SEPSIS

Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs.[5] This initial stage is followed by suppression of the immune system.[9] Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion.[2] There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection.[3] The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever.[3] Severe sepsis causes poor organ function or blood flow.[10] The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow.[10] Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement.[10]

SEPSIS

Sepsis

Andrew J Brent

Abstract

Sepsis occurs when a dysregulated host response to infection causes

potentially life-threatening organ dysfunction. It is usually caused by

bacterial infection and carries a 30% mortality, causing millions of

deaths worldwide each year. New definitions have recently been pub-

lished for clinical practice and research. Effective management re-

quires prompt recognition, antimicrobial therapy, source control and

supportive treatment. Early, appropriate antimicrobial therapy is asso-

ciated with improved survival from sepsis. Rapid identification and

control of the source of infection (e.g. drainage of pus) is equally

important in many cases. These and other elements of the initial man-

agement of sepsis are incorporated into the ‘Sepsis Six’ bundle of

care.

Keywords Antibiotics; antimicrobial therapy; infection; MRCP;

sepsis; septic shock

Definitions

Sepsis describes a syndrome of life-threatening organ dysfunc-

tion caused by a dysregulated host response to infection. It is

usually caused by bacterial infection. Various definitions have

been proposed for both clinical practice and research. The pre-

vious definition of a systemic inflammatory response syndrome

(SIRS) to infection was poorly discriminative. Two new defini-

tions were published in 2016 as part of management guidelines

from an international critical care task force (Sepsis-3)' and the

UK National Institute for Health and Care Excellence (NICE)? —

see below.

Epidemiology

Sepsis has a mortality of approximately 30%, causing around 5

million deaths worldwide and >40,000 deaths in the UK annu-

ally. Common presenting syndromes include pneumonia, intra-

abdominal and urinary sepsis, and skin and soft tissue in-

fections. Causative agents depend on the syndrome, host and

clinical context. Gram-negative infections account for an

increasingly large proportion of cases, particularly of healthcare-

associated infections.’ Risk factors for infection are summarized

in Table 1.

Pathophysiology

Highly conserved microbial structures, like lipopolysaccharide

(endotoxin) in Gram-negative bacteria, trigger pattern recogni-

tion receptors (e.g. Toll-like receptors) causing a cytokine

cascade, leucocyte, complement and coagulation activation, and

Andrew J Brent macp PhD DTM&H is a Consultant and Honorary

Senior Clinical Lecturer in Infectious Diseases at Oxford University

Hospitals Foundation Trust and the University of Oxford, UK.

Competing interests: none declared.

MEDICINE i:

Sepsis occurs when a dysregulated host response to infection

causes potentially life-threatening organ dysfunction with a

mortality of approximately 30%

Early recognition and treatment of sepsis saves lives

Management includes antimicrobial therapy, source control

and supportive care

vascular endothelial dysfunction.’ Microvascular thrombosis

caused by dysregulated coagulation, combined with vasodilata-

tion and hypotension, causes tissue hypoperfusion, and oxidative

stress worsens mitochondrial dysfunction.

The downstream effect of this proinflammatory response is

impaired tissue oxygenation. The resulting tissue injury releases

endogenous proinflammatory molecules that perpetuate the in-

flammatory response and organ dysfunction. Compensatory anti-

inflammatory mechanisms increase vulnerability to secondary

infections. The balance between pro- and anti-inflammatory ef-

fects and the resulting clinical phenotype vary during an episode

and between patients.

Clinical presentation

Clinical features of sepsis are related to the systemic inflamma-

tory response, the infection focus and organ dysfunction (Table

2).° Symptoms and signs vary considerably and can be subtle,

particularly in young children and elderly or immunocompro-

mised individuals.

Septic shock occurs when severe sepsis leads to circulatory

failure and metabolic abnormalities, defined as persisting hypo-

tension requiring vasopressors to maintain mean arterial pres-

sure >65 mmHg and serum lactate concentration >2 mmol/litre

despite adequate fluid resuscitation. It carries a mortality of

>40%.'

Screening and diagnosis

Screening for sepsis is now routine in many settings. However,

there is no consensus on the best screening approach.

The Sepsis-3 guidelines’ advocate two-stage screening of

adults with suspected infection to identify those at highest risk of

poor outcome. Sepsis is defined as the presence of >2 ‘quick

SOFA (qSOFA)’ parameters (respiratory rate >22/minute, altered

mentation, systolic blood pressure <100 mmHg) plus an increase

of >2 in the Sequential Organ Failure Assessment (SOFA) score.

The 2016 NICE Sepsis guidelines’ risk-stratify adult and

paediatric patients with suspected infection according to the

presence of ‘high-risk’ (Table 2) and ‘moderate-to-high-risk’

criteria. These are incorporated into age- and setting-dependent

algorithms dictating further investigation and treatment. How-

ever, their complexity has attracted criticism, and high-quality

evidence to justify much of the complexity is lacking.

Several large studies have demonstrated the superiority of

Sepsis-3 over the old SIRS criteria for predicting adverse outcome

Please cite this article in press as: Brent AJ, Sepsis, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.07.010

SEPSIS

Risk factors for sepsis

Increased risk of « Environmental factors (hygiene,

infection sanitation)

e Susceptibility of individual organs to

infection, e.g.:

e Chronic obstructive pulmonary

disease, bronchiectasis — respira-

tory infections

o Lymphoedema, ulcers, psoriasis,

etc. — skin infections

o Urethral catheter — urinary tract

infections

Impaired immune e Congenital immunodeficiency

response syndromes

° HIV/AIDS

e Neutropenia

e Splenectomy/hyposplenism

e latrogenic (corticosteroids, chemo-

therapy, biological agents)

e Other chronic conditions (e.g.

malnutrition, diabetes mellitus,

malignancy)

Increased risk of organ failure from

reduced physiological reserve, e.g.

heart failure, chronic respiratory dis-

ease, chronic kidney disease

Neonates and infants (immature im-

munity, limited physiological reserve)

e Elderly patients (immune senescence,

co-morbidity)

Ethnicity (incidence higher among

some racial groups)

e Sex (incidence higher among male

patients)

e Specific immune defects, e.g. defect

in terminal complement pathway

leading to increased risk of menin-

gococcal sepsis

Pre-existing organ e

dysfunction

Extremes of age e

Other genetic factors e

Infection management e Delayed or inappropriate initial

treatment of bacterial infections in-

creases risk of progression to sepsis

Table 1

and death among adult inpatients with suspected infection. The

limited data available to date suggest that the NICE criteria are

less discriminating. Interestingly, in a recent large study, the

National Early Warning Score (NEWS) was more discrimi-

nating than SIRS or qSOFA among >30,000 adult inpatients.”

Using a generic early warning score to identify the sickest pa-

tients is attractive because early warning scores are already

embedded in clinical practice, and sepsis is only one (albeit

important) cause of clinical deterioration. Sepsis may be incor-

porated into NEWS2, to be published later this year.

The best approach to sepsis screening among children, preg-

nant women and non-hospital settings is even less clear. Identi-

fying sepsis in children is particularly challenging because viral

MEDICINE i:

infections that do not require antimicrobial therapy represent a

large proportion of the presenting caseload. Early data suggest

poor specificity of the NICE algorithms, and a number of different

paediatric early warning scores and alternative screening tools

are used.

Management

The key principles of management are prompt recognition, early

appropriate antimicrobial therapy, source control, supportive

treatment and antimicrobial stewardship (Table 3). Elements of

the initial management of sepsis are incorporated into the Sepsis

Six bundle of care.

Rapid clinical assessment is indicated for all patients with

suspected sepsis. As for other medical emergencies, use an

‘assess and treat’ approach to quickly establish the key elements

of the history and examination, and — if the working diagnosis of

sepsis is confirmed — start treatment. Rapid delivery of a bundle

of care comprising elements of the Sepsis Six (Table 3) has been

associated with reduced mortality in sepsis.”

Investigations aim to confirm the presence, source and severity of

infections and alternative diagnoses (Table 3). Where possible, it is

important to obtain samples for microbiology before administering

antibiotics to maximize culture sensitivity. Except in exceptional

circumstances, at least one set of blood cultures should be ob-

tained. The timing of other cultures (e.g. urine, cerebrospinal fluid,

repeat blood cultures for suspected endocarditis) depends on the

clinical presentation, illness severity and likely delay in obtaining a

sample; in general, however, antibiotics should not be delayed in

true sepsis. Ifin doubt, discuss the patient urgently with a senior or

infection specialist.

Antimicrobial therapy should be administered as rapidly as

possible in sepsis, and within 1 hour, as early appropriate anti-

biotics are associated with improved survival.* The choice of

initial empirical antibiotic therapy depends on the presenting

clinical syndrome (including likely focus of infection, neu-

tropenia, etc.) and should follow local guidelines based on the

most likely pathogens and susceptibility profiles. The need, route

of administration and choice of antibiotics should be reviewed

daily in light of clinical progress and investigations.

Source control is equally crucial to the management of many

focal infections and should be performed as rapidly as possible. It

includes removal of infected lines/devices, drainage of collec-

tions, nephrostomy insertion for an infected-obstructed renal

system, washout of infected joints, etc. Although some patients

may first need to be stabilized, source control is in some cases

(e.g. necrotizing fasciitis) just as or more important than anti-

microbial therapy.

Supportive treatment includes oxygen to treat hypoxia and

ensure good tissue oxygenation, and intravenous fluids to opti-

mize tissue perfusion. Vasopressors and inotropes may be

required in septic shock, mechanical ventilation for severe

pneumonia or acute respiratory distress syndrome, and renal

replacement therapy for acute kidney injury. Patients who

Please cite this article in press as: Brent AJ, Sepsis, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.07.010

Clinical features of sepsis

Mechanism

Systemic inflammatory response

Infection focus including signs of inflammation

(pain, warmth, swelling, erythema, loss of

function)

Organ dysfunction

NICE high-risk (‘red flag’) sepsis criteria

AKI: acute kidney injury.

SEPSIS

Examples

e Fever, hypothermia, rigors

e Tachycardia, tachypnoea, respiratory distress

e Altered mental state, delirium, acute functional decline

syndrome)

e Pneumonia: dyspnoea, cough, tachypnoea, hypoxia

e Urinary sepsis: dysuria, frequency, pain

e Skin/soft tissue infection: erysipelas, cellulitis, abscess

e Meningitis: headache, neck stiffness, photophobia

e Cardiovascular: hypotension/shock caused by vasodilation (warm peripheries), or

myocardial injury + hypovolaemia (cool peripheries + mottled skin)

e Acute respiratory distress syndrome: tachypnoea, hypoxia

e AKI: oliguria, fluid overload, acidosis

e Metabolic: acidosis (AKI; tissue hyperperfusion causing lactic acidosis)

e Endocrine: impaired glycaemic control, adrenocortical dysfunction (including Waterhouse

—Friedrichsen syndrome — acute adrenal haemorrhage), sick euthyroid syndrome

e Objective evidence of new altered mental state

e Respiratory rate >25/minute or new hypoxia (SaO, breathing air <92% or <88% in

chronic obstructive pulmonary disease)

e Heart rate >130/minute

e Systolic blood pressure <90 mmHg, or more than 40 mmHg below normal

e Not passed urine for >18 hours or urine output <0.5 mV/kg per hour

e Mottled/ashen skin, non-blanching rash, cyanosis of skin, lips or tongue

* Note overlap between mechanisms and features of systemic inflammation and organ dysfunction.

Table 2

Sepsis management

Rapid assessment

Immediate management

Monitoring and

treatment escalation

Source identification and control

‘Assess and treat’ approach to confirm diagnosis and start treatment

‘Sepsis Six’ care bundle to be delivered as soon as possible and within 1 hour:

ea Pe Np

Blood (tother) cultures; consider source control (see below)

Venous blood gas (including lactate, haemoglobin, electrolytes)

Start monitoring urine output (consider urinary catheter)

Give oxygen to keep SaO, at 94-98%

Give intravenous fluids guided by clinical response and lactate concentration

Give empirical intravenous antibiotics according to local guidelines

Complete clinical assessment and initial investigations, including full blood count, urea and

electrolytes, liver function tests, C-reactive protein, clotting; + other cultures (e.g. urine, cere-

brospinal fluid, pus), chest X-ray

Transfer patient to appropriate care setting (e.g. high-dependency, intensive care)

Ensure regular monitoring of vital signs (e.g. every 30 minutes, depending on clinical response

and setting)

Inform senior clinician responsible for patient. Ensure regular continuing clinical review

Organize additional investigations (e.g. imaging) to confirm site of infection

Remove/drain any controllable source of infection as soon as possible, e.g. removal of infected

lines, drainage of collections, washout of infected joints

(continued on next page)

Please cite this article in press as: Brent AJ, Sepsis, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.07.010

SEPSIS

Table 3 (continued)

e Vasopressors, inotropes (consider corticosteroids for refractory shock)

Critical care Further organ support as required, including:

e Mechanical ventilation

e Renal replacement therapy

Antimicrobial stewardship °

Review antimicrobial therapy daily in light of clinical progress and investigations

e Consider switching to oral antibiotics, narrowing or changing therapy in the light of microbiology

results, or stopping antibiotics if no longer indicated

* Target Sa0, 88-92% if risk of type 2 (hypercapnoeic) respiratory failure.

Table 3

present in septic shock or who fail to respond to initial therapy

should be referred early to intensive care for further organ

support.

Although supportive treatment is important to allow time for

antimicrobial therapy and perhaps source control to contain the

infection, attempts at ‘early goal-directed therapy’ to achieve

intensive physiological homeostasis, defined by specific haemo-

dynamic indices, has not shown benefit in large randomized

controlled trials.”

Adjunctive therapies are, despite several clinical trials, not

supported by available evidence for standard management of

sepsis. Intravenous immunoglobulin has a specific role in man-

agement of severe group A streptococcal infections, including

toxic shock, syndrome and possibly necrotizing fasciitis.” Corti-

costeroids are sometimes given for refractory septic shock (e.g.

hydrocortisone 200 mg/day) in addition to vasopressors and

inotropes; however, high-quality evidence is lacking.’

Prevention

Strategies include management of underlying risk factors (Table

1), vaccination, prophylactic antibiotics for selected groups (e.g.

in asplenia) and timely treatment of infections to prevent pro-

gression to sepsis. rd

TEST YOURSELF

KEY REFERENCES

1 Singer M, Deutschman CS, Seymour CW, et al. The Third Inter-

national Consensus Definitions for Sepsis and Septic Shock

(Sepsis-3). J Am Med Assoc 2016; 315: 801—10.

2 National Institute for Health and Care Excellence. Sepsis: recogni-

tion, diagnosis and early management. NICE guideline no. 51. 2016,

http://www.nice.org.uk/guidance/ng51. [Accessed 26 May 2017].

3 Angus DC, van der Poll T. Severe sepsis and septic shock. N Eng! J

Med 2013; 369: 840—51.

4 Churpek M, Snyder A, Han X, et al. Quick Sepsis-related Organ

Failure Assessment, systemic inflammatory response syndrome,

and early warning scores for detecting clinical deterioration in

infected patients outside the intensive care unit. Am J Respir Crit

Care Med 2017; 195: 906-11.

5 Daniels R, Nutbeam T, McNamara G, et al. The sepsis six and the

severe sepsis resuscitation bundle: a prospective observational

cohort study. Emerg Med J 2011; 28: 507-12.

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SEPSIS