Stephen Trzeciak, R. Phillip Dellinger and Joseph E. Parrillo

Chapter Outline

Overview

This chapter pertains to pathophysiology, assessment, and management of septic shock, the most severe and overt manifestation of the septic condition. This discussion will specifically focus on cardiovascular and hemodynamic aspects. Other critically important elements of sepsis pathophysiology, assessment, and management (i.e., beyond the cardiovascular and hemodynamic aspects) will be addressed in a separate chapter (see Chapter 25, Sepsis and Multiple Organ Dysfunction). This chapter is also focused specifically on the adult patient with septic shock, as principles and evidence may differ in important ways in the pediatric population.

Historical Perspective

The word sepsis originated from the Greek language. Sepsis was synonymous with putrefaction and pertained to the bacteria-mediated decomposition of organic matter.¹ The term persisted for more than 2700 years with essentially unchanged meaning.² In the twentieth century, our modern understanding of the term sepsis became rooted in a disease in which the clinical manifestations were attributed to severe infection and the release of pathogenic bacterial products into the patient’s bloodstream.^3,4

The term shock comes from the French word “choquer,” meaning “to collide with.” This is particularly appropriate terminology for shock due to sepsis, given our modern understanding of the sepsis pathophysiology, whereby the body’s host defenses essentially collide with the invading microorganism, triggering a profound proinflammatory host response.¹

Contemporary Definitions

Shock is defined as a failure of the cardiovascular system to maintain effective tissue perfusion. If effective tissue perfusion is not promptly restored, cellular dysfunction and acute organ failure may occur and may become irreversible, leading to acute organ system failure. When shock develops because of a systemic inflammatory response to infection, it is termed septic shock. The American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) first published consensus conference definitions for sepsis syndromes more than 20 years ago,⁵ and these definitions were revisited and further developed by international consensus in 2003.⁶ Septic shock was defined as infection-induced hypotension (systolic blood pressure <90 mm Hg [or a drop of >40 mm Hg] plus signs of tissue hypoperfusion despite adequate fluid resuscitation). The concurrent presence of clinical signs of tissue hypoperfusion (e.g., metabolic acidosis, encephalopathy, acute lung injury, oliguria, acute kidney injury, peripheral extremity discoloration, or impaired capillary refill) is an integral component of making the diagnosis of septic shock, because baseline blood pressure can vary among patients, and patients with lower baseline blood pressure may tolerate an arterial pressure lower than the values stated here without being in circulatory shock. The overarching purpose and major impact of the efforts to establish the contemporary definitions given here was the promotion of uniformity in inclusion criteria for sepsis clinical trials.⁷

Epidemiology

Severe sepsis (sepsis plus acute organ system dysfunction) is a common and deadly disease with major public health implications. Although heterogeneity of definitions of sepsis has historically made the incidence of severe sepsis and septic shock difficult to precisely measure, estimates of the incidence have been possible. Using the International Classification of Diseases (ICD)-9 codes for infection and organ dysfunction, Angus and coworkers estimated that 751,000 cases of severe sepsis occur in the United States every year.⁸ Figure 23.1 displays the incidence of severe sepsis in the United States compared to other common diseases. The incidence of severe sepsis currently exceeds the incidence of lung and colon cancer, venous thromboembolic disease, and acquired immune deficiency syndrome (AIDS),^8–11 and the incidence is projected to increase by 1.5% per year, resulting in more than 1 million cases of severe sepsis annually by the year 2020.⁸ The incidence of sepsis and septic shock is known to be increasing because of a longer lifespan for patients with severe chronic medical conditions that predispose them to acquiring sepsis. This includes an increase in the number of immunocompromised patients in the community, number of infections caused by resistant organisms, increased use of intravascular catheters, and aging of the population.⁸

Sepsis is the leading cause of death among critically ill patients¹² and is responsible for as many deaths annually in the United States as acute myocardial infarction.⁸ Figure 23.2 displays control arm mortality rates in septic shock clinical trials.¹ In a recent large multicenter registry study, septic patients with both arterial hypotension and severe lactic acidosis experienced a 46% mortality rate, whereas the mortality rate for arterial hypotension or severe lactic acidosis alone was 37% and 30%, respectively.¹³ Overall, severe sepsis in general ranks as the tenth leading cause of death in the United States, with 215,000 deaths annually and an estimated 30% in-hospital mortality rate.^8,14 Figure 23.3 displays the mortality rate for severe sepsis compared to other high-profile diseases that may require critical care (acute ischemic stroke, acute myocardial infarction, and trauma).^8,15–17 The apparent disparity in mortality rates across these diseases may be explained in part by differences in the conventional approach to treatment, as acute ischemic stroke, acute myocardial infarction, and trauma are all typically treated with aggressive interventions in a time-sensitive fashion. Similar to the “golden hour” concept for trauma care that was first recognized more than 30 years ago¹⁸ we are now beginning to understand that early aggressive interventions for sepsis can also have an impact on outcome.

It is also important to recognize that, in addition to a high mortality rate, severe sepsis and septic shock are associated with serious risk of morbidity among survivors.19,20 A systematic review of the literature found that sepsis survivors had substantially diminished quality of life and a sharply reduced long-term survival after typical short-term (i.e., 28-day) outcomes are assessed.¹⁹ Among older adults, severe sepsis has been associated with major persistent cognitive impairment and functional disability that could have a substantial impact on those patients’ ability to live independently.²⁰ Taken together, even among patients who survive the sepsis insult, the development of severe sepsis or septic shock can represent a pivotal event in the trajectory of a patient’s life.

Pathogenesis

Septic shock results when infectious microorganisms in the bloodstream induce a profound inflammatory response causing hemodynamic decompensation. The pathogenesis involves a complex response of cellular activation that triggers the release of a multitude of proinflammatory mediators. This inflammatory response causes activation of leukocytes and endothelial cells, as well as activation of the coagulation system. The excessive inflammatory response that characterizes septic shock is driven primarily by the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1) that are produced by monocytes in response to an infection. Although TNF-α and IL-1 are central to the pathophysiology of septic shock and act synergistically to induce hypotension in experimental models, a number of other vital mediators are also known to play a major role, including high-mobility group box 1 (HMGB1) protein.²¹ Another important recent advance in our understanding of septic shock pathophysiology has been identification of the close link that exists between the proinflammatory response of septic shock and activation of the coagulation system (e.g., clinical or subclinical disseminated intravascular coagulation [DIC]).²² Although the systemic inflammatory response of sepsis triggers profound macrocirculatory and microcirculatory changes that impair tissue perfusion, another important mechanism playing a role in the development of acute organ dysfunction in septic shock is apoptosis (programmed cell death). Accelerated apoptosis is known to be a critical pathogenic event in this disease. In addition, certain genetic polymorphisms are becoming recognized as major determinants of susceptibility to infection, as well as risk of death from septic shock. Key steps in the pathogenesis of septic shock are shown in Figure 23.4.

Clinical Presentation

Patients with septic shock will typically manifest signs of systemic inflammation including fever or hypothermia, tachycardia, tachypnea, and elevation or reduction of the white blood cell count. Although the absence of arterial hypotension does not necessarily exclude the possibility of subclinical tissue hypoperfusion,²³ the hallmark of septic shock is arterial hypotension despite adequate volume resuscitation requiring vasoactive drugs for hemodynamic support. Other signs of potential tissue hypoperfusion may include lactic acidosis, oliguria, encephalopathy, or diminished capillary refill in the extremities. Patients with septic shock typically have multiple organ system dysfunctions; clinical evidence of other organ system dysfunction may range from subtle abnormalities to overt organ failure. Multiorgan system involvement in sepsis may include cardiovascular, respiratory, renal, central nervous system, hepatic, metabolic, or hematologic dysfunction. Respiratory system dysfunction manifests as acute lung injury or, in the most extreme cases, the acute respiratory distress syndrome (ARDS). Sepsis-induced renal dysfunction typically manifests with oliguria and may progress to acute renal failure requiring dialysis. Central nervous system dysfunction will manifest as encephalopathy, which may range from mild cognitive impairment to overt coma. Cholestasis is a common manifestation of hepatic dysfunction in sepsis, but in the presence of severe shock, ischemic hepatitis (“shock liver”) may occur. Metabolic derangements of septic shock include a loss of glycemic control (hyper- or hypoglycemia) as well as metabolic acidosis. Septic shock is commonly associated with a consumptive coagulopathy, which is likely present in almost all patients at least subclinically,²⁴ but may also manifest clinically with thrombocytopenia, prolongation of the prothrombin time, or in the most severe cases, overt DIC.

The multiple organ dysfunction associated with septic shock is not only a critical event in the pathogenesis of this disease, but is also closely linked with mortality rate.8,25,26 There is an approximate 20% increase in septic shock mortality rate with each additional organ system that fails.⁸ Early evidence of organ failure is an especially strong predictor of death.^26,27 Early improvement in organ function (e.g., 0-24 hour improvement in the Sequential Organ Failure Assessment [SOFA] score^28,29) is closely related to sepsis survival, whereas later improvement after the first 24 hours has little predictive value.²⁷ These data, garnered largely from observational studies as well as placebo arms of interventional trials, support the concept that aggressive therapy for sepsis to reverse (or prevent the development of) acute organ system failure within the first 24 hours is closely associated with eventual outcome.

Hemodynamic Profile of Septic Shock

The hemodynamic profile of septic shock is the most complex hemodynamic profile of all shock etiologies (Fig. 23.5). What sets septic shock apart from other causes of circulatory shock is the fact that there may be multiple different mechanisms of circulatory shock occurring simultaneously.^1,30 Septic shock may have features of (1) hypovolemic shock (poor cardiac filling secondary to severe systemic capillary leak and increased venous capacitance), (2) cardiogenic shock (infection-induced myocardial depression), and (3) distributive shock (arteriolar vasodilation with tissue hypoperfusion in the face of an adequate cardiac output).¹

Microcirculatory and Mitochondrial Dysfunction

After restoration of adequate cardiac filling pressures and achievement of optimal cardiac output in patients with septic shock, tissue dysoxia may still occur via a number of pathogenic mechanisms. These mechanisms of tissue dysoxia in the face of a normal or a supranormal cardiac output may be due to either (1) microcirculatory dysfunction or (2) mitochondrial dysfunction. These pathogenic mechanisms impair the way in which individual cells can either receive or utilize oxygen, respectively.