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Sepsis in adults

The r ight c l in ica l informat ion, r ight where it ' s needed

Last updated: Jun 06, 2017

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 5

Aetiology 5

Pathophysiology 6

Classification 7

Prevention 9

Diagnosis 9

Case history 9

Step-by-step diagnostic approach 9

Risk factors 15

History & examination factors 16

Diagnostic tests 18

Differential diagnosis 21

Diagnostic criteria 22

Treatment 27

Step-by-step treatment approach 27

Treatment details overview 32

Treatment options 34

Follow up 47

Recommendations 47

Complications 47

Prognosis 49

Guidelines 51

Diagnostic guidelines 51

Treatment guidelines 51

Online resources 54

References 55

Images 66

Disclaimer 68

Findings are generally non-specific and secondary to primary infection. They include malaise, leukocytosis,tachypnoea, and pulse >90 bpm.

◊

Sepsis can progress rapidly to multi-organ failure and shock, and is often fatal. Survival is dependent on a highindex of suspicion of sepsis, early recognition and immediate intervention.

◊

Patients with evidence of sepsis, including signs of organ dysfunction, require immediate hospital assessment.◊

Empirical broad-spectrum antibiotic therapy (based on the most probable pathogens) should be administeredas soon as possible, and always within the first hour following recognition.

◊

Blood cultures, as well as cultures of all wounds or other potentially infected body fluids, should be performedas indicatedby symptomsand the riskprofileof thepatient, ideally before the initiationof antimicrobial treatment.

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Any source of infection should be controlled as a matter of urgency, preferably within 6 hours followingrecognition.

◊

Evidenceofhypoperfusionor shock shouldbe identifiedand treatedwith immediate intravenous fluid challenges,if present. Shock that fails to respond to fluid challengesnecessitatesurgent critical care referral for considerationof vasopressors and/or inotropes.

◊

Summary

Definition

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to an infection.[1] The

definition of sepsis was updated in 2016 following publication of the Third International Consensus Definitions for Sepsis

and Septic Shock (Sepsis-3).[1]

The2016consensusdefinitions also recommend that theSequential (or Sepsis-related)OrganFailureAssessment (SOFA)

criteria and 'quick' (q)SOFAcriteria beused to identify sepsis, inplaceof thecurrentlyused systemic inflammatory response

syndrome (SIRS) criteria, which were the basis for the previous definition of sepsis.[1] [2] SOFA is an ICU-basedmortality

score and qSOFA is a rapid, shortened version of SOFA designed for use outside the ICU. The SOFA scores are not in

themselves clinical predictors of sepsis, and they rely on clinical suspicion for the scores to be assessed. Furthermore,

qSOFA has not been prospectively validated, and its place in clinical practice has not been fully established. Although the

SIRS criteria are no longer recommended and have limitations, they are well established after many years of use.[3] At

present it is unclearwhich clinical scorewill best guide sepsis care; therefore, theSIRS criteria remain the current standard

for identifying sepsis and are likely to remain relevant in medical care, at least in the short term.

SIRS is amulti-system response that can result from infection (localisedor general), aswell as fromnon-infectious causes

(e.g., trauma, burns, or pancreatitis).[4] [5] [6] [7] [8] It is defined by the presence of 2 ormore criteria from the following:

temperature >38.3°C (101°F) or <36.0°C (96.8°F); tachycardia >90 bpm; tachypnoea >20 breaths/minute or PaCO2 <4.3

kPa (32mmHg); hyperglycaemia (blood glucose >7.7mmol/L [>140mg/dL]) in the absence of diabetesmellitus; acutely

altered mental status; leukocytosis (WBC count >12×10^9/L [12,000/microlitre]); leukopenia (WBC count <4×10^9/L

[4000/microlitre]); or a normal WBC count with >10% immature forms.[5] [Surviving Sepsis Campaign: evaluation for

severe sepsis screening tool]

When using the SIRS criteria, sepsis is the presence of SIRS (i.e., 2 or more SIRS criteria) resulting specifically from an

infection.

In the first international consensus definitions, which date from 1991, severe sepsis was defined as sepsis associated

with organ dysfunction, hypoperfusion, or hypotension; septic shock was defined as sepsis with hypotension despite

adequate fluid replacement.[5] These definitions remain clinically established in many clinical settings.

However, the2016 third international consensus (Sepsis-3) definitions state that the term 'severe sepsis' shouldbemade

redundant in light of the revisions to thedefinitionof sepsis.[1]Septic shockhas alsobeen redefined as a subset of sepsis,

in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than

with sepsis alone.[1]

In 2016, the National Institute for Health and Care Excellence (NICE) published guidance on the recognition, diagnosis,

and early management of sepsis, which highlighted that the Sepsis-3 international consensus definitions of sepsis have

limited use in the early identification of people at risk of sepsis.[9] The NICE guidelines propose amove away from using

the SIRS criteria, and do not immediately support the use of the SOFA/qSOFA criteria. Instead NICE proposes a risk

stratification approach to categorise patients into 3 groups according to their risk of severe illness or death from sepsis:

high risk; moderate to high risk; or low risk. The risk stratification is based on the patient’s: history (e.g., altered mental

state; urine output; impaired immunity; or recent trauma, surgery, or invasive procedure), appearance (e.g., signs of

potential infection; mottled or ashen appearance; cyanosis of skin, lips, or tongue; or non-blanching rash of skin), and

clinical evaluation (e.g., temperature, heart rate, respiratory rate, blood pressure, level of consciousness, and oxygen

saturation).

This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.4BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use

of this content is subject to our disclaimer. © BMJ Publishing Group Ltd 2017. All rights reserved.

BasicsSepsis in adultsBASICS

http://www.survivingsepsis.org/SiteCollectionDocuments/ScreeningTool.pdf


http://bestpractice.bmj.com

Epidemiology

In 2007, septicaemia was recorded as the 10th leading cause of death in the US.[11] In the US, there are as many as

750,000 to 900,000 cases per year, resulting in around 200,000 deaths per year.[12]Most epidemiological studies find

sepsis to be more common in men than in women. Patients older than 65 years of age are particularly susceptible, with

one study finding almost two-thirds of cases to be in people over 65.[13] This study recorded 215,000 sepsis-associated

deaths (9.3% of all deaths in the US during the study period).

The population-based incidence of sepsis is estimated to be as high as 176 to 380 cases per 100,000 per year.[14] [15]

[16] [17]Theannual incidenceof sepsis in theEUhasbeenestimatedat 90.4 casesper 100,000population.[18]However,

incidence rates depend on the definition of sepsis, with rates in Canada cited as 15.7 cases per 100,000 population per

year requiring admission to ICU.[19]Nonetheless, it is likely that there are asmany as 20million cases of sepsis annually

worldwide, with a mortality rate of around 35%. This equates to approximately 20,000 deaths per day andmakes sepsis

the second leading cause of death after vascular disease.[20] The incidence of sepsis is likely to be rising. In England,

data from theHospital EpisodeStatistics (HES) releasedby theHealth andSocial Care InformationCentre (HSCIC) in 2015

shows there were nearly 123,000 cases of sepsis recorded alone in 2013/14.[21]

Aetiology

Causative agents vary significantly depending on the region, hospital size, season, and type of unit (neonatal,

transplantation, oncology, or haemodialysis units).[22] [23] [24] [25] [26] [27] [28] [29] [30] [31]

It should be noted that pathogenic organisms are identified in only around half of cases of sepsis.[32]Where organisms

are identified, bacteria (gram-positive and gram-negative) are identified as the causative organism in approximately 90%

ofcases,withgram-positivebacteria and fungal infections increasing in frequency.[33]Since themid-1980s, the frequency

of gram-positive sepsis (mainly caused by Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and

streptococci) has surpassed that of gram-negative sepsis (mainly caused by Enterobacteriaceae, especially Escherichia

coli andKlebsiella pneumoniae, andbyPseudomonas aeruginosa). However,E coli remains themost prevalent pathogen

causing sepsis.[4] [19] [22] [34] [35] Some experts believe that the host response to some viral infections so closely

mimics sepsis that it should be considered as such.

In themajorityof casesof sepsis arising in thecommunity, thecausativeorganismswill be sensitive, frequentlyendogenous

bacteria. In the UK, a report of the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) study in

sepsis published inNovember2015highlighted thatnearly 75%of casesof sepsis aroseas a result of community-acquired

infection.[32] However, it should be acknowledged that resistance patterns of organisms continue to change and can

differ greatly according to region. For example, in one large multi-centre European study, >50% of isolates in ICU were

methicillin-resistant S aureus (MRSA).[36] Over the last two decades, vancomycin-resistant enterococci (VREs) have

emerged, with >10% of enterococci being VREs.[37] Just as concerning is the significant number of E coli isolates that

are now resistant to amoxicillin/clavulanic acid (around 40%).[38]MRSA is increasingly prevalent in the community, with

community-acquired MRSA presenting as a severe pneumonia, often with cavitation, in patients with a recent coryzal

illness. In the UK, sepsis is the most common direct cause of maternal death, ahead of venous thromboembolism.[39]

Following pregnancy (in the 6-week postnatal period), group A streptococci are themost common causative agent.[40]

Studies tend to broadly concur on the relative frequencies of sources of infection.[10] [36] In the SOAP study, the

respiratory tract accounted for 60%; the bloodstream 20%; abdomen 26%; skin 14%; and urinary system 12%.[36] The

Surviving Sepsis Campaign observational study of over 15,000 patients showed slightly fewer patients with respiratory

5This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use


BASIC

SBasicsSepsis in adults


sources (44.4%) and a greater frequency of urosepsis (20.8%).[10]However, in 20% to 30% of patients, a definite source

of infection is not found.[13]

The leading fungal pathogen causing sepsis has been identified as Candida.[22] In a European point-prevalence study,

fungi were isolated from 17% of ICU patients with nosocomial infection.[41] Fungi are more prevalent as isolates in

patientswith secondaryor tertiary peritonitis, withCandida identified inup to20%ofpatientswithGI tract perforation.[42]

Risk factors include faecal soiling of the peritoneum, recurrent GI perforation, immunosuppressive therapy for neoplasm

or in post-transplant patients, and thepresenceof inflammatory diseases. Thesepatients carry ahigh risk ofmortality.[43]

Pathophysiology

Sepsis is a syndrome comprising an immune system-mediated collection of physiological responses to an infectious

agent. Clinical signs such as fever, tachycardia, and hypotension are common but the clinical course depends on the

type and resistance profile of infectious organism, the site and size of the infecting insult, and the genetically determined

or acquired properties of the host's immune system.

Immune-system activation:

• Pathogen entry and survival is facilitated by tissue contamination (surgery or infection), foreign body insertion

(catheters), and immune status (immunosuppression).[44]

• The innate immune system is activated by bacterial cell wall products, such as lipopolysaccharide, binding to host

receptors, including Toll-like receptors (TLRs).[45] [46] These are widely found on leukocytes andmacrophages,

and some types are found on endothelial cells.[47] At least 10 TLRs have been described in humans. These have

specificity for different bacterial, fungal, or viral products, and genetic polymorphisms are associated with a

predisposition to shock with gram-negative organisms.[48]

• Activation of the innate immune system results in a complex series of cellular and humoural responses, each with

amplification steps:[7]

• Pro-inflammatory cytokines suchas tumournecrosis factor (TNF)-alphaand interleukins1and6are released,

which in turn activate immune cells.

• Reactive oxygen species, nitric oxide (NO), proteases, and pore-formingmolecules are released, which bring

about bacterial killing. NO is responsible for vasodilatation and increased capillary permeability, and has

been implicated in sepsis-inducedmitochondrial dysfunction.[49]

• The complement system is activated, and mediates activation of leukocytes, attracting them to the site of

infection where they can directly attack the organism (phagocytes, cytotoxic T lymphocytes), identify it for

attackbyothers (antigenpresentingcells, B lymphocytes), ‘remember’ it in caseof future infection (memory

cells, B lymphocytes), and cause the increased production and chemotaxis of more T helper cells.[50]

The endothelium and coagulation system:

• The vascular endothelium plays a major role in the host’s defence to an invading organism, but also in the

development of sepsis. Activated endothelium not only allows the adhesion andmigration of stimulated immune

cells, but becomes porous to large molecules such as proteins, resulting in the tissue oedema.





• Alterations in the coagulation systems include an increase in procoagulant factors, such as plasminogen activator

inhibitor type I and tissue factor, and reduced circulating levels of natural anticoagulants, including antithrombin

III and activated protein C (APC), which also carry anti-inflammatory andmodulatory roles.[51] [52]

Inflammation and organ dysfunction:

• Throughvasodilatation (causing reducedsystemic vascular resistance) and increasedcapillarypermeability (causing

extravasation of plasma), sepsis results in relative and absolute reductions in circulating volume.

• A number of factors combine to produce multiple organ dysfunctions. Relative and absolute hypovolaemia are

compounded by reduced left ventricular contractility to produce hypotension. Initially, through an increased heart

rate, cardiacoutput increases tocompensateandmaintainperfusionpressures,butas thiscompensatorymechanism

becomes exhausted, hypoperfusion, and shock may result.

• Impaired tissue oxygen delivery is exacerbated by pericapillary oedema. This means that oxygen has to diffuse a

greater distance to reach target cells. There is a reduction of capillary diameter due to mural oedema and the

pro-coagulant state results in capillary microthrombus formation.

• Additional contributing factors include disordered blood flow through capillary beds, resulting from a combination

of shunting of blood through collateral channels and an increase in blood viscosity secondary to loss of red cell

flexibility.[53] As a result, organs may become hypoxic, even though gross blood flow to an organmay increase.

These abnormalities may lead to lactic acidosis, cellular dysfunction, and multi-organ failure.[54]

• Cellular energy levels fall as metabolic activity begins to exceed production. However, cell death appears to be

uncommon in sepsis, implying that cells shutdownaspart of the systemic response. This couldexplainwhy relatively

few histological changes are found at autopsy, and the eventual rapid resolution of severe symptoms, such as

complete anuria and hypotension, once the systemic inflammation resolves.[55]

Classification

Third InternationalConsensusDefinitions forSepsisandSepticShock (Sepsis-3)(2016)[1]

• Sepsis has been redefined as life-threatening organ dysfunction caused by a dysregulated host response to an

infection.

• Owing to revisions to the definition of sepsis, the term 'severe sepsis' (as previously defined in the 1991/2001

international consensus definitions) should be made redundant.

• Septic shock has also been re-defined as a subset of sepsis in which particularly profound circulatory, cellular, and

metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Septic shock can be

defined clinically as a patient diagnosedwith sepsis, with persistent hypotension requiring vasopressors tomaintain

a mean arterial pressure (MAP)≥ 65mmHg, and a lactate level> 2 mmol/L (>18mg/dL), despite adequate fluid

resuscitation.



BASIC

SBasicsSepsis in adults


First International Consensus Definitions for Sepsis and Septic Shock (1991)[5][8] [10]

• In the 1991 definitions (which were reviewed in 2001) sepsis is defined as a systemic inflammatory response to a

new infection, and severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion, or

hypotension.

• Sepsiswithhypoperfusion isdefinedby thepresenceofacutecirculatory failure, characterisedbyarterial hypotension

(systolic BP <90mmHg, reduced by >40mmHg from baseline or mean arterial pressure [MAP] of <65mmHg), or

other evidence of hypoperfusion, such as serum lactate >2mmol/L (>18mg/dL).

• Septic shock is defined as being present when hypoperfusion persists for at least 1 hour despite adequate fluid

resuscitation and is unexplained by other causes. However, hypoperfusion is in itself a clinical emergency and

should be corrected as soon as is practicable. The distinction between hypoperfusion and shock in this context is

theoretical; in reality the urgency is identical.

Although the 1991 definitions have been superseded by the 2016 Sepsis-3 definitions, these changes have prompted

much debate and the 1991 definitions remain in widespread clinical use while the controversies are resolved.

Sepsis: recognition, diagnosis and early management (National Institute forHealth and Care Excellence, 2016)[9]

In 2016, the UK National Institute for Health and Care Excellence (NICE) published guidelines on sepsis recommending

that patients with suspected sepsis should be stratified according to risk of severe illness or death from sepsis (i.e., low

risk, moderate to high risk, and high risk).





Case history

Case history #1

A 78-year-old woman presents to hospital for an elective right haemicolectomy. She has a past medical history of

hypertension, angina on exertion, and diabetes mellitus. She is independently mobile, does her own shopping, and

has a 30-pack-a-year history of smoking. The operation was uncomplicated. On day 5 post-surgery, she becomes

confused. On examination, she has a GlasgowComaScale score of 14/15. She has a temperature of 38.5°C (101.3°F),

a respiratory rate of 28 breaths/minute, and oxygen saturations of 92% on 2 L of oxygen. She is tachycardic at 118

bpm, andher BP is 110/65mmHg.On chest auscultation, shehas coarse crackles in the right lower zone. Her surgical

wound appears to be healing well and her abdomen is soft and not tender.

Other presentations

Sepsismay complicate benign primary infections found in any age group and requires a high suspicion for the clinical

signs of systemic inflammatory response (tachycardia, fever, tachypnoea, or respiratory compromise).

Altered mental status may also be a presenting feature, especially in older patients. Mild disorientation or confusion

is common with more severe presentations, including significant anxiety, agitation, and loss of consciousness.

Other features that may be present include reduced urine output; a mottled or ashen appearance; cyanosis of skin,

lips, or tongue; or presence of a non-blanching rash on the skin.[9]

Step-by-step diagnostic approach

Sepsis is a spectrumofdisease,where there is a systemic anddysregulatedhost response toan infection.[1]Presentation

may range fromnon-specific or non-localised symptoms (e.g., feeling unwell with a normal temperature), to severe signs

with evidence of multi-organ dysfunction and septic shock. Risk of progression to fulminant disease is determined by

various factors, including:

• Magnitude and nature of the infective focus

• Timing and quality of interventions

• Genetic and acquired predisposition of the patient.

Early recognition and diagnosis is essential because early treatment is associated with significant short- and long-term

benefits in outcome.[59] [60] [61] [62] [63] [9]

Diagnostic criteriaThere is ongoing debate about the most appropriate criteria for diagnosing sepsis in clinical practice, with several

different approaches suggested. These include use of the systemic inflammatory response syndrome (SIRS) criteria

in the presence of infection; the Sequential (or sepsis-related) Organ Failure Assessment (SOFA) score recommended

by the Sepsis-3 international consensus group; and use of a risk stratification system as recommended by guideline

groups in the US and UK.

In practice, sepsis is usually diagnosed by the clinical identification of an infection in a patient whomeets the clinical

criteria for SIRS. According to the international consensus definition published in 1991 (and reviewed in 2001), SIRS



DIAGNOSIS

DiagnosisSepsis in adults


is defined by the presence of two or more criteria from a collection of clinical signs and laboratory investigations as

follows. (Hyperglycaemia and acutely alteredmental status are not part of the original criteria for SIRS, but have since

been included by the Surviving Sepsis Campaign in their screening tool.)[5] [Surviving Sepsis Campaign: evaluation

for severe sepsis screening tool]

• Temperature> 38.3°C (101°F) or <36.0°C (96.8°F)

• Tachycardia> 90 bpm

• Tachypnoea> 20 breaths/minute or PaCO2 <4.3 kPa (32 mmHg)

• Leukocytosis (WBC count> 12x10^9/L [12,000/microlitre])

• Leukopenia (WBC count <4x10^9/L [4000/microlitre])

• Normal WBC count with> 10% immature forms.

• Hyperglycaemia (blood glucose> 7.7 mmol/L [>140mg/dL]) in the absence of diabetes mellitus

• Acutely altered mental status.

In 2016, the definition of sepsis was updated by the Third International Consensus Group (Sepsis-3) to reflect greater

understanding of the disease. This step was taken because the SIRS criteria were found to be too non-specific to be

useful in defining sepsis: they defined sepsis as life-threatening organ dysfunction caused by a dysregulated host

response to an infection. Rather than using the SIRS criteria to identify these patients (upon which the previous

definition was based), the Sepsis-3 advised that sepsis should be defined using the SOFA criteria.[1] The SOFA score

is calculated based on the assessment of the following systems (with a score of ≥2 in a patient with a suspected

infection being suggestive of sepsis):[1]



DiagnosisSepsis in adultsDIAGNOSIS




Sequential (or Sepsis-related) Organ Failure Assessment (SOFA) criteria

Created by BMJ, adapted from Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score

to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society

of Intensive Care Medicine. Intensive Care Med 1996;22:707-710.

As the SOFA score has primarily been validated on patients in an ICU setting and requires multiple laboratory test

results, theThird InternationalConsensusGroupsuggested theuseof the 'quickSOFA' (qSOFA) asabedsideassessment

to identify thoseat riskof deteriorationdue to sepsis. This is a simple clinical assessment that assesses for thepresence

of at least 2 of the following:[1]

• Altered mental state

• Systolic blood pressure ≤100mmHg

• Respiratory rate≥ 22 breaths/minute.

However, since the introduction of qSOFA, a large study in the US found that it had poor sensitivity (particularly when

comparedwith other bedside early warning scores and the SIRS criteria) andwas a late indicator of deterioration.[64]

Further studies will be needed to determine the optimal screening methods for early recognition of sepsis.

The 2016 Sepsis-3 definitions also recommend that the term 'severe sepsis', as previously defined, should be made

redundant in light of revisions to the definition of sepsis.[1] Septic shock has also been redefined as a subset of sepsis

in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality

than with sepsis alone.[1] According to the 2016 international consensus definition, septic shock should be defined

as sepsis with both of the following (despite adequate volume resuscitation):[1]

• Persistent hypotension requiring vasopressors to maintain mean MAP ≥65mmHg, and

• Serum lactate> 2mmol/L (>18mg/dL).

Patientswith septic shock (as definedby theSepsis-3) are associatedwithhospitalmortality rates greater than40%.[1]

In 2016, the National Institute for Health and Care Excellence (NICE) published guidelines which focus on the early

recognition and identification of sepsis.[9] In a move away from the SIRS and SOFA criteria recommended by the

international consensus definitions, the NICE guidelines recommend a risk stratification approach to identify early

those patients at highest risk. The approach involves categorising a patient as being at low risk,moderate to high risk,

or high risk of severe illness or death from sepsis, based on the following criteria:

• History (alteredbehaviour; alteredmental state; functional ability; impaired immunity; or recent trauma, surgery,

or invasive procedure)

• Respiratory (respiratory rate; new need for oxygen to maintain saturation)

• Systolic blood pressure

• Circulation and hydration (raised heart rate; urine output)

• Skin (signs of infection; mottled or ashen appearance; cyanosis of skin, lips, or tongue; non-blanching rash of

skin).



DIAGNOSIS



This focus on early identification of patients at risk of sepsis is shared with the American College of Emergency

Physicians (ACEP) Expert Panel on Sepsis in their tool DART (Detect, Act, Reassess, Titrate).[65] The NICE guidelines

also provide further recommendations for in-hospital clinical assessment and laboratory investigations (e.g., venous

blood test for blood gas, including glucose and lactate measurement; blood culture; FBC; CRP; urea and serum

electrolytes; creatinine; andcoagulation) inpatientswith suspected sepsis basedon their risk profile and symptoms.[9]

There are multiple scoring systems and definitions for sepsis and sepsis with organ dysfunction. None is perfect and

many seek tomeasure similar variables. Furthermore, theNICE sepsis guidelinespublished in theUKhavehighlighted

a limitation of the international consensus definitions in that they are unproven in the early identification of people

at risk of sepsis.[9] At present, SIRS and the earlier international consensus definitions of sepsis, severe sepsis, and

septic shock remain clinically established in most clinical settings.

Initial evaluationSepsismaypresent initiallywithnon-specific, non-localised symptoms, suchas feelingunwellwithnormal temperature.

Sepsis should be considered if a patient presents with signs or symptoms that indicate possible infection, regardless

of temperature.[9] This is because, although fever is frequently associated with sepsis, hypothermia is a common

presenting sign andcarries aworseprognosis. [66] Initial assessment includes identifying the likely sourceof infection,

identifying risk factors for sepsis, determining the need for urgent source control (e.g., incision and drainage of an

abscess), and identifying abnormalities of behaviour, circulation, or respiration.

As for all acutely ill patients, initial evaluation should follow the ABCDE format, to include assessment of the airway,

respiratory, and circulatory sufficiency, and conscious level (Glasgow Coma Scale or AVPU [Alert, responds to Voice,

responds to Pain, Unresponsive]). Attention should be paid to seeking other signs of organ dysfunction (jaundice,

purpura fulminans,[Fig-2] cyanosis), and signs of circulatory insufficiency including oliguria, mottling of the skin, and

prolonged capillary refill times.[Fig-1] Oxygen saturation, respiratory rate, heart rate, BP, temperature, and accurate

hourly fluid balance (including urine output) should be monitored. It is important to seek clinical evidence for the

source of infection. This will aid diagnosis and provide vital information as to the patient's risk factors for sepsis. Risk

factors strongly associated with sepsis include: underlying malignancy, impaired immunity (e.g., due to illness or

drugs), recent surgery or other invasive procedures, breached skin integrity (e.g., wounds, skin infection), indwelling

catheter, intravenous drug misuse, age >65 years or frailness, pregnancy or recent pregnancy, haemodialysis, hx of

alcoholism, immunocompromise, and diabetes mellitus.

Sepsis is typically diagnosedwhen therearealterations in conscious level, hypotension, andorgan failure,manifesting

as oliguria, hypoxaemia, jaundice, or petechial rash. However, delayed diagnosis and intervention are associated with

increased morbidity, and a high index of suspicion in all patients with abnormal signs and a possibility of infection

should be maintained.

InvestigationsInitial investigations cover 4 purposes:

• To identify causative organisms

• To evaluate for organ dysfunction

• To identify the source of infection

• To prognosticate, to aid in the selection of an appropriate level of care.





Priority shouldbegiven to those investigations thatwill help to answer important clinical questions, suchas the source

of infection and severity of illness. Cultures of blood and other fluids will take 48 to 72 hours to yield sensitivities of

causative organisms (if identified), but are far less sensitive if delayed until after antimicrobial administration.

Investigations to identify causative organisms:

• Bloodcultures shouldbe taken immediately, andpreferablybeforeantibiotics are started, provided their sampling

will not delay administration of antibiotics. Ideally, at least one set should be taken percutaneously, and one set

from any vascular access device that has been in situ for more than 24 hours.[67] [68] Other cultures (e.g.,

sputum, cerebrospinal fluid (CSF), pleural fluid, joint fluid, stool, andurine) should be taken as clinically indicated.

• If no localising signs are present, examination and culture of all potential sites of infection including wounds,

catheters, prosthetic implants, epidural sites, and pleural or peritoneal fluid, as indicated by the clinical

presentation and history, is required.

• If meningitis is suspected (e.g., headache, photophobia, neck stiffness, vomiting), a lumbar puncture (LP) for

CSF microscopy and culture should be performed. A CT scan prior to performing an LP to exclude raised

intracranial pressure is required if there is any clinical suspicion of this.

• If an enclosed collection such as an abscess or empyema is suspected, it is recommended that this be drained

and cultured early in the course of the illness (within 6 hours following identification).[69]

• Intubated patients inwhom there is a suspicion of pneumonia should have tracheal aspirates, broncho-alveolar

lavage, or protected brush specimens taken.

Evaluation for organ dysfunction:

• Baseline assessment of liver function tests (notably bilirubin), an FBC (with differential), coagulation (INR, PTT),

serum creatinine, and blood urea.

• Serum electrolytes and glucose are frequently deranged, and should be measured at baseline and regularly

until the patient improves.

• Elevated serum lactate highlights tissue hypoperfusion, and is most reliably assessed using an arterial blood

gas (ABG) sample.[70]However, in practice, a venous blood gas (VBG) sample is generally used, as it is generally

easier and quicker to obtain compared with ABG. Most patients do not undergo ABG sampling unless there is

respiratory compromise.

• Markers of inflammation, including CRP and procalcitonin, are of use in determining clinical progress and

response to therapy. Serial measures of procalcitonin can be useful as a guide to the need to continue or stop

empiric antibiotics.[71]However, evidence for the prognostic value of procalcitonin is unclear,[72] and the use

of procalcitonin in the identification of sepsis is excluded frommany guidelines.

Investigations to identify the source of the infection:

• Thesourceof infectionmaybe immediatelyevident; forexample,withclassical signsandsymptomsofpneumonia

(purulent sputum, dyspnoea, tachypnoea, cyanosis) or peritonism (abdominal pain, guarding, distension,

tenderness, absent bowel sounds). However, in many patients the origin must be actively sought.



DIAGNOSIS



• Diagnostic studies may identify a source of infection that requires removal of a foreign body or drainage to

maximise the likelihoodof a satisfactory response to therapy.Chest x-raysandultrasoundscanscanbeperformed

at the bedside. Examinations such as CT scanning require transfer of potentially unstable patients and the

benefit should be weighed against the risk.

• In patients at risk of, or with symptoms compatible with, bacterial endocarditis, a transthoracic or

transoesophageal echocardiogram isuseful. This is alsohelpful todifferentiatebetweenhypovolaemic, cardiac,

and septic shock, aswell as alternativediagnoses suchas valvular abnormalities, pulmonaryembolus,myocardial

ischaemia (with segmental orglobal dysfunction), hypovolaemia, andpulmonaryhypertension. If readily available,

an echocardiogrammay also be appropriate in patients with sepsis of unknown origin.

• AnECGshouldbearranged tohelpexcludeotherdifferential diagnoses, includingMI, pericarditis, andmyocarditis.

Sepsis also predisposes tomyocardial dysfunction (particularly in septic shock)[73] and arrhythmias (e.g., atrial

fibrillation).[9]

Certain investigations carry prognostic value and can help determine the need for critical care:

• Lactate measurement is a useful assessment of perfusion once a diagnosis of sepsis has been established.

Increasing levels of lactate are associatedwith increasing levels of anaerobicmetabolism. Persistently elevated

lactate levelsmay parallel the degree of hypoperfusion or organ failure. High lactate carries adverse prognostic

value if elevated to >2mmol/L (>18mg/dL), and still worse outcomes are associated with levels >4 mmol/L

(>36mg/dL).[9] Lactate clearance (the rate at which lactate is cleared over a period of 6 hours) has been

demonstrated to be as useful as more invasive tests, such as central venous oxygen saturation, in determining

a patient’s response to treatment.[74] [75]

• Studieswith traumapatientshaveevaluated lactate levels againstAcutePhysiologyandChronicHealthEvaluation

(APACHE) scores and lactate clearance rates and found lactate levels to be inferior in informing the prognosis.

However, an APACHE score takes 24 hours to calculate.[76]

• Analternativemeasure is serumprocalcitonin levels.However, evidence for theprognostic valueofprocalcitonin

is unclear,[77] and the use of procalcitonin in the identification of sepsis is excluded frommany guidelines.

Changes inprocalcitonin levelsmayoccur later than thatof lactate, althoughchanges inbothmarkers combined

arehighlypredictiveofoutcomebetween24and48hours.[78] Itmay, therefore, havegreaterutility inpermitting

early cessation of antimicrobial therapy.[72] [79]

• Someexperts recommend theuseof shock index (heart ratedividedby systolic BP) as apredictor of requirement

for critical care, with one group finding an index of >0.9 to be predictive.[80]

• More recently, non-invasive impedance echocardiography has been shown, if a cardiac index of <2 is identified,

to predict poor outcome.[81]

Patients suffering fromseptic shockwhohavenot responded to initial fluid resuscitationwill require invasivemonitoring

and treatment in high dependency units.

Emerging testsThe PhenoTest™ BC Kit can identify 14 species of bacteria and 2 species of yeast that commonly cause bloodstream

infections,while alsoprovidingguidanceonantibiotic sensitivity. The test compares theorganism'sDNA toadatabase,

and then uses time-lapse images to analyse the organism’s response to antibiotics. It can identify a positive blood





culture in 1.5 hours and guide antibiotic treatment in 6.5 hours. However, the test has been associated with false

positive results.[82]

A number of other rapid detectionmethods for early pathogen detection and antimicrobial susceptibility testing are

in clinical testing at present. Such assays could be of significant value in the personalised care of septic patients in

the near future.

Risk factors

Strong

underlyingmalignancy

• Incidence ratesof sepsis areup to995casesper100,000per year inpatientswithmalignancy. Immunosuppression

(including both the severity and duration of neutropenia where present), recurrent infections, invasive

catheterisations, and treatment of resistant organisms contribute to the increased risk (odds ratio [OR] 9.77, 95%

confidence interval [CI] 9.67 to 9.88).[35]

age >65 years

• Associated with an increased risk of sepsis (relative risk [RR] 7.0, 95% CI 5.6 to 8.7).[19]

• Risk of sepsis is particularly high in people aged >75 years or those who are frail.[9]

immunocompromise

• Associated with an increased risk of sepsis.

• Immunocompromisemayarise fromtreatment (e.g., chemotherapy, corticosteroids, orother immunosuppressants),

underlying disease (e.g., diabetes, sickle cell), or surgery (e.g., splenectomy).[9] [56]

haemodialysis

• Associated with an increased risk of sepsis (RR 208.7, 95% CI 142.9 to 296.3).[19]

alcoholism

• Associated with an increased risk of sepsis (RR 5.6, 95% CI 3.8 to 8.0).[19]

diabetesmellitus

• Decreased resistance to infections, complications of diabetes, and increased surgical complications play a role (RR

5.9, 95% CI 4.4 to 7.8).[19]

recent surgery or other invasive procedures

• Risk of sepsis is high in people who have had surgery or other invasive procedures in the past 6 weeks.[9]

• Risk of sepsis is particularly high following oesophageal, pancreatic, or elective gastric surgery.[57]

breached skin integrity

• Risk of sepsis is high in people with any breach of skin integrity (e.g., cuts, burns, blisters, or skin infection).[9]

indwelling lines or catheters

• Risk of sepsis is high in people with indwelling lines or catheters.[9]

intravenous drugmisuse

• Risk of sepsis is high in people whomisuse drugs intravenously.[9]



DIAGNOSIS



pregnancy

• Pregnancy or recent pregnancy is a risk factor for the development of sepsis.[9] In theUK, the estimated incidence

of sepsis inpregnancyhasbeen reported tobe47casesper100,000maternitiesper year,[58]whereas theestimated

annual incidence among people aged 18 to 19 years in a general population has been reported to be around 29.6

cases per 100,000.[13]

• Risk of sepsis among womenmay be higher if they have impaired immunity, gestational diabetes, diabetes (or

other comorbid condition), needed invasiveprocedures duringpregnancy (e.g., caesarean section, forcepsdelivery,

removal of retained products of conception), had prolonged rupture of membranes during pregnancy, have or

have been in close contact with people with group A streptococcal infection (e.g., scarlet fever), or have continued

vaginal bleeding or an abnormal vaginal discharge with odour.[9]

Weak

urban residence

• May predispose to increased exposure to infections and drug-resistant pathogens (RR 2.4, 95% CI 1.2 to 5.6).[19]

lung disease

• Weakly associated with sepsis (RR 3.8, 95% CI 2.6 to 5.4).[19]

male sex

• May be at greater risk (OR 1.28, 95% CI 1.24 to 1.32).[14]

non-white ancestry

• May be at increased risk (OR 1.90, 95% CI 1.80 to 2.00).[14]

winter season

• Seasonal infections (e.g., respiratory infections in winter) are weakly associated with sepsis.

• Sepsis is 1.4 times more likely to occur in the winter than in the autumn.[28]

History & examination factors

Key diagnostic factors

presence of risk factors (common)

• Key risk factors include: underlying malignancy, age older than 65 years, immunocompromise, haemodialysis,

alcoholism, and diabetes mellitus.

high (>38°C) or low (<36°C) temperature (common)

• Temperature should not be used as the sole predictor of sepsis and should not be used to rule sepsis either in or

out.

• Fever may not be apparent in the following groups of people with sepsis: older people or those who are very frail,

people undergoing treatment for cancer, immunocompromised people, and severely ill people with sepsis.

• Temperature rise can result from a physiological response (e.g., after surgery or trauma).

tachycardia (common)

• Heart rate >90 bpm (>100 bpm in pregnant women).





tachypnoea (common)

• Respiratory rate >20 breaths/minute.

acutely alteredmental status (common)

• Due to impaired cerebral perfusion and inflammatory cytokines.

poor capillary refill, mottling of the skin, or ashen appearance (common)

• Signs of circulatory insufficiency.[Fig-1]

signs associated with specific source of infection (common)

• The source of infectionmaybe immediately evident; for example, with classical signs and symptomsof pneumonia

(purulent sputum,dyspnoea, tachypnoea, cyanosis) orperitonism (abdominal pain, guarding, distension, tenderness,

absent bowel sounds). However, in many patients the origin must be actively sought.

low oxygen saturation (common)

• Sign of circulatory insufficiency.

arterial hypotension (common)

• Systolic BP <90mmHg, mean arterial pressure (MAP) <65mmHg, or reduction in systolic BP >40mmHg from

baseline.

• May be present when sepsis leads to organ dysfunction.

• The use of vasopressor agents to correct hypotension does not exclude shock.

decreased urine output (common)

• Urine output <0.5 mL/kg/hour for at least 2 hours, or no urine passed in the last 18 hours.


cyanosis (common)

• Sign of circulatory insufficiency.

Other diagnostic factors

purpura fulminans (common)

• Sign of organ dysfunction.[Fig-2]

jaundice (uncommon)

• Sign of organ dysfunction.

ileus (uncommon)




DIAGNOSIS



Diagnostic tests

1st test to order

ResultTest

WBC count >12×10^9/L(12,000/microlitre)(leukocytosis); WBC count<4×10^9/L (4000/microlitre)(leukopenia); or a normal WBCcount with >10% immatureforms; low platelets

FBC with differential

• WBC count is sensitive but not specific for the diagnosis of sepsis.• Non-infectious injury (e.g., crush injury), cancer, and immunosuppressiveagents

can also cause either increased or decreased WBC counts.• Thrombocytopenia of non-haemorrhagic originmayoccur in patientswhoare

severely ill with sepsis.

serum electrolytes frequentlyderanged; blood ureamay beelevated

blood urea and serum electrolytes

• Bloodurea is performedwith serumcreatinine toevaluate for renal dysfunction.• Serum electrolytes should be measured at baseline and regularly until the

patient improves.

may be elevatedserum creatinine

• Elevated creatinine may occur in sepsis associated with renal dysfunction.

elevated bilirubin, ALT, AST,alkaline phosphatase, andgamma-GT

LFT

• Baseline test.• Sepsis can originate from hepatic or peri-hepatic infections.• Comorbidity of underlying hepatic disease can affect drug metabolism and

outcome in sepsis.• Septic shock can compromise hepatic blood flow andmetabolism, including

lactate.

may be prolongedcoagulation studies (INR, aPTT)

• Baseline test, especially before central line placement.

may be elevated or, morerarely, low

serum glucose

• May be elevated, with or without known history of diabetes, due to the stressresponse and to altered glucose metabolism.

• Hyperglycaemia is associated with increased morbidity and mortality.• Spontaneous or iatrogenic hypoglycaemia also poses significant dangers.[83]

[84]• The Surviving Sepsis Campaign recommends the maintenance of

normoglycaemia (above lower limit of normal, but <10mmol/L [180mg/dL]),preferably with the use of an insulin infusion protocol.[79]

• Rarely, glucose may be low, suggesting acute liver failure.

may be elevated; levels >2mmol/L (>18mg/dL)associated with adverseprognosis; even worseprognosis with levels >4mmol/L (>36mg/dL)

lactate levels

• Elevated serum lactate highlights tissue hypoperfusion, and is most reliablyassessed using an ABG sample.[70]

• Increasing levels of lactate are associated with increasing levels of anaerobicmetabolism. Persistently elevated lactate levels may parallel the degree ofmalperfusion or organ failure.

• High lactate carries adverse prognostic value if elevated to >2mmol/L (>18mg/dL), and still worse outcomes are associated with levels >4 mmol/L (>36mg/dL).

• Lactate clearance (the rate at which lactate is cleared over a period of 6 hours)has been demonstrated to be as useful as more invasive tests, such as centralvenousoxygensaturation, indeterminingapatient’s response to treatment.[74][75]





ResultTest

elevatedCRP

• Baseline test. A marker for inflammation.

may be positive for organismblood culture

• Blood cultures should be taken immediately, and preferably before antibioticsare started, provided their samplingwill not delay administrationof antibiotics.

• Ideally, at least one set should be taken percutaneously, and one set from anyvascular access device that has been in situ for more than 24 hours.[67] [68]

may be positive for organismother cultures (e.g., of sputum, stool, urine, wounds, catheters, prostheticimplants, epidural sites, pleural or peritoneal fluid)

• Other cultures (for example, of sputum, stool, and urine) should be taken asclinically indicated.

• If meningitis is suspected, a lumbar puncture (LP) for CSF microscopy andculture should be performed. A CT scan prior to performing a LP to excluderaised intracranial pressure is required if there is any clinical suspicion of this.

• If an enclosed collection such as an abscess or empyema is suspected, it isrecommended that this be drained and cultured early in the course of theillness (within 6 hours following identification).[69]

• Intubated patients, in whom there is a suspicion of pneumonia, should havetracheal aspirates, broncho-alveolar lavage, or protected brush specimenstaken.

• If no localising signs are present, examination and culture of all potential sitesof infection, including wounds, catheters, prosthetic implants, epidural sites,and pleural or peritoneal fluid, as indicated by the clinical presentation andhistory, is required.

PaCO2 <4.3 kPa (32mmHg) isone of the diagnostic criteriafor systemic inflammatoryresponsesyndrome(SIRS);maybe hypoxaemia, hypercapnia

arterial blood gas (ABG) or venous blood gas (VBG)

• ABG evaluation facilitates optimisation of oxygenation, and is indicative ofmetabolic status (acid-base balance).

• In ventilated patients, it helps to determine optimal positive end-expiratorypressure (PEEP), while minimising adverse levels of inspiratory pressure andunnecessarily high FiO2.

• Differentiationof respiratory frommetabolic acidosis allowsmetabolicdemandsto be identified and treated.

• Lactate levels are most reliably assessed using an ABG sample. However, inpractice, a venous bloodgas (VBG) sample is oftenused, as it is generally easierand quicker to obtain compared with ABG. Most patients do not undergo ABGsampling unless there is a respiratory component.

• Repeat bloodgases are indicateddependingon theclinical stateof thepatient.

may show evidence ofinfection,suchasconsolidationor pleural effusion, cardiacabnormalities, or apneumothorax

chest x-ray

• Required to look for cause of sepsis.• Achest x-ray is always indicatedafter central venouspressureandendotracheal

tube placement to rule out malposition and complications.

may show evidence ofischaemia, atrial fibrillation, orother arrhythmia; may benormal

ECG

• An ECG should be arranged to help exclude other differential diagnoses,including myocardial infarction, pericarditis, and myocarditis. Sepsis alsopredisposes to myocardial dysfunction (particularly in septic shock)[73] andarrhythmias (e.g., atrial fibrillation).[9]



DIAGNOSIS



Other tests to consider

ResultTest

elevated WBC count, presenceof organism onmicroscopy,and positive culture

lumbar puncture

• Performed ifmeningitis suspected, providednosuspicionof raised intracranialpressure. A CT scan is required prior to performing an LP to exclude raisedintracranial pressure if there is any clinical suspicion of this.

• Bacterial meningitis: WBC count >1×10^9/L (1000/microlitre); protein iselevated; glucose is normal or reduced; cell differential is predominantlyneutrophils.

• Viral meningitis may be associated with lower WBC counts and predominantlymphocytes.

inadequate left ventricularfilling suggests hypovolaemia;vegetations, if endocarditis iscause of sepsis

echocardiogram (transthoracic or transoesophageal)

• A transthoracic or transoesophageal echocardiogram is useful in patients atrisk of, or with symptoms compatible with, bacterial endocarditis.

• If readily available, may also be appropriate in patients with sepsis of unknownorigin.

• Also helpful to differentiate between hypovolaemic, cardiac, and septic shock.• Maydeterminealternativediagnoses, suchasvalvular abnormalities, pulmonary

embolus,myocardial ischaemia, segmentalorglobaldysfunction,hypovolaemia,and pulmonary hypertension.

maydemonstrateabscess, fluidcollection,pneumoperitoneumfrom perforated viscus,obstruction of GI/renal/biliarytracts

ultrasound scan

• Including but not limited to abdominal ultrasound scan.• May indicate source of infection (e.g., dilated common bile duct indicating

biliary obstruction).

abscess, effusionmay bedemonstrated

CT chest or abdomen

• If clinically indicated to establish source of infection.• Requires transfer of potentially unstable patients and the benefit should be

weighed against the risk.

elevatedserum procalcitonin

• Evidence for the prognostic value of procalcitonin is unclear,[77] and its usein the identification of sepsis is excluded frommany guidelines.

• Changes in procalcitonin levels may occur later than that of lactate, althoughchanges in bothmarkers combined are highly predictive of outcomebetween24 and 48 hours.[78] It may, therefore, have greater utility in permitting earlycessation of antimicrobial therapy.[72]

• Seldom used in practice.

Emerging tests

ResultTest

may be positive for organismandguideantimicrobial therapy

PhenoTest™ BC Kit

• Can identify 14 speciesof bacteria and2 speciesof yeast that commonly causebloodstream infections, while also providing guidance on antibiotic sensitivity.

• Compares theorganism'sDNA to adatabase, and thenuses time-lapse imagesto analyse the organism’s response to antibiotics.

• Can identify a positivebloodculture in1.5hours andguide antibiotic treatmentin 6.5 hours.

• Has been associated with false positive results.[82]





Differential diagnosis

Differentiating testsDifferentiating signs /symptoms

Condition

• Specific tests are directed byclinical suspicion of underlyingcause.

• Associatedmedical interventions(e.g., catheterisation, surgicalprocedures, ventilation) cansubsequently lead tosuperimposed infections tomakesepsis a continual threat andpossibility.

• SIRS can result as a non-specificfinding from a host of otherdisease states, includingpostoperative recovery, trauma,burns, transplant rejection,hyperthyroidism, Addisoniancrisis, blood product transfusionreactions, serum sickness,immunisations, and CNSinfarction or haemorrhages.

Non-infectious causes ofsystemic inflammatoryresponse syndrome (SIRS)

• Ischaemic changes on ECG.• Elevated CK-MB and troponin.

• Symptoms suggesting MI arecentral, squeezing chest painradiatingdown the left armor intothe jaw. Pain may be felt in theepigastric region.

• Patients may present incardiogenic shock.

Myocardial infarction (MI)

• ECGmay have upward concaveST-segmentelevationgloballyandPR-segment depression.

• Echomay demonstrate apericardial effusion; absence ofLV wall motion abnormalities.

• Patients present with sharp,stabbing, pleuritic chest pain(typically better on sitting up andleaning forward, and worse withlying down).

Pericarditis

• ECGmay show non-specificST-segment and T-waveabnormalities.

• Inflammatory markers may beelevated.

• Two-dimensional echodemonstratesglobal and regionalLV motion abnormalities anddilatation.

• Patients typically present with aviral prodrome, dyspnoea, orunderlying autoimmunecondition, such as SLE.

• Medications such as antibiotics,thiazide diuretics, antiepileptics,digoxin, lithium, amitriptyline, anddobutamine may be suggestiveof drug aetiology.

Myocarditis

• Elevated serum amylase, lipase,glucose; low calcium.

• May present with abdominal painand hypovolaemia.

• There may be a history ofgallstones, alcohol use, or viralinfections (e.g., mumps).

Acute pancreatitis

• CT pulmonary angiogram showsa filling defect in the pulmonaryarteries.

• Presents with acute dyspnoea,pleuritic chest pain, andhypotension.

Massive pulmonary embolism



DIAGNOSIS



Differentiating testsDifferentiating signs /symptoms

Condition

• Biopsies of blood smear, bonemarrow, tumour, or lymph nodesmay identify neoplastic cells.

• Identification of a specificinfectious agent is definitive indifferentiating sepsis from SIRS.

• May present with fever,leukocytosis, anaemia,tachycardia, multi-organdysfunction, and dyspnoea andthus meet diagnostic criteria for(suspected) sepsis.

• The immunocompromise mayadditionally facilitatedevelopment of infections or theincreased clinical suspicion ofundiagnosed infection.

Leukaemia

• The caffeine-halothanecontracture test (CHCT) is mostcommonly used to screen forsusceptibility, as ryanodinereceptor gene (RYR1)identification is gaining in clinicalimportance.[86]

• TheCHCT requiresmusclebiopsyand testing in select regionallaboratories after resolutionof theepisode.

• Neither test is clinically useful todirect therapy in the acutesituation.

• This is a rare conditioncharacterised by severehyperthermia (>41.1°C [106°F])and muscle rigidity followingadministration of anaestheticagents (e.g., succinylcholine forintubation). Lactic acidosis,hyperkalaemia, rhabdomyolysis,hypoxia, andarrhythmiasmayalsooccur.[85]

• Malignant hyperthermia is aninherited disorder (autosomaldominant) and a high index ofsuspicion is necessary if there isa positive family history.[85]

Malignant hyperthermia

• Clinical diagnosis. Specific testsare not readily available.

• This includes neurolepticmalignant syndrome,serotonergic syndrome, deliriumtremens, and metformin lacticacidosis.

• History of causative drug use.

Drug-induced fever and coma

Diagnostic criteria

There are multiple scoring systems and definitions for sepsis and sepsis with organ dysfunction. None is perfect and

many seek tomeasure similar variables. The systemic inflammatory response syndrome (SIRS) criteria and the1991/2001

international consensus definitions of sepsis, severe sepsis, and septic shock remain clinically established inmost clinical

settings. TheSequential (Sepsis-related)OrganFailureAssessment (SOFA) score is recommended in the2016 international

consensus definitions, and may replace SIRS, but it is important to recognise that the clinical utility of any score relies

on individual practitioner clinical assessment and decision-making.

Third InternationalConsensusdefinitions for sepsis andseptic shock (Sepsis-3)(2016)[1]

1. Sepsis: the third international consensus definition of sepsis published in 2016 redefines sepsis as life-threatening

organ dysfunction caused by a dysregulated host response to infection. According to the 2016 consensus definitions,





an increase in SOFA score of 2 or more constitutes organ dysfunction. The SOFA score is calculated based on the

assessment of the following systems in the ICU setting:

• Respiratory (PaO2/FiO2 ratio)

• Neurological (as assessed by the Glasgow coma scale)

• Cardiovascular (mean arterial pressure [MAP] or administration of vasopressors)

• Coagulation (platelet count)

• Renal (creatinine level and urine output)

• Hepatic (bilirubin level).

The 2016 consensus definitions recommend that the SOFA criteria should replace the previously recommended SIRS

criteria. Furthermore, the 'quick' (q)SOFAcriteria are recommended for useoutsideof the ICU setting to promptly identify

patients with suspected infection who are likely to have a poor outcome. According to the 2016 consensus definitions,

patients with 2 or more of the following qSOFA criteria are likely to have poor outcomes typical of sepsis:

• Alteration in mental status

• Systolic blood pressure ≤100mmHg

• Respiratory rate ≥22 per minute.

2. Severe sepsis: in light of the revisions to the definition of sepsis, the 2016 consensus definitions recommend that the

term 'severe sepsis' (as defined in the 1991/2001 consensus definitions) should be made redundant.

3. Septic shock: the definition of septic shock has been redefined as a subset of sepsis in which particularly profoundcirculatory, cellular, andmetabolic abnormalities are associated with a greater risk ofmortality thanwith sepsis alone.[1]According to the 2016 consensus definitions, septic shock is defined as sepsis with both:

• Persistent hypotension requiring vasopressors to maintain MAP ≥65mmHg, and

• Serum lactate level >2 mmol/L (>18mg/dL) despite adequate volume resuscitation.

Revised International Consensus definitions for sepsis and septic shock: SIRSin the presence of infection (2001)[5]

These criteria have in principle been superseded by the Sepsis-3 definitions. However, they remain in widespread use in

clinical practice.

1. Definitive diagnosis requires clinical identification of infection in a patient who alsomeets the clinical criteria for SIRS.According to the revised consensus conference definition published in 2001, SIRS is defined by the presence of 2 ormore criteria from a collection of clinical signs and laboratory investigations as follows: [Surviving Sepsis Campaign:evaluation for severe sepsis screening tool]

• Temperature >38.3°C (101°F) or <36.0°C (96.8°F)

• Tachycardia >90 bpm



DIAGNOSIS





• Tachypnoea >20 breaths/minute or PaCO2 <4.3 kPa (32 mmHg)

• Hyperglycaemia (blood glucose >7.7 mmol/L [>140mg/dL]) in the absence of diabetes mellitus

• Acutely altered mental status

• Leukocytosis (WBC count >12×10^9/L [12,000/microlitre])

• Leukopenia (WBC count <4×10^9/L [4000/microlitre])

• Normal WBC count with >10% immature forms.

2. Sepsis: when SIRS is present in an individual patient and the cause is thought likely to be an infection, sepsis is present.

3. Severe sepsis: present when sepsis leads to dysfunction of 1 or more organ systems, and includes the subset septic

shock. Organ dysfunction variables are:

• Arterial hypoxaemia (PaO2/FiO2 ratio <300) with new pulmonary infiltrates

• A new or increased oxygen requirement to maintain SpO2 >90%

• Acute oliguria (urine output <0.5 mL/kg/hour for at least 2 hours)

• Serum creatinine >176.8 micromol/L (2.0 mg/dL)

• Coagulation abnormalities (INR >1.5 or aPTT >60 seconds)

• Thrombocytopenia (platelets <100 × 10^9/L [100,000/microlitre])

• Hyperbilirubinaemia (total bilirubin >68.42 micromol/L [4 mg/dL])

• Arterial hypotension (systolic BP <90mmHg, mean BP <65mmHg, or reduction in systolic BP >40mmHg from

baseline)

• Serum lactate >2mmol/L (>18mg/dL).

4. Septic shock is defined as:

• Arterial hypotension (systolic BP <90mmHg, mean BP <65mmHg, or reduction in systolic BP >40mmHg from

baseline) persisting for at least 1 hour, despite adequate fluid resuscitation, or

• Serum lactate >4mmol/L (>36mg/dL) after adequate fluid resuscitation.

The use of vasopressor agents to correct hypotension does not exclude shock.

Sepsis: recognition, diagnosis and early management (National Institute forHealth and Care Excellence, 2016)[9]

In the UK, the National Institute for Health and Care Excellence (NICE) has published guidance on the recognition,

diagnosis, and earlymanagement of sepsis, which includes specific criteria for risk stratification of adults with suspected

sepsis. The criteria are as follows:

Low risk of severe illness or death from sepsis:





• Normal behaviour

• No history of acute deterioration of functional ability, impaired immunity, or trauma/surgery in the past 6 weeks

• Normal respiratory rate (i.e., <21 breaths per minute) and no oxygen requirement to maintain saturation

• Normal blood pressure (i.e., systolic blood pressure >100mmHg)

• Normal heart rate (i.e., ≤90 beats per minute; <100 beats per minute in pregnant women) and no new onset

arrhythmias

• Normal urine output in the past 18 hours

• Normal temperature

• No non-blanching rash.

Moderate to high risk of severe illness or death from sepsis:

• History of new onset of altered behaviour or mental state (reported by patient, friend, or relative)

• History of acute deterioration of functional ability

• Impaired immunity (e.g., from illness or drugs)

• Trauma, surgery, or invasive procedures in the past 6 weeks

• Respiratory rate 21-24 breaths per minute

• Systolic blood pressure 91-100mmHg

• Heart rate 91-130 beats per minute (100-130 beats per minute in pregnant women), or new onset arrhythmia

• No urine passed in previous 12-18 hours (for catheterised patients, 0.5-1.0 mL/kg of urine passed per hour)

• Tympanic temperature <36°C

• Signs of potential infection (e.g., redness, swelling or discharge at surgical site, or breakdown of wound).

High risk of severe illness or death from sepsis:

• Objective evidence of new altered mental state

• Respiratory rate ≥25 breaths per minute

• New need for oxygen (>40% FiO2) tomaintain saturation >92% (or >88% in known chronic obstructive pulmonary

disease)

• Systolic blood pressure ≤90mmHg, or systolic blood pressure >40mmHg below normal

• Heart rate >130 beats per minute

• No urine passed in previous 18 hours (for catheterised patients, <0.5 mL/kg of urine passed per hour)



DIAGNOSIS



• Mottled or ashen appearance; cyanosis of skin, lips, or tongue; non-blanching rash of skin.

Acute Physiology and Chronic Health Evaluation II score (APACHE II)[87]

The APACHE score is commonly used to establish illness severity in the ICU and predict the risk of death. [APACHE IIcalculator] There is a high risk of death if the score is ≥25.

Other sepsis risk-scoringmodels

Several other models have been developed for use in the ICU, including APACHE III, the Simplified Acute PhysiologyScore, and Mortality Probability Model II.[34] [88] [89]

Patient group-specific scoring systems have also been developed. For example, the Predisposition Insult Response andOrgan failure (PIRO) and Mortality in Emergency Department Sepsis (MEDS) scores have been developed to risk-stratifypatients with sepsis or septic shock who are admitted to the accident and emergency department;[90] the Sepsis inObstetrics Score (SOS) has been developed to risk-stratify pregnant or postnatal women with sepsis.[91] These scoringsystems can assist in the identification andmanagement of sepsis in specific patient groups.[92]

There are numerous ongoing studies investigating techniques for 'staging' the severity of sepsis using a variety ofblood-bornemarkers.[77] [93] Although some techniques have shown initial promise, the evidence base remains weak,and they have an unclear role in future clinical practice.




http://www.mdcalc.com/apache-ii-score/



Step-by-step treatment approach

Early recognition and treatment of sepsis is key to improving outcomes. Treatment guidelines have been produced by

the Surviving Sepsis Campaign and remain themost widely accepted standards.[79] Current best practice is based upon

evidence for care bundles in sepsis.[79] [94] [95] They include:

• Obtain blood cultures prior to administration of antibiotics

• Administer broad-spectrum antibiotics that target the suspected pathogen(s)

• Administer 30 mL/kg crystalloid for hypotension or lactate ≥4mmol/L (≥36mg/dL)

• Obtain serial measurement of blood lactate

• Use vasopressors to maintain a mean arterial pressure (MAP) ≥65mmHg in patients refractory to fluid therapy

• Inpatientswith an initial lactate≥4mmol/L (≥36mg/dL), orwhoarepersistently hypotensive (i.e.,MAP<65mmHg),

assess volume status and perfusion using either a repeat focused examination (including vital signs and

cardiopulmonary, capillary refill, pulse, and skin findings), or 2 of the following methods:

• Measurement of central venous pressure (CVP)

• Measurement of central venous oxygen saturation (ScvO2)

• Bedside cardiovascular ultrasound

• Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge.

In the UK, the National Institute for Health and Care Excellence (NICE) guidelines recommend administering crystalloid

if thepatienthasa lactate≥2mmol/L (≥18mg/dL) andat leastonehigh riskcriterion.[9]Crystalloidsarealso recommended

if the patient has a lactate >2mmol/L (>18mg/dL) and at least twomoderate to high risk criteria, or evidence of acute

kidney injury. Crystalloid can be considered in patients with a lactate <2mmol/L (<18mg/dL) if they have at least one

high risk criterion.[9]

The Sepsis SixOne bundle dealing with basic therapies, the ‘Sepsis Six’, has been shown to improve outcomes in septic patients. If

the 6 factors are completed within the first hour following recognition of sepsis, the associated mortality has been

reported to reduce by as much as 50%.[63] The 6 factors are as follows:

• Administer high-flow oxygen to maintain target oxygen saturations greater than 94% (or 88%-92% in people

at risk of hypercapnic respiratory failure)

• Take blood cultures

• Give intravenous antibiotics

• Start intravenous fluid resuscitation

• Check lactate level

• Monitor hourly urine output.



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ENT

TreatmentSepsis in adults


Patientswhoare refractory to initial treatments, in particular thosewith septic shock,may require invasivemonitoring

and consideration for organ support (e.g., central venous catheter and vasopressors), so management on a high

dependency unit or ICUmay well be required.

Oneaspectof basic intervention, thedeliveryof appropriate rapid fluid challenges, is intended to restore the imbalance

between oxygen supply and demand to the tissues. Patients who fail to respond to the rapid delivery of adequate

volumes of intravenous fluids are in septic shock. The immediate priority in this group of patients is the restoration

of the circulation and oxygen delivery.

Early goal-directed fluid therapy has previously been the gold standard of care,[6] [59] [62] [83] [79] [96] [97] but

several randomised, prospective studies have found no discernible benefit with this therapy over usual care.[98] [99]

[100] [101] [102] However, the central tenets of early goal-directed therapy (e.g., restoration of circulating volume,

correction of hypotension, and assessing cardiac output) remain important to the management of sepsis and have

now become standard practice in many emergency departments.

Monitoring of vital signs and response to fluid therapy is essential. Assessment of oxygenation via pulse oximetry and

serial lactate measurements should be performed, along with monitoring of urinary output. A failure of lactate to

improve with therapy is indicative of a poor outcome. Lactate clearance has been shown to correlate positively with

survival.[74] All patients receiving vasopressors should have an arterial catheter inserted as soon as it is practical to

do so to aid more accurate monitoring of arterial blood pressure.[79]

Antibiotic therapyBroad-spectrum intravenous antibiotics should be given before a pathogen is identified.[79] [103] [104] They are

recommended within the first hour once sepsis is diagnosed, preferably after cultures have been taken.[79] [9] The

delivery of appropriate antibiotics within the first hour is of critical importance inmaximising chances of survival.[63]

[105] [106] [107]

Knowledge of locally prevalent pathogens and their antibiotic resistance patterns are important when deciding

empirical therapy.[103] [12]Empirical antibiotic recommendationswill benecessarily individualisedat the institutional

level, based on local antibiotic protocols. Once culture and sensitivity results are available, antibiotics can be tailored

to the known pathogens. Cultures should be repeated (e.g., at 6-hour to 8-hour intervals) if there are persistent or

repeated fever spikes, or there is the identification of a new site of infection. Antibiotics should be given targeted to

the presumed site of infection. If there is no clinical evidence to suggest a site of infection, empirical broad-spectrum

antibiotics should still be given.

Empirical antibiotics should benarrowed as soon as a pathogenhas been identified and sensitivities are available.[79]

Respiratory sourceRespiratory infectionsaccount forapproximately30%to50%ofcases.Monotherapyappearsaseffectiveascombination

therapy in community-acquired pneumonia, although someunits prefer combination therapy in patientswith severe

pneumonia requiring critical care admission.[108]Treatment regimens should cover common respiratory pathogens

and atypical organisms such as Legionella pneumophilia.

Antibiotics listed are suggested as guidance only. Local or national policy, which may take into account specialist

knowledge of sensitivity patterns, should be sought and adhered to when possible. Combination therapy should

include a beta-lactam (such as benzyl penicillin, cefotaxime, or amoxicillin/clavulanate), with a macrolide (such as

azithromycin). A suitable monotherapy treatment regimen is to use a respiratory quinolone, such as moxifloxacin or

levofloxacin, or alternatively, doxcycline. Thesemonotherapy regimens are suitable for patientswith penicillin allergy.



TreatmentSepsis in adultsTR

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Risk factors for the presence of multiple drug-resistant pathogens (MDRPs) for Pseudomonas aeruginosa and for

methicillin-resistantStaphylococcus aureus (MRSA)will affect choiceof antimicrobial agents and shouldbeevaluated.

These include hospitalisation (for >48 hours, including residence in nursing home) or systemic antibiotic use within

the previous 90 days. A history of MRSA infection or colonisation should be sought. Recently, increasing numbers of

cases of community-acquired MRSA pneumonia have been reported, particularly in association with influenza virus

infection. Mortality rates appear somewhat higher than for non-MRSA severe pneumonia at 33%.[109]

MRSAshouldbeconsidered inpatientspresentingwithparticularly severecommunity-acquiredpneumonia, especially

in the presence of haemoptysis, shock, and an influenza-like prodromal illness.[110] [111] [112]

In high-risk patients, a broader spectrum of cover can be achieved using a carbapenem such as imipenem/cilastatin,

or an antipseudomonal penicillin such as piperacillin/tazobactam in combination with an aminoglycoside such as

gentamicin. Tigecycline is an alternative for patients with penicillin allergy; however, monotherapy with this drug

shouldbeusedwith cautionas itmaybeassociatedwith an increased riskofmortality. Expert advice shouldbe sought

before using tigecycline.[113] In patients at risk of MRSA, or with unusual severity of pneumonia with haemoptysis,

vancomycin or linezolid should be added to one of the above regimens. In patients with significant risk factors for

Pseudomonas infection (bronchiectasis, systemic corticosteroiduse,malnourishment) consideration shouldbegiven

to the addition of ciprofloxacin to one of the above regimens.

Urinary tract sourceUrinary tract infections account for approximately 10% to 20% of cases. Ensuring patency of the urinary tract is vital.

Cover should include gram-negative coliforms and Pseudomonas. Antibiotics listed are suggested as guidance only.

Local or national policy, which may take into account specialist knowledge of sensitivity patterns, should be sought

and adhered to when possible. A suitable treatment regimen is to use a combination of either ampicillin or a

cephalosporin, such as cefotaxime with gentamicin. Ciprofloxacin is a suitable alternative in patients with penicillin

allergy.

Abdominal sourceInfection arising from abdominal sources accounts for approximately 20% to 25% of cases. Gram-positive and

gram-negative organisms including anaerobes should be covered. Peritonitis or intra-peritoneal abscesses require

urgent surgical drainage or (where appropriate) percutaneous drainage.


knowledge of sensitivity patterns, should be sought and adhered to when possible. Treatment with ampicillin or

cefotaxime with metronidazole and gentamicin is a suitable regimen, or alternatively piperacillin/tazobactam with

gentamicin. A regimen of tigecycline and gentamicin is a suitable choice in patients with penicillin allergy.

Patients with recurrent perforation of the large intestine are at increased risk of invasive fungaemia. An azole, such

as fluconazole, or an echinocandin, such as micafungin, should be added to the antibacterial cover. Non-albicans

species of Candida are increasingly resistant to azoles.[42] [43] [114]

Soft-tissue and joint sourceThisheterogeneousgroupof infections includes septic arthritis,wound infections, cellulitis, andacute super-infections

arising from chronic ulceration, and accounts for approximately 5% to 10% of cases. A high index of suspicion should

also be held for necrotising fasciitis, which requires immediate surgical intervention (as does septic arthritis). Most

infections arepolymicrobial, andbroad-spectrumcover against gram-positive andgram-negativeorganisms including

anaerobes should be used.



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knowledge of sensitivity patterns, should be sought and adhered to when possible. A suitable regimen is to use

flucloxacillin (or tigecycline in penicillin-allergic patients) togetherwithmetronidazole. Alternatively, clindamycinmay

be used. If the patient has risk factors for MRSA, vancomycin (or alternatively linezolid) should be added.

If necrotising fasciitis is suspected, clindamycin together with flucloxacillin or tigecycline would be a sensible choice.

CNS sourceCNS infections are a relatively uncommon but potentially devastating cause of sepsis, accounting for under 5% of

cases. Meningococcal septicaemia can be extremely rapidly fatal, and if survived, can lead to greater morbidity than

other forms. Immediate antibiotic therapy in suspected cases is essential.


knowledge of sensitivity patterns, should be sought and adhered to when possible. Suspected meningitis or

meningococcal septicaemia shouldbe treated immediatelyusinga third-generationcephalosporin, suchasceftriaxone

or cefotaxime. For patients with penicillin allergy, vancomycin with chloramphenicol is a suitable alternative. Some

suggest the addition of rifampicin to either regimen to aid penetration.

For patients over 50 years, and those with a history of alcoholism or other debilitating illness, or at increased risk of

infection with Listeria, cephalosporins alone provide inadequate cover. Ampicillin should be added to the regimen,

provided the patient is not allergic to penicillin. For those allergic to penicillin, erythromycin or

trimethoprim/sulfamethoxazole can be substituted.

Patientswith amore insidiousonset ofCNSsymptomsshouldbe suspectedashaving viral encephalitis. Viruses cause

sepsis extremely rarely, but early use of antiviral agents such as acyclovir may improve outcome.

Corticosteroids for bacterial meningitis can improve neurological outcomes.[115]

Sepsis of unknown originIntensive efforts, including imaging, should be undertaken to attempt to evaluate the source of infection. Urgent

broad-spectrum coverage to include all common pathogens should be administered.


knowledge of sensitivity patterns, should be sought and adhered to when possible. Carbapenems give appropriately

broad cover, with imipenem or meropenem being suitable choices. Piperacillin/tazobactam with gentamicin is an

alternative. If the patient has risk factors for MRSA, vancomycin should be added.

Fluid resuscitationEarly, vigorous fluid resuscitation in sepsis-induced hypoperfusion is needed with at least 30 mL/kg body weight of

crystalloid given within the first 3 hours.[79] Additional fluid may be required, but this should be guided by thorough

clinical assessment of the patient's haemodynamic status.[79]

Repeated fluid bolusesof crystalloid (typical volume500mL) givenover 5 to30minutesmaybeeffective in correcting

hypotension secondary to hypovolaemia. Boluses of a colloid solution (typical volume 250-300mL) may be used as

an alternative, but no evidence supports the use of colloids over other fluids such as crystalloids or albumin

solution.[116] [117] [118] [119] [120] [121] [122] [123] [124]Solutions containing starchmaybeharmful and should

be avoided.[79] Evidence has shown that solutions containing hydroxyethyl starch are associated with a greater risk

of renal dysfunction and adverse outcome.[125] [126] [127] [128] [129] [130] [131] In some countries hydroxyethyl

starch solutions are no longer available. sepsis is defined as a systemic inflammatory response to a new infection; and




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MENT


Normal saline andalbumin shouldbegivenaccording to local protocols. Current evidence suggests that resuscitation

using albumin-containing solutions is safe, but evidence of its efficacy is insufficient to recommend its use over

crystalloids.[124] [132] [133] Red cell or plasma transfusion may be considered to target specific deficiencies but

should not be used for volume augmentation. Aggressive red cell transfusion has not been shown to improve

outcomes.[134]

Patients should bemonitored closely for signs of fluid overload (e.g., pulmonary or systemic oedema).[135] Changes

in inferior vena cava (IVC) diameter during respiration (visualised using bedside ultrasound) have been shown to be

anaccuratemeansof judging fluid responsiveness, and requirement for further intravenous fluids. In thespontaneously

breathing patient, a collapsed or collapsing IVC suggest that cardiac output will improve with additional fluid

resuscitation. In the mechanically ventilated patient, an increase in IVC size >18% (or visible to the naked eye) with

positive pressure ventilation, fluid responsiveness is expected.[136] [137]One systematic review has shown passive

leg raising to be an accurate predictor of fluid responsiveness in ventilated patients, regardless of ventilator mode or

technique, and with flow variables (e.g., cardiac output) having greater accuracy compared with pulse pressure.[138]

Glycaemic control in the critically illThere has been a shift of opinion and practice regarding glycaemic control in the critically ill. Since 2001, the use of

tight glycaemic control in septic patients has been advocated. However, more recent evidence suggests an increase

in adverseevents (e.g., severehypoglycaemia) inpatientsmanagedwith tight glycaemic control (target bloodglucose

6.1 mmol/L).[127] [139] An international randomised controlled trial demonstrated an increase in the absolute risk

of death at 90daysby2.6percentagepoints in thepatient groupmanagedwith intensiveglycaemic control compared

with thegroupmanagedwith conventional glycaemic control (bloodglucose target of 10mmol/L [180mg/dL]).[140]

The American Diabetes Association recommends a general glucose goal of 7.8 to 10.0 mmol/L (140-180mg/dL) in

critically ill diabetic patients, preferably with use of an insulin infusion protocol.[141] The Surviving Sepsis Campaign

recommends the use of validated insulin infusion protocols targeting a blood glucose level of <10mmol/L (180

mg/dL).[79]

Persistent haemodynamic instabilityIf hypotension persists, with a MAP of <65mmHg, a vasopressor should be started.[79] [142] Noradrenaline

(norepinephrine) administered via a central venous catheter is the drug of choice as it increases MAP. Vasopressin or

adrenaline can be added to noradrenaline to achieve the target MAP (≥65mmHg), or vasopressin can be added to

wean noradrenaline.[79] Dopamine is an option, but should only be given to highly selected patients as it has been

associatedwithhighermortality thannoradrenaline.[79] [143] [144]All infusionsof vasoactivemedications to correct

shock should be given via a secure catheter in a central vein with high flow, such as via a central venous catheter,

unless resources do not permit this and the situation is urgent. The use of low-dose dopamine for renal protection is

not recommended.[79]

Adjunctive therapiesIn patients with low cardiac output despite adequate fluid resuscitation, inotropes (e.g., dobutamine) can be added.

Low cardiac output suspected through clinical examination (prolonged capillary refill times, low urine output, poor

peripheral perfusion) can be confirmed through the use of cardiac output monitoring or by sampling central venous

orpulmonaryarterial blood tomeasureoxygensaturations.Heart rate shouldbekept<100bpmtominimisemyocardial

oxygen demand.[142]

According toa landmark studypublished in2002,[145]corticosteroidsmaybebeneficial in patientswith septic shock

that is refractory to fluids and vasopressor agents. However, current evidence for giving corticosteroids to patients

with sepsis or septic shock appears to be mixed.[146] [147] [148] [149] [150] [151] [152] Current guidelines



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recommend that low-dose corticosteroids are given only to patients whose BP is poorly responsive to both fluid

resuscitation and vasopressor therapy.[79] The use of the ACTH stimulation test to guide corticosteroid therapy is

no longer recommended, as it may be unreliable in critically ill patients and response does not predict efficacy of

corticosteroids.

Other more novel therapies include bathing patients with chlorhexidine washes, which may decrease the rate of

hospital-acquired infections,[153] and antioxidants such as acetylcysteine. These agents have been used as an

adjuvant therapy in sepsis with the aim of decreasing the levels of reactive oxygen species. However, they have been

found to be ineffective and their use is not currently recommended.[154]

Standard ICU supportive careAll patients with sepsis should be considered for admission to the high dependency unit or ICU.[59] [135]

General intensive care measures include stress ulcer prophylaxis with histamine H2 receptor antagonists or proton

pump inhibitors (in patients at risk of GI bleeding), DVT prophylaxis (with heparin and compression stockings), enteral

or parenteral nutrition, and glycaemic control.[79] [96] [155]

Transfusion of packed cells may be required. Despite studies of early goal-directed therapy transfusing to a target

haemoglobin concentration of >100 g/L (10 g/dL), it is recommended that a lower threshold of 70 g/L (7 g/dL) be

used.[79] Reasons for this include resource usage and a number of studies in the general critical care population

showing no improvementwith a higher haemoglobin threshold comparedwith a lower haemoglobin threshold,[134]

and potential harm associated with liberal transfusion.[156] A higher haemoglobin level may be necessary in certain

circumstances (myocardial ischaemia, severe hypoxaemia, acute haemorrhage, cyanotic heart disease, or lactic

acidosis).[79] In the initial resuscitative phase, particularlywith the application of early goal-directed therapy, a higher

haematocrit of ≥30%may be appropriate.[59]

Patients requiring prolonged ventilatory support should receive lung-protective ventilation using minimal peak

inspiratory pressures (<30 cmH2O) and permissive hypercapnia to specifically limit pulmonary compromise.[157]

FiO2 should be titrated to lowest effective levels to prevent oxygen toxicity and maintain central venous oxygen

tension. Patients should be placed in a semi-recumbent position with the head elevated to 30° to 45°.[79]

Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications, druginteractions, and alternative dosing. ( see Disclaimer )

( summary )Acute

TreatmentTx linePatient group

antibiotics1stpresumed or confirmed sepsis

fluid resuscitationplus

standard supportive ICU careadjunct

vasopressorsadjunct

dobutamineadjunct

corticosteroidsadjunct




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MENT


( summary )Acute

broad-spectrum respiratory pathogen cover toinclude atypicals

pluslikely source of infection:pneumonia, without risk factorsfor multiple drug-resistantpathogens or MRSA

broad-spectrumcoverof respiratorypathogens toincludemultipledrug-resistantpathogens(MDRPs)

pluslikely source of infection:pneumonia, with risk factors formultipledrug-resistantpathogens

antibiotic coverage for MRSAadjunct

antipseudomonal quinoloneadjunct

broad-spectrum cover for predominantgram-negative coliforms and Pseudomonas

pluslikely source of infection: UTI

broad-spectrum cover for gram-positive andgram-negative organisms, including anaerobes

pluslikely source of infection:intra-abdominal

azole or echinocandinadjunct

broad-spectrumgram-positiveandgram-negativecover, including anaerobes

pluslikely source of infection:soft-tissue or joint infection (notnecrotising fasciitis), MRSA notsuspected

broad-spectrum cover to include MRSApluslikely source of infection:soft-tissue or joint infection (notnecrotising fasciitis), MRSAsuspected

broad-spectrum cover to include group AStreptococci and gram-negative organisms

pluslikely source of infection:necrotising fasciitis suspected

broad-spectrum cover to include Neisseriameningitidis, Streptococcus pneumoniae, andother common gram-positive causative agents

pluslikely source of infection: CNS

rifampicinadjunct

antibiotic cover for Listeriaadjunct

antiviral cover for HSVadjunct

broad-spectrumgram-positiveandgram-negativecover

plussepsis of unknown source orwhere source is unclear, MRSAnot suspected

broad-spectrum cover to include MRSAplussepsis of unknown source orwhere source is unclear, MRSAsuspected



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Treatment options

Acute


antibiotics1stpresumed or confirmed sepsis

» Broad-spectrum intravenous antibiotics should begiven before a pathogen is identified.[79] [103] [104]They are recommended within the first hour oncesepsis is diagnosed, preferably after cultureshavebeentaken.[79] [9] The delivery of appropriate antibioticswithin the first hour is of critical importance inmaximising chances of survival.[63] [105] [107] [106]

» Appropriate antibiotic administration typicallyprecedes identification of specific pathogen.

» Once culture and sensitivity results are known,antibiotics should be narrowed if it is possible to doso.[79]

» When choosing empirical therapy, the suspectedsource of infection or causative organism, localresistance patterns, and the patient's immune statusneed to be considered.[54] [103]

fluid resuscitationplus

» Early, vigorous fluid resuscitation in sepsis-inducedhypoperfusion is needed and admission to the highdependency unit or ICU should be considered.[59][135] At least 30 mL/kg body weight of crystalloidshould be givenwithin the first 3 hours.[79]Additionalfluid may be required, but this should be guided bythorough clinical assessment of the patient'shaemodynamic status.[79] Repeated fluid boluses ofcrystalloid (typical volume 500mL) given over 5 to 30minutes may be effective in correcting hypotensionsecondary to hypovolaemia. Boluses of a colloidsolution (typical volume 250-300mL) may be used asan alternative, but no evidence supports the use ofcolloidsoverother fluids suchascrystalloidsor albuminsolution.[116] [117] [118] [119] [120] [121] [122] [123][124] Resuscitation with crystalloids requires morevolume than colloids.

» In the UK, the National Institute for Health and CareExcellence (NICE)guidelines recommendadministeringcrystalloid if the patient has a lactate ≥2mmol/L (≥18mg/dL) and at least one high risk criterion.[9]Crystalloids are also recommended if the patient hasa lactate >2mmol/L (>18mg/dL) and at least twomoderate to high risk criteria, or evidence of acutekidney injury. Crystalloid can be considered in patientswith a lactate <2mmol/L (<18mg/dL) if they haveleast one high risk criterion.




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Acute

TreatmentTx linePatient group» Solutions containing starch may be harmful andshould be avoided.[79] Evidence has shown thatsolutionscontaininghydroxyethyl starchareassociatedwith a greater risk of renal dysfunction and adverseoutcome.[128] [129] [130] [131] In some countrieshydroxyethyl starch solutions are no longer available.

» Red cell or plasma transfusionmay be considered totarget specific deficiencies but should not be used forvolume augmentation. Aggressive red cell transfusionhas not been shown to improve outcomes.[134]

»Normal salineandalbumin shouldbegivenaccordingto local protocols. Current evidence suggests thatresuscitation using albumin-containing solutions issafe, but evidence of its efficacy is insufficient torecommend its use over crystalloids.[124] [132] [133]

»Patients shouldbemonitoredclosely for signsof fluidoverload (e.g., pulmonary or systemic oedema).[135][138]

standard supportive ICU careadjunct

» All patients with sepsis should be considered foradmission to the high dependency unit or ICU.[59][135]

» General intensive caremeasures include stress ulcerprophylaxis with histamineH2 receptor antagonists orproton pump inhibitors (in patients at risk of GIbleeding), DVT prophylaxis (with heparin andcompression stockings), enteral orparenteral nutrition,and glycaemic control.[155] [96] [79] The AmericanDiabetes Association recommends a general glucosegoalof7.8 to10.0mmol/L (140-180mg/dL) incriticallyill diabetic patients, preferably with use of an insulininfusionprotocol.[141]TheSurvivingSepsisCampaignrecommends the use of validated insulin infusionprotocols targeting a blood glucose level of <10mmol/L (180mg/dL).[79]

» Transfusion of packed cellsmay be required. Despitestudies of early goal-directed therapy transfusing to atarget haemoglobin concentration of >100 g/L (>10g/dL), it is recommended that a lower threshold of 70g/L (7 g/dL) be used.[79] Reasons for this includeresource usage and a number of studies in the generalcritical care population showing no improvementwithahigherhaemoglobin thresholdcomparedwitha lowerhaemoglobin threshold,[134] and potential harmassociated with liberal transfusion.[156] A higherhaemoglobin level may be necessary in certaincircumstances (myocardial ischaemia, severehypoxaemia, acute haemorrhage, cyanotic heartdisease, or lactic acidosis).[79] In the initial resuscitative



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ENT



Acute

TreatmentTx linePatient groupphase, particularly with the application of earlygoal-directed therapy, a higher haematocrit of ≥30%may be appropriate. [59]

» Patients requiring prolonged ventilatory supportshould receive lung protective ventilation usingminimal peak inspiratory pressures (<30 cmH2O) tospecifically limit pulmonary compromise.[157] FiO2should be titrated to lowest effective levels to preventoxygen toxicity and maintain central venous oxygentension.Patients shouldbeplaced inasemi-recumbentposition with the head elevated to 30° to 45°.[79]

vasopressorsadjunct

» Patients unresponsive to fluid resuscitation may betreatedwithvasopressors. Patients requiringvasoactivesupport (those with septic shock) are identified by asystolic BP <90mmHg, mean arterial pressure (MAP)<65mmHg, or lactate ≥4mmol/L (≥36mg/dL),persisting after adequate fluid resuscitation.[79]

» MAP should be maintained between 65 and 90mmHg.

» Noradrenaline (norepinephrine) administered via acentral venous catheter is the drug of choice as itincreasesMAP.Vasopressinor adrenalinecanbeaddedto noradrenaline to achieve the target MAP (≥65mmHg).[79]

» Dopamine is an option, but should only be given tohighly selected patients as it has been associated withhigher mortality than noradrenaline.[79] [143] [144]

» The use of low-dose dopamine for renal protectionis not recommended.[79]

Primary options

» noradrenaline (norepinephrine): 0.02 to 0.5micrograms/kg/minute intravenously initially,titrate to effect, maximum30micrograms/minute

OR

» noradrenaline (norepinephrine): 0.02 to 0.5micrograms/kg/minute intravenously initially,titrate to effect, maximum30micrograms/minute

--AND--

» vasopressin: 0.01 to 0.03 units/minuteintravenously initially, titrate to effect-or-» adrenaline (epinephrine): 0.05 to 2micrograms/kg/minute intravenously initially,titrate to effect




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Acute


Secondary options

» dopamine: 5-20 micrograms/kg/minuteintravenously, titrate to effect

dobutamineadjunct

» Dobutamine is the first choice inotrope for patientswith low cardiac output and adequate left ventricularfilling pressure (or adequate fluid administration) andadequate mean arterial pressure (MAP).[79] [135]

Primary options

» dobutamine: 0.5 to 1 microgram/kg/minuteintravenously initially, followed by 2-20micrograms/kg/minute

corticosteroidsadjunct

» According to a landmark study published in2002,[145]corticosteroidsmaybebeneficial inpatientswith septic shock that is refractory to fluids andvasopressor agents. In this study, 7-day treatmentwithlow doses of hydrocortisone and fludrocortisone wasshown to significantly reduce the risk of death in septicshock without increasing adverse events.[145]However, current evidence for giving corticosteroidsto patients with sepsis or septic shock appears to bemixed.[146] [147] [148] [149] [150] [151] [152]

» Current guidelines recommend that low-dosecorticosteroids are given only to patients whose BP ispoorly responsive to both fluid resuscitation andvasopressor therapy.[79] Fludrocortisone may or maynot be added to hydrocortisone therapy.

» Although the proposed mechanism of action ofcorticosteroids in septic shock is in the correction ofrelative adrenal insufficiency, the use of the ACTHstimulation test to guide corticosteroid therapy is nolonger recommendedas itmaybeunreliable incriticallyill patients and response does not predict efficacy ofcorticosteroids.[79] [148]

Primary options

» hydrocortisone: 50 mg intravenously every 6hours

OR

» hydrocortisone: 50 mg intravenously every 6hours-and-



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ENT



Acute

TreatmentTx linePatient group» fludrocortisone: 0.05 mg orally daily

broad-spectrum respiratory pathogen cover toinclude atypicals

pluslikely source of infection:pneumonia, without risk factorsfor multiple drug-resistantpathogens or MRSA

» Monotherapy appears as effective as combinationtherapy in community-acquired pneumonia, althoughsomeunits prefer combination therapy inpatientswithsevere pneumonia requiring critical careadmission.[108]

» For patients with suspected pneumonia, risk factorsfor the presence ofmultiple drug-resistant pathogens(MDRPs) and for methicillin-resistant Staphylococcusaureus (MRSA)will affect choiceofantimicrobial agents,and should be evaluated. Risk factors includehospitalisation for >48 hours (including residence innursing home), or systemic antibiotic use within theprevious 90 days.

» When choosing empirical therapy, the suspectedsource of infection or causative organism, localresistance patterns, and the patient's immune statusneed to be considered.[54] Antibiotics listed aresuggested as guidance only. Local or national policy,which may take into account specialist knowledge ofsensitivity patterns, should be sought and adhered towhen possible.

Primary options

no penicillin allergy

» cefotaxime: 1-2 g intravenously every 8 hours-or-»amoxicillin/clavulanate: 1.2g intravenously every8 hoursDose consists of 1 g amoxicillin plus 0.2 mgclavulanate.

--AND--

» azithromycin: 500mg intravenously every 24hours-or-» clarithromycin: 500mg intravenously every 12hours

Secondary options

penicillin allergy

» moxifloxacin: 400mg intravenously every 24hours

OR

penicillin allergy




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MENT


Acute

TreatmentTx linePatient group» levofloxacin: 500mg intravenouslyevery12hours

OR

penicillin allergy

»doxycycline: 100mg intravenouslyevery12hours

broad-spectrumcoverof respiratorypathogens toincludemultipledrug-resistantpathogens(MDRPs)

pluslikely source of infection:pneumonia, with risk factors formultipledrug-resistantpathogens » For patients with suspected pneumonia, risk factors

for the presence of MDRPs will affect choice ofantimicrobial agents, and should be evaluated. Riskfactors includehospitalisation for >48hours (includingresidence in nursing home), or systemic antibiotic usewithin the previous 90 days.


» Tigecycline is analternative for patientswithpenicillinallergy; however, monotherapy with this drug shouldbe used with caution as it may be associated with anincreased risk of mortality. Expert advice should besought before using tigecycline.[113]

Primary options


» imipenem/cilastatin: 1 g intravenously every 8hoursDose refers to imipenem component.-or-»piperacillin/ tazobactam:4.5g intravenouslyevery8 hoursDose consists of 4 g piperacillin plus 0.5 gtazobactam.

--AND--

»gentamicin:5mg/kg intravenouslyevery24hours

Secondary options

penicillin allergy

» tigecycline: 100mg intravenously initially,followed by 50mg every 12 hours

antibiotic coverage for MRSAadjunct



TREATM

ENT



Acute

TreatmentTx linePatient group» Patients presenting with particularly severecommunity-acquired pneumonia, especially if there isa history of haemoptysis, and patients with recenthospitalisation or history of MRSA infection shouldreceive additional coverage for MRSA.[111]

» Vancomycin levels need to be monitored.

Primary options

» vancomycin: 1 g intravenously every 12 hours

OR

» linezolid: 600mg intravenously every 12 hours

antipseudomonal quinoloneadjunct

»Patientswithbronchiectasis, thosewhotakesystemiccorticosteroids, or those who are malnourished are atrisk of infection with Pseudomonas aeruginosa andshouldbeadditionally treatedwithanantipseudomonalquinolone.[158]

Primary options

» ciprofloxacin: 400mg intravenously every 8-12hours

broad-spectrum cover for predominantgram-negative coliforms and Pseudomonas

pluslikely source of infection: UTI

» If urinary stasis is present, drainage is of immediateimportance.


Primary options


» ampicillin: 1-2 g intravenously every 6 hours-or-» cefotaxime: 1-2 g intravenously every 8 hours-or-»amoxicillin/clavulanate: 1.2g intravenously every8 hoursDose consists of 1 g amoxicillin plus 0.2 mgclavulanate.




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Acute


--AND--


Secondary options

penicillin allergy

» ciprofloxacin: 500mg intravenously every 12hours

broad-spectrum cover for gram-positive andgram-negative organisms, including anaerobes

pluslikely source of infection:intra-abdominal

» Control and drainage of an intra-abdominal sourceof infection is of immediate importance.


Primary options


» amoxicillin: 1 g intravenously every 6 hours-or-» cefotaxime: 1-2 g intravenously every 8 hours

--AND--

» metronidazole: 500mg intravenously every 8hours

--AND--


OR


»piperacillin/tazobactam:4.5g intravenouslyevery8 hoursDose consists of 4 g piperacillin plus 0.5 gtazobactam.-and-»gentamicin:5mg/kg intravenouslyevery24hours

Secondary options

penicillin allergy

» tigecycline: 100mg intravenously initially,followed by 50mg every 12 hours



TREATM

ENT



Acute

TreatmentTx linePatient group-and-»gentamicin:5mg/kg intravenouslyevery24hours

azole or echinocandinadjunct

» Patients with recurrent perforation of the largeintestine are at increased risk of invasive fungaemia.Anazole, suchas fluconazole, or anechinocandin, suchas micafungin, should be added to the antibacterialcover.Non-albicans speciesofCandidaare increasinglyresistant to azoles.[42] [43] [114]

Primary options

» fluconazole: consult specialist for guidance ondose

OR

» micafungin: consult specialist for guidance ondose

broad-spectrumgram-positiveandgram-negativecover, including anaerobes

pluslikely source of infection:soft-tissue or joint infection (notnecrotising fasciitis), MRSA notsuspected

» When choosing empirical therapy, the suspectedsource of infection or causative organism, localresistance patterns, and the patient's immune statusneed to be considered.[54] Antibiotics listed aresuggested as guidance only. Local or national policy,which may take into account specialist knowledge ofsensitivity patterns, should be sought and adhered towhen possible. Metronidazole should be consideredasempirical therapy if anaerobic infection is suspected.

Primary options


» flucloxacillin: 2 g intravenously every 6 hours-or-» nafcillin: 1-2 g intravenously every 4-6 hours

--AND--

» metronidazole: 500mg intravenously every 8hours

Secondary options

penicillin allergy

» clindamycin: 300-600mg intravenously every 6hours

OR

penicillin allergy




EAT

MENT


Acute

TreatmentTx linePatient group» tigecycline: 100mg intravenously initially,followed by 50mg every 12 hours-and-» metronidazole: 500mg intravenously every 8hours

broad-spectrum cover to include MRSApluslikely source of infection:soft-tissue or joint infection (not » When choosing empirical therapy, the suspected

source of infection or causative organism, localnecrotising fasciitis), MRSAsuspected resistance patterns, and the patient's immune status

need to be considered.[54] Antibiotics listed aresuggested as guidance only. Local or national policy,which may take into account specialist knowledge ofsensitivity patterns, should be sought and adhered towhen possible.

» In cases of suspected MRSA-associated soft-tissueor joint infections, vancomycin or linezolid is typicallyadded to the antibiotic therapy.

Primary options


OR

» linezolid: 600mg intravenously every 12 hours

broad-spectrum cover to include group AStreptococci and gram-negative organisms

pluslikely source of infection:necrotising fasciitis suspected

» If necrotising fasciitis is suspected, surgical controland debridement is of immediate importance.

» Once culture and sensitivity results are known,antibiotics shouldbeadjusted if required; 90%of casesare polymicrobial.


Primary options


» flucloxacillin: 2 g intravenously every 6 hours-or-» nafcillin: 1-2 g intravenously every 6 hours

--AND--



TREATM

ENT



Acute

TreatmentTx linePatient group» clindamycin: 300-600mg intravenously every 6hours

Secondary options

penicillin allergy

» tigecycline: 100mg intravenously initially,followed by 50mg every 12 hours-and-» clindamycin: 300-600mg intravenously every 6hours

broad-spectrum cover to include Neisseriameningitidis, Streptococcus pneumoniae, andother common gram-positive causative agents

pluslikely source of infection: CNS

»Suspectedmeningitis ormeningococcal septicaemiashouldbe treated immediatelyusinga third-generationcephalosporin, such as ceftriaxone or cefotaxime. Forpatients with penicillin allergy, vancomycin withchloramphenicol is a suitablealternative. Somesuggestthe addition of rifampicin to either regimen to aidpenetration.


Primary options


» ceftriaxone: 2 g intravenously every 12 hours

OR


» cefotaxime: 2 g intravenously every 6 hours

Secondary options

penicillin allergy

» vancomycin: 1 g intravenously every 12 hours-and-» chloramphenicol: 1 g intravenously every6hours

rifampicinadjunct




EAT

MENT


Acute

TreatmentTx linePatient group» Some experts suggest the addition of rifampicin tothe standard antibiotic regimen to aid penetration.

Primary options

» rifampicin: 600mg intravenously every 24 hours

antibiotic cover for Listeriaadjunct

» For patients over 50 year,s and those with history ofalcoholism or other debilitating illness, or at increasedrisk of infection with Listeria, cephalosporins aloneprovide inadequate cover. Ampicillin should be addedto the regimen, provided the patient is not allergic topenicillin. For those allergic to penicillin, erythromycinor trimethoprim/sulfamethoxazole canbesubstituted.

Primary options


» ampicillin: 2 g intravenously every 6 hours

Secondary options

penicillin allergy

» erythromycin: 1 g intravenously every 6 hours

OR

penicillin allergy

» trimethoprim/sulfamethoxazole: 20 mg/kg/dayintravenously given in divided doses every 6 hoursDose refers to trimethoprim component.

antiviral cover for HSVadjunct

» For patients in whomHSV encephalitis is suspected(symptoms of confusion, seizure or with CSF findingsconsistent with viral meningitis), empirical coveragewith acyclovir is recommended.

Primary options

»aciclovir: 5-10mg/kg intravenously every8hours

broad-spectrumgram-positiveandgram-negativecover

plussepsis of unknown source orwhere source is unclear, MRSAnot suspected » Intensive efforts, including imaging, should be

undertaken to attempt to evaluate the source ofinfection. Urgent broad-spectrumcoverage to includeall common pathogens should be administered.



TREATM

ENT



Acute

TreatmentTx linePatient group» When choosing empirical therapy, the suspectedsource of infection or causative organism, localresistance patterns, and the patient's immune statusneed to be considered.[54] Antibiotics listed aresuggested as guidance only. Local or national policy,which may take into account specialist knowledge ofsensitivity patterns, should be sought and adhered towhen possible.

Primary options

» imipenem/cilastatin: 1 g intravenously every 8hoursDose refers to imipenem component.

OR

» meropenem: 1 g intravenously every 8 hours

OR

»piperacillin/tazobactam:4.5g intravenouslyevery8 hoursDose consists of 4 g piperacillin plus 0.5 gtazobactam.-and-»gentamicin:5mg/kg intravenouslyevery24hours

broad-spectrum cover to include MRSAplussepsis of unknown source orwhere source is unclear, MRSAsuspected

» Intensive efforts, including imaging, should beundertaken to attempt to evaluate the source ofinfection. Urgent broad-spectrumcoverage to includeall common pathogens should be administered.

» When choosing empiric therapy, the suspectedsource of infection or causative organism, localresistance patterns, and the patient's immune statusneed to be considered.[54] Antibiotics listed aresuggested as guidance only. Local or national policy,which may take into account specialist knowledge ofsensitivity patterns, should be sought and adhered towhen possible. Vancomycin is used if MRSA issuspected.

Primary options


--AND--

» imipenem/cilastatin: 1 g intravenously every 8hoursDose refers to imipenem component.-or-» meropenem: 1 g intravenously every 8 hours




EAT

MENT


Recommendations

Monitoring

Standardmonitoringof vital signs, pulse oximetry, ECG, regular laboratory tests, andurinary output by catheterisationare routinely performed. All patients receiving vasopressors should have an arterial catheter inserted as soon as it ispractical to do so, to aid more accurate monitoring of arterial blood pressure.[79]

Patientswith evidence of circulatory dysfunction or shock should bemanaged in a critical care or higher dependencyarea. Central venous catheters will be required to ensure reliable delivery of vasoactive medication. The principles ofEarly Goal-Directed Therapy[59] remain relevant in ongoing care for patients with shock.

Central venous pressure (CVP)may be used in combinationwith clinical assessment and othermonitoringmodalitiesto guide ongoing fluid resuscitation. Additional monitoring techniques include the use of stroke volume variability(an index of change in stroke volume with each contraction), cardiac ejection time (corrected for heart rate) andchanges in inferior vena cava (IVC) diameter during respiration (visualised using bedside ultrasound).[136] [137]Mechanical ventilation can alter cardiac filling pressures and affectmeasurement. CVP valuesmust be correctedwithincreasing levels of positive end-expiratory pressure (PEEP) or haemodynamic parameters.[59] [169] In thespontaneously breathingpatient, a collapsedor collapsing IVC suggest that cardiacoutputwill improvewith additionalfluid resuscitation. In the mechanically ventilated patient, if IVC size increases by >18% (or visible to the naked eye)with positive pressure ventilation, fluid responsiveness is expected. One systematic review has shown passive legraising to be an accurate predictor of fluid responsiveness in ventilated patients, regardless of ventilator mode ortechnique, and with flow variables (e.g., cardiac output) having greater accuracy compared with pulse pressure.[138]

Central venous cathetersmay also be used to sample central venous oxygen saturation (ScvO2), which gives a globalindication of the balance between tissue oxygen demand and supply. If ScvO2 is low (<70%), it is likely that oxygendelivery is inadequate and the need for blood transfusion (to increase oxygen carrying capacity) or inotropes (toincrease cardiac output) should be assessed. Other measures of the adequacy of oxygen delivery are increasinglyused, including the use of lactate clearance rate over the first 6 hours. Lactate clearance has been shown to correlatepositively with survival.[74]

Theuse of pulmonary artery cathetersmay be an advantage in selected patientswith suspected cardiac compromise

or complicated presentations. It is not considered to be essential as a first-line routinemonitor, and its use in clinical

practice has been largely superseded by less invasive cardiac output monitoring modalities, including oesophageal

Doppler, arterial pulse contour analysis, and thermodilution/indicator dilution techniques.

Patient instructions

Complications

LikelihoodTimeframeComplications

highshort termrenal dysfunction

Transient oliguria is common and is related to hypotension. Rarely, anuria occurs.[163]Acute kidney injury is relativelycommon but is rarely associated with histological change or with any need for long-term renal replacement therapy.

Correction of volume depletion and hypotension generally reverses oliguria.[163]

highshort termhypotension



FOLLO

WUP

Follow upSepsis in adults



Volumedepletion is causedby reducedoral intake, increased venous capacitance, increased fluid lossesdue topyrexia,

capillary leakage leading to oedema, tachypnoea, diarrhoea, and possibly bleeding. Persistent hypotension is often

due to a combination of low systemic vascular resistance, hypovolaemia and reductions in cardiac output from

myocardial failure, excessive PEEP, or acidosis.

Fluid resuscitation is given with either colloids or crystalloids, and early central venous pressure (CVP) monitoring is

indicated if rapid response is not achieved. Vasopressors can be started for persistent hypotension or inotropes for

myocardial failure. Caution is required to prevent tachyarrhythmia.

mediumshort termARDS

Respiratory failure often progresses quickly and is indicated by a respiratory rate >30/minute, even though arterial

oxygen levels may be normal.

ARDSmay resolve completely or can progress to fibrosing alveolitis with persistent hypoxaemia.[162]

Intubationandventilation reduce respiratorymuscleoxygendemandand the riskof aspirationandcerebral anoxia.[163]Lung protective ventilation (low tidal volumes) should be used.[4] Tidal volumes should be reduced over 1 to 2 hoursto a target of 6 mL/kg of predicted body weight. Minimum positive end-expiratory pressure (PEEP) is recommendedto prevent lung collapse at end expiration.[79]

mediumshort termmyocardial dysfunction and failure

Myocardial dysfunctionwith biventricular dilatation is a recognised complication of sepsis, but is usually transient andnot commonly severe.Death frommyocardial failure is rare.[135]Circulatingmyocardial depressant factors are thoughtresponsible.

After adequate filling pressures have been achieved, inotropic agents should be considered to maintain an adequate

cardiac index, mean arterial pressure (MAP), mixed venous oxygen saturation, and urine output.

Clinicians should define specific goals and desired endpoints of inotropic therapy in patients with sepsis and titratetherapy to those end points. These end points should be refined at frequent intervals as patient's clinical statuschanges.[135]

mediumshort termmultiple organ system failure

The inflammatory response in sepsis causes widespread tissue injury. Multi-organ dysfunction may be partly causedby apoptosis of immune, epithelial, and endothelial cells and a shift to an anti-inflammatory phenotype, compoundedby impaired organ perfusion due to hypotension, low cardiac output states, circulatory microthrombi, a disorderedmicrocirculation, and tissue oedema.[4]

Failure of each additional organ increases the average risk of death by 15% to 20%. Lung dysfunction tends to occurearly and persists. Serious CNS dysfunction or liver function often occur hours to days after sepsis onset and persistsfor variable periods of time. Most organ failures resolve within a month in surviving patients.[163]

Treatment ofmulti-organ failure in sepsis is primarily supportive. It includes effective antibiotic therapy, goal-directed

therapy (to reverse hypotension, anaemia, coagulopathy, bleeding, and shock), and standard supportive ICU care. This

may include dialysis, ventilatory support, and sedation.

lowshort termhepatic encephalopathy



Follow upSepsis in adultsFO

LLOWUP



Rarely, liver dysfunction may lead to hepatic encephalopathy.[161] Hepatic encephalopathy results primarily fromnitrogen absorption from the gut bypassing effective hepatic clearance, resulting in electrolyte abnormalities.

The mainstay of therapy includes laxatives to empty the bowel, prevention of GI bleeding, and avoidance of nitrogen

intake and sedative drugs, which further suppress consciousness.

lowshort termDIC

Occurs in sepsis when leukocytes and endothelial cells are activated or injured by toxic substances released during

infection or shock. The injured cells generate tissue factor on the cell surface, activating the coagulation cascade. In

acute DIC, an explosive generation of thrombin depletes clotting factors and platelets. This activates the fibrinolytic

system.

DIC leads to bleeding into the subcutaneous tissues, skin, and mucous membranes occurs, along with occlusion of

blood vessels caused by fibrin in the microcirculation.

Treatmentof theunderlyingdisease is themainstayofmanagementof either acuteor chronicDIC,withbloodproductsto control bleeding.[164]

mediumlong termneurological sequelae

The incidence and severity of complications from sepsis depend on the pathogen, duration of disease, age, and

presence of comorbidities.

Focal neurological deficits and hearing loss occur in up to 30%of patients with bacterial meningitis. Themortality and

morbidity is higher for pneumococcal meningitis than for meningococcal meningitis.

Polyneuropathy occurs in 70% of patients with sepsis and multi-organ failure. The use of neuromuscular blockingagents may increase the severity of polyneuropathy.[165] [166]

highvariabledeath

Theexact causeof death in sepsis ismulti-factorial, exhibitinggreat individual variability.[161]Death fromseptic shocktypically occurs due to multi-organ failure, unresponsiveness to treatments, or secondary infection.[54]

Predictors of death include vasopressor use, development of ARDS, failure to improve with early critical care therapy,and severity of underlying illness.[167]

Patients with sepsis have an increased mortality risk for at least 1 year after the septic episode.[168]

Administration of early effective antibiotic therapy and fluid challenges are paramount to reduce mortality.[59]

Prognosis

Theprognosis inpatientswith sepsis andseptic shock is guardedatbest. Themortality rate fromsepsishasbeenestimatedin a number of studies to be between 28% and 50%.[159] [160]More recently, the SOAP study in Europe observed anoverall hospitalmortality of 36%,[36]and theSurvivingSepsisCampaign reportedmortality by theendof an improvementproject to be 31%.[10]



FOLLO

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Follow upSepsis in adults


ICU-specific mortality has been shown to be 27% to 32% in patients with sepsis, and 50% to 70% in patients with septicshock, compared with 14% in ICU patients without sepsis.[4] [12]

Multi-organ compromise is common in advanced sepsis with variable residual morbidity.[4] [8]



Follow upSepsis in adultsFO

LLOWUP


Diagnostic guidelines

Europe

Sepsis: recognition, diagnosis and early management

Last published: 2016Published by: National Institute for Health and Care Excellence

Summary: This guideline covers the recognition and diagnosis of sepsis for all populations. The guideline committeeidentified that thekey issues tobe includedwere: recognitionandearly assessment aswell as diagnostic andprognosticvalue of blood markers for sepsis.

Sepsis - a clinical toolkit for emergency departments

Last published: 2014Published by: College of Emergency Medicine

Summary: Aims to provide operational solutions to the complexities that challenge the reliable identification andmanagement of sepsis, and to complement clinical toolkits designed for other clinical areas.

Latin America

Guidelines for thetreatmentofseveresepsisandsepticshock:managementof the infectiousagent - diagnosis

Last published: 2010Published by: Brazilian Medical Association

Summary: This guideline provides a comprehensive overview of the diagnosis of sepsis.

Oceania

Sepsis toolkit

Last published: 2014Published by: Clinical Excellence Commission

Summary: Sepsis pack produced in Australia to achieve system-wide improvements in early sepsis recognition andmanagement.

Treatment guidelines

Europe

Sepsis: recognition, diagnosis and early management

Last published: 2016Published by: National Institute for Health and Care Excellence

Summary: Thisguidelinecovers theearlymanagementof sepsis for all populations. Theguidelinecommittee identifiedthat the key issues to be included were initial treatment, escalating care, identifying the source of infection, earlymonitoring, information and support for patients and carers, and training and education.



GUIDELIN

ES

GuidelinesSepsis in adults

https://www.nice.org.uk/guidance/ng51

http://www.rcem.ac.uk/RCEM/Quality_Policy/Clinical_Standards_Guidance/RCEM_Guidance/RCEM/Quality-Policy/Clinical_Standards_Guidance/RCEM_Guidance.aspx

http://www.scielo.br/pdf/rbti/v23n2/en_a05v23n2.pdf


http://www.cec.health.nsw.gov.au/patient-safety-programs/adult-patient-safety/sepsis-kills/sepsis-tools



Europe

Sepsis - a clinical toolkit for emergency departments

Last published: 2014Published by: College of Emergency Medicine

Summary: Aims to provide operational solutions to the complexities that challenge the reliable identification andmanagement of sepsis, and to complement clinical toolkits designed for other clinical areas.

British consensus guidelines on intravenous fluid therapy for adult surgical patients

Last published: 2011Published by: British Association for Parenteral and Enteral Nutrition; AssociationforClinical Biochemistry; AssociationofSurgeonsofGreatBritain and Ireland; Societyof Academic and Research Surgery; Renal Association; Intensive Care Society

Summary: These guidelines provide evidence-based recommendations for good perioperative fluid prescribingpractices in patients undergoing various surgical procedures.

Haemodynamicmanagement of severe sepsis: recommendations of the French IntensiveCare Societies (SFAR/SRLF) Consensus Conference, 13 October 2005, Paris, France

Last published: 2006Published by: French Intensive Care Societies

Summary: Evidence-based consensus guideline focusing on haemodynamicmanagement of severe sepsis in adultsand children.

International

Surviving sepsis campaign guidelines for management of sepsis and septic shock - 2016

Last published: 2016Published by: International Surviving Sepsis Campaign Guidelines Committee

Summary: These evidence-based guidelines provide the following recommendations for the treatment of sepsis andseptic shock. Initial fluid resuscitation should be done with crystalloid, with at least 30 mL/kg in the first 3 hours inpatients with sepsis-induced hypoperfusion. In patients who continue to require substantial amounts of crystalloid tomaintain adequate mean arterial pressure, addition of albumin should be considered. It is recommended to avoidhydroxyethyl starch formulations. It is recommended that intravenous antibiotics are started within the first hour ofrecognising severe sepsis (preferably after cultureshavebeen taken). Vasopressors are recommended if fluid challengefails to restore adequate BP. Dobutamine can be used to increase cardiac output if cardiac output is low despite fluidresuscitation and vasopressors. Intravenous hydrocortisone should be given only to patients whose BP is poorlyresponsive to both fluid resuscitation and vasopressor therapy.

North America

Standards of medical care in diabetes - 2017

Last published: 2017Published by: American Diabetes Association

Summary: This guideline provides a comprehensive overview of the management of this condition.



GuidelinesSepsis in adultsGUIDELINES

http://www.rcem.ac.uk/RCEM/Quality_Policy/Clinical_Standards_Guidance/RCEM_Guidance/RCEM/Quality-Policy/Clinical_Standards_Guidance/RCEM_Guidance.aspx

http://www.bapen.org.uk/resources-and-education/education-and-guidance/clinical-guidance

http://www.ncbi.nlm.nih.gov/pmc/issues/140271/

http://www.ncbi.nlm.nih.gov/pmc/issues/140271/

http://www.survivingsepsis.org/GUIDELINES/Pages/default.aspx

http://professional.diabetes.org/content/clinical-practice-recommendations


North America

Management of patients with infections caused bymethicillin-resistant Staphylococcusaureus

Last published: 2011Published by: Infectious Diseases Society of America

Summary: Evidence-based consensus guideline for the management of patients with methicillin-resistant S aureus(MRSA) infections, prepared by an expert panel of the Infectious Diseases Society of America. The guidelines areintended forusebyhealth careproviderswhocare for adult andpaediatric patientswithMRSA infections. Theguidelinesdiscuss themanagementof a variety of clinical syndromesassociatedwithMRSAdisease, including skin and soft-tissueinfections, bacteraemiaandendocarditis, pneumonia, boneand joint infections, andCNS infections. Recommendationsare provided regarding antimicrobial selection and dosing, suggested level of care and location, and ongoingmanagement.

Severe sepsis and septic shock: review of the literature and emergency departmentmanagement guidelines

Last published: 2006Published by: Emergency Department Sepsis Education Program and Strategiesto Improve Survival (ED-SEPSIS) Working Group

Summary: Early recognition andmanagement of severe sepsis or septic shock optimises outcome. Continuousmonitoringof vital signs and laboratory examination is needed to facilitateearly recognition. Rigorous clinical evaluationandappropriate cultures (includingblood, urine, and site-specific) shouldbeobtainedbeforegivingantibiotics. Empiricalantibiotics should be started as soon as possible. Ideally, site-specific regimens should be given if possible. Earlygoal-directed therapy should be started as soon as possible, with monitoring of central venous pressure (CVP) andmixed venous oxygen saturation (SVO2). After achievement of the target haemodynamic goals (CVP8-12mmHg;MAP65-90mmHg; SVO2 >70%) serial lactate levels should be obtained to evaluate response to therapy. Depending on thesiteof infection, sourcecontrol (drainage) shouldbeaggressively performed. Patients requiringmechanical ventilationshould be treated with low tidal volume to maintain end-inspiratory plateau pressure <30 cmH2O. Vasopressors arerequired for refractory shock or organ dysfunction.



GUIDELIN

ES

GuidelinesSepsis in adults

http://www.idsociety.org/Organism/#Bacteria

http://www.idsociety.org/Organism/#Bacteria

http://www.annemergmed.com/issues?issue_key=S0196-0644%2806%29X0083-5

http://www.annemergmed.com/issues?issue_key=S0196-0644%2806%29X0083-5


Online resources

1. Surviving Sepsis Campaign: evaluation for severe sepsis screening tool (external link)

2. APACHE II calculator (external link)



Online resourcesSepsis in adultsONLINERESO

URCES




Key articles

• Russell JA. Management of sepsis. N Engl J Med. 2006;355:1699-1713. Abstract

• National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and earlymanagement. July 2016.

https://www.nice.org.uk (last accessed 17 May 2017). Full text

• DiamentD, SalomãoR,RigattoO, et al. Guidelines for the treatmentof severe sepsis and septic shock:management

of the infectious agent - diagnosis. December 2010. http://www.scielo.br (last accessed 17 May 2017). Full text

• Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334-1349. Abstract

References

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic

Shock (Sepsis-3). JAMA. 2016 23;315:801-810. Full text Abstract

2. SeymourCW, LiuVX, IwashynaTJ, et al. Assessmentof clinical criteria for sepsis: for the third international consensus

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3. ChurpekMM, Zadravecz FJ, WinslowC, et al. Incidence andprognostic value of the systemic inflammatory response

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4. Russell JA. Management of sepsis. N Engl J Med. 2006;355:1699-1713. Abstract

5. LevyMM, FinkMP,Marshall JC, et al. 2001SCCM/ESICM/ACCP/ATS/SIS International SepsisDefinitionsConference.

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Abstract

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Abstract

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http://www.nejm.org/doi/full/10.1056/NEJMoa022139#t=article








http://content.digital.nhs.uk/article/2021/Website-Search?q=sepsis&area=both&size=50&sort=Relevance#top






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http://www.cdc.gov/mmwr/PDF/rr/rr5116.pdf




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RENCES





http://www.nejm.org/doi/full/10.1056/NEJM199902113400601#t=articleTop


http://www.nejm.org/doi/full/10.1056/NEJM200005043421801#t=article

http://www.nejm.org/doi/full/10.1056/NEJM200005043421801#t=article















Images

Figure 1: Capillary refill time. Top image: normal skin tone; middle image: pressure applied for 5 seconds; bottom image:time to hyperaemia measured

From the collection of Ron Daniels, MB, ChB, FRCA; used with permission

Figure 2: Severe purpura fulminans, most commonly associated with pneumococcal septicaemia

From the collection of Ron Daniels, MB, ChB, FRCA; used with permission



ImagesSepsis in adultsIM

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Figure 3: Sequential (or Sepsis-related) Organ Failure Assessment (SOFA) criteria

Created by BMJ, adapted from Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment)score todescribeorgandysfunction/failure.Onbehalf of theWorkingGrouponSepsis-RelatedProblemsof theEuropeanSociety of Intensive Care Medicine. Intensive Care Med 1996;22:707-710.



IMAGES

ImagesSepsis in adults


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Contributors:

// Authors:

Ron Daniels, MBChB, FRCA

Chief ExecutiveUnited Kingdom Sepsis Trust, Chief Executive, Global Sepsis Alliance , Programme Director , Survive Sepsis , Consultant in CriticalCare and Anaesthesia, Heart of England NHS Foundation Trust, Birmingham, UKDISCLOSURES: RD has received payment for consultancy on sepsis from Kimal Plc, manufacturers of vascular access devices,from the Northumbria Partnership, a patient safety collaborative, and, where annual leave or other income was compromised infulfilling his charity duties, from theUKSepsis Trust. RDhas received sponsorship to attend and speak at onemeeting fromAbbottDiagnostics.He isCEOof theUKSepsis Trust andGlobal SepsisAlliance, andadvisesHMGovernment, theWorldHealthOrganisationand NHS England on sepsis. Each of these positions demands that he express opinion on strategies around the recognition andmanagement of sepsis.

TimNutbeam, MSc, Dip IMC FRCEM

Consultant in Emergency MedicineClinical Academic, University of Plymouth, Lead Doctor, Devon Air Ambulance Trust, Derriford Hospital, Plymouth , UKDISCLOSURES: TN is a clinical advisor to the UK Sepsis Trust.

Edward Berry, MBChB, MCEM

Specialty Registrar in Emergency MedicineDerriford Hospital , Plymouth , UKDISCLOSURES: EC declares that he has no competing interests.

// Acknowledgements:

Dr Ron Daniels, Dr Tim Nutbeam, and Dr Edward Berry would like to gratefully acknowledge Dr Lewys Richmond and Dr PaulKempen, the previous contributors to this monograph.DISCLOSURES: LR and PK declare that they have no competing interests.

// Peer Reviewers:

StevenM. Opal, MD, FIDSA

Professor of MedicineInfectious Disease Division, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RIDISCLOSURES: SMO declares that he has no competing interests.

Laura Evans, MD, MSc, FCCP, FCCM

Associate ProfessorNYU School of Medicine, Medical Director of Critical Care, Bellevue Hospital Center, New York, NYDISCLOSURES: LE serves as the guidelines co-chair and on the steering committee of the Surviving Sepsis Campaign.