Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most commonly known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and septic shock are medical emergencies and antibiotics are given within an hour of diagnosis.

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Definition and Diagnostic Criteria

Definition

  • Sepsis: A potentially life-threatening organ dysfunction caused by a dysregulated host response to infection
  • Septic shock: Sepsis with a substantial increase in mortality risk due to circulatory and cellular/metabolic abnormalities

Diagnostic criteria

  • Criteria for sepsis: 
    • Suspected (or documented) infection, AND
    • Increase in ≥ 2 SOFA (Table 1) points (previously ≥ 2 SIRS [Table 2] points)
  • Criteria for septic shock:
    • Suspected (or documented) infection, AND
    • Vasopressor therapy necessary to maintain mean arterial pressure (MAP) ≥ 65 mm Hg despite adequate IV crystalloid administration AND
    • Serum lactate > 2.0 mmol/L despite adequate IV crystalloid administration
  • Quick SOFA (qSOFA): 
    • A simple bedside tool outside the ICU and in the preclinical setting:
      • In patients with suspected infection: 2 of the following 3 criteria indicate poor outcomes (prolonged ICU course or death) and triggers further investigation, frequent monitoring, escalation of treatment, and ICU admission as appropriate
      • In patients without previous suspicion of infection: triggers consideration of infection
    • Criteria:
      • Systolic BP < 100 mm Hg 
      • Respiratory rate ≥ 22/min
      • Altered mentation
  • SIRS: no longer used for the diagnosis of sepsis
Organ/System SOFA Score Indication
Respiratory System

PaO2/FiO2 (mm Hg)

0

+1

+2

+3

 

+4

≥ 400

300-399

200-299 

100-199 + mechanically ventilated

< 100 + mechanically ventilated

Nervous System

Glasgow Coma Scale

0

+1

+2

+3

+4

15

13-14

10-12

6-9

< 6

Cardiovascular System

Mean arterial pressure (MAP) OR need for vasopressors

0

+1

+2

 

+3

 

 

+4

MAP ≥ 70 mm Hg

MAP < 70 mm Hg

Dopamine ≤ 5 μg/kg/min or dobutamine (any dose)

Dopamine > 5 μg/kg/min OR epinephrine ≤ 0.1 μg/kg/min OR norepinephrine ≤ 0.1 μg/kg/min

Dopamine > 15 μg/kg/min OR epinephrine > 0.1 μg/kg/min OR norepinephrine > 0.1 μg/kg/min

Liver

Bilirubin (mg/dl)

0

+1

+2

+3

+4

< 1.2

1.2-1.9

2-5.9

6-11.9

≥ 12

Coagulation

Platelets×103/μl

0

+1

+2

+3

+4

≥ 150

100-149

50-99

20-49

< 20

Kidneys

Creatinine (mg/dl) or urine output

0

+1

+2

+3

+4

< 1.2

1.2-1.9

2-3.4

3.4-4.9 or < 500 mL/day

> 5.0 or < 200 mL/day

Table 1: The sequential organ failure assessment (SOFA) score quantifies the number and severity of organ failure. It assesses 6 organ systems. Each organ system is given 0-4 points based on severity of involvement. The overall SOFA score ranges from 0 (no organ failure) to 24 (most severe) points.

Criteria Indication SIRS Score
Fever > 38°C (100°F) OR < 36°C (96.8°F) +1
Tachypnea > 20 breaths per minute +1
Tachycardia > 90 beats per minute +1
Abnormal leukocyte count > 12,000/μl OR < 4,000/μl OR band cell > 10% +1

Table 2: The systemic inflammatory response syndrome (SIRS) score. Although SIRS has been eliminated from the new definition of sepsis, it remains an important tool in the assessment of the systemic response to diverse insults excluding infection.

Etiology, Risk Factors, Epidemiology, and Pathophysiology

Etiology

  • May be community-acquired or hospital-acquired
  • Source of infection:
    • Identified in a third of patients 
    • Most commonly pneumonia, followed by intra-abdominal and genitourinary infections
  • Cultures:
    • Blood cultures: positive in a third of patients
    • Negative cultures from all sites are common
  • Most common gram-positive pathogens:
    • Staphylococcus aureus
    • Streptococcus pneumonia
  • Most common gram-negative pathogens:
    • Escherichia coli
    • Klebsiella spp.
    • Pseudomonas aeruginosa
  • Fungi: reported in about 20% of cases.
  • Viruses: reported in only 1% of cases.

Risk Factors

  • Chronic diseases (e.g., chronic obstructive pulmonary disease, HIV infection, and cancer)
  • Immunosuppression 
  • Prior organ dysfunction
  • Delay in diagnosis and treatment
  • Incidence is higher in extremes of age, male sex, and black patients

Epidemiology

  • Leading cause of death in hospitalized patients
  • Nearly 20% of all global deaths
  • Incidence in the US: 3 in 1,000 people 
  • Septic shock occurs in 30% of sepsis cases.

Pathogenesis

Pathogen load and virulence + host genetic composition and comorbidities result in a complex, exaggerated, and prolonged host response to infection which evolves over time.

  1. Recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors on innate immune cells ⇒ inflammatory response (e.g., release of tumor necrosis factor) ⇒ tissue damage and necrotic cell death ⇒ release of damage-associated molecular patterns (DAMPs) ⇒ further activation of leukocytes ⇒ microvascular changes: endothelial cell dysfunction + coagulation and complement activation
  2. Macrovascular changes: vasodilation and hypotension 
  3. Microvascular changes + macrovascular changes ⇒ Vascular leak, edema, intravascular volume depletion ⇒ Impaired tissue oxygenation, cellular alterations such as greater glycolysis (lactate production), mitochondrial injury and release of oxygen species ⇒ increasing organ damage

Clinical Manifestations and Laboratory Features

Clinical manifestations vary extensively based on initial site of infection, offending pathogen, sequence of organ dysfunction, patient immune status and comorbidities, and time from onset to diagnosis and treatment. Main features include:

  • Skin and peripheral pulses:
    • Early septic shock with low volume status: cold extremities and narrow pulse pressure reflecting increased systemic vascular resistance (SVR) and reduced cardiac output (CO).
    • With progression of shock or volume repletion: relatively warm extremities and widening of pulse pressure reflecting reduced SVR and increased CO.
  • Respiratory failure:
    • Symptoms and signs of acute respiratory distress syndrome (ARDS) including  tachypnea, shallow breathing, use of accessory muscles, fatigue with paradoxical abdominal movement, bilateral rales, hypoxia and bilateral pulmonary infiltrates not explained by heart failure, occurring within 7 days of suspected infection 
  • Cardiac failure:
    • Hypotension, tachycardia, tachypnea, and rales subsequent to pulmonary edema
  • Acute kidney injury with decreased urinary output and azotemia/uremia
  • Neurologic presentation and complications: 
    • Altered mental status including delirium and coma
    • No focal lesions on imaging and global encephalopathy on electroencephalography
    • Critical-illness polyneuropathy and myopathy especially prolonged ICU stay
    • Chronic moderate to severe cognitive impairment
  • Other clinical/laboratory features and complications: ileus, elevated liver enzymes, disseminated intravascular coagulation, adrenal failure, sick euthyroid syndrome

Diagnostic Approach

Sepsis does not always present with apparent infection and organ dysfunction. 

  1. Suspect sepsis in any patient presenting with any of the following and check qSOFA
    (step 2):

    • Any infection without apparent organ dysfunction 
    • Any new-onset and unexplained organ dysfunction without apparent infection
    • Abnormal vital signs such as fever, tachypnea, tachycardia, or low blood pressure
    • Altered mental status
  2. Check qSOFA: With a positive qSOFA (≥ 2 criteria) or suspicion of sepsis despite a negative qSOFA (< 2 criteria), check SOFA (step 3).
  3. Check SOFA: With an increase of ≥ 2 SOFA points from baseline (baseline is considered zero without a prior history of organ dysfunction), initiate hour-1 bundle (step 4). 
  4. Initiate hour-1 bundle (see Management): During therapy, closely monitor for response to interventions and criteria of septic shock.

Management

Sepsis and septic shock are medical emergencies!

Endotracheal intubation and mechanical ventilatory support

  • May be indicated any time during the evaluation and management of a patient with sepsis.
  • Common indications include: significant hypoxemia (PaO2 < 60 mm Hg or oxygen saturation < 90 %), hypoventilation (rising PCO2), increased work of breathing, significantly altered level of consciousness, inability to protect airways with risk of aspiration, persistent metabolic acidosis with pH < 7.20

Hour-1 bundle

The hour-1 bundle encourages physicians to act as quickly as possible. Ideally, the following steps, some if required, should begin within the 1st hour after the diagnosis of sepsis. 

  1. Measure serum lactate level (remeasure lactate if > 2 mmol/L).
  2. Obtain blood cultures (positive in only 30 % of patients with presumed sepsis) before initiating antibiotics.
  3. Initiate broad-spectrum antibiotics (Table 3). Choice depends on: 
    • Suspected site of infection
    • The environment of infection onset (e.g., community, nursing home or hospital)
    • Patient’s immune status and comorbidities (e.g., empirical antifungals only in patients with high risk for invasive candidiasis such as those on cancer chemotherapy with low leukocyte counts) 
    • Microbial susceptibility patterns
  4. Intravenous (IV) crystalloids: Rapidly administer (30 mL/kg) if hypotensive (mean arterial pressure < 65 mm Hg) and/or lactate ≥ 4 mmol/L.
  5. Vasopressors: 
    • Administer if hypotensive during or after resuscitation with IV crystalloids.
    • First choice: norepinephrine, plus vasopressin to increase mean arterial pressure and reduce norepinephrine use

Monitoring for response to interventions

The following non-invasive monitoring methods are currently considered appropriate:

  • Arterial pulse contour analysis
  • Focused echocardiography (cardiac output, beat-to-beat stroke volume, and pulse pressure variation)
  • Passive leg-raise maneuver
  • Inferior vena cava collapsibility on ultrasound

Controlling source of infection to reduce mortality rate

  • Mainly pulmonary, abdominal, urinary, or soft tissue infections
  • Source is identified in about one-third of patients.

Glucocorticoids

  • Should not be used routinely
  • Weak recommendation: Initiate IV hydrocortisone if septic shock does not respond to fluids and vasopressors.
  • Wean steroids if vasopressors are no longer needed.

Additional measures

  • Red blood cell transfusion: only recommended if hemoglobin is < 7 g/dL
  • Insulin therapy: Maintain glucose < 180 mg/dL
  • Prophylaxis for deep venous thrombosis: low-dose unfractionated heparin or low-molecular-weight heparin (LMWH) if no contraindications such as active bleeding or significant thrombocytopenia 
  • Close monitoring and treatment of electrolyte abnormalities
  • Nutritional support: enteral route is preferred
  • Effectively communicate sepsis status during hand-offs.

De-escalation of care

  • Reduce/stop medications, including fluids, vasopressors, and antibiotics according to patient needs, response to therapy, and culture results.
Type of Patient Choice of Antibiotic
Immunocompetent Any of the following:

  • Piperacillin-tazobactam
  • Cefepime
  • Meropenem or imipenem-cilastatin
  • Aztreonam, ciprofloxacin, or levofloxacin if allergic to beta-lactam antibiotics

PLUS: 

  • Vancomycin (or linezolid) if risk of MRSA is high or with septic shock
Neutropenic (< 500 neutrophils/ul) Any of the following:

  • Piperacillin-tazobactam
  • Cefepime
  • Meropenem or imipenem-cilastatin

PLUS: 

  • Vancomycin (or linezolid), tobramycin, and caspofungin
Splenectomy Any of the following:

  • Ceftriaxone 
  • Levofloxacin or moxifloxacin if allergic to beta-lactams

PLUS: 

  • Vancomycin (or linezolid)
Associated with pneumonia Refer to the treatment of community-acquired and ventilator-acquired pneumonia.
Associated with severe intra-abdominal infections Any of the following:

  • Piperacillin-tazobactam
  • Cefepime or ceftazidime
  • Meropenem or imipenem-cilastatin
  • Ciprofloxacin or levofloxacin

PLUS:

  • Metronidazole

Table 3: Choice of empirical antibiotic therapy in adult patients with sepsis. All antibiotics are administered intravenously.

Prognosis and Prevention

Prognosis

  • In the US, infection is the 5th cause of productive years of life lost due to premature death.
  • Mortality ranges from 20-50 % (higher in septic shock)
  • In survivors: 
    • Hospital readmission (about 40 % within 3 months)
    • Early death
    • Physical and neurocognitive dysfunction
    • Mood disorders

Prevention

The incidence of sepsis may be reduced with the following:

  • Adherence to infection control measures and protocols at hospitals and other healthcare facilities
  • Avoiding unnecessary antibiotic use
  • Limiting use of indwelling devices and catheters
  • Judicious use of immunosuppressive medication
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