Sepsis

Sepsis is an acute life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. Without prompt intervention, patients frequently progress to septic shock and multiple organ failure. The precipitating infection is often bacterial, typically originating in the respiratory, genitourinary, or gastrointestinal systems or in the skin or soft tissue. Clinical features include fever, tachycardia, confusion, and signs of the primary infection. Sepsis screening tools incorporating common clinical variables and laboratory values are used to facilitate early identification of sepsis. Favorable patient outcomes rely on early detection, effective resuscitation measures (e.g., aggressive fluid therapy and appropriate use of vasopressors), and early administration of antibiotics. The diagnostic workup of sepsis should occur in parallel with resuscitation efforts and focuses on identifying the site of infection and causative pathogen for definitive treatment.

Definitions and criteria in this section apply to adult patients.

Third International Consensus Definitions for Sepsis and Septic Shock ^[1][2]

• Sepsis: a severe, life-threatening condition that results from a dysregulation of the patient's response to an infection, causing tissue and organ damage and subsequent organ dysfunction ^[1]
• Septic shock: a sepsis syndrome accompanied by circulatory and metabolic abnormalities that can significantly increase mortality ^[1]
  • Diagnostic criteria
    • Persistent hypotension: Vasopressors are required to maintain mean arterial pressure (MAP) ≥ 65 mm Hg.
    • Persistent lactic acidosis: lactate > 2 mmol/L (18 mg/dL) despite adequate fluid resuscitation

Organ dysfunction secondary to sepsis is defined as an acute increase of ≥ 2 in the total SOFA score due to the infection.

Other definitions of sepsis syndromes ^{[1][3][4][5][6]}

• Systemic inflammatory response syndrome (SIRS) : a group of physiological and immune-mediated reactions that are triggered in response to an infectious or noninfectious insult (e.g., an acute inflammatory process or trauma) ^[1][3]
  • SIRS is diagnosed if ≥ 2 of the following 4 criteria are fulfilled:
    • Temperature: > 38°C or < 36°C
    • Heart rate: > 90/min
    • Respiratory rate: > 20/min or PaCO₂ < 32 mm Hg
    • White blood cell count: > 12,000/mm³, < 4000/mm³, and/or > 10% band cells
• Sepsis: ≥ 2 SIRS criteria PLUS a suspected or confirmed underlying infection ^[1]
• Severe sepsis: sepsis PLUS dysfunction of at least one organ or system ^[1]
• Multiple organ dysfunction syndrome (MODS) : ^[1]
  • Progressive, but potentially reversible, dysfunction of several organs and/or systems ^[7]
  • The more organs that are affected, the greater the mortality risk.
• Bacteremia: the presence of viable bacteria in the bloodstream, with or without clinical signs of infection ^[8]

See also “Etiology of bloodstream infections.”

• Common sources of sepsis: ^[1][9]
  • Respiratory: pneumonia (most common cause of sepsis)
  • Abdominal infections (e.g., intraabdominal abscess)
  • Genitourinary: pyelonephritis
  • Skin and soft tissue infections
  • Implanted devices (e.g., central venous catheter, port-a-cath, urinary catheter, endotracheal tube)
• Pathogens
  • Bacterial: gram-positive bacteria (most common in the US); gram-negative bacteria
  • Fungal, viral, or parasitic infection (rare)
• Common risk factors
  • Age: < 1 year or > 75 years
  • Primary comorbidities (diabetes mellitus, cirrhosis, community acquired pneumonia, bacteremia, alcohol use disorder)
  • Immunosuppression (neutropenia, corticosteroid treatment)
  • Intensive care or prolonged admission (nosocomial infections)
  • Recent antibiotic or corticosteroid treatment
  • Invasive medical devices (e.g., endotracheal tubes, intravenous lines, urinary catheters)

Implanted devices are an important risk factor and a common source of infection. ^[1]

References:^{[10][11][12][13][14][15][16]}

Sepsis is a hyperinflammatory systemic reaction.

1. Local activation of inflammatory mediators (complement system, mast cells, macrophages) results in vessel dilation and further release of proinflammatory cytokines (esp. TNFα, IL-1).
2. Generalized endothelial disruption → capillary leak → generalized edema due to a shift of intravascular fluid and albumin into the surrounding tissue
3. Intravascular hypovolemia; → excessive triggering of the extrinsic coagulation cascade → disseminated intravascular coagulation (DIC) and microvascular thrombosis
4. Decreased oxygen utilization and tissue ischemia; → widespread cellular injury → organ dysfunction (commonly multisystem)

An adequate immune response requires a balance between proinflammatory (antiinfectious) and antiinflammatory signals!

• General features
  • Fever , chills, and diaphoresis
  • Tachycardia
  • Tachypnea
  • Generalized edema (capillary leak)
• Features of organ dysfunction (see SOFA score)
  • CNS impairment: altered mental status
  • Cardiovascular failure: hypotension
  • Coagulopathy → disseminated intravascular coagulation → petechiae, purpura
  • Liver failure: jaundice
  • Kidney failure: oliguria
  • Respiratory failure; : symptoms of acute respiratory distress syndrome (ARDS)
• Features of septic shock
  • Hypotension (MAP < 65 mm Hg)
  • Altered skin and soft tissue perfusion
    • Early presentation: warm skin and normal capillary refill time (warm shock)
    • Late presentation: cold, cyanotic, pale, and/or mottled skin and prolonged capillary refill time (cold shock)
• Features of the primary infection: e.g., clinical features of pneumonia, meningismus, peritonitis, clinical features of pyelonephritis, clinical features of infective endocarditis

The following recommendations are consistent with the 2021 Surviving Sepsis Campaign guidelines and the American College of Emergency Physicians (ACEP) task force consensus statement for adults with suspected sepsis in the emergency department. ^[2][17]

Sepsis is a medical emergency. Be vigilant for early signs of sepsis and begin treatment as soon as sepsis is suspected.

Approach ^[2]

Perform diagnostics and treatment simultaneously in patients with suspected sepsis.

• Sepsis surveillance
  • Use a sepsis screening tool to identify at-risk patients following local protocols.
  • Consider empiric management of high-risk patients even if screening tools are negative. ^[18]
• Initial evaluation
  • Perform a clinical evaluation using the ABCDE approach.
  • Establish IV access, continuous cardiac monitoring, and continuous pulse oximetry.
  • Obtain the following initial studies immediately:
    • Serum lactate: Elevated lactate predicts sepsis severity and helps guide resuscitation. ^[19][20]
    • Two sets of blood cultures (aerobic and anaerobic) prior to antibiotics (if possible) ^[20][21]
    • See “Septic workup” for additional investigations that are typically included in initial studies.
• Initial management: Provide immediate hemodynamic support and respiratory support for unstable patients without delay.
  • Fluid resuscitation: Infuse 30 mL/kg of crystalloid fluid in 3 hours. ^[2][22]
  • Vasopressors for septic shock; : Administer if hypotension persists (during or after fluid resuscitation); target MAP ≥ 65 mm Hg. ^[2]
  • Antibiotics for sepsis: Begin empiric broad-spectrum or directed antibiotics within 1–3 hours. ^[2][22][23]
• Next steps
  • Continuous reassessment of hemodynamic parameters
  • Supportive care for sepsis.
  • Begin source control for sepsis.

Sepsis management is an iterative process requiring frequent reassessments. Favorable outcomes depend on early detection, effective resuscitation, and early administration of antibiotics. ^[2][17]

Hour-1 bundle for sepsis ^[2][20][22]

• Definition: a group of critical measures that should be performed within 60 minutes of recognizing patients with septic shock or a high pretest probability (PTP) of sepsis. ^[2][22][23]
• Five essential elements
  • Obtain serum lactate.
  • Draw blood cultures prior to antibiotic administration.
  • Begin rapid IV fluid bolus if MAP < 65 mm Hg or lactate ≥ 4 mmol/L.
  • Use vasopressors to keep MAP ≥ 65 mm Hg.
  • Administer broad-spectrum antibiotics. ^[2]

Hour-1 bundle: lactate + cultures + fluids + vasopressors + antibiotics

Disposition ^[2]

• Admit unstable patients with sepsis to the ICU within 6 hours.
• If available, consider using a critical care transition program for patients discharged from ICU to other hospital settings after stabilization.
• Consider transfer to a rehabilitation program upon hospital discharge for patients with the following:
  • Mechanical ventilation for > 48 hours
  • ICU stay > 72 hours

The main goals of the diagnostic workup in a patient with suspected sepsis are to determine the presence and severity of organ dysfunction and to identify the source of infection. See the “Definitions” section for diagnostic criteria. ^[1][4][22]

Positive cultures are not mandatory for the diagnosis of sepsis.

Sepsis screening tools ^[2][17]

• Goal: early identification of patients with sepsis to reduce mortality ^[2][24]
• Commonly used tools ^[24]
  • SIRS criteria ^[1][3]
  • Quick SOFA score (qSOFA) ^[25]
    • Can predict poor outcomes; not recommended as a sole screening tool for sepsis ^[2][26][27]
    • Considered positive if ≥ 2 of the following are present:
      • Altered mental status
      • Systolic blood pressure ≤ 100 mm Hg
      • Respiratory rate ≥ 22/min
• Limitations: Accuracy is low and can vary. ^[2][27][28]

The qSOFA score is not recommended as a sole screening tool for sepsis or septic shock. ^[2]

Laboratory studies

In addition to serum lactate and blood cultures (at least two sets), obtain the following studies to support the diagnosis and evaluate for organ dysfunction.

• CBC: variable findings
  • Leukocytosis or leukopenia
  • Thrombocytosis or thrombocytopenia
• CRP, procalcitonin: typically elevated ^[20]
• BMP and electrolytes
  • Renal function: ↑ BUN and ↑ creatinine
  • Glucose: hyperglycemia, hypoglycemia
  • Electrolyte derangements
• Liver chemistry and synthetic function tests: hyperbilirubinemia, ↑ INR, ↑ ALT, ↑ AST
• Coagulation panel, D dimer: ↑ prothrombin time, ↑ activated partial thromboplastin time, ↓ antithrombin III, ↑ D dimer may be present (see “Disseminated intravascular coagulation”)
• Consider amylase, lipase (if pancreatitis is suspected)
• Blood gas: to identify possible acid-base disturbances and assess oxygenation

Identifying the source of infection

Microbiology

• In addition to blood cultures, consider additional cultures guided by clinical judgment (see “Etiology”).
  • Urinalysis and urine culture (See “Urinary tract infection” and “Pyelonephritis”)
  • Sputum culture (See “Diagnosis of pneumonia”)
  • Consider also: CSF , wound secretion, tissue/fluid
• Diagnostic procedures as indicated to obtain samples for cultures (e.g., lumbar puncture, thoracentesis, paracentesis, arthrocentesis)
• Pan cultures are discouraged unless the source of infection is unclear. ^[20]

When possible, obtain the additional samples before starting antibiotic treatment, but do not delay antibiotics if samples are not rapidly available.

Imaging

Direct decisions based on clinical suspicion. Examples of commonly performed imaging include:

• Chest x-ray: if pneumonia is suspected and/or to determine if ARDS is present as a complication (see “Diagnosis of pneumonia”)
• Abdominal x-ray: if a perforation or obstruction is suspected (pneumoperitoneum, air-fluid levels)
• Ultrasound
  • Abdominal ultrasound: initial abdomen assessment in most cases (see “Diagnosis of acute abdominal pain”)
  • Soft tissue: initial assessment of cellulitis and, in most cases, soft tissue abscess (see “Skin and soft tissue infections”)
• CT scan: for a more detailed assessment of thoracic and abdominal/pelvic pathology
• Echocardiography: to identify valve vegetations (see “Infective endocarditis”)

See also “Immediate hemodynamic support” and “Septic shock.”

IV fluids ^[29][2]

• Initial fluid resuscitation: rapid infusion of 30 mL/kg crystalloid fluid ^[2][17]
  • Indication: sepsis-induced hypoperfusion or septic shock
  • Timing: Initiate immediately and complete within 3 hours.
• Ongoing IV fluid management ^[20]
  • Continuously reevaluate fluid responsiveness.
  • See “Hemodynamic reassessment in sepsis.”
  • Consider albumin if a large volume of crystalloid fluid has been given. ^[2]

Vasopressors for septic shock ^[2][23]

See “Septic shock” and “Vasopressors” for further details.

• Indication: persistent hypotension during or after fluid resuscitation
• Target: MAP ≥ 65 mm Hg ^[2]
• First line: norepinephrine ^[2]
• Second line: Consider adding vasopressin if hypotension persists with moderate doses of norepinephrine. ^[2]
• Third line: Consider adding epinephrine if hypotension persists despite norepinephrine AND vasopressin. ^[2]
• Refractory tissue hypoperfusion : Consider adding dobutamine OR switching to epinephrine alone. ^[2]

Consider starting vasopressor infusion through a peripheral IV to avoid delays while awaiting central venous access. ^[2]

Hemodynamic reassessment in sepsis ^{[2][17][23][30]}

Continuously monitor hemodynamic parameters and volume status to guide IV fluids and/or vasopressor therapy.

• Hemodynamic parameters ^[20][31]
  • Vital signs: mean arterial pressure, heart rate, respiratory rate
  • Clinical indicators of organ perfusion: capillary refill time, urine output, mental status
  • Biomarkers: serum lactate , base excess
  • Advanced monitoring: cardiac index and stroke volume, echocardiography
• Fluid responsiveness assessment ^[2]
  • Passive leg raise test
  • Fluid challenge
  • Consider adding IVC ultrasound. ^{[17][32][33][34]}
• Consider protocolized resuscitation targets.
  • Lactate-guided fluid resuscitation strategy
  • Early goal-directed therapy
  • Protocols targeting capillary refill time ≤ 3 seconds ^[2][30][35]

If possible, use invasive BP monitoring to facilitate continuous reassessment. ^[2]

Respiratory support ^[2][36][37]

Respiratory dysfunction is a common feature of sepsis. Patients with sepsis frequently have tachypnea, signs of increased work of breathing, and/or hypoxia.

• Start oxygen therapy as needed. ^[38]
• Secure the airway and assess for indications for invasive mechanical ventilation.
  • See “High-risk indications for mechanical ventilation.”
  • See “Hemodynamic compromise in mechanically ventilated patients.”
• Consider screening for ARDS to ensure early identification. ^[37]
  • See “Berlin criteria for ARDS.”
  • See “Lung-protective ventilation strategy.”

Shock and metabolic acidosis are both associated with a high risk of peri-intubation mortality. ^[4][39]

Corticosteroids ^[2][17]

• Administer stress dose corticosteroids to patients with risk factors for adrenal crisis.
• Consider adjuvant IV corticosteroids if there is an ongoing need for vasopressor therapy. ^[2]
• Typical agent: hydrocortisone ^[2]

Approach

• Begin broad-spectrum antibiotics as soon as possible after sepsis is identified, ideally after blood cultures have been drawn. ^[2]
  • Shock or probable sepsis : Administer antibiotics within 1 hour.
  • Possible sepsis and no shock: Initiate rapid investigation; administer antibiotics within 3 hours if concern for sepsis persists.
  • Low probability of sepsis and no shock: Do not start antibiotics; continue patient observation.
• Follow local antimicrobial stewardship guidelines.
  • Choose empiric therapy based on:
    • Source of infection
    • Local prevalence of common and resistant pathogens
    • Prior infections, immune status , and comorbidities
    • Presence of implanted devices (e.g., urinary catheter, central lines)
  • Narrow therapy once the pathogen and antibiogram have been identified. ^[4]
• Ensure source control for sepsis as early as possible.

Empiric antibiotic therapy for sepsis ^{[20][40][41][42][43]}

There is little consensus regarding the optimal empiric antibiotic regimens for patients with sepsis and septic shock, especially if the source of infection is unclear.

Evident source of infection ^[4]

If the source of infection is clear, follow local hospital protocols to administer antibiotics that cover the most common causative pathogens.

Unclear source of infection ^{[40][41][42][51]}

The following regimens are examples commonly mentioned in the literature; follow local hospital protocols when available.

Antifungal therapy ^[20]

• Risk factors for fungemia include:
  • Immunocompromised status (e.g., neutropenia, transplant, chemotherapy)
  • Indwelling vascular devices (e.g., hemodialysis catheters or central lines, TPN)
  • Prolonged antibiotic courses
• Consider empiric antifungals (in consultation with an ID specialist) for high-risk patients only, e.g., those with: ^[2]
  • Severe sepsis or septic shock
  • Recent treatment with other antifungals
  • Suspected resistant Candida species
• Treatment options
  • Echinocandins: e.g., micafungin , caspofungin , anidulafungin
  • Azoles: e.g., fluconazole , voriconazole
  • Liposomal formulations (if the patient can not tolerate echinocandins): e.g., amphotericin B

Source control for sepsis ^[2][23]

Identify and eliminate sources of infection that cannot be adequately treated with antimicrobials as soon as possible (e.g., within 6–12 hours). ^[2]

• Remove infected intravascular catheters or devices after replacement with an alternative.
• Arrange drainage of contained infections (e.g., abscesses, cholangitis) and/or surgical resection of infected tissue
• Consult the appropriate specialty for definitive treatment of the infectious source, e.g.:
  • Surgery for:
    • Acute abdomen (e.g., peritonitis due to GI perforation or ischemic bowel)
    • Most abscesses
    • Necrotic tissue (e.g., necrotizing fasciitis)
    • Infected implanted devices
  • Interventional radiology for:
    • Nephrostomy or drain placement in obstructive pyelonephritis
    • Percutaneous drainage of intrathoracic or intraperitoneal abscess

• Fluids, nutrition, and electrolytes ^[20][42]
  • Maintenance fluids: Consider after initial fluid therapy for stable patients at risk of hypovolemia.
    • Aim for euvolemia.
    • See “Clinical signs of fluid balance” for details.
  • Bowel rest or enteral feeds: indication depends on the source of infection and level of consciousness
  • Electrolyte repletion
• Transfusions: Consider as needed. ^[20][42]
  • pRBCs for the following hemoglobin thresholds:
    • < 7 g/dL in all patients
    • < 10 g/dL in patients with cardiac ischemia, severe hypoxemia, or severe bleeding
  • Platelets for the following platelet count thresholds:
    • < 10,000/mm³ in all patients
    • < 20,000/mm³ in patients with a high risk of bleeding
    • < 50,000/mm³ in patients with active bleeding or planned surgery or invasive procedure
  • FFP to correct coagulopathy in patients with active bleeding or a planned invasive procedure
• Other supportive measures ^[20][42]
  • Normoglycemia: insulin as needed for target glucose of 140–180 mg/dL (see “Inpatient management of hyperglycemia”)
  • VTE prophylaxis with LMWH if there are no contraindications ^[2]
  • Stress ulcer prophylaxis in patients with risk factors for GI bleeding ^[2]
  • Renal replacement therapy (RRT) in patients with absolute indications for RRT ^[2]

• Use a sepsis screening tool (e.g., SIRS criteria) in at-risk patients.
• Obtain IV access and blood samples including 2 sets of blood cultures and serum lactate.
• Begin continuous cardiac and respiratory monitoring.
• Consider invasive BP monitoring and central venous line insertion if septic shock is present.
• Initiate fluid resuscitation with 30 mL/kg of crystalloid fluid.
• Add vasopressors if shock persists despite adequate fluid resuscitation.
• Provide respiratory support as needed.
• Start empiric broad-spectrum antibiotic therapy (within 1 hour for septic shock or high PTP of sepsis).
• Conduct frequent reassessments, e.g., hemodynamic parameters, serial serum lactate, fluid balance monitoring
• Consult ICU early.
• Complete evaluation for organ dysfunction, e.g., CBC, BMP, liver chemistries, blood gas, coagulation panel
• Consider additional imaging and cultures (urine, wound, sputum) based on clinical suspicion.
• Arrange source control for sepsis, e.g., remove infected intravascular catheters, consult surgery for acute abdomen
• Start supportive care, e.g., maintenance of normoglycemia, nutritional support, VTE prophylaxis
• Identify and treat complications, e.g., DIC, ARDS, AKI
• Admit to critical care unit.

The following is a list of noninfectious conditions that may mimic sepsis. ^[4][23]

• Other causes of hypotension/shock
  • Hypovolemic shock
  • Dehydration
  • Acute anemia, blood loss (e.g., due to trauma, GI bleeding)
  • See “Shock” for more details.
• Cardiovascular diagnoses
  • Congestive heart failure
  • Cardiac contusion (trauma)
  • Myocardial infarction
  • Cardiogenic shock
  • Tamponade
• Respiratory diagnoses
  • Acute respiratory distress syndrome
  • Tension pneumothorax
  • Pulmonary embolism
• Toxicological
  • Poisoning
  • Overdose/withdrawal
  • Drug-induced symptoms
  • Neuroleptic malignant syndrome
• Miscellaneous
  • Pancreatitis
  • Disseminated intravascular coagulation
  • Vasculitis
  • Anaphylaxis
  • Hyperthyroidism and thyroid storm
  • Diabetic ketoacidosis
  • Hypothalamic injury
  • Adrenal dysfunction

• Common complications ^[43]
  • Acute respiratory distress syndrome
  • Acute kidney injury
  • Diffuse intravascular coagulopathy
  • Acute liver failure
  • Myocardial dysfunction, e.g., cardiomyopathy, acute coronary syndrome
  • Multiple organ failure
• Critical illness polyneuropathy ^[53]
  • Definition: axonal injury, particularly to the motor neurons, as a sequela of sepsis and multiple organ dysfunction
  • Clinical features
    • Predominantly distal, symmetrical, flaccid paralysis of the extremities with muscle atrophy; may affect the diaphragm
    • Absent or reduced reflexes
    • Dysesthesias in a glove-and-stocking distribution may be present
    • Preservation of cranial nerve function
    • May be associated with critical illness myopathy : flaccid quadriparesis (proximal > distal); facial muscle weakness, sensation normal, tendon reflexes normal or ↑
  • Diagnosis: typical clinical features, sepsis, and electrophysiological evidence of motor and sensory neuropathy
    • Electromyography (EMG): spontaneous activity (e.g., fibrillations)
    • Nerve conduction studies: normal velocity, reduced amplitude
  • Treatment: no specific treatment available, usually gradual spontaneous resolution (weeks to months)

Critical illness polyneuropathy is a common cause of prolonged weaning from mechanical ventilation in patients with sepsis.

We list the most important complications. The selection is not exhaustive.

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