Sepsis

Overview

Sepsis is a syndrome characterised by life-threatening organ dysfunction due to a dysregulated host response to an infection.

Septic shock is a more severe form of sepsis, where circulatory, cellular, and metabolic abnormalities are present. It is associated with a higher risk of mortality.

In hospital, septic shock can be defined as sepsis with persisting hypotension requiring inotropes to maintain a mean arterial pressure (MAP) of ≥65 mmHg and hyperlactataemia with serum lactate >2 mmol/L, where MAP is driving tissue perfusion.

Pathophysiology

The pathophysiology of sepsis is not fully understood and is thought to depend on host factors (e.g. genetics, age, and comorbidities) and pathogen factors (e.g. type, virulence, burden), and the environment.

Infection can lead to an excessive immune response, including the release of pro-inflammatory cytokines that activate more inflammatory cells, reactive oxygen species which can increase capillary permeability, and complement activation, which aids the attraction of leukocytes to the site of infection. Activated vascular endothelium can become ‘leaky’ as capillary permeability increases to allow immune cells to migrate to infection sites. This can cause tissue oedema as fluid leaks out, vasodilation, and can reduce blood pressure.

Cardiac output increases in an attempt to maintain a sufficient blood pressure, but this can get exhausted and result in hypotension and shock. Less oxygen can get to tissues, and this is worsened by tissue oedema. Cellular metabolic activity begins to exceed their supply of energy and oxygen, switching to anaerobic respiration, and increasing the production of lactate. These factors combined can cause cellular dysfunction, lactic acidosis, and multi-organ failure.

Risk Factors

• Extremes of age – infants <1 year old, people >75 years old, and frailty
• Immunocompromised states – such as HIV, liver cirrhosis, diabetes mellitus, sickle cell disease, asplenia
• Immunosuppressive drugs – such as anti-cancer treatment, corticosteroids, or drugs like disease-modifying antirheumatic drugs (DMARDs)
• Recent surgery, trauma, or invasive procedure
• Skin breaches – cuts, burns, skin infections, wounds, indwelling lines, catheters
• Intravenous drug use
• Excess alcohol consumption 
• Pregnancy/postpartum

Presentation

Sepsis can be difficult to identify and can present differently depending on a person’s age, comorbidities, and the underlying cause. Since it can be caused by an infection by almost any pathogen, its presentation varies widely. Some features include:

• An infection causing significant deterioration/illness – including people who do not improve as expected or suddenly deteriorate
• Changes in appearance/behaviour, looking unwell, agitation
• Non-specific features such as malaise
• Fever is not always present, some people can be hypothermic
• Tachycardia, tachypnoea, and/or hypotension may be present
• Features of poor perfusion include:
  • Prolonged capillary refill time
  • Mottled/ashen skin, cyanosis, pallor
  • Cold peripheries 
• Oliguria can suggest volume depletion and/or acute kidney injury

NEWS Score

Overview

The National Early Warning Score 2 (NEWS2) is a scoring system that can be used to identify unwell patients early and escalate care. It involves measuring a patient’s pulse, blood pressure, respiratory rate, oxygen saturation, level of consciousness, and temperature.

Normal observations are scored 0, whereas abnormal values are given higher scores up to 3. Each parameter’s score is added up to give an overall NEWS2 score, which above certain thresholds, prompts different escalation steps.

Trends in these parameters are more useful than single measurements. For instance, some patients may have a normal score at one time, which then decreases progressively with further measurement, suggesting possible deterioration.

Care must be taken when interpreting NEWS2 scores as some people may be seriously unwell and have a normal news score, such as an awake and alert patient with acute coronary syndrome with a pulse of 85 bpm, a blood pressure of 137/75 mmHg, a respiratory rate of 18 /min, oxygen saturations of 96%, a temperature of 37.0°C.

Patients with COPD

Patients with COPD who are known to retain CO₂ have a separate oxygen saturation scale as their targets are 88-92%. On the previous NEWS score, this would have continuously crossed the threshold suggesting the need to escalate care.

Thresholds

A total score of 0-4 is considered should trigger a ‘ward-based response’:

• Usually an assessment made by a competent registered nurse or equivalent
• They may decide to change how often the patient is monitored or escalate as required.

A score of 3 in a single parameter should trigger an ‘urgent ward-based response’:

• Usually an assessment is made by a clinician competent in the assessment and treatment of acute illness and recognising when escalation to critical care is appropriate (usually a ward-based doctor)
• They may decide to change how often the patient is monitored or escalate as required.

A total score of 5-6 is a trigger threshold for an ‘urgent response’:

• Usually an assessment is made by a clinician competent in the assessment and treatment of acute illness and recognising when escalation to critical care is appropriate (usually a ward-based doctor)
• They may decide to escalate care to a team with critical care skills (e.g. a critical care outreach team)

A total score of 7 or more is a trigger threshold for an ‘urgent or emergency response’:

• This should prompt emergency assessment by a clinical team/critical care outreach team with critical care competencies (including airway management)
• This usually involves transferring the patient to a higher-dependency care area

Figure 1: National Early Warning Score 2 (NEWS2). © Royal College of Physicians 2017.

Management

Overview

The initial management of sepsis involves the ‘Sepsis Six’ treatment bundle within the first hour of sepsis is suspected. This can be remembered with ‘BUFALO’:

• Blood cultures – ideally before giving antibiotics, but they should not delay treatment 
• Urine output – urine output and fluid balance should be checked hourly
• Fluids – give an intravenous bolus of 500 mL of a crystalloid
• Antibiotics – give an intravenous broad-spectrum antibiotic empirically
• Lactate, blood gas, and glucose measurements – higher lactate is associated with higher mortality rates, serial measurements should be taken and their trends assessed
• Oxygen – give oxygen to maintain saturations >94% or 88-92% if at risk of carbon dioxide retention (e.g. COPD)

In some cases, people may need critical care transfer for central venous access and inotropes (which increase cardiac output by increasing cardiac contractility) or vasopressors (which increase blood pressure by increasing peripheral vascular resistance) to maintain perfusion pressure.

Investigations

Tests and their findings in sepsis may include:

• Blood culture – identifies causative organism
• Full blood count (FBC) – may show leukocytosis, thrombocytopenia can suggest disseminated intravascular coagulopathy (DIC) 
• C-reactive protein (CRP) – may be elevated
• Urea and electrolytes (U&Es) – may show evidence of acute kidney injury
• Liver function tests (LFTs) – may be deranged due to ischaemic hepatitis and cholestasis
• Clotting screen – abnormal results may suggest DIC
• Urinalysis, culture, and microscopy – if a urinary infection source is suspected
• Chest X-ray – if a pulmonary source of infection is suspected

Complications

Death – sepsis is the leading cause of avoidable death. Up to 3/10 people with sepsis die, with the highest death rates at the extremes of age (infants <1 year old and people >60 years old). Sepsis is the leading cause of maternal death in the UK.

Organ failure – including acute kidney injury (AKI), hepatitis and cholestasis, heart failure, acute respiratory distress syndrome, and bone marrow suppression. Up to 6/10 people with sepsis have AKI, which increases the risk of mortality.

Secondary/recurrent infection – people who survive sepsis may develop further infection or have latent viruses reactivated due to an impaired immune response. Persisting compensatory anti-inflammatory responses can also contribute to immunosuppression.

Disseminated intravascular coagulopathy (DIC) – toxic substances result in the expression of tissue factor on cell surfaces, activating the clotting cascade, resulting in microvascular thrombosis and platelet consumption, resulting in haemorrhage. This can cause occlusion of vessels resulting in further complications such as loss of digits and limbs and pulmonary embolism.

Neurological complications – including encephalopathy, delirium, neuromuscular weakness. 

Prognosis

• Multiple organ dysfunction, extremes of age, and comorbidities are associated with a worse prognosis