Sepsis

Sepsis is an acute life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. Some patients progress to failure in the physiologic function of several organs and systems (multiple organ dysfunction syndrome) or septic shock, in which specific circulatory and metabolic abnormalities are present (i.e., hypotension and elevated lactate despite fluids). Initial infection is generally bacterial, with the most common origins being the respiratory, genitourinary, gastrointestinal, and dermatological systems or soft tissue. Patients can present with fever, tachycardia, confusion, and signs of the primary infection. The quick SOFA score may be used to identify patients with sepsis. Outcomes depend on early detection (obtaining blood cultures and measuring lactate), effective resuscitation measures (fluids and vasopressors), and early administration of antibiotics. Once the patient is stable, the diagnostic workup consists of identifying the source of infection and responsible pathogen in order to provide specific treatment and control the source of infection.

Definitions and criteria in this section apply to adult patients.

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

• 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 MAP ≥ 65 mm Hg.
    • Persistent lactic acidosis: lactate > 2 mmol/L (18 mg/dL) despite adequate fluid resuscitation

Other definitions of sepsis syndromes ^{[1][2][3][4][5]}

• Systemic inflammatory response syndrome (SIRS criteria): a constellation of physiological and immune-mediated reactions of the body to an infection or noninfectious insult (e.g., an acute inflammatory process or trauma) ^[1][2]
  • At least 2 of the following 4 criteria are required to define SIRS:
    • 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 or < 4,000/mm³ or > 10% immature bands
• Sepsis: 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)
  • Progressive and potentially reversible failure in the physiologic function of several organs and/or systems ^[6]
  • The more organs that are affected, the greater the mortality risk
• Bacteremia: the presence of bacteria in the bloodstream, confirmed on blood cultures ^[3]

Sequential organ failure assessment score (SOFA score) ^[1][7]

• Used in critical care settings as a tool to identify organ failure and predict mortality
• The score should be calculated after 24 hours of ICU admission and then every 48 hours.
• Should not be used to diagnose sepsis

The SOFA score is not designed to diagnose sepsis.

• 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, alcoholism)
  • 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!

• Fever , chills, and diaphoresis
• Tachycardia
• Tachypnea
• 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)
• Additionally in septic shock
  • Hypotension (MAP < 65 mm Hg)
  • Initially warm skin and normal capillary refill time (warm shock) → cold cyanotic, pale, or mottled skin with prolonged capillary refill time (cold shock)
• Features of the primary infection
• Generalized edema (capillary leak)

Diagnostic and treatment measures should be conducted simultaneously in a patient suspected of having sepsis. Success depends on early detection, early and effective resuscitation, and early antibiotic therapy.

Sepsis is a medical emergency and clinicians should have a high index of suspicion.

Approach

1. Sepsis surveillance: Identify patients with potential sepsis.
   • Quick SOFA criteria : ^[1]
     • Consider positive if ≥ 2 of the following are present:
       • Alteration in mental status
       • Systolic blood pressure ≤ 100 mm Hg
       • Respiratory rate ≥ 22/min
   • The SIRS criteria also commonly still used to identify patients at risk of sepsis.
2. Initial clinical evaluation (should follow ABCDE approach)
   • IV access, vital signs, monitor
   • Initial labs
     • Serum lactate: Elevated lactate reflects hypoperfusion and is associated with worse outcomes. ^[7][17]
     • 2 sets of blood cultures (aerobic and anaerobic) before administering antibiotics (if possible) ^[7][18]
     • Additional serum for further laboratory studies may be obtained at this time (see “Diagnostics”).
   • If there is any concern for septic shock and/or respiratory failure or airway compromise: Provide immediate hemodynamic and respiratory support (See “Vasopressors for septic shock”).
3. Initial resuscitation and ongoing clinical reassessment
   • Provide hemodynamic support.
     • Fluid resuscitation: Administer 30 mL/kg (minimum) of crystalloid fluids (see “Initial resuscitation” section). ^[19]
     • If there is persistent hypotension; during or after fluid resuscitation, start vasopressors and titrate to maintain a MAP ≥ 65 mm Hg. (see “Vasopressors for septic shock”).
   • Start empiric broad-spectrum antibiotics (see “Antibiotic therapy for sepsis”). ^[20]
   • Continuous reassessment of the clinical response to resuscitation to guide the decision to escalate fluids or pressors
4. Supportive care

Initial resuscitation includes IV access, fluid resuscitation (and potentially vasopressor support), and broad-spectrum antibiotics.

2018 Surviving Sepsis Campaign recommendations for initial management ^[7]

• Hour-1 bundle for sepsis
  • Initially proposed for all patients with sepsis, but this recommendation is somewhat controversial ^[20]
  • Five measures to start within the first hour of recognizing sepsis: ^[19][20]
    • Blood cultures
    • Serum lactate
    • IV fluids
    • Vasopressors
    • Antibiotics

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

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 “Definitions” section for diagnostic criteria. ^[1][3][19]

Positive cultures are not mandatory for the diagnosis of sepsis.

Laboratory studies

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

• CBC: variable findings
  • Leukocytosis or leukopenia
  • Thrombocytosis or thrombocytopenia
• CRP, procalcitonin: typically elevated ^[7]
• 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. ^[7]

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”)

IV fluids

• Initial resuscitation: rapid crystalloid infusion of 30 mL/kg ^[7][19]
  • Indications: sepsis and/or signs of hypoperfusion are present (e.g., hypotension, elevated lactate) ^[7]
  • Start immediately (within the first hour of presentation) and complete within 3 hours.
  • There is no benefit of colloids over crystalloids for most patients.
  • See also “IV fluids” for more details regarding fluid options.
• Additional fluids: The decision to give additional fluids should be informed by fluid responsiveness (see “Clinical reassessment” below) There is no unified consensus on an ideal fluid resuscitation strategy for patients with sepsis after the initial administration of crystalloids. ^[7]

Clinical reassessment ^{[7][19][20][21][22]}

Hemodynamic and perfusion status should be continually reassessed to determine whether additional fluids are indicated (i.e., whether the patient is fluid responsive or not) or hemodynamic support should be escalated (i.e., whether vasopressor support is needed).

Clinical reassessment should be a continuous and iterative process throughout the resuscitation process.

Options for assessing perfusion status ^[7][23]

• Mean arterial pressure (MAP)
• Clinical parameters: e.g., heart rate, urine output, capillary refill, signs of poor peripheral perfusion
• Invasive vascular monitoring
  • Central venous access (e.g., CVP, PCWP): Consider for shock refractory to initial therapy or requiring vasopressors. ^[23]
  • Arterial catheters: recommended for all patients receiving vasopressor medication
• Biomarkers: serum lactate , base excess
• Cardiac function monitoring: devices that measure cardiac index, echocardiography

Available strategies and goals ^[7][19][22]

• Lactate-guided fluid resuscitation strategy ^[19][22]
  • If initial lactate level is elevated (> 2 mmol/L), remeasure every 2–4 hours until normalized.
  • Treatment target: ↓ 20% in serum lactate every 2–4 hours until normal
    • Down-trending lactate: Continue fluid resuscitation until normalized.
    • Persistent hypotension and/or lactate does not decrease as expected: aggressive fluid resuscitation and consider adding vasopressors (see “Resuscitation of septic shock”)
  • Disadvantages ^[20][22]
    • Elevated lactate is not specific to sepsis.
    • This strategy may lead to fluid overload.
• Early goal-directed therapy (EGDT) ^[7]
  • Treatment targets
    • CVP ≥ 8 cm H₂O ^[7]
    • Central venous O₂ saturation ≥ 70%
• MAP treatment target: ≥ 65 mm Hg

6–10 L of IV fluids may be necessary during the first 24 hours. ^[3]

Vasopressors for septic shock ^{[7][19][20][21][22]}

• Indications: persistent hypotension during or after fluid resuscitation
• Goal: maintain MAP ≥ 65 mm Hg ^[7]
• Stepwise escalation
  • First-line: norepinephrine
  • If MAP is still low after norepinephrine:
    • Add vasopressin
    • OR add continuous IV epinephrine infusion (off-label)
  • To decrease norepinephrine dosage: add vasopressin
• Additional options
  • Dopamine
    • Indicated as an alternative vasopressor in select cases (e.g., low risk of tachyarrhythmia, bradycardia) ^[7]
    • Should not be used for renal protection ^[7]
  • Dobutamine : Consider for hypoperfusion that persists despite fluids and initial vasopressors. ^[7]
• See “Vasopressors” for more recommendations.

Respiratory support

• Address hypoxemia if present: Secure airway and start oxygen therapy as needed.
• Consider mechanical ventilation (see “Indications for invasive mechanical ventilation”).
  • See “High-risk indications for mechanical ventilation.”
  • See “Hemodynamic compromise in mechanically ventilated patients.”
• Maintain a high index of suspicion for ARDS to ensure early identification (see “Berlin criteria for ARDS”).

Corticosteroids ^[7][25]

• E.g., hydrocortisone
• Consider as adjuvant therapy if hypotension is refractory to the first vasopressor.
• Consider for patients with suspected adrenal insufficiency or patients taking long-term steroids.

General recommendations

• Broad-spectrum antibiotics are part of the hour-1 bundle and should be started early (ideally as soon as possible after blood cultures have been drawn).
• Choice of empiric antimicrobial therapy should be guided by:
  • Source of infection
  • Local prevalence of common and resistant pathogens
  • Prior infections, immune status , and patient comorbidities
  • Presence of implanted devices (e.g., urinary catheter, central lines)
• Therapy should be narrowed once the pathogen is identified. ^[3]
• Control the source of infection as early as possible.

Antibiotic therapy for sepsis ^{[7][21][25][26][27]}

There is no consensus regarding empiric antibiotic regimens for patients with sepsis and septic shock, especially when the source of infection is unclear. The regimens mentioned here are examples commonly mentioned in the literature.

Evident source of infection ^[3]

• Start antibiotics effective against common pathogens of the source.
• Some common infections responsible for sepsis include:
  • Pneumonia: See “Treatment of pneumonia.”
  • Pyelonephritis: See “Empiric antibiotic therapy for complicated pyelonephritis.”
  • Intraabdominal infection: See “Empiric antibiotic therapy for intraabdominal infections.”

Unclear source of infection ^{[21][25][26][28]}

Antifungal therapy ^[7]

• Risk factors for fungal infections include:
  • Immunocompromised status (e.g., neutropenia, transplant, chemotherapy)
  • Indwelling vascular devices (e.g., hemodialysis catheters or central lines, TPN)
  • Prolonged antibiotic courses
• Indications: severe illness, septic shock, recently treated with other antifungal agents, suspicion of resistant Candida species
• The decision to start empiric antifungals should be made with infectious disease specialists.
• Treatment options
  • Echinocandins: e.g., micafungin , caspofungin , anidulafungin
  • Azoles: e.g., fluconazole , voriconazole
  • Liposomal formulations (if intolerance to echinocandins): e.g., amphotericin B

Source control ^[7][20]

• Ideally, specific measures to control the source of infection should take place a maximum of 6–12 hours after the diagnosis is made.
• Examples
  • Abscess drainage
  • Debridement of infected necrotic tissue (e.g., necrotizing fasciitis)
  • Removal of infected devices
  • Operative management of surgical pathologies (e.g., intraabdominal abscess, gastrointestinal perforation, ischemic bowel, volvulus, cholecystitis, cholangitis)
  • Nephrostomy/drain placement in obstructive pyelonephritis/abscess

• Fluids, nutrition, and electrolytes ^[7][25]
  • Maintenance fluids: Consider after initial fluid therapy for stable patients at risk of hypovolemia.
    • Aim for a neutral fluid balance.
    • See “Intravenous fluid therapy” for further details.
  • Bowel rest or enteral feeds: indication depends on the source of infection and level of consciousness
  • Electrolyte repletion
  • Normoglycemia: insulin as needed for target glucose of 140–180 mg/dL (see “Inpatient management of hyperglycemia”)
• Transfusions: to consider as needed ^[7][25]
  • 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 a planned surgery/invasive procedure
  • FFP to correct coagulopathy in patients with active bleeding or a planned invasive procedure
• Other supportive measures ^[7][25]
  • VTE prophylaxis
  • Renal replacement therapy: e.g., for patients with concomitant severe acute kidney injury
  • Stress ulcer prophylaxis: on a case-by-case basis

• Use the qSOFA score for early recognition of sepsis.
• Establish IV access, continuous monitoring, and draw initial laboratory studies.
  • At least 2 sets of blood cultures
  • Serum lactate
  • Samples for additional laboratory studies
• Identify patients with septic shock (e.g., hypotension, elevated lactate).
• Begin resuscitation measures.
  • Initial fluid resuscitation with 30 mL/kg of crystalloid.
  • Add vasopressors if shock persists despite adequate fluid resuscitation.
  • Provide respiratory support as needed.
  • Consider the need for central venous access.
• Start empiric broad-spectrum antimicrobial therapy (ideally within the first hour).
• Continue diagnostic evaluation.
  • Organ dysfunction screening: e.g., CBC, BMP, liver chemistries, blood gas, coagulation panel, D-dimer
  • Infectious source identification: e.g., additional cultures , imaging
  • Evaluation for complications (e.g., DIC, ARDS)
• Consult ICU early.
• Consider interventions for infectious source control.
• Supportive care (e.g., normoglycemia, nutritional support, VTE prophylaxis)
• Conduct frequent clinical reassessments.

The following is a list of noninfectious conditions that may mimic sepsis. ^[3][20]

• 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

• Critical illness polyneuropathy
  • 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 a patient with sepsis!
References:^[30]

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

• One-Minute Telegram 8-2020-2/3: Should a cocktail of vitamin C, thiamine, and hydrocortisone be given to all patients with septic shock?
• One-Minute Telegram 3-2020-2/3: If they’re septic and you know it … raise their legs?

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