Sepsis

Sepsis is an acute life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. The previously widely used term “systemic inflammatory response syndrome” (SIRS) is now considered outdated because its criteria were too simplified. Initial infection is generally bacterial and commonly of respiratory, genitourinary, gastrointestinal, dermatological, or soft tissue origin. Risk factors include immunocompromise, chronic comorbidities (e.g., diabetes mellitus), young or old age, and lengthy or invasive medical care. Patients may present with fever, tachycardia, confusion, and signs of the primary infection. Organ dysfunction is determined using a sequential organ failure assessment (SOFA) score that considers multiple parameters, but may be quickly evaluated and assumed if two of the following findings are present: tachypnea, hypotension, and altered mental status. Diagnostic workup focuses on determining the responsible pathogen via cultures and identifying the source of infection (e.g., via imaging, ECG, lumbar puncture). Laboratory findings are largely nonspecific. Prompt, aggressive treatment is vital to survival and consists of resuscitation, empiric antibiotic therapy, and control of the infectious source.

2015 criteria and SOFA classification (The third international consensus definitions for sepsis and septic shock, Sepsis-3)

• Sepsis: acute and life-threatening organ dysfunction due to abnormal host response to infection
  • Organ dysfunction: an acute change in total SOFA score ≥ 2 points
  • Infection: may be confirmed (via culture) or suspected
• Septic shock consists of the following parameters:
  • Sepsis +
  • Significant circulatory, metabolic, and cellular abnormalities +
  • Requiring vasopressor therapy to maintain a mean blood pressure of ≥ 65 mmHg and presence of increased lactate levels > 2 mmol/L (18 mg/dL) in the absence of hypovolemia
• The term “severe sepsis” is no longer used
• Quick SOFA criteria (qSOFA): to predict mortality in adult patients with suspected infection outside of the ICU (e.g., ward, emergency unit, or prior to hospitalization)
  • Positive if ≥ 2 of the following are present:
    • Altered mental status (Glasgow Coma Scale < 15) ^[8]
    • Respiratory rate: ≥ 22 breaths per minute
    • Systolic BP: ≤ 100 mmHg
  • If positive then the patient should be assessed for organ dysfunction via the SOFA score.

Sequential Organ Failure Assessment score (SOFA score) ^[8][9]

Organ dysfunction and score	0	1	2	3	4
Respiration PaO2/FiO2 (mmHg)	≥ 400	< 400	< 300	< 200 with respiratory support	< 100 with respiratory support
Coagulation Platelets x 103/mm3	≥ 150	< 150	< 100	< 50	< 20
Liver Bilirubin (mg/dL)	< 1.2	1.2–1.9	2.0–5.9	6.0–11.9	> 12.0
Cardiovascular system	MAP ≥ 70 mmHg	MAP < 70 mmHg	Dopamine < 5, or dobutamine (any dose)*	Dopamine > 5.1–15, or epinephrine ≤ 0.1, or norepinephrine ≤ 0.1*	Dopamine > 15, or epinephrine > 0.1, or norepinephrine > 0.1*
Central nervous system Glasgow Coma Scale	15	13–14	10–12	6–9	< 6
Renal system Creatinine (mg/dL) or urine output (mL/d)	< 1.2	1.2–1.9	2.0–3.4	3.5–4.9 or < 500	> 5.0 or < 200
Abbreviations: PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen; MAP = mean arterial blood pressure * Catecholamine doses are administered as μg/kg /min for ≥ 1 hour

References:^{[3][10][8][11][12][13]}

• Sepsis is the state of 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 (anti-infectious) and anti-inflammatory signals!

• Patients typically present with a poor overall condition and generalized edema (capillary leak).
• 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
  • Severe hypotension (< 65 mmHg) requiring vasopressor therapy despite normovolemia/adequate fluid therapy
  • 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

Origin	Example of infection	Characteristic features
CNS	Meningitis	Meningism, altered mental status, photophobia
Respiratory	Pneumonia	Cough, tachypnea, dyspnea, pleuritic chest pain, crackles, bronchial breath sounds
Cardiac	Endocarditis	New heart murmur
Abdominal	Any cause of acute abdomen (e.g., appendicitis)	Abdominal pain, peritonism, possible distension, vomiting
Pelvic	Pelvic inflammatory disease	Cervical motion tenderness, abnormal vaginal discharge
Urinary	Pyelonephritis, Urosepsis	Dysuria, frequency, flank pain
Bone	Osteomyelitis	Local pain (possibly exacerbated with movement), tenderness, warmth, erythema
Soft tissue	Abscess	Local warmth, erythema, tenderness with firm or fluctuant swelling (possibly indurated or draining pus) Possible foreign body at the site of inflammation

References:^[1][2][14]

• Immediate resuscitation (respiratory and circulatory support)
  • Intubation and mechanical ventilation may be required if the following is present: respiratory insufficiency, dyspnea, persistent hypotension, or poor peripheral perfusion
  • Fluid resuscitation (hypotension and hypoperfusion)
    • Initial volume resuscitation: crystalloid fluids, e.g., 0.9% sodium chloride or lactated Ringer's solution in rapidly infused boluses (500–1000 ml)
    • The use of colloid fluids is the subject of ongoing debate, e.g., HES (300–500 ml)
    • Vasopressors (catecholamines) may be necessary when patients remain hypotensive despite fluid resuscitation (e.g., norepinephrine)
• Empiric antibiotic treatment: begin immediately after blood cultures have been drawn, preferably within 1 hour after recognition
  • Antibiotic regimen should initially be very broad, considering the primary infectious focus (lungs, urinary tract, etc.) as well as the local rates of resistance
  • Treat for MRSA until ruled out: vancomycin or linezolid/daptomycin in combination with either:
    • Piperacillin/tazobactam, cefepime, or carbapenems if Pseudomonas infection is likely
    • 3^rd generation cephalosporin (e.g., ceftriaxone or cefotaxime) if Pseudomonas infection is unlikely
  • Antifungal treatment in cases of documented fungemia (not routinely used)
  • The clinical course or laboratory tests may require escalation of the antibiotic regimen
• Control infectious source
  • Remove any foreign bodies
  • Surgically drain abscesses or perform debridement on infectious wounds
  • Manage any complications of surgery (e.g., ileus, peritonitis, anastomotic insufficiency, osteomyelitis)
• Reassess the success of the therapeutic management every 48–72 hours based on clinical presentation and diagnostic parameters
• Other therapy considerations
  • Glucocorticoids; (e.g., prednisone or dexamethasone): if there is an increased risk of cerebral edema
  • Insulin-based control of blood glucose levels: control of stress-induced hyperglycemia results in a shorter length of stay in the ICU, even in non-diabetic patients.

In addition to immediate resuscitation and empiric therapy, the infectious focus must be identified and treated!
References:^{[15][1][2][17][18]}

• 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 and sepsis AND
    • Electrophysiological evidence of motor and sensory neuropathy
      • Nerve conduction studies: normal velocity, reduced amplitude
      • Electromyography (EMG): spontaneous activity (e.g., fibrillations)
  • 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:^[19]

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