Sepsis and Septic Shock

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 common 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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  • 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


  • Mortality ranges from 20%50% (higher in septic shock)
  • More common in survivors: 
    • Hospital readmission (about 40% within 3 months)
    • Early death
    • Physical and neurocognitive dysfunction
    • Mood disorders
    • Low quality of life
  • Leading cause of death in hospitalized patients
  • Nearly 20% of all global deaths
  • Higher incidence in extremes of age, male sex, and Black patients 
  • Septic shock follows in 30% of sepsis cases.

Risk factors

  • Chronic diseases (e.g., chronic obstructive pulmonary disease, HIV infection, and cancer)
  • Immunosuppression 
  • Prior organ dysfunction
  • Delay in diagnosis and treatment

Etiology and Pathophysiology


  • May be community- or hospital-acquired
  • Source of infection:
    • Identified in ⅓ of patients 
    • Most commonly pneumonia, followed by intra-abdominal and genitourinary infections
  • Cultures:
    • Blood cultures: positive in ⅓ 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


Pathogen load and virulence + host genetic composition and comorbidities result in a complex, exaggerated, and prolonged host response to infection that 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
Pathogenesis of sepsis

Pathogenesis of sepsis

Image by Lecturio.

Clinical Presentation

  • 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: relatively warm extremities and widening of pulse pressure reflecting reduced SVR and increased CO
  • Respiratory failure:
    • Symptoms of acute respiratory distress syndrome (ARDS) including tachypnea, shallow breathing, use of accessory muscles, fatigue with paradoxical abdominal movement, bilateral rales (crackles), hypoxia, and bilateral pulmonary infiltrates not explained by heart failure 
  • Cardiac failure:
    • Hypotension
    • Tachycardia
    • Tachypnea
    • Rales subsequent to pulmonary edema
  • Acute kidney injury (AKI) 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 if especially prolonged intensive care unit (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


General approach

  1. Suspect sepsis in a patient presenting with any of the following:
    • Infection without apparent organ dysfunction 
    • 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 quick sequential organ failure assessment (qSOFA) score: 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”): Closely monitor for response to interventions and criteria of septic shock.

Diagnostic criteria

  • Criteria for sepsis: 
    • Suspected (or documented) infection
    • Increase in ≥ 2 SOFA points 
  • Criteria for septic shock:
    • Suspected (or documented) infection
    • Vasopressor therapy necessary to maintain mean arterial pressure (MAP) ≥ 65 mm Hg despite adequate IV crystalloid administration
    • Serum lactate > 2.0 mmol/L despite adequate IV crystalloid administration
  • qSOFA: 
    • A simple bedside tool for use outside the ICU and in the preclinical setting:
      • In patients with suspected infection: having ≥ 2 of the following 3 criteria indicates poor outcomes (prolonged ICU course and 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 blood pressure < 100 mm Hg 
      • Respiratory rate ≥ 22/min
      • Altered mentation 
  • Systemic inflammatory response syndrome (SIRS): no longer used for the diagnosis of sepsis
Table 1: The sequential organ failure assessment (SOFA) score
Organ/systemSOFA scoreIndication
Respiratory system: PaO2/FiO2 (mm Hg)0≥ 400
+ 1300–399
+ 2200–299
+ 3100–199 + mechanically ventilated
+ 4< 100 + mechanically ventilated
Nervous system: Glascow coma scale015
+ 113–14
+ 210–12
+ 4< 6
Cardiovascular system: mean arterial pressure (MAP) OR need for vasopressors0MAP ≥ 70 mm Hg
+ 1MAP < 70 mm Hg
+ 2Dopamine ≤ 5 μg/kg/min or dobutamine (any dose)
+ 3Dopamine > 5 μg/kg/min OR epinephrine ≤ 0.1 μg/kg/min OR norepinephrine ≤ 0.1 μg/kg/min
+ 4Dopamine > 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
+ 11.2–1.9
+ 22–5.9
+ 36–11.9
+ 4≥ 12
Coagulation: platelets × 103/μL0≥ 150
+ 1100–149
+ 250–99
+ 320–49
+ 4< 20
Kidneys: creatinine (mg/dL) or urine output0< 1.2
+ 11.2–1.9
+ 22–3.4
+ 33.4–4.9 or < 500 mL/day
+ 4> 5.0 or < 200 mL/day
The 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.


Sepsis and septic shock are medical emergencies!

Respiratory support

  • Indications for endotracheal intubation and mechanical ventilatory support: 
    • Significant hypoxemia (PaO2 < 60 mm Hg or oxygen saturation < 90%)
    • Hypoventilation (rising PCO2
    • Significantly altered level of consciousness 
    • Inability to protect airways with risk of aspiration 
    • Persistent metabolic acidosis with pH < 7.20
  • Goal: arterial oxygen saturation of 92%95%

Hour-1 bundle

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

  1. Monitor serum lactate level (remeasure  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.
  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.
    • 1st choice: norepinephrine, plus vasopressin to increase mean arterial pressure and reduce norepinephrine use


  • 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


  • Should not be used routinely
  • Dexamethasone has been shown to reduce mortality in patients with coronavirus disease 2019 (COVID-19) who are receiving respiratory support.
  • 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: A blood glucose target of 140–180 mg/dL (7.7 to 10 mmol/L) is recommended. 
  • Prophylaxis for deep venous thrombosis: low-dose unfractionated heparin or low-molecular-weight heparin (LMWH) if no contraindications exist, 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.
Table: Choice of empirical antibiotic therapy in adult patients with sepsis (all antibiotics administered intravenously)
Patient’s immune statusChoice of antibiotic
ImmunocompetentAny of the following:
  • Piperacillin-tazobactam
  • Cefepime
  • Meropenem or imipenem-cilastatin
  • Aztreonam, ciprofloxacin, or levofloxacin if allergic to beta-lactam antibiotics
Vancomycin (or linezolid) if risk of MRSA is high or if in septic shock
Neutropenic (< 500 neutrophils/μL)Any of the following:
  • Piperacillin-tazobactam
  • Cefepime
  • Meropenem or imipenem-cilastatin
Vancomycin (or linezolid), tobramycin, and caspofungin
SplenectomyAny of the following:
  • Ceftriaxone
  • Levofloxacin or moxifloxacin if allergic to beta-lactams
Vancomycin (or linezolid)
Associated with pneumoniaRefer to the treatment of community- and ventilator-acquired pneumonia.
Associated with severe intra-abdominal infectionsAny of the following:
  • Piperacillin-tazobactam
  • Cefepime or ceftazidime
  • Meropenem or imipenem-cilastatin
  • Ciprofloxacin or levofloxacin


  1. Singer M, Deutschman CS, Seymour CW, et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810. doi:10.1001/jama.2016.0287.
  2. Kasper DL, Fausi AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. (2018). Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Education.
  3. Weiss SL, Peters MJ, Alhazzani W, et al. (2020). Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children, Pediatric Critical Care Medicine.
  4. Surviving Sepsis Campaign. 1-Hour Bundle.
  5. Kalil Andre. Septic Shock. New York, NY. WebMD. Retrieved Oct 5, 2020, from

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