Sepsis

What is sepsis?¹

Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection.²

Septic shock is associated with particularly profound circulatory, cellular and metabolic abnormalities, with a greater risk of mortality than with sepsis alone.

• Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection.

• Septic shock describes circulatory, cellular, and metabolic abnormalities which are associated with a greater risk of mortality than sepsis alone.

Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L in the absence of hypovolaemia. This combination is associated with hospital mortality rates greater than 40%.³

The Surviving Sepsis Campaign (SSC) was established to raise awareness of severe sepsis and to improve its management. The SSC is a collaboration between several groups worldwide and its aim is to reduce the mortality from sepsis.⁴

Pathophysiology of sepsis¹

The exact pathophysiology of sepsis is unknown, but it is thought to be a multifactorial response to an infecting pathogen that may be amplified by host factors (eg, genetics, age, and co-morbidities), the pathogen (type, virulence, and burden), and the environment.

The exact mechanism of cell injury is not fully known, but it is suspected that immune and coagulation systems are switched on by infection and cause dysfunction of one or more organs with variable severity. It is thought this involves the early activation of both pro-inflammatory responses (leading to cellular and tissue damage) and anti-inflammatory responses (leading to immunosuppression). Resulting tissue hypoxia, mitochondrial dysfunction, macrovascular and microvascular dysfunction, and cell death are thought to be mediators of organ dysfunction.

The most common sites of infection leading to sepsis are the respiratory, gastrointestinal, renal and genitourinary tracts, as well as blood, skin, soft tissue, bone and joint sources.

Studies indicate an equal prevalence of Gram-positive and Gram-negative bacterial infections in sepsis, particularly Staphylococcus aureus, Pseudomonas species, and Escherichia coli. In children, Neisseria meningitides and Haemophilus influenzae may also be involved. Rarely, fungal, viral, or parasitic infections are the cause. No causative pathogen is identified in about one-third of people with sepsis.

How common is sepsis? (Epidemiology)

Sepsis is a leading cause of morbidity and mortality for children worldwide. Globally, an estimated 22 cases of childhood sepsis per 100,000 person-years and 2,202 cases of neonatal sepsis per 100,000 live births occur, translating into 1.2 million cases of childhood sepsis per year.⁵

The most recent global estimates for sepsis incidence and mortality were based on data for adults admitted to hospital in seven high-income countries and reported 19.4 million sepsis incident cases and 5.3 million sepsis-related deaths annually.⁶ As only high-income countries are represented this may be a significant underestimate. However, it has been deduced that more than 1 in 1,000 people in developed countries develop sepsis each year and between a third and a half of them progress to severe sepsis. The figures for developing countries are likely to be far higher.

Risk factors¹

There is usually an abscess or nidus of infection, which may be occult. Risk factors for developing sepsis include the following:

• The very young (under 1 year) and older people (over 75 years), or people who are very frail.

• People who have impaired immune systems because of illness or drugs, including:

• People having treatment for cancer with chemotherapy.

• People who have impaired immune function (eg, people with diabetes, people who have had a splenectomy, or people with sickle cell disease.

• People taking long-term steroids.

• People taking immunosuppressant drugs to treat non-malignant disorders such as rheumatoid arthritis.

• People who have had surgery, or other invasive procedures, in the past 6 weeks.

• People with any breach of skin integrity (eg, cuts, burns, blisters or skin infections.

• People who misuse drugs intravenously.

• People with indwelling lines or catheters.

• People who are pregnant, have given birth or had a termination of pregnancy or miscarriage in the past 6 weeks.

Risk factors for early-onset neonatal infection:

• Suspected or confirmed infection in another baby in the case of a multiple pregnancy.

• Invasive group B streptococcal infection in a previous baby or maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy.

• Pre-term birth following spontaneous labour before 37 weeks' gestation.

• Confirmed rupture of membranes for more than 18 hours before a pre-term birth.

• Confirmed prelabour rupture of membranes at term for more than 24 hours before the onset of labour.

• Intrapartum fever higher than 38°C if there is suspected or confirmed bacterial infection.

• Chorioamnionitis.

Symptoms of sepsis (presentation)⁷

• Patients may have presented a few days earlier with a focus of infection.

• Patients may then deteriorate rapidly despite having the appropriate oral antibiotics.

• People with sepsis may have non-specific, non-localised presentations, eg, feeling very unwell, and may not have a high temperature.

• There may be concerns expressed by the person and their family or carers, eg, changes from usual behaviour.

• Also enquire about symptoms relating to a possible focus of infection - eg, cough, urinary symptoms, recent travel.

• Ask about frequency of micturition in the past 18 hours.

• Presenting features for children may include feeling abnormally cold to touch, looking mottled and blue or with very pale skin, a rash that does not fade with pressure, raised respiratory rate and being very lethargic and difficult to wake up.

• Young children may not feed, may have repeated vomiting or may not pass any urine and so not have wet nappies.

Assessment⁷

A high degree of vigilance is required for early identification of a patient with sepsis in primary care. Evaluate risk level using the person's history, physical examination results and criteria based on age. The NICE guideline includes stratification of risk from sepsis in under 5s, children aged 5 to 11, children and young people aged 12 to 15, and for those aged 16 years and older.

Assess people with any suspected infection to identify:

• Possible source of infection.

• Factors that increase risk of sepsis.

• Any indications of clinical concern, such as new-onset abnormalities of behaviour, circulation or respiration.

Use a structured set of observations to assess people in a face-to-face setting to stratify risk if sepsis is suspected.

Ask how often the person urinated in the past 18 hours, any recent fever or rigors, and whether they have recently presented with symptoms or signs that could indicate sepsis.

Use the national early warning score (NEWS2) - see 'Sepsis screening' below - to assess people with suspected sepsis who are aged 16 or over, are not and have not recently been pregnant, and are in an acute hospital setting, acute mental health setting or ambulance.

Consider using an early warning score to assess people with suspected sepsis who are:

• Aged under 16, in any setting.

• Pregnant or have recently been pregnant, in any setting.

• Aged 16 or over, in a community or custodial setting.

Suspect neutropenic sepsis in people who become unwell and:

• Are having or have had systemic anticancer treatment within the last 30 days.

• Are receiving or have received immunosuppressant treatment for reasons unrelated to cancer.

Use clinical judgement to determine whether any past treatment may still be likely to cause neutropenia. Refer patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care.

Initial examination

Assess temperature, heart rate, respiratory rate, blood pressure, level of consciousness, oxygen saturation and capillary refill time. In community settings, measure oxygen saturation if equipment is available and taking a measurement does not cause a delay in assessment or treatment. Examine people with suspected sepsis for (see also Meningococcal Disease):

• Mottled or ashen appearance.

• Cyanosis of the skin, lips or tongue.

• Non-blanching petechial or purpuric rash.

• Any breach of skin integrity (eg, cuts, burns or skin infections).

• Other rash indicating potential infection.

As part of the initial assessment, carry out a thorough clinical examination to look for sources of infection, including sources that might need drainage or other interventions.

Sepsis screening⁸

The National Early Warning Score (NEWS) is a tool developed by the Royal College of Physicians which improves the detection and response to clinical deterioration in adult patients and is a key element of patient safety and improving patient outcomes.

The National Early Warning System (NEWS) was introduced by the Royal College of Physicians in 2012. In December 2017, an updated version of NEWS, NEWS2, was published. See the reference link for further information.

The National Early Warning System (NEWS2) is based on a simple scoring system in which a score is allocated to physiological measurements already undertaken when patients present to, or are being monitored in, hospital. NEWS is more accurate in predicting 10- and 30-day mortality than other systems when patients present to A&E with suspected sepsis.⁹

Six simple physiological parameters form the basis of the scoring system:

1. Respiratory rate
2. Oxygen saturations
3. Temperature
4. Systolic blood pressure
5. Pulse rate
6. Level of consciousness

A score is allocated to each as they are measured, the magnitude of the score reflecting how extremely the parameter varies from the norm. The score is then aggregated.

Evidence suggests using the system is associated with improved patient outcomes.¹⁰

Management of sepsis⁷

The following is a brief summary of the NICE guidance. See the reference link to the NICE guideline for further information.

Managing suspected sepsis outside acute hospital settings

Refer people with suspected sepsis for emergency medical care if:

• They meet any high risk criteria, or

• Their immunity is impaired by drugs or illness and they meet any moderate to high risk criteria.

Use the most appropriate means of transport (usually 999 ambulance). Pre-alert secondary care (through GP or ambulance service) when any high risk criteria are met in a person under 16 with suspected sepsis outside of an acute hospital, and transfer them immediately.

Managing the condition while awaiting transfer

In remote and rural locations where transfer time to emergency department is routinely more than 1 hour, ensure GPs have mechanisms in place to give antibiotics to people with high risk criteria in pre-hospital settings.

If immediate transfer to hospital is not required

Assess people who are outside acute hospital settings with suspected sepsis and any moderate to high risk criteria to:

• Make a definitive diagnosis of their condition.

• Decide whether their condition can be treated safely outside hospital.

If a definitive diagnosis is not reached or the person's condition cannot be treated safely outside an acute hospital setting, refer them urgently for emergency care.

Managing suspected sepsis in acute hospital settings

Initial investigations to find the source of infection
Start looking for the source of infection and take microbiological and blood samples before giving an antimicrobial.

Initial blood tests should include blood gas, including glucose and lactate measurement, blood culture, full blood count, C-reactive protein, renal function and electrolytes, liver function tests and clotting screen.

Give a broad-spectrum antimicrobial at the maximum recommended dose, without delay (within 1 hour of identifying that they meet any high risk criteria), if antibiotics have not already been given for this episode of sepsis.

When the source of infection is confirmed or microbiological results are available: review the choice of antibiotic(s) and change the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate.

Give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria).

Refer to a critical care specialist or team for them to review, including their need for central venous access and initiation of inotropes or vasopressors.

See the NICE guideline reference link for further information.

Prognosis¹

Organ dysfunction is an important predictor of prognosis, with multiple organ involvement being associated with a higher risk of mortality.

Extremes of age and the presence of co-morbidities are also associated with a worse prognosis.

A UK Sepsis Trust report cites an overall mortality rate in England of 28.9%. A UK observational cohort study of 91 intensive care units (n = 56,673) found that the hospital mortality rate of adults admitted with sepsis ranged from 17% in people aged 16–19 years, to 64% in people aged over 85 years.

A diagnosis of septic shock is associated with hospital mortality rates greater than 40%. An international study of the association between following Surviving Sepsis Campaign (SSC) performance criteria and mortality rate found the overall hospital mortality for people with sepsis and septic shock was 32.8%.

The case fatality rate of sepsis may be falling over time, presumably due to increased awareness and reporting of suspected sepsis, faster diagnosis, and improved management protocols.
Survivors of sepsis have higher rates of mortality following hospital discharge compared with control populations.

Compared to non-sepsis admissions, sepsis survivors have a greater risk of re-admission, with 30-day re-admission rates averaging between 19–32%.

People who survive sepsis may have long-term physical, psychological, and cognitive impairments.

Complications of sepsis¹

• Death (see 'Prognosis' section above).

• Organ failure: this may be multi-system and includes acute kidney injury, cholestasis, heart failure, acute respiratory distress syndrome (ARDS) or acute lung injury, and bone marrow suppression.

• Recurrent and secondary infection.

• Malnutrition.

• Coagulopathy: this may cause thromboembolism or disseminated intravascular coagulation (DIC) characterised by microthrombosis and haemorrhage.

• Physical impairments: a reduced quality of life may result from chronic pain and fatigue.

• Encephalopathy and delirium may lead to reduced mobility and neuromuscular weakness, as well as longer lasting neurocognitive deficits such as memory problems and reduced concentration.

• Psychological sequelae may include anxiety about recurrent infection and sepsis, post-traumatic stress disorder, loss of confidence and self-esteem.

Post-sepsis syndrome¹¹

Post-sepsis syndrome (PSS) is associated with several pathophysiologic mechanisms that negatively affect quality of life, long-term health and lifespan. These pathophysiologic mechanisms include immune dysregulation, persistent inflammation, oxidative stress and mitochondrial dysfunction.

PSS can manifest in various ways including:

• Physical difficulties include fatigue, weakness, breathlessness, chest pains, oedema, arthralgia, poor appetite, visual disturbance, sensory disturbance and recurrent infections.

• Psychological difficulties may include anxiety, depression, post-traumatic stress disorder, nightmares, insomnia, poor concentration and memory disturbance.

Original document (2016) produced in collaboration with Dr Ron Daniels of The UK Sepsis Trust.