Sepsis

Michael C. Scott and Michael E. Winters

BACKGROUND

Approximately 650,000 cases of sepsis are diagnosed each year in the United States, making it one of the most common causes of critical illness encountered by the emergency physician.¹ Despite significant advances in management, more than 200,000 patients die annually from this devastating disease.² It is therefore imperative that the emergency physician be expert in the recognition and treatment of patients with sepsis, severe sepsis, and septic shock.

DEFINITIONS

The most widely used definition of sepsis is the presence of infection (presumed or confirmed) combined with signs of a systemic inflammatory response.³ Traditionally, an inflammatory response is diagnosed by the presence of at least two of the four criteria for the systemic inflammatory response syndrome (SIRS). Recently, updated international guidelines for the management of severe sepsis and septic shock expand upon the traditional SIRS criteria (Table 31.1). The clinical spectrum of sepsis includes patients with severe sepsis and septic shock. Severe sepsis is defined as sepsis with evidence of organ dysfunction or tissue hypoperfusion (Table 31.2).³ The simplest and most objective marker of the onset of severe sepsis is an elevated lactate level. Lactate levels >4 mmol/L suggest significant tissue hypoperfusion and warrant aggressive resuscitation. Although an elevated lactate level is not specific to sepsis, it has been used as an inclusion criterion for severe sepsis in the majority of studies of patients with severe sepsis or septic shock. Septic shock is defined as the presence of arterial hypotension despite adequate fluid resuscitation, commonly defined as at least 20 to 30 mL/kg of a crystalloid solution.³

HISTORY AND PHYSICAL EXAM

The clinical presentation of patients with sepsis depends on the source of infection. For patients with suspected sepsis, the history and physical exam should be directed toward the most common sources of infection (Table 31.3). Patients with sepsis do not always present with overt signs of arterial hypotension and shock. Many, notably the elderly, will present with more subtle signs of illness, including altered mental status, fatigue, and lethargy. A complete physical exam, including assessment of mental status, a thorough skin examination, and complete neurologic examination, should be performed in any patient with suspected infection. Septic shock is a form of distributive shock. Patients in the early stages of this illness may have warm, seemingly well-perfused extremities rather than the cool, dusky appearance of patients with other forms of circulatory shock.

DIAGNOSTIC EVALUATION

Initial laboratory and radiographic testing should be directed toward the most likely source of infection (Table 31.3). Current guidelines recommend obtaining at least two sets of blood cultures before initiating antimicrobial therapy, provided that the time needed to draw these cultures does not delay the initiation of therapy more than 45 minutes.³ For patients with indwelling catheters, at least one blood culture should be obtained from the vascular device.³ Obtaining timely blood cultures is essential for identifying the pathogenic organism and narrowing the spectrum of antimicrobial therapy. Additional blood samples should be sent for a complete blood count, a comprehensive metabolic panel, a coagulation profile, serum lactate measurement, venous blood gas analysis to determine pH, and central venous oxygen saturation if an internal jugular or subclavian central line has been placed. In addition to blood work, urinalysis and urine culture should also be obtained in any patient with suspected sepsis.

Radiographic studies should be obtained to determine if source control of an infection is required. Because the pulmonary system is the most common source of infection in patients with sepsis, unless there is another clear location of infection, a chest radiograph is essential. Additional testing, such as computed tomography or ultrasound, may be obtained based on the suspected location of infection. In critically ill patients without an obvious source of infection, an intra-abdominal infection is likely, and diagnostic testing with computed tomography or ultrasound should be considered.

MANAGEMENT GUIDELINES

Management of the critically ill ED patient with sepsis includes early administration of antimicrobial therapy; quantitative, protocol-guided hemodynamic resuscitation; and critical adjunctive therapy, including the use of corticosteroids, blood product transfusion, glucose control, and mechanical ventilation. The recently updated international guidelines for the management of patients with severe sepsis and septic shock are summarized in the following sections.³

Antimicrobial Therapy and Source Control

Early administration of appropriate antibiotics is paramount to improving survival in patients with severe sepsis or septic shock. In 2006, a landmark study demonstrated a 7.6% decrease in mortality for every hour delay in administering effective antimicrobial therapy for patients with septic shock.⁴ As a result of this study and several others demonstrating similar findings, current guidelines recommend that effective antimicrobial therapy be administered within 1 hour after the recognition of septic shock and severe sepsis.³ Initial antimicrobial therapy should be broad spectrum and effective against the most likely causative organism. When selecting empiric antimicrobial medications, the emergency physician must take into account the site of infection, local hospital and community susceptibility patterns, the presence of comorbid illnesses, recent antibiotic exposure (within the previous 3 months), and the patient’s medical history.³ Despite the fact that many patients with severe sepsis or septic shock have evidence of acute kidney injury (AKI), all patients should receive an initial full loading dose of antimicrobial medications.³ For neutropenic patients or those with multidrug-resistant organisms, combination antimicrobial therapy (i.e., a beta-lactam antibiotic and either an aminoglycoside or fluoroquinolone) is recommended.³ Combination therapy is also recommended for patients with septic shock and respiratory failure.³

A confirmed nidus of infection (e.g., intra-abdominal abscess, empyema, infected device, or necrotizing soft tissue infection) may be resistant to antimicrobial agents. In these cases, source control is essential and should be undertaken within 12 hours of diagnosis, provided the patient can safely undergo the required procedure.³

Protocol-Guided Hemodynamic Resuscitation

In 2001, a landmark study demonstrated significantly reduced mortality with use of a protocol-guided resuscitation with quantitative endpoints, delivered to patients with sepsis-induced hypotension within 6 hours of their presentation to an emergency department.⁵ The hemodynamic targets of their study were central venous pressure (CVP), mean arterial pressure (MAP), urine output, and central venous oxygen saturation (ScvO₂). While the findings of the study are still being debated, current guidelines have remained consistent in their recommended hemodynamic targets (Table 31.4) within the first 6 hours of therapy for patients with sepsis-induced hypotension.³

Though current guidelines recommend protocol-guided therapy for patients with severe sepsis and septic shock, a recently published multi-center trial has questioned the utility of this approach. The ProCESS trial⁶ was a randomized, controlled, multi-center study designed to evaluate three treatment groups in patients with severe sepsis and septic shock: 1) protocol-based early goal-directed therapy (identical to the original EGDT protocol), 2) protocol-based standard therapy (derived from current literature and expert consensus), and 3) standard therapy (no predetermined resuscitation protocol). In the standard therapy group, care was left to the discretion of the treating physician. Importantly, investigators found no difference in 60-day, 90-day, and 1-year mortality between the three groups. While many clinicians have cited this trial to debate the utility of early goal-directed therapy, it is important to note that ProCESS was carried out in large, academic centers throughout the United States. These centers were required to adhere to the non-resuscitative aspects of care recommended by the Surviving Sepsis Campaign (e.g., prompt administration of antibiotics). Furthermore, baseline mortality was significant different between these two trials. Given these limitations, it is unclear whether “standard therapy” can be expected to be the same at centers outside of those involved in the ProCESS trial. Pending the publication of two additional trials (ARISE and PROMISE), protocol-based resuscitation should focus on early identification of patients with sepsis, early antibiotics, adequate fluid administration, and an appropriate assessment of the adequacy of circulation.

The continuous assessment of tissue perfusion is another essential component of the initial resuscitation of septic patients. In recent years, significant emphasis has been placed on global markers of tissue perfusion, namely, serum lactate and ScvO₂. Current guidelines continue to recommend continuous or intermittent monitoring of ScvO₂ as a marker of tissue perfusion³ using either a subclavian or internal jugular central venous catheter. Depending on the patient and resources available to the emergency physician, central venous access may not be feasible. In these patients, guidelines recommend monitoring serial serum lactate values.³ In patients with elevated values (i.e., lactate >4 mmol/L), resuscitation should target the normalization of serum lactate. Currently, there is no consensus on the optimal interval to measure serial lactate values. It is the authors’ opinion that serum lactate (venous or arterial) should be measured every 2 to 3 hours in the septic patient.

Intravenous Fluids

The administration of intravenous fluids to restore intravascular volume is central to the hemodynamic resuscitation of the septic patient. Currently, isotonic crystalloid solutions are the fluid of choice for patients with severe sepsis or septic shock.³ For patients with sepsis-induced hypoperfusion, a minimum of 30 mL/kg of crystalloids should be administered.³ While there is no evidence that clearly demonstrates the superiority of a particular crystalloid fluid, there is mounting evidence of the harm of normal saline. The supra-physiologic concentration of chloride in normal saline has been associated with increased kidney injury and need for renal replacement therapy (RRT).⁷ Recent literature has focused on the use of “balanced” fluids (e.g., lactated Ringer’s, Plasma-Lyte) for resuscitation in sepsis, particularly in patients with significant acidosis.⁸ When large amounts of crystalloid solution are required, guidelines allow for the consideration of albumin. The addition of albumin to crystalloid fluid resuscitation is based on the results of the 2004 SAFE trial, in which the use of albumin in a subgroup of patients with severe sepsis demonstrated a trend toward an improved mortality rate.⁹ Hydroxyethyl starch solutions are not recommended as a result of several studies demonstrating their harmful effects.^3,10–12

Current guidelines recommend titration of intravenous fluids to achieve a CVP of 8 to 12 mm Hg—with a higher goal of 12 to 15 mm Hg for those receiving mechanical ventilation—as a physiologic target for resuscitation in patients with severe sepsis or septic shock.³ CVP, however, is a poor marker of fluid status and responsiveness in the critically ill patient. Recent studies have focused on the use of dynamic markers of fluid responsiveness, such as pulse pressure variation, stroke volume variation, passive leg raise, and respirophasic changes in the diameter of the inferior vena cava as measured by bedside ultrasound. While no one dynamic technique has been proven superior, most provide better assessment of fluid responsiveness than the CVP. For this reason, current guidelines do allow for the use of dynamic indices to guide intravenous fluid therapy.³

Vasopressors

When intravenous fluid therapy fails to maintain adequate arterial perfusion pressure (MAP ≥ 65 mm Hg), a vasopressor medication should be administered. Historically, norepinephrine and dopamine have been the most common first-line agents. However, recent publications suggest that dopamine is associated with a higher rate of tachyarrhythmias and may result in increased mortality when given to patients in cardiogenic shock.¹³ A subsequent related meta-analysis demonstrated that for patients in septic shock, dopamine is associated with increased mortality when compared with norepinephrine.¹⁴ As a result of these reports, norepinephrine is recommended as the initial vasopressor agent of choice for patients with fluid-refractory septic shock.³ When an additional vasopressor agent is required to maintain sufficient perfusion pressure, either epinephrine or vasopressin is recommended.³ Vasopressin should not be used as a single agent. Rather, it should be used in combination with norepinephrine and maintained at a stable dose of 0.03 to 0.04 units/min. Because of its higher incidence of tachyarrhythmias and association with an increased mortality rate, dopamine should be avoided, except in patients with absolute or relative bradycardia.³ Phenylephrine is another popular vasopressor used to maintain adequate perfusion pressure in patients with a number of critical illnesses, especially given its presumed decreased risk of adverse events compared to other vasopressor medications when given peripherally. However, its use in patients with septic shock is not recommended, except as salvage therapy or in those with documented high cardiac output and low MAP.³

Inotropes

Inotropic therapy should be considered in the presence of myocardial dysfunction (i.e., elevated cardiac filling pressures with a low cardiac output) or when evidence suggests persistent tissue hypoperfusion (i.e., rising or unchanged serum lactate, low ScvO₂) despite augmentation of intravascular volume and optimization of MAP. With studies suggesting the rate of sepsis-induced myocardial dysfunction to be as high as 44%,¹⁵ the availability of rapid assessment with bedside ultrasound allows the early institution of appropriate inotropic therapy. Dobutamine is the initial inotropic agent of choice, up to a maximum dose of 20 μg/kg/min. Titration to a predefined, supranormal level of cardiac output is not recommended.³

Glucocorticoids

Research findings differ as to the effect of glucocorticoids on mortality rates in patients with sepsis. Current guidelines recommend low-dose glucocorticoids (hydrocortisone 200 mg/d) in patients with persistent hypotension despite optimal fluid and vasopressor therapy.³ This recommendation is based on the drug’s benefit in earlier reversal of shock. Continuous (rather than intermittent) administration of hydrocortisone is recommended to decrease the incidence of hypernatremia and hyperglycemia, both of which are associated with increased morbidity and mortality. A patient’s response to an adrenocorticotropic hormone stimulation test has not been found to be predictive of his/her response to glucocorticoids; therefore, this test is not recommended.

Blood Transfusion

In the early goal-directed therapy (EGDT) protocol, administration of blood transfusion to a goal hemoglobin of 10 g/dL was an important step in the management of patients with persistent tissue hypoperfusion (low ScvO₂) despite achieving the goals for CVP and MAP.⁵ The use of this transfusion threshold has become one of the most controversial components of the protocol. Currently, there are several ongoing trials evaluating individual components of the EGDT protocol including blood transfusion. The results of these studies are not available at the time of this publication. While the optimal hemoglobin during early resuscitation of the patient with severe sepsis or septic shock has not been clearly defined, it is clear that blood transfusions in the critically ill patient can be harmful. As a result, guidelines recommend maintaining a hemoglobin concentration between 7 and 9 g/dL in patients who have been resuscitated and no longer have evidence of tissue hypoperfusion.³ It may be reasonable to target a higher hemoglobin level for those with active myocardial ischemia or hemorrhage.

Mechanical Ventilation

Patients with severe sepsis and septic shock are at significant risk for developing acute respiratory distress syndrome (ARDS). Guidelines strongly recommend the use of low tidal volume ventilation in patients who have sepsis-induced ARDS and who require mechanical ventilation. Specifically, an initial tidal volume of 6 mL/kg of predicted body weight should be used, and plateau pressures should be kept under 30 cm H₂O.³

NEW DIRECTIONS

Historically, the pathophysiology of severe sepsis and septic shock was thought to result primarily from inflammatory mediators that, on a macrovascular level, cause a maldistribution of blood flow, resulting in impaired tissue oxygen delivery. Recent research, focusing on microcirculatory and mitochondrial dysfunction, suggests that it is, rather, the ability to increase oxygen consumption in response to increased oxygen delivery that best predicts which patients with septic shock will survive and which will not.¹⁶

Microcirculatory dysfunction in sepsis is thought to result from two distinct mechanisms. First, sepsis produces significant heterogeneity in blood flow even within a particular tissue, organ, or vascular bed. This maldistribution at the microcirculatory level can result in significant cellular hypoxia, despite a seemingly normal systemic perfusion pressure. Second, sepsis is associated with endothelial damage. Whether due to the direct effect of select microorganisms or to inflammatory mediators, endothelial dysfunction inhibits the ability of oxygen to move from the vessel lumen to the tissues. The result is a relative hypoxia despite adequate blood flow. Endothelial dysfunction has been the target of recent sepsis research, though no promising therapies have yet proved beneficial.

Markers of microcirculatory dysfunction, such as elevated lactate levels, have been shown to correlate with poor outcomes in patients with sepsis.^17,18 It also appears that microvascular resuscitation (i.e., increased capillary recruitment) correlates with improved global perfusion (e.g., decreased lactate levels) despite little to no improvement in macrovascular assessments (e.g., improved MAP). These results have led to investigations of a variety of microcirculatory monitoring and resuscitative techniques.^19,20

Evidence indicates that sepsis also results in mitochondrial dysfunction,²¹ leading to impaired oxidative phosphorylation. This results in “cytopathic hypoxia,” the inability to use delivered oxygen and produce adenosine triphosphate. Sepsis-induced mitochondrial dysfunction is another emerging area of study.²²

CONCLUSION

The past decade has seen great leaps forward in the management of sepsis, although this disease continues to impose a tremendous burden in terms of mortality rates. Many of these advances apply directly to the emergency physician’s management of these patients. It is vital that emergency physicians continue to embrace their role as the frontline managers of this deadly disease.

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