Jennifer M. Reifel Saltzberg, MD, MPHjreifelsaltzberg@umem.org,     Department of Emergency Medicine, University of Maryland School of Medicine, 110 South Paca Street, 6th Floor, Suite 200, Baltimore, MD 21201, USA

A common cause of fever with signs of shock is sepsis. Sepsis describes the spectrum of illness caused by severe infection. The incidence of sepsis is increasing and mortality can be high. Diagnosing the disease and implementing treatment early can decrease mortality. Early treatment includes empirical antibiotics and resuscitation. The diverse physiology present in sepsis can make the resuscitation complex; many different types of hemodynamic monitoring may be necessary. Even with this complexity, an organized approach can improve patient outcomes.

Keywords

• Sepsis • Septic shock • Severe sepsis • Early goal-directed therapy • Resuscitation • Sepsis bundles

Key points

Fever with signs of shock is a common presentation in the emergency department and requires prompt evaluation and treatment. When the underlying cause is infectious, the patient is diagnosed with sepsis, specifically septic shock. Sepsis is the systemic response to infection that manifests as a continuum of illness from mild vital sign abnormalities to cardiovascular collapse. The disease is widespread, and the incidence is growing.1–3 In the past 12 years, effective therapy for sepsis has been developed and has reduced mortality, hospital length of stay, and treatment costs when implemented in a timely manner.4–7

Other causes of fever with signs of shock include pulmonary embolus; toxidromes such as salicylate toxicity and neuroleptic malignant syndrome; and endocrine emergencies such as adrenal crisis, pheochromocytoma, or diabetic ketoacidosis. These other possible diagnoses require specific interventions, but treatment of sepsis should not be delayed because it is time dependent and does not worsen most other possible illnesses. Sepsis care can begin while the diagnosis is being confirmed. The importance of this early diagnosis and treatment means that the emergency department plays a fundamental role in reducing the mortality associated with sepsis.

Epidemiology

Severe sepsis and septic shock are common clinical scenarios. In the United States, the incidence is 3 cases per 1000, or 751,000 cases annually.1 Many of these cases present to an emergency department first. Severe sepsis accounts for more than 500,000 emergency department visits each year.1,8 Despite improvements in antibiotic therapy and expansion of preventive measures such as vaccines, the incidence of sepsis has been increasing1,8 as much as 8.7% per year.9

The sepsis-related mortality in the United States is an estimated 215,000 deaths per year, with 9.3% of all deaths attributed to sepsis.1 This mortality is not uniform across the country and ranges from 41 to 88 deaths per 100,000, depending on the state.10 The geographic variability of sepsis mortality is also shown between countries even when matched for relative level of available resources. A study in Australia11 showed that patients admitted to an intensive care unit (ICU) with sepsis had a mortality of 24.7%. In Spain, a similar population had a mortality of 37.5%.12 Internationally the most common infectious source of sepsis is respiratory, accounting for 44% of cases.1,9 There is some geographic variability in the source; intra-abdominal infections are more common in Mexico, accounting for 47% of ICU sepsis admissions.13

Pathophysiology

An infection stimulates an inflammatory response, which, under some circumstances, becomes systemic and causes sepsis. Early triggers of sepsis are inflammatory mediators such as tumor necrosis factor α and interleukin-1.14 The activity of these cytokines decreases later in sepsis, when other mediators of an antiinflammatory response, including interleukin-4 and interleukin-10, become more prevalent.14 This downregulation of the inflammatory system has been shown histologically with a decrease in B cells, dendritic cells, and CD4 T cells in spleens of septic patients.14 A patient’s location along this continuum of inflammation and antiinflammatory response is influenced by host characteristics and comorbidities as well as the infectious agent.

The inflammatory pathways that are activated in sepsis interact with the blood hemostasis pathways. When an infection and its response are localized, the two systems slow local blood flow through the microcirculation and increase endothelial permeability, allowing the immune system to clear the pathogen.15 When the response is generalized, as in sepsis, the actions of the inflammatory and blood hemostasis pathways decrease blood flow through the microcirculation systemically and limit oxygen delivery.16 Nitric oxide (NO) is also produced, but the amount changes with time like the other inflammatory mediators. Initially, NO causes vasodilation, but then its production decreases and vasoconstriction occurs. These processes contribute to arteriovenous shunting and blood pressure abnormalities.16

Microcirculatory changes might be difficult to measure at the onset of illness, but as the disease progresses, these changes contribute to the overall clinical picture. Decreased systemic vascular resistance and capillary leak caused by endothelial dysfunction15 combine with insensible fluid losses from fever, tachypnea, and poor oral intake to cause hypovolemia and distributive shock. Some patients have cardiogenic dysfunction caused by an interaction of multiple secondary mediators acting on the cardiac tissue.17 These diverse influences cause variability of the clinical presentation: some patients have hypotension and high cardiac output, others show hypovolemia and low cardiac output, and others have no hypotension but show evidence of microcirculatory deficits and tissue hypoperfusion.

The treatment of sepsis is based on optimizing the cardiovascular system to improve oxygen delivery in the microcirculation. Therapies targeting secondary mediators are not generalizable and are still under investigation.14,18 The diagnosis of sepsis must consider the disease in its various clinical presentations, and treatment must adapt to changes in the patient’s hemodynamics as the disease progresses.

Case definition

The last 2 decades have witnessed significant progress toward a better definition of sepsis. A set of criteria is now used to define cases and facilitate early detection (Fig. 1). The severity of illness is also important to categorize, because it is explicitly connected to intervention, treatment targets, and outcome. Sepsis is stratified by inflammation, end-organ involvement, and tissue hypoperfusion. Even patients with uncomplicated sepsis are important to identify early. Glickman and colleagues19 documented that uncomplicated sepsis progressed to more serious stages of illness in 22.7% of patients within 72 hours. A plan for management and reevaluation is important at all levels of disease.

Patients could have signs of inflammation due to causes other than infection. Systemic inflammatory response syndrome (SIRS) can be caused by infection, trauma, thermal injury, pancreatitis, or pulmonary embolism (Fig. 2). SIRS is diagnosed when 2 of the following criteria are present: body temperature greater than 38°C or less than 36°C; heart rate greater than 90 beats per minute; respiratory rate greater than 20 breaths per minute or Paco2 less than 32 mm Hg; and a white blood cell count greater than 12,000/mm3, less than 4000/mm3, or with more than 10% immature forms.20 Sepsis is diagnosed when SIRS is caused by a suspected infection. These criteria simplify the diagnosis and are useful, but they do...