Box 39.1 THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS)

Box 39.2 DEFINITION OF SEVERE SEPSIS

EPIDEMIOLOGY

Sepsis affects approximately 750,000 people in the United States annually and is associated with a mortality rate of 40–70% in its most severe form. The incidence continues to increase as the American population ages and as increasingly complex treatments are applied for conditions such as cancer and organ transplantation that require significant immunosuppression of the host. A majority of cases occur in patients with significant comorbidities. Significant risk factors include increasing age, immunosuppression, and chronic illnesses (such as chronic obstructive pulmonary disease or diabetes mellitus). While there exist no agreed upon optimal biomarkers of sepsis, various risk stratification tools, including the Acute Physiology and Chronic Health Evaluation (APACHE) II score, can be used to quantify the severity of illness and estimate the risk of death from sepsis.

CLINICAL PRESENTATION AND DIAGNOSIS

The clinical manifestations of sepsis can vary greatly from one patient to another. Not infrequently, this variability in presentation contributes to diagnostic uncertainty in cases of sepsis, especially early in the course of illness. Difficulty in early recognition of the septic response has hampered the identification of patients who might benefit from early aggressive management of sepsis, as described below. All too often patients are identified farther into the course of the inflammatory “storm,” by which time rescue strategies to restore adequate tissue perfusion and oxygen delivery are likely not as effective. There is no single specific diagnostic test for sepsis; rather, the diagnosis hinges on physical findings and laboratory values consistent with SIRS in the presence of suspected or identified underlying infection. Moreover, early localization of the primary source of infection is critical for optimal therapy. Thus, the clinician must be on the lookout for signs and symptoms attributable to the primary infection as well as to those that might reflect the inflammatory response to infection. It is equally important to keep an open mind in the diagnostic process, as many patients who present with signs or symptoms consistent with SIRS and shock may have alternative or concomitant diagnoses (e.g., cardiogenic or hemorrhagic shock) that explain their presentation.

    As noted above, the four signs that comprise the SIRS (box 39.1) are common but not requisite in sepsis. One example of the variability in the clinical presentation is that elderly patients with sepsis often present without fever. Other common findings on physical examination include delirium, confusion, and tachypnea that might represent nonspecific effects of a variety of different possible sources of infection. Thus, it is important to search for manifestations of the primary infectious insult that are specific to the initial site of infection. For example, patients with sepsis due to pneumonia may present with fever, a productive cough, evidence of lung consolidation on percussion and auscultation of the chest, and presence of an infiltrate on chest radiography. Sepsis originating from an infection of the urinary tract can present with dysuria, urinary frequency or incontinence, suprapubic tenderness on physical examination, and the presence of pyuria on examination of a urine specimen. An abdominal source of infection might manifest itself with nausea, vomiting, diarrhea, and/or the presence of rebound or guarding on physical examination. The wide variability in clinical presentation requires vigilance on the part of the providers caring for patients with sepsis.

    Laboratory abnormalities in septic patients can sometimes help point toward a source of sepsis (e.g., elevated bilirubin and alkaline phosphatase levels in cholecystitis or cholangitis), but more often reveal nonspecific indices of infection and inflammation, including a leukocytosis with a left shift and thrombocytopenia. Patients can develop an anion gap acidosis due to the accumulation of lactic acid in the setting of organ hypoperfusion. In fact, an elevated lactate level (e.g., ≥4 mmol/L) has been proposed by some as a possible marker that should heighten suspicion for the presence of sepsis, even though the lactate level can be elevated from other causes of tissue hypoperfusion (e.g., ischemic bowel). Unfortunately, once the lactate level is elevated in sepsis, end-organ hypoperfusion and damage may already have occurred. This end-organ effect has been referred to as the multiple organ dysfunction syndrome, and laboratory evidence of renal and hepatic insufficiency are often hallmarks of this syndrome. Additionally, coagulopathy can occur due to the development of disseminated intravascular coagulation. Hyperglycemia is a common finding among patients with underlying diabetes and, even in patients without previously diagnosed underlying diabetes, elevated glucose levels are often seen during critical illness, likely as a result of a stress response.

    In patients with suspected infection who do not manifest focal signs, symptoms, physical findings, or laboratory data pointing at the source of sepsis, a continued search must be pursued while the patient is treated with broad-spectrum antibiotics and stabilized. Cultures of blood, urine, and sputum should be obtained on presentation. Samples of fluid from other potential sources of infection should also be sent for culture as the clinical scenario dictates (e.g., spinal fluid if meningitis is suspected, or ascitic fluid if spontaneous bacterial peritonitis might be a concern). If the patient’s condition deteriorates on empirical antibiotic therapy with an unknown source of infection and/or the initial microbiological workup is negative, a more aggressive workup may be indicated including early consideration of additional imaging by computed tomography. More invasive testing is often necessary in critically ill patients to identify (or exclude) possible sources of infection. For example, if a patient with suspected bacterial pneumonia worsens on broad-spectrum antibacterial agents, bronchoscopy with bronchoalveolar lavage in order to culture the pathogenic organism may be helpful.

PATHOPHYSIOLOGY

As described above, sepsis can develop following microbial infection of a normally sterile cavity. One useful framework for thinking about the pathogenesis of sepsis is the “PIRO” concept that was described by an international panel of experts at the 2001 Symposium on Intensive Care and Emergency Medicine. PIRO is an acronym that stands for predisposition, infection, response, and organ dysfunction.

    With regard to predisposition, the response to a particular infection varies greatly from one individual to another. For example, it is not uncommon for an elderly patient to present with a urinary tract infection and subsequent bacteremia as a result of translocation of the organisms into the bloodstream. Some of these patients will have a fulminant course complicated by septic shock and organ dysfunction. In contrast, other patients will remain normotensive and asymptomatic despite the circulating microbes. The predisposition of some patients to developing sepsis is likely related to a combination of genetic and environmental factors. Immune suppression, either drug-induced or due to comorbid conditions such as malignancy or cirrhosis, weakens the host response to infection and predisposes patients toward the development of sepsis. It is likely that genetic variation also plays an important role in the response to infection, as demonstrated by studies that have shown possible differences in the risk of sepsis among individuals with polymorphisms in various genes.

    The site and microbiology of the antecedent infection plays a key role in the pathogenesis of this syndrome. The microbiology of sepsis has shifted over time. Prior to 1990, intra-abdominal infections were the most common. Recently, studies have shown that pulmonary infection (i.e., pneumonia) is the most frequent source, accounting for approximately 40% of sepsis cases. Moreover, although a large percentage of sepsis cases had traditionally been attributed to infection with gram-negative bacterial organisms, recent years have seen an increase in numbers of infections attributed to gram-positive bacteria and infections with nonbacterial organisms such as fungi or viruses. Increasing prevalence of infections with fungi and viruses has been associated with an increase in numbers of immunocompromised hosts as a result of chemotherapy treatments for cancer or immune suppression for organ transplantation.

    The host response to infection is one of the key determinants in the pathophysiology of sepsis. Recognition of microbes by cells of the innate immune system results in the release of numerous proinflammatory cytokines. Downstream effects of this inflammatory response include recruitment of neutrophils to the tissues and development of hypotension as a result of vasodilatation. Cytokines that are thought to be important to the inflammatory response include, but are not limited to, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-1β. Many of these cytokines are known to be important early in the course of sepsis (i.e., within the first 6–24 hours), and other proteins such as extracellular high-mobility group B-1 (HMGB1) have been identified as late-acting mediators in the course of sepsis. HMGB1 is a cytokine-like protein that is not released until nearly 24 hours into the course of sepsis and may play a key role in the development of organ dysfunction later in the course of this syndrome. Following the production of proinflammatory cytokines, it has been proposed that the host can develop a compensatory response through production of antiinflammatory cytokines such that a period of relative “immune compromise” for the host can develop later in the septic response.

    Other key components of the host’s response to sepsis include activation of the coagulation and neuroendocrine systems. Endothelial damage leads to expression of tissue factor and subsequent activation of the clotting cascade, followed by the formation of thrombin. Some experts hypothesize that this process may play a role in containing invading pathogens. Deficiency of several fibrinolytic proteins, including protein C, further enhances the procoagulant milieu. The stress response also results in the development of peripheral insulin resistance and hyperglycemia, as well as in activation of the hypothalamic-pituitary axis and secretion of a number of key hormones including adrenocorticotropic hormone (ACTH) and vasopressin. Insufficient production of these hormones during sepsis have led to the concept that critical illness might result in states of “relative adrenal insufficiency” and “vasopressin deficiency,” respectively. Management strategies that have arisen in response to the appreciation of these pathophysiological processes are discussed in more detail below.

    Although the exact mechanism of organ dysfunction in patients with severe sepsis is unknown, tissue hypoperfusion as a result of hypotension and vasodilatation likely plays an important role. Moreover, significant interest has arisen in the concept of microcirculatory dysfunction as an important contributor to this process. Inflammation and a local activation of clotting mechanisms are needed to combat infection as described above, but if left unchecked these processes can lead to progressive organ dysfunction. Thrombosis of the microvasculature can lead to shunting of blood flow away from vital organs and result in impaired local oxygen delivery to the tissues. As an alternative or perhaps coexisting phenomenon, inability of the tissues to use delivered oxygen as a result of the development of mitochondrial dysfunction has been proposed as a possible mechanism of organ dysfunction.

MANAGEMENT

EARLY MANAGEMENT

The prompt recognition and treatment of severe sepsis is necessary in order to correct metabolic derangements, optimize oxygen delivery, and prevent the development of organ dysfunction. The initial approach to the patient involves stabilization with a focus on maintaining adequate circulation, securing the airway, and ensuring adequate oxygenation and ventilation. Intubation of the airway with an endotracheal tube and support of breathing with mechanical ventilation is necessary for those patients that are unable to protect their airway or for those that present with inability to sustain adequate oxygenation or ventilation. Assessment of the blood pressure, pulse, and signs/symptoms of perfusion as described above are important to ensure presence of adequate circulation. Obtaining early intravenous access with large bore peripheral catheters and/or central venous catheters is critical for the facilitation of aggressive volume resuscitation and administration of medications.

SOURCE CONTROL

A key component in the management of patients with sepsis is controlling the source of the infection. This requires the early administration of broad-spectrum antibiotics as well as drainage or removal of any indwelling sources of infection. Examples of infectious sources that require removal include infected venous catheters, soft tissue abscesses, and empyema (table 39.1). It is recommended that broad-spectrum antibiotics to cover all suspected sources of infection be administered within the first hour of presentation—each hour of delay in antibiotic treatment has been associated with an increased mortality rate. If cultures reveal a specific organism, the antibiotic regimen can be tailored accordingly. Recommended duration of antibiotic therapy varies greatly depending on the initial source and severity of infection.

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