Sepsis in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

in hospital: sepsis highly suspected and unknown or unclear source of bacterial infection

1st line – broad-spectrum intravenous antibiotics

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1st line –

broad-spectrum intravenous antibiotics

Start treatment immediately if a senior clinical decision-maker (e.g., ST3 level doctor in the UK) makes a diagnosis of suspected sepsis,based on acute deterioration (e.g., National Early Warning Score 2 [NEWS2] score of 5 or more, or a similar trigger using another validated scoring system) in a patient with known or likely infection.[41][42]

For any acutely ill and deteriorating patient with a suspected or known bacterial infection and suspected sepsis, above all else prioritise (if needed):[3][47]

Securing their airway
Correcting hypoxaemia
Establishing venous access for the early administration of antibiotics and fluids.

Where there is evidence of a bacterial infection and sepsis is strongly suspected (based on acute deterioration [e.g., NEWS2 score of 5 or more, or a similar trigger using another validated scoring system]), give broad-spectrum intravenous antibiotics according to the timeframes below:[3][41][43][45][47]

Within 1 hour of initial severity assessment for patients with a NEWS2 score of 7 or more calculated on initial assessment in the accident and emergency department or on ward deterioration, (or with a score of 5 or 6 if there are additional clinical or carer concerns, continuing deterioration or lack of improvement, neutropenia, or blood gas/laboratory evidence of organ dysfunction)
- A patient is also at high risk of severe illness or death from sepsis if they have a NEWS2 score below 7 and a single parameter contributes 3 points to their NEWS2 score and a medical review has confirmed that they are at high risk.[3]
or
Within 3 hours for patients with a NEWS2 score of 5 or 6.

Give antibiotics before a pathogen is identified but after blood cultures have been taken.[3][41][43][47] Only give antibiotics if they have not been given before for this episode of sepsis.[3]

The Surviving Sepsis Campaign international guideline recommends empirical combination therapy (using at least two antibiotics of different antimicrobial classes covering gram-negative bacilli) for patients at high risk of infection from multidrug resistant (MDR) organisms, particularly in those with septic shock.[43]
- Initial use of multidrug therapy is often required, given the frequency of MDR bacteria in many parts of the world and associations between delays in active therapy and worse outcomes.[43]
- Single agents are recommended for patients with a low risk for MDR organisms.[43]

Follow local policy and consider discussing with microbiology/infectious disease colleagues to determine the most appropriate choice.

Once a decision is made to give antibiotics, do not delay administration any further.[3]
Use a 'start smart then focus' approach.[41][136]

More info: Antimicrobial resistance

NHS England recommends following a 'start smart then focus’ approach for antibiotic use in people with sepsis.[41]This is derived from Public Health England guidance, which outlines an evidence-based approach to improving antimicrobial prescribing and stewardship in hospital settings.[136]The prevalence of antimicrobial resistance (AMR) has risen alarmingly over the last 50 years and no new classes of antibiotics have been developed in decades. By 2050 it is estimated that AMR will kill 10 million people per year, more than cancer and diabetes combined.[142]The relationship between antibiotic exposure and antibiotic resistance is unambiguous not only at the population level but also in individual patients.[143][144]

Start smart – in the context of sepsis:[136]

Do not start antimicrobial therapy unless there is clear evidence of infection
Take a thorough drug allergy history
Initiate prompt effective antibiotic treatment within 1 hour of diagnosis (or as soon as possible) in patients with sepsis who are critically ill (e.g., septic shock, sepsis associated with rapid deterioration, or NEWS2 score of 7 or more calculated on initial assessment in the accident and emergency department or on ward deterioration) or with life-threatening infections. Avoid inappropriate use of broad-spectrum antibiotics[3][45]
Comply with local antimicrobial prescribing guidance
Document clinical indication (and disease severity if appropriate), drug name, dose, and route on drug chart and in clinical notes
Include review/stop date or duration
Obtain cultures prior to starting therapy where possible (but do not delay therapy).

Then focus – in the context of sepsis:[136]

Review the clinical diagnosis and the continuing need for antibiotics at 48 to 72 hours* and document in a clear plan of action – the ‘antimicrobial prescribing decision’
The ‘antimicrobial prescribing decision’ options are:
1. Stop antibiotics if there is no evidence of infection
2. Switch antibiotics from intravenous to oral
3. Change antibiotics – ideally to a narrower spectrum, or broader if required
4. Continue and document next review date or stop date
It is essential that the review and subsequent decision is clearly documented in the clinical notes and on the drug chart where possible (e.g., ‘stop antibiotic’).

*In clinical practice, daily prompting about de-escalation is encouraged.

The UK’s Academy of Medical Royal Colleges recommends stratifying patients with suspected sepsis according to severity of illness at presentation, allowing a 3-hour window to investigate patients with less severe illness (e.g., NEWS2 score of 5 or 6). This should improve accuracy of treatment and help to reduce antimicrobial resistance.[45]

Target the presumed site of infection.[3][43]

If there is no clinical evidence to suggest a specific site of infection but a senior clinical decision-maker strongly suspects the presence of a bacterial infection, still give empirical broad-spectrum intravenous antibiotics.[3][41] Choose an empirical antibiotic based on:[145][146]

Local antibiotic protocols and resistance patterns
- Consult microbiology/infectious disease colleagues to determine the most appropriate choice
The likely causative organism
The patient’s immune function.

Practical tip

Check local policies regarding repeat cultures, which are particularly indicated if there are persistent or repeated fever spikes or if you identify a potential new site of infection. Observations from studies to date support taking as many as four blood culture sets over a 24-hour period for >99% test sensitivity.[147]

Practical tip

If a patient has a mild allergy (e.g., rash) to an unknown antibiotic, you should still give empirical broad-spectrum antibiotics if indicated to prevent delay in the treatment of sepsis, which is likely to worsen outcome. If the antibiotic is known and is part of the empirical protocol for your hospital, discuss with potential alternatives with a microbiologist.

Evidence: 1- and 3-hour antibiotic targets

There is widespread agreement that antibiotics should be offered to people with sepsis, within a timeframe that depends on their risk of severe illness or death. The UK National Institute for Health and Care Excellence (NICE), the Surviving Sepsis Campaign (SSC) and the UK Academy of Medical Royal Colleges (AOMRC) all recommend a 1-hour target time threshold for patients at high risk and a 3-hour target time threshold for patients at moderate risk.[43][45]

Two meta-analyses published in 2015 and 2020 compared outcomes for patients with sepsis and septic shock given either immediate (within 1 hour of onset) or early (between 1 and 3 hours from onset) antibiotics; neither meta-analysis identified a difference in mortality between these thresholds.[148][149] One 2021 systematic review (without meta-analysis) of 35 sepsis studies concluded that two-thirds of studies reported an association between early administration of antibiotic therapy and patient outcome, but there was widespread variation in metrics and no robust time thresholds emerged.[150] Almost all of the studies included in these reviews were observational.[148][149][150]

The 2021 update of the SSC guideline recommends that patients with possible sepsis without shock should receive a time-limited course of rapid investigation with administration of antimicrobials within 3 hours if there is persisting concern for infection.[43] Similarly, 2022 guidance from the UK’s AOMRC, based largely on the evidence above, recommends a 3-hour window for investigating and treating patients with less severe illness, while continuing to recommend a 1-hour target for treating patients with more severe illness (e.g., NEWS2 score of 7 or more, or septic shock). The recommended timeframes in the Sepsis Trust’s Sepsis Six bundle have since been adjusted in line with AOMRC guidance.[43][45][47]

In their discussion NICE highlighted that the reason for the longer target time threshold for those at moderate risk was to give more time to establish the diagnosis and guide antibiotic choice, and that the 3-hour limit is a maximum not an aim.

In intensive care settings only, consider prolonged infusion when giving beta-lactam antibiotics to patients with sepsis (apart from those with kidney-related complications).[151] Note that prolonged infusion times are not licensed, as most manufacturers advise infusion of beta-lactam antibiotics over 15 to 60 minutes.

Evidence: Prolonged antibiotic infusion

Intravenous antibiotics, administered over 3 hours, are linked to lower death rates in sepsis.[151]Prolonged infusion should be easy to apply in the intensive care setting, without the need for additional training or equipment.

A systematic review and meta-analysis pooled the results of 22 randomised controlled trials involving 1876 adults with sepsis. The trials compared prolonged versus short-term administration of any antipseudomonal beta-lactam. Carbapenems were studied in nine trials, penicillins in nine trials, and cephalosporins in eight trials.[151]
- Prolonged infusion was associated with lower all-cause mortality than short-term infusion, with 13.6% deaths compared with 19.8% (risk ratio [RR] 0.70, 95% CI 0.56 to 0.87; 17 studies, 1597 participants).
- There was no significant difference between prolonged and short-term infusion for clinical cure or improvement (RR 1.06, 95% CI 0.96 to 1.17; 11 studies, 1219 participants).
- There was no difference in reported adverse events between the groups (RR 0.88, 95% CI 0.71 to 1.09; 7 studies, 980 participants).
- Two trials had no incidence of antibiotic resistance, and two trials had no difference in resistance between the two methods of antibiotic administration (RR 0.60, 95% CI 0.15 to 2.38).

Narrow choice of antibiotic as soon as a pathogen has been identified and sensitivities are available.[43][137] Assess the need to de-escalate antimicrobial therapy daily.[43]

Studies have shown that daily prompting about antimicrobial de-escalation is effective and may be associated with improved outcomes.[197][198]

Continue broad-spectrum coverage to include all common pathogens if the source is unknown or unclear.[3]

Bear in mind that a definite source of infection cannot be found in 20% to 30% of people with sepsis.[9]

Use the shortest effective course of antibiotics.[199]

Unnecessarily prolonged antibiotic treatment is associated with resistance. See More info: Antimicrobial resistance above.

Consult local microbiology guidance for other specific recommendations on de-escalation.

Most protocols will recommend switching from intravenous to oral antibiotics as soon as possible.

The Surviving Sepsis Campaign (SSC) recommends shorter over longer courses of antibiotics for patients with an initial diagnosis of sepsis or septic shock and adequate source control.[43]

The optimal duration of antibiotic treatment in patients with sepsis remains contentious, with concerns regarding not only under-treatment but also the potential encouragement of antibiotic resistance. Consider seeking advice from microbiology/infectious disease colleagues.

Baseline serum procalcitonin is increasingly being used in critical care settings to guide decisions on how long to continue antibiotic therapy.[43][103][104][105]

Procalcitonin is a peptide precursor of calcitonin, which is responsible for calcium homeostasis.
The SSC suggests using procalcitonin alongside clinical evaluation to decide when to discontinue antimicrobials.[43]

Plus – reassess and monitor

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Plus –

reassess and monitor

Treatment recommended for ALL patients in selected patient group

Ensure frequent and ongoing monitoring.[3]

Standard monitoring of vital signs, pulse oximetry, level of consciousness, and urinary output is important for any patient with suspected sepsis.
The UK National Institute for Health and Care Excellence (NICE) recommends continuous or half-hourly monitoring (depending on setting) for any patient considered to be at high risk of deterioration (e.g., using an early warning score such as NEWS2).[3]
For more information, see Risk stratification under Diagnosis recommendations.

Use a track-and-trigger scoring system such as the National Early Warning Score 2 (NEWS2) to identify any signs of deterioration.[3] Your monitoring should include:

Vital signs: heart rate, blood pressure, oxygen saturations, respiratory rate, and temperature
- Measure blood pressure via an arterial line if the patient does not respond to initial treatment or needs vasoactive drugs. It provides precise, continuous monitoring, and access for arterial blood sampling
Hourly urine output[3][47]
Lactate
- The lactate level should decrease if the patient is clinically improving
- Frequency of repeat lactate measurement depends on the cause of sepsis and treatment given.

Measure serum lactate, on a blood gas, to monitor response to treatment[3][43][47]

Lactate is a marker of stress and may be a marker of a worse prognosis (as a reflection of the degree of stress). Raised serum lactate highlights the possibility of tissue hypoperfusion and may be present in many conditions.[75][76]
Lactate may normalise quickly after fluid resuscitation. Patients whose lactate levels fail to normalise after adequate fluids are the group that fare worst.
Lactate >4 mmol/L (>36 mg/dL) is associated with worse outcomes.
- One study found in-hospital mortality rates as follows:[77]
  - Lactate <2 mmol/L (<18 mg/dL): 15%
  - Lactate 2.1 to 3.9 mmol/L (19 to 35mg/dL): 25%
  - Lactate >4 mmol/L (>36 mg/dL): 38%.

Do not be falsely reassured by a normal lactate (<2 mmol/L [<18 mg/dL]).

This does not rule out the patient being acutely unwell or at risk of deterioration or death due to organ dysfunction. Lactate helps to provide an overall picture of a patient's prognosis but you must take into account the full clinical picture of the individual patient in front of you including their NEWS2 score to determine when/whether to escalate treatment.[3]

Practical tip

Lactate is typically measured using a blood gas analyser, although laboratory analysis can also be performed.

Traditionally, arterial blood gas has been recommended as the ideal means of measuring lactate accurately. However, in the emergency department setting it is more practical and quicker to use venous blood gas, which is recommended by NICE.[3] Evidence suggests good agreement at lactate levels <2 mmol/L (<18 mg/dL) with small disparities at higher lactate levels.[78][79][80]

In the UK, use physiological track-and-trigger systems to monitor all adult patients in acute hospital settings.[3]

Consider using a validated scale such as the Glasgow Coma Scale or AVPU ('Alert, responds to Voice, responds to Pain, Unresponsive') scale to monitor the mental state of a patient with suspected sepsis. [ Glasgow Coma Scale Opens in new window ] [3]

Practical tip

AVPU should raise concerns if the assessment shows the patient is anything other than 'alert'.

Any patient with sepsis may be at significant risk of severe illness or death so it is vital to consider escalation of care to senior colleagues and/or healthcare facilities where increased and more advanced monitoring can be given (e.g., high-dependency unit/intensive care unit).[7][173][174]

Bear in mind that some patients (e.g., those who are frail) may not be suitable for management in intensive care settings. Consider the patient’s preferences for future care and their baseline health including their resuscitation status when determining the limits of treatment. Use this to feed into a personalised care plan appropriate to the individual patient.[45]

Consult local protocols for specific escalation routes but in general:

Ensure urgent review by a senior clinician (e.g., ST3 level doctor or higher in the UK) of any patient with a NEWS2 score of 5 or more calculated on initial assessment in the accident and emergency department or on ward deterioration:[3][41][45]
- Within 30 minutes of initial severity assessment for any patient with an aggregate NEWS2 score of 7 or more; or with a score of 5 or 6 if there is clinical or carer concern, continuing deterioration or lack of improvement, surgically remediable sepsis, neutropenia, or blood gas/laboratory evidence of organ dysfunction (including elevated serum lactate - see below)
- Within 1 hour of initial severity assessment for any patient with an aggregate NEWS2 score of 5 or 6
Inform the responsible consultant if a patient is at high risk of severe illness or death from sepsis (e.g., NEWS2 score of 7 or more) does not respond within 1 hour of any intervention (antibiotics/fluid resuscitation/oxygen).[3] Ensure the senior clinical decision-maker attends in person.

Signs that the person is not responding to resuscitation include lack of improvement or worsening:[3]

Tachycardia
Level of consciousness
Blood pressure
Respiratory rate
Blood lactate
Urine output
Peripheral perfusion
Blood gases.

Consider alerting critical care immediately if the patient is acutely unwell and:

Is likely to require central venous access and the initiation of inotropes or vasopressors[3]
- This includes any patient with evidence of circulatory dysfunction or shock, or those who do not respond to initial therapy (as outlined above), including initial fluid resuscitation within 1 hour.
Has any feature of septic shock
- See Shock
Has neutropenia
- See Febrile neutropenia
Is immunodeficient

Practical tip

Ensure a clear escalation plan has been discussed and agreed with the clinical team; include specific points of contact for nursing staff if you are leaving a patient for later review.

Involve a senior colleague and/or consider transferring to critical care sooner rather than later if the patient is not improving, or deemed high-risk. Examples include if the patient:

Is not responding to fluids
Needs inotropic support
Has a low Glasgow Coma Scale score
Needs ventilatory support.

Plus – identify the infection source

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Plus –

identify the infection source

Treatment recommended for ALL patients in selected patient group

Make intensive efforts to identify the anatomical site of infection as soon as possible.[3][43] Consider the need for urgent source control as soon as the patient is stable.

Start with a thorough and focused clinical history and examination, as well as initial investigations including imaging.[3]
Consider all lines and catheters as potential sources. Remove lines where appropriate.[43]
- Assume that any intravenous route is likely to either be the source of the infection, or will seed infections in the bloodstream, making eradication particularly difficult. Therefore, the priority for source control is often to remove any intravenous devices after alternative vascular access has been obtained.[43]
Involve the relevant surgical team early on if surgical or radiological intervention is suitable for the source of infection.[3][45] The surgical team or interventional radiologist should seek senior advice about the timing of intervention and carry the intervention out as soon as possible, in line with the advice received.[3]
- In practice, this may mean early transfer of the patient to a surgical centre if there are no facilities at your hospital.

Common non-specific signs and symptoms include:[21][43]

Those associated with a specific source of infection. Signs and symptoms of possible infection sources Opens in new window The most common sources are:[61]
- Respiratory tract (cough/pleuritic chest pain)
- Urinary tract (flank pain/dysuria)
- Abdominal/upper gastrointestinaI tract (abdominal pain)
- Skin/soft tissue (abscess/wound/catheter site)
- Surgical site or line/drain site
Tachypnoea
High (>38°C [>100.4°F]) or low (<36°C [<96.8°F]) temperature, sometimes with rigors
Tachycardia
Acutely altered mental status
Low oxygen saturation
Hypotension
Decreased urine output
- Ask the patient when they last passed urine
Poor capillary refill, mottling of the skin, or ashen appearance
Cyanosis
Malaise/lethargy
Nausea/vomiting/diarrhoea
Purpura fulminans (a very late sign but may be seen on presentation)
Ileus
Jaundice.

Practical tip

Jaundice is a rare sign of sepsis unless it is associated with a specific source of infection ( biliary sepsis).

[Figure caption and citation for the preceding image starts]: Capillary refill time. Top image: normal skin tone; middle image: pressure applied for 5 seconds; bottom image: time to hyperaemia measuredFrom the collection of Ron Daniels, MB, ChB, FRCA; used with permission [Citation ends].[Figure caption and citation for the preceding image starts]: Severe purpura fulminans; classically associated with meningococcal sepsis but can occur with pneumococcal sepsisFrom the collection of Ron Daniels, MB, ChB, FRCA; used with permission [Citation ends].

If your examination of the patient identifies a clear source of infection, consider the need for urgent source control, as soon as the patient is stable, particularly for:[43]

Gastrointestinal sources (such as visceral abscesses, cholangitis, or peritonitis secondary to perforation)
Severe skin infections (e.g., necrotising fasciitis)
Infection involving an indwelling device, where a procedure or surgery is likely to be required.

Give immediate, targeted antibiotics in people with sepsis thought to arise from a central nervous system source (e.g., suspected meningitis or meningococcal sepsis).[3]

Immediately give a third-generation cephalosporin such as ceftriaxone.
In community settings, pre-hospital administration of benzylpenicillin is recommended.
Follow local policy and consider discussing with microbiology/infectious disease colleagues to determine the most appropriate choice; use a 'start smart then focus' approach.[41][136]

Practical tip

If intravenous access is not feasible or is likely to lead to a delay in starting antibiotics and fluids, use intra-osseous access as an interim measure.

Consider – fluid resuscitation

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Consider –

fluid resuscitation

Additional treatment recommended for SOME patients in selected patient group

Give 500 mL of crystalloid fluid, with a sodium content between 130 mmol/L and 154 mmol/L (130 to 154 mEq/L) (e.g., 0.9% sodium chloride or Hartmann’s solution), over less than 15 minutes to patients who need fluid resuscitation (if either lactate is over 2 mmol/L or systolic blood pressure is less than 90 mmHg).[3][41][67]

Give this intravenous fluid bolus, if indicated, without delay (within 1 hour of identifying a patient is at high risk).[3]
Consider giving an intravenous fluid bolus to patients with a high risk of severe illness or death from sepsis if lactate is 2 mmol/L or lower.[3]
Reassess the patient’s haemodynamic status after the first bolus to consider whether a second is required.[3] If there is no response to either the first or second bolus, ensure the senior clinical decision-maker attends in person.[3]

Intravenous fluid resuscitation may be lifesaving in patients with hypotension. This is because in sepsis there is vasodilation and capillary leakage, which means that patients can rapidly become intravascularly deplete.[3]

In patients with sepsis-induced hypoperfusion (as indicated by a systolic blood pressure <90 mmHg, a raised lactate level, or signs of organ dysfunction), the Surviving Sepsis Campaign international guideline recommends a total of at least 30 mL/kg of intravenous crystalloid over the first 3 hours.[43]
- If the patient’s initial lactate level is raised, the guideline recommends serial lactate measurements to guide the need for further intravenous fluids (with the goal of normalising lactate levels).[43]

Practical tip

The delivery of appropriate rapid fluid challenges is intended to restore the imbalance between oxygen supply and demand to the tissues. Patients who do not respond to rapid delivery of adequate volumes of intravenous fluids are in septic shock and need immediate referral to critical care. The immediate priority in this group of patients is to restore the circulation and oxygen delivery.

Practical tip

Monitor patients closely for signs of fluid overload such as pulmonary or systemic oedema before and after each additional fluid bolus, as they may require large volumes of fluid to support their circulating volume.[43][152][153]

Check local protocols for specific recommendations on fluid choice. There is debate, based on conflicting evidence, on whether there is a benefit in using normal saline or balanced crystalloid in critically ill patients.

Practical tip

Be aware that large volumes of normal saline as the sole fluid for resuscitation may lead to hyperchloremic acidosis.

Also note that use of lactate-containing fluid in a patient with impaired liver metabolism may lead to a spuriously elevated lactate level, so results need to be interpreted with other markers of volume status.

Evidence: Choice of fluid

Evidence from two large randomised controlled trials (RCTs) suggests there is no difference between normal saline and a balanced crystalloid for critically ill patients in mortality at 90 days, although results from two meta-analyses including these RCTs point to a possible small benefit of balanced solutions compared with normal saline.

There has been extensive debate over the choice between normal saline (an unbalanced crystalloid) versus a balanced crystalloid (such as Hartmann’s solution [also known as Ringer’s lactate] or Plasma-Lyte®). Clinical practice varies widely, so you should check local protocols.

In 2021-2022 two large double-blind RCTs were published assessing intravenous fluid resuscitation in intensive care unit (ICU) patients with a balanced crystalloid solution (Plasma-Lyte) versus normal saline: the Plasma-Lyte 148 versus Saline (PLUS) trial (53 ICUs in Australia and New Zealand; N=5037) and the Balanced Solutions in Intensive Care Study (BaSICS) trial (75 ICUs in Brazil; N=11,052).[154][155]
- In the PLUS study, 45.2% of patients were admitted to ICU directly from surgery (emergency or elective), 42.3% had sepsis, and 79.0% were receiving mechanical ventilation at the time of randomisation.
- In BaSICS, almost half the patients (48.4%) were admitted to ICU after elective surgery and around 68% had some form of fluid resuscitation before being randomised.
- Both found no difference in 90-day mortality overall or in prespecified subgroups for patients with acute kidney injury (AKI), sepsis, or post-surgery. They also found no difference in the risk of AKI.
- In BaSICS, for patients with traumatic brain injury, there was a small decrease in 90-day mortality with normal saline; however, the overall number of patients was small (<5% of total included in the study) so there is some uncertainty about this result. Patients with traumatic brain injury were excluded from PLUS as the authors felt these patients should be receiving saline or a solution of similar tonicity.
A meta-analysis of 13 RCTs (including PLUS and BaSICS) confirmed no overall difference, although the authors did highlight a non-significant trend towards a benefit of balanced solutions for risk of death.[156]
A subsequent individual patient data meta-analysis included 6 RCTs of which only PLUS and BaSICS were assessed as being at low risk of bias. There was no statistically significant difference in in-hospital mortality (odds ratio [OR] 0.96, 95% CI 0.91 to 1.02). However, the authors argued that using a Bayesian analysis there was a high probability that balanced solutions reduced in-hospital mortality, although they acknowledged that the absolute risk reduction was small.[157]
- A pre-specified sub-group analysis of patients with traumatic brain injury (N=1961) found that balanced solutions increased the risk of in-hospital mortality compared with normal saline (OR 1.42, 95% CI 1.10 to 1.82)
Previous evidence has been mixed.
- One 2015 double-blind, cluster randomised, double-crossover trial conducted in 4 ICUs in New Zealand (N=2278), the 0.9% Saline vs Plasma-Lyte® for ICU fluid Therapy (SPLIT) trial, found no difference for in-hospital mortality, AKI, or use of renal-replacement therapy.[158]
- However, a 2018 US multicentre unblinded cluster-randomised trial - the isotonic Solutions and Major Adverse Renal events Trial (SMART), among 15,802 critically ill adults receiving ICU care - found possible small benefits from balanced crystalloid (Ringer’s lactate or Plasma-Lyte®) compared with normal saline. The 30-day outcomes showed a non-significant reduced mortality in the balanced crystalloid group versus the normal saline group (10.3% vs. 11.1%; odds ratio [OR] 0.90, 95% CI 0.80 to 1.01) and a major adverse kidney event rate of 14.3% versus 15.4%, respectively (OR 0.91, 95% CI 0.84 to 0.99).[159]
One 2019 Cochrane review included 21 RCTs (N=20,213) assessing balanced crystalloids versus normal saline for resuscitation or maintenance in a critical care setting.[160]
- The 3 largest RCTs in the Cochrane review (including SMART and SPLIT) all examined fluid resuscitation in adults and made up 94.2% of participants (N=19,054).
- There was no difference in in‐hospital mortality (OR 0.91, 95% CI 0.83 to 1.01; high-quality evidence as assessed by GRADE), acute renal injury (OR 0.92, 95% CI 0.84 to 1.00; GRADE low), or organ system dysfunction (OR 0.80, 95% CI 0.40 to 1.61; GRADE very low).

The Surviving Sepsis Campaign 2021 guideline update makes a weak recommendation (low-quality evidence) in favour of administering a balanced crystalloid (such as Hartmann's solution [Ringer's lactate] or Plasma-Lyte®) to patients with sepsis, based on evidence published prior to the BaSICS trial results.

Subgroup analysis of patients with sepsis within the BaSICS trial showed no difference in 90-day mortality between patients given normal saline (an unbalanced crystalloid) versus a balanced crystalloid. However, the authors comment that the subgroup analysis should be considered as hypothesis-generating only.[154] Further RCTs are awaited.

Practical tip

To guide the need for further intravenous fluids, it can sometimes be helpful to use bedside ultrasound to monitor changes in inferior vena cava (IVC) diameter during respiration.[161][162]

In the spontaneously breathing patient: consider additional fluid resuscitation if there is a collapsed (or collapsing) IVC.
In the mechanically ventilated patient: an increase in IVC size >18% (or visible to the naked eye) with positive pressure ventilation suggests fluid-responsiveness.

Practical tip

Use the passive leg-raising test to predict fluid-responsiveness if adequate monitoring is available.[67][163]

This is a useful indicator of fluid-responsiveness, which should be assessed using devices that can continuously monitor cardiac output in real time (e.g., Pulse index Continuous Cardiac Output [PiCCO] monitor or oesophageal Doppler), usually in an intensive care unit rather than a general ward setting.
Sit the patient upright at 45° and tilt the entire bed through 45°.
Patients with a positive test have a >10% increase in cardiac output or stroke volume, indicating more fluids may be required.
The passive leg-raise response may be misleading in conscious patients who are uncomfortable or in pain when lying flat.

Consider – oxygen

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Consider –

oxygen

Additional treatment recommended for SOME patients in selected patient group

If indicated, give oxygen. Monitor controlled oxygen therapy. An upper SpO₂ limit of 96% is reasonable when administering supplemental oxygen to most patients with acute illness who are not at risk of hypercapnia.

Evidence suggests that liberal use of supplemental oxygen (target SpO₂ >96%) in acutely ill adults is associated with higher mortality than more conservative oxygen therapy.[138]
A lower target SpO₂ of 88% to 92% is appropriate if the patient is at risk of hypercapnic respiratory failure.[50]

Evidence: Target oxygen saturation in acutely ill adults

Too much supplemental oxygen increases mortality.

Evidence from a large systematic review and meta-analysis supports conservative/controlled oxygen therapy versus liberal oxygen therapy in acutely ill adults who are not at risk of hypercapnia.

Guidelines differ in their recommendations on target oxygen saturation in acutely unwell adults who are receiving supplemental oxygen.
- The 2017 British Thoracic Society (BTS) guideline recommends a target SpO₂ range of 94% to 98% for patients not at risk of hypercapnia, whereas the 2022 Thoracic Society of Australia and New Zealand (TSANZ) guideline recommends 92% to 96%.[50][164]
- The 2022 Global Initiative For Asthma (GINA) guidelines recommend a target SpO₂ range of 93% to 96% in the context of acute asthma exacerbations.[165]
One systematic review including a meta-analysis of data from 25 randomised controlled trials published in 2018 found that in adults with acute illness, liberal oxygen therapy (broadly equivalent to a target saturation >96%) is associated with higher mortality than conservative oxygen therapy (broadly equivalent to a target saturation ≤96%).[138] In-hospital mortality was 11 per 1000 higher for the liberal oxygen therapy group versus the conservative therapy group (95% CI 2-22 per 1000 more). Mortality at 30 days was also higher in the group who had received liberal oxygen (relative risk 1.14, 95% CI 1.01 to 1.29). The trials included adults with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Studies that were limited to people with chronic respiratory illness or psychiatric illness, or patients on extracorporeal life support, receiving hyperbaric oxygen therapy, or having elective surgery, were all excluded from the review.
An upper SpO₂ limit of 96% is therefore reasonable when administering supplemental oxygen to patients with acute illness who are not at risk of hypercapnia. However, a higher target may be appropriate for some specific conditions (e.g., pneumothorax, carbon monoxide poisoning, cluster headache, or sickle cell crisis).[166]
In 2019 the BTS reviewed its guidance in response to this systematic review and meta-analysis and decided an interim update was not required.[167]
- The committee noted that the systematic review supported the use of controlled oxygen therapy to a target.
- While the systematic review showed an association between higher oxygen saturations and higher mortality, the BTS committee felt the review was not definitive on what the optimal target range should be. The suggested range of 94% to 96% in the review was based on the lower 95% confidence interval and the median baseline SpO₂ from the liberal oxygen groups, along with the earlier 2015 TSANZ guideline recommendation.
Subsequently, experience during the COVID-19 pandemic has also made clinicians more aware of the feasibility of permissive hypoxaemia.[168] The BTS guidance is due for a review in 2022.

Management of oxygen therapy in patients in intensive care is specialised and informed by further evidence (not covered in this summary) that is more specific to this setting.[169][170][171]

There is no specific evidence to show that giving oxygen improves clinical outcomes in sepsis. However, respiratory failure will lead to tissue hypoxia and anaerobic respiration. This is likely to lead to acidosis and consequently a poorer outcome.[172]

Consider – standard intensive care unit supportive care

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Consider –

standard intensive care unit supportive care

Additional treatment recommended for SOME patients in selected patient group

Bear in mind that some patients (e.g., those who are frail) may not be suitable for management in intensive care settings. Consider the patient’s preferences for future care and their baseline health including their resuscitation status when determining the limits of treatment. Use this to feed into a personalised care plan appropriate to the individual patient.[45]

Consult local protocols for specific escalation routes but in general:

Ensure urgent review by a senior clinician (e.g., ST3 level doctor or higher in the UK) of any patient with a National Early Warning Score 2 (NEWS2) score of 5 or more calculated on initial assessment in the accident and emergency department or on ward deterioration:[3][41][45]
- Within 30 minutes of initial severity assessment for any patient with an aggregate NEWS2 score of 7 or more; or with a score of 5 or 6 if there is clinical or carer concern, continuing deterioration or lack of improvement, surgically remediable sepsis, neutropenia, or blood gas/laboratory evidence of organ dysfunction (including elevated serum lactate)
- Within 1 hour of initial severity assessment for any patient with an aggregate NEWS2 score of 5 or 6
Inform the responsible consultant if a patient is at high risk of severe illness or death from sepsis (e.g., NEWS2 score of 7 or more) does not respond within 1 hour of any intervention (antibiotics/fluid resuscitation/oxygen).[3] Ensure the senior clinical decision-maker attends in person.
- Signs that the person is not responding to resuscitation include lack of improvement or worsening:[3]
  - Tachycardia
  - Level of consciousness
  - Blood pressure
  - Respiratory rate
  - Blood lactate
  - Urine output
  - Peripheral perfusion
  - Blood gases.

Consider alerting critical care immediately if the patient is acutely unwell and:
- Is likely to require central venous access and the initiation of inotropes or vasopressors[3]
  - This includes any patient with evidence of circulatory dysfunction or shock, or those who do not respond to initial therapy (as outlined above) including initial fluid resuscitation within 1 hour.
- Has any feature of septic shock
  - See Shock
- Has neutropenia
  - See Febrile neutropenia
- Is immunodeficient.

Practical tip

Ensure a clear escalation plan has been discussed and agreed with the clinical team; include specific points of contact for nursing staff if you are leaving a patient for later review.

Involve a senior colleague and/or consider transferring to critical care sooner rather than later if the patient is not improving, or deemed high-risk. Examples include if the patient:

Is not responding to fluids
Needs inotropic support
Has a low Glasgow Coma Scale score
Needs ventilatory support.

For any patient with suspected sepsis, consider the need for referral to a high-dependency unit for management by the critical care team.[177][178]

The following interventions should only be initiated by experienced members of the critical care team:[179]

Glycaemic control
Vasoactive drugs (vasopressors/inotropes)
Corticosteroids.

Additional intensive care measures that will be considered include:[43][180][181]

Stress ulcer prophylaxis (in people at risk of gastrointestinal bleeding)
- With an H2 antagonist or proton-pump inhibitor
Deep venous thrombosis prophylaxis
- With heparin and compression stockings
Enteral or parenteral nutrition
Administration of human albumin solution 4% to 5% in patients with sepsis and shock who have not responded to substantial volumes of crystalloids[3][43]
Transfusion of packed cells
- Consult local protocols for recommended threshold
- The Surviving Sepsis Campaign recommends using a threshold of 70 g/L (7 g/dL).[43]

Evidence: Threshold for transfusion of packed cells

In the general critical care population there is no improvement with blood transfusions given at a higher haemoglobin threshold compared with a lower haemoglobin threshold. Overall, a more restrictive transfusion strategy is recommended; however, individual patient factors should be taken into account.

The 2021 Surviving Sepsis Campaign guideline recommends a restrictive transfusion strategy for adults with sepsis or septic shock.[43] The guideline identifies the following evidence.

One multicentre parallel group randomised controlled trial (RCT) in people >16 years of age with septic shock (N=998) compared blood transfusion at a lower haemoglobin threshold with a higher threshold.[182]
- There was no difference in 90-day mortality between groups (risk ratio [RR] 0.94, 95% CI 0.78 to 1.09).
- The results were similar using different methods of analysis (adjusted for risk factors at baseline, and per-protocol analyses).
- Ischaemic events, severe adverse reactions, and need for life support were also similar.
A second multicentre RCT (838 critically ill adults) compared a restrictive strategy of red-cell transfusion with a liberal strategy.[183]
- Overall, 30-day mortality was similar in the two groups (18.7% vs. 23.3%, P = 0.11). Results were similar in the subgroup of patients with sepsis or septic shock (N=218) (22.8% vs. 29.7%, P = 0.36).
- The 30-day mortality rates were significantly lower in patients who were less acutely ill and in patients younger than 55 years old with the restrictive transfusion strategy. However, this was not the case in those with clinically significant cardiac disease.
- The mortality rate during hospitalisation was significantly lower in the restrictive-strategy group (22.3% vs. 28.1%, P = 0.05).
One single-centre RCT in critically ill adult cancer patients with septic shock (N=300) also compared a liberal with a restrictive strategy.[184]
- 28-day mortality was less in the liberal group, although this difference was not statistically significant (45% vs. 56%, HR 0.74, 95% CI 0.53 to 1.04). However 90-day mortality was significantly reduced in the liberal group (HR 0.72, 95% CI 0.53 to 0.97).
- There was no difference in duration of intensive care or hospital stay between groups.
Meta-analysis of the three studies found no difference in 28-day mortality (OR 0.99, 95% CI 0.67 to 1.46, quality of evidence as assessed by GRADE moderate).[43]

The guideline concluded that the evidence did not favour one strategy over the other. The authors therefore based their recommendation on resource use, cost-effectiveness, and health equity concerns.

There may be a case to consider giving transfusions at a higher haemoglobin level in some patients (e.g., people with myocardial ischaemia, severe hypoxaemia, or acute haemorrhage).[43]

In the initial resuscitative phase, transfusion to achieve a higher haematocrit of ≥30% may be appropriate.[177]

In patients requiring prolonged ventilatory support, give lung-protective ventilation using minimal peak inspiratory pressures (<30 cm H ₂O) and permissive hypercapnia to specifically limit pulmonary compromise .[185]

Titrate fraction of inspired oxygen (FiO ₂) to lowest effective levels to prevent oxygen toxicity and maintain central venous oxygen tension.

Glycaemic control

Although patients with sepsis are often hyperglycaemic, the optimal glucose target is unknown.

The Surviving Sepsis Campaign guideline recommends targeting a blood glucose level <10.0 mmol/L (<180 mg/dL).[43]

The UK National Institute for Health and Care Excellence makes no recommendations on glycaemic control in sepsis.[3]

Evidence: Glycaemic control

Recent years have seen a shift in opinion and practice regarding glycaemic control in critically ill people. Since 2001, the use of tight glycaemic control has been advocated in people with sepsis. More recent evidence, however, suggests an increase in adverse events (e.g., severe hypoglycaemia) in patients managed with very tight glycaemic control (targeting a blood glucose below 6.1 mmol/L [110 mg/dL]).[186][187]The conflicting evidence has led to variations in recommendations in different countries and settings. Follow your local protocol.

An international randomised controlled trial (RCT) of 6104 critically ill medical and surgical patients found increased 90-day mortality (odds ratio 1.14, 95% CI 1.02 to 1.28) with tighter glucose control, possibly due to more frequent episodes of hypoglycaemia.[188]
A 2010 systematic review of 6 RCTs and a meta-analysis investigating tight glucose control (4.4 to 6.1 mmol/L [80-110 mg/dL]) versus less strict glucose control in critically ill patients in the intensive care unit setting found no significant improvement in mortality with tight glucose control, but it was associated with significantly more hypoglycaemic episodes compared with less strict glucose control.[189]
An RCT of critically ill patients in a primarily surgical intensive care setting found lower patient mortality with tight glucose control, 4.4 to 6.1 mmol/L (80-110 mg/dL), compared with ‘conventional’ more liberal glucose control.[190]

Consider – vasopressor (should only be initiated by experienced members of the critical care team)

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Consider –

vasopressor (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

Vasopressors are used in a critical care setting to maintain a mean arterial pressure (MAP) ≥65 mmHg if the patient is unresponsive to fluid resuscitation.[3][43][179]

Failure to respond to initial fluid resuscitation is a sign of septic shock.[1]
Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines.
Noradrenaline (norepinephrine) is the vasopressor of choice, mainly because it increases MAP.[43]
- Noradrenaline is the vasopressor recommended by the Surviving Sepsis Campaign guideline.[43] The UK National Institute for Health and Care Excellence makes no recommendation on the choice of vasopressor.[3]
- If further vasopressor therapy is required to maintain adequate blood pressure, add vasopressin to noradrenaline.[43]

Practical tip

Vasopressors are usually administered via central venous access due to concerns of extravasation and tissue ischaemia. However, the Surviving Sepsis Campaign supports short-term (less than 6 hours) peripheral administration of vasopressors in a vein proximal to the antecubital fossa, depending on local availability, and expertise in placement, of central venous catheters.[43] Central venous access should be secured as soon as possible

These patients should also have an arterial catheter inserted as soon as possible to ensure more accurate monitoring of arterial blood pressure.[43]

Evidence: Choice of vasopressor

Although a systematic review of 23 randomised trials of patients with shock found no convincing evidence for the superiority of one vasopressor over another,more recent meta-analyses reported a higher mortality associated with dopamine than with noradrenaline.[191][192]

Primary options

noradrenaline (norepinephrine): 0.4 to 0.8 mg/hour intravenous infusion initially, adjust dose according to response

Secondary options

noradrenaline (norepinephrine): 0.4 to 0.8 mg/hour intravenous infusion initially, adjust dose according to response

and

vasopressin: 0.01 units/minute intravenous infusion initially, adjust dose according to response, maximum 0.03 units/minute

Consider – inotrope (should only be initiated by experienced members of the critical care team)

Back

Consider –

inotrope (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

Inotropes can be considered for patients with low cardiac output despite adequate fluid resuscitation and vasopressor therapy.[3][43]

Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines.
The Surviving Sepsis Campaign guideline recommends either adding dobutamine to noradrenaline or using adrenaline (epinephrine) alone for people with persistent hypoperfusion despite adequate volume status and arterial blood pressure.[43]

The UK National Institute for Health and Care Excellence makes no specific recommendations on inotrope selection in patients with sepsis.[3]

Practical tip

Suspect low cardiac output if the clinical examination reveals prolonged capillary refill times, low urine output, or poor peripheral perfusion. Confirm with cardiac output monitoring or by sampling central venous or pulmonary arterial blood to measure oxygen saturations.

When using inotropes, keep the patient’s heart rate at less than 100 beats per minute to minimise myocardial ischaemia.[179]

Primary options

dobutamine: 2.5 to 10 micrograms/kg/minute intravenous infusion initially, adjust dose according to response, maximum 40 micrograms/kg/minute

adrenaline (epinephrine): 2-10 micrograms/minute intravenous infusion initially, adjust dose according to response

Consider – corticosteroid (should only be initiated by experienced members of the critical care team)

Back

Consider –

corticosteroid (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

The Surviving Sepsis Campaign guideline recommends intravenous hydrocortisone for patients with an ongoing requirement for vasopressor therapy.[43]

The UK National Institute for Health and Care Excellence does not give any recommendations on the use of corticosteroids for managing sepsis in adults.[3]

Evidence: Benefits and harms of corticosteroids

In adults with sepsis, intravenous low-dose corticosteroids may reduce organ failure at 7 days, and duration of mechanical ventilation, vasopressor therapy, and intensive care stay. However, whether corticosteroids reduce short or longer-term mortality is unclear. Possible harms include an increased risk of neuromuscular weakness, hyperglycaemia, and hypernatraemia with corticosteroids compared with no corticosteroids.

The Surviving Sepsis Campaign (SSC) 2021 guideline made a weak recommendation for using intravenous low-dose corticosteroids for adults with septic shock and an ongoing need for vasopressors (overall evidence assessed as moderate using GRADE). This was a slight change from the prior 2016 recommendation due to the publication of three subsequent randomised controlled trials (VANISH, ADRENAL, and APROCHSS) and a meta-analysis including these studies (22 RCTs, N=7297).[43][193]

Duration of shock was reduced in patients who received corticosteroids compared with placebo (mean difference -1.52 days, 95% CI -1.71 to -1.32 days, quality of evidence as assessed by GRADE moderate).
- Corticosteroids also reduced organ failure at 1 week, duration of mechanical ventilation, and intensive care stay, and increased vasopressor-free days.
However, there was no difference in short-term mortality (risk ratio [RR] 0.96, 95% CI 0.91 to 1.02, GRADE high) with similar results for longer-term mortality (RR 0.96, 95% CI 0.90 to 1.02, GRADE moderate).
Corticosteroid use possibly increased neuromuscular weakness (RR 1.21, 95% CI 1.01 to 1.45, GRADE low).
- Corticosteroids also increased the risk of any adverse event but there was considerable heterogeneity.
No trials reported quality-of-life outcomes.
The guideline also noted that uncertainties remain about the optimal dose, timing of initiation, and duration of treatment.

Other systematic reviews have considered low-dose corticosteroids in adults and children with sepsis ( with or without shock). They have included slightly different studies and come to slightly different conclusions, particularly about mortality.

A Cochrane review (search date July 2019) included 61 trials (12,192 participants, 53 trials in adults only). There were no new studies comparing low-dose corticosteroids with placebo since ADRENAL and APROCHSS.[194]
- 2-day, 90-day, and hospital mortality were reduced with use of corticosteroids (GRADE moderate). However, there was no difference in mortality at 6 months to 1 year (GRADE low).
- Intensive care and hospital length of stay were significantly reduced with corticosteroids (GRADE high).
- Corticosteroids increased the risk of hypernatraemia (GRADE high) and probably increased the risk of hyperglycaemia (GRADE moderate). They also increased the risk of muscle weakness (GRADE high). They did not seem to increase the risk of superinfection (GRADE moderate).
- There was no significant difference in gastroduodenal bleeding, stroke, cardiac events, or neuropsychiatric events.
A rapid clinical practice guideline was published in 2018 triggered by publication of ADRENAL and APROCHSS.[195] The panel made a weak recommendation for the use of corticosteroids in adults and children with sepsis ( with and without shock). This guideline was also underpinned by a systematic review (42 RCTs, N=10,194).[196]
- The guideline panel concluded that it was uncertain whether corticosteroids reduced short-term mortality at 28 to 31 days (1.8% absolute risk reduction, 95% CI, 4.1% reduction to 0.8% increase, GRADE low), although they did seem to reduce longer-term mortality at 60 days to 1 year (2.2% absolute risk reduction; 95% CI, 4.1% reduction to 0%, GRADE moderate).
- Other results were similar to those of the SSC 2021 guideline and the Cochrane systematic review.
  [Figure caption and citation for the preceding image starts]: BMJ Rapid Recommendations: intravenous corticosteroids plus usual care versus usual care onlyLamontagne F, et al. BMJ 2018;362:k3284 [Citation ends].

Primary options

hydrocortisone sodium succinate: 50 mg intravenously every 6 hours

in the community: sepsis highly suspected and bacterial infection confirmed or highly suspected

1st line – refer for emergency medical care in hospital

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1st line –

refer for emergency medical care in hospital

Use your clinical judgement supported by physiological assessment.[51] Use National Early Warning Score 2 (NEWS2) scoring (encouraged by NHS England) to refer urgently to hospital any acutely unwell patient with suspected or confirmed infection according to the following triggers:[41] NHS England: Sepsis Opens in new window

Score 7 or more
- Make an emergency referral to hospital (via blue-light ambulance) for immediate critical care input.
Score 5-6 total, or 3 or more on any single parameter
- Make an immediate referral to an acute care setting and ensure the patient is reviewed by an acute clinician within an hour.

Track and trigger map developed by the West of England Academic Health Science Network National Early Warning Score project team Opens in new window

Alternatively, refer for emergency medical care in hospital (usually by blue-light ambulance in the UK) any acutely unwell patient with suspected or confirmed infection who:[3]

Meets one or more of the UK National Institute for Health and Care Excellence (NICE) high-risk criteria (red flags)
- Objective evidence of new altered mental state (e.g., new deterioration in Glasgow Coma Scale score/AVPU ['Alert, responds to Voice, responds to Pain, Unresponsive'] scale)
- Respiratory rate: ≥25 breaths per minute OR new need for oxygen (40% or more fraction of inspired oxygen [FiO ₂]) to maintain saturation >92% (or >88% in known chronic obstructive pulmonary disease)
- Heart rate: >130 beats per minute
- Systolic blood pressure ≤90 mmHg or more than 40 mmHg below normal
- Not passed urine in previous 18 hours, or for catheterised patients passed <0.5 mL/kg of urine per hour
- Mottled or ashen appearance
- Cyanosis of skin, lips, or tongue
- Non-blanching petechial or purpuric rash of skin
Is at risk of neutropenic sepsis and presents with symptoms and signs of infection
- See Febrile neutropenia.

Carefully consider whether emergency medical care is required or whether the patient can be safely managed in the community with safety netting advice.[3] See box below on safety netting advice.

Practical tip

If you need to refer a patient for emergency medical care in hospital, it is important to inform the hospital clinical team that the patient is on the way. This will enable the hospital to initiate appropriate treatment as soon as the patient arrives.

In a patient with signs and symptoms of an infection and evidence of physiological deterioration, presume sepsis until it can safely be excluded. Take a cautious approach when deciding whether it is safe to treat the patient’s infection in the community. Using your clinical judgement in making a decision is paramount. In particular, carefully consider the need for hospital admission if:[51][73][202]

The patient has one or more NICE high-risk criteria for sepsis
The patient appears seriously unwell to you, based on experience and clinical judgement
The patient lives alone with poor access to communication and/or transport
A carer or parent expresses serious concern about the patient (e.g., “they’re just not right”).

For details of the NICE risk criteria, see Diagnosis recommendations.

Treat the patient’s infection in line with local protocols and accepted practice. Antimicrobial prescribing guidelines from Public Health England and NICE are available for general practitioners in the UK.[200][201]

Practical tip

If you decide that the patient is safe to treat in the community, written and verbal safety netting is vital.[51] Ensure the information is clear and specific rather than generalised advice; for example, do not say “come back if you get worse” – instead, specify key symptoms to watch out for (such as a non-blanching rash, change in behaviour or mental state, mottled skin, or ashen appearance) and explain where and how to access immediate medical care both in and out of hours.[51]

If you give the patient any safety netting advice, ensure you document this clearly in their medical notes, along with the patient’s observations and whether you have offered them any antibiotics. The 2015 national confidential enquiry into sepsis deaths found recorded evidence that safety netting advice had been provided in fewer than one quarter of cases.[61]

The UK Sepsis Trust advises the following acronym:[47]

Slurred speech or confusion
Extreme shivering or muscle pain
Passing no urine (in a day)
Severe breathlessness
‘ I feel I might die’
Skin mottled, ashen, blue, or very pale.

Advise the patient to call the emergency services if any of these symptoms develop. If the patient has a change in condition or deterioration that is not covered by the acronym above, advise them to arrange another appointment to see their general practitioner or to call their out of hours service provider.

It is also good practice to consider arranging a next-day review appointment or telephone call; if you will be unable to review the patient yourself, provide a written handover for your colleagues.

Ambulance crews should evaluate the risk of severe illness or death from sepsis using NEWS2 and consider a time-critical transfer and pre-alerting the hospital for patients with suspected or confirmed infection who either have consecutive NEWS2 scores of 5 or above or show cause for significant clinical concern.[3] Paramedics who are thinking about giving antibiotics should follow local guidelines or seek advice from more senior colleagues, if needed.[3]

For patients at high risk of severe illness or death from sepsis who are in an acute mental health setting, follow local emergency protocols on treatment and ambulance transfer.[3]

Consider – oxygen

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Consider –

oxygen

Additional treatment recommended for SOME patients in selected patient group

If you have decided to refer the patient for emergency medical care and have called for an emergency ambulance, you should start oxygen therapy while awaiting the ambulance if resources are available to do so.[50] Pulse oximetry should be available in all locations where emergency oxygen is used.[50]

Monitor controlled oxygen therapy. An upper SpO₂ limit of 96% is reasonable when administering supplemental oxygen to most patients with acute illness who are not at risk of hypercapnia.

Evidence suggests that liberal use of supplemental oxygen (target SpO₂ >96%) in acutely ill adults is associated with higher mortality than more conservative oxygen therapy.[138]
A lower target SpO₂ of 88% to 92% is appropriate if the patient is at risk of hypercapnic respiratory failure.[50]

Evidence: Target oxygen saturation in acutely ill adults

Too much supplemental oxygen increases mortality.

Evidence from a large systematic review and meta-analysis supports conservative/controlled oxygen therapy versus liberal oxygen therapy in acutely ill adults who are not at risk of hypercapnia.

Guidelines differ in their recommendations on target oxygen saturation in acutely unwell adults who are receiving supplemental oxygen.
- The 2017 British Thoracic Society (BTS) guideline recommends a target SpO₂ range of 94% to 98% for patients not at risk of hypercapnia, whereas the 2022 Thoracic Society of Australia and New Zealand (TSANZ) guideline recommends 92% to 96%.[50][164]
- The 2022 Global Initiative For Asthma (GINA) guidelines recommend a target SpO₂ range of 93% to 96% in the context of acute asthma exacerbations.[165]

One systematic review including a meta-analysis of data from 25 randomised controlled trials, published in 2018, found that in adults with acute illness, liberal oxygen therapy (broadly equivalent to a target saturation >96%) is associated with higher mortality than conservative oxygen therapy (broadly equivalent to a target saturation ≤96%).[138] In-hospital mortality was 11 per 1000 higher for the liberal oxygen therapy versus the conservative therapy group (95% CI, 2-22 per 1000 more). Mortality at 30 days was also higher in the group who had received liberal oxygen (relative risk 1.14, 95% CI 1.01 to 1.29). The trials included adults with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Studies that were limited to people with chronic respiratory illness or psychiatric illness, or patients on extracorporeal life support, receiving hyperbaric oxygen therapy, or having elective surgery, were all excluded from the review.
An upper SpO₂ limit of 96% is therefore reasonable when administering supplemental oxygen to patients with acute illness who are not at risk of hypercapnia. However, a higher target may be appropriate for some specific conditions (e.g., pneumothorax, carbon monoxide poisoning, cluster headache, or sickle cell crisis).[166]
In 2019 the BTS reviewed its guidance in response to this systematic review and meta-analysis and decided an interim update was not required.[167]
- The committee noted that the systematic review supported the use of controlled oxygen therapy to a target.
- While the systematic review showed an association between higher oxygen saturations and higher mortality, the BTS committee felt the review was not definitive on what the optimal target range should be. The suggested range of 94% to 96% in the review was based on the lower 95% confidence interval and the median baseline SpO₂ from the liberal oxygen groups, along with the earlier 2015 TSANZ guideline recommendation.
Subsequently, experience during the COVID-19 pandemic has also made clinicians more aware of the feasibility of permissive hypoxaemia.[168] The BTS guidance is due for a review in 2022.
Management of oxygen therapy in patients in intensive care is specialised and informed by further evidence (not covered in this summary) that is more specific to this setting.[169][170][171]

Consider – broad-spectrum antibiotics

ACUTE

in hospital: sepsis highly suspected and clear source of bacterial infection identified

1st line – targeted antibiotics according to local protocols

Back

1st line –

targeted antibiotics according to local protocols

Once a definitive source has been identified, if appropriate to continue treating the patient with antibiotics, choose a treatment regimen in line with local or national policy (which will take into account specialist knowledge of resistance patterns).[43][137] Also consider discussing with microbiology/infectious disease colleagues to determine the most appropriate choice.

Assess the need to de-escalate antimicrobial therapy daily.[43]

Studies have shown that daily prompting about antimicrobial de-escalation is effective and may be associated with improved outcomes.[197][198]

Use the shortest effective course of antibiotics.[199]

Unnecessarily prolonged antibiotic treatment is associated with resistance.

More info: Antimicrobial resistance

Start smart – in the context of sepsis:[136]

Do not start antimicrobial therapy unless there is clear evidence of infection
Take a thorough drug allergy history
Initiate prompt effective antibiotic treatment within 1 hour of diagnosis (or as soon as possible) in patients with sepsis who are critically ill (e.g., septic shock, sepsis associated with rapid deterioration, or NEWS2 score of 7 or more calculated on initial assessment in the accident and emergency department or on ward deterioration) or with life-threatening infections. Avoid inappropriate use of broad-spectrum antibiotics[3][45]
Comply with local antimicrobial prescribing guidance
Document clinical indication (and disease severity if appropriate), drug name, dose, and route on drug chart and in clinical notes
Include review/stop date or duration
Obtain cultures prior to starting therapy where possible (but do not delay therapy).

Then focus – in the context of sepsis:[136]

Review the clinical diagnosis and the continuing need for antibiotics at 48 to 72 hours* and document in a clear plan of action – the ‘antimicrobial prescribing decision’
The ‘antimicrobial prescribing decision’ options are:
1. Stop antibiotics if there is no evidence of infection
2. Switch antibiotics from intravenous to oral
3. Change antibiotics – ideally to a narrower spectrum, or broader if required
4. Continue and document next review date or stop date
It is essential that the review and subsequent decision is clearly documented in the clinical notes and on the drug chart where possible (e.g., ‘stop antibiotic’).

*In clinical practice, daily prompting about de-escalation is encouraged.

Consult local microbiology guidance for other specific recommendations on de-escalation.

Most protocols will recommend switching from intravenous to oral antibiotics as soon as possible.

The Surviving Sepsis Campaign (SSC) recommends shorter over longer courses of antibiotics for patients with an initial diagnosis of sepsis or septic shock and adequate source control.[43] The optimal duration of antibiotic treatment in patients with sepsis remains contentious, with concerns regarding not only under-treatment but also the potential encouragement of antibiotic resistance. Consider seeking advice from microbiology/infectious disease colleagues.

Baseline serum procalcitonin is increasingly being used in critical care settings to guide decisions on how long to continue antibiotic therapy.[43][103][104][105]

Procalcitonin is a peptide precursor of calcitonin, which is responsible for calcium homeostasis.
The SSC suggests using procalcitonin alongside clinical evaluation to decide when to discontinue antimicrobials.[43]

Respiratory

Ensure treatment regimens cover common respiratory pathogens and atypical organisms such as Legionella pneumophila.

The respiratory tract is the most common site of infection in people with sepsis.[20][61]
See Overview of pneumonia.

Abdominal

Ensure gram-positive and gram-negative organisms including anaerobes are covered.[175]

Arrange urgent surgical drainage or percutaneous drainage (where appropriate) for peritonitis or intra-peritoneal abscesses.[176]

Urinary tract

Ensure gram-negative coliforms and Pseudomonas are covered. Ensuring patency of the urinary tract is vital.

In people older than 65 years of age, genitourinary tract infections are the most common cause of sepsis.[21][22]

Soft tissue and joint

Includes septic arthritis, wound infections, cellulitis, and acute super-infections arising from chronic ulceration. Most infections are polymicrobial. Ensure gram-positive and gram-negative organisms including anaerobes are covered.

Beware necrotising fasciitis, which requires immediate surgical intervention (as does septic arthritis).

Practical tip

Necrotising fasciitis is notoriously difficult to diagnose. The initial symptoms are non-specific and the clinical course is often slower than might be expected. Typically, the first sign is pain disproportionate to the clinical findings, followed or accompanied by fever.[74]

See Necrotising fasciitis.

Central nervous system

Relatively uncommon but potentially devastating source of sepsis. Beware meningococcal sepsis, which can be extremely rapidly fatal; if survived, can lead to greater morbidity than other forms of sepsis.

Give immediate, targeted antibiotics in people with sepsis thought to arise from a central nervous system source.[3]

Immediately give a third-generation cephalosporin, such as ceftriaxone, for suspected meningitis or meningococcal sepsis.[3]

Plus – reassess and monitor

Back

Plus –

reassess and monitor

Treatment recommended for ALL patients in selected patient group

Ensure frequent and ongoing monitoring.[3]

Standard monitoring of vital signs, pulse oximetry, level of consciousness, and urinary output is important for any patient with suspected sepsis.
The UK National Institute for Health and Care Excellence (NICE) recommends continuous or half-hourly monitoring (depending on setting) for any patient considered to be at high risk of deterioration.[3]
For more information, see Risk stratification under Diagnosis recommendations.

Use a track-and-trigger scoring system such as National Early Warning Score 2 (NEWS2) to identify any signs of deterioration.[3] Your monitoring should include:

Vital signs: heart rate, blood pressure, oxygen saturations, respiratory rate, and temperature
- Measure blood pressure via an arterial line if the patient does not respond to initial treatment or needs vasoactive drugs. It provides precise, continuous monitoring, and access for arterial blood sampling
Hourly urine output[3][47]
Lactate
- The lactate level should decrease if the patient is clinically improving
- Frequency of repeat lactate measurement depends on the cause of sepsis and treatment given.

Measure serum lactate, on a blood gas, to monitor response to treatment.[43][47]

Lactate is a marker of stress and may be a marker of a worse prognosis (as a reflection of the degree of stress). Raised serum lactate highlights the possibility of tissue hypoperfusion and may be present in many conditions.[75][76]
Lactate may normalise quickly after fluid resuscitation. Patients whose lactate levels fail to normalise after adequate fluids are the group that fare worst.
Lactate >4 mmol/L (>36 mg/dL) is associated with worse outcomes.
- One study found in-hospital mortality rates as follows:[77]
  - Lactate <2 mmol/L (<18 mg/dL): 15%
  - Lactate 2.1 to 3.9 mmol/L (19 to 35mg/dL): 25%
  - Lactate >4 mmol/L (>36 mg/dL): 38%.

Do not be falsely reassured by a normal lactate (<2 mmol/L [<18 mg/dL]).

This does not rule out the patient being acutely unwell or at risk of deterioration or death due to organ dysfunction. Lactate helps to provide an overall picture of a patient's prognosis but you must take into account the full clinical picture of the individual patient in front of you including their NEWS2 score to determine when/whether to escalate treatment.[3]

Practical tip

Lactate is typically measured using a blood gas analyser, although laboratory analysis can also be performed.

In the UK, use physiological track-and-trigger systems to monitor all adult patients in acute hospital settings.[3]

Practical tip

AVPU should raise concerns if the assessment shows the patient is anything other than 'alert'.

Bear in mind that some patients (e.g., those who are frail) may not be suitable for management in intensive care settings. Consider the patient’s preferences for future care and their baseline health including their resuscitation status when determining the limits of treatment. Use this to feed into a personalised care plan appropriate to the individual patient.[45]

Consult local protocols for specific escalation routes but in general:

Ensure urgent review by a senior clinician (e.g., ST3 level doctor or higher in the UK) of any patient with a NEWS2 score of 5 or more calculated on initial assessment in the accident and emergency department or on ward deterioration:[3][41][45]
- Within 30 minutes of initial severity assessment for any patient with an aggregate NEWS2 score of 7 or more; or with a score of 5 or 6 if there is clinical or carer concern, continuing deterioration or lack of improvement, surgically remediable sepsis, neutropenia, or blood gas/laboratory evidence of organ dysfunction (including elevated serum lactate - see below)
- Within 1 hour of initial severity assessment for any patient with an aggregate NEWS2 score of 5 or 6
Inform the responsible consultant if a patient is at high risk of severe illness or death from sepsis (e.g., NEWS2 score of 7 or more) does not respond within 1 hour of any intervention (antibiotics/fluid resuscitation/oxygen).[3] Ensure the senior clinical decision-maker attends in person.
- Signs that the person is not responding to resuscitation include lack of improvement or worsening:[3]
  - Tachycardia
  - Level of consciousness
  - Blood pressure
  - Respiratory rate
  - Blood lactate
  - Urine output
  - Peripheral perfusion
  - Blood gases.

Consider alerting critical care immediately if the patient is acutely unwell and:
- Is likely to require central venous access and the initiation of inotropes or vasopressors[3]
  - This includes any patient with evidence of circulatory dysfunction or shock, or those who do not respond to initial therapy (as outlined above) including initial fluid resuscitation within 1 hour.
- Has any feature of septic shock
  - See Shock
- Has neutropenia
  - See Febrile neutropenia
- Is immunodeficient

Practical tip

Ensure a clear escalation plan has been discussed and agreed with the clinical team; include specific points of contact for nursing staff if you are leaving a patient for later review.

Involve a senior colleague and/or consider transferring to critical care sooner rather than later if the patient is not improving, or deemed high-risk. Examples include if the patient:

Is not responding to fluids
Needs inotropic support
Has a low Glasgow Coma Scale score
Needs ventilatory support.

Plus – urgent source control

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Plus –

urgent source control

Treatment recommended for ALL patients in selected patient group

Once a site of infection has been identified, early and adequate source control is critical. Consider the need for urgent source control, as soon as the patient is stable, particularly for:[43]

Gastrointestinal sources (such as visceral abscesses, cholangitis, or peritonitis secondary to perforation)
Severe skin infections (e.g., necrotising fasciitis)
Infection involving an indwelling device, where a procedure or surgery is likely to be required.

Give immediate, targeted antibiotics in people with sepsis thought to arise from a central nervous system source (e.g., suspected meningitis or meningococcal sepsis).[3]

Immediately give a third-generation cephalosporin such as ceftriaxone.
In community settings, pre-hospital administration of benzylpenicillin is recommended.
Follow local policy and consider discussing with microbiology/infectious disease colleagues to determine the most appropriate choice; use a ‘start smart then focus’ approach.[41][136]

Practical tip

If intravenous access is not feasible or is likely to lead to a delay in starting antibiotics and fluids, use intra-osseous access as an interim measure.

Consider – fluid resuscitation

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Consider –

fluid resuscitation

Additional treatment recommended for SOME patients in selected patient group

Give this intravenous fluid bolus, if indicated, without delay (within 1 hour of identifying a patient is at high risk).[3]
Consider giving an intravenous fluid bolus to patients with a high risk of severe illness or death from sepsis if lactate is 2 mmol/L or lower.[3]

Reassess the patient’s haemodynamic status after the first bolus to consider whether a second is required.[3] If there is no response to either the first or second bolus, ensure the senior clinical decision-maker attends in person.[3]

In patients with sepsis-induced hypoperfusion (as indicated by a systolic blood pressure <90 mmHg, a raised lactate level, or signs of organ dysfunction), the Surviving Sepsis Campaign international guideline recommends a total of at least 30 mL/kg of intravenous crystalloid over the first 3 hours.[43]
- If the patient’s initial lactate level is raised, the guideline recommends serial lactate measurements to guide the need for further intravenous fluids (with the goal of normalising lactate levels).[43]

Practical tip

Check local protocols for specific recommendations on fluid choice. There is debate, based on conflicting evidence, on whether there is a benefit in using normal saline or balanced crystalloid in critically ill patients.

Practical tip

Be aware that large volumes of normal saline as the sole fluid for resuscitation may lead to hyperchloraemic acidosis.

Evidence: Choice of fluid

In 2021-2022 two large double-blind RCTs were published assessing intravenous fluid resuscitation in intensive care unit (ICU) patients with a balanced crystalloid solution (Plasma-Lyte) versus normal saline: the Plasma-Lyte 148 versus Saline (PLUS) trial (53 ICUs in Australia and New Zealand; N=5037) and the Balanced Solutions in Intensive Care Study (BaSICS) trial (75 ICUs in Brazil; N=11,052).[154][155]
- In the PLUS study, 45.2% of patients were admitted to ICU directly from surgery (emergency or elective), 42.3% had sepsis, and 79.0% were receiving mechanical ventilation at the time of randomisation.
- In BaSICS, almost half the patients (48.4%) were admitted to ICU after elective surgery and around 68% had some form of fluid resuscitation before being randomised.
- Both found no difference in 90-day mortality overall or in prespecified subgroups for patients with acute kidney injury (AKI), sepsis, or post-surgery. They also found no difference in the risk of AKI.
- In BaSICS, for patients with traumatic brain injury, there was a small decrease in 90-day mortality with normal saline; however, the overall number of patients was small (<5% of total included in the study) so there is some uncertainty about this result. Patients with traumatic brain injury were excluded from PLUS as the authors felt these patients should be receiving saline or a solution of similar tonicity.
A meta-analysis of 13 RCTs (including PLUS and BaSICS) confirmed no overall difference, although the authors did highlight a non-significant trend towards a benefit of balanced solutions for risk of death.[156]
A subsequent individual patient data meta-analysis included 6 RCTs of which only PLUS and BaSICS were assessed as being at low risk of bias. There was no statistically significant difference in in-hospital mortality (OR 0.96, 95% CI 0.91 to 1.02). However, the authors argued that using a Bayesian analysis there was a high probability that balanced solutions reduced in-hospital mortality, although they acknowledged that the absolute risk reduction was small.[157]
- A pre-specified sub-group analysis of patients with traumatic brain injury (N=1961) found that balanced solutions increased the risk of in-hospital mortality compared with normal saline (OR 1.42, 95% CI 1.10 to 1.82).
Previous evidence has been mixed.
- One 2015 double-blind, cluster randomised, double-crossover trial conducted in 4 ICUs in New Zealand (N=2278), the 0.9% Saline vs Plasma-Lyte® for ICU fluid Therapy (SPLIT) trial, found no difference for in-hospital mortality, AKI, or use of renal-replacement therapy.[158]
- However, a 2018 US multicentre unblinded cluster-randomised trial - the isotonic Solutions and Major Adverse Renal events Trial (SMART), among 15,802 critically ill adults receiving ICU care - found possible small benefits from balanced crystalloid (Ringer’s lactate or Plasma-Lyte®) compared with normal saline. The 30-day outcomes showed a non-significant reduced mortality in the balanced crystalloid group versus the normal saline group (10.3% vs. 11.1%; odds ratio [OR] 0.90, 95% CI 0.80 to 1.01) and a major adverse kidney event rate of 14.3% versus 15.4%, respectively (OR 0.91, 95% CI 0.84 to 0.99).[159]
One 2019 Cochrane review included 21 RCTs (N=20,213) assessing balanced crystalloids versus normal saline for resuscitation or maintenance in a critical care setting.[160]
- The 3 largest RCTs in the Cochrane review (including SMART and SPLIT) all examined fluid resuscitation in adults and made up 94.2% of participants (N=19,054).
- There was no difference in in‐hospital mortality (OR 0.91, 95% CI 0.83 to 1.01; high-quality evidence as assessed by GRADE), acute renal injury (OR 0.92, 95% CI 0.84 to 1.00; GRADE low), or organ system dysfunction (OR 0.80, 95% CI 0.40 to 1.61; GRADE very low).

Subgroup analysis of patients with sepsis within the BaSICS trial showed no difference in 90-day mortality between patients given normal saline (an unbalanced crystalloid) versus a balanced crystalloid. However, the authors comment that the subgroup analysis should be considered as hypothesis-generating only.[154] Further RCTs are awaited.

Practical tip

To guide the need for further intravenous fluids, it can sometimes be helpful to use bedside ultrasound to monitor changes in inferior vena cava (IVC) diameter during respiration.[161][162]

In the spontaneously breathing patient: consider additional fluid resuscitation if there is a collapsed (or collapsing) IVC.
In the mechanically ventilated patient: an increase in IVC size >18% (or visible to the naked eye) with positive pressure ventilation suggests fluid-responsiveness.

Practical tip

Use the passive leg-raising test to predict fluid-responsiveness if adequate monitoring is available.[67][163]

This is a useful indicator of fluid-responsiveness, which should be assessed using devices that can continuously monitor cardiac output in real time (e.g., Pulse index Continuous Cardiac Output (PiCCO) monitor or oesophageal Doppler), usually in an intensive care unit rather than general ward setting.
Sit the patient upright at 45° and tilt the entire bed through 45°.
Patients with a positive test have a >10% increase in cardiac output or stroke volume, indicating more fluids may be required.
The passive leg-raise response may be misleading in conscious patients who are uncomfortable or in pain when lying flat.

Consider – oxygen

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Consider –

oxygen

Additional treatment recommended for SOME patients in selected patient group

Monitor controlled oxygen therapy. An upper SpO₂ limit of 96% is reasonable when administering supplemental oxygen to most patients with acute illness who are not at risk of hypercapnia.

Evidence suggests that liberal use of supplemental oxygen (target SpO₂ >96%) in acutely ill adults is associated with higher mortality than more conservative oxygen therapy.[138]
A lower target SpO₂ of 88% to 92% is appropriate if the patient is at risk of hypercapnic respiratory failure.[50]

Evidence: Target oxygen saturation in acutely ill adults

Too much supplemental oxygen increases mortality.

Evidence from a large systematic review and meta-analysis supports conservative/controlled oxygen therapy versus liberal oxygen therapy in acutely ill adults who are not at risk of hypercapnia.

Guidelines differ in their recommendations on target oxygen saturation in acutely unwell adults who are receiving supplemental oxygen.
- The 2017 British Thoracic Society (BTS) guideline recommends a target SpO₂ range of 94% to 98% for patients not at risk of hypercapnia, whereas the 2022 Thoracic Society of Australia and New Zealand (TSANZ) guideline recommends 92% to 96%.[50][164]
- The 2022 Global Initiative For Asthma (GINA) guidelines recommend a target SpO₂ range of 93% to 96% in the context of acute asthma exacerbations.[165]
A systematic review including a meta-analysis of data from 25 randomised controlled trials, published in 2018, found that in adults with acute illness, liberal oxygen therapy (broadly equivalent to a target saturation >96%) is associated with higher mortality than conservative oxygen therapy (broadly equivalent to a target saturation ≤96%).[138] In-hospital mortality was 11 per 1000 higher for the liberal oxygen therapy versus the conservative therapy group (95% CI, 2-22 per 1000 more). Mortality at 30 days was also higher in the group who had received liberal oxygen (relative risk 1.14, 95% CI 1.01 to 1.29). The trials included adults with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Studies that were limited to people with chronic respiratory illness or psychiatric illness, or patients on extracorporeal life support, receiving hyperbaric oxygen therapy, or having elective surgery were all excluded from the review.
An upper SpO₂ limit of 96% is therefore reasonable when administering supplemental oxygen to patients with acute illness who are not at risk of hypercapnia. However, a higher target may be appropriate for some specific conditions (e.g., pneumothorax, carbon monoxide poisoning, cluster headache, or sickle cell crisis).[166]
In 2019 the BTS reviewed its guidance in response to this systematic review and meta-analysis and decided an interim update was not required.[167]
- The committee noted that the systematic review supported the use of controlled oxygen therapy to a target.
- While the systematic review showed an association between higher oxygen saturations and higher mortality, the BTS committee felt the review was not definitive on what the optimal target range should be. The suggested range of 94% to 96% in the review was based on the lower 95% confidence interval and the median baseline SpO₂ from the liberal oxygen groups, along with the earlier 2015 TSANZ guideline recommendation.
Subsequently, experience during the COVID-19 pandemic has also made clinicians more aware of the feasibility of permissive hypoxaemia.[168] The BTS guidance is due for a review in 2022.
Management of oxygen therapy in patients in intensive care is specialised and informed by further evidence (not covered in this summary) that is more specific to this setting.[169][170][171]

Consider – standard intensive care unit supportive care

Back

Consider –

standard intensive care unit supportive care

Additional treatment recommended for SOME patients in selected patient group

Bear in mind that some patients (e.g., those who are frail) may not be suitable for management in intensive care settings. Consider the patient’s preferences for future care and their baseline health including their resuscitation status when determining the limits of treatment. Use this to feed into a personalised care plan appropriate to the individual patient.[45]

Consult local protocols for specific escalation routes but in general:

Ensure urgent review by a senior clinician (e.g., ST3 level doctor or higher in the UK) of any patient with a National Early Warning Score 2 (NEWS2) score of 5 or more calculated on initial assessment in the accident and emergency department or on ward deterioration:[3][41][45]
- Within 30 minutes of initial severity assessment for any patient with an aggregate NEWS2 score of 7 or more; or with a NEWS2 score of 5 or 6 if there is clinical or carer concern, continuing deterioration or lack of improvement, surgically remediable sepsis, neutropenia, or blood gas/laboratory evidence of organ dysfunction (including elevated serum lactate - see below)
- Within 1 hour of initial severity assessment for any patient with an aggregate NEWS2 score of 5 or 6
Inform the responsible consultant if a patient is at high risk of severe illness or death from sepsis (e.g., NEWS2 score of 7 or more) does not respond within 1 hour of any intervention (antibiotics/fluid resuscitation/oxygen).[3] Ensure the senior clinical decision-maker attends in person.
- Signs that the person is not responding to resuscitation include lack of improvement or worsening:[3]
  - Tachycardia
  - Level of consciousness
  - Blood pressure
  - Respiratory rate
  - Blood lactate
  - Urine output
  - Peripheral perfusion
  - Blood gases.

Consider alerting critical care immediately if the patient is acutely unwell and:
- Is likely to require central venous access and the initiation of inotropes or vasopressors[3]
  - This includes any patient with evidence of circulatory dysfunction or shock, or those who do not respond to initial therapy (as outlined above) including fluid resuscitation within 1 hour.
- Has any feature of septic shock
  - See Shock
- Has neutropenia
  - See Febrile neutropenia
- Is immunodeficient.

Practical tip

Ensure a clear escalation plan has been discussed and agreed with the clinical team; include specific points of contact for nursing staff if you are leaving a patient for later review.

Involve a senior colleague and/or consider transferring to critical care sooner rather than later if the patient is not improving, or deemed high-risk.Examples include if the patient:

Is not responding to fluids
Needs inotropic support
Has a low Glasgow Coma Scale score
Needs ventilatory support.

For any patient with suspected sepsis, consider the need for referral to a high-dependency unit for management by the critical care team.[177][178]

The following interventions should only be initiated by experienced members of the critical care team:[179]

Glycaemic control
Vasoactive drugs (vasopressors/inotropes)
Corticosteroids.

Additional intensive care measures that will be considered include:[43][180][181]

Stress ulcer prophylaxis (in people at risk of gastrointestinal bleeding)
- With an H2 antagonist or proton-pump inhibitor
Deep venous thrombosis prophylaxis
- With heparin and compression stockings
Enteral or parenteral nutrition
Administration of human albumin solution 4% to 5% in patients with sepsis and shock who have not responded to substantial volumes of crystalloids[3][43]
Transfusion of packed cells
- Consult local protocols for recommended threshold
- The Surviving Sepsis Campaign recommends using a threshold of 70 g/L (7 g/dL).[43]

Evidence: Threshold for transfusion of packed cells

The 2021 Surviving Sepsis Campaign guideline recommends a restrictive transfusion strategy for adults with sepsis or septic shock.[43] The guideline identifies the following evidence.

One multicentre parallel group randomised controlled trial (RCT) in people >16 years of age with septic shock (N=998) compared blood transfusion at a lower haemoglobin threshold with a higher threshold.[182]
- There was no difference in 90-day mortality between groups (risk ratio [RR] 0.94, 95% CI 0.78 to 1.09).
- The results were similar using different methods of analysis (adjusted for risk factors at baseline, and per-protocol analyses).
- Ischaemic events, severe adverse reactions, and need for life support were also similar.
A second multicentre RCT (838 critically ill adults) compared a restrictive strategy of red-cell transfusion with a liberal strategy.[183]
- Overall, 30-day mortality was similar in the two groups (18.7% vs. 23.3%, P = 0.11). Results were similar in the subgroup of patients with sepsis or septic shock (N=218) (22.8% vs. 29.7%, P = 0.36).
- The 30-day mortality rates were significantly lower in patients who were less acutely ill and in patients younger than 55 years old with the restrictive transfusion strategy. However, this was not the case in those with clinically significant cardiac disease.
- The mortality rate during hospitalisation was significantly lower in the restrictive-strategy group (22.3% vs. 28.1%, P = 0.05).
A single-centre RCT in critically ill adult cancer patients with septic shock (N=300) also compared a liberal with a restrictive strategy.[184]
- 28-day mortality was less in the liberal group, although this difference was not statistically significant (45% vs. 56%, HR 0.74, 95% CI 0.53 to 1.04). However 90-day mortality was significantly reduced in the liberal group (hazard ratio [HR] 0.72, 95% CI 0.53 to 0.97).
- There was no difference in duration of intensive care or hospital stay between groups.
Meta-analysis of the three studies found no difference in 28-day mortality (odds ratio [OR] 0.99, 95% CI 0.67 to 1.46, quality of evidence as assessed by GRADE moderate).[43]

The guideline concluded that the evidence did not favour one strategy over the other. The authors therefore based their recommendation on resource use, cost-effectiveness, and health equity concerns.

There may be a case to consider giving transfusions at a higher haemoglobin level in some patients (e.g., people with myocardial ischaemia, severe hypoxaemia, or acute haemorrhage).[43]

In the initial resuscitative phase, transfusion to achieve a higher haematocrit of ≥30% may be appropriate.[177]

Titrate fraction of inspired oxygen (FiO ₂) to lowest effective levels to prevent oxygen toxicity and maintain central venous oxygen tension.

Glycaemic control

Although patients with sepsis are often hyperglycaemic, the optimal glucose target is unknown.

The Surviving Sepsis Campaign guideline recommends targeting a blood glucose level <10.0 mmol/L (<180 mg/dL).[43]

NICE makes no recommendations on glycaemic control in sepsis.[3]

Evidence: Glycaemic control

An international randomised controlled trial (RCT) of 6104 critically ill medical and surgical patients found increased 90-day mortality (odds ratio 1.14, 95% CI 1.02 to 1.28) with tighter glucose control, possibly due to more frequent episodes of hypoglycaemia.[188]
A 2010 systematic review of 6 RCTs and a meta-analysis investigating tight glucose control (4.4 to 6.1 mmol/L [80-110 mg/dL]) versus less strict glucose control in critically ill patients in the intensive care unit setting found no significant improvement in mortality with tight glucose control, but it was associated with significantly more hypoglycaemic episodes compared with less strict glucose control.[189]
An RCT of critically ill patients in a primarily surgical intensive care setting found lower patient mortality with tight glucose control, 4.4 to 6.1 mmol/L (80-110 mg/dL), compared with ‘conventional’ more liberal glucose control.[190]

Consider – vasopressor (should only be initiated by experienced members of the critical care team)

Back

Consider –

vasopressor (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

Vasopressors are used in a critical care setting to maintain a mean arterial pressure (MAP) ≥65 mmHg if the patient is unresponsive to fluid resuscitation.[3][43][179]

Failure to respond to initial fluid resuscitation is a sign of septic shock.[1]
Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines.
Noradrenaline (norepinephrine) is the vasopressor of choice, mainly because it increases MAP.[43]
- Noradrenaline is the vasopressor recommended by the Surviving Sepsis Campaign guideline.[43] The UK National Institute for Health and Care Excellence makes no recommendation on the choice of vasopressor.[3]
- If further vasopressor therapy is required to maintain adequate blood pressure, add vasopressin to noradrenaline.

Practical tip

These patients should also have an arterial catheter inserted as soon as possible to ensure more accurate monitoring of arterial blood pressure.[43]

Evidence: Choice of vasopressor

Primary options

noradrenaline (norepinephrine): 0.4 to 0.8 mg/hour intravenous infusion initially, adjust dose according to response

Secondary options

noradrenaline (norepinephrine): 0.4 to 0.8 mg/hour intravenous infusion initially, adjust dose according to response

and

vasopressin: 0.01 units/minute intravenous infusion initially, adjust dose according to response, maximum 0.03 units/minute

Consider – inotrope (should only be initiated by experienced members of the critical care team)

Back

Consider –

inotrope (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

Inotropes can be considered for patients with low cardiac output despite adequate fluid resuscitation and vasopressor therapy.[3][43]

Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines.
The Surviving Sepsis Campaign guideline recommends either adding dobutamine to noradrenaline or using adrenaline (epinephrine) alone for people with persistent hypoperfusion despite adequate volume status and arterial blood pressure.[43]
The UK National Institute for Health and Care Excellence makes no specific recommendations on inotrope selection in patients with sepsis.[3]

Practical tip

When using inotropes, keep the patient’s heart rate at less than 100 beats per minute to minimise myocardial ischaemia.[179]

Primary options

dobutamine: 2.5 to 10 micrograms/kg/minute intravenous infusion initially, adjust dose according to response, maximum 40 micrograms/kg/minute

adrenaline (epinephrine): 2-10 micrograms/minute intravenous infusion initially, adjust dose according to response

Consider – corticosteroid (should only be initiated by experienced members of the critical care team)

Back

Consider –

corticosteroid (should only be initiated by experienced members of the critical care team)

Additional treatment recommended for SOME patients in selected patient group

The Surviving Sepsis Campaign guideline recommends intravenous hydrocortisone for patients with an ongoing requirement for vasopressor therapy.[43]

The UK National Institute for Health and Care Excellence does not give any recommendations on the use of corticosteroids for managing sepsis in adults.[3]

Evidence: Benefits and harms of corticosteroids

Duration of shock was reduced in patients who received corticosteroids compared with placebo (mean difference -1.52 days, 95% CI -1.71 to -1.32 days, quality of evidence as assessed by GRADE moderate).
- Corticosteroids also reduced organ failure at 1 week, duration of mechanical ventilation, and intensive care stay; and increased vasopressor-free days.
However, there was no difference in short-term mortality (risk ratio [RR] 0.96, 95% CI 0.91 to 1.02, GRADE high) with similar results for longer-term mortality (RR 0.96, 95% CI 0.90 to 1.02, GRADE moderate).
Corticosteroid use possibly increased neuromuscular weakness (RR 1.21, 95% CI 1.01 to 1.45, GRADE low).
- Corticosteroids also increased the risk of any adverse event but there was considerable heterogeneity.
No trials reported quality-of-life outcomes.
The guideline also noted that uncertainties remain about the optimal dose, timing of initiation, and duration of treatment.

A Cochrane review (search date July 2019) included 61 trials (12,192 participants, 53 trials in adults only). There were no new studies comparing low-dose corticosteroids with placebo since ADRENAL and APROCHSS.[194]
- 28-day, 90-day, and hospital mortality were reduced with use of corticosteroids (GRADE moderate). However, there was no difference in mortality at 6 months to 1 year (GRADE low).
- Intensive care and hospital length of stay were significantly reduced with corticosteroids (GRADE high).
- Corticosteroids increased the risk of hypernatraemia (GRADE high) and probably increased the risk of hyperglycaemia (GRADE moderate). They also increased the risk of muscle weakness (GRADE high). They did not seem to increase the risk of superinfection (GRADE moderate).
- There was no significant difference in gastroduodenal bleeding, stroke, cardiac events, or neuropsychiatric events.
A rapid clinical practice guideline was published in 2018 triggered by publication of ADRENAL and APROCHSS.[195] The panel made a weak recommendation for the use of corticosteroids in adults and children with sepsis ( with and without shock). This guideline was also underpinned by a systematic review (42 RCTs, N=10,194).[196]
- The guideline panel concluded that it was uncertain whether corticosteroids reduced short-term mortality at 28 to 31 days (1.8% absolute risk reduction, 95% CI, 4.1% reduction to 0.8% increase, GRADE low), although they did seem to reduce longer-term mortality at 60 days to 1 year (2.2% absolute risk reduction; 95% CI, 4.1% reduction to 0%, GRADE moderate).
- Other results were similar to those of the SSC 2021 guideline and the Cochrane systematic review. [Figure caption and citation for the preceding image starts]: BMJ Rapid Recommendations: intravenous corticosteroids plus usual care versus usual care onlyLamontagne F, et al. BMJ 2018;362:k3284 [Citation ends].

Primary options

hydrocortisone sodium succinate: 50 mg intravenously every 6 hours

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Sepsis in adults

Treatment algorithm

in hospital: sepsis highly suspected and unknown or unclear source of bacterial infection

broad-spectrum intravenous antibiotics

More info: Antimicrobial resistance

Practical tip

Practical tip

Evidence: 1- and 3-hour antibiotic targets

Evidence: Prolonged antibiotic infusion

reassess and monitor

Practical tip

Practical tip

Practical tip

identify the infection source

Practical tip

Practical tip

fluid resuscitation

Practical tip

Practical tip

Practical tip

Evidence: Choice of fluid

Practical tip

Practical tip

oxygen

Evidence: Target oxygen saturation in acutely ill adults

standard intensive care unit supportive care

Practical tip

Evidence: Threshold for transfusion of packed cells

Glycaemic control

Evidence: Glycaemic control

vasopressor (should only be initiated by experienced members of the critical care team)

Practical tip

Evidence: Choice of vasopressor

Primary options

Secondary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Secondary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

Secondary options

inotrope (should only be initiated by experienced members of the critical care team)

Practical tip

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

corticosteroid (should only be initiated by experienced members of the critical care team)

Evidence: Benefits and harms of corticosteroids

Primary options

These drug options and doses relate to a patient with no comorbidities.

Primary options

Drug choice, dose and interactions may be affected by the patient's comorbidities. Check your local drug formulary.

Primary options

in the community: sepsis highly suspected and bacterial infection confirmed or highly suspected

refer for emergency medical care in hospital

Practical tip

Practical tip

oxygen

Evidence: Target oxygen saturation in acutely ill adults

broad-spectrum antibiotics

in hospital: sepsis highly suspected and clear source of bacterial infection identified

targeted antibiotics according to local protocols

More info: Antimicrobial resistance

Respiratory

Abdominal

Urinary tract

Soft tissue and joint

Practical tip

Central nervous system

reassess and monitor

Practical tip

Practical tip

Practical tip

urgent source control

Practical tip

fluid resuscitation

Practical tip

Practical tip