Severe Infections and Sepsis Syndrome

The incidence of sepsis and septic shock has been increasing since the 1930s, and most likely this will continue. The reasons for this increasing incidence include:

  • increased use of invasive devices such as intravascular catheters
  • widespread use of cytotoxic and immunosuppressive drug therapies for cancer and transplantation
  • increased lifespan of patients with cancer and diabetes who are prone to sepsis development
  • increase in infections due to antibiotic-resistant organisms

Definitions
Infection
An inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.

Bacteremia
The presence of viable bacteria in the blood.

Systemic inflammatory response syndrome (SIRS)
A widespread inflammatory response to a variety of severe clinical insults (infectious or non-infectious causes). This syndrome is clinically recognized by the presence of two or more of the following:

  • Temperature >38.5ºC or <35.0ºC
  • Heart rate >90 beats/min
  • Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
  • WBC >12,000 cells/mm3, <4000 cells/mm3, or with >10 percent immature (band) forms

Sepsis
The systemic response to infection. The clinical signs describing SIRS are present together with definitive evidence of infection.

Severe sepsis
Sepsis is considered severe when it is associated with organ dysfunction, or organ hypoperfusion. The manifestations of organ dysfunction and hypoperfusion may include:

  • Areas of mottled skin
  • Capillary refilling time ≥ 3 seconds
  • Urinary output <0.5 mL/kg for at least 1 hour or renal replacement therapy.
  • Lactate >2 mmol/L
  • Abrupt change in mental status.
  • Platelets count <100,000 /mL or disseminated intravascular coagulation (DIC).
  • Acute lung injury, acute respiratory distress syndrome.
  • Cardiac dysfunction.

Septic shock
Sepsis with hypotension despite adequate fluid resuscitation combined with perfusion abnormalities. Patients who require inotropic or vasopressor support despite adequate fluid resuscitation are in septic shock.

Refractory septic shock
Septic shock with need for dopamine >15μg/kg per minute or norepinephrine or epinephrine >0.25 μg/kg per minute to maintain mean blood pressure above 60mmHg.

Diagnosis
History
Symptoms of sepsis are usually nonspecific and include fever, chills, and constitutional symptoms of fatigue, malaise, anxiety, or confusion. Inquiry for localizing symptoms as clues to the etiology of sepsis is important.

Physical
A thorough physical examination including assessment of the general condition/appearance of the patient, vitals, and signs of focal infection such as neck stiffness for meningitis is always essential.

Laboratory Studies
Laboratory tests are useful in suspected sepsis or septic shock because they allow assessment of the general hematologic and metabolic condition of the patient and they enable detection the specific microbial etiology of infection.

  • CBC with differential (Leukocytosis, leucopenia, thrombocytopenia, anemia)
  • Metabolic assessment with determination of serum electrolyte levels, including magnesium, calcium, phosphate, and glucose levels
  • Assessment of renal and hepatic function with analysis of serum creatinine, BUN, bilirubin, alkaline phosphate, and alanine aminotransferase levels. Elevated serum lactate levels indicate that significant tissue hypoperfusion exists.
  • ABG assessment.
  • Coagulation should be assessed by assessing the prothrombin time and activated partial thromboplastin time. Patients with clinical evidence of coagulopathy require additional testing to determine the presence of DIC.
  • Microbiologic testing including blood cultures, urinalysis, urine culture, gram stain and culture of sputum or tissue from sites of potential infection.

Imaging Studies
A variety of imaging modalities are useful to document a clinically suspected focal infection. A chest radiograph should be obtained when the patient has evidence of a pulmonary infection. Ultrasonography is the imaging modality of choice when a biliary tract source is suspected. CT scanning is the imaging modality of choice for evaluating intra-abdominal abscesses and retroperitoneal sources of infection.

Differential Diagnosis
Many noninfectious conditions may mimic severe sepsis/septic shock. Examples include:

  • acute adrenal insufficiency
  • acute pancreatitis
  • pulmonary embolism
  • myocardial infarction
  • diabetic ketoacidosis
  • anaphylaxis
  • burns
  • trauma
  • occult hemorrhage
  • dissecting or ruptured aortic aneurysm
  • cardiac tamponade
  • thyroid storm
  • malignant hyperthermia
  • heatstroke

Management
The mortality rate from sepsis and multi-organ failure remains high, but early recognition and prompt therapeutic intervention positively affects outcome.

Recognition of sepsis or impending sepsis
Initial clinical manifestations are often subtle and subsequently become rapidly progressive. Altered mental status, tachycardia, tachypnea, ileus, oliguria, thrombocytopenia, or general “failure to thrive” may be pointers to early sepsis.

Establishment of a specific etiology
Identification of specific focus of infection followed by prompt medical / surgical therapy is imperative. Sources of sepsis in the abdomen and soft tissue infections frequently require percutaneous/surgical drainage procedures, or debridement.

Institution of appropriate antibiotic therapy
The timely administration of intravenous antibiotic therapy is a key factor in the management of sepsis. As soon as cultures are drawn from possible infectious sources, empiric broad-spectrum antibiotic therapy should be initiated. The choice of antibiotics should be based on the suspected focus of infection, whether the infection is community or hospital-acquired, suspicion of potential pathogens, drug resistance patterns in a particular hospital, previous antibiotic use, and known drug allergies and the degree of host immunity. Culture and sensitivity results should be reviewed frequently and antibiotics should be adjusted.

Hemodynamic management of sepsis
Patients who have septic shock should be treated in an ICU, with accurate intra-arterial blood pressure monitoring and right heart catheterization. Resuscitation should be titrated to clinical end points, including vital signs, skin perfusion, urine output, and indices of tissue perfusion, such as lactate concentration and mixed venous oxygen saturation.

Fluid infusion should be the first step in the hemodynamic support of patients who have septic shock. For those who are not responsive initially to aggressive fluid challenge, vasopressors such as dopamine, phenylephrine, norepinephrine, vasopressin, and, in refractory cases, epinephrine should be added.

Use of agents that are specifically directed against mediators of sepsis

Human recombinant activated protein C (drotrecognin alfa)
This agent exerts an antithrombotic effect by inhibiting factors VA and VIIIA. A multi-center trial that used activated protein C showed a reduction in mortality, particularly in patients with APACHE II >24 and at least one new organ dysfunction.

The major adverse effect of drotrecognin alfa is serious bleeding; contraindications to its use include active bleeding, head trauma, recent (within 3 months) hemorrhagic stroke, recent (within 2 months) intracranial or intraspinal surgery, end-stage liver disease, chronic renal failure, or the use of drugs that significantly affect coagulation.

Steroids
The mortality in patients with septic shock is related to baseline cortisol status and the ability to respond to ACTH stimulation. Mortality is highest in patients who have elevated baseline cortisol levels and are unable to generate a stimulated level greater than 90μ/L.

In general supraphysiologic doses of steroids are not beneficial and an ACTH stimulation test should be performed before steroid administration. Low-dose steroid replacement should be considered only in patients who have documented adrenal insufficiency.

Prognosis
Despite the tremendous advances in diagnosis and therapy, the mortality rate for patients with severe sepsis and septic shock remains high. Mortality rates attributable to severe sepsis and septic shock of 20% to 50%, with mortality rates up to 80% to 85% with septic shock and multiple organ failure.

These observations underscore the importance of early aggressive management of the septic patient and suggest that our future focus should also be directed toward prevention of sepsis.