Sepsis

Sepsis is an acute life-threatening condition characterised by organ dysfunction caused by a dysregulated host response to infection, usually bacterial. It’s related to systemic inflammatory response syndrome (SIRS) in pathomechanism. It has a very high mortality rate and can lead to multiple organ dysfunction syndrome (MODS) and death.

Septic shock is defined as “A subset of sepsis in which underlying circulatory and cellular or metabolic abnormalities lead to substantially increased mortality risk.” As the name implies it implies the state where a person has sepsis and circulatory shock, often of the distributive type. A person is said to be in septic shock if:

• The patient has sepsis, and:
• Vasopressors are required to maintain a mean blood pressure of above 65 mmHg, and:
• The serum level of lactate is > 2.0 mM

A third term, "severe sepsis" was used until 2016, when the Sepsis-3 guideline revised the definition of sepsis. Sepsis-3 also included the deviation from using SIRS criteria to using SOFA criteria.

Etiology

• Primary infection
  • Pneumonia
  • Genitourinary infections
  • Gastrointestinal infections
  • Skin infections
  • Soft tissue infections
• Pathogens
  • Gram positive bacteria
  • Gram negative bacteria
• Risk factors
  • Age < 1 year
  • Age > 65 year
  • Comorbidities
    • Diabetes mellitus
    • Cancer
    • Obesity
    • Cirrhosis
    • Alcoholism
  • Immunosuppression
  • Being in an intensive care unit
  • Invasive medical treatment
    • Endotracheal tube
    • Intravenous lines
    • Urinary catheters

The most common primary infection that leads to sepsis is pneumonia, especially community-acquired pneumonia. The pathogen is more frequently gram positive than gram negative; fungal, viral or parasitic etiology is rare.

Bacteraemia is found in 50% of cases of sepsis.

Pathomechanism

The underlying mechanism of sepsis is a hyperinflammatory systemic reaction. A normal, physiological immune response requires a balance of proinflammatory and anti-inflammatory signals. In sepsis, this balance is lost. The exact mechanism that leads to the loss of this balance is not well known. Hyperactivation of the innate immune system occurs, which leads to decreased oxygen delivery to tissues.

In gram negative bacteria the LPS molecule of their cell envelope is recognized by TLR4 receptors on macrophages and other immune cells. In gram positive bacteria the cell wall is recognized by TLR2 receptors on the same cells. The immune cells will then produce inflammatory cytokines like TNF-α, IL-1, IL-6 and IL-8. This has multiple consequences:

• The endothelium will become dysfunctional, allowing fluid and other molecules to cross in the interstitium. Fluid is lost to the interstitium, decreasing the oxygenation of tissues
• Cells will be damaged, releasing damage-associated molecular patterns (DAMP) that are recognized by immune cells and cause further inflammation

As fluid is lost to the interstitium, intravascular hypovolaemia occurs. DIC occurs due to endothelial dysfunction and intravascular hypovolaemia. Widespread tissue ischaemia and decreased tissue oxygenation causes widespread cell injury and thereby multisystem organ dysfunction.

Clinical features

• Fever
• Tachycardia
• Tachypnoea
• Features of organ dysfunction, depending on which organs are affected
  • ARDS
  • Hypotension
  • Acute renal failure, oliguria
  • Altered mental status
  • DIC

Diagnosis and evaluation

Organ dysfunction must be present for the diagnosis of sepsis. The definition of “organ dysfunction” can itself be difficult to accurately establish. To help with this, a set of assessment criteria called “sequential organ failure assessment score” or SOFA score can help. These criteria assess the function of important organ systems like lungs, liver, CNS, kidneys, circulation and the coagulation and gives scores from 0 (normal function) to 4 (worst function). The score for each organ system is then summed up. Acute organ dysfunction is defined as an acute change in total SOFA score of 2 points or more.

Sepsis used to be evaluated by the criteria of “systemic inflammatory response syndrome” (SIRS), but that is not recommended anymore. Sepsis now has its own criteria (SOFA).

Diagnosis of sepsis can be difficult. A series of criteria called qSOFA (quick SOFA) can be used to screen for sepsis. qSOFA is said to be positive of 2 or more of the following criteria are present:

• Altered mental status (GCS < 15)
• Respiratory rate > 22 breaths per minute
• Systolic blood pressure < 100 mmHg

If qSOFA is positive, blood cultures should be performed to look for the pathogen and the patient should be evaluated for organ dysfunction according to the SOFA system. Blood tests should be performed to measure the following:

• CBC (complete blood count)
• Procalcitonin – a serum protein that increases significantly in sepsis
• CRP – which signals inflammation
• Lactate – which is proportional to the degree of tissue hypoxia
• Thrombocytes - thrombocytopaenia is common

Treatment

Management according to the 2016 surviving sepsis campaign (SSC). The therapeutic goals are:

• Central venous pressure 8 – 12 mmHg
• Mean arterial pressure > 65 mmHg
• Urine output > 0,5 mL/bwkg/hour
• SvcO2 > 70%

Empiric antibiotic treatment should begin immediately after blood cultures has been drawn; mortality increases the longer the patient goes without antibiotic therapy. The goal should be to administer antibiotics within 1 hour of recognition of the diagnosis. Any source of infection, like foreign bodies, abscesses or infected wounds should be assessed and treated appropriately.

Depending on the patient’s condition, fluid therapy, intubation and/or vasopressors might be necessary to maintain ventilation and circulation.

Specific steps of management:

• Within 1 hour
  • Obtain two sets of blood cultures
  • Measure lactate and the other components of SOFA
  • Broad-spectrum antibiotics
• Initial resuscitation with crystalloid, at least 30 mL/kg in the first 3 hours
  • If insufficient, use vasopressor (norepinephrine is first choice)
  • If insufficient, use hydrocortisone
• As soon as possible and if necessary
  • Source control in case of localized infection
    • Drainage of infection, necrectomy, etc
  • Blood products
    • RBCs in case of Hb < 7,0 g/dL or acute bleeding
    • Thrombocytes in case of thrombocytopaenia
  • Glucose control
  • Early enteral feeding
  • Sedation – not too deep. Preferably in an arousable state
  • Lung-protective ventilation
  • Urinary catheterisation
  • Bicarbonate in case of severe metabolic acidosis
  • Organ support
    • ECMO
    • Renal replacement therapy
• Prophylaxis for
  • Venous thromboembolism (UFH or LMWH)
  • Stress ulcer (PPI)