Sepsis, Severe Sepsis, and Septic Shock

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Chapter 32 Sepsis, Severe Sepsis, and Septic Shock

David Shimabukuro, MDCM , Richard H. Savel, MD, FCCM, Michael A. Gropper, MD, PhD

1 What is sepsis?

Sepsis is an overwhelming inflammatory and coagulopathic response to a source of infection, usually from the lung or abdomen. If not recognized early, or not treated properly and aggressively, it is often a lethal syndrome. Please note that it is different from bacteremia, which only refers to the presence of bacteria in the bloodstream.

2 Explain the nomenclature for disorders related to sepsis

In 1991, the American College of Chest Physicians and the Society of Critical Care Medicine determined the nomenclature for disorders related to sepsis. The following terms describe the progression of signs and symptoms regarding this somewhat confusing terminology:

image Systemic inflammatory response syndrome (SIRS): characterized by

image Temperature > 38° C or < 36° C
image Heart rate > 90 beats/min
image Respiratory rate > 20 breaths/min or the need for mechanical ventilation
image White blood cell count > 12,000 cells/mm3 or < 4000 cells/mm3

image Sepsis: a suspected or documented source of infection plus two or more SIRS criteria.

image Severe sepsis: sepsis with acute sepsis-induced organ dysfunction of one or more organ systems.

image Septic shock: a subset of severe sepsis syndrome in which the organ dysfunction is cardiovascular, that is, a subset of severe sepsis in which there is cardiovascular dysfunction. Specifically, sepsis-induced hypotension (mean arterial pressure [MAP] < 65 mm Hg) that persists despite adequate and aggressive volume resuscitation. Patients will often require vasopressors to keep MAP ≥ 65 mm Hg.

image Multiple organ dysfunction syndrome (MODS): Failure in more than one organ system that requires acute intervention. Once the patient reaches this degree of illness, the chances of making a meaningful recovery can often be quite low.

In 2001, the International Sepsis Definitions Conference convened to once again address the difficulties in defining sepsis. During this meeting, conference members expressed the need for a better, more sophisticated way to stage the severity of sepsis. At this time PIRO was introduced. Over the past several years, several studies have been published correlating a total PIRO score with mortality. However, the studies are not identical, and they still need to be corroborated by other investigators. In brief, PIRO represents the following:

Predisposition: age, medical history, genotype (in the future)

Infection/insult: location of infection, organism, and/or cause of infection

Response: SIRS criteria

Organ dysfunction: location and number of organ dysfunction

3 What is the incidence of sepsis?

Septic shock and MODS are relatively common and associated with substantial mortality and consumption of health care resources. In 2007, an estimated 700,000 cases of severe sepsis or MODS occurred in the United States alone. This was a substantial increase over 2003. The numbers continue to rise every year. The incidence of sepsis is substantially higher in elderly than in younger people. The projected growth of the elderly population in the United States will contribute to an increase in incidence of 1.5% per year, yielding an estimated 934,000 and 1,110,000 cases by the years 2010 and 2020, respectively. The present annual cost of severe sepsis and septic shock in the United States is estimated at $25 billion.

4 How does the nomenclature relate to outcome?

Previous studies have shown that as the disorder progresses from SIRS to septic shock, the mortality rate increases. Of interest, some data support the concept that, although the degree of illness at presentation may have some correlation with outcomes, it is the change in clinical status from baseline that may have the closest correlation with outcomes. Regardless, sepsis progresses to MODS with tragic consequences. The mortality rate for patients with acute renal failure in the setting of sepsis ranges from 50% to 80%. For most patients with sepsis syndrome, the failure of three or more organ systems results in a mortality rate > 90%. The organ systems most often affected early in the process are pulmonary, hematologic, renal, and cardiovascular. Despite the growing number of patients with septic shock and increase in likelihood of death with multiple organ failure, overall mortality appears to be declining in recent years. This could be related to an improvement in therapy and improvement in supportive measures but is more likely related to medical coding issues and the heterogeneity of the disease and the available data.

5 Discuss current understanding of the pathogenesis of sepsis and septic shock

Sepsis syndrome begins with the invasion and growth of microorganisms (gram positive, gram negative, fungal, or viral) in a normally sterile tissue space. The endothelium is damaged by infection, trauma, or other insult, and activation of the host immune response begins. Tumor necrosis factor α, interleukin (IL)-6, and IL-8 are associated with the activation of an inflammatory cascade and chemotaxis of leukocytes, monocytes, and macrophages. Antiinflammatory substances such as IL-4, IL-10, prostaglandins, and other components of the immune system work to maintain homeostasis in the face of an infectious insult. Sepsis syndrome develops when the balance between the proinflammatory and antiinflammatory substances is lost.

The coagulation pathway plays a critical role in sepsis. The complement system, vasoregulatory system (nitric oxide, bradykinin, prostaglandins), the coagulation cascade (tissue factor, protein C, thrombin, antithrombin III), and fibrinolysis (fibrin, plasmin, and plasminogen-activating factor) play roles as well. The result is the development of a vicious circle that promotes, both locally and systemically, further inflammation, release of oxygen free radicals, and deposition of microvascular thrombi, resulting in a cycle of ischemia, reperfusion injury, and tissue hypoxia. Global tissue hypoxia independently contributes to endothelial activation and further disruption of the homeostatic balance among coagulation, vascular permeability, and vascular tone. These are key mechanisms leading to microcirculatory failure, refractory tissue hypoxia, and organ dysfunction.

It is becoming clear that the processes of coagulation and inflammation are tightly linked. Recent studies have shown that patients with severe sepsis have depleted levels of protein C, protein S, and antithrombin III.

6 Which microorganisms are most commonly associated with sepsis?

A recent study of nosocomial bloodstream infections found the following infecting organisms in the intensive care unit (ICU):

image Gram positive (65%): coagulase-negative staphylococci (36% of isolates), Staphylococcus aureus (17%), enterococci (10%).

image Gram negative (25%):Escherichia coli (4%), Klebsiella sp. (4%), Pseudomonas aeruginosa (5%), Enterobacter sp. (5%), Serratia sp. (2%), Acinetobacter sp. (2%). Clinically, however, the problem of resistant gram-negative organisms in the ICU is rapidly becoming a serious one nationwide.

image Fungi (9%): primarily Candida species (albicans 54%, glabrata 19%, parapsilosis 11%, tropicalis 11%).

Coagulase-negative staphylococci, Pseudomonas species, Enterobacter species, Serratia species, and Acinetobacter species were more likely to cause infections in patients in ICUs. The proportion of S. aureus isolates with methicillin resistance increased from 22% in 1995 to 57% in 2001.

7 What are the most common primary sources of infection?

In decreasing order of incidence, there are lung, blood, abdomen, urinary tract, skin, and other sites.

8 What clinical signs and symptoms should raise suspicion of SIRS, sepsis, and underlying organ dysfunction?

image Respiratory: cyanosis, tachypnea, orthopnea, increased sputum (yellow or green, frothy), hypoxemia (PaO2/FiO2 < 300), oxygen saturation < 90%.

image Cardiovascular: need for vasopressors, chest pain, pulmonary edema, arrhythmias, cardiac index < 2.5, heart rate > 100 beats/min, decreased systemic vascular resistance, increased cardiac output.

image Renal: urine output < 0.5 mL/kg/hr, increased blood urea nitrogen level, increased creatinine level, acute renal failure, acidosis, worsening base deficit.

image Hepatic: elevated aspartate aminotransferase, alanine aminotransferase, or γ-glutamyl transferase levels; prolonged bleeding time; asterixis; encephalopathy; elevated bilirubin level. This is often referred to as ischemic hepatopathy or shock liver.

image Immunologic: fever with temperature > 38° C or hypothermia, chills, leukocytosis with or without left shift, neutropenia.

image Hematologic: weakness, pallor, poor capillary refill, easy bruising, spontaneous bleeding, anemia, increased prothrombin or partial thromboplastin time, decreased fibrinogen, disseminated intravascular coagulation (elevated D-dimer levels).

image Gastrointestinal: anorexia, ileus, inability to tolerate tube feedings, nausea, vomiting, hypoalbuminemia.

image Endocrine: hyperglycemia, hypoglycemia, adrenal insufficiency, weight loss.

image Neurologic: weakness, confusion, delirium, psychoses, seizures.

image Metabolic: elevated serum lactate level.

9 What are the Surviving Sepsis Campaign Guidelines? What are some of the high points?

This document was originally published in 2004 and was codified by 11 international critical care organizations. It was updated in 2008. It provides a state-of-the-art evidence-based approach to the management of severe sepsis and septic shock. Some of the highlights of this important document are in Box 32-1.

Box 32-1 Highlights of the Surviving Sepsis Campaign Guidelines

Initial Resuscitation

The initial resuscitation phase of a patient with severe sepsis or in septic shock should be completed within 6 hours of identification, usually signified by an elevated serum lactate level. Current recommendations are to rapidly place a catheter with central venous access, although this is not essential before fluid administration. Regardless of type of venous access, aggressive fluid therapy with a challenge of 1 L (10-20 mL/kg) of crystalloid over a 30-minute period should be performed. The target central venous pressure (CVP) is between 8 and 12 mm Hg in a patient breathing spontaneously; for a patient receiving mechanical ventilation a higher CVP goal is likely needed. The goal blood pressure is a MAP ≥ 65 mm Hg. If after adequate volume resuscitation has occurred (typically after 3-5 L of crystalloid) and the patient continues to have hypotension, vasopressors should be started to keep the MAP at goal. Vasopressors may also be needed during the fluid resuscitation. It is currently recommended that norepinephrine or dopamine be used as first-line agents when vasopressors are required to maintain an adequate MAP. Vasopressin and/or epinephrine infusions can be added if the norepinephrine or dopamine is ineffective. Inotropic agents should be used only if clear evidence of myocardial dysfunction exists (elevated filling pressures and low cardiac output). These agents should be delivered through a central venous catheter as soon as possible. Immediately after the start of the fluid challenge, samples for blood cultures should be drawn, if not already done. Appropriate intravenous broad-spectrum antibiotic therapy should be administered within the first hour of the initial resuscitation phase. If possible, a source should be identified and measures taken to control the infection (i.e., drainage of an abscess). Clearance of lactate (and resolution of metabolic acidosis) from the blood during resuscitation suggests that the resuscitation has been effective.

Adjunctive Therapy Within the First 24 Hours

Bicarbonate Therapy

It has been common practice to give bicarbonate therapy for vasopressor-dependent patients to improve hemodynamics. However, it is important to state that—to the extent that it has been studied—no data support this intervention. Current recommendations are not to give bicarbonate for hypoperfusion-induced lactic acidosis unless the serum pH is < 7.15.

Blood Product Administration

Red blood cell transfusions should only occur when the hemoglobin level has fallen to < 7.0 g/dL, with a target hemoglobin level of 7.0 to 9.0 g/dL. However, it may need to be higher in special circumstances (i.e., myocardial ischemia, acute hemorrhage, acute stroke). Fresh frozen plasma should not be administered to correct coagulation abnormalities unless the patient is bleeding.

Glucose

Recent data in critically ill patients—primarily patients who have had cardiac surgery—revealed multiple improved outcomes with the use of “tight glucose control.” Current recommendations for critically ill patients, including those with severe sepsis, include some form of a glucose control protocol using low-dose insulin infusion. Though the precise glucose target for the critically ill patient remains controversial, ≤ 150 mg/dL is the current recommendation in the Surviving Sepsis Guidelines.

Mechanical Ventilation of Sepsis-Induced Acute Lung Injury or Acute Respiratory Distress Syndrome

The lungs are the most common organ system to fail in patients with sepsis, many of whom eventually require mechanical ventilation. The lungs are the most likely source of initial infection as well, and patients are at great risk for nosocomial and ventilator-associated pneumonias.

The recent definitions and guidelines for management of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have made a significant impact on identification of patients with these disorders. Diagnosis of ALI and ARDS is based on the following criteria: bilateral infiltrates, PaO2/FiO2 < 300 (ALI) or < 200 (ARDS), and no evidence of a cardiac source (e.g., left atrial hypertension) for respiratory distress. The ARDS Network (a multicenter organization aimed at treating ARDS) has identified a protective ventilation strategy, based on lower tidal volumes and use of positive end-expiratory pressure, which significantly decreases the mortality rate of patients with ARDS. It is currently recommended that patients with ALI or ARDS receive mechanical ventilation with a goal tidal volume of 6 mL/kg of predicted body weight and/or with plateau pressures ≤ 30 cm H2O. The head of the bed should also be kept elevated between 30 and 40 degrees.

Steroids

The use of intravenous steroids in patients with persistent vasopressor-dependent septic shock is controversial but may be considered for refractory shock. At this time, laboratory testing of serum cortisol levels is not recommended.

Consideration for Limitation of Support

Severe sepsis and septic shock are serious diseases with significant mortality. It is important for the multidisciplinary critical care team to be in frequent communication with the family with appropriate updates regarding the status and prognosis of their loved one so that the family can set realistic expectations. It is paramount that the team be aware of any previous wishes the patient may have had regarding resuscitation, heroic measures, and artificial life support.

10 What is an evidence-based approach to the use of the pulmonary artery catheter (PAC)?

Since its initial description in the New England Journal of Medicine in 1970, the PAC has been an important tool for the critical care clinician. Its major roles have been to

1. Distinguish cardiogenic from noncardiogenic pulmonary edema

2. Determine which particular shock state (cardiogenic, distributive, hypovolemic) a patient may be in

3. Serve as a guide for therapeutic interventions for patients in shock

Recent data from large randomized trials have been unable to document a particular subgroup of patients in which the use of the PAC has been associated with improved outcomes. Multiple complex reasons are behind these results, which are still being debated in the literature. Nevertheless, it can be stated with some certainty that the placement of a PAC is no longer a requirement for the successful diagnosis and management of a patient with sepsis.

Key Points Sepsis, Severe Sepsis, and Septic Shockimage

1. Sepsis = Infection + Two or more SIRS criteria.

2. Severe sepsis = Sepsis plus acute organ dysfunction.

3. Heterogenous disease leads to difficulties with intervention trials.

4. Complex pathophysiology involves the immune system and coagulation homeostasis.

5. The Surviving Sepsis Campaign Guidelines provide a reasonable evidence-based approach to the current management of severe sepsis and septic shock.

Websitesimage

Society of Critical Care Medicine: www.sccm.org

Surviving Sepsis Campaign: www.survivingsepsis.org

Bibliography

1 Dellinger R.P., Carlet J.M., Masur H., et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.

2 Lagu T., Rothberg M.B., Shieh M.S., et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40:754–761.

3 Levy M.M., Macias W.L., Vincent J.L., et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med. 2005;33:2194–2201.

4 Richard C., Warszawski J., Anguel N., et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2003;290:2713–2720.

5 Sandham J.D., Hull R.D., Brant R.F., et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med. 2003;348:5–14.

6 Wisplinghoff H., Bischoff T., Tallent S.M., et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–317.

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