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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
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
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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.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.6BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
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BasicsSepsis in adultsBASICS
• 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.
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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).
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BasicsSepsis in adultsBASICS
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
9This 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
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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]
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.10BMJ 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.
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).
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DIAGNOSIS
DiagnosisSepsis in adults
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.
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DiagnosisSepsis in adultsDIAGNOSIS
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.
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DIAGNOSIS
DiagnosisSepsis in adults
• 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
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DiagnosisSepsis in adultsDIAGNOSIS
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]
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DIAGNOSIS
DiagnosisSepsis in adults
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).
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DiagnosisSepsis in adultsDIAGNOSIS
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.
• May be present when sepsis leads to organ dysfunction.
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)
• May be present when sepsis leads to organ dysfunction.
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DIAGNOSIS
DiagnosisSepsis in adults
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]
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DiagnosisSepsis in adultsDIAGNOSIS
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]
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DIAGNOSIS
DiagnosisSepsis in adults
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]
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DiagnosisSepsis in adultsDIAGNOSIS
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
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DIAGNOSIS
DiagnosisSepsis in adults
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,
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DiagnosisSepsis in adultsDIAGNOSIS
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
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DIAGNOSIS
DiagnosisSepsis in adults
• 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:
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DiagnosisSepsis in adultsDIAGNOSIS
• 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)
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DIAGNOSIS
DiagnosisSepsis in adults
• 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.
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DiagnosisSepsis in adultsDIAGNOSIS
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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TREATM
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.
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TreatmentSepsis in adultsTR
EAT
MENT
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.
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. 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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TREATM
ENT
TreatmentSepsis in adults
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 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.
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. 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.
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. 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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TreatmentSepsis in adultsTR
EAT
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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TREATM
ENT
TreatmentSepsis in adults
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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TreatmentSepsis in adultsTR
EAT
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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TREATM
ENT
TreatmentSepsis in adults
Treatment options
Acute
TreatmentTx linePatient group
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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of this content is subject to our disclaimer. © BMJ Publishing Group Ltd 2017. All rights reserved.
TreatmentSepsis in adultsTR
EAT
MENT
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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TREATM
ENT
TreatmentSepsis in adults
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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TreatmentSepsis in adultsTR
EAT
MENT
Acute
TreatmentTx linePatient group
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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TREATM
ENT
TreatmentSepsis in adults
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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TreatmentSepsis in adultsTR
EAT
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.
» 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.
» 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
no penicillin allergy
» 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
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TREATM
ENT
TreatmentSepsis in adults
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.
» 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
» 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.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.40BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
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TreatmentSepsis in adultsTR
EAT
MENT
Acute
TreatmentTx linePatient group
--AND--
»gentamicin:5mg/kg intravenouslyevery24hours
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.
» 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
» amoxicillin: 1 g intravenously every 6 hours-or-» cefotaxime: 1-2 g intravenously every 8 hours
--AND--
» metronidazole: 500mg intravenously every 8hours
--AND--
»gentamicin:5mg/kg intravenouslyevery24hours
OR
no penicillin allergy
»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
41This 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
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TREATM
ENT
TreatmentSepsis in adults
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
no penicillin allergy
» 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
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TreatmentSepsis in adultsTR
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
» vancomycin: 1 g intravenously every 12 hours
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.
» 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
» flucloxacillin: 2 g intravenously every 6 hours-or-» nafcillin: 1-2 g intravenously every 6 hours
--AND--
43This 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
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TREATM
ENT
TreatmentSepsis in adults
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.
» 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
» ceftriaxone: 2 g intravenously every 12 hours
OR
no penicillin allergy
» 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
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TreatmentSepsis in adultsTR
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
no penicillin allergy
» 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.
45This 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
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TREATM
ENT
TreatmentSepsis in adults
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
» vancomycin: 1 g intravenously every 12 hours
--AND--
» imipenem/cilastatin: 1 g intravenously every 8hoursDose refers to imipenem component.-or-» meropenem: 1 g intravenously every 8 hours
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 06, 2017.46BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
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TreatmentSepsis in adultsTR
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
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FOLLO
WUP
Follow upSepsis in adults
LikelihoodTimeframeComplications
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
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Follow upSepsis in adultsFO
LLOWUP
LikelihoodTimeframeComplications
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]
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FOLLO
WUP
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]
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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.
51This 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
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GUIDELIN
ES
GuidelinesSepsis in adults
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.
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GuidelinesSepsis in adultsGUIDELINES
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.
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GUIDELIN
ES
GuidelinesSepsis in adults
Online resources
1. Surviving Sepsis Campaign: evaluation for severe sepsis screening tool (external link)
2. APACHE II calculator (external link)
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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
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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
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ImagesSepsis in adultsIM
AGES
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.
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IMAGES
ImagesSepsis in adults
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IMER
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.
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