John Gough
EPIDEMIOLOGY
The majority of sepsis is caused by gram-negative and gram-positive bacteria; however, sepsis can be caused by any class of microorganism including fungi, myco-bacteria, viruses, rickettsiae, and protozoa.
Predisposing factors for gram-negative bacterial sepsis include diabetes mellitus, lymphoproliferative diseases, cirrhosis, burns, invasive procedures, and chemotherapy.
Risk factors for gram-positive sepsis include vascular catheters, burns, indwelling mechanical devices, and injection drug use.
Nonbacterial sepsis is more commonly seen in immu-nocompromised individuals.
DEFINITIONS
SIRS (systemic inflammatory response syndrome): Not synonymous with sepsis. SIRS is a means of stratifying patients with an inflammatory response and is defined by identifying at least two of the following criteria:
A. Core temperature—>38.3°C (100.9°F) (>38.5°C [101.3°F] in children), or <36°C (96.8°F)
B. Tachycardia—>90 bpm (>2 SD [standard deviations] above normal for children, or in <1 year bradycardia [10th percentile for age] in absence of external stimuli, long-term use of drugs, or pain)
C. Mean respiratory rate—>20 breaths/min (>2 SD above normal for age in children) or Paco2 <32
D. Leukocyte count—>12,000/mm3, or <4000/mm3, or >10% bands (in children elevated or depressed for age)
Sepsis: A systemic response to infection, manifested by two or more of the SIRS criteria
Severe sepsis: Sepsis plus either cardiovascular organ dysfunction or acute respiratory distress syndrome (ARDS), or two other organ dysfunctions
Septic shock: Acute circulatory failure characterized by persistent arterial hypotension
CLINICAL FEATURES
Hyperthermia or hypothermia may be seen with sepsis.
The most frequent mental status change is obtunda-tion. Neurologic findings are nonfocal and range from mild disorientation to confusion, lethargy, agitation, and coma.
Cardiovascular manifestations in the early stages commonly include tachycardia, wide pulse pressure, and vasodilation. Cardiac output (CO) and stroke volume are usually initially maintained. As sepsis progresses, hypotension is common.
Respiratory manifestations—tachypnea and hypox-emia—are common. Sepsis is the most common condition associated with acute lung injury and ARDS.
Renal manifestations include acute renal failure with azotemia, oliguria, and active urinary sediment. Factors associated with the development of renal failure in septic shock include hypotension, dehydration, aminoglycoside administration, and pigmenturia.
The most frequent hepatic abnormality is cholestatic jaundice. Concentrations of transaminase, alkaline phosphatase, and bilirubin increase. Red blood cell hemolysis causes jaundice.
Major blood loss secondary to upper GI bleeding occurs in only a small percentage of patients with sepsis. However, minor blood loss may be seen within 24 hours.
The most frequent hematologic changes are neutropenia or neutrophilia, thrombocytopenia, and disseminated intravascular coagulation (DIC). Neutrophilic leukocytosis with a “left shift” is common. Neutropenia, occurring rarely, is associated with an increase in mortality.
Thrombocytopenia frequently arises as a consequence of DIC, although isolated thrombocytopenia is present in >30% of cases of sepsis. Thrombocytopenia may be an early clue to bacteremia, and serial platelet measurements may be useful in evaluating the patient’s response to therapy.
DIC is a frequent finding in patients with septic shock. Gram-negative infections precipitate DIC more readily than do gram-positive infections. Laboratory studies suggesting the presence of DIC include thrombocytopenia, prolonged prothrombin and activated partial thromboplastin values, decreased fibrin-ogen and antithrombin III levels, and increased fibrin monomer, fibrin split products, and D-dimer levels.
Hyperglycemia can develop, even without a history of diabetes. Uncontrolled hyperglycemia is a significant risk for adverse outcome. Hypoglycemia is reported but uncommon.
Blood gas analysis performed early in the course of septic shock usually demonstrates respiratory alka-losis. As perfusion worsens and continues, tissue hypoxia generates more lactic acid and metabolic acidosis worsens.
Cutaneous lesions that occur as a result of sepsis can be divided into five categories: direct bacterial involvement of the skin and underlying soft tissues (cellulitis, erysipelas, and fasciitis); lesions from hematogenous seeding of the skin or the underlying tissue (petechiae, pustules, cellulitis, ecthyma gan-grenosum); lesions resulting from hypotension and/or DIC (acrocyanosis and necrosis of peripheral tissues); lesions secondary to intravascular infections (microemboli and/or immune complex vasculitis); and lesions caused by toxins (toxic shock syndrome).
DIAGNOSIS AND DIFFERENTIAL
Septic shock should be suspected in any patient with a temperature of >38.3°C (>100.9°F) (>38.5°C [101.3°F] in children) or <36°C (<96.8°F) and a systolic blood pressure of <90 mm Hg (or 2 SD below normal for age in children) with evidence of inadequate organ perfusion. The hypotension of septic shock does not typically reverse with rapid volume replacement.
Other common features of sepsis include obtunda-tion; hyperventilation; hot, flushed skin; and a widened pulse pressure.
In elderly, very young, or immunocompromised patients, the clinical presentation may be atypical, with no fever or localized source of infection.
The differential diagnosis of septic shock includes the other nonseptic causes of shock such as cardiogenic, hypovolemic, anaphylactic, neurogenic, obstructive (pulmonary embolism, tamponade), and endocrine (adrenal insufficiency, thyroid storm) causes.
There is no specific laboratory test for the diagnosis of septic shock. Basic laboratory studies should include a complete blood count and platelet count; DIC panel; levels of serum electrolytes; liver function panel; renal function panel; arterial blood gas analysis and lactic acid level; and urinalysis. Blood should be typed and crossmatched if low hematocrit is suspected.
A chest radiograph (CXR) should be part of the basic evaluation. Flat and upright abdominal views are helpful in patients in whom perforation is suspected as a potential source of abdomen-related sepsis. Use of CT scanning and US should be obtained when appropriate.
Perform lumbar puncture in any patient with a clinical presentation compatible with meningitis. In individuals with papilledema, focal neurologic deficits, or the potential for brain abscess or epidural or subdural empyema, defer lumbar puncture until an imaging study is performed. If meningitis is an important consideration, however, give an empiric antimicrobial prior to the imaging study.
Obtain at least two separate sets of specimens for blood cultures. Perform gram staining and culture of secretions from any potential site of infection.
C-reactive protein (CRP) levels are elevated in sepsis. Procalcitonin level has greater sensitivity, specificity, and overall accuracy, and better predictive power in sepsis and septic shock than does CRP level.
Serum lactate acid level can help in determining prognosis. Patients with higher early clearance of lactic acid have improved outcomes; those with intermediate to high lactate levels have a higher mortality.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
EARLY GOAL-DIRECTED THERAPY
(1) Optimization of oxygenation, ventilation, and circulation; (2) initiation of drug therapy, including antibiotics; and (3) control of the source of sepsis. Studies have demonstrated that mortality rates for goal-directed therapy are lower than with usual care.
The ABCs of resuscitation should be addressed. Aggressive airway management with high-flow oxygen (keeping oxygen saturation greater than 90%) through endotracheal intubation may be necessary.
Hemodynamic stabilization: rapid infusion of crystalloid IV fluid (LR or NS) at 500 mL (20 mL/kg in children) every 5 to 10 minutes should be accomplished. Often, 4 to 6 L (60 mL/kg in children) is necessary.
In the early goal-directed therapy guidelines, early invasive monitoring (central venous pressure and, in appropriate cases, monitoring via arterial catheter) is recommended. Current recommendations are to maintain central venous pressures between 8 and 12 mm Hg, mean arterial pressure >65 mm Hg, and venous oxygenation saturation level >70%. Keep the patient’s hematocrit at >30%.
If there is no hemodynamic response after administration of 3 to 4 L of fluid, or if there are signs of fluid overload, an infusion of dopamine or norepinephrine can be started. The dopamine dose ranges from 5 to 20 micrograms/kg/min. If there is no response to an infusion of 20 micrograms/kg/min, start norepinephrine to keep the mean arterial pressure at least at 65 mm Hg. Usual doses of norepinephrine range from 2.5 to 20 micrograms/kg/min. Once the blood pressure and perfusion have been stabilized by norepinephrine, use the lowest dose that maintains blood pressure to minimize vasoconstriction.
Pediatric septic shock requires a different approach to inotropic support. Low cardiac output is associated with mortality. Oxygen delivery, not oxygen extraction, is the major determinant of oxygen consumption. Infants <6 months of age are insensitive to dopamine and dobutamine. Pediatric dopamine-resistant shock commonly responds to norepinephrine or epinephrine.
The source of infection must be removed (eg, removal of indwelling catheters and incision and drainage of abscesses).
Empiric antibiotic therapy is ideally begun after obtaining cultures, but administration should not be delayed. Dosages should be the maximum allowed and given intravenously. A partial list of initial doses is listed below.
ADULTS (NON-NEUTROPENIC)
When the source is unknown, therapy should be effective against gram-positive and gram-negative organisms. In adults imipenem 500 milligrams IV every 6 hours can be used.
Alternatives include ertapenem, 1 gram IV every 24 hours, plus vancomycin, 15 milligrams/kg every 6 hours or 1 gram IV every 12 hours.
If pneumonia is a suspected source: ceftriaxone, 1 to 2 grams IV every 12 hours, plus azithromycin, 500 milligrams IV, then 250 milligrams IV every 24 hours, or levofloxacin, 750 milligrams IV every 24 hours, or moxifloxacin, 400 milligrams IV every 24 hours, plus vancomycin, 15 milligrams/kg IV every 6 hours, or 1 gram IV every 12 hours.
If a biliary source is suspected: ampicillin/sulbactam, 3 grams IV every 6 hours, or piperacillin/tazobactam, 4.5 grams IV every 6 hours, or ticarcillin/clavulanate, 3.1 grams IV every 4 hours.
When an intra-abdominal source is suspected: imipenem, 500 milligrams IV every 6 hours to 1 gram IV q8 hours, or meropenem, 1 gram IV 8 hours, or doripenem, 500 milligrams IV every 8 hours, or ertapenem, 1 gram IV every 24 hours, or ampicillin/sulbactam, 3 grams IV every 6 hours, or piperacillin/tazobactam, 4.5 grams IV every 6 hours.
If a urinary source: piperacillin/tazobactam, 4.5 grams IV every 6 hours, or ampicillin, 1 to 2 grams IV every 4 to 6 hours, plus gentamicin, 1.0 to 1.5 milligrams/kg every 8 hours.
With IV drug use or indwelling devices, there is a high probability of gram-positive etiology; vancomycin 15 milligrams/kg IV every 6 hours or 1 gram IV every 12 hours is recommended.
CHILDREN (NON-NEUTROPENIC)
Neonates <1 week of age: ampicillin, 25 milligrams/kg IV every 8 hours, plus cefotaxime, 50 milligrams/kg IV every 12 hours.
Neonates 1 to 4 weeks: ampicillin, 25 milligrams/kg IV every 6 hours, plus cefotaxime, 50 milligrams/kg IV every 8 hours.
Infants over 3 months: ceftriaxone, 75 milligrams/kg IV every 24 hours, or cefotaxime, 50 milligrams/kg IV every 8 hours.
Children over 3 months: ceftriaxone, 75 to 100 milligrams/kg every 24 hours, or cefotaxime, 50 milligrams/kg IV every 8 hours. Consider vancomycin, 15 milligrams/kg IV every 6 hours, or 1 gram IV every 12 hours.
NEUTROPENIC CHILDREN AND ADULTS
Ceftazidime, 2 grams IV every 8 hours; for children, 50 milligrams/kg IV every 8 hours up to adult dosage or imipenem, 500 milligrams IV every 6 hours to 1 gram IV every 8 hours; for children: age >3 months, 15 to 25 milligrams/kg IV every 6 hours; age 1 to 3 months, 25 milligrams/kg IV every 6 hours; age 1 to 4 weeks, 25 milligrams/kg IV every 8 hours; age <1 week, 25 milligrams/kg IV every 12 hours, select one agent above plusvancomycin, 15 milligrams/kg IV 6 hours.
DIC should be treated with fresh-frozen plasma, 15 to 20 mL/kg initially, to keep PT at 1.5 to 2 times normal, and treated with a platelet infusion of 6 U, to maintain a serum concentration of at least 50,000/μL.
Corticosteroids are not recommended for septic patients who are not in shock. Dosages of hydro-cortisone should be ≤300 milligrams/d. An adren-ocorticotropic hormone stimulation test is not recommended, and hydrocortisone is preferred over dexamethasone.
Current international guidelines recommend “judicious glycemic control” to keep glucose levels <150 milligrams/dL in patients with septic shock.
For further reading in Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th ed., see Chapter 146, “Septic Shock,” by Jonathan Jui.