(See Table 271-1) Animals mount both local and systemic responses to microbes that traverse their epithelial barriers and enter underlying tissues. Fever or hypothermia, leukocytosis or leukopenia, tachypnea, and tachycardia are the cardinal signs of the systemic response, that is 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 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 developed by consensus conference committees in 1992 and 2001 and have been widely used; there is evidence that the different stages may form a continuum.
Table 271–1. Definitions Used to Describe the Condition of Septic Patients |Favorite Table|Download (.pdf)
Table 271–1. Definitions Used to Describe the Condition of Septic Patients
|Bacteremia||Presence of bacteria in blood, as evidenced by positive blood cultures|
|Septicemia||Presence of microbes or their toxins in blood|
|Systemic inflammatory response syndrome (SIRS)||Two or more of the following conditions: (1) fever (oral temperature >38°C) or hypothermia (<36°C); (2) tachypnea (>24 breaths/min); (3) tachycardia (heart rate >90 beats/min); (4) leukocytosis (>12,000/μL), leucopenia (<4,000/μL), or >10% bands; may have a noninfectious etiology|
|Sepsis||SIRS that has a proven or suspected microbial etiology|
|Severe sepsis (similar to "sepsis syndrome")||Sepsis with one or more signs of organ dysfunction—for example:|
|1. Cardiovascular: Arterial systolic blood pressure ≤90 mmHg or mean arterial pressure ≤70 mmHg that responds to administration of intravenous fluid|
|2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation|
|3. Respiratory: PaO2/FIO2 ≤250 or, if the lung is the only dysfunctional organ, ≤200|
|4. Hematologic: Platelet count <80,000/μL or 50% decrease in platelet count from highest value recorded over previous 3 days|
|5. Unexplained metabolic acidosis: A pH ≤7.30 or a base deficit ≥5.0 mEq/L and a plasma lactate level >1.5 times upper limit of normal for reporting lab|
|6. Adequate fluid resuscitation: Pulmonary artery wedge pressure ≥12 mmHg or central venous pressure ≥8 mmHg|
|Septic shock||Sepsis with hypotension (arterial blood pressure <90 mmHg systolic, or 40 mmHg less than patient's normal blood pressure) for at least 1 h despite adequate fluid resuscitation; |
|Need for vasopressors to maintain systolic blood pressure ≥90 mmHg or mean arterial pressure ≥70 mmHg|
|Refractory septic shock||Septic shock that lasts for >1 h and does not respond to fluid or pressor administration|
|Multiple-organ dysfunction syndrome (MODS)||Dysfunction of more than one organ, requiring intervention to maintain homeostasis|
|Predisposition–infection–response–organ dysfunction (PIRO)||A grading system that stratifies patients according to four key aspects of illness; attempts to define subgroups of patients, reducing heterogeneity in clinical trials|
|Critical illness–related corticosteroid insufficiency (CIRCI)||Inadequate corticosteroid activity for the patient's severity of illness; should be suspected when hypotension is not relieved by fluid administration|
Sepsis can be a response to any class of microorganism. Microbial invasion of the bloodstream is not essential, 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 271-2). 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; specific identification of microbial DNA or RNA in blood or tissue samples is also used. In some case series, a majority of patients with a clinical picture of severe sepsis or septic shock have had negative microbiologic data.
Table 271–2. Microorganisms Involved in Episodes of Severe Sepsis at Eight Academic Medical Centers |Favorite Table|Download (.pdf)
Table 271–2. Microorganisms Involved in Episodes of Severe Sepsis at Eight Academic Medical Centers
|Microorganism||Episodes with Bloodstream Infection, % (n = 436)||Episodes with Documented Infection but No Bloodstream Infection, % (n = 430)||Total Episodes, % (n = 866)|
Severe sepsis 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 30 years, and the annual number of cases is now >700,000 (˜3 per 1000 population). Approximately two-thirds 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 immunosuppressive drugs, indwelling catheters, and mechanical devices 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.
Most cases of severe sepsis are triggered by bacteria or fungi that do not ordinarily cause systemic disease in immunocompetent hosts (Table 271-2). To survive within the human body, these microbes often exploit deficiencies in host defenses, indwelling catheters or other foreign matter, or obstructed fluid drainage conduits. Microbial pathogens, in contrast, can circumvent innate defenses because they (1) lack molecules that can be recognized by host receptors (see below) or (2) elaborate toxins or other virulence factors. In both cases, the body can mount a vigorous inflammatory reaction that results in severe sepsis yet fails to kill the invaders. The septic response may also be induced by microbial exotoxins that act as superantigens (e.g., toxic shock syndrome toxin 1; Chap. 135) as well as by many pathogenic viruses.
Host Mechanisms for Sensing Microbes
Animals have exquisitely sensitive mechanisms for recognizing and responding to certain highly conserved microbial molecules. Recognition of the lipid A moiety of lipopolysaccharide (LPS, also called endotoxin; Chap. 120) is the best-studied example. A host protein (LPS-binding protein) binds lipid A and transfers the LPS to CD14 on the surfaces of monocytes, macrophages, and neutrophils. LPS then is passed to MD-2, that is bound to 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 lipopeptides elicit responses in animals that are generally similar to those induced by LPS; whereas these molecules also may be transferred by CD14, they interact with different TLRs. Having numerous TLR-based receptor complexes (11 different TLRs have been identified so far in humans) allows animals to recognize many conserved microbial molecules; others include lipopeptides (TLR2/1, TLR2/6), flagellin (TLR5), undermethylated DNA sequences (TLR9), and double-stranded RNA (TLR3, TLR7). The ability of some TLRs to serve as receptors for host ligands (e.g., hyaluronans, heparan sulfate, saturated fatty acids) raises the possibility that they also play a role in producing noninfectious sepsis-like states. Other host pattern-recognition proteins that are important for sensing microbial invasion include the intracellular NOD1 and NOD2 proteins, which recognize discrete fragments of bacterial peptidoglycan; early complement components (principally in the alternative pathway); and mannose-binding lectin and C-reactive protein, which activate the classic complement pathway.
A host's ability to recognize certain microbial molecules may influence both the potency of its own defenses 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 gram-negative 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, they are typically confined to the subepithelial tissue by a localized inflammatory response. 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. One exception is Neisseria meningitidis. Its hexaacyl LPS seems to be shielded from host recognition by its polysaccharide capsule. This protection may allow meningococci to transit undetected from the nasopharyngeal mucosa into the bloodstream, where they can infect vascular endothelial cells and release large amounts of endotoxin. Host recognition of lipid A may nonetheless influence pathogenesis, as meningococci that produce pentaacyl LPS were isolated from the blood of patients with less severe coagulopathy than was found in patients whose isolates produced hexaacyl lipid A. 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 has been shown by engineering a virulent strain of Y. pestis, which makes tetraacyl LPS at 37°C, to produce hexaacyl LPS; unlike its virulent parent, the mutant strain stimulates local inflammation and is rapidly cleared from tissues. For at least one large class of microbes—gram-negative aerobic bacteria—the pathogenesis of sepsis thus depends, at least in part, upon whether the bacterium's major signal molecule, LPS, can be sensed by the host.
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, enhance the permeability of local blood vessels, recruit neutrophils to the site of infection, and elicit pain. 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.
Cytokines and Other Mediators
Cytokines can exert endocrine, paracrine, and autocrine effects (Chap. 314). 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 the characteristic abnormalities of SIRS. In animals, larger doses of TNF-α induce shock and death.
Although TNF-α is a central mediator, it is only one of many proinflammatory molecules that contribute to innate host defense. Chemokines, most prominently interleukin (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 (IFN) 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.
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. 58). 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, while 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. 143). Evidence points to tissue factor–expressing microparticles derived from leukocytes as a potential trigger for intravascular coagulation. Contact-system activation occurs during sepsis but contributes more to the development of hypotension than to disseminated intravascular coagulation (DIC).
Elaborate control mechanisms operate within both local sites of inflammation and the systemic compartment.
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 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 by inactivating LPS in mice.
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 the presence of 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.
Systemic responses to infection also diminish cellular responses to microbial molecules. Circulating levels of anti-inflammatory cytokines (e.g., 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-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 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. There is also evidence that these responses may be immunosuppressive.
The acute-phase response increases the blood concentrations of numerous molecules that have 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 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.
It can thus be concluded 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. Elucidating how they contribute to lethality—i.e., become maladaptive—remains a major challenge for sepsis research.
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 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. Apoptotic death of B cells, follicular dendritic cells, and CD4+ T lymphocytes also may contribute significantly to the immunosuppressive state.
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-fibrinthrombi 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. While 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-fibrinthrombi, 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 a state of "hibernation" in which ATP production is diminished as oxidative phosphorylation decreases; nitric oxide 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 structural.
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 either improved oxygen delivery or left-to-right shunting.
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. Remarkably, recent findings indicate that exogenous nitrite can protect mice from challenge with TNF or LPS. Nitrite provides a storage pool from which nitric oxide can be generated in hypoxic and/or acidic conditions. These findings should renew interest in the possibility of exploiting nitric oxide metabolism to improve survival rates among septic patients.
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. 143). 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 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 Staphylococcus 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.
The pathogenesis of severe sepsis thus 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 are probably important as well, yet despite much study only a few allelic polymorphisms (e.g., in the IL-1β gene) 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 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 N. meningitidis (or, less commonly, H. influenzae) should be suspected (Fig. e7-42); in a patient who has been bitten by a tick while in an endemic area, petechial lesions also suggest Rocky Mountain spotted fever (Fig. 174-1). 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. 152-1). 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, while 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.
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 (PaO2/FIO2, <300) indicate the development of acute lung injury; more severe hypoxemia (PaO2/FIO2, <200) denotes the acute respiratory distress syndrome (ARDS). 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 Pneumocystis may be clinically indistinguishable from ARDS.
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.
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 low systemic vascular resistance, and death results from refractory shock or the failure of multiple organs rather than from cardiac dysfunction per se.
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 ACTH (CoSyntropin®) stimulation test is not useful for detecting less profound degrees of corticosteroid deficiency in patients who are critically ill. The concept of critical illness–related corticosteroid insufficiency (CIRCI; Table 271-1) 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. meningitidis bacteremia, disseminated tuberculosis, AIDS (with cytomegalovirus, Mycobacterium avium-intracellulare, or Histoplasma capsulatum disease), or the prior use of drugs that diminish glucocorticoid production, such as glucocorticoids, megestrol, etomidate, or ketoconazole.
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.
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 upon biopsy of septic organs.
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.
Patients with severe sepsis are often 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, varicella-zoster virus, or cytomegalovirus infections; the latter are thought to contribute to adverse outcomes in some instances.
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 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 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. 344). Hypoglycemia occurs rarely. The serum albumin level declines as sepsis continues. Hypocalcemia is rare.
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 271-1); 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 271-1) include pancreatitis, burns, trauma, 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.
Definitive etiologic diagnosis requires isolation of the 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 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.
Treatment: 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 microorganisms. 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.
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.
It is therefore very important to promptly initiate empirical antimicrobial therapy that is effective against both gram-positive and gram-negative bacteria (Table 271-3). 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 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, or has been hospitalized in an intensive care unit for a prolonged period. The chosen antimicrobial regimen should be reconsidered daily in order to provide maximal efficacy with minimal resistance, toxicity, and cost.
Table 271–3. Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function |Favorite Table|Download (.pdf)
Table 271–3. Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function
|Clinical Condition||Antimicrobial Regimens (Intravenous Therapy)|
|Immunocompetent adult||The many acceptable regimens include (1) piperacillin-tazobactam (3.375 g q4–6h); (2) imipenem-cilastatin (0.5 g q6h) 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.|
|Neutropenia (<500 neutrophils/μL)||Regimens include (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q8h); (2) piperacillintazobactam (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) or a lipid formulation of amphotericin B should be added if the patient is hypotensive or has been receiving broad-spectrum antibacterial drugs.|
|Splenectomy||Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin-resistant 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) or aztreonam (2 g q8h) should be used.|
|IV drug user||Vancomycin (15 mg/kg q12h)|
|AIDS||Cefepime (2 g q8h) or piperacillin-tazobactam (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.|
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, since "appropriate" antimicrobial regimens seem to be beneficial in both culture-negative and culture-positive cases.
Removal of the Source of Infection
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 intensive care 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. Even in patients without 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. Sonographic or CT imaging of the upper abdomen may disclose evidence of cholecystitis, bile duct dilatation, and pus collections in the liver, subphrenic space, or spleen.
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. Circulatory adequacy is assessed by measurement 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 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. 272). Titrated doses of norepinephrine or dopamine 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.
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. More recently, a randomized clinical trial that compared vasopressin plus norepinephrine with norepinephrine alone in 776 patients with pressor-dependent septic shock found no difference between treatment groups in the primary study outcome, 28-day mortality. Although vasopressin may have benefited patients who required less norepinephrine, its role in the treatment of septic shock seems to be a minor one overall.
CIRCI should be strongly considered 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 septic shock without increasing long-term survival.
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.
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.
In patients with prolonged severe sepsis (i.e., 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; when heparin is contraindicated, compression 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 below ∼150 mg/dL. Patients receiving intravenous insulin must be monitored frequently (every 1–2 h) for hypoglycemia.
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 in 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 factor pathway inhibitor (Fig. 271-1). 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 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 prominent 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 infections (e.g., pneumonia). The goal of the predisposition–infection–response–organ dysfunction (PIRO) grading system for classification of septic patients (Table 271-1) is similar. Other investigators have used specific biomarkers, 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. Multivariate risk stratification based on easily measurable clinical variables should be used with each of these approaches.
Mortality rates among patients who received tissue factor pathway inhibitor (TFPI) or placebo, shown as the running average over the course of the clinical trial. The drug seemed highly efficacious at the interim analysis in December 2000, but this trend reversed later in the trial. Demonstrating that therapeutic agents for sepsis have consistent, reproducible efficacy has been extremely difficult, even within well-defined patient populations. (Reprinted with permission from Abraham et al.)
Recombinant activated protein C (aPC) was the first drug to be approved by the U.S. Food and Drug Administration 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 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. A second trial of aPC in high-risk patients is now under way in Europe. Given the drug's known toxicity (increased risk of severe bleeding) and uncertain performance in clinical practice, many experts are awaiting the results of the European trial before recommending further use of aPC. Other agents in ongoing or planned clinical trials include intravenous immunoglobulin, a small-molecule endotoxin antagonist (eritoran), and granulocyte-macrophage colony-stimulating factor that was recently reported to restore monocyte immunocompetence in patients with sepsis-associated immunosuppression.
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 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.
The Surviving Sepsis Campaign
An international consortium has advocated "bundling" multiple therapeutic maneuvers into a unified algorithmic approach that will become the standard of care for severe sepsis. In theory, such a strategy could improve care by mandating measures that seem to bring maximal benefit, such as the rapid administration of appropriate antimicrobial therapy; on the other hand, this approach would deemphasize physicians' experience and judgment and minimize the consideration of potentially important differences between patients. Bundling multiple therapies into a single package also obscures the efficacy and toxicity of the individual measures. Caution should be engendered by the fact that two of the key elements of the initial algorithm have now been withdrawn for lack of evidence, while a third remains unproven and controversial.
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 estimates of the risk of dying of severe sepsis. Age and prior health status are probably the most important risk factors (Fig. 271-2). In patients with no known preexisting morbidity, the case-fatality rate remains below 10% until the fourth decade of life, after which it gradually increases to exceed 35% in the very elderly. Death is significantly more likely in severely septic patients with preexisting illness, especially during the third to fifth decades. Septic shock is also a strong predictor of short- and long-term mortality.
Influence of age and prior health status on outcome from 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, S. 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 Angus et al., 2001.)
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. 131) 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 (e.g., SIRS, sepsis) 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.