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]

o 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]

o 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 PaCO  < 32 mm Hg 2

 White blood cell count > 12,000/mm  or < 4,000/mm  or > 3 3

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) 
o Progressive and potentially reversible failure in the physiologic function of
several organs and/or systems  [6]

o 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
Etiology

 Common sources of sepsis:  [1][9]

o Respiratory: pneumonia (most common cause of sepsis)

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

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!

Clinical features

 Fever ,chills, and diaphoresis
 Tachycardia
 Tachypnea
 Features of organ dysfunction (see SOFA score)
o CNS impairment: altered mental status
o Cardiovascular failure: hypotension
o Coagulopathy → disseminated intravascular
coagulation → petechiae, purpura
o Liver failure: jaundice
o Kidney failure: oliguria
o Respiratory failure: symptoms of acute respiratory distress
syndrome (ARDS) 
 Additionally in septic shock
o Hypotension (MAP < 65 mm Hg)
o 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) 

Management
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.
o 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
o The SIRS criteria also commonly still used to identify patients at risk of
sepsis.
2. Initial clinical evaluation (should follow ABCDE approach)
o IV access, vital signs, monitor
o 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”).
o 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
o Provide hemodynamic support.
 Fluid resuscitation: Many patients may benefit from around 30
mL/kg 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”).
o Start empiric broad-spectrum antibiotics (see “Antibiotic therapy for
sepsis”).  [20]

o 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

o Initially proposed for all patients with sepsis, but this recommendation
is somewhat controversial   [20]

o 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

Diagnosis
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

o Leukocytosis or leukopenia
o Thrombocytosis or thrombocytopenia
 CRP, procalcitonin: typically elevated  [7]
 BMP and electrolytes
o Renal function: ↑ BUN and ↑ creatinine
o Glucose: hyperglycemia, hypoglycemia 
o 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”).
o Urinalysis and urine culture (See “Urinary tract infection” and
“Pyelonephritis”)
o Sputum culture (See “Diagnosis of pneumonia”)
o 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
o Abdominal ultrasound: initial abdomen assessment in most cases (see
“Diagnosis of acute abdominal pain”)
o 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”)
Initial resuscitation and clinical reassessment
See also “Immediate hemodynamic support” and “Septic shock”.

IV fluids   [7][19][21]

 Initial resuscitation: rapid crystalloid infusion of 30 mL/kg

 o Indications: sepsis and/or signs of hypoperfusion are present (e.g., hypotension,
elevated lactate)  [7]

o Start immediately (within the first hour of presentation) and complete

within 3 hours.
o There is no benefit of colloids over crystalloids for most patients.
o See also “IV fluids” for more details regarding fluid options.
 Additional fluids: The decision to give additional fluids should be informed by fluid
responsiveness   [7]

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

Clinical reassessment  [7][19][20][22][23]

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).

 Monitor hemodynamic parameters  [7][24]
o Vital signs: e.g., mean arterial pressure (MAP), heart rate
o Other clinical parameters: e.g.,urine output, capillary refill, signs of poor peripheral
perfusion
o Consider invasive vascular monitoring (if vasopressors are used). 
o Biomarkers: e.g., serum lactate , base excess
o Cardiac function monitoring: e.g., devices that measure cardiac
index, echocardiography
 Consider protocolized resuscitation targets
o Lactate guided fluid resuscitation strategy
o Early goal-directed therapy
Clinical reassessment should be a continuous and iterative process throughout the resuscitation
process.

Vasopressors for septic shock   [7][19][20][22][23]

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

 Indication: persistent hypotension during or after fluid resuscitation to maintain MAP ≥ 65 mm

Hg  [7]

 First-line: norepinephrine 
 Second-line: if MAP persistently low
o Add vasopressin 
 o OR add continuous IV epinephrine infusion (off-label)  
 Third-line: consider as alternate vasopressors in select cases , or as an
additional vasopressor for refractory tissue hypoperfusion.  [7]

o Dopamine    [7]

o Dobutamine 

Respiratory support
 Address hypoxemia if present: Secure airway and start oxygen therapy as needed.
 Consider mechanical ventilation (see “Indications for invasive mechanical ventilation”).
o See “High-risk indications for mechanical ventilation.”
o See “Hemodynamic compromise in mechanically ventilated patients.”
 Maintain a high index of suspicion for ARDS to ensure early identification (see “Berlin criteria for
ARDS”).
Shock and metabolic acidosis are both associated with a high risk of peri-intubation mortality.  [3][25]

Corticosteroids  [7][26]

 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.
Infection control

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:
o Source of infection 
o Local prevalence of common and resistant pathogens
o Prior infections, immune status , and patient comorbidities 
o 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][22][26][27][28]

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:
o Pneumonia: See “Treatment of pneumonia.”
o Pyelonephritis: See “Empiric antibiotic therapy for complicated
pyelonephritis.”
o Intraabdominal infection: See “Empiric antibiotic therapy for intraabdominal
infections.”

Unclear source of infection  [22][26][27][29]

Antifungal therapy  [7]

 Risk factors for fungal infections include:

o Immunocompromised status (e.g., neutropenia, transplant, chemotherapy)
o Indwelling vascular devices (e.g., hemodialysis catheters or central lines, TPN)
o 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
o Echinocandins: e.g., micafungin , caspofungin , anidulafungin 
o Azoles: e.g., fluconazole , voriconazole 
o 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
o Abscess drainage
o Debridement of infected necrotic tissue (e.g., necrotizing fasciitis)
o Removal of infected devices 
o Operative management of surgical pathologies (e.g.,
intraabdominal abscess, gastrointestinal
perforation, ischemic bowel, volvulus, cholecystitis, cholangitis)
o Nephrostomy/drain placement in obstructive pyelonephritis/abscess
Supportive therapy
 Fluids, nutrition, and electrolytes  [7][26]

o 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.
o Bowel rest or enteral feeds: indication depends on the source of infection
and level of consciousness
o Electrolyte repletion
 o Normoglycemia: insulin as needed for target glucose of 140–180 mg/dL (see
“Inpatient management of hyperglycemia”)
 Transfusions: to consider as needed  [7][26]

o 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
o Platelets for the following platelet count thresholds:
 < 10,000/mm  in all patients
3

 < 20,000/mm  in patients with a high risk of bleeding

3

 < 50,000/mm  in patients with active bleeding or a planned

3

surgery/invasive procedure
o FFP to correct coagulopathy in patients with active bleeding or a planned
invasive procedure
 Other supportive measures  [7][26]

o VTE prophylaxis
o Renal replacement therapy: e.g., for patients with concomitant severe acute
kidney injury
o Stress ulcer prophylaxis: on a case-by-case basis 

Acute management checklist

Use the qSOFA score for early recognition of sepsis.

  Establish IV access, continuous monitoring, and draw initial laboratory studies.

o At least 2 sets of blood cultures 
o Serum lactate
o Samples for additional laboratory studies

  Identify patients with septic shock (e.g., hypotension, elevated lactate).

  Begin resuscitation measures.

o Initial fluid resuscitation with 30 mL/kg of crystalloid.
o Add vasopressors if shock persists despite adequate fluid resuscitation.
o Provide respiratory support as needed.
o Consider the need for central venous access.
   Start empiric broad-spectrum antimicrobial therapy (ideally within the first hour).
  Continue diagnostic evaluation.
o Organ dysfunction screening: e.g., CBC, BMP, liver chemistries, blood
gas, coagulation panel, D-dimer
o Infectious source identification: e.g., additional cultures  , imaging
o 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. 

Differential diagnoses

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

 Other causes of hypotension/shock

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

Complications

 Critical illness polyneuropathy

o Definition: axonal injury, particularly to the motor neurons, as a
sequela of sepsis and multiple organ dysfunction
o 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 ↑
o 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
o 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!