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 
- 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 
- Septic shock: a sepsis syndrome accompanied by circulatory and metabolic abnormalities that can significantly increase mortality 
Other definitions of sepsis syndromes 
- 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) 
- Sepsis: SIRS criteria PLUS a suspected or confirmed underlying infection 
- Severe sepsis: sepsis PLUS dysfunction of at least one organ or system 
Multiple organ dysfunction syndrome (MODS)
- Progressive and potentially reversible failure in the physiologic function of several organs and/or systems 
- The more organs that are affected, the greater the mortality risk
- Bacteremia: the presence of bacteria in the bloodstream, confirmed on blood cultures 
Sequential organ failure assessment score (SOFA score) 
- 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
|SOFA score |
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Platelets x 103/mm3
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Glasgow Coma Scale
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The SOFA score is not designed to diagnose sepsis.
- Common sources of sepsis: 
- 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. 
Sepsis is a hyperinflammatory systemic reaction.
- Local activation of inflammatory mediators (complement system, mast cells, macrophages) results in vessel dilation and further release of proinflammatory cytokines (esp. TNFα, IL-1).
- Generalized endothelial disruption → capillary leak → generalized edema due to a shift of intravascular fluid and albumin into the surrounding tissue
- Intravascular hypovolemia → excessive triggering of the extrinsic coagulation cascade → disseminated intravascular coagulation (DIC) and microvascular thrombosis
- 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
- Features of organ dysfunction (see )
- Additionally in septic 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.
- Sepsis surveillance: Identify patients with potential sepsis.
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. 
- 2 sets of blood cultures (aerobic and anaerobic) before administering antibiotics (if possible) 
- 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”).
Initial resuscitation and ongoing clinical reassessment
- Provide hemodynamic support.
- Fluid resuscitation: Many patients may benefit from around 30 mL/kg of crystalloid fluids (see “Initial resuscitation” section). 
- 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”). 
- Continuous reassessment of the clinical response to resuscitation to guide the decision to escalate fluids or pressors
- Provide hemodynamic support.
- Supportive care
2018 Surviving Sepsis Campaign recommendations for initial management 
- Hour-1 bundle for sepsis
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. 
Positive cultures are not mandatory for the diagnosis of sepsis.
- CBC: variable findings
- CRP, procalcitonin: typically elevated 
- BMP and electrolytes
- 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
- In addition to blood cultures, consider additional cultures guided by clinical judgment (see “Etiology”).
- 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. 
When possible, obtain the additional samples before starting antibiotic treatment, but DO NOT DELAY ANTIBIOTICS if samples are not rapidly available.
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)
- CT scan: for a more detailed assessment of thoracic and abdominal/pelvic pathology
- Echocardiography: to identify valve vegetations (see “Infective endocarditis”)
Initial resuscitation and clinical reassessment
IV fluids 
Initial resuscitation: rapid crystalloid infusion of 30 mL/kg
- Indications: sepsis and/or signs of hypoperfusion are present (e.g., hypotension, elevated lactate) 
- 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 
6–10 L of IV fluids may be necessary during the first 24 hours. 
Clinical reassessment 
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).
- Vital signs: e.g., mean arterial pressure (MAP), heart rate
- Other clinical parameters: e.g.,urine output, capillary refill, signs of poor peripheral perfusion
- Consider invasive vascular monitoring (if vasopressors are used).
- Biomarkers: e.g., serum lactate , base excess
- Cardiac function monitoring: e.g., devices that measure cardiac index, echocardiography
Consider protocolized resuscitation targets
Clinical reassessment should be a continuous and iterative process throughout the resuscitation process.
Vasopressors for septic shock 
- Indication: : persistent hypotension during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg 
- First-line: norepinephrine
- Second-line: if MAP persistently low
- Third-line: consider as alternate vasopressors in select cases , or as an additional vasopressor for refractory tissue hypoperfusion. 
- Address hypoxemia if present: Secure airway and start oxygen therapy as needed.
- Consider mechanical ventilation (see “ ”).
- Maintain a high index of suspicion for ARDS to ensure early identification (see “Berlin criteria for ARDS”).
- 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:
- Therapy should be narrowed once the pathogen is identified. 
- Control the source of infection as early as possible.
Antibiotic therapy for sepsis 
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 
- Start antibiotics effective against common pathogens of the source.
- Some common infections responsible for sepsis include:
Unclear source of infection 
|Empiric antibiotic regimens for sepsis with unclear source|
|Patient characteristics||Commonly used regimens|
Unknown risk factors
At risk for specific pathogens
Antifungal therapy 
- Risk factors for fungal infections include:
- 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
Source control 
- Ideally, specific measures to control the source of infection should take place a maximum of 6–12 hours after the diagnosis is made.
- 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 
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”)
- Maintenance fluids: Consider after initial fluid therapy for stable patients at risk of hypovolemia.
Transfusions: to consider as needed 
- pRBCs for the following hemoglobin thresholds:
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 
- Use the qSOFA score for early recognition of sepsis.
- Establish IV access, continuous monitoring, and draw initial laboratory studies.
- Identify patients with septic shock (e.g., hypotension, elevated lactate).
- Begin resuscitation measures.
- Start empiric broad-spectrum antimicrobial therapy (ideally within the first hour).
- Continue diagnostic evaluation.
- 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. 
- Other causes of hypotension/shock
- Cardiovascular diagnoses
- Respiratory diagnoses
Critical illness polyneuropathy
- Definition: axonal injury, particularly to the motor neurons, as a sequela of sepsis and multiple organ dysfunction
- 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
- Treatment: no specific treatment available, usually gradual spontaneous resolution (weeks to months)
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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