AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Clinicians often use the terms sepsis and septic shock without a commonly understood definition. In August 1991, a consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine developed the following definitions to clarify the terminology used to describe the spectrum of disease that results from severe infection.

The basis of sepsis is the presence of infection and the subsequent physiologic alterations in response to that infection, namely the activation of the inflammatory cascade. Systemic inflammatory response syndrome (SIRS) is a term used to define this clinical condition, and it is considered present if abnormalities in 2 of the following 4 clinical parameters exist: (1) body temperature, (2) heart rate, (3) respiratory rate, and (4) peripheral leukocyte count.

Sepsis is defined as the presence of SIRS in the setting of infection. Severe sepsis is defined as sepsis with evidence of end-organ dysfunction as a result of hypoperfusion. Septic shock is defined as sepsis with persistent hypotension despite fluid resuscitation and resulting tissue hypoperfusion.

Bacteremia is defined as the presence of viable bacteria within the liquid component of blood. Bacteremia may be primary (without an identifiable focus of infection) or, more often, secondary (with an intravascular or extravascular focus of infection). While sepsis is commonly associated with bacterial infection, bacteremia is not a necessary ingredient in the activation of the massive inflammatory response that results in severe sepsis. In fact, fewer than 50% of cases of sepsis are associated with bacteremia.

Pathophysiology

Sepsis is characterized by a massive inflammatory response to infection by a specific pathogen. In the case of bacterial infection, the inciting event is the interaction of exotoxins contained within the bacterial cell wall with the host immune cells. Cellular activation occurs with the release of cytokine and noncytokine mediators, the most notorious of which are tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6). These factors are implicated in the diffuse activation of a systemic inflammatory response. As a result, mediators with vasodilatory and endotoxic properties are released systemically, including prostaglandins, thromboxane A2, and nitric oxide. This results in vasodilation and endothelial damage, which leads to hypoperfusion and capillary leak. In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.

The following systems and mediators are stimulated in septic shock:

• Arachidonic acid metabolites (eg, leukotrienes, prostaglandins, thromboxanes)
• The complement system
• IL-1 and IL-6
• TNF-alpha
• The coagulation cascade
• The fibrinolytic system
• Catecholamines
• Glucocorticoids
• Prekallikrein
• Bradykinin
• Histamines
• Beta-endorphins
• Enkephalins
• Adrenocorticoid hormone
• Circulating myocardial depressant factor(s)

Septic shock develops in fewer than half of patients with bacteremia. It occurs in about 40% of patients with gram-negative bacteremia and in about 20% of patients with Staphylococcus aureus bacteremia. Therefore, it is not only the presence of diffuse bacterial infection itself that leads to sepsis but also the triggering of the inflammatory and coagulation cascades.

From a study of 1,342 episodes of sepsis syndrome in 1,166 patients who were examined during 16 months in 8 academic medical centers, infection was documented by means of a positive culture result in 866 (65%) cases, whether the source was blood, urine, sputum, or other body fluid. Only 436 (32%) of the total cases had a positive blood culture result, with the other 430 (32%) positive culture results coming from another source without bacteremia. Of the 866 documented infections, 39% were due to gram-negative bacteria, 31% due to gram-positive bacteria, 6% due to fungi, 2% due to intra-abdominal anaerobes, 5% due to other or unclassified organisms, and 17% due to polymicrobial infection.

Frequency

United States

Data was published recently in the New England Journal of Medicine summarizing a retrospective study conducted by the National Center for Health Statistics. They looked at a massive database that included 500 hospitals from around the United States and identified more than 10 million patients who were diagnosed with sepsis. This accounted for 1.3% of all hospitalizations. The overall incidence of sepsis increased 3-fold over this period of time from 83 cases per year per 100,000 population to 240 cases per year per 100,000 population.

The reasons for this increase may include increased elderly population, increased recognition of disease, increased performance of invasive procedures and organ transplantation, increased use of immunosuppressive agents and chemotherapy, increased use of indwelling lines and devices, and increase in chronic diseases such as end-stage renal disease and HIV. Of interesting note, in 1987 gram-positive organisms surpassed gram-negative organisms as the most common cause of sepsis, which holds true today.

Mortality/Morbidity

The National Center for Health Statistics study showed a reduction in hospital mortality rates for sepsis over the years from 28% to 18%; however, more overall deaths occurred due to the increased incidence of sepsis. Sepsis is a continuum of disease, and mortality of course depends on the definition of sepsis as mentioned in Background. In large studies, the mortality rate of severe sepsis has been quoted anywhere from 30-50%, whereas simply meeting SIRS criteria carries a mortality of less than 10%.

• Significant complications from sepsis include central nervous system dysfunction, adult respiratory distress syndrome (ARDS), liver failure, acute renal failure (ARF), and disseminated intravascular coagulation (DIC). In different studies, the reported incidence rates of these complications in sepsis is about 19% for CNS dysfunction, 2-8% for ARDS, 12% for liver failure, 9-23% for ARF, and 8-18% for DIC.
• In septic shock, ARDS has been observed in about 18% of cases, DIC in about 38%, and renal failure in about 50%.

Race

The incidence of sepsis is higher in the nonwhite population, with the incidence in black men being the highest at 331 cases per year per 100,000 population.

Sex

Although the number of cases of sepsis between men and women are about equal, when adjusting for the higher population of women in the United States, men are more likely to develop sepsis.

Age

Men tend to develop sepsis earlier in life than women, with the mean age of onset at age 57 years versus age 61 years, respectively.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Symptoms of sepsis usually are nonspecific and include fever, chills, and constitutional symptoms of fatigue, malaise, anxiety, or confusion. These symptoms are not pathognomonic for infection and may be seen in a wide variety of noninfectious inflammatory conditions. Alternatively, they may be absent in serious infections, especially in elderly individuals.
• Systemic inflammatory response syndrome (SIRS) is defined by the presence of at least 2 of the following 4 criteria:
• • Temperature higher than 38°C or lower than 36°C
  • Heart rate greater than 90 beats per minute
  • Respiratory rate greater than 20 breaths per minute
  • WBC count higher than 12,000/mm³ or lower than 4,000/mm³ or with more than 10% immature forms (bands)
• Fever is a common feature of sepsis. The clinician should inquire about fever onset (abrupt or gradual), duration, and maximal temperature. Abrupt fever onset has been correlated with large infectious burden. A correlation between the degree of maximal temperature and the presence of a serious infection also exists.
• Altered mental status is perhaps the most consistent clinical feature in sepsis. Mild disorientation or confusion is especially common in elderly individuals. More severe manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtunded or comatose states. The cause of these mental status abnormalities is not entirely understood, but in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a cause.
• Increased respiratory rate is also a common and often unappreciated feature of sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed as a cause. As tissue hypoperfusion ensues, the respiratory rate also increases in order to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious.
• The following localizing symptoms are some of the most useful clues to the etiology of both fever and sepsis:
• • Head and neck infections - Earache, sore throat, sinus pain or congestion, nasal congestion or exudate, swollen lymph glands
  • Chest and pulmonary infections - Cough (especially if productive), pleuritic chest pain, dyspnea
  • Abdominal and GI infections - Abdominal pain, nausea, vomiting, diarrhea
  • Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethral discharge, dysuria, frequency, urgency
  • Bone and soft-tissue infections - Focal pain or tenderness, focal erythema, edema, fluctuance

Physical

• The physical examination should first involve assessment of the general condition. Does the patient appear acutely ill? Assess airway, breathing, and circulation (ABCs) and overall mental status.
• • Obtain a full set of vital signs. The temperature should be taken orally or rectally, preferably the latter for the greatest accuracy.
  • Narrow pulse pressure and tachycardia are the earliest signs of shock.
  • Early sepsis is characterized by peripheral vasodilation an increased cardiac output (warm shock). This is characterized by tachycardia, warm extremities, and adequate capillary refill.
  • As sepsis progresses, stroke volume and cardiac output decrease as a result of toxic mediators. This is characterized by signs of poor distal perfusion such as cool and clammy extremities, delayed capillary refill, altered mental status, and decreased urine output.
• Perform a complete physical examination looking specifically for signs of infection. The following physical findings suggest a focal (usually bacterial) infection:
• • CNS infection - Profound depression in mental status, meningismus
  • Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal exudate, stridor, cervical lymphadenopathy
  • Chest and pulmonary infections - Localized rales or evidence of consolidation
  • Cardiac infections - Regurgitant valvular murmur
  • Abdominal and GI infections - Focal tenderness, guarding or rebound, rectal tenderness or swelling
  • Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, cervical motion pain, adnexal tenderness or masses, cervical discharge
  • Bone and soft-tissue infections - Focal erythema, joint effusion, tenderness, fluctuance, pain with passive range of motion
  • Skin infections - Petechiae, purpura, erythema, fluctuance

Causes

Sepsis is a disease seen most frequently in elderly persons and in those with comorbid conditions that predispose to infection. Patients who are immunocompromised are especially at high risk, including those with cancer on chemotherapeutic agents, those with end-stage renal or liver disease, those with advanced HIV, or those on steroids for chronic conditions. Patients with indwelling catheters are also at high risk. Typical examples include indwelling vascular catheters and urinary catheters.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC with differential
• • The WBC count and the white cell differential are somewhat helpful in predicting bacterial infection, albeit an elevated WBC count is not specific of infection.
    • In the setting of fever without localizing signs of infection, a WBC count greater than 15,000/mm³ or a neutrophil band count greater than 1500/mm³ has about a 50% correlation with bacterial infection.
    • The WBC count is also a component of the SIRS criteria, with WBC >12 or WBC <4 or bands >10% being positive.
  • Hemoglobin concentration dictates oxygen-carrying capacity in blood, which is crucial in sepsis to maintain adequate tissue perfusion. The goal is to maintain hematocrit greater than 30% and hemoglobin greater than 10 g/dL.
  • Platelets are an acute-phase reactant and are typically elevated in the setting of inflammation. However, platelet counts may decrease in the setting of DIC.
• Comprehensive chemistry panel
• • Sodium and chloride levels are abnormal in severe dehydration.
  • Bicarbonate can point to acute acidosis.
  • Blood urea nitrogen and creatinine levels can point to severe dehydration or renal failure.
  • Glucose control is important in the management of sepsis, with hyperglycemia associated with higher mortality.
  • Liver function tests (LFTs) and bilirubin, alkaline phosphatase, and lipase levels are important in evaluating for multiorgan failure or a potential source of sepsis (eg, biliary disease, pancreatitis, hepatitis).
  • Serum lactate level correlates with mortality, with a level greater than 4 mmol/L associated with a precipitous increase.
• Coagulation studies (PT/PTT)
• • Prothrombin time (PT) and activated partial thromboplastin time (PTT) are elevated in DIC.
  • Fibrinogen levels are decreased and fibrin split products are increased in the setting of DIC.
• Blood cultures
• • Blood cultures should be obtained in patients who have suspected sepsis in order to isolate a specific organism to tailor antibiotic therapy. Note, however, that blood cultures are positive in fewer than 50% of cases of sepsis. This rate exceeds 50% in patients with severe sepsis with evidence of end-organ damage.
  • A set of cultures from an indwelling intravenous catheter is especially important, as these catheters are a frequent source of bacteremia.
• Urinalysis and urine culture
• • Urinary tract infection is a common source of sepsis, especially in elderly patients. Febrile adults without localizing symptoms or signs have a rate of occult urinary tract infection of 10-15%.
  • Again, obtaining a culture is important in order to isolate a specified organism and to tailor antibiotic therapy.
• Gram stain and culture, when applicable
• • Sputum specimen should be obtained if pneumonia is suspected.
  • Abscesses should be drained promptly, and pus should be sent to the microbiology laboratory for analysis.
  • CSF specimen should be obtained if meningitis is suspected.

Imaging Studies

• Imaging should be performed as appropriate to search for a source of infection.
• Chest radiography
• • Infiltrates are detected with a chest radiograph in about 5% of febrile adults without localizing signs of infection; therefore, a chest radiography should be routine in the workup of fever with an unclear etiology.
  • Chest radiography is useful in detecting radiographic evidence of acute respiratory distress syndrome (ARDS), which carries a high mortality rate. Evidence of ARDS on a chest radiograph should prompt early intubation and mechanical ventilation, even if the patient has not yet shown signs of respiratory distress.
• Abdominal plain films should be obtained if clinical evidence of bowel obstruction or perforation exists.
• Abdominal ultrasonography is indicated when evidence of acute cholecystitis (eg, right upper quadrant [RUQ] abdominal tenderness, fever, vomiting, elevated LFTs, bilirubin, and alkaline phosphatase) exists. Surgery may be urgently necessary in the setting of acute cholecystitis and sepsis.
• Abdominal CT scan should be obtained if the patient has abdominal or flank tenderness in the setting of sepsis. Certain abdominal processes may require urgent operative intervention (eg, diverticular abscess, ischemic bowel, appendicitis, perinephric abscess).
• Plain radiographs of the extremities may be helpful when deep soft-tissue infection is suspected.
• • These films can show evidence of soft-tissue gas formation; however, necrotizing fasciitis is a clinical diagnosis (eg, extreme pain, crepitus, bullae, hemorrhage, foul-smelling exudates), and these patients should be taken immediately to the operating room (OR) in the setting of sepsis without imaging.
  • Plain radiographs can also show evidence of osteomyelitis, although MRI is much more sensitive for making this diagnosis.

Procedures

• Orotracheal intubation and mechanical ventilation
• • Intubation should be considered early in the course of sepsis in order to optimize ventilation and oxygenation, even in the absence of frank hypoxia and respiratory distress.
  • Delivering oxygen at an FiO₂ of 1.0 directly to the trachea is far superior to delivery via a nonrebreather oxygen mask. Mechanical ventilation, with appropriate sedation and paralysis, also eliminates the work of breathing and decreases the basal metabolic rate by about 30%.
• Intravenous access
• • Two large-bore (16-gauge) intravenous lines should be placed if sepsis is suspected in order to administer aggressive fluid resuscitation and broad-spectrum antibiotics.
  • A central venous (CV) catheter should be placed in the internal jugular or subclavian vein in patients with septic shock if hypotension is refractory to a crystalloid fluid bolus of 1-2 L. A CV catheter allows for administration of medication directly to the heart as well as the measurement of central venous pressure (CVP), which is a surrogate for volume status.
• Urinary catheter (Foley catheter)
• • A urinary catheter should be placed in order to follow urinary output, a surrogate to gauge cardiac output and tissue perfusion.
  • Normal urinary output in an adult is about 0.5 mL/kg/h or about 30-50 mL/h for most adults.
• Cutaneous or soft-tissue abscess drainage
• • A soft-tissue abscess should be drained promptly in the setting of sepsis because the patient's condition will not improve until the inciting bacteria is removed.
  • Superficial abscesses can be drained in the ED; however, deep abscesses should be treated in the OR for drainage.
  • A thorough search for abscesses should be performed in sepsis of unclear etiology, with particular attention paid to the rectal and perianal area.
• A lumbar puncture should be performed if clinical evidence or suspicion for meningitis or encephalitis exists.
• • Broad-spectrum antibiotics to cover meningitis should be administered before starting the procedure.
  • If evidence of increased intracranial pressure (papilledema) or focal mass lesions (focal defects, preceding sinusitis or otitis) exists, antibiotics should be started and a head CT scan should be obtained. CSF cultures will not be effective by the administration of antibiotics for at least several hours.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

The initial treatment of sepsis and septic shock involves the administration of supplemental oxygen and volume infusion with isotonic crystalloids. Prehospital personnel should initiate these therapies.

Emergency Department Care

The treatment for sepsis has evolved considerably over the past 10 years as it has transitioned from a disease that primarily concerned only critical care physicians to one that has a major impact in the emergency department. Early recognition and early aggressive therapy for patients with sepsis have a significant impact on mortality.

Rivers et al brought this issue to the forefront with their landmark article in the New England Journal of Medicine in 2001, where they instituted a treatment protocol for patients with septic shock, termed Early Goal Directed Therapy (EGDT). EGDT emphasizes early recognition of patients with potential sepsis in the ED, early broad-spectrum antibiotics, and a rapid crystalloid fluid bolus, followed by goal-directed therapy for those patients who remain hypotensive or severely ill after this initial therapy. Those patients who did not respond to an initial fluid bolus and antibiotics received a CV catheter in the internal jugular or subclavian vein to measure central venous pressure (CVP) and an arterial catheter to directly measure arterial blood pressure.

EGDT is basically a three-step process aimed at optimizing tissue perfusion.

• The first step involves titrating crystalloid fluid administration to CVP, or administering 500 mL boluses of fluid until the CVP measures between 8 and 12 mm Hg. CVP is a surrogate for intravascular volume, as excess circulating blood volume is contained within the venous system. Only after the CVP is greater than 8 mm Hg should vasopressors be considered.
• The second step, if the patient has not improved with fluid alone, is to administer vasopressors to attain a mean arterial pressure (MAP) greater than 65 mm Hg.
• The third step is to evaluate the central venous oxygen saturation (SvO₂). This is obtained from the CV line, which, in turn, is a surrogate for peripheral tissue oxygenation and cardiac output. An SvO₂ of less than 70% is considered abnormal and indicative of suboptimal therapy. In this case, the hematocrit is checked and blood transfused until a hematocrit greater than 30% is attained. Once this is attained and the SvO₂ is still low, dobutamine is initiated to increase cardiac output.

Rivers et al were able to enroll 263 patients who met criteria for septic shock:

• Suspected infection
• 2 of the 4 SIRS criteria
• Persistent systolic blood pressure <90 mm Hg after initial fluid bolus or lactate > 4 mmol/L

These patients were randomized to EGDT versus "standard" therapy, which still included placement of a CV line and arterial catheter (both relatively aggressive measures and probably not standard in most EDs). Despite this, he found an absolute mortality benefit of 16% with EGDT (30% mortality with EGDT vs 46% mortality with standard therapy).

When the data were examined closely, it was found that the patients in the EGDT group received, on average, more crystalloid fluid (5.0 L vs 3.5 L) and a much higher percentage of patients received blood transfusion (64% vs 18%). The resulting average SvO₂ measured after therapy was 95% for the EGDT group versus 60% in the standard group. These data attest to the fact that sepsis is likely grossly undertreated in the average ED setting.

• Address A and B of the ABCs: Supplemental oxygen should be administered to all patients with suspected sepsis. Early intubation and mechanical ventilation should be strongly considered for patients with an oxygen requirement, dyspnea or increased respiratory rate, hypotension, or those with evidence of poor peripheral perfusion.
• Patients with suspected sepsis should receive an initial crystalloid fluid bolus of 20-30 mL/kg (1-2 L) as well as broad-spectrum antibiotics.
• Selection of particular antibiotic agents is empiric based on an assessment of the patient's underlying host defenses, the potential sources of infection, and the most likely responsible organisms. Antibiotics must have a broad spectrum and cover gram-positive, gram-negative, and anaerobic bacteria because all classes of these organisms produce identical clinical pictures. Antibiotics must be given parenterally in doses adequate to achieve bactericidal serum levels. Many studies have revealed that clinical improvement correlates with the achievement of serum bactericidal levels rather than with the number of antibiotics given.
• Antistaphylococcal coverage is recommended in patients with a history of intravenous drug use or in those with indwelling vascular catheters or devices. Coverage directed against anaerobes should be included in patients with intra-abdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns. Immunocompetent patients usually can be treated with a single drug with broad-spectrum coverage such as a third-generation cephalosporin. Immunocompromised patients usually require dual-antibiotic coverage with broad-spectrum antibiotics that have overlapping coverages. Within these general guidelines, no single combination of antibiotics is clearly superior to others.
• For patients who have persistent hypotension after this initial treatment, 500 mL boluses (10 mL/kg in children) should be administered every 15 minutes to attain a CVP of 8-12 mm Hg. It is not unusual to require 4-6 L of isotonic crystalloid in order to achieve this goal.
• Patients should be monitored for signs of volume overload and need for intubation; these signs include dyspnea, pulmonary rales, or pulmonary edema on the chest radiograph. Improvement, stabilization, and normalization in the patient's mental status, heart rate, BP, capillary refill, and urinary output indicate adequate volume resuscitation.
• Colloid resuscitation (with albumin or hetastarch) has no proven benefit compared with isotonic crystalloid resuscitation (isotonic sodium chloride solution or lactated Ringer solution).
• Vasopressors should be started once a CVP of 8-12 mm Hg is achieved and the patient remains hypotensive. Vasopressors are titrated to achieve a mean arterial pressure (MAP) greater than 65 mm Hg.
• Norepinephrine is now the first agent recommended in treating septic shock refractory to volume resuscitation. Norepinephrine has predominantly alpha-receptor activity, which is effective in vasodilatory shock. The dose ranges from 5 mcg/min up to 20 mcg/min, and it is not based on the weight of the patient.
• Dopamine is an agent that is commonly used in the treatment of septic shock. Its beta-receptor effects are equal to its alpha-receptor effect; therefore, it has a greater effect on cardiac contractility than does norepinephrine. This may however have deleterious effects in the setting of sepsis where the heart is already maximally physiologically stimulated. Doses range from 2-20 mcg/kg/min.
• The overall treatment goal is to achieve a central venous oxygen saturation (SvO₂) of greater than 70%. SvO₂ can be measured from a venous blood gas analysis, or it can be measured in a continuous fashion with the use of stand-alone bedside monitors that are now available in many ICUs and in some EDs. Rivers et al utilized such a device in their study. If the above treatments do not achieve an SvO₂ greater than 70%, then oxygen carrying capacity and cardiac output must be addressed.
• Transfuse packed RBCs until the hematocrit is greater than 30%.
• Administer dobutamine to increase cardiac output in order to optimize red cell delivery to peripheral tissues. Dobutamine is a pure beta-agonist, resulting in increased cardiac contractility and heart rate. Doses range from 2-20 mcg/kg/min.
• Administration of steroids (eg, methylprednisolone, hydrocortisone, dexamethasone) has theoretical benefits in the setting of severe sepsis by inhibiting the massive inflammatory cascade that is unleashed. Cortisol is a naturally occurring stress hormone that promotes vascular tone and endothelial integrity. It has been shown experimentally to potentiate the effect of vasopressors. A large randomized trial in the 1980s showed a lack of benefit with high-dose methylprednisolone at 30 mg/kg for all patients with septic shock.
• • More recent data show that steroids can be beneficial for patients with relative adrenal insufficiency and in lower doses. A study in JAMA in 2002 looked at 299 patients with septic shock all who were intubated, persistently hypotensive despite fluids and vasopressors, and had evidence of end-organ failure. Patients were administered a cortisol stimulation test (Cort stim test), which involves measuring cortisol levels before and 30 minutes after administration of cosyntropin (ACTH) 0.25 mg IV. An increase in cortisol less than 10 mcg/dL was considered "nonresponder," and thus adrenally insufficient. Of the 299 patients with septic shock, 77% were nonresponders. All patients were randomized to low-dose steroids (hydrocortisone 50 mg q6h and fludrocortisone 50 mcg daily) versus placebo. For nonresponders, there was an absolute benefit in mortality of 10% (53% vs 43% mortality rate) for those who received steroids.
  • While performing the Cort stim test in the ED may not be practical due to time and resource constraints, it is worth noting that greater than 75% of patients with vasopressor-refractory hypotension were adrenally insufficient. Therefore, steroids should be empirically administered to this group of patients. A common choice is hydrocortisone 100 mg IV; a good alternative is dexamethasone 10 mg IV. The added benefit of dexamethasone is that it does not interfere with the Cort stim test because it does not affect the hypothalamic-pituitary-adrenal axis.
• Activated protein C (APC) is an endogenous protein that modulates inflammation and coagulation. Specifically, it inhibits TNF-alpha, IL-1, and IL-6, the mediators thought to play a major role in initiating the inflammatory response seen in sepsis. In addition, it inhibits monocyte and neutrophil adhesion to endothelial cells, and it inhibits thrombin and fibrin production, and thus prevents microvascular thrombi. APC levels have been shown to be low in sepsis.
• • A study appeared in the New England Journal of Medicine in 2001 looking at 1,690 patients with sepsis and organ dysfunction who were randomized to recombinant human APC (drotrecogin alpha) or placebo. Of note, this study excluded patients who were expected to die within 28 days (eg, end-stage cancer), those with end-stage renal disease or cirrhosis, and those with HIV and a CD4 count less than 50. There was an absolute benefit of 6% in mortality at 28 days with the administration of APC (25% mortality rate vs 31% in the placebo group). They reported a 13% benefit in the sickest patients (817 patients with an APACHE II score > 25) and an 18% benefit for the sickest patients with pneumonia (317 patients with APACHE II score > 25 and pneumonia).
  • The drawback to APC is an increased incidence of bleeding complications because it inhibits coagulation. Overall bleeding complications were 3.5% in the APC group versus 2.0% in the placebo group (n=0.06). For this reason, APC is contraindicated in patients with a known hypercoagulable condition, recent major surgery, intracranial surgery or stroke within 3 months, any history of arteriovenous malformation (AVM), and cerebral aneurysm or mass.
  • This is a very expensive therapy, on the order of thousands of dollars, and is best instituted in the ICU under the care of a critical care physician. Nevertheless, it is good to keep this in mind in the ED and identify patients who may benefit, especially those who are most critical and those with pneumonia.

Consultations

• Patients with sepsis who respond to the initial ED treatment (eg, oxygen administration, intravenous fluids, antibiotics) and who are hemodynamically stable can be admitted to a general hospital unit, optimally to one with close nursing observation and monitoring. Such patients do not require continuous hemodynamic monitoring and do not usually require admission to an ICU. Consultation with a family practitioner, general internist, pediatrician, or surgeon who can admit the patient is appropriate.
• Patients who do not respond to initial ED treatment or those who are in septic shock require admission to an ICU for continuous monitoring and observation. Consultation with a critical care physician or internist with appropriate expertise is appropriate. Perhaps more important than the primary training is the current knowledge, experience, and interest of the physician.
• Obtain surgical consultation if an infectious process amenable to surgery is suspected because certain conditions will only get worse until surgical intervention is done. Examples include intra-abdominal processes such as cholecystitis, ischemic bowel, diverticular abscess, perinephric abscess, impacted and infected ureteral stone, deep cutaneous or perirectal abscess, or necrotizing fasciitis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The most important aspect of medical therapy for septic patients includes adequate oxygen delivery, crystalloid fluid administration, and broad-spectrum antibiotics. Although colloid solution is mentioned, mortality benefit of colloid over crystalloid has never been proven. Blood transfusion is also important for patients with low hemoglobin concentrations. Vasopressors are important for patients who are refractory to adequate fluid resuscitation. Steroid administration should be strongly considered in patients refractory to both fluids and vasopressors, and recombinant human APC is a new therapy that should be considered in the ICU.

Drug Category: Isotonic crystalloid

These agents are standard fluids used for initial volume resuscitation. These fluids expand intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays in intravascular spaces; therefore, large quantities may be required to maintain adequate circulating volume.

Drug Category: Colloids

Colloid solutions provide an oncotically active substance that expands plasma volume to a greater degree than do isotonic crystalloids and reduce the incidence of pulmonary and cerebral edema. About 50% of the administered colloid stays in the intravascular space.

Drug Category: Antibiotics

Empiric antibiotics that cover the infecting organism, started early, is the only proven medical treatment, other than volume replacement, in septic shock. To provide the necessary coverage, broad-spectrum and/or multiple antibiotics are started. Monodrug therapy is possible in immunocompetent children with a third-generation cephalosporin (eg, cefotaxime, ceftriaxone, cefuroxime). Monodrug therapy is possible in immunocompetent adults with either an antipseudomonal penicillin or a carbapenem. Combination therapy in children involves a penicillinase-resistant synthetic penicillin and a third-generation cephalosporin. Combination therapy in adults uses one of the following: a third-generation cephalosporin plus anaerobic coverage (eg, clindamycin, metronidazole) or a fluoroquinolone plus clindamycin. All initial antibiotics in septic shock should be administered IV.

Drug Category: Sympathomimetic agents

These drugs augment both coronary and cerebral blood flow during a low blood flow state.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with SIRS, sepsis, and septic shock require admission to the hospital.
• If patients with suspected sepsis respond to early goal-directed therapy (EGDT) in the ED and show no evidence of end-organ hypoperfusion, then they can be admitted to a regular hospital bed for further treatment and close observation.
• Patients with septic shock or severe sepsis with evidence of end-organ hypoperfusion require admission to an ICU for continued goal-directed therapy.

Transfer

• Patients with severe sepsis and septic shock require admission to an ICU for careful monitoring and goal-directed therapy.
• If an appropriate ICU bed or physician is not available, the patient should be transferred with advanced life support monitoring to another hospital with the available resources.

Deterrence/Prevention

• Progression from SIRS to septic shock may be prevented with EGDT, including early identification, aggressive fluid resuscitation, broad-spectrum-antibiotic administration, and surgical intervention when indicated.

Complications

• Acute respiratory distress syndrome (ARDS) is a major complication of sepsis and septic shock. The rate of ARDS varies from 2-6% in patients with SIRS to 18% in patients with septic shock.
• DIC is a major complication of sepsis and septic shock. The rate of DIC varies from 8-19% in patients with SIRS to 38% in patients with septic shock.
• ARF is a major complication of sepsis and septic shock. The rate of ARF varies from 9-19% in patients with SIRS to 51% in patients with septic shock.

Prognosis

• The mortality rate of sepsis varies widely based on factors such as severity of illness upon hospital presentation, patient age and comorbid conditions, nature of infection, and infecting organism. The reported mortality rate in sepsis and septic shock varies according to the underlying host condition, infecting organism, aggressiveness of treatment in the ED, and the subsequent development of complications. The mortality rate for severe sepsis is quoted as anywhere between 30% and 50%.
• • Studies have shown that appropriate antibiotic administration (ie, antibiotics that are effective against ultimate cultured organism) has a significant influence on mortality. For this reason, initiating broad-spectrum coverage until the specific organism is cultured and antibiotic sensitivities are determined is important.
  • End-organ failure is a major contributor to mortality in sepsis and septic shock. The complications with the greatest adverse effect on survival are ARDS, DIC, and ARF.

Patient Education

• For excellent patient education resources, visit eMedicine's Shock Center and Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Shock and Sepsis (Blood Infection).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize early sepsis in the ED and administer broad-spectrum antibiotics concurrent with a rapid fluid bolus
• Failure to intubate and mechanically ventilate a hypotensive patient before the patient is in frank respiratory distress or failure
• Failure to admit a patient who is normotensive but has evidence of end-organ dysfunction to an ICU for goal-directed therapy
• Failure to provide adequate ongoing crystalloid fluid resuscitation (4-6 L in general) before instituting vasopressor therapy
• Failure to recognize the importance of oxygen-carrying capacity and the importance of blood transfusion for a hematocrit less than 30%
• Failure to consult a surgeon for potential intra-abdominal infection or deep-space abscess requiring intervention in the OR

Special Concerns

• Compared with younger patients, elderly patients are more susceptible to sepsis, have less physiologic reserve to tolerate the insult from infection, and are more likely to have underlying diseases; all of these factors adversely affect survival. In addition, elderly patients are more likely to have atypical or nonspecific presentations with sepsis.
• This article does not cover sepsis of the neonate or infant. Although many of the concepts of EGDT apply to children as well, special consideration must be given to neonates, infants, and small children regarding fluid resuscitation, appropriate antibiotic coverage, intravenous access, and vasopressor therapy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 13, 2006