Introduction

Sepsis is among the oldest medical conditions described, yet remains a leading cause of death. The Centers for Disease Control and Prevention estimate that 1.5 million people in the United States are affected each year, with a resulting 250,000 American deaths annually. For many, if not most, hospitals, sepsis is the main cause of mortality, and in a 2016 report contributed to $24 billion in annual costs (AHRQ-HC cost and utilization project; June 2016). From a global perspective, sepsis affects over 30 million people each year, with over 5 million deaths. For these reasons, it is imperative that sepsis be recognized early and treated as a medical emergency.

All providers will encounter patients with sepsis, regardless of their practice site or clinical focus; thus it is important for everyone to have an understanding of sepsis. How patients present with sepsis varies depending on age, and for the purposes of this review, pediatric patients will be excluded.

Epidemiology of Sepsis

The incidence of sepsis has increased over the last several decades. This is presumed to be secondary to increased rates of detection and diagnosis, aging populations, high numbers of patients who are immunocompromised, and use of more invasive and foreign medical devices (e.g., cardiovascular implantable electronic devices, ventricular assist devices, vascular catheters, prosthetic heart valves).

Seasonal variation of sepsis has also been described, with increased prevalence in the winter months, presumably due to influenza and other respiratory infections. Respiratory infections are the leading cause of sepsis throughout the year. Gram-positive organisms remain the primary pathogens, but Gram-negative organisms contribute a significant proportion of identified causes of sepsis. Fungi have continued to rise in incidence, possibly related to the increasing numbers of immunocompromised patients. Finally, a significant percentage of sepsis cases—between approximately 25% and 50%—have no pathogen identified and are therefore deemed to be culture-negative sepsis cases.

Pathophysiology and Definitions of Sepsis

Sepsis has long been considered the body’s dysregulated host response to infection. During a 1992 consensus conference the phrase systemic inflammatory response syndrome (SIRS) was coined to refer to activation of the immune system, regardless of cause, hypothesizing that SIRS could be triggered by infection, trauma, or other inflammatory processes like pancreatitis. Thus early definitions of sepsis focused on the presence of two or more SIRS criteria in the setting of infection. Patients with sepsis plus organ dysfunction, evidence of hypoperfusion, or hypotension were defined as having severe sepsis, whereas septic shock was defined as persistent hypotension despite adequate fluid resuscitation. These sepsis syndrome definitions remained in place essentially unchanged until recently (2001 international sepsis definitions conference) ( Table 16.1 ).

This all changed in 2016 with the publication of a task force’s proposed revisions to the consensus definition. The task force was convened by two critical care societies to develop updated definitions to better reflect the advancements in the understanding of sepsis pathophysiology along with a desire to differentiate sepsis from uncomplicated infection. Noting that SIRS criteria did not necessarily indicate a dysregulated host response to infection and that many hospitalized patients have SIRS criteria who never develop infection, the task force determined that the inclusion of SIRS into the sepsis definition was unhelpful (i.e., SIRS + infection = sepsis). Instead, the task force elected to focus the new sepsis definition on patients already suspected of being infected. This infected population would be defined as sepsis if they had life-threatening organ dysfunction caused by a dysregulated host response to their infection. Additionally, the term severe sepsis was eliminated by the task force and septic shock was considered a subset of sepsis with profound circulatory or metabolic dysfunction associated with higher risk of mortality (JAMA sepsis 3). Table 16.2 compares old sepsis definitions with new ones. To reduce confusion throughout the remainder of this review, the term sepsis 3 or septic shock 3 will be utilized when referring to the new definitions. The new sepsis 3 definitions better reflect this pathophysiology along with pertinent clinical criteria for diagnosis.

The bottom line on definitions is that all definitions are still relevant. The Centers for Medicare and Medicaid Services (CMS) continues to utilize SIRS in their definition; thus administratively, the old definitions remain important. Hopefully, CMS will change to the new definitions in the future. Until that time, clinical practice and research will often utilize the newer definitions, given the increased simplicity and objectivity of the criteria.

With any infection, the host has a complex response, including proinflammatory and antiinflammatory cascades; activation of multiple immune cells, including macrophages and neutrophils; and normally remains regulated and does not harm a host. In sepsis 3, there is a dysregulated host response, which includes immune system dysregulation with sepsis-induced inflammation resulting in host injury via cellular damage and apoptosis leading to both organ failure and secondary immunosuppression. The immunosuppression of sepsis 3 is marked by lymphopenia that evolves within the first few days and predisposes patients to an increased risk of secondary infections.

Despite the emergence of sepsis 3, competing definitions remain, primarily in the form of the sepsis core measure. Due to the significant impact sepsis has had across the United States, CMS established the SEP-1 core measure in 2015, with its unique set of definitions for severe sepsis and septic shock. These definitions were developed to retrospectively monitor adherence to bundled sepsis treatment, hoping to highlight areas of opportunity for hospitals. The CMS severe sepsis definition is based on provider documentation of severe sepsis or the clinical criteria of SIRS, documentation of infection, and new organ dysfunction. The definition of septic shock is similar to severe sepsis, with the addition of either initial lactate ≥4.0 or persistent hypotension after fluid resuscitation ( Table 16.3 ).

TABLE 16.3

Severe Sepsis vs. Sepsis Shock

CMS: Severe Sepsis	CMS: Septic Shock
Clinical criteria (each within 6 hours of each other) 1. SIRS criteria (two or more) 2. Documentation of suspected/known infection 3. New organ dysfunction	Clinical criteria (each within 6 hours of each other) 1. SIRS criteria (two or more) 2. Documentation of suspected/known infection 3. New organ dysfunction 4. Either: a. Initial lactate ≥4.0 or b. Persistent hypotension in the hour after 30 mL/kg of crystalloid fluids are complete
OR	OR
Provider documentation 1. Provider documents suspected, possible, or ruled-out severe sepsis	Provider documentation 1. Provider documents suspected, possible, or ruled-out septic shock

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