Sepsis is where the body launches a large immune response to an infection, causing systemic inflammation and organ dysfunction.
Pathophysiology
Macrophages, lymphocytes and mast cells recognise pathogens. These immune cells release vast amounts of cytokines, like interleukins and tumour necrosis factor, that activate the immune system. This immune activation leads to systemic inflammation and the release of other chemicals, such as nitrous oxide (causing vasodilation).
Many of these cytokines cause the endothelial lining of blood vessels to become more permeable. A permeable endothelial lining allows fluid to leak out of the blood and into the extracellular space, resulting in oedema and reduced intravascular volume. Oedema creates a gap between the blood and the tissues, reducing the amount of oxygen that reaches the tissues.
Activation of the coagulation system leads to the deposition of fibrin deposition and the formation of blood clots (thrombi) throughout the circulation, compromising organ and tissue perfusion. The formation of blood clots consumes platelets and clotting factors, leading to thrombocytopenia (low platelets) and uncontrolled bleeding (haemorrhage). This process is called disseminated intravascular coagulopathy (DIC).
Tissues have an inadequate oxygen supply, leading to anaerobic respiration. Lactic acid is a waste product of anaerobic respiration. Therefore, the serum lactate rises, and metabolic acidosis occurs.
Septic Shock
Septic shock occurs when the arterial blood pressure drops despite adequate fluid resuscitation, resulting in organ hypoperfusion. Anaerobic respiration begins, and the serum lactate level rises. It is diagnosed with:
- Low mean arterial pressure (below 65 mmHg) despite fluid resuscitation (requiring vasopressors)
- Raised serum lactate (above 2 mmol/L)
Septic shock requires aggressive treatment with IV fluids to improve blood pressure and tissue perfusion. Patients should be escalated to high dependency or intensive care for treatment with vasopressors such as noradrenaline. Vasopressors are medications that cause vasoconstriction (narrowing of blood vessels), increasing systemic vascular resistance and consequently mean arterial pressure (MAP), helping to improve tissue perfusion.
Sepsis-Related Organ Failure Assessment
The Sepsis-related (or Sequential) Organ Failure Assessment (SOFA) criteria can be used to assess the severity of organ dysfunction, most often in the intensive care unit. It takes into account signs of organ dysfunction:
- Hypoxia
- Increased oxygen requirements
- Requiring mechanical ventilation
- Low platelets (thrombocytopenia)
- Reduce Glasgow Coma Scale (GCS)
- Raised bilirubin
- Reduce blood pressure
- Raised creatinine
Risk Factors
Any condition causing immune dysfunction, frailty or a predisposition to infection is a risk factor for sepsis:
- Very young or old patients (under 1 or over 75 years)
- Chronic conditions, such as COPD and diabetes
- Chemotherapy, immunosuppressants or steroids
- Surgery, recent trauma or burns
- Pregnancy and childbirth
- Indwelling medical devices, such as catheters or central lines
Presentation
The National Early Warning Score (NEWS2) is used to help identify acutely unwell patients, including those with sepsis. Six parameters are measured:
- Temperature
- Heart rate
- Respiratory rate
- Oxygen saturation
- Blood pressure
- Consciousness level
Additional signs of infection include:
- Signs of potential sources, such as cellulitis, discharge from a wound, cough or dysuria
- Reduced urine output
- Mottled skin
- Cyanosis
- Arrhythmias, such as new-onset atrial fibrillation
- A non-blanching rash can indicate meningococcal septicaemia
Additional points to be aware of are:
- A raised respiratory rate (tachypnoea) is often an early sign of sepsis
- Elderly patients often present with non-specific findings, such as confusion, drowsiness or simply “off legs”
- Neutropenic or immunosuppressed patients may have normal observations despite being life-threateningly unwell
Investigations
Blood tests for patients with suspected sepsis include:
- Full blood count for the white cell count and neutrophils
- U&Es for kidney function and acute kidney injury
- LFTs for liver function and as a possible source of infection
- CRP to assess for inflammation
- Blood glucose for hyperglycaemia and hypoglycaemia
- Clotting to assess for disseminated intravascular coagulopathy (DIC)
- Blood cultures to assess for bacteraemia
- Blood gas for lactate, pH and glucose
Additional investigations can help locate the source of the infection:
- Urine dipstick and urine culture
- Chest x-ray
- CT scan if an intra-abdominal infection or abscess is suspected
- Lumbar puncture for meningitis or encephalitis
Management
Every hospital will have a sepsis protocol and pathway. Patients should be escalated to the senior decision maker and the appropriate level of care, including HDU or ICU, if needed.
The NICE guidelines (updated 2017) recommend patients are risk stratified into low, medium and high risk. High-risk patients need urgent attention and management. Moderate-risk patients may be managed in the community where the diagnosis is clear, and it is safe to do so. Safety-netting advice is essential when managing patients in the community, giving clear instructions about when they need further medical attention.
Patients with suspected sepsis should be assessed and start treatment within 1 hour of presenting. The sepsis six involves three tests and three treatments.
Sepsis Six
Three tests:
- Serum lactate
- Blood cultures
- Urine output
Three treatments:
- Oxygen to maintain oxygen saturation 94-98% (or 88-92% in COPD)
- Empirical broad-spectrum antibiotics
- IV fluids
Neutropenic Sepsis
Neutropenic sepsis refers to sepsis in someone with a absolute neutrophil count below 0.5 x 109/L (or likely to fall to this level). It is a life-threatening medical emergency.
A low neutrophil count is usually the consequence of anti-cancer or immunosuppressant treatment. Medications that may cause neutropenia include:
- Chemotherapy (for cancer)
- Clozapine (for schizophrenia)
- Hydroxychloroquine (for rheumatoid arthritis)
- Methotrexate (for rheumatoid arthritis)
- Sulfasalazine (for rheumatoid arthritis)
- Carbimazole (for hyperthyroidism)
- Quinine (for malaria)
- Infliximab (a monoclonal antibody used for various autoimmune conditions)
- Rituximab (a monoclonal antibody used for various autoimmune conditions and cancers)
A low threshold is required for suspecting neutropenic sepsis in patients on chemotherapy or medications that may cause neutropenia. Any temperature above 38ºC is treated as neutropenic sepsis until proven otherwise. They require emergency admission and careful management due to the high mortality risk.
Each local hospital will have a neutropenic sepsis policy. Treatment involves immediate broad-spectrum antibiotics, such as piperacillin with tazobactam (tazocin). The other management aspects are the same as for sepsis but with particularly close monitoring and a low threshold for escalation.
Last updated July 2023
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