Recommendations

Urgent

Start treatment immediately if a senior clinical decision-maker makes a diagnosis of suspected sepsis.[41][42] NHS England: Sepsis

  • Sepsis is suspected 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 more detail on when to suspect sepsis, see Diagnosis recommendations.

  • In the UK, a senior clinical decision-maker is CT3/ST3 or higher, or a trained nurse with prescribing rights in acute care.[41]

Treat suspected sepsis (i.e., new organ dysfunction related to severe infection) promptly. Establish venous access early so you can proceed without delay to:[3][41][46]

  • Give within 1 hour of the risk being recognised:

    1. Intravenous antibiotics: where there is evidence of a bacterial infection, administer broad-spectrum empirical intravenous antibiotics before a pathogen is identified

      1. 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]

      2. Target the presumed site of infection if known

      3. Take bloods immediately, preferably before antibiotics are started (although sampling should not delay the administration of antibiotics)[3][43][48][49]

      4. Narrow the choice of antibiotic as soon as a pathogen has been identified and sensitivities are available[43][137]

    2. Intravenous fluids: 500 mL of crystalloid, with sodium in the range 130 to 154 mmol/L (130 to 154 mEq/L), over less than 15 minutes, if there is any sign of circulatory insufficiency

      1. Repeat if clinically indicated

      2. Do not exceed 30 mL/kg

    3. Oxygen: as needed, to maintain target oxygen saturations >94%[3][46][47]

      1. 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] Therefore, a reasonable approach in practice is to maintain a target oxygen saturation of 94% to 96% in acutely ill patients who are not at risk of hypercapnia

      2. Target saturation of 88% to 92% in people at risk of hypercapnic respiratory failure (e.g., those with COPD)

  • Take within 1 hour of the risk being recognised:

    1. Blood cultures

    2. Lactate level

    3. Hourly urine output.

Consult local protocols for specific routes of escalation. In general, in hospital:

  • Discuss with the admitting consultant,[3] and consider alerting critical care immediately if the patient is acutely unwell and:

    • Has a NEWS2 score of 7 or more, persisting high lactate (more than 4 mmol/L [36 mg/dL]) despite fluid resuscitation, or a systolic blood pressure of less than 90 mmHg[3]

      • Discuss with the admitting consultant[3]

    • Has hypotension that doesn’t respond to initial fluid resuscitation

    • Is likely to require central venous access and the initiation of inotropes or vasopressors[3]

    • Has any feature of septic shock

      • See our topic Shock

    • Has neutropenia

    • Is immunodeficient.

  • Urgently discuss with a consultant or call them to attend if the patient:[41]

    • Is treated with intravenous antibiotics and/or a fluid bolus for sepsis

    • Does not respond to initial therapy (antibiotics/fluid resuscitation/oxygen) within the first hour.[3][41] Failure to respond to treatment is defined as:[3]

      • Systolic blood pressure remains less than 90 mmHg

      • Persistent reduced level of consciousness

      • Respiratory rate more than 25 breaths per minute or the new need for mechanical ventilation

      • Lactate has not reduced by more than 20%.

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 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.

Urgent: in the community

Refer for emergency medical care in hospital (usually by blue-light ambulance in the UK) any patient who is acutely ill with a suspected infection and is:[3]

  • Deemed to be at high risk of deterioration due to organ dysfunction, as measured by a formal risk stratification process such as NEWS2, which is recommended by NHS England, or the UK National Institute for Health and Care Excellence high-risk criteria[3][41][43]

  • At risk of neutropenic sepsis.

Start oxygen therapy, if indicated, while awaiting the ambulance if resources are available to do so.[139][140]

Ensure you have a mechanism in place to administer antibiotics, if needed, to any high-risk patient (either at your practice or via the ambulance service) if the transfer to hospital is likely to be delayed.

Key Recommendations

Sepsis is a medical emergency.[3][43] The key to improving outcomes is early recognition and prompt treatment, as appropriate, of patients with suspected or confirmed infection who are deteriorating and at risk of organ dysfunction.[3][43]

  • Always use your clinical judgement.[41]

  • Take into account the full clinical picture of the individual patient in front of you including their NEWS2 score.

Identify and treat underlying source

Early and adequate source identification and control is critical. Undertake intensive efforts, including imaging, to attempt to identify the source of infection in all patients with sepsis.[3][43]

  • Consider the need for urgent source control as soon as the patient is stable.

  • The respiratory tract is the most common site of infection in most people with sepsis.[20][60] However, in people over age 65 years, the most common site is the genitourinary tract.[21][22]

  • Where organisms are identified, bacteria (gram-positive and gram-negative) are the causative organism in the majority of people with sepsis, with gram-positive bacterial and fungal infections increasing in frequency.[141] 

Protocolised approaches

Your institution may use a guideline-based care bundle as an aide-memoire to ensure key interventions are carried out in a timely way as appropriate for the individual patient. Check local protocols for the recommended approach in your area. Examples include the following.

The Sepsis Six resuscitation bundle from the UK Sepsis Trust[46]

Sepsis Six is a practical checklist of interventions that must be completed within 1 hour of identifying suspected sepsis.[46] The original paper outlining this approach, published in 2011, remains the only published evidence on Sepsis Six.[55] The six interventions are:[46]

  • Ensure a senior clinician attends

  • Give oxygen if required

  • Obtain intravenous access/take blood cultures

  • Give intravenous antibiotics

  • Give intravenous fluids

  • Monitor.

The 2018 1-hour care bundle from the Surviving Sepsis Campaign (SSC)[45]

The SSC proposes a 1-hour care bundle, based on the premise that the temporal nature of sepsis means benefit from even more rapid identification and intervention. The SSC identifies the start of the bundle as patient arrival at triage. It draws out five investigations and interventions to be completed within the first hour:[45]

  • Measure lactate level and remeasure if the initial lactate level is greater than 2 mmol/L (18 mg/dL)

  • Obtain blood cultures before administration of antibiotics

  • Administer broad-spectrum intravenous antibiotics

  • Begin rapid administration of crystalloid at 30 mL/kg for hypotension or lactate level greater than or equal to 4 mmol/L (36 mg/dL)

  • Start vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean arterial pressure level greater than or equal to 65 mmHg.

Although early identification and prompt, tailored treatment are key to the successful management of sepsis, none of the published protocolised approaches are supported by evidence.[57][58] Therefore, your clinical judgement is a key part of any approach.[41]

Reassess and monitor

Ensure frequent reassessment of the patient’s haemodynamic status throughout the initial resuscitation period. Make sure any patient with suspected sepsis has frequent and ongoing monitoring (e.g., using an early warning score such as NEWS2).

  • Depending on the facilities available, consider continuous monitoring, or a minimum of once every 30 minutes.[3]

  • Include:

    • Oxygen saturation

    • Respiratory rate

    • Heart rate

    • Blood pressure

    • Temperature

    • Hourly fluid balance (including urine output)

    • Lactate level.

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

Be aware that a patient with a NEWS2 score of less than 5 might also have or develop sepsis. In this group, continue to be aware of the risk of sepsis and specifically look for indicators that suggest the possibility of underlying infection and sepsis:[41]

  • A single NEWS parameter of 3 or more

  • Non-blanching rash/mottled/ashen/cyanotic skin

  • Responds only to voice or pain, or unresponsive

  • Not passed urine in last 18 hours or urine output <0.5 mL/kg/hour

  • Lactate ≥2 mmol/L (≥18 mg/dL).

Full recommendations

The overarching goals are to:

  • Resuscitate the patient and restore haemodynamic stability using supportive measures to correct hypoxaemia, hypotension, and impaired tissue oxygenation (hypoperfusion)

  • Rapidly identify the source of infection; contain and treat

  • Where there is evidence of a bacterial infection, start effective broad-spectrum intravenous antibiotics within an hour of the risk being recognised;[41] switch to a targeted antibiotic once the pathogen has been confirmed[3]

  • Maintain organ system function, guided by cardiovascular monitoring, and interrupt the progression of organ failure.

Early recognition of sepsis is critically important, but this can be challenging as patients often present with subtle and/or non-specific signs.[142]

In practice, you should make a diagnosis of suspected sepsis and start immediate treatment if the patient is acutely unwell and meets both of the following criteria:[3][41]

  1. Signs or symptoms suggestive of infection are present

    AND

  2. Your clinical assessment of the patient indicates a risk of deterioration due to organ dysfunction.

Always use your clinical judgement when assessing the risk of deterioration due to sepsis, alongside a systematic approach to assessing vital observations.[3][41] Consult local guidelines for the recommended approach.

  • The National Early Warning Score 2 (NEWS2) is the most widely used early warning score in the UK National Health Service. NHS England: Sepsis

    • In hospital: use NEWS2 or an alternative early warning score.[41][42][44] NEWS2 is endorsed by NHS England for use in this setting.[41]

    • In the community: use an early warning score such as NEWS2, which is recommended by NHS England[41] and the Royal College of General Practitioners in the UK,[50] or the UK National Institute for Health and Care Excellence high-risk criteria.[3]

      • None is validated in primary care.[50]

  • NHS England and the Royal College of Physicians in the UK set the threshold for starting immediate sepsis treatment as a NEWS2 score of 5 or more.[41][42] 

  • You should strongly suspect sepsis and consider the need to start immediate treatment if the patient:

    • Has any single NEWS2 parameter score of 3 or more OR

    • Has a non-blanching rash or has mottled/ashen/cyanotic skin OR

    • Is unresponsive or only responds to voice or pain OR

    • Has not passed urine for 18 or more hours (or urine output <0.5 mL/kg/hour if catheterised) OR

    • Has a lactate level ≥2 mmol/L (≥18 mg/dL).[41]

See Diagnosis recommendations for full details of risk stratification.

Start treatment immediately if a senior clinical decision-maker 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]

  • In the UK, a senior clinical decision-maker is CT3/ST3 or higher, or a trained nurse with prescribing rights in acute care.[41]

The first hour

For any acutely ill and deteriorating patient with a suspected or known bacterial infection and suspected sepsis, above all else prioritise (if needed):[3][46]

  • Securing their airway

  • Correcting hypoxaemia

  • Establishing venous access for the early administration of antibiotics and fluids.

Early and adequate source identification and control is critical. 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 intravenous 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 or cefotaxime.

  • 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.

Intravenous antibiotics

Where there is evidence of a bacterial infection and a senior clinical decision-maker strongly suspects sepsis (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 promptly (e.g., within 1 hour of the risk of sepsis being recognised).[3][41][43][46] Do this before a pathogen is identified but after blood cultures have been taken.[3][41][43][46]

  • 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.

  • Use a ‘start smart then focus’ approach.[41][136] 

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.[143]The relationship between antibiotic exposure and antibiotic resistance is unambiguous not only at the population level but also in individual patients.[144][145]

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 or life-threatening infections. Avoid inappropriate use of broad-spectrum antibiotics

  • 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.

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:[146][147]

  • 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. These are indicated particularly 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.[148]

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 delays 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 potential alternatives with a microbiologist.

There is widespread agreement that appropriate and timely recognition of sepsis and subsequent resuscitation are key approaches to managing severely ill patients with sepsis. However, guideline-derived antibiotic delivery goals (as outlined by the UK National Institute for Health and Care Excellence [NICE], the Surviving Sepsis Campaign [SSC], and the UK Sepsis Trust) have been challenged owing to gaps in the evidence and concerns about over-treament of individual patients and the subsequent effect on antimicrobial resistance.[57][58]

The 1-hour antibiotic targets outlined by NICE,[3] the SSC,[45] and the UK Sepsis Trust (Sepsis Six)[46] are derived from data that appear to draw a direct correlation between each hour of delayed treatment of the patient with sepsis and an increased risk of further deterioration or death.[93][149][150] However, examining some of these data closely shows that 1-hour antibiotic targets may not be possible or necessarily advantageous for all patients with eventual sepsis diagnoses.[58]

  • A retrospective cohort study of hypotensive inpatients with sepsis, published in 2006, first described a potential link between timing of antibiotics and outcomes.[149]

    • The authors noted 79.9% survival if septic patients received in vitro-active antibiotics within 1 hour of the onset of hypotension, with a subsequent 7.6% survival rate decrement with each additional hour to treatment.

    • Looking closely at the data, however, there was a lower survival rate (52%) among patients who received antibiotics before hypotension compared with those who received them within the first few hours of the onset of septic shock.

    • Commentators note that ascribing a biological effect to antibiotics for either the improvement or the decreased survival is endemic to observational or natural experiment designs, which are prone to confounding and bias in their interpretation of results.[58]

  • More recently, another retrospective cohort study of 3929 patients with sepsis described an 8% hourly incremental increased risk of progression to septic shock with longer time to antibiotics.[150]

    • There was little change in rate of worsening (progression to septic shock rate) until after 5 hours; by then, approximately 75% of patients had received antibiotics. The remaining 25% of the cohort (who were treated later than the first patient group) differed from those treated earlier. Notably, the later-treated group had more comorbidities.

    • As noted in a commentary on the study, this is in line with what is commonly seen in clinical practice: sepsis is harder to recognise in people with comorbidities, and patients with sepsis and comorbid illness have a worse prognosis in general.[58]

  • Another recent trial randomised 2672 patients with suspected sepsis (>95% without shock) to receive antibiotics in an ambulance or ‘quickly’ in an emergency department. The median 96-minute-earlier administration was not linked to improved outcomes, regardless of illness severity.[93]

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.

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).

Intravenous fluids

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 there is any sign of circulatory insufficiency).[3][41][66]

  • 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, seek senior support.[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] 

Practical tip

Be aware that large volumes of normal saline as the sole fluid for resuscitation may lead to hyperchloraemic 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 from critically ill patients in general (not specifically people with sepsis) suggests that there is no difference in benefit between normal saline and a balanced crystalloid (such as Hartmann's solution, Ringer's lactate, or Plasma-Lyte®), and therefore either choice of fluid is reasonable.[154]

  • Check local protocols for specific recommendations on fluid choice.

Evidence from a large randomised controlled trial (RCT) suggests there is no difference between normal saline and a balanced crystalloid in mortality at 90 days, and therefore either option is a reasonable choice for the resuscitation of critically ill patients.

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®). Evidence from critically ill patients points to no benefits from using a balanced crystalloid in preference to normal saline. Clinical practice varies widely, so you should check local protocols.

  • The Balanced Solutions in Intensive Care Study (BaSICS) trial, a large double-blind RCT conducted at 75 intensive care units (ICUs) in Brazil (N=11,052), was published in 2021.[154] It assessed intravenous fluid resuscitation in ICU patients with a balanced crystalloid solution (Plasma-Lyte®) versus normal saline.

    • 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.

    • There was no difference in 90-day mortality (adjusted hazard ratio 0.97, 95% CI 0.90 to 1.05). There was also no difference in acute kidney injury or use of renal-replacement therapy.

    • Pre-specified subgroup analysis was undertaken for patients with sepsis, acute kidney injury, or traumatic brain injury, and for those post-elective surgery. There was no difference in 90-day mortality in any subgroup except for patients with traumatic brain injury where there was a small benefit favouring 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.

  • 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, acute kidney injury, or use of renal-replacement therapy.[155]

    • 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).[156]

  • 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.[157]

    • 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 2017 guideline from the UK National Institute for Health and Care Excellence (NICE) concluded that there is insufficient evidence to recommend one crystalloid over another.

  • NICE recommends choosing a crystalloid with sodium in the range 130 to 154 mmol/L for all adults in hospital who need resuscitation with intravenous fluid therapy.[158]

  • One 2020 exceptional review by NICE, which included the SMART study, concluded there was no need to update the guidance at the current time.[159]

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.[160][161]

  • 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.[66][162] 

  • 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.

Oxygen

If indicated, give oxygen to maintain target oxygen saturations >94%.[3][46][47] 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] Therefore, a reasonable approach in practice is to maintain a target oxygen saturation of 94% to 96% in acutely ill patients who are not at risk of hypercapnia.

A lower target saturation of 88% to 92% is appropriate if the patient is at risk of hypercapnic respiratory failure (e.g., those with COPD).[3][46][47]

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 non-hypercapnic acutely ill adults.

  • 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 2015 Thoracic Society of Australia and New Zealand (TSANZ) guideline recommends 92% to 96%.[47][163]

  • A systematic review including a meta-analysis of data from 25 RCTs, 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 (risk ratio [RR] 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. The review excluded studies that were limited to people with chronic respiratory illness or psychiatric illness, patients on extracorporeal life support, those receiving hyperbaric oxygen therapy, or patients having elective surgery.

  • 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, and sickle cell crisis).[164]

  • In 2019 the BTS reviewed its guidance in response to this systematic review and meta-analysis and decided an interim update was not required.[47]

    • 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 TSANZ guideline recommendation.

  • Management of oxygen therapy in patients in intensive care is specialised and informed by further evidence that is more specific to this setting.[165][166][167]

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.[168]

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 National Institute for Health and Care Excellence (NICE) in the UK recommends continuous or half-hourly monitoring (depending on setting) for any patient considered to be at high risk of deterioration (defined in the NICE guideline as meeting one or more of its high-risk criteria for severe illness or death from sepsis).[3] 

  • See the Risk stratification subsection of Diagnosis recommendations for more information.

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][46]

    • The lactate level should decrease if the patient is clinically improving

    • Frequency of repeat lactate measurement depends on cause of sepsis and treatment given.

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 ] [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][169][170] 

  • 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 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.

Consult local protocols for specific escalation routes but in general:

  • Ensure immediate review by a senior clinician (CT3/ST3 or higher in the UK) of any patient with a NEWS2 score of 5 or more, or who meets one or more of the UK National Institute for Health and Care Excellence sepsis high-risk criteria. Also ensure the patient is discussed with a consultant[3][41] 

  • Discuss with the admitting consultant[3] and consider alerting critical care immediately if the patient is acutely unwell and:

    • Has a National Early Warning Score 2 (NEWS2) score of 7 or more, persisting high lactate (more than 4 mmol/L [36 mg/dL]) despite fluid resuscitation, or a systolic blood pressure of less than 90 mmHg[3]

      • Discuss with the admitting consultant[3]

    • Has hypotension that doesn’t respond to initial fluid resuscitation

    • Is likely to require central venous access and the initiation of inotropes or vasopressors[3] 

    • Has any feature of septic shock

      • See our topic Shock

    • Has neutropenia

      • See our topic Febrile neutropenia

    • Is immunodeficient

  • Urgently discuss with a consultant or call them to attend if the patient:[41]

    • Is treated with intravenous antibiotics and/or a fluid bolus for sepsis

    • Does not respond to initial therapy (antibiotics/fluid resuscitation/oxygen) within the first hour.[3][41] Failure to respond to treatment is defined as:[3]

      • Systolic blood pressure remains less than 90 mmHg

      • Persistent reduced level of consciousness

      • Respiratory rate more than 25 breaths per minute or the new need for mechanical ventilation

      • Lactate has not reduced by more than 20%

  • Refer to critical care any patient who is likely to require central venous access and 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).

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.

Make intensive efforts to identify the anatomical source 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]

  • If you suspect an abdominal or pelvic source, involve the relevant surgical team early, particularly if surgery is likely.[3]

    • In practice, this may mean early transfer of the patient to a surgical centre if there are no facilities at your hospital.

[43]Switch to a targeted antibiotic as soon as culture and sensitivity results are available and a pathogen has been identified.[43][137]

Tailor antibiotics based on source

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.

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][60]

  • See our topic Overview of pneumonia.

Abdominal

Ensure gram-positive and gram-negative organisms including anaerobes are covered.[171]

Arrange urgent surgical drainage or percutaneous drainage (where appropriate) for peritonitis or intra-peritoneal abscesses.[172]

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.[76] 

See our topic 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 or cefotaxime, for suspected meningitis or meningococcal sepsis.[3]

  • In community settings, give benzylpenicillin before referring to hospital.[3]

Unknown or unclear

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]

For any patient with suspected sepsis, consider the need for referral to a high-dependency unit for management by the critical care team.[173][174]

Refer to critical care as soon as possible any patient who does not respond to initial therapy, and in particular anyone:

  • With hypotension that doesn’t respond to initial fluid resuscitation

  • Who is likely to require central venous access and initiation of inotropes or vasopressors[3]

  • With any feature of septic shock

    • See our topic Shock

  • With neutropenia

    • See our topic Febrile neutropenia

  • Who is immunodeficient.

The following interventions should only be initiated by experienced members of the critical care team:[3][175]

  • Glycaemic control

  • Vasoactive drugs (vasopressors/inotropes)

  • Corticosteroids.

Additional intensive care measures that will be considered include:[43][176][177]

  • 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[3][43] who have not responded to substantial volumes of crystalloids

  • 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]

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.[178]

    • 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.[179]

    • 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 strategy with a restrictive strategy.[180]

    • 28-day mortality was less in the liberal group, although this difference was not statistically significant (45% vs. 56%, hazard ratio [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 (odds ratio 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., those 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.[173] 

In patients requiring prolonged ventilatory support, give lung-protective ventilation using minimal peak inspiratory pressures (<30 cm H2O) and permissive hypercapnia to specifically limit pulmonary compromise.[181]

  • Titrate fraction of inspired oxygen (FiO2) 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 National Institute for Health and Care Excellence (NICE) in the UK makes no recommendations on glycaemic control in sepsis.[3]

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]).[182][183]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.[184] 

  • 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.[185]

  • 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.[186]

Vasoactive drugs

Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines.

Vasopressors for persistent haemodynamic instability

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][175]

  • Failure to respond to initial fluid resuscitation is a sign of septic shock.[1] 

  • 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] NICE 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]

Although a systematic review of 23 randomised trials of patients with shock found no convincing evidence for the superiority of one vasopressor over another[187]more recent meta-analyses reported a higher mortality associated with dopamine than with noradrenaline.[188]

Inotropes

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

  • 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]

  • NICE 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.[175]

Corticosteroids

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

  • NICE does not give any recommendations on the use of corticosteroids for managing sepsis in adults.[3]

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][189]

  • 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.[190]

    • 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.[191] 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).[192]

    • 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.

BMJ Rapid Recommendations: intravenous corticosteroids plus usual care versus usual care only[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].

Antibiotics

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.[193][194]

Use the shortest effective course of antibiotics.[195]

  • Unnecessarily prolonged antibiotic treatment is associated with resistance. See More info: Antimicrobial resistance in the section Prompt management for all patients with suspected sepsis 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][105][106][107]

  • 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]

Serum lactate

Measure serum lactate, on a blood gas, to monitor response to treatment.[3][43][46]

  • 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.[77][78] 

  • 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:[79]

      • Lactate <2 mmol/L (<18 mg/dL): 15%

      • Lactate 2.1 to 3.9 mmol/L (19 to 35 mg/dL): 25%

      • Lactate >4 mmol/L (>36 mg/dL): 38%.

Sepsis guidelines from the UK National Institute for Health and Care Excellence (NICE) and NHS England recommend escalating treatment depending on lactate level.[3][41] Alert critical care immediately if the patient is acutely unwell and has persistent lactate >4 mmol/L (>36 mg/dL)[3] despite fluid resuscitation.

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. You must take into account the full clinical picture of the individual patient in front of you including their National Early Warning Score 2 (NEWS2) score.

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.[80][81][82]

The best available evidence supports lactate clearance (the rate at which lactate is cleared over a period of 6 hours) as being as useful as more invasive tests, such as central venous oxygen saturation (ScvO2), in determining a patient’s response to treatment.[196][197][198][199][200][201]

  • In one study that looked at patients with septic shock who were treated to normalise central venous and mean arterial pressure, additional management to normalise lactate clearance compared with additional management to normalise ScvO2 did not result in significantly different in-hospital mortality.[197]

    • Of 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographics, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalisation.

    • Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% CI 17% to 30%) compared with 25 (17%, 95% CI 11% to 24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.

  • Several trials have assessed the diagnostic accuracy of percentage lactate clearance over 0 to 6 hours. It is worth noting that these studies provide very low-quality evidence, owing mainly to a presumed lack of blinding of treating physicians to the patient’s lactate status.  

    • The studies’ findings agree that lactate clearance early in the hospital course is associated with decreased mortality rate. Patients with higher lactate clearance after 6 hours of emergency department intervention had improved outcomes compared with those with lower lactate clearance.[196][198][199][200][201]

Referring to hospital

Use your clinical judgement. 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

  • 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

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/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 [FiO2]) 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 rash of skin

  • Is at risk of neutropenic sepsis and presents with symptoms and signs of infection

    • See our topic 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. 

If you have decided to refer the patient for emergency medical care and have called for an emergency ambulance, the UK Sepsis Trust/NICE general practitioner toolkit recommends that, if indicated, you should start oxygen therapy while awaiting the ambulance if resources are available to do so.[139][140] 

  • Give oxygen immediately to maintain target oxygen saturations >94%.[3][46][47] 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] Therefore, a reasonable approach in practice is to maintain a target oxygen saturation of 94% to 96% in acutely ill patients who are not at risk of hypercapnia.

  • Target saturation of 88% to 92% in people at risk of hypercapnic respiratory failure (e.g., those with COPD).[3][46][47]

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 non-hypercapnic acutely ill adults.

  • 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 2015 Thoracic Society of Australia and New Zealand (TSANZ) guideline recommends 92% to 96%.[202][163]

  • A systematic review including a meta-analysis of data from 25 RCTs, 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%).[164]

    • 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 (risk ratio [RR] 1.14, 95% CI 1.01-1.29).

    • The trials included adults with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. The review excluded studies that were limited to people with chronic respiratory illness or psychiatric illness, patients on extracorporeal life support, those receiving hyperbaric oxygen therapy, or patients having elective surgery.

  • 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, and sickle cell crisis).[164]

  • In 2019 the BTS reviewed its guidance in response to this systematic review and meta-analysis and decided an interim update was not required.[47]

    • 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 TSANZ guideline recommendation.

  • Management of oxygen therapy in patients in intensive care is specialised and informed by further evidence that is more specific to this setting.[165][166][203]

Ensure you have a mechanism in place to administer antibiotics to any high-risk patient (either at your practice or via the ambulance service) if the transfer time to hospital is likely to be more than 1 hour.

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.

Management in the community

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:[50][74][140] 

  • The patient has one or more risk factors for sepsis (as listed above)

  • 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”).

See our section Diagnosis recommendations for details of the NICE risk criteria.

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.[204][205]

Practical tip

If you decide that the patient is safe to treat in the community, written and verbal safety netting is vital.[50] Ensure the information is clear and specific rather than generalised advice; for example, do not say to “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.[50]

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.[60]

The UK Sepsis Trust advises the following acronym:[140] 

  • 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.[139] 

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