Definitions and Clinical Manifestations

The clinical manifestations of sepsis include the local symptoms and signs of the inciting infection as well as systemic signs, which are manifestations of the body’s response to the infection. Although the clinical features of the infection are relatively specific to the anatomic site, the systemic response is not. The systemic response, formally called the systemic inflammatory response syndrome (SIRS), includes both vital sign (fever, tachycardia, and tachypnea) and laboratory (leukocytosis or leukopenia) abnormalities (Table 10.1).

Consider sepsis severe when associated with hypoperfusion, organ dysfunction, or hypotension. Criteria for organ dysfunction have been specified (see Table 10.1). Septic shock is defined as refractory hypotension despite an adequate intravenous fluid volume challenge (> 20 to 30 mL/kg of crystalloid, or approximately 1 to 1.5 L). This categorization is important clinically, as it informs both triage and therapeutic decisions and has prognostic value.

Pathophysiology

The severity of an infection depends on both the pathogen’s virulence and the body’s pathophysiologic response to the infection. The Toll-like receptor (TLR) family plays an important and proximal role in both pathogen recognition (innate immunity) and initiation of the hosts’ inflammatory response. TLR-2 recognizes peptidoglycan in the cell wall of gram-positive pathogens; TLR-4 detects lipopolysaccharide in the outer membrane of gram-negative pathogens. This family of receptors also recognizes viral and fungal pathogens.

TLRs also play an integral role in the initiation of the “cytokine storm” of sepsis. These inflammatory cytokines stimulate neutrophils and endothelial cells, including the activation of procoagulant pathways. This adaptive immune reaction, through a complex, interactive relationship, augments innate immune activation to enable a more effective response to the infection. Simultaneously activated biologic pathways down-regulate and control this response; however, the host’s immune response may become maladaptive, resulting in organ dysfunction, circulatory shock, and death. The specific mechanisms that regulate this response, and the genetics underlying their control, currently represent intense areas of investigation. Although the multifactorial pathophysiology of organ dysfunction extends beyond the scope of this chapter, circulatory shock plays a central role. Shock is an important and early clinical manifestation of severe sepsis, and treatment of shock may be lifesaving. Therefore, it is important to understand the pathophysiology and hemodynamics of septic shock.

Activated neutrophils release mediators, which increase microvasculature permeability. This leads to third spacing and further exacerbates the decrease in intravascular fluid volume typically present on admission because of anorexia and external fluid losses (sweating, gastrointestinal, etc.). In addition, activated endothelial cells induce nitric oxide production, which leads to widespread vasodilatation (low systemic vascular resistance) impairing the compensatory response to hypovolemia. Furthermore, in up to 60% of patients with septic shock, a sepsis-induced cardiomyopathy (SIC) contributes to the circulatory derangements. Serum troponin levels are a sensitive marker of SIC and proportional to both the severity of cardiac dysfunction and patient prognosis. However, the underlying pathophysiology does not involve coronary ischemia or infarction.

Importantly, although widespread vasodilation (and low afterload) is a central feature of septic shock, the physical exam findings characteristic of a high cardiac output state (i.e., “warm shock”) are often absent on initial presentation. Rather, septic patients commonly present with findings consistent with a low cardiac output (i.e., “cold shock”), exhibiting a narrow pulse pressure, cool extremities, and mottled skin. This apparent paradox can be reconciled by dismissing the notion that vasodilation directly allows a reflex increase in cardiac output. A cardiac output rise in response to systemic vasodilation requires sufficient driving pressure (i.e., the mean systemic pressure; Pms) to the venous system to allow an increase in venous return, as cardiac output must equal venous return. Pms, as determined by the venous blood volume and compliance of the venous blood vessels, is often decreased on patient presentation because of profound hypovolemia and sepsis-induced venodilation (which increases venous compliance), respectively. Furthermore, SIC, present in many patients, further contributes to the impairment in cardiac output. This pathophysiology can lead to the findings of poor extremity perfusion on admission, as well as a low central venous pressure (CVP) and central venous oxygen saturation (ScvO₂).

Nevertheless, after repletion of intravascular volume, which may require up to 7 to 9 L in the first 24 hours, the classic findings of warm shock become manifest in most patients, including a wide pulse pressure and warm, well-perfused, extremities. This adaptive response to volume repletion occurs in most patients and is essential for survival. Even with SIC, an increase in end diastolic volume (preload) as a result of ventricular dilatation compensates for the reduction in inotropy, along with decreased afterload from arterial vasodilatation.

Differential Diagnosis

A limited set of disorders can mimic the warm shock (low afterload) state characteristic of well-resuscitated septic shock (Box 10.1); however, in those patients presenting in cold shock, one must consider a broader differential including disorders associated with a low cardiac output and high afterload. This broader differential includes all the other categories of shock including hypovolemic, cardiogenic, and obstructive. Although this includes a long list of disorders, initial findings on history and physical exam (e.g., clinical setting and absence of jugular venous distention and rales) usually allow one to readily exclude cardiogenic and obstructive shock from initial consideration.

Recognition

It is vitally important to recognize sepsis promptly, particularly when severe, as delays will reduce the effectiveness of lifesaving interventions. Early recognition may be challenging, particularly in the hospitalized patient, as clinical presentations can vary widely—and at times may be subtle—depending on the source of infection and host comorbidities. In sick patient populations, SIRS criteria have low diagnostic utility, as they are overly sensitive and nonspecific. In addition, in some particularly vulnerable populations such as the elderly or in those taking immunosuppressive medications, the clinical manifestation of both the infection and the SIRS response may be markedly attenuated despite overwhelming infection. In these patients, the signs of organ dysfunction (e.g., delirium or oliguria) may be the only clinical clue of underlying severe sepsis. This underscores the importance of maintaining a high degree of clinical suspicion for the presence of sepsis as the underlying cause of any clinical deterioration in the critically ill patient. Given the adverse impact of recognition delays on the effectiveness of some interventions, it is prudent to initiate treatment presumptively for severe sepsis, unless—or until—an alternative diagnosis has been established.

Recognizing the inherent challenges in diagnosing sepsis, a 2001 consensus conference reviewed the conventional definitions of sepsis (see the definition section). Although the definitions were not altered, the consensus panel added other clinical signs, associated commonly with sepsis, to the existing list of criteria that should raise the suspicion of sepsis. These include unexplained hyperglycemia, change in mental status, significant edema, and a markedly positive fluid balance (> 20 mL/kg over 24 hours).

Diagnosis

When suspecting a patient has sepsis, it is important to both establish the etiology of infection and assess the severity of sepsis. Finding a specific source of infection supports the diagnosis of sepsis (versus other systemic conditions), informs the appropriate choice of antibiotics, and facilitates source control. The severity of sepsis dictates which interventions, including ICU transfer, are indicated immediately.

In addition to a focused history and physical examination, it is important to obtain cultures and directed radiographic imaging to localize the source of infection. Ideally, obtain all cultures prior to antibiotic administration, to preserve their diagnostic sensitivity. However, pathogens grow in blood cultures in only half of even the most acutely ill patients.

Sepsis severity is readily established by physical exam and routine laboratory studies (see Table 10.1). Although some of these patients may be cared for on the general ward, when there is cardiovascular dysfunction, additional lifesaving interventions may be indicated. Specifically, septic shock or cryptic septic shock (lactate ≥ 4 mM/L, with a normal or high blood pressure) warrants early goal-directed therapy (EGDT) and prompt ICU transfer. Thus, a serum lactate should be obtained promptly in all patients with suspected sepsis, regardless of whether any other signs of organ dysfunction exist. In addition to high serum lactate levels (lactate ≥ 4 mM/L), intermediate lactate levels (i.e., ≥ 2 mmol/L) are associated with increased morbidity and mortality, independent of other organ dysfunction or level of blood pressure. The utility of serum lactate to risk-stratify the septic patient has been demonstrated across the continuum of care, from the pre-hospital environment to the emergency department to the ward and ICU patient. Conversely, the septic shock patient who maintains a normal serum lactate level throughout resuscitation appears to have a more favorable prognosis (Hernandez et al, 2012). Finally, in the proximal phase of resuscitation, transient hypotension (Marchick et al, 2009) and both abnormally low (< 70%) and abnormally high (≥ 90%) maximal ScvO₂ measures (Pope et al, 2011) identify patients at risk of subsequent adverse events (e.g., mortality).

Antimicrobial Therapy

Timely administration of effective broad-spectrum antimicrobial therapy remains paramount in the initial management of the septic patient. Mortality increases nearly 8% for every hour delay in antibiotics administration beyond the first hour of hypotension. In addition, if the initial antimicrobial regimen is ineffective against the pathogen, mortality increases despite subsequent administration of appropriate antibiotics based on culture data. Therefore, empiric broad-spectrum antimicrobial therapy should be administered within 1 hour of identification of septic shock. Furthermore, in patients with severe sepsis, a delay in administering antimicrobial therapy until after shock recognition is associated with increased mortality (Puskarich et al, 2011).

When choosing an empiric antibiotic regimen, always consider the likely source(s) of infection, coupled with prior culture results (i.e., patient colonization), courses of antimicrobials (to avoid the same class of agents), drug allergies, and the hospital antibiogram. Guidelines from the Infectious Disease Society of America and Surviving Sepsis Campaign have general recommendations for antimicrobial regimens suitable for specific sources of infection. These need to be modified by host- and hospital-specific factors. For example, immunosuppressed patients should be covered for all potential opportunistic pathogens.

After 3 days of treatment, de-escalate the antibiotic regimen to the narrowest spectrum possible based on available cultures, or discontinue antibiotics completely if an alternative diagnosis is established. However, if the patient fails to respond to the initial antibiotics, consider changing the drug regimen with a parallel, systematic search for a localized source of infection.

Source Control

Prompt removal or drainage of the likely source(s) of infection can be lifesaving, for similar reasons that antimicrobials must be given rapidly. The importance of physically removing a large quantity of pathogens from the body cannot be underscored. Antimicrobials alone will lyse or neutralize pathogens; however, these pathogens and their cellular debris may still cause harm through activation of a variety of immunologic reactions. Thus, it is imperative to search for and remove all likely sources of infection as soon as possible. If the patient remains in shock and no source is apparent, particularly if there are no localizing symptoms or signs, prompt removal of all endovascular lines and devices is indicated. In addition, once the patient has stabilized it is reasonable to perform cross-sectional imaging (computed tomography) of the chest, abdomen, and pelvis to search for a source.