIRS). SIRS may have an infectious or a noninfectious etiology. If infection is suspected or proven, a patient with SIRS is said to have sepsis.When sepsis is associated with dysfunction of organs distant from the site of infection, the patient has severe 163 sepsis. Severe sepsis may be accompanied by hypotension or evidence of hypoperfusion.When hypotension cannot be corrected by infusing fluids, the diagnosis is septic shock. These definitions were proposed by consensus conference committees in 1992 and 2001 and are now widely used; there is evidence that the different stages form a continuum. As sepsis progresses to septic shock, the risk of dying increases substantially. Sepsis is usually reversible, whereas patients with septic shock often succumb despite aggressive therapy.


ETIOLOGY

Severe sepsis can be a response to any class of microorganism. Microbial invasion of the bloodstream is not essential for the development of severe sepsis, since local inflammation can also elicit distant organ dysfunction and hypotension. In fact, blood cultures yield bacteria or fungi in only ∼20–40% of cases of severe sepsis and 40–70% of cases of septic shock. Individual gram-negative or gram-positive bacteria account for ∼70% of these isolates; the remainder are fungi or a mixture of microorganisms (Table 15-2). In patients whose blood cultures are negative, the etiologic agent is often established by culture or microscopic examination of infected material from a local site. In some case series, a majority of patients with a clinical picture of severe sepsis or septic shock have had negative microbiologic data.


EPIDEMIOLOGY

The septic response is a contributing factor in >200,000 deaths per year in the United States. The incidence of severe sepsis and septic shock has increased over the past 20 years, and the annual number of cases is now >700,000 (∼3 per 1000 population). Approximately twothirds of the cases occur in patients with significant underlying illness. Sepsis-related incidence and mortality rates increase with age and preexisting comorbidity. The rising incidence of severe sepsis in the United States is attributable to the aging of the population, the increasing longevity of patients with chronic diseases, and the relatively high frequency with which sepsis develops in patients with AIDS.The widespread use of antimicrobial agents, immunosuppressive drugs, indwelling catheters and mechanical devices, and mechanical ventilation also plays a role. Invasive bacterial infections are prominent causes of death around the world, particularly among young children. In Sub-Saharan Africa, for example, careful screening for positive blood cultures found that community-acquired bacteremia accounted for at least one-fourth of deaths of children >1 year of age. Nontyphoidal Salmonella species, Streptococcus pneumoniae, Haemophilus influenzae, and Escherichia coli were the most commonly isolated bacteria. Bacteremic children often had HIV infection or were severely malnourished.


PATHOPHYSIOLOGY

Most cases of severe sepsis are triggered by bacteria or fungi that do not ordinarily cause systemic disease in immunocompetent hosts (Table 15-2). These microbes probably exploit deficiencies in innate host defenses (e.g., phagocytes, complement, and natural antibodies) to survive within the body. Microbial pathogens, in contrast, are able to circumvent innate defenses by elaborating toxins or other virulence factors. In both cases, the body can fail to kill the invaders despite mounting a vigorous inflammatory reaction that can result in severe sepsis. The septic response may also be induced by microbial exotoxins that act as superantigens (e.g., toxic shock syndrome toxin 1; Chap. 35). Host Mechanisms for Sensing Microbes Animals have exquisitely sensitive mechanisms for recognizing and responding to conserved microbial molecules. Recognition of the lipid A moiety of lipopolysaccharide (LPS, also called endotoxin; Chap. 2) is the best-studied example.A host protein (LPS-binding protein, or LBP) binds lipid A and transfers the LPS to CD14 on the surfaces of monocytes, macrophages, and neutrophils. LPS then is passed to MD-2, which interacts with Toll-like receptor (TLR) 4 to form a molecular complex that transduces the LPS recognition signal to the interior of the cell.This signal rapidly triggers the production and release of mediators, such as tumor necrosis factor (TNF; see below), that amplify the LPS signal and transmit it to other cells and tissues. Bacterial peptidoglycan and lipoteichoic acids elicit responses in animals that are generally similar to those induced by LPS; whereas these molecules also bind CD14, they interact with different TLRs. Having numerous TLRbased receptor complexes (10 different TLRs have been identified so far in humans) allows animals to recognize many conserved microbial molecules. The ability of some of the TLRs to serve as receptors for host ligands (e.g., hyaluronans, heparan sulfate, saturated fatty acids) raises the possibility that these molecules play a role in producing noninfectious sepsis-like states.


Other host pattern-recognition proteins that are important for sensing microbial invasion and initiating host inflammation include the intracellular NOD1 and NOD2 proteins, which recognize discrete fragments of bacterial peptidoglycan; complement (principally the alternative pathway); mannose-binding lectin; and C-reactive protein. The ability to recognize certain microbial molecules may influence both the potency of the host defense and the pathogenesis of severe sepsis. For example, MD- 2–TLR4 best senses LPS that has a hexaacyl lipid A moiety (i.e., one with six fatty acyl chains). Most of the commensal aerobic and facultatively anaerobic gramnegative bacteria that trigger severe sepsis and shock (including E. coli, Klebsiella, and Enterobacter) make this lipid A structure. When they invade human hosts, often through breaks in an epithelial barrier, infection is typically localized to the subepithelial tissue. Bacteremia, if it occurs, is intermittent and low-grade, as these bacteria are efficiently cleared from the bloodstream by TLR4- expressing Kupffer cells and splenic macrophages. These mucosal commensals seem to induce severe sepsis most often by triggering severe local tissue inflammation rather than by circulating within the bloodstream. In contrast, gram-negative bacteria that do not make hexaacyl lipid A (Yersinia pestis, Francisella tularensis, Vibrio vulnificus, Pseudomonas aeruginosa, and Burkholderia pseudomallei, among others) are poorly recognized by MD-2–TLR4. These bacteria usually enter the body via nonmucosal routes—e.g., as a result of bites, cuts, or inhalation—and initially induce relatively little inflammation.When they do trigger severe sepsis, it is often in the setting of massive bacterial growth throughout the body. Engineering a virulent strain of Y. pestis to produce hexaacyl lipid A has rendered it avirulent in mice; this result attests to the importance of TLR4-based bacterial recognition in host defense.


For most gram-negative bacteria, the pathogenesis of sepsis thus depends, at least in part, on whether the bacterium’s LPS is sensed by the host receptor MD-2–TLR4. Local and Systemic Host Responses to 165 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, enhance the permeability of local blood vessels, recruit neutrophils to the site of infection, and elicit pain. These phenomena 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. Cytokines and Other Mediators Cytokines can exert endocrine, paracrine, and autocrine effects.TNF-á stimulates leukocytes and vascular endothelial cells to release other cytokines (as well as additional TNF-á), 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-á are not elevated in individuals with localized infections, they increase in most patients with severe sepsis or septic shock. Moreover, IV infusion of TNF-á can elicit the characteristic abnormalities of SIRS. In animals, larger doses of TNF-á induce shock, disseminated intravascular coagulation (DIC), and death.


Although TNF-á is a central mediator, it is only one of many proinflammatory molecules that contribute to innate host defense. Chemokines, most prominently interleukin (IL) 8, attract circulating neutrophils to the infection site. IL-1â exhibits many of the same activities as TNF-á. TNF-á, IL-1â, interferon (IFN) ã, IL-12, and other cytokines probably interact synergistically with one another and with additional mediators. High-mobility group B-1, a transcription factor, can also be released from cells and interact with microbial products to induce host responses late in the course of the septic response. 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. Intravascular fibrin deposition, thrombosis, and DIC can also be important features of the systemic response. IL-6 and other mediators promote intravascular coagulation initially by inducing blood monocytes and vascular endothelial cells to express tissue factor. 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 protein C, whereas fibrinolysis is prevented by increased 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. 44). Contact-system activation occurs during sepsis but contributes more to the development of hypotension than to DIC. Control Mechanisms Elaborate control mechanisms operate within both local sites of inflammation and the systemic circulation. Local Control Mechanisms Host recognition of invading microbes within subepithelial tissues typically ignites immune responses that rapidly kill the invader and then subside to allow tissue recovery. The anti-inflammatory forces that put out the fire and clean up the battleground include molecules that neutralize or inactivate microbial signals. Among these molecules are LPS; intracellular factors (e.g., suppressor of cytokine signaling 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. Systemic Control Mechanisms The signaling apparatus that links microbial recognition to cellular responses in tissues is less active in the blood. For example, whereas LBP plays a role in recognizing the presence of LPS, in plasma it also prevents LPS signaling by transferring LPS molecules into plasma lipoprotein particles, which sequester the lipid A moiety so that it cannot interact with cells. At the high concentrations found in blood, LBP also inhibits monocyte responses to LPS, and the soluble (circulating) form of CD14 strips off LPS that has bound to monocyte surfaces.


Systemic responses to infection also diminish cellular responses to microbial molecules. Circulating levels of anti-inflammatory cytokines (e.g., IL-6 and IL-10) increase even in patients with mild infections. Glucocorticoids inhibit cytokine synthesis by monocytes in vitro; the increase in blood cortisol levels early in the systemic response presumably plays a similarly inhibitory role. Epinephrine inhibits the TNF-á 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 neutrophil-endothelial adhesion in uninflamed organs. The available evidence thus suggests that the body’s systemic responses to injury and infection normally prevent inflammation within organs distant from a site of infection. The acute-phase response increases the blood concentrations of numerous molecules that have anti-inflammatory actions.


Blood levels of IL-1 receptor antagonist (IL- 1Ra) often greatly exceed those of circulating IL-1â, for example, and this excess may result in inhibition of the binding of IL-1â to its receptors. High levels of soluble TNF receptors neutralize TNF-á that enters the circulation. Other acute-phase proteins are protease inhibitors; these may neutralize proteases released from neutrophils and other inflammatory cells. 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 50 molecules have been found in patients with septic shock. Although high concentrations of both pro- and antiinflammatory molecules are found, the net mediator balance in the plasma of these extremely sick patients may actually 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. Apoptotic death of B cells, follicular dendritic cells, and CD4+ T lymphocytes also may contribute significantly to the immunosuppressive state. Endothelial Injury Most 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-á induce vascular endothelial cells to produce and release cytokines, procoagulant molecules, plateletactivating factor (PAF), 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 increased vascular permeability, microvascular thrombosis, DIC, and hypotension. 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 giving nitroprusside intravenously; these observations suggest a neuroendocrine basis for the loss of capillary filling. Oxygen utilization by tissues may also be impaired by a state of “hibernation” in which ATP production is diminished as oxidative phosphorylation decreases because of mitochondrial dysfunction; nitric oxide or its metabolites may be responsible for inducing this response. 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 anatomic.


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 is independent of oxygen delivery. The blood lactate level may be normal or increased, and normalization of the central venous oxygen saturation (SvO2) may reflect either improved oxygen delivery or left-to-right shunting. Prominent hypotensive molecules include nitric oxide, â-endorphin, bradykinin, PAF, and pro-stacyclin. 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 PAF receptor antagonist nor a bradykinin antagonist improved survival rates among patients with septic shock, and a nitric oxide synthetase inhibitor, L-NG-methylarginine HCl, actually increased the mortality rate. 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 well with blood endotoxin levels and with the occurrence of DIC (Chap. 44).


In most patients with nosocomial infections, 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 abdominal source was eightfold more likely to be associated with severe sepsis than was bacteremic urinary tract infection, even after the investigators con- 167 trolled 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 Staphylococcus aureus or Streptococcus pyogenes, since the T-cell activation induced by these toxins produces a cytokine profile that differs substantially from that elicited by gramnegative bacterial infection. In summary, the pathogenesis of severe sepsis may differ according to the infecting microbe, the ability of the host’s innate defense mechanisms to sense it, the site of the primary infection, the presence or absence of immune defects, and the prior physiologic status of the host. Genetic factors may also be important. For example, studies in different ethnic groups have identified associations between allelic polymorphisms in TLR4, caspase 12L,TNF-á, and IFN-ã genes and the risk of developing severe sepsis. Further studies in this area are needed.


CLINICAL MANIFESTATIONS

The manifestations of the septic response are usually superimposed on the symptoms and signs of the patient’s underlying illness and primary infection.The rate at which signs and symptoms develop may differ from patient to patient, and there are striking individual variations in presentation. For example, some patients with sepsis are normo- or hypothermic; the absence of fever is most common in neonates, in elderly patients, and in persons with uremia or alcoholism. Hyperventilation 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. 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 Neisseria meningitidis (or, less commonly, H. influenzae) should be suspected (Fig. 44-1); in a patient who has been bitten by a tick while in an endemic area, petechial lesions also suggest Rocky Mountain spotted fever (Fig. 75-1). A cutaneous lesion seen almost exclusively in neutropenic patients is ecthyma gangrenosum, usually caused by P. aeruginosa. It is a bullous lesion, surrounded by edema that undergoes central hemorrhage and necrosis (Fig. 53-1). 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 suffered a dog bite may indicate bloodstream infection due to Capnocytophaga canimorsus or C. cynodegmi. Generalized erythroderma in a septic patient suggests the toxic shock syndrome due to S. aureus or S. pyogenes. 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. 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, which is promoted by arterial vasodilation.


MAJOR COMPLICATIONS

Cardiopulmonary Complications Ventilation-perfusion mismatching produces a fall in arterial PO2 early in the course. Increasing alveolar capillary permeability results in an increased pulmonary water content, which decreases pulmonary compliance and interferes with oxygen exchange. Progressive diffuse pulmonary infiltrates and arterial hypoxemia (PaO2/FIO2, compliance and interferes with <200) indicate the development of the acute respiratory distress syndrome (ARDS). 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 Pneumocystis may be clinically indistinguishable from ARDS. Sepsis-induced hypotension (see “Septic Shock” earlier in the chapter) 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. 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 dilatation 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 a low systemic vascular resistance, and death results from refractory shock or the failure of multiple organs rather than from cardiac dysfunction per se. 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 hypotension or capillary injury, although some patients also have glomerulonephritis, renal cortical necrosis, or interstitial nephritis.


Drug-induced renal damage may complicate therapy, particularly when hypotensive patients are given aminoglycoside antibiotics. Coagulopathy Although thrombocytopenia occurs in 10–30% of patients, the underlying mechanisms are not understood. Platelet counts are usually very low (<50,000/ìL) in patients with DIC; these low counts may reflect diffuse endothelial injury or microvascular thrombosis. Neurologic Complications 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.


LABORATORY FINDINGS

Abnormalities that occur early in the septic response may include leukocytosis with a left shift, thrombocytopenia, hyperbilirubinemia, and proteinuria. Leukopenia may develop.The neutrophils may contain toxic granulations, Döhle’s bodies, or cytoplasmic vacuoles. As the septic response becomes more severe, thrombocytopenia worsens (often with prolongation of the 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, which 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, which may exacerbate hypotension. Hypoglycemia occurs rarely.The serum albumin level, initially within the normal range, declines as sepsis continues. Hypocalcemia is rare.


DIAGNOSIS

There is no specific diagnostic test for the septic response. Diagnostically sensitive findings in a patient with suspected or proven infection include fever or hypothermia, tachypnea, tachycardia, and leukocytosis or leukopenia (Table 15-1); acutely altered mental status, thrombocytopenia, an elevated blood lactate level, or hypotension also should suggest the diagnosis.The septic 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. Noninfectious etiologies of SIRS (Table 15-1) include pancreatitis, burns, trauma, adrenal insufficiency, pulmonary embolism, dissecting or ruptured aortic aneurysm,myocardial infarction, occult hemorrhage, cardiac tamponade, post–cardiopulmonary bypass syndrome, anaphylaxis, and drug overdose.


Definitive etiologic diagnosis requires isolation of the microorganism from blood or a local site of infection. At least two blood samples (10 mL each) should be obtained (from different venipuncture sites) for culture. Because gram-negative bacteremia is typically low-grade (<10 organisms/mL of blood), prolonged incubation of cultures may be necessary; S. aureus grows more readily and is detectable in blood cultures within 48 h in most instances. 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 of infected cutaneous lesions may help establish the microbial etiology. 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. 


SEVERE SEPSIS AND SEPTIC SHOCK

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 eliminate the offending microorganism. Most emergency centers now aim to initiate these measures within 1 h of the patient’s presentation with severe sepsis or shock.Rapid assessment and diagnosis are therefore essential.


ANTIMICROBIAL AGENTS

Antimicrobial chemotherapy should be initiated as soon as samples of blood and other relevant sites have been cultured. 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. It is important, pending culture results, to initiate empirical antimicrobial therapy that is effective against both gram-positive and gram-negative bacteria (Table 15-3). 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, as 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 â-lactam agent. 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 bacterial isolate(s).


REMOVAL OF THE SOURCE OF INFECTION

Removal or drainage of a focal source of infection is essential. Sites of occult infection should be sought carefully. Indwelling IV 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. In patients with abnormalities on chest radiographs, 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 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.


HEMODYNAMIC, RESPIRATORY, AND METABOLIC SUPPORT

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. 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 pulmonary capillary wedge pressure should be maintained at 12–16 mmHg or the central venous pressure at 8–12 cm H2O. 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 to maintain a mean arterial blood pressure of >65 mmHg (systolic pressure, >90 mmHg) and a cardiac index of ≥4 L/min per m2. If these guidelines cannot be met by volume infusion, vasopressor therapy is indicated. Circulatory adequacy is also assessed by clinical parameters (mentation, urine output, skin perfusion) and, when possible, by measurements of oxygen delivery and consumption. A study of “early goal-directed therapy” (EGDT) found that prompt resuscitation based on maintenance of the SvO2 at >70% was associated with significantly improved survival of patients who were admitted to an emergency department with severe sepsis.


The treatment algorithm included rapid administration of fluids, antibiotics, and vasopressor support; erythrocyte transfusion (to maintain the hematocrit above 30%); and administration of dobutamine if fluids, erythrocytes, and pressors did not result in an SvO2 of >70%. The extent to which the different components of the EGDT algorithm contribute to the overall effect has not been examined in controlled trials. In particular, neither the use of SvO2 to manage therapy nor the need for continuous SvO2 monitoring with a pulmonary artery catheter has been formally confirmed. A multicenter study (sponsored by the National Institutes of Health) of the efficacy of the EGDT approach is in progress. In patients with septic shock, plasma vasopressin levels increase transiently but then decrease dramatically. Studies have found that vasopressin infusion can reverse septic shock in some patients, reducing or eliminating the need for catecholamine pressors. An adequately powered and randomized trial of vasopressin infusion has not been performed. Vasopressin is a potent vasoconstrictor that may be most useful in patients who have vasodilatory shock and relative resistance to other pressor hormones. Adrenal insufficiency is very likely when the plasma cortisol level is <15 ìg/dL in a patient with severe sepsis.


Generally accepted criteria for partial adrenal insufficiency have not been devised; major problems have been the inability to raise cortisol levels in extremely stressed individuals above high baseline values in response to cosyntropin (á1–24–ACTH) and the high frequency of hypoalbuminemia, which decreases total but not free (active) plasma cortisol levels. Adrenal insufficiency should be strongly considered in septic patients with refractory hypotension, fulminant meningococcal bacteremia, disseminated tuberculosis, AIDS, or prior use of glucocorticoids, megestrol, etomidate, or ketoconazole. Hydrocortisone (50 mg IV every 6 h) may be given as a trial therapeutic intervention. If clinical improvement occurs over 24–48 h, most experts would continue hydrocortisone therapy, tapering and discontinuing it after 5–7 days. Improved recommendations regarding hydrocortisone therapy may come from the European CORTICUS trial. Ventilator therapy is indicated for progressive hypoxemia, hypercapnia, 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. The use of erythrocyte transfusion continues to be debated. In the study of EGDT, packed erythrocytes were given to raise the hematocrit to 30% if the patient’s SvO2 was <70%. The extent to which this intervention contributed to the improvement reported in patients who received the EGDT regimen is uncertain. 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 171 have acute renal failure may benefit greatly from hemodialysis or hemofiltration.


GENERAL SUPPORT

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, which is not strong, favors the enteral delivery route. Prophylactic heparinization to prevent deep venous thrombosis is indicated for patients who do not have active bleeding or coagulopathy. Recovery is also assisted by preventing skin breakdown, nosocomial infections, and stress ulcers. Investigators in Belgium reported in 2001 that maintaining blood glucose levels in the normal range (80–110 mg/dL) greatly improved survival rates among patients who had just undergone major surgery and had received IV glucose feeding for the previous 24 h. The same group then studied intensive glucose control in critically ill medical patients and found a survival benefit only for patients who remained in the intensive care unit for ≥3 days. Hypoglycemia was much more common in the intensive-insulin group. Until more experience with intensive glucose control is reported, it seems reasonable to maintain glucose levels of <150 mg/dL during the first 3 days of severe sepsis and then to target the normoglycemic range if the patient remains in the intensive care unit for a longer period. Frequent monitoring of blood glucose levels is indicated to avoid hypoglycemia during intensive insulin therapy.


OTHER MEASURES

Despite aggressive management, many patients with severe sepsis or septic shock die. Numerous interventions have been tested for their ability to improve survival in patients with severe sepsis. The list includes endotoxin-neutralizing proteins, inhibitors of cyclooxygenase or nitric oxide synthase, anticoagulants, polyclonal immunoglobulins, glucocorticoids, and antagonists to TNF-á, IL-1, PAF, and bradykinin. Unfortunately, none of these agents has improved rates of survival among patients with severe sepsis/septic shock in more than one large, randomized, placebo-controlled clinical trial. This lack of reproducibility has had many contributing factors, including (1) heterogeneity in the patient populations studied 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 (Fig. 15-1). 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, even within a carefully selected patient population, argues strongly that a sepsis intervention should show significant survival benefit in more than one placebo-controlled clinical trial before it is accepted as part of routine clinical practice. Recombinant activated protein C (aPC) was the first drug to be approved by the U.S.


Food and Drug Administration (FDA) for the treatment of patients with severe sepsis or septic shock. In a single randomized controlled trial in which drug or placebo was given within 24 h of the patient’s first sepsis-related organ dysfunction, 28-day mortality was significantly lower among recipients of aPC than among patients who received placebo (24.7% vs 30.8%; p <.005). In addition, aPC recipients were more likely than placebo recipients to have severe bleeding (3.5% vs 2%). Survival improved only for patients who had an APACHE II score of ≥25 during the 24 h before initiation of aPC infusion.Midtrial changes in the protocol and drug were followed by improvement in the apparent efficacy of aPC. The FDA approved aPC for use in adults (>18 years of age) who meet the APACHE II criterion and have a low risk of hemorrhage-related side effects. aPC is administered as a constant IV infusion of 24 ìg/kg per hour for 96 h. Each patient’s clotting parameters must be monitored carefully. aPC should not be given to patients who have platelet counts of <30,000/ìL or to patients who have dysfunction of one organ system and have had surgery during the previous 30 days. Treatment with aPC should not be started >24 h after the onset of severe sepsis, nor should it be used in the patient subsets— e.g., patients with pancreatitis or AIDS—that were excluded from the clinical trial. Although the theoretical rationale for treating septic patients with anticoagulants is strong and studies have found that aPC may have anti-inflammatory and antiapoptotic properties in vitro, two additional randomized, placebo-controlled trials of aPC were stopped when interim analyses showed lack of efficacy.


One trial was in children, and the other was in adults with APACHE II scores of ≤25. aPC has not been tested again in the patient population for which it was approved by the FDA: adults with high APACHE II scores. Some experts have advocated “bundling” of multiple therapeutic maneuvers into a unified, algorithmic approach to management that would become the standard of care for severe sepsis.The proposed resuscitation (6-h) bundle incorporates most of the elements discussed above for acute (EGDT) resuscitation. The management (24-h) bundle includes three measures of uncertain or marginal benefit: tight control of blood glucose, administration of low-dose hydrocortisone, and treatment with aPC. Bundling of therapies obscures the efficacy and toxicity of the individual interventions and allows little room for individualizing therapy. The use of bundling in an industry-sponsored marketing program for aPC (the Surviving Sepsis Campaign) has also been criticized. 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. The authors proposed that neutralizing one of many different mediators may help patients who are very sick, whereas disrupting the mediator balance may be harmful to those whose adaptive defense mechanisms are still working. This analysis suggests that if more aggressive early resuscitation improves survival rates among sicker patients, it should become more difficult to show additional benefit from other therapies; that is, if early resuscitation improves patients’ status, moving them into a “less severe illness” category, the addition of another agent is less likely to be beneficial.


PROGNOSIS

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. Prognostic stratification systems such as APACHE II indicate that factoring in the patient’s age, underlying condition, and various physiologic variables can yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of underlying disease most strongly influences the risk of dying. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis.


PREVENTION

Prevention offers the best opportunity to reduce morbidity and mortality. 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/ìL), and by more aggressively treating localized nosocomial infections. Indiscriminate use of antimicrobial agents and glucocorticoids should be avoided, and optimal infectioncontrol measures (Chap. 13) should be used. Several studies point to associations between allelic polymorphisms in specific genes and risk of severe sepsis; if these associations prove to be broadly applicable, such polymorphisms can be used prospectively to identify highrisk patients and to target preventive and/or therapeutic measures to them. 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 (e.g., SIRS, sepsis) on at least 1 previous day in the hospital. Research is needed to develop adjunctive agents that can damp the septic response before organ dysfunction or hypotension occurs.  ​