1.
General
Guideline Title
Sepsis:recognition, diagnosis and earlymanagement.
Bibliographic Source(s)
NationalGuideline Centre. Sepsis:recognition, diagnosis and earlymanagement. London(UK):NationalInstitute for Healthand Care
Excellence (NICE); 2016 Jul13. 50 p. (NICEguideline; no. 51).
Guideline Status
This is the current release ofthe guideline.
This guideline meets NGC's 2013 (revised) inclusioncriteria.
Recommendations
Major Recommendations
Note fromthe NationalGuideline Clearinghouse (NGC):The guideline was developed bythe NationalGuideline Centre onbehalfofthe National
Institute for Healthand Care Excellence (NICE). See the "AvailabilityofCompanionDocuments"field for the fullversionofthis guidance and
related appendices.
The wordingused inthe recommendations inthis guideline (for example, words suchas 'offer' and 'consider') denotes the certaintywithwhichthe
recommendationis made (the strengthofthe recommendation) and is defined at the end ofthe "Major Recommendations"field.
IdentifyingPeople withSuspected Sepsis
This guidance should be used together withthe algorithms organised byage group and treatment locationand the risk stratificationtools inthe
originalguideline document (see the "ClinicalAlgorithm[s]"field).
Think 'could this be sepsis?' ifa personpresents withsigns or symptoms that indicate possible infection.
Take into account that people withsepsis mayhave non-specific, non-localised presentations, for example, feelingveryunwell, and maynot have a
hightemperature.
Payparticular attentionto concerns expressed bythe personand their familyor carers, for example, changes fromusualbehaviour.
Assess people who might have sepsis withextra care iftheycannot give a good history(for example, people withEnglishas a second language or
people withcommunicationproblems).

2.
Assess people withanysuspected infectionto identify:
Possible source ofinfection
Factors that increase risk ofsepsis (see "Risk Factors for Sepsis,"below)
Anyindications ofclinicalconcern, suchas newonset abnormalities ofbehaviour, circulationor respiration
Identifyfactors that increase risk ofsepsis (see "Risk Factors for Sepsis,"below) or indications ofclinicalconcernsuchas newonset abnormalities
ofbehaviour, circulationor respirationwhendecidingduringa remote assessment whether to offer a face-to-face-assessment and ifso, onthe
urgencyofface-to-face assessment.
Use a structured set ofobservations (see "Face-to-face Assessment ofPeople withSuspected Sepsis,"below) to assess people ina face-to-face
settingto stratifyrisk (see "StratifyingRisk ofSevere Illness or DeathfromSepsis,"below) ifsepsis is suspected.
Consider usinganearlywarningscore to assess people withsuspected sepsis inacute hospitalsettings.
Suspect neutropenic sepsis inpatients havinganticancer treatment who become unwell. (This recommendationis fromNICE's guideline on
neutropenic sepsis [see the NGC summaryofthe NICEguideline Neutropenic sepsis:preventionand management ofneutropenic sepsis incancer
patients].)
Refer patients withsuspected neutropenic sepsis immediatelyfor assessment insecondaryor tertiarycare. (This recommendationis fromNICE's
guideline onneutropenic sepsis [see the NGC summaryofthe NICEguideline Neutropenic sepsis:preventionand management ofneutropenic
sepsis incancer patients].)
Treat people withneutropenic sepsis inline withNICE's guideline onneutropenic sepsis (see the NGC summaryofthe NICEguideline
Neutropenic sepsis:preventionand management ofneutropenic sepsis incancer patients).
Risk Factors for Sepsis
Take into account that people inthe groups beloware at higher risk ofdevelopingsepsis:
The veryyoung(under 1 year) and older people (over 75 years) or people who are veryfrail
People who have impaired immune systems because ofillness or drugs, including:
People beingtreated for cancer withchemotherapy(see "IdentifyingPeople withSuspected Sepsis,"above)
People who have impaired immune function(for example, people withdiabetes, people who have had a splenectomy, or people with
sickle celldisease)
People takinglong-termsteroids
People takingimmunosuppressant drugs to treat non-malignant disorders suchas rheumatoid arthritis
People who have had surgery, or other invasive procedures, inthe past 6 weeks
People withanybreachofskinintegrity(for example, cuts, burns, blisters or skininfections)
People who misuse drugs intravenously
People withindwellinglines or catheters
Take into account that womenwho are pregnant, have givenbirthor had a terminationofpregnancyor miscarriage inthe past 6 weeks are ina
highrisk group for sepsis. Inparticular, womenwho:
Have impaired immune systems because ofillness or drugs (see "IdentifyingPeople withSuspected Sepsis,"above)
Have gestationaldiabetes or diabetes or other comorbidities
Needed invasive procedures (for example, caesareansection, forceps delivery, removalofretained products ofconception)
Had prolonged rupture ofmembranes
Have or have beeninclose contact withpeople withgroup Astreptococcalinfection, for example, scarlet fever
Have continued vaginalbleedingor anoffensive vaginaldischarge
Take into account the followingrisk factors for early-onset neonatalinfection:
Invasive group Bstreptococcalinfectionina previous baby
Maternalgroup Bstreptococcalcolonisation, bacteriuria or infectioninthe current pregnancy
Prelabour rupture ofmembranes
Pretermbirthfollowingspontaneous labour (before 37 weeks' gestation)
Suspected or confirmed rupture ofmembranes for more than18 hours ina pretermbirth

3.
Intrapartumfever higher than38°C, or confirmed or suspected chorioamnionitis
Parenteralantibiotic treatment givento the womanfor confirmed or suspected invasive bacterialinfection(suchas septicaemia) at anytime
duringlabour, or inthe 24-hour periods before and after the birth(this does not refer to intrapartumantibiotic prophylaxis)
Suspected or confirmed infectioninanother babyinthe case ofa multiple pregnancy
(This recommendationis fromNICE's guideline onneonatalinfection[see the NGC summaryofthe NICEguideline Antibiotics for early-onset
neonatalinfection. Antibiotics for the preventionand treatment ofearly-onset neonatalinfection].)
Face-to-face Assessment ofPeople withSuspected Sepsis
Assess temperature, heart rate, respiratoryrate, blood pressure, levelofconsciousness and oxygensaturationinyoungpeople and adults with
suspected sepsis.
Assess temperature, heart rate, respiratoryrate, levelofconsciousness, oxygensaturationand capillaryrefilltime inchildrenunder 12 years with
suspected sepsis. (This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline
Feverishillness inchildren:assessment and initialmanagement inchildrenyounger than5 years].)
Measure blood pressure ofchildrenunder 5 years ifheart rate or capillaryrefilltime is abnormaland facilities to measure blood pressure, including
a correctly-sized blood pressure cuff, are available. (This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC
summaryofthe NICEguideline Feverishillness inchildren:assessment and initialmanagement inchildrenyounger than5 years].)
Measure blood pressure ofchildrenaged 5 to 11 years who might have sepsis iffacilities to measure blood pressure, includinga correctly-sized
cuff, are available.
Onlymeasure blood pressure inchildrenunder 12 years incommunitysettings iffacilities to measure blood pressure, includinga correctly-sized
cuff, are available and takinga measurement does not cause a delayinassessment or treatment.
Measure oxygensaturationincommunitysettings ifequipment is available and takinga measurement does not cause a delayinassessment or
treatment.
Examine people withsuspected sepsis for mottled or ashenappearance, cyanosis ofthe skin, lips or tongue, non-blanchingrashofthe skin, any
breachofskinintegrity(for example, cuts, burns or skininfections) or other rashindicatingpotentialinfection.
Ask the person, parent or carer about frequencyofurinationinthe past 18 hours.
StratifyingRisk ofSevere Illness or DeathfromSepsis
Use the person's historyand physicalexaminationresults to grade risk ofsevere illness or deathfromsepsis usingcriteria based onage (see Tables
1, 2, and 3 inthe originalguideline document).
Adults, Childrenand YoungPeople Aged 12 Years and Over
Table 1 inthe originalguideline document demonstrates risk stratificationtoolfor adults, childrenand youngpeople aged 12 years and over with
suspected sepsis (a downloadable versionofthis table is also available).
Recognise that adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and anyofthe symptoms or signs beloware at
highrisk ofsevere illness or deathfromsepsis:
Objective evidence ofnewaltered mentalstate
Respiratoryrate of25 breaths per minute or above, or newneed for 40%oxygenor more to maintainoxygensaturationmore than92%(or
more than88%inknownchronic obstructive pulmonarydisease)
Heart rate of130 beats per minute or above
Systolic blood pressure of90 mmHgor less, or systolic blood pressure more than40 mmHgbelownormal
Not passed urine inprevious 18 hours (for catheterised patients, passed less than0.5 ml/kg/hour)
Mottled or ashenappearance
Cyanosis ofthe skin, lips or tongue
Non-blanchingrashofthe skin
Recognise that adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and anyofthe symptoms or signs beloware at
moderate to highrisk ofsevere illness or deathfromsepsis:

4.
Historyofnew-onset changed behaviour or change inmentalstate, as reported bythe person, a friend or relative
Historyofacute deteriorationoffunctionalability
Impaired immune system(illness or drugs, includingoralsteroids)
Trauma, surgeryor invasive procedure inthe past 6 weeks
Respiratoryrate of21 to 24 breaths per minute, heart rate of91 to 130 beats per minute or new-onset arrhythmia or ifpregnant, heart rate
of100 to 130 beats per minute
Systolic blood pressure of91 to 100 mmHg
Not passed urine inthe past 12 to 18 hours (for catheterised patients, passed 0.5–1 ml/kg/hour)
Tympanic temperature less than36°C
Signs ofpotentialinfection, includingincreased redness, swellingor discharge at a surgicalsite, or breakdownofa wound
Consider adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who do not meet anyhighor moderate to highrisk
criteria to be at lowrisk ofsevere illness or deathfromsepsis.
ChildrenAged 5 to 11 Years
Table 2 inthe originalguideline document shows risk stratificationtoolfor childrenaged 5 to 11 years withsuspected sepsis (a downloadable
versionofthis table is also available).
Recognise that childrenaged 5 to 11 years withsuspected sepsis and anyofthe symptoms or signs beloware at highrisk ofsevere illness or death
fromsepsis:
Has objective evidence ofaltered behaviour or mentalstate, or appears illto a healthcare professional, or does not wake (or ifroused, does
not stayawake)
Respiratoryrate:
Aged 5 years, 29 breaths per minute or more
Aged 6 to 7 years, 27 breaths per minute or more
Aged 8 to 11 years, 25 breaths per minute or more
Oxygensaturationofless than90%inair or increased oxygenrequirement over baseline
Heart rate:
Aged 5 years, 130 beats per minute or more
Aged 6 to 7 years, 120 beats per minute or more
Aged 8 to 11 years, 115 beats per minute or more
Or heart rate less than60 beats per minute at anyage
Mottled or ashenappearance
Cyanosis ofthe skin, lips or tongue
Non-blanchingrashofthe skin
Recognise that childrenaged 5 to 11 years withsuspected sepsis and anyofthe symptoms or signs beloware at moderate to highrisk ofsevere
illness or deathfromsepsis:
Not respondingnormallyto socialcues or decreased activity, or parent or carer concernthat the child is behavingdifferentlyfromusual
Respiratoryrate:
Aged 5 years, 24 to 28 breaths per minute
Aged 6 to 7 years, 24 to 27 breaths per minute
Aged 8 to 11 years, 22 to 24 breaths per minute
Oxygensaturationofless than92%inair or increased oxygenrequirement over baseline
Heart rate:
Aged 5 years, 120 to 129 beats per minute
Aged 6 to 7 years, 110 to 119 beats per minute
Aged 8 to 11 years, 105 to 114 beats per minute
Or capillaryrefilltime of3 seconds or more
Reduced urine output, or for catheterised patients passed less than1 ml/kgofurine per hour
Have legpainor cold hands and feet
Consider childrenaged 5 to 11 years withsuspected sepsis who do not meet anyhighor moderate to highrisk criteria to be at lowrisk ofsevere
illness or deathfromsepsis.

5.
ChildrenAged under 5 Years
Table 3 inthe originalguideline document shows risk stratificationtoolfor childrenaged under 5 years withsuspected sepsis. This table is adapted
fromNICE's guideline onfever inunder 5s (see the NGC summaryofthe NICEguideline Feverishillness inchildren:assessment and initial
management inchildrenyounger than5 years). Adownloadable versionofthis table is also available.
Recognise that childrenaged under 5 years withsuspected sepsis and anyofthe symptoms or signs beloware at highrisk ofsevere illness or death
fromsepsis:
Behaviour:
No response to socialcues
Appears illto a healthcare professional
Does not wake, or ifroused does not stayawake
Weak, high-pitched or continuous cry
Heart rate:
Aged under 1 year, 160 beats per minute or more
Aged 1 to 2 years, 150 beats per minute or more
Aged 3 to 4 years, 140 beats per minute or more
Heart rate less than60 beats per minute at anyage
Respiratoryrate:
Aged under 1 year, 60 breaths per minute or more
Aged 1 to 2 years, 50 breaths per minute or more
Aged 3 to 4 years, 40 breaths per minute or more
Grunting
Apnoea
Oxygensaturationofless than90%inair or increased oxygenrequirement over baseline
Mottled or ashenappearance
Cyanosis ofthe skin, lips or tongue
Non-blanchingrashofthe skin
Aged under 3 months and temperature 38°C or more
Temperature less than36°C
(This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness in
children:assessment and initialmanagement inchildrenyounger than5 years].)
Recognise that childrenaged under 5 years withsuspected sepsis and anyofthe symptoms or signs beloware at moderate to highrisk ofsevere
illness or deathfromsepsis:
Behaviour:
No response to socialcues
No smile
Wakes onlywithprolonged stimulation
Decreased activity
Parent or carer concernthat the child is behavingdifferentlyfromusual
Respiratoryrate:
Aged under 1 year, 50 to 59 breaths per minute
Aged 1 to 2 years, 40 to 49 breaths per minute
Aged 3 to 4 years, 35 to 39 breaths per minute
Oxygensaturation91%or less inair or increased oxygenrequirement over baseline
Nasalflaring
Heart rate:
Aged under 1 year, 150 to 159 beats per minute
Aged 1 to 2 years, 140 to 149 beats per minute
Aged 3 to 4 years, 130 to 139 beats per minute
Capillaryrefilltime of3 seconds or more
Reduced urine output, or for catheterised patients passed less than1 ml/kgofurine per hour

6.
Is pale or flushed or has pallor ofskin, lips or tongue reported byparent or carer
Aged 3 to 6 months and temperature 39°C or over
Have legpainor cold hands or feet
(This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness in
children:assessment and initialmanagement inchildrenyounger than5 years].)
Consider childrenaged under 5 years withsuspected sepsis who do not meet anyhighor moderate to highrisk criteria to be at lowrisk ofsevere
illness or deathfromsepsis. (This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICE
guideline Feverishillness inchildren:assessment and initialmanagement inchildrenyounger than5 years].)
Children, YoungPeople and Adults withSuspected Sepsis
Temperature in Suspected Sepsis
Do not use a person's temperature as the sole predictor ofsepsis.
Do not relyonfever or hypothermia to rule sepsis either inor out.
Ask the personwithsuspected sepsis and their familyor carers about anyrecent fever or rigors.
Take into account that some groups ofpeople withsepsis maynot develop a raised temperature. These include:
People who are older or veryfrail
People havingtreatment for cancer
People severelyillwithsepsis
Younginfants or children
Take into account that a rise intemperature canbe a physiologicalresponse, for example after surgeryor trauma.
Heart Rate in Suspected Sepsis
Interpret the heart rate ofa personwithsuspected sepsis incontext, takinginto account that:
Baseline heart rate maybe lower inyoungpeople and adults who are fit
Baseline heart rate inpregnancyis 10 to 15 beats per minute more thannormal
Older people withaninfectionmaynot develop anincreased heart rate
Older people maydevelop a newarrhythmia inresponse to infectionrather thananincreased heart rate
Heart rate response maybe affected bymedicines suchas beta-blockers
Blood Pressure in Suspected Sepsis
Interpret blood pressure inthe context ofa person's previous blood pressure, ifknown. Be aware that the presence ofnormalblood pressure does
not exclude sepsis inchildrenand youngpeople.
Confusion, Mental State and Cognitive State in Suspected Sepsis
Interpret a person's mentalstate inthe context oftheir normalfunctionand treat changes as beingsignificant.
Be aware that changes incognitive functionmaybe subtle and assessment should include historyfrompatient and familyor carers.
Take into account that changes incognitive functionmaypresent as changes inbehaviour or irritabilityinbothchildrenand inadults withdementia.
Take into account that changes incognitive functioninolder people maypresent as acute changes infunctionalabilities.
Oxygen Saturation in Suspected Sepsis
Take into account that ifperipheraloxygensaturationis difficult to measure ina personwithsuspected sepsis, this mayindicate poor peripheral
circulationbecause ofshock.
ManagingSuspected Sepsis Outside Acute HospitalSettings
Refer allpeople withsuspected sepsis outside acute hospitalsettings for emergencymedicalcare1 bythe most appropriate means oftransport

7.
(usually999 ambulance) if:
Theymeet anyhighrisk criteria (see Tables 1, 2, and 3 inthe originalguideline document) or
Theyare aged under 17 years and their immunityis impaired bydrugs or illness and theyhave anymoderate to highrisk criteria
Assess allpeople withsuspected sepsis outside acute hospitalsettings withanymoderate to highrisk criteria to:
Make a definitive diagnosis oftheir condition
Decide whether theycanbe treated safelyoutside hospital
Ifa definitive diagnosis is not reached or the personcannot be treated safelyoutside anacute hospitalsetting, refer themurgentlyfor emergency
care.
Provide people withsuspected sepsis, who do not have anyhighor moderate to highrisk criteria informationabout symptoms to monitor and how
to access medicalcare iftheyare concerned.
Managingand TreatingSuspected Sepsis inAcute HospitalSettings
Adults, Childrenand YoungPeople Aged 12 Years and Over withSuspected Sepsis Who Meet 1 or More HighRisk Criteria
For adults, childrenand youngpeople aged 12 years and over who have suspected sepsis and 1 or more highrisk criteria:
Arrange for immediate reviewbythe senior clinicaldecisionmaker2 to assess the personand think about alternative diagnoses to sepsis
Carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine
Aclottingscreen
Give a broad-spectrumantimicrobialat the maximumrecommended dose without delay(within1 hour ofidentifyingthat theymeet anyhigh
risk criteria inanacute hospitalsetting) inline withrecommendations inthe "Antibiotic Treatment inPeople withSuspected Sepsis"section
below.
Discuss witha consultant3
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and anyhighrisk criteria and lactate over 4 mmol/litre, or
systolic blood pressure less than90 mmHg:
Give intravenous fluid bolus without delay(within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting) inline
withrecommendations inthe "Intravenous Fluids inPeople withSuspected Sepsis"sectionand
Refer4 to criticalcare5 for reviewofmanagement includingneed for centralvenous access and initiationofinotropes or vasopressors
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and anyhighrisk criteria and lactate between2 and 4
mmol/litre:
Give intravenous fluid bolus without delay(within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting) inline
withrecommendations inthe "Intravenous Fluids inPeople withSuspected Sepsis"section
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and anyhighrisk criteria and lactate below2 mmol/litre:
Consider givingintravenous fluid bolus (inline withrecommendations in"Intravenous Fluids inPeople withSuspected Sepsis"section)
Monitor people withsuspected sepsis who meet anyhighrisk criteria continuously, or a minimumofonce every30 minutes dependingonsetting.
Physiologicaltrack and trigger systems should be used to monitor alladult patients inacute hospitalsettings. (This recommendationis adapted from
NICE's guideline onacutelyillpatients inhospital .)
Monitor the mentalstate ofadults, childrenand youngpeople aged 12 years and over withsuspected sepsis. Consider usinga scale suchas the
GlasgowComa Scale (GCS) or ('alert, voice, pain, unresponsive') scale.

8.
Alert a consultant to attend inpersonifanadult, child or youngpersonaged 12 years or over withsuspected sepsis and anyhighrisk criteria fails
to respond within1 hour ofinitialantibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated byanyof:
Systolic blood pressure persistentlybelow90 mmHg
Reduced levelofconsciousness despite resuscitation
Respiratoryrate over 25 breaths per minute or a newneed for mechanicalventilation
Lactate not reduced bymore than20%ofinitialvalue within1 hour
Adults, Childrenand YoungPeople Aged 12 Years and Over withSuspected Sepsis Who Meet 2 or More Moderate to HighRisk Criteria
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis and 2 or more moderate to highrisk criteria, or systolic blood
pressure 91 to 100 mmHg, carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine
and arrange for a clinician6 to reviewthe person's conditionand venous lactate results within1 hour ofmeetingcriteria inanacute hospital
setting.
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet 2 or more moderate to highrisk criteria and have
lactate over 2 mmol/litre or evidence ofacute kidneyinjury7, treat as highrisk and followrecommendations inthe "Adults, Childrenand Young
People Aged 12 Years and Over withSuspected Sepsis Who Meet 1 or More HighRisk Criteria"sectionabove.
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have
lactate ofless than2 mmol/litre, no evidence ofacute kidneyinjury7 and inwhoma definitive conditioncannot be identified:
Repeat structured assessment at least hourly
Ensure reviewbya senior clinicaldecisionmaker2 within3 hours ofmeeting2 or more moderate to highrisk criteria inanacute hospital
settingfor considerationofantibiotics
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have
lactate ofless than2 mmol/litre, no evidence ofacute kidneyinjury7 and inwhoma definitive conditionor infectioncanbe identified and treated:
manage the definitive condition
ifappropriate, discharge withinformationdependingonthe setting(see recommendations under ","below)
Adults, Childrenand YoungPeople Aged 12 Years and Over withSuspected Sepsis Who Meet Only1 Moderate to HighRisk Criterion
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet only1 moderate to highrisk criterion:
Arrange clinician6 reviewwithin1 hour ofmeetingcriterionfor clinicalassessment inanacute hospitalsetting
Performblood tests ifindicated
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet only1 moderate to highrisk criterionand inwhom
a definitive conditioncanbe identified and treated:
Manage the definitive condition
Ifappropriate, discharge withinformationdependingonsetting(see recommendations under "Informationat Discharge for People Assessed
for Suspected Sepsis, But Not Diagnosed withSepsis"below)
For adults, childrenand youngpeople aged 12 years and over withsuspected sepsis who meet only1 moderate to highrisk criterion, have lactate
ofless than2 mmol/litre, no evidence ofacute kidneyinjury7 and inwhoma definitive conditioncannot be identified:
Repeat structured assessment at least hourly.
Ensure reviewbya senior clinicaldecisionmaker2 within3 hours ofmeetingmoderate to highcriterioninanacute hospitalsettingfor

9.
considerationofantibiotics
Adults, Childrenand YoungPeople Aged 12 Years and Over withSuspected Sepsis and No HighRisk or Moderate to HighRisk Criteria
Arrange clinicalassessment8 ofadults, childrenand youngpeople aged 12 years and over who have suspected sepsis and no highrisk or moderate
to highrisk criteria and manage accordingto clinicaljudgement.
ChildrenAged 5 to 11 Years
Children Aged 5 to 11 Years with Suspected Sepsis Who Meet 1 or More High Risk Criteria
For childrenaged 5 to 11 years who have suspected sepsis and 1 or more highrisk criteria:
Arrange for immediate reviewbythe senior clinicaldecisionmaker9 to assess the child and think about alternative diagnoses to sepsis
Carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine
Aclottingscreen
Give a broad-spectrumantimicrobial(see "Antibiotic Treatment inPeople withSuspected Sepsis,"below) at the maximumrecommended
dose without delay(within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting)
Discuss witha consultant
For childrenaged 5 to 11 years withsuspected sepsis and anyhighrisk criteria and lactate over 4 mmol/litre:
Give intravenous fluid bolus without delay(within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting) inline
withrecommendations under "Intravenous Fluids inPeople withSuspected Sepsis,"belowand
Refer4 to criticalcare5 for reviewofcentralaccess and initiationofinotropes or vasopressors
For childrenaged 5 to 11 years withsuspected sepsis and anyhighrisk criteria and lactate between2 and 4 mmol/litre:
Give intravenous fluid bolus as soonas possible (within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting)
inline withrecommendations in"Intravenous Fluids inPeople withSuspected Sepsis"
For childrenaged 5 to 11 years withsuspected sepsis and anyhighrisk criteria and lactate below2 mmol/litre:
Consider givingintravenous fluid bolus inline withrecommendations under "Intravenous Fluids inPeople withSuspected Sepsis,"below
Monitor childrenwithsuspected sepsis who meet anyhighrisk criteria continuously, or a minimumofonce every30 minutes dependingonsetting.
Physiologicaltrack and trigger systems should be used to monitor allchildreninacute hospitalsettings. (This recommendationis adapted from
NICE's guideline onacutelyillpatients inhospital .)
Monitor the mentalstate ofchildrenaged 5 to 11 years withsuspected sepsis. Consider usingthe GCS or AVPUscale.
Alert a consultant to attend inpersonifa child aged 5 to 11 years withsuspected sepsis and anyhighrisk criteria fails to respond within1 hour of
initialantibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated byanyof:
Reduced levelofconsciousness despite resuscitation
Heart rate or respiratoryrate fulfilhighrisk criteria
Lactate remains over 2 mmol/litre after 1 hour
Children Aged 5 to 11 Years with Suspected Sepsis Who Meet 2 or More Moderate to High Risk Criteria
For childrenaged 5 to 11 years who have suspected sepsis and 2 or more moderate to highrisk criteria:
Carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement

10.
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine
Arrange for a clinicianto reviewthe person's conditionand venous lactate results within1 hour ofmeetingcriteria inanacute hospitalsetting
For childrenaged 5 to 11 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria and have lactate over 2 mmol/litre, treat
as highrisk and followrecommendations under "ChildrenAged 5 to 11 Years withSuspected Sepsis Who Meet 1 or More HighRisk Criteria,"
above.
For childrenaged 5 to 11 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have lactate ofless than2 mmol/litre,
and inwhoma definitive conditioncannot be identified:
Repeat structured assessment at least hourly
Ensure reviewbya senior clinicaldecisionmaker9 within3 hours ofmeeting2 or more moderate to highrisk criteria inanacute hospital
settingfor considerationofantibiotics
For childrenaged 5 to 11 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have lactate ofless than2 mmol/litre,
and inwhoma definitive conditionor infectioncanbe identified and treated:
Manage the definitive condition, and
Ifappropriate, discharge withinformationdependingonsetting(see recommendations under "Informationat Discharge for People Assessed
for Suspected Sepsis, But Not Diagnosed withSepsis,"below)
Children Aged 5 to 11 Years with Suspected Sepsis Who Meet Only 1 Moderate to High Risk Criterion
For childrenaged 5 to 11 years withsuspected sepsis who meet only1 moderate to highrisk criterion:
Arrange clinician6 reviewwithin1 hour ofmeeting1 moderate to highrisk criterioninanacute hospitalsettingfor clinicalassessment and
Performblood tests ifindicated
For childrenaged 5 to 11 years withsuspected sepsis who meet only1 moderate to highrisk criterionand inwhoma definitive conditioncanbe
identified and treated:
Manage the definitive condition
Ifappropriate, discharge withinformationdependingonsetting(see "Informationat Discharge for People Assessed for Suspected Sepsis,
But Not Diagnosed withSepsis,"below)
For childrenaged 5 to 11 years withsuspected sepsis who meet only1 moderate to highrisk criterion, and inwhoma definitive conditioncannot
be identified:
Repeat structured assessment at least hourly
Ensure reviewbya senior clinicaldecisionmaker9 within3 hours ofmeetinga moderate to highrisk criterioninanacute hospitalsettingfor
considerationofantibiotics
Children Aged 5 to 11 Years with Suspected Sepsis and No High Risk or Moderate to High Risk Criteria
Arrange clinicalassessment10 ofchildrenaged 5 to 11 years who have suspected sepsis and no highrisk or moderate to highrisk criteria and
manage accordingto clinicaljudgement.
ChildrenAged Under 5 Years
Children Aged under 5 Years with Suspected Sepsis Who Meet 1 or More High Risk Criteria
For childrenaged under 5 years who have suspected sepsis and 1 or more highrisk criteria:
Arrange for immediate reviewbythe senior clinicaldecisionmaker11 to assess the child and think about alternative diagnoses to sepsis (for
example bronchiolitis)

11.
Carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine
Aclottingscreen
Give a broad-spectrumantimicrobialat the maximumrecommended dose without delay(within1 hour ofidentifyingthat theymeet anyhigh
risk criteria inanacute hospitalsetting; see "Antibiotic Treatment inPeople withSuspected Sepsis,"below)
Discuss witha consultant
For childrenaged under 5 years withsuspected sepsis and anyhighrisk criteria and lactate over 4 mmol/litre:
Give intravenous fluid bolus without delay(inline withrecommendations under "Intravenous Fluids inPeople withSuspected Sepsis,"
below), and
Refer4 to criticalcare5 for reviewofcentralaccess and initiationofinotropes or vasopressors
For childrenaged under 5 years withsuspected sepsis and anyhighrisk criteria and lactate between2 and 4 mmol/litre:
Give intravenous fluid bolus without delay(within1 hour ofidentifyingthat theymeet anyhighrisk criteria inanacute hospitalsetting) inline
withrecommendations under "Intravenous Fluids inPeople withSuspected Sepsis,"below.
For childrenaged under 5 years withsuspected sepsis and anyhighrisk criteria and lactate below2 mmol/litre, consider givingintravenous fluid
bolus inline withrecommendations under "Intravenous Fluids inPeople withSuspected Sepsis,"below.
Monitor childrenaged under 5 years withsuspected sepsis who meet anyhighrisk criteria continuously, or a minimumofonce every30 minutes
dependingonsetting. Physiologicaltrack and trigger systems should be used to monitor allchildreninacute hospitalsettings. (This
recommendationis adapted fromNICE's guideline onacutelyillpatients inhospital .)
Monitor the mentalstate ofchildrenunder 5 years withsuspected sepsis. Consider usingthe GCS or AVPUscale.
Alert a consultant to attend inpersonifa child aged under 5 years withsuspected sepsis and anyhighrisk criteria fails to respond within1 hour of
initialantibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated byanyof:
Reduced levelofconsciousness despite resuscitation
Heart rate or respiratoryrate fulfilhighrisk criteria
Lactate over 2 mmol/litre after 1 hour
Give parenteralantibiotics to infants aged under 3 months as follows:
Infants younger than1 monthwithfever
Allinfants aged 1 to 3 months withfever who appear unwell
Infants aged 1 to 3 months withwhite blood cellcount less than5×109/litre or greater than15×109/litre
(This recommendationis fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness inchildren:
assessment and initialmanagement inchildrenyounger than5 years].)
Children Aged under 5 Years with Suspected Sepsis Who Meet 2 or More Moderate to High Risk Criteria
For childrenaged under 5 years withsuspected sepsis and 2 or more moderate to highrisk criteria:
Carryout a venous blood test for the following:
Blood gas, includingglucose and lactate measurement
Blood culture
Fullblood count
C-reactive protein
Urea and electrolytes
Creatinine

12.
Arrange for a clinician6 to reviewthe person's conditionand venous lactate results within1 hour ofmeeting2 or more moderate to highrisk
criteria inanacute hospitalsetting
For childrenaged under 5 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria and have lactate over 2 mmol/litre, treat
as highrisk and followrecommendations under "ChildrenAged under 5 Years withSuspected Sepsis Who Meet 1 or More HighRisk Criteria,"
above.
For childrenaged under 5 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have lactate ofless than2 mmol/litre,
and inwhoma definitive conditioncannot be identified:
Repeat structured assessment at least hourly
Ensure reviewbya senior clinicaldecisionmaker11 within3 hours ofmeeting2 or more moderate to highrisk criteria inanacute hospital
settingfor considerationofantibiotics
For childrenaged under 5 years withsuspected sepsis who meet 2 or more moderate to highrisk criteria, have lactate ofless than2 mmol/litre,
and inwhoma definitive conditionor infectioncanbe identified and treated:
Manage the definitive condition, and
Ifappropriate, discharge withinformationdependingonthe setting(see "Informationat Discharge for People Assessed for Suspected
Sepsis, But Not Diagnosed withSepsis,"below)
Children under 5 Years with Suspected Sepsis Who Meet Only 1 Moderate to High Risk Criterion
For childrenaged under 5 years withsuspected sepsis who meet only1 moderate to highrisk criterion:
Arrange clinicianreviewwithin1 hour ofmeetinga moderate to highrisk criterionfor clinicalassessment, and
Performblood tests ifindicated
For childrenaged under 5 years withsuspected sepsis who meet only1 moderate to highrisk criterionand inwhoma definitive conditioncanbe
identified and treated:
Manage the definitive condition
Ifappropriate, discharge withinformationdependingonthe setting(see "Informationat Discharge for People Assessed for Suspected
Sepsis, But Not Diagnosed withSepsis,"below)
For childrenaged under 5 years withsuspected sepsis who meet only1 moderate to highrisk criterionand inwhoma definitive conditioncannot
be identified:
Repeat structured assessment at least hourly
Ensure reviewbya senior clinicaldecisionmaker11 within3 hours ofmeetinga moderate to highrisk criterioninanacute hospitalsettingfor
considerationofantibiotics
Children Aged under 5 Years with Suspected Sepsis and No High Risk or Moderate to High Risk Criteria
Arrange clinicalassessment8 ofchildrenaged under 5 years who have suspected sepsis and no highrisk or moderate to highrisk criteria and
manage accordingto clinicaljudgement.
Antibiotic Treatment inPeople withSuspected Sepsis
Pre-alert secondarycare (throughgeneralpractitioner [GP] or ambulance service) whenanyhighrisk criteria are met ina personwithsuspected
sepsis outside ofanacute hospital, and transfer themimmediately.
Ensure urgent assessment mechanisms are inplace to deliver antibiotics whenanyhighrisk criteria are met insecondarycare (within1 hour of
meetinga highrisk criterioninanacute hospitalsetting).
Ensure GPs and ambulance services have mechanisms inplace to give antibiotics for people withhighrisk criteria inpre-hospitalsettings in
locations where transfer time is more than1 hour.
For patients inhospitalwho have suspected infections, take microbiologicalsamples before prescribinganantimicrobialand reviewthe
prescriptionwhenthe results are available. For people withsuspected sepsis take blood cultures before antibiotics are given. (This

13.
recommendationis adapted fromNICE's guideline onantimicrobialstewardship .)
Ifmeningococcaldisease is specificallysuspected (fever and purpuric rash) give appropriate doses ofparenteralbenzylpenicillinincommunity
settings and intravenous ceftriaxone inhospitalsettings. (This recommendationis adapted fromNICE's guideline onmeningitis [bacterial] and
meningococcalsepticaemia inunder 16s .)
For allpeople withsuspected sepsis where the source ofinfectionis clear use existinglocalantimicrobialguidance.
For people aged 18 years and over who need anempiricalintravenous antimicrobialfor a suspected infectionbut who have no confirmed
diagnosis, use anintravenous antimicrobialfromthe agreed localformularyand inline withlocal(where available) or nationalguidelines. (This
recommendationis adapted fromNICE's guideline onantimicrobialstewardship .)
For people aged up to 17 years (for neonates see recommendationbelow) withsuspected communityacquired sepsis ofanycause give
ceftriaxone 80 mg/kgonce a daywitha maximumdose of4 gdailyat anyage. (This recommendationis adapted fromNICE's guideline on
meningitis [bacterial] and meningococcalsepticaemia inunder 16s .)
For people aged up to 17 years withsuspected sepsis who are alreadyinhospital, or who are knownto have previouslybeeninfected withor
colonised withceftriaxone-resistant bacteria, consult localguidelines for choice ofantibiotic.
For childrenyounger than3 months, give anadditionalantibiotic active against listeria (for example, ampicillinor amoxicillin). (This
recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness inchildren:
assessment and initialmanagement inchildrenyounger than5 years].)
Treat neonates presentinginhospitalwithsuspected sepsis intheir first 72 hours withintravenous benzylpenicillinand gentamicin. (This
recommendationis adapted fromNICE's guideline onneonatalinfection[see the NGC summaryofthe NICEguideline Antibiotics for early-onset
neonatalinfection. Antibiotics for the preventionand treatment ofearly-onset neonatalinfection].)
Treat neonates who are more than40 weeks corrected gestationalage who present withcommunityacquired sepsis withceftriaxone 50 mg/kg
unless alreadyreceivinganintravenous calciuminfusionat the time. If40 weeks corrected gestationalage or belowor receivinganintravenous
calciuminfusionuse cefotaxime 50 mg/kgevery6 to 12 hours, dependingonthe age ofthe neonate.
Followthe recommendations inNICE's guideline onantimicrobialstewardship:systems and processes for effective antimicrobialmedicine
whenprescribingand usingantibiotics to treat people withsuspected or confirmed sepsis.
Intravenous Fluids inPeople withSuspected Sepsis
Ifpatients over 16 years need intravenous fluid resuscitation, use crystalloids that containsodiuminthe range 130–154 mmol/litre witha bolus of
500 mlover less than15 minutes. (This recommendationis fromNICE's guideline onintravenous fluid therapyinadults inhospital[see the NGC
summaryofthe NICEguideline Intravenous fluid therapyinadults inhospital].)
Ifchildrenand youngpeople up to 16 years need intravenous fluid resuscitation, use glucose-free crystalloids that containsodiuminthe range 130–
154 mmol/litre, witha bolus of20 ml/kgover less than10 minutes. Take into account preexistingconditions (for example, cardiac disease or
kidneydisease), because smaller fluid volumes maybe needed. (This recommendationis fromNICE's guideline onintravenous fluid therapyin
childrenand youngpeople inhospital[see the NGC summaryofthe NICEguideline Intravenous fluid therapyinchildrenand youngpeople in
hospital].)
Ifneonates need intravenous fluid resuscitation, use glucose-free crystalloids that containsodiuminthe range 130–154 mmol/litre, witha bolus of
10–20 ml/kgover less than10 minutes. (This recommendationis fromNICE's guideline onintravenous fluid therapyinchildrenand youngpeople
inhospital[see the NGC summaryofthe NICEguideline Intravenous fluid therapyinchildrenand youngpeople inhospital].)
Reassess the patient after completionofthe intravenous fluid bolus, and ifno improvement give a second bolus. Ifthere is no improvement after a
second bolus alert a consultant to attend (inline withrecommendations under "Managingand TreatingSuspected Sepsis inAcute Hospital
Settings,"above).
Use a pump, or syringe ifno pump is available, to deliver intravenous fluids for resuscitationto childrenunder 12 years withsuspected sepsis who
need fluids inbolus form.
Ifusinga pump or flowcontroller to deliver intravenous fluids for resuscitationto people over 12 years withsuspected sepsis who need fluids in
bolus formensure device is capable ofdeliveringfluid at required rate, for example at least 2000 ml/hour inadults.

14.
Do not use starchbased solutions or hydroxyethylstarches for fluid resuscitationfor people withsepsis. (This recommendationis adapted from
NICE's guidelines onintravenous fluid therapyinadults inhospitaland intravenous therapyinchildrenand youngpeople inhospital[see the NGC
summaries ofthe NICEguidelines Intravenous fluid therapyinadults inhospitaland Intravenous fluid therapyinchildrenand youngpeople in
hospital].)
Consider humanalbuminsolution4%to 5%for fluid resuscitationonlyinpatients withsepsis and shock. (This recommendationis adapted from
NICE's guideline onintravenous fluid therapyinadults inhospital[see the NGC summaryofthe NICEguideline Intravenous fluid therapyinadults
inhospital].)
UsingOxygeninPeople withSuspected Sepsis
Give oxygento achieve a target saturationof94%to 98%for adult patients or 88%to 92%for those at risk ofhypercapnic respiratoryfailure.
Oxygenshould be givento childrenwithsuspected sepsis who have signs ofshock or oxygensaturation(SpO2) ofless than91%whenbreathing
air. Treatment withoxygenshould also be considered for childrenwithanSpO2 ofgreater than92%, as clinicallyindicated. (This recommendation
is adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness inchildren:assessment and
initialmanagement inchildrenyounger than5 years].)
Findingthe Source ofInfectioninPeople withSuspected Sepsis
Carryout a thoroughclinicalexaminationto look for sources ofinfection, includingsources that might need surgicaldrainage, as part ofthe initial
assessment.
Tailor investigations ofthe sources ofinfectionto the person's clinicalhistoryand findings onexamination.
Consider urine analysis and chest X-rayto identifythe source ofinfectioninallpeople withsuspected sepsis.
Consider imagingofthe abdomenand pelvis ifno likelysource ofinfectionis identified after clinicalexaminationand initialtests.
Involve the adult or paediatric surgicaland gynaecologicalteams earlyonifintra-abdominalor pelvic infectionis suspected incase surgical
treatment is needed.
Do not performa lumbar puncture without consultant instructionifanyofthe followingcontraindications are present:
Signs suggestingraised intracranialpressure or reduced or fluctuatinglevelofconsciousness (GlasgowComa Scale score less than9 or a
drop of3 points or more)
Relative bradycardia and hypertension
Focalneurologicalsigns
Abnormalposture or posturing
Unequal, dilated or poorlyresponsive pupils
Papilloedema
Abnormal'doll's eye' movements
Shock
Extensive or spreadingpurpura
After convulsions untilstabilised
Coagulationabnormalities or coagulationresults outside the normalrange or platelet count below100x109/litre or receivinganticoagulant
therapy
Localsuperficialinfectionat the lumbar puncture site
Respiratoryinsufficiencyinchildren
(This recommendationis adapted fromNICE's guideline onmeningitis [bacterial] and meningococcalsepticaemia inunder 16s
.)
Performlumbar puncture inthe followingchildrenwithsuspected sepsis (unless contraindicated; see contraindications inthe recommendation
above).
Infants younger than1 month
Allinfants aged 1 to 3 months who appear unwell
Infants aged 1 to 3 months witha white blood cellcount less than5×109/litre or greater than15×109/litre

15.
(This recommendationis adapted fromNICE's guideline onfever inunder 5s [see the NGC summaryofthe NICEguideline Feverishillness in
children:assessment and initialmanagement inchildrenyounger than5 years].)
Informationand Support for People withSepsis and Their Families and Carers
People Who Have Sepsis and Their Families and Carers
Ensure a care teammember is nominated to give informationto families and carers, particularlyinemergencysituations suchas inthe emergency
department. This should include:
Anexplanationthat the personhas sepsis, and what this means
Anexplanationofanyinvestigations and the management plan
Regular and timelyupdates ontreatment, care and progress
Ensure informationis givenwithout usingmedicaljargon. Check regularlythat people understand the informationand explanations theyare given.
Give people withsepsis and their familymembers and carers opportunities to ask questions about diagnosis, treatment options, prognosis and
complications. Be willingto repeat anyinformationas needed.
Give people withsepsis and their families and carers informationabout nationalcharities and support groups that provide informationabout sepsis
and the causes ofsepsis.
Informationat Discharge for People Assessed for Suspected Sepsis, But Not Diagnosed withSepsis
Give people who have beenassessed for sepsis but have beendischarged without a diagnosis ofsepsis (and their familyor carers, ifappropriate)
verbaland writteninformationabout:
What sepsis is, and whyit was suspected
What tests and investigations have beendone
Instructions about whichsymptoms to monitor
Whento get medicalattentioniftheir illness continues
Howto get medicalattentioniftheyneed to seek help urgently
Confirmthat people understand the informationtheyhave beengiven, and what actions theyshould take to get help iftheyneed it.
Informationat Discharge for People at Increased Risk ofSepsis
Ensure people who are at increased risk ofsepsis (for example after surgery) are told before discharge about symptoms that should prompt them
to get medicalattentionand howto get it.
See NICE's guideline onneutropenic sepsis for informationfor people withneutropenic sepsis [see the NGC summaryofthe NICEguideline
Neutropenic sepsis:preventionand management ofneutropenic sepsis incancer patients].)
Informationat Discharge for People Who Have Had Sepsis
Ensure people and their families and carers, ifappropriate, have beeninformed that theyhave had sepsis.
Ensure discharge notifications to GPs include the diagnosis ofsepsis.
Give people who have had sepsis (and their families and carers, whenappropriate) opportunities to discuss their concerns. These mayinclude:
Whytheydeveloped sepsis
Whether theyare likelyto develop sepsis again
Ifmore investigations are necessary
Details ofanycommunitycare needed, for example, related to peripherallyinserted centralvenous catheters (PICC) lines or other
intravenous catheters
What theyshould expect duringrecovery
Arrangements for follow-up, includingspecific criticalcare followup ifrelevant
Possible short-termand long-termproblems
Give people who have had sepsis and their families and carers informationabout nationalcharities and support groups that provide information

16.
about sepsis and causes ofsepsis.
Advise carers theyhave a legalright to have a carer's assessment oftheir needs, and give theminformationonhowtheycanget this.
See NICE's guideline onrehabilitationafter criticalillness inadults for recommendations onrehabilitationand followup
after criticalillness.
See NICE's guideline onmeningitis (bacterial) and meningococcalsepticaemia inunder 16s for followup ofpeople who
have had meningococcalsepticaemia.
Trainingand Education
Ensure allhealthcare staffand students involved inassessingpeople's clinicalconditionare givenregular, appropriate traininginidentifyingpeople
who might have sepsis. This includes primary, communitycare and hospitalstaffincludingthose workingincare homes.
Ensure allhealthcare professionals involved intriage or earlymanagement are givenregular appropriate traininginidentifying, assessingand
managingsepsis. This should include:
Risk stratificationstrategies
Localprotocols for earlytreatments, includingantibiotics and intravenous fluids
Criteria and pathways for escalation, inline withtheir healthcare setting
Footnotes
1Emergency carerequires facilities for resuscitation to beavailableand dependingon local services may beemergency department, medical admissions unit and for children may be
paediatricambulatory unit or paediatricmedical admissions unit.
2A 'senior clinical decision maker' for peopleaged 18 years or over should besomeonewho is authorised to prescribeantibiotics, such as adoctor of gradeCT3/ST3 or aboveor
equivalent, such as an advanced nursepractitioner with antibioticprescribingresponsibilities, dependingon local arrangements. A 'senior decision maker' for peopleaged 12 to 17 years
is apaediatricor emergency carequalified doctor of gradeST4 or aboveor equivalent.
3Appropriateconsultant may betheconsultant under whomthepatient is admitted or aconsultant coveringacutemedicine, anaesthetics.
4Referral may beaformal referral process or discussion with specialist in intensivecareor intensivecareoutreach team.
5Critical caremeans an intensivist or intensivecareoutreach team, or specialist in intensivecareor paediatricintensivecare.
6A 'clinician' should beamedically qualified practitioner or equivalent who has antibioticprescribingresponsibilities.
7For definition of acutekidney injury, seeNICE's guidelineon acutekidney injury (seetheNGCsummary of Acutekidney injury. Prevention, detection and management of acute
kidney injury up to thepoint of renal replacement therapy).
8Clinical assessment should becarried out by amedically qualified practitioner or equivalent who has antibioticprescribingresponsibilities.
9A 'senior clinical decision maker' for children aged 5 to 11 years is apaediatricor emergency caredoctor of gradeST4 or aboveor equivalent.
10This should beby amedically qualified practitioner or equivalent with prescribingresponsibilities.
11A 'senior clinical decision maker' for children aged under 5 years is apaediatricqualified doctor of gradeST4 or above.
Definitions
StrengthofRecommendations
Some recommendations canbe made withmore certaintythanothers. The Guideline Development Group (GDG) makes a recommendationbased
onthe trade-offbetweenthe benefits and harms ofanintervention, takinginto account the qualityofthe underpinningevidence. For some
interventions, the GDGis confident that, giventhe informationit has looked at, most patients would choose the intervention. The wordingused in
the recommendations inthis guideline denotes the certaintywithwhichthe recommendationis made (the strengthofthe recommendation).
Interventions That Must (or Must Not) Be Used
The GDGusuallyuses 'must' or 'must not' onlyifthere is a legaldutyto applythe recommendation. Occasionally'must' (or 'must not') is used ifthe
consequences ofnot followingthe recommendationcould be extremelyserious or potentiallylife threatening.
Interventions That Should (or Should Not) Be Used – a 'Strong' Recommendation
The GDGuses 'offer' (and similar words suchas 'refer' or 'advise') whenconfident that, for the vast majorityofpatients, aninterventionwilldo

17.
more good thanharm, and be cost effective. Similar forms ofwords (for example, 'Do not offer…') are used whenthe GDGis confident that an
interventionwillnot be ofbenefit for most patients.
Interventions That Could Be Used
The GDGuses 'consider' whenconfident that aninterventionwilldo more good thanharmfor most patients, and be cost effective, but other
options maybe similarlycost effective. The choice ofintervention, and whether or not to have the interventionat all, is more likelyto depend onthe
patient's values and preferences thanfor a strongrecommendation, and so the healthcare professionalshould spend more time consideringand
discussingthe options withthe patient.
Clinical Algorithm(s)
The followingclinicalalgorithms are provided onthe NationalInstitute for Healthand Care Excellence (NICE) Web site :
Algorithmfor managingsuspected sepsis inadults and youngpeople aged 18 years and over inanacute hospitalsetting
Algorithmfor managingsuspected sepsis inadults and youngpeople aged 18 years and over outside anacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenaged 5–11 years inanacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenaged 5–11 years outside anacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenaged under 5 years inanacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenaged under 5 years outside anacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenand youngpeople aged 12–17 years inanacute hospitalsetting
Algorithmfor managingsuspected sepsis inchildrenand youngpeople aged 12–17 years outside anacute hospitalsetting
Inaddition, a NICEpathwaytitled "Sepsis overview"is provided onthe NICEWeb site .
Scope
Disease/Condition(s)
Sepsis includingseptic shock
Guideline Category
Diagnosis
Evaluation
Management
Risk Assessment
Treatment
Clinical Specialty
CriticalCare
EmergencyMedicine
FamilyPractice
Geriatrics
Infectious Diseases

18.
InternalMedicine
Obstetrics and Gynecology
Pediatrics
Intended Users
Advanced Practice Nurses
Allied HealthPersonnel
EmergencyMedicalTechnicians/Paramedics
HealthCare Providers
Hospitals
Nurses
Patients
PhysicianAssistants
Physicians
Public HealthDepartments
Guideline Objective(s)
To ensure healthcare systems inallclinicalsettings consider sepsis as animmediate life-threateningconditionthat should be recognised and
treated as anemergency
To outline the immediate actions required for those withsuspicionofsepsis and who are at highest risk ofmorbidityand mortalityfrom
sepsis
To provide a framework for risk assessment, treatment and follow-up or 'safety-netting' ofpeople not requiringimmediate resuscitation
To ensure that allpeople withsepsis due to anycause are recognised and initialtreatment initiated before definitive treatment onother
specific pathways is instituted
Target Population
Allpopulations withsuspected or confirmed sepsis, their families and carers
Interventions and Practices Considered
Diagnosis/Evaluation/Risk Assessment
1. Identifyingpeople at increased risk ofsepsis
2. Use ofscoringsystems
3. Assessment ofphysiologicalsigns and symptoms
Heart rate
Respiratoryrate
Blood pressure
Levelofconsciousness
Oxygensaturation
Capillaryrefilltime
Temperature

19.
Urine output
Skinappearance
Behaviour
Mentalstate, cognitive state
4. Risk stratification
Management/Treatment
1. Managingsuspected sepsis outside acute hospitalsettings
Referralto emergencycare
Assessment ofcondition
2. Managingand treatingsuspected sepsis inacute hospitalsettings
Blood tests for diagnosis ofsepsis (blood gases, glucose, lactate, blood culture, fullblood count, urea and electrolytes, creatinine,
clottingscreen, C-reactive protein)
Antimicrobialtreatments
Intravenous fluid administration
Escalationofcare (e.g., directionto senior healthcare professionalor criticalcare provider)
3. Use ofinotropic agents and vasopressors
4. Use ofsupplementaloxygen
5. Monitoring
6. Findingsource ofinfection
Clinicalinvestigations
Urinalysis
X-rayand other imaging
Lumbar puncture
7. Providinginformation, education, and support to patients, families, and carers
8. Educationand trainingprogrammes to improve recognition, diagnosis, and management ofsepsis
Note: Thefollowingareconsidered but not recommended: assessment for disseminated intravascular coagulation, useof bicarbonatefor acid-basebalance, early goal-directed therapy
(EGDT).
Major Outcomes Considered
Sensitivity, specificity, positive and negative predictive value ofdiagnostic tests
28-daymortalityrate
Clinicalresolution
Health-related qualityoflife
Criticalcare admission
Progressionto severe sepsis
Treatment failure
Appropriate or inappropriate use ofantibiotics
Durationoftreatment
Hospitalre-admission
Lengthofhospitalstay
Complications
Admissionto criticalcare as a proxyfor progressionto severe sepsis
Durationofcriticalcare stay
Number oforgans supported
Adverse events
Patient satisfaction, includingunderstanding
Reductionintime to diagnosis
Time to shock reversal
Methodology

20.
Methods Used to Collect/Select the Evidence
Hand-searches ofPublished Literature (PrimarySources)
Hand-searches ofPublished Literature (SecondarySources)
Searches ofElectronic Databases
Description of Methods Used to Collect/Select the Evidence
Note fromthe NationalGuideline Clearinghouse (NGC):The guideline was developed bythe NationalGuideline Centre onbehalfofthe National
Institute for Healthand Care Excellence (NICE). See the "AvailabilityofCompanionDocuments"field for the fullversionofthis guidance and
related appendices.
Developingthe ReviewQuestions and Outcomes
Reviewquestions were developed ina PICO framework (patient, intervention, comparisonand outcome) for interventionreviews; ina framework
ofpopulation, indextests, reference standard and target conditionfor reviews ofdiagnostic test accuracy; and usingpopulation, presence or
absence offactors under investigation(for example, prognostic factors) and outcomes for prognostic reviews.
This use ofa framework guided the literature searchingprocess, criticalappraisaland synthesis ofevidence, and facilitated the development of
recommendations bythe Guideline Development Group (GDG). The reviewquestions were drafted bythe NGC technicalteamand refined and
validated bythe GDG. The questions were based onthe keyclinicalareas identified inthe scope (see AppendixA).
Atotalof18 reviewquestions were identified.
Fullliterature searches, criticalappraisals and evidence reviews were completed for allthe specified reviewquestions, except for source of
infection, earlygoal-directed therapy(EGDT) and centralvenous (CV) access. The recommendations for source ofinfectionand CVaccess are
based ondiscussions, consensus and expert opinionofthe GDGand were also informed byother reviewquestions. The rationale for these
decisions is explained inmore detailinrelevant chapters ofthe fullversionofthe guideline. The reviewonEGDTonlyincludes a recent systematic
reviewonthree large multi-centre randomised controlled trials (RCTs), the ProMISe, ARISE, and ProCESS trials. This systematic reviewwas
considered to adequatelyaddress the EDGTreviewquestion.
Searchingfor Evidence
ClinicalLiterature Search
Systematic literature searches were undertakento identifyallpublished clinicalevidence relevant to the reviewquestions. Searches were
undertakenaccordingto the parameters stipulated withinthe NICEguidelines (see the "AvailabilityofCompanionDocuments"field). Databases
were searched usingrelevant medicalsubject headings, free-text terms and study-type filters where appropriate. Studies published inlanguages
other thanEnglishwere not reviewed. Where possible, searches were restricted to articles published inEnglish. Allsearches were conducted in
MEDLINE, EMBASE, and The Cochrane Library. Additionalsubject specific databases were used for one question:CINAHLand PsycINFO
for informationsupport. Allsearches were updated on9 October 2015. No papers added to the databases after this date were considered.
Searchstrategies were qualityassured bycross-checkingreference lists ofhighlyrelevant papers, analysingsearchstrategies inother systematic
reviews, and askingGDGmembers to highlight anyadditionalstudies. The questions, the studytypes applied, the databases searched and the
years covered canbe found inAppendixGofthe fullversionofthe guideline.
The titles and abstracts ofrecords retrieved bythe searches were sifted for relevance, withpotentiallysignificant publications obtained infulltext.
These were assessed against the inclusioncriteria.
Duringthe scopingstage, a searchwas conducted for guidelines and reports onthe Web sites listed belowfromorganisations relevant to the topic.
Searchingfor unpublished literature was not undertaken. Allreferences sent bystakeholders were considered.
Guidelines InternationalNetwork database (www.g-i-n.net )
NationalHealthService (NHS) Evidence Search(www.evidence.nhs.uk )
TRIP database (https://www.tripdatabase.com/ )
Sepsis Alliance (http://www.sepsisalliance.org /)
The UK Sepsis Trust (http://sepsistrust.org /)

21.
Center for Sepsis Control&Care (http://www.cscc.uniklinikum-jena.de/cscc/en/CSCC-p-7.html )
HealthEconomic Literature Search
Systematic literature searches were also undertakento identifyhealtheconomic evidence withinpublished literature relevant to the review
questions. The evidence was identified byconductinga broad searchrelatingto sepsis and bacterialmeningitis populations inthe NHS Economic
EvaluationDatabase (NHS EED), the HealthTechnologyAssessment database (HTA) and the HealthEconomic Evaluations Database (HEED)
withno date restrictions. The HealthEconomic EvaluationDatabase ceased productionin2014 withaccess ceasinginJanuary2015. Additionally,
the searchwas runonMEDLINEand EMBASEusinga specific economic filter, from2012, to ensure recent publications that had not yet been
indexed bythe economic databases were identified. Studies published inlanguages other thanEnglishwere not reviewed. Where possible,
searches were restricted to articles published inEnglish.
The healtheconomic searchstrategies are included inAppendixG. Allsearches were updated on9 October 2015. No papers added to the
databases after this date were considered.
Evidence ofEffectiveness
The evidence was reviewed followingthe steps shownschematicallyinFigure 1 inthe fullversionofthe guideline document:
Potentiallyrelevant studies were identified for eachreviewquestionfromthe relevant searchresults byreviewingtitles and abstracts. Full
papers were thenobtained.
Fullpapers were reviewed against pre-specified inclusionand exclusioncriteria to identifystudies that addressed the reviewquestioninthe
appropriate population(reviewprotocols are included inAppendixC ofthe fullversionofthe guideline).
A20%sample ofeachofthe stages ofthe reviewingprocess was qualityassured bya second reviewer to eliminate anypotentialofreviewer bias
or error.
Inclusionand ExclusionCriteria
The inclusionand exclusionofstudies was based onthe reviewprotocols, whichcanbe found inAppendixC. Excluded studies byreview
question(withthe reasons for their exclusion) are listed inAppendixL. The GDGwas consulted about anyuncertaintyregardinginclusionor
exclusion.
The guideline populationwas defined to be adults, children(includingneonates) and youngpeople at risk ofdevelopingsepsis. For some review
questions, the reviewpopulationalso included people withdefinite sepsis, severe sepsis or septic shock. The reviewoninformationand support
also included families and carers ofpeople who had sepsis or severe sepsis, and people who had survived episodes ofsevere sepsis. For the
reviewoneducationand training, the reviewpopulationwas defined as allhealthcare professionals involved inthe diagnosis, management and
monitoringofsepsis.
The subgroups considered included children, adults, pregnant women, people at higher risk ofinfection, and different settings ofcare delivery. For
some reviewquestions, the evidence was grouped bypredefined subgroup analysis based onseverityofillness.
Randomised trials, non-randomised trials, and observationalstudies (includingdiagnostic or prognostic studies) were included inthe evidence
reviews as appropriate.
Literature reviews, posters, letters, editorials, comment articles, unpublished studies and studies not inEnglishwere excluded. The review
protocols are presented inAppendixC.
Evidence ofCost-effectiveness
The GDGis required to make decisions based onthe best available evidence ofbothclinicaland cost-effectiveness. Guideline recommendations
should be based onthe expected costs ofthe different options inrelationto their expected healthbenefits (that is, their "cost effectiveness") rather
thanthe totalimplementationcost. Thus, ifthe evidence suggests that a strategyprovides significant healthbenefits at anacceptable cost per patient
treated, it should be recommended evenifit would be expensive to implement across the whole population.
Evidence oncost-effectiveness related to the keyclinicalissues beingaddressed inthe guideline was sought. The healtheconomist:
Undertook a systematic reviewofthe published economic literature.
Literature Review

22.
The healtheconomist:
Identified potentiallyrelevant studies for eachreviewquestionfromthe economic searchresults byreviewingtitles and abstracts. Fullpapers
were thenobtained.
Reviewed fullpapers against pre-specified inclusionand exclusioncriteria to identifyrelevant studies (see belowfor details).
Inclusion and Exclusion Criteria
Fulleconomic evaluations (studies comparingcosts and healthconsequences ofalternative courses ofaction:cost–utility, cost-effectiveness, cost–
benefit and cost–consequences analyses) and comparative costingstudies that addressed the reviewquestioninthe relevant populationwere
considered potentiallyincludable as economic evidence.
Studies that onlyreported cost per hospital(not per patient), or onlyreported average cost-effectiveness without disaggregated costs and effects,
were excluded. Literature reviews, abstracts, posters, letters, editorials, comment articles, unpublished studies and studies not inEnglishwere
excluded. Studies published before 1999 and studies fromnon-Organisationfor Economic Co-operationand Development (OECD) countries or
the USAwere also excluded, onthe basis that the applicabilityofsuchstudies to the present UK NHS context is likelyto be too lowfor themto
be helpfulfor decision-making.
Remainingstudies were prioritised for inclusionbased ontheir relative applicabilityto the development ofthis guideline and the studylimitations.
For example, ifa highquality, directlyapplicable UK analysis was available, thenother less relevant studies maynot have beenincluded. Where
exclusions occurred onthis basis, this is noted inthe relevant sectioninthe fullversionofthe guideline.
For more details about the assessment ofapplicabilityand methodologicalqualitysee Table 7 inthe fullversionofthe guideline and the economic
evaluationchecklist (AppendixGofthe NICEguidelines manual2012) and the healtheconomics reviewprotocolinAppendixC.
Number of Source Documents
Refer to the article selectionreviews inthe fullguideline appendices (AppendixEfor clinicalarticles and AppendixF for economic articles [see the
"AvailabilityofCompanionDocuments"field]) for flowcharts and detailed informationonthe totalnumber ofstudies identified, selected, and
excluded for eachguideline topic.
Methods Used to Assess the Quality and Strength of the Evidence
WeightingAccordingto a RatingScheme (Scheme Given)
Rating Scheme for the Strength of the Evidence
OverallQualityofOutcome Evidence inGradingofRecommendations Assessment, Development and Evaluation(GRADE)
Level Description
High Further researchis veryunlikelyto change confidence inthe estimate ofeffect.
Moderate Further researchis likelyto have animportant impact onconfidence inthe estimate ofeffect and maychange the estimate.
Low Further researchis verylikelyto have animportant impact onconfidence inthe estimate ofeffect and is likelyto change the
estimate.
Very Low Anyestimate ofeffect is veryuncertain.
Methods Used to Analyze the Evidence
Meta-Analysis
ReviewofPublished Meta-Analyses
Systematic ReviewwithEvidence Tables

23.
Description of the Methods Used to Analyze the Evidence
Note fromthe NationalGuideline Clearinghouse (NGC):The guideline was developed bythe NationalGuideline Centre onbehalfofthe National
Institute for Healthand Care Excellence (NICE). See the "AvailabilityofCompanionDocuments"field for the fullversionofthis guidance and
related appendices.
Evidence ofEffectiveness
The evidence was reviewed followingthe steps shownschematicallyinFigure 1 ofthe fullversionofthe guideline:
Relevant studies were criticallyappraised usingthe appropriate checklist as specified inthe NICEguidelines manual(see the "Availabilityof
CompanionDocuments"field).
Keyinformationwas extracted onthe study's methods, PICO (patient, intervention, comparisonand outcome) factors and results. These
were presented insummarytables (ineachreviewchapter ofthe fullversionofthe guideline) and evidence tables (inAppendixH).
Summaries ofevidence were generated byoutcome (included inthe relevant reviewchapters) and were presented inGuideline
Development Group (GDG) meetings:
Randomised studies:data were meta-analysed where appropriate and reported inGradingofRecommendations Assessment,
Development and Evaluation(GRADE) profiles (for interventionreviews)
Observationalstudies:data were presented as a range ofvalues inGRADEprofiles.
Prognostic studies:data were presented as a range ofvalues, usuallyinterms ofthe relative effect as reported bythe authors
Diagnostic studies:for reviews ofdiagnostic tests, diagnostic randomised controlled trials (RCTs) were the first line approachand, as
withinterventionreviews, evidence summaries were generated. Ifno evidence was found fromdiagnostic RCTs, diagnostic accuracy
studies were reviewed. Coupled sensitivityand specificityvalues were summarised inforest plots. Accuracymeasures were meta-
analysed and reported as pooled results where appropriate. Where meta-analysis was performed, coupled sensitivityand specificity
values were also presented onsummaryreceiver operatingcharacteristic (sROC) plots alongwiththe results ofthe meta-analysis (the
summarysensitivityand specificitypoint and 95%confidence region) and the summarycurve. Where evidence was not meta-
analysed, because studies differed inpopulationor outcome, thenno alternative poolingstrategies were carried out, onthe basis that
suchpoolingwould have little meaning. Results fromsingle studies were presented.
Qualitative studies:eachstudywas summarised ina table where possible, otherwise presented ina narrative.
A20%sample ofeachofthe above stages ofthe reviewingprocess was qualityassured bya second reviewer to eliminate anypotentialof
reviewer bias or error.
Methods ofCombiningClinicalStudies
Data Synthesis for Intervention Reviews
Where possible, meta-analyses were conducted to combine the results ofstudies for eachreviewquestionusingCochrane ReviewManager
(RevMan5) software. Fixed-effects (Mantel-Haenszel) techniques were used to calculate risk ratios (relative risk) for the binaryoutcomes, suchas
mortality, criticalcare admissionand adverse events.
For continuous outcomes, measures ofcentraltendency(mean) and variation(standard deviation) were required for meta-analysis. Data for
continuous outcomes, suchas health-related qualityoflife, lengthofstayinintensive care unit (ICU) or hospital, and the number oforgans
supported, were analysed usinganinverse variance method for poolingweighted meandifferences and, where the studies had different scales,
standardised meandifferences were used. Ageneric inverse variance optioninRevMan5 was used ifanystudies reported solelythe summary
statistics and 95%confidence interval(95%CI) or standard error; this included anyhazard ratios reported. However, incases where standard
deviations were not reported per interventiongroup, the standard error (SE) for the meandifference was calculated fromother reported statistics
(p values or 95%CIs); meta-analysis was thenundertakenfor the meandifference and SEusingthe generic inverse variance method inRevMan5.
Whenthe onlyevidence was based onstudies that summarised results bypresentingmedians (and interquartile ranges), or onlyp values were
given, this informationwas assessed interms ofthe study's sample size and was included inthe GRADEtables without calculatingthe relative or
absolute effects. Consequently, aspects ofqualityassessment suchas imprecisionofeffect could not be assessed for evidence ofthis type.
Data Synthesis for Prognostic Factor Reviews
Avarietyofprognostic effect measures were extracted frompapers, dependingonthe type ofoutcome.
For binaryoutcomes, odds ratios, risk ratios or hazard ratios (withtheir 95%CIs) for the independent effect ofeachprognostic factor onthe
outcome were extracted. Beta coefficients for dichotomous outcomes were normallyconverted to anodds ratio (OR) bytakingthe anti-natural

24.
logarithmofthe beta coefficient (as Beta coefficient = lnOR).
For continuous outcomes, the Beta coefficients (or standardised beta coefficients) withtheir 95%CIs for the independent effect ofeachprognostic
factor were extracted.
RCTs, pooled analyses ofpatient leveldata, and prospective or retrospective cohort studies were included. Case-controlstudies were excluded
because oftheir highrisk ofrecallbias. Allnon-RCTstudies were required to have considered allkeyconfounders previouslyidentified bythe
GDGat the protocolstage for that outcome. Studies not consideringthese keyconfounders were excluded. For a confounder to be regarded as
havingbeenadequatelyconsidered, it would have to have beenincluded inthe multivariable analysis (althoughina step-wise modelit would not
necessarilyhave to be present inthe finalmodel) or would have to have beenshownto be matched across risk factor or outcome groups at
baseline.
Data Synthesis for Diagnostic Test Accuracy Reviews
For the reviews ofdiagnostic accuracy, the followingmeasures were used:
The coupled sensitivity and specificity values at a given threshold:Coupled forest plots ofsensitivityand specificitywiththeir 95%CIs across
studies were produced for eachtest (and for eachclinicallyrelevant threshold), usingRevMan5. Inorder to do this, 2×2 tables (the number oftrue
positives, false positives, true negatives and false negatives) were directlytakenfromthe studywhere possible, or else were derived fromrawdata
or calculated fromthe set oftest accuracystatistics.
Data were meta-analysed whendata were available from3 or more studies (givendata were reported at the same threshold or withina defined
range ofsimilar thresholds). To do this, data were entered into a bivariate modelusingWinBUGS. Ifthe modeldid not converge due to
heterogeneity, the pooled estimate was not presented. Adiagnostic meta-analysis was not conducted because the included populationand the
patient outcomes inthe included studies were too different fromeachother. Where meta-analysis was performed, inadditionto the forest plots,
the coupled sensitivityand specificityvalues were also presented onsummaryreceiver operatingcharacteristic (sROC) plots for visualinformation
alongwiththe results ofthe meta-analysis (the summarysensitivityand specificitypoint and 95%confidence region) and the summarycurve. To do
this, bivariate WinBUGS modeloutputs were entered into RevMan5.
Pooled sensitivityand specificityvalues were reported inthe clinicalevidence profile tables (or, ifmeta-analysis was not performed, results from
single studies were presented). For comparisonofmultiple indextests (or betweendifferent thresholds for the same test), the sensitivityand
specificityvalues were compared betweentests.
Data Synthesis for Qualitative Study Reviews
Where possible a meta-synthesis was conducted to combine qualitative studyresults. This guideline includes two qualitative reviewquestions; one
oninformation, educationand support considered to be usefulbypeople who are at risk ofdevelopingsepsis, have sepsis or have survived
episodes ofsepsis, and one onthe availabilityofeducationtrainingprogrammes for healthcare professionals to recognise, diagnose and manage
sepsis. Whenever studies identified a qualitative theme, this was extracted and the maincharacteristics were summarised. Whenallthemes were
extracted fromstudies, commonconcepts were categorised and tabulated. This included informationonhowmanystudies had identified this
theme. Afrequentlyidentified theme mayindicate animportant issue for the review, but frequencyoftheme is not the onlyindicator ofimportance.
Studytype and populationinqualitative researchcandiffer widelymeaningthat themes that mayonlybe identified byone or a fewstudies can
provide important newinformation. Therefore for the purpose ofthe qualitative reviewinthis guideline the categorisationofthemes was exhaustive,
that is allthemes were accounted for inthe synthesis. The GDGcould thendrawconclusions onthe relative merits ofeachofthe themes and how
theymayhelp informingrecommendations.
See Section4.3.2 inthe fullversionofthe guideline document for additionalinformationondata synthesis for different types ofstudies.
Appraisingthe QualityofEvidence byOutcomes
Interventional Studies
The evidence for outcomes fromthe included RCTs and, where appropriate, observationalstudies were evaluated and presented usingan
adaptationofthe 'GRADEtoolbox' developed bythe internationalGRADEworkinggroup (www.gradeworkinggroup.org
). The software developed bythe GRADEworkinggroup (GRADEpro) was used to assess the qualityofeachoutcome,
takinginto account individualstudyqualityfactors and the meta-analysis results. Results were presented inGRADEprofiles 'GRADEtables'),
whichconsist of2 sections:the 'Clinicalevidence profile' table includes details ofthe qualityassessment while the 'Clinicalevidence summaryof
findings' table includes pooled outcome data, where appropriate, anabsolute measure ofinterventioneffect and the summaryofqualityofevidence
for that outcome. Inthis table, the columns for interventionand controlindicate summarymeasures and measures ofdispersion(suchas meanand

25.
standard deviationor medianand range) for continuous outcomes and frequencyofevents (n/N:the sumacross studies ofthe number ofpatients
withevents divided bysumofthe number ofcompleters) for binaryoutcomes. Reportingor publicationbias was onlytakeninto considerationin
the qualityassessment and included inthe 'Clinicalevidence profile' table ifit was apparent.
The evidence for eachoutcome was examined separatelyfor the qualityelements listed and defined inTable 2 ofthe fullversionofthe guideline.
Eachelement was graded usingthe qualitylevels listed inTable 3 ofthe fullversionofthe guideline. The maincriteria considered inthe ratingof
these elements are discussed below. Footnotes were used to describe reasons for gradinga qualityelement as havingserious or veryserious
problems. The ratings for eachcomponent were summed to obtainanoverallassessment for eachoutcome (see the "RatingScheme for the
Strengthofthe Evidence"field).
The GRADEtoolboxis currentlydesigned onlyfor randomised trials and observationalstudies but the qualityassessment elements and outcome
presentationwere adapted for diagnostic accuracystudies.
Gradingthe QualityofClinicalEvidence
After results were pooled, the overallqualityofevidence for eachoutcome was considered. The followingprocedure was adopted whenusing
GRADE:
1. Aqualityratingwas assigned, based onthe studydesign. RCTs started as High, observationalstudies as Low, and uncontrolled case series
as Lowor Verylow.
2. The ratingwas thendowngraded for the specified criteria:risk ofbias (studylimitations), inconsistency, indirectness, imprecisionand
publicationbias. These criteria are detailed inthe fullversionofthe guideline. Evidence fromobservationalstudies (whichhad not previously
beendowngraded) was upgraded ifthere was:a large magnitude ofeffect, a dose–response gradient, and ifallplausible confoundingwould
reduce a demonstrated effect or suggest a spurious effect whenresults showed no effect. Eachqualityelement considered to have 'serious'
or 'veryserious' risk ofbias was rated downby1 or 2 points respectively.
3. The downgraded or upgraded marks were thensummed and the overallqualityratingwas revised. For example, allRCTs started as High
and the overallqualitybecame Moderate, Lowor Verylowif1, 2 or 3 points were deducted respectively.
4. The reasons or criteria used for downgradingwere specified inthe footnotes.
The details ofthe criteria used for eachofthe mainqualityelements for alltypes ofstudies are discussed further inSections 4.3.4.1.1 to 4.3.4.1.4
ofthe fullversionofthe guideline. Refer to Sections 4.3.4.2 and 4.3.4.3 for informationondiagnostic and prognostic studies, respectively.
AssessingClinicalImportance
The GDGassessed the evidence byoutcome inorder to determine ifthere was, or potentiallywas, a clinicallyimportant benefit, a clinically
important harmor no clinicallyimportant difference betweeninterventions. To facilitate this, binaryoutcomes were converted into absolute risk
differences (ARDs) usingGRADEpro software:the mediancontrolgroup risk across studies was used to calculate the ARDand its 95%CI from
the pooled risk ratio.
The assessment ofbenefit, harm, or no benefit or harmwas based onthe point estimate ofabsolute effect for interventionstudies whichwas
standardised across the reviews. The GDGconsidered for most ofthe outcomes inthe interventionreviews that ifat least 100 participants per
1000 (10%) achieved (ifpositive) the outcome ofinterest inthe interventiongroup compared to the comparisongroup thenthis interventionwould
be considered beneficial. The same point estimate but inthe opposite directionwould applyifthe outcome was negative.
This assessment was carried out bythe GDGfor eachcriticaloutcome, and anevidence summarytable was produced to compile the GDG's
assessments ofclinicalimportance per outcome, alongside the evidence qualityand the uncertaintyinthe effect estimate (imprecision).
Evidence Statements
Evidence statements are summarystatements that are presented after the GRADEprofiles, summarisingthe keyfeatures ofthe clinical
effectiveness evidence presented. The wordingofthe evidence statements reflects the certaintyor uncertaintyinthe estimate ofeffect. The
evidence statements encompass the followingkeyfeatures ofthe evidence:
Anindicationofthe directionofeffect (ifone treatment is beneficialor harmfulcompared to the other, or whether there is no difference
betweenthe 2 tested treatments)
Adescriptionofthe overallqualityofevidence
Evidence ofCost-effectiveness
The GDGis required to make decisions based onthe best available evidence ofbothclinicaland cost-effectiveness. Guideline recommendations

26.
should be based onthe expected costs ofthe different options inrelationto their expected healthbenefits (that is, their "cost effectiveness") rather
thanthe totalimplementationcost. Thus, ifthe evidence suggests that a strategyprovides significant healthbenefits at anacceptable cost per patient
treated, it should be recommended evenifit would be expensive to implement across the whole population.
Evidence oncost-effectiveness related to the keyclinicalissues beingaddressed inthe guideline was sought. The healtheconomist:
Undertook a systematic reviewofthe published economic literature.
Literature Review
The healtheconomist:
Criticallyappraised relevant studies usingthe economic evaluations checklist as specified inthe NICEguidelines manual
Extracted keyinformationabout the studies' methods and results into evidence tables (included inAppendixI)
Generated summaries ofthe evidence inNICEeconomic evidence profiles (included inthe relevant chapter for eachreviewquestion) – see
belowfor details.
NICEEconomic Evidence Profiles
The NICEeconomic evidence profile has beenused to summarise cost and cost-effectiveness estimates. The economic evidence profile shows an
assessment ofapplicabilityand methodologicalqualityfor eacheconomic evaluation, withfootnotes indicatingthe reasons for the assessment.
These assessments were made bythe healtheconomist usingthe economic evaluationchecklist fromthe NICEguidelines manual. It also shows the
incrementalcosts, incrementaleffects (for example, quality-adjusted life years [QALYs]) and incrementalcost-effectiveness ratio for the base case
analysis inthe evaluation, as wellas informationabout the assessment ofuncertaintyinthe analysis. See Table 7 ofthe fullversionofthe guideline
for more details.
Ifa non-UK studywas included inthe profile, the results were converted into pounds sterlingusingthe appropriate purchasingpower parity.
UndertakingNewHealthEconomic Analysis
No newhealtheconomic analysis was undertakenfor this guideline due to feasibility.
The GDGoriginallyidentified the timingofantimicrobialtreatment as the highest priorityarea for originaleconomic modelling. This questionwas
originallyintended to determine the cost-effectiveness ofearlyempiricalantibiotic use compared to the use oftargeted antibiotics following
diagnosis. This questionchanged followingagreement ofthe protocoland examined the timingofempiricalantibiotics. The clinicalevidence for this
questionindicates that earlyempiricalantimicrobials (given<1 hour) result inlower mortalitythandelayed use. The GDGwere confident that any
resource implications, and therefore costs, would be offset bythe benefits interms ofreduced mortality. As a result the GDGagreed that the cost-
effectiveness could be deduced without the need to model. Thus, this area was no longer a priorityofeconomic modelling.
Anadditionallower priorityofa pathwayapproach(the impact ofidentifyingand treatingpeople withsepsis) was also considered. However a
pathwayapproachwas considered unfeasible due to the large number ofunknowns inthe epidemiologyofsepsis.
Cost-effectiveness Criteria
NICE's report 'Socialvalue judgements:principles for the development ofNICEguidance' sets out the principles that GDGs should consider when
judgingwhether aninterventionoffers good value for money. Ingeneral, aninterventionwas considered to be cost effective ifeither ofthe
followingcriteria applied (giventhat the estimate was considered plausible):
The interventiondominated other relevant strategies (that is, it was bothless costlyinterms ofresource use and more clinicallyeffective
compared withallthe other relevant alternative strategies), or
The interventioncosts less than£20,000 per QALYgained compared withthe next best strategy
Ifthe GDGrecommended aninterventionthat was estimated to cost more than£20,000 per QALYgained, or did not recommend one that was
estimated to cost less than£20,000 per QALYgained, the reasons for this decisionare discussed explicitlyinthe 'Recommendations and link to
evidence’ sectionofthe relevant chapter, withreference to issues regardingthe plausibilityofthe estimate or to the factors set out in'Socialvalue
judgements:principles for the development ofNICEguidance'.
Ifa studyreported the cost per life year gained but not QALYs, the cost per QALYgained was estimated bymultiplyingbyanappropriate utility
estimate to aid interpretation. The estimated cost per QALYgained is reported inthe economic evidence profile witha footnote detailingthe life-
years gained and the utilityvalue used. WhenQALYs or life years gained are not used inthe analysis, results are difficult to interpret unless one

27.
strategydominates the others withrespect to everyrelevant healthoutcome and cost.
Inthe Absence ofEconomic Evidence
Whenno relevant published studies were found, and a newanalysis was not prioritised, the GDGmade a qualitative judgement about cost-
effectiveness byconsideringexpected differences inresource use betweenoptions and relevant UK NationalHealthService (NHS) unit costs,
alongside the results ofthe clinicalreviewofeffectiveness evidence.
The UK NHS costs reported inthe guideline are those that were presented to the GDGand were correct at the time recommendations were
drafted. Theymayhave changed subsequentlybefore the time ofpublication. However, the GDGmembers have no reasonto believe theyhave
changed substantially.
Methods Used to Formulate the Recommendations
Expert Consensus
InformalConsensus
Description of Methods Used to Formulate the Recommendations
Note fromthe NationalGuideline Clearinghouse (NGC):The guideline was developed bythe NationalGuideline Centre onbehalfofthe National
Institute for Healthand Care Excellence (NICE). See the "AvailabilityofCompanionDocuments"field for the fullversionofthis guidance and
related appendices.
Who Developed This Guideline?
AmultidisciplinaryGuideline Development Group (GDG) comprisinghealthprofessionals, laymembers and researchers developed this guideline.
The group met approximatelyevery6 weeks duringthe development ofthe guideline.
Stafffromthe NationalGuideline Centre provided methodologicalsupport and guidance for the development process. The teamworkingonthe
guideline included a project manager, document editor, systematic reviewers (researchfellows), healtheconomists and informationscientists. They
undertook systematic searches ofthe literature, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where
appropriate, and drafted the guideline incollaborationwiththe GDG.
DevelopingRecommendations
Over the course ofthe guideline development process, the GDGwas presented with:
Evidence tables ofthe clinicaland economic evidence reviewed fromthe literature. Allevidence tables are inAppendices Hand I.
Summaries ofclinicaland economic evidence and quality(as presented inChapters 5-16 ofthe fullversionofthe guideline)
Forest plots (see AppendixK)
Recommendations were drafted onthe basis ofthe GDG's interpretationofthe available evidence, takinginto account the balance ofbenefits,
harms and costs betweendifferent courses ofaction. This was either done formallyinaneconomic model, or informally. Firstly, the net benefit
over harm(clinicaleffectiveness) was considered, focusingonthe criticaloutcomes. Whenthis was done informally, the GDGtook into account
the clinicalbenefits and harms whenone interventionwas compared withanother. The assessment ofnet benefit was moderated bythe importance
placed onthe outcomes (the GDG's values and preferences), and the confidence the GDGhad inthe evidence (evidence quality). Secondly,
whether the net benefit justified anydifferences incosts was assessed.
Whenclinicaland economic evidence was ofpoor quality, conflictingor absent, the GDGdrafted recommendations based ontheir expert opinion.
The considerations for makingconsensus-based recommendations include the balance betweenpotentialharms and benefits, the economic costs
compared to the economic benefits, current practices, recommendations made inother relevant guidelines, patient preferences and equalityissues.
The consensus recommendations were agreed throughdiscussions inthe GDG. The GDGalso considered whether the uncertaintywas sufficient to
justifydelayingmakinga recommendationto await further research, takinginto account the potentialharmoffailingto make a clear
recommendation.
The GDGconsidered the 'strength' ofrecommendations. This takes into account the qualityofthe evidence but is conceptuallydifferent. Some

28.
recommendations are 'strong' inthat the GDGbelieves that the vast majorityofhealthcare and other professionals and patients would choose a
particular interventioniftheyconsidered the evidence inthe same waythat the GDGhas. This is generallythe case ifthe benefits clearlyoutweigh
the harms for most people and the interventionis likelyto be cost effective. However, there is oftena closer balance betweenbenefits and harms,
and some patients would not choose aninterventionwhereas others would. This mayhappen, for example, ifsome patients are particularlyaverse
to some side effect and others are not. Inthese circumstances the recommendationis generallyweaker, althoughit maybe possible to make
stronger recommendations about specific groups ofpatients.
The GDGfocused onthe followingfactors inagreeingthe wordingofthe recommendations:
The actions healthprofessionals need to take
The informationreaders need to know
The strengthofthe recommendation(for example the word 'offer' was used for strongrecommendations and 'consider' for weak
recommendations)
The involvement ofpatients (and their carers ifneeded) indecisions ontreatment and care
ConsistencywithNICE's standard advice onrecommendations about drugs, waitingtimes and ineffective interventions (see Section9.3 in
the NICEguidelines manual[see the "AvailabilityofCompanionDocuments"field])
The mainconsiderations specific to eachrecommendationare outlined inthe 'Recommendations and link to evidence' sections withineachchapter
ofthe fullversionofthe guideline.
Rating Scheme for the Strength of the Recommendations
StrengthofRecommendations
Some recommendations canbe made withmore certaintythanothers. The Guideline Development Group (GDG) makes a recommendationbased
onthe trade-offbetweenthe benefits and harms ofanintervention, takinginto account the qualityofthe underpinningevidence. For some
interventions, the GDGis confident that, giventhe informationit has looked at, most people would choose the intervention. The wordingused in
the recommendations inthis guideline denotes the certaintywithwhichthe recommendationis made (the strengthofthe recommendation).
Interventions That Must (or Must Not) Be Used
The GDGusuallyuses 'must' or 'must not' onlyifthere is a legaldutyto applythe recommendation. Occasionally'must' (or 'must not') is used ifthe
consequences ofnot followingthe recommendationcould be extremelyserious or potentiallylife threatening.
Interventions That Should (or Should Not) Be Used – a 'Strong' Recommendation
The GDGuses 'offer' (and similar words suchas 'refer' or 'advise') whenconfident that, for the vast majorityofpeople, aninterventionwilldo
more good thanharm, and be cost effective. The GDGuses similar forms ofwords (for example, 'Do not offer…') whentheyare confident that an
interventionwillnot be ofbenefit for most people.
Interventions That Could Be Used
The GDGuses 'consider' whenconfident that aninterventionwilldo more good thanharmfor most people, and be cost effective, but other
options maybe similarlycost effective. The choice ofintervention, and whether or not to have the interventionat all, is more likelyto depend onthe
person's values and preferences thanfor a strongrecommendation, and so the healthcare professionalshould spend more time consideringand
discussingthe options withthe person.
Cost Analysis
See the relevant chapters inthe fullversionofthe guideline (see the "AvailabilityofCompanionDocuments"field) for specific cost-effectiveness
considerations for eachguideline reviewquestion.
Method of Guideline Validation
ExternalPeer Review
InternalPeer Review

29.
Description of Method of Guideline Validation
ValidationProcess
This guidance is subject to a 6-week public consultationand feedback as part ofthe qualityassurance and peer reviewofthe document. All
comments received fromregistered stakeholders are responded to inturnand posted onthe NationalInstitute for Healthand Care Excellence
(NICE) Web site.
Evidence Supporting the Recommendations
Type of Evidence Supporting the Recommendations
The type ofevidence supportingthe recommendations is not specificallystated.
Refer to "Evidence statements"sections inthe fullversionofthe guideline for discussionofthe evidence supportingeachrecommendation.
Type ofStudies
For most interventionreviews inthis guideline, parallelrandomised controlled trials (RCTs) were included because theyare considered the most
robust type ofstudydesignthat could produce anunbiased estimate ofthe interventioneffects. Ifthe Guideline Development Group (GDG)
believed RCTdata were not appropriate or there was limited evidence fromRCTs, well-conducted non-randomised studies were included. Please
refer to AppendixC inthe fullguideline appendices (see the "AvailabilityofCompanionDocuments"field) for fulldetails onthe studydesignof
studies selected for eachreviewquestion. For example, the reviewquestiononescalationofcare did not include anyRCTs as randomlyassigning
people withsepsis to either be referred to a senior healthcare professionalor remainunder the care ofstaffwithless experience would be highly
unethical. The same applies to the reviewquestionontimingofantimicrobialtreatment:randomlyassigningpeople withsepsis to a delayed
interventionwould be unethical. The reviews oninotropic agents or vasopressors also included observationalstudies as the GDGagreed that the
evidence presented bythose studies could help informrecommendations.
For reviews ofdiagnostic tests, diagnostic RCTs were considered the first line approach, inwhichpatients are randomised to one diagnostic test or
another followed bytreatment, and patient outcomes are assessed. Ifno evidence was identified fromdiagnostic RCTs, diagnostic accuracywas
reviewed usingprospective and retrospective cohort studies inwhichthe indextest(s) and the reference standard test are applied to the same
patients ina cross-sectionaldesign. Two-gate studydesigns (sometimes referred to as case-control) were excluded. These are cross-sectional
studies whichcompare the results ofthe indextest inpatients withanalreadyestablished diagnosis ofthe target condition, withhealthycontrols.
This studydesignis unrepresentative ofpractice and is unlikelyto containthe fullspectrumofhealthand disease over whichthe test would be
used. Studies ofthis designmaylead to the selective inclusionofcases withmore advanced disease and over estimations ofsensitivity. The
inclusionofhealthycontrols is likelyto lead to over-estimations ofspecificity.
For prognostic reviews, RCTs, pooled analysis ofpatient leveldata, and retrospective cohort or prospective cohort studies were included. Case-
controlstudies were excluded because oftheir highrisk ofrecallbias.
Where data fromobservationalstudies were included, the GDGdecided that the results for eachoutcome should be presented separatelyfor each
studyand meta-analysis was not conducted.
Benefits/Harms of Implementing the Guideline Recommendations
Potential Benefits
Earlyrecognitionofsepsis increases the possibilitythat the patient willreceive appropriate and timelytreatment and this provides the best chance
ofreducingmorbidityand mortality.
See the "Trade-offbetweenclinicalbenefits and harms"sections inthe fullversionofthe guideline (see the "AvailabilityofCompanionDocuments"
field) for additionaldiscussionofbenefits ofspecific interventions.