Sepsis 2017

DEFINITIONS :
• Sepsis exists on a continuum of severity ranging
from infection and bacteremia to sepsis and
septic shock, which can lead to multiple organ
dysfunction syndrome (MODS) and death.
• The definitions of sepsis and septic shock have
rapidly evolved since the early 1990s .
• The systemic inflammatory response syndrome
(SIRS) is no longer included in the definition since
it is not always caused by infection.

DEFINITIONS :
• Systemic inflammatory response syndrome :(SIRS) criteria to
identify those with sepsis has fallen out of favor since it is
considered by many experts that SIRS criteria are present in many
hospitalized patients who do not develop infection, and their
ability to predict death is poor when compared with other scores
such as the SOFA score .
• It is a form of dysregulated inflammation. It was previously
defined as two or more abnormalities in T, HR, respiration, or
WBC .
• SIRS may occur in several conditions related, or not, to infection.
Noninfectious conditions classically associated with SIRS include
autoimmune disorders, pancreatitis, vasculitis, thromboembolism,
burns, or surgery.

DEFINITIONS :
• Early sepsis — Infection and bacteremia may be early forms of
infection that can progress to sepsis.
• There is no formal definition of early sepsis.
• Monitoring those suspected of having sepsis is critical for its
prevention.
• All patients with infection or bacteremia are at risk of developing
sepsis and represent early phases in the continuum of sepsis
severity:
●Infection is defined as the invasion of normally sterile tissue by
organisms resulting in infectious pathology.
●Bacteremia is the presence of viable bacteria in the blood.

First International Consensus Definitions
for Sepsis and Septic Shock (1991)
• In the 1991 definitions (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.
• Sepsis with hypoperfusion is defined by the presence of acute
circulatory failure: arterial hypotension (SBP <90 mmHg, reduced
by >40 mmHg from baseline or [MAP] of <65 mmHg), or other
evidence of hypoperfusion, such as serum lactate >2 mmol/L (>18
mg/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.

Third International Consensus Definitions
for Sepsis and Septic Shock (Sepsis-3) 2016
• Sepsis has been redefined as life-threatening
organ dysfunction caused by a dysregulated
host response to a new infection.
• Septic shock has also been redefined 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.

EPIDEMIOLOGY
• Incidence — In the late 1970s, it was
estimated that 164,000 cases of sepsis
occurred in the United States (US) each year .
• Rates are increasing
●One national database analysis of discharge
records from hospitals in the US estimated an
annual rate of more than 1,665,000 cases of
sepsis between 1979 and 2000 .

EPIDEMIOLOGY
• Another retrospective population-based
analysis reported increased rates of sepsis and
septic shock from 13 to 78 cases per 100,000
between 1998 and 2009 .
• A retrospective analysis of an international
database reported a global incidence of 437
per 100,000 person-years for sepsis between
the years 1995 and 2015.

EPIDEMIOLOGY
• In an analysis of 27 academic hospitals, between 2005 and
2014 rates of septic shock determined by clinical criteria
increased from 12.8 to 18.6 per 1000 hospital admissions
and mortality decreased from 55 to 51 percent .
• The increased rate of sepsis is thought to be a consequence
of advancing age, immunosuppression, and multidrug-
resistant infection .
• It is also likely to be due to the increased detection of early
sepsis from aggressive sepsis education and awareness
campaigns.

EPIDEMIOLOGY
• The incidence of sepsis varies among the different
racial and ethnic groups, but appears to be highest
among African-American males .
• The incidence is also greatest during the winter,
probably due to the increased prevalence of
respiratory infections .
• Older patients ≥65 years of age account for the
majority (60 to 85 percent) of all episodes of sepsis;
with an increasing aging population, it is likely that the
incidence of sepsis will continue to increase in the
future.

EPIDEMIOLOGY
• Pathogens :
• Gram positive bacteria are most frequently identified in patients .
• Cases of Gram negative sepsis remains substantial.
• The incidence of fungal sepsis has increased over the past decade, but
remains lower than bacterial sepsis .
• In half of cases of sepsis, an organism is not identified (culture negative
sepsis) .
• Disease severity : The severity of disease appears to be increasing .
• The proportion of patients with sepsis who also had at least one
dysfunctional organ increased from 26 to 44 percent between 1993 and
2003 .
• The most common manifestations of severe organ dysfunction were
acute respiratory distress syndrome, acute renal failure, and
disseminated intravascular coagulation .

ETIOLOGY
• Causative agents vary significantly depending on the
region, hospital size, season, and type of unit
(neonatal, transplantation, oncology, or haemodialysis
units).
• Pathogenic organisms are identified in only around half
of cases of sepsis.Where organisms are identified,
bacteria (gram-positive and gram-negative) are
identified as the causative organism in approximately
90% of cases, with gram-positive bacteria and fungal
infections increasing in frequency.

ETIOLOGY
• Since the mid-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 and Klebsiella pneumoniae, and by Pseudomonas
aeruginosa).
• However, E coli remains the most prevalent pathogen
causing sepsis.
• Some experts believe that the host response to some viral
infections so closely mimics sepsis that it should be
considered .

ETIOLOGY
• In the UK, a study in sepsis published in November
2015 highlighted that nearly 75% of cases of sepsis
arose as a result of community-acquired infection ,
where the causative organisms will be sensitive,
frequently endogenous bacteria.
• But the 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).

ETIOLOGY
• Over the last 2 decades, vancomycin-resistant enterococci
(VREs) have emerged, with >10% of enterococci being
VREs.
• The significant number of E coli isolates that are now
resistant to amoxicillin/clavulanic acid (around 40%).
• MRSA is also 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.

ETIOLOGY
• The leading fungal pathogen causing sepsis has been
identified as Candida.
• In a European point-prevalence study, fungi were isolated
from 17% of ICU patients with nosocomial infection.
• Fungi are more prevalent as isolates in patients with
secondary or tertiary peritonitis, withCandida identified in
up to 20% of patients with GI tract perforation.
• Risk factors include faecal soiling of the peritoneum,
recurrent GI perforation, immunosuppressive therapy for
neoplasm or in post-transplant patients, and the presence
of inflammatory diseases. These patients carry a high risk of
mortality.

SITE OF INFECTION
• The respiratory tract accounted for 44.4 - 60%.
• the bloodstream 20%
• abdomen 26%
• skin 14%
• urinary system 12 - 20.8 %.
• In 20% to 30% of patients, a definite source of
infection is not found.

Sequential (sepsis-related) Organ
Failure Assessment (SOFA)

• It was initially designed to sequentially assess the
severity of organ dysfunction in patients who
were critically ill from sepsis.
• Since multiple organ dysfunction is common in
critically ill patients, it has since been used to
predict mortality in those with organ failure from
other causes including those with acute liver
failure from acetaminophen overdose, chronic
liver failure , and cancer, as well as in patients
who have undergone cardiac surgery or
hematopoietic stem cell transplant .

• SOFA uses simple measurements of major organ
function to calculate a severity score. The scores
are calculated 24 hours after admission to the
ICU and every 48 hours thereafter (thus, the
term "Sequential" Organ Failure Assessment).
• The mean and the highest scores are most
predictive of mortality.
• Scores that increase by about 30 percent are
associated with a mortality of at least 50 %.

• The SOFA severity score is based upon the following
measurements of organ function :
●Respiratory system – the ratio of arterial oxygen tension
to fraction of inspired oxygen (PaO2/FiO2)
●Cardiovascular system – the amount of vasoactive
medication necessary to prevent hypotension
●Hepatic system – the bilirubin level
●Coagulation system – the platelet concentration
●Neurologic system – the Glasgow coma score
●Renal system – the serum creatinine or urine output

Identification of early sepsis (qSOFA)
• The 2016 SCCM/ESICM task force have described this assessment score
for patients outside the intensive care unit as a way to facilitate the
identification of patients potentially at risk of dying from sepsis.
• This score is a modified version of the Sequential (Sepsis-related) Organ
Failure Assessment score (SOFA) called the quickSOFA (qSOFA) score.
• A score ≥2 is associated with poor outcomes due to sepsis.
• The qSOFA score is easy to calculate since it only has three components,
each of which are readily identifiable at the bedside and are allocated
one point:
●Respiratory rate ≥22/minute
●Altered mentation
●Systolic blood pressure ≤100 mmHg

qSOFA
• The qSOFA score was originally validated in 2016 as most useful in
patients suspected as having sepsis outside of the (ICU) .
• It is validated in the emergency department (ED) and confirmed to be
less valuable in the ICU setting .
• Among 879 patients presenting to the ED with suspected infection, the
predictive validity of qSOFA for in hospital mortality was similar to that
of the full SOFA score (3 percent mortality for qSOFA and SOFA scores
less than 2 versus 24 and 18 percent mortality for qSOFA and SOFA
scores greater than or equal to 2, respectively).
• In addition, qSOFA was superior to the systemic inflammatory response
syndrome criteria (SIRS) .
• Further studies that demonstrate improved clinically meaningful
outcomes due to the use of qSOFA compared to clinical judgement are
warranted before it can be routinely used to predict in hospital mortality

qSOFA
• The SOFA score does not diagnose sepsis, identify those whose organ
dysfunction is truly due to infection, or determine individual treatment
strategies or individual outcome.
• The SOFA score helps identify patients, as a group, who potentially have
a high risk of death from infection.
• The quick SOFA (qSOFA) score is a tool to help identify patients with
early sepsis outside of the ICU.
• Patients are assigned one point each for the following clinical features
which can be easily measured at the bedside: RR ≥22/min, altered
mentation, and SBP ≤100 mmHg.
• Patients with two or more of these features were reported to have a
poor outcomes from sepsis.

qSOFA
• Sepsis – Sepsis is now defined as life-threatening organ
dysfunction caused by a dysregulated host response to
infection.
• As an organ dysfunction score, SOFA can be used to
identify those whose organ dysfunction is "life-
threatening" such that an increase in the SOFA score ≥2
is associated with a mortality of ≥10 percent.
• Septic shock – Patients with a SOFA score ≥2 who also
have a vasopressor requirement and an elevated
lactate >2 mmol/L (>18 mg/dL)despite adequate fluid
resuscitation have a predicted mortality of 40 percent.

qSOFA
• There are no clear guidelines to help the clinician identify
the presence of infection or to causally link an identified
organism with sepsis.
• The clinician is reliant upon clinical suspicion derived from
the signs and symptoms of infection as well as supporting
radiologic and microbiologic data and response to therapy.
• The term severe sepsis, which originally referred to sepsis
that was associated with tissue hypoperfusion (eg, elevated
lactate, oliguria) or organ dysfunction (eg, elevated
creatinine, coagulopathy) , is no longer used since the 2016
sepsis and septic shock definitions include patients with
evidence of tissue hypoperfusion and organ dysfunction.

qSOFA
• Septic shock — Septic shock is a type of vasodilatory or distributive
shock.
• Septic shock is defined as sepsis that has circulatory, cellular, and
metabolic abnormalities that are associated with a greater risk of
mortality than sepsis alone .
• Clinically, this includes patients who fulfill the criteria for sepsis
who, despite adequate fluid resuscitation, require vasopressors to
maintain a mean arterial pressure (MAP) ≥65 mmHg and have a
lactate >2 mmol/L (>18 mg/dL).
• Per predictions from the SOFA score, patients who fulfill these
criteria for septic shock have a higher mortality than those who do
not (≥40 versus ≥10 percent).

Multiple organ dysfunction syndrome
• (MODS) refers to progressive organ dysfunction in an acutely ill
patient, such that homeostasis cannot be maintained without
intervention.
• It is at the severe end of the severity of illness spectrum of both
infectious (sepsis, septic shock) and noninfectious conditions (eg,
SIRS from pancreatitis).
• MODS can be classified as primary or secondary:
●Primary MODS is the result of a well-defined insult in which
organ dysfunction occurs early and can be directly attributable to
the insult itself (eg, renal failure due to rhabdomyolysis).
●Secondary MODS is organ failure that is not in direct response to
the insult itself, but is a consequence of the host's response (eg,
acute respiratory distress syndrome in patients with pancreatitis).

Multiple organ dysfunction syndrome
• There are no universally accepted criteria for individual organ dysfunction
in MODS. However, progressive abnormalities of the following organ-
specific parameters are commonly used to diagnose MODS and are also
used in scoring systems (eg, SOFA ) to predict ICU mortality
• ●Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of
inspired oxygen (FiO2) ratio
• ●Hematology – Platelet count
• ●Liver – Serum bilirubin
• ●Renal – Serum creatinine (or urine output)
• ●Brain – Glasgow coma score
• ●Cardiovascular – Hypotension and vasopressor requirement
• In general, the greater the number of organ failures, the higher the
mortality, with the greatest risk being associated with respiratory failure
requiring mechanical ventilation.

RISK FACTORS
• The risk factors for septic shock were the fifth leading cause of
years of productive life lost due to premature mortality . Risk
factors for sepsis include the following :
• Intensive care unit admission – Approximately 50 percent of
intensive care unit (ICU) patients have a nosocomial infection .
• Bacteremia – Patients with bacteremia often develop systemic
consequences of infection. In a study of 270 blood cultures, 95
percent of positive blood cultures were associated with sepsis, or
septic shock .
• Advanced age (≥65 years) – is an independent predictor of
mortality due to sepsis.
• Immunosuppression – Comorbidities that depress host-defense
(eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism) and
immunosuppressant medications are common among patients with
sepsis, or septic shock.

RISK FACTORS
• Diabetes and cancer – Diabetes and some cancers may alter the
immune system, result in an elevated risk for developing sepsis, and
increase the risk of nosocomial sepsis.
• Community acquired pneumonia – Severe sepsis (as defined by the
old definition) and septic shock develop in approximately 48 and 5
percent, respectively, of patients hospitalized with community-
acquired pneumonia .
• Previous hospitalization – Hospitalization is thought to induce an
altered human microbiome, particularly in patients who are treated
with antibiotics. Previous hospitalization has been associated with a
three-fold increased risk of developing sepsis in the subsequent 90
days . Patients with hospitalizations for infection-related conditions,
especially Clostridium difficile infection, are at greatest risk.

RISK FACTORS
• Genetic factors – genetic factors can increase the
risk of infection.
• Genetic studies of susceptibility to infection have
initially focused on defects of antibody
production, or a lack of T cells, phagocytes,
natural killer cells, or complement. Recently,
genetic defects have been identified that impair
recognition of pathogens by the innate immune
system, increasing susceptibility to specific
classes of microorganisms .

CLINICAL PRESENTATION
• Symptoms and signs : are nonspecific but may include the following:
• ●Symptoms and signs specific to an infectious source (eg, SX of pneumonia, pain
and purulent exudate in a surgical wound may suggest an underlying abscess).
• ●Arterial hypotension (eg, [SBP] <90 mmHg, [MAP] <70 mmHg, an SBP decrease
>40 mmHg, or less than two standard deviations below normal for age).
• A sphygmomanometer may be unreliable in hypotensive patients, an arterial
catheter may be needed.
• ●Temperature >38.3 or <36ºC.
• ●Heart rate >90 beats/min or more than two SD above the normal value for age.
• ●Tachypnea, respiratory rate >20 breaths/minute.
• ●Signs of end-organ perfusion:
• •Warm, flushed skin may be present in the early phases of sepsis. As sepsis
progresses to shock, the skin may become cool due to redirection of blood flow
to core organs.
• Decreased capillary refill, cyanosis, or mottling may indicate shock.

• •Additional signs of hypoperfusion include altered mental status,
obtundation or restlessness, and oliguria or anuria.
• •Ileus or absent bowel sounds are often an end-stage sign of
hypoperfusion.
• These findings may be modified by preexisting disease or medications.
As examples, older patients, diabetic patients, and patients who take
beta-blockers may not exhibit an appropriate tachycardia as blood
pressure falls.
• Younger patients frequently develop a severe and prolonged tachycardia
and fail to become hypotensive until acute decompensation later occurs,
often suddenly.
• Patients with chronic hypertension may develop critical hypoperfusion at
a higher blood pressure than healthy patients (ie, relative hypotension).

Laboratory signs
• Nonspecific and may be associated with
abnormalities due to the underlying cause
• Leukocytosis or leukopenia
• Normal WBC with >10% immature forms.
• Hyperglycemia
• CRP> standard deviations above normal
• Hypoxemia PAO2/FIO2 <300
• Acute oliguria
• Cr increase >0.5 mg/dl
• Coagulation abn INR >1.5 OR APTT>60
• Thromboytopenia <100.000/microl

Laboratory signs
• ●Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or
70 micromol/L).
• ●Adrenal insufficiency (eg, hyponatremia, hyperkalemia),
and the euthyroid sick syndrome can also be found in
sepsis.
• ●Hyperlactatemia (An elevated serum lactate (eg,
>2 mmol/L) can be a manifestation of organ hypoperfusion
in the presence or absence of hypotension and is an
important component of the initial evaluation, since not
readily distinguish sepsis from nonseptic systemic
inflammation .
• elevated lactate is associated with poor prognosis .
• A serum lactate level ≥4 mmol/L is consistent with, but not
diagnostic of, septic shock.

Laboratory signs
• ●Plasma procalcitonin more than two standard deviations above
the normal value (not routinely performed in many centers) –
Elevated serum procalcitonin levels are associated with bacterial
infection and sepsis .
• Evidence for the prognostic value of procalcitonin is unclear and
its use in the identification of sepsis is excluded from many
guidelines.
• Combined changes in procalcitonin and lactate levels may be
highly predictive of outcome between 24 and 48 hours, and may
aid prognostication and the decision to reduce duration of
antimicrobial therapy.
• Seldom used in practice.

• Imaging — non specific except those associated with
infection in a specific site (eg, pneumonia on chest
radiography, fluid collection on computed tomography
of the abdomen).
• Microbiology — +ve culture is highly supportive of the
diagnosis of sepsis but is not necessary.
• A culprit organism is frequently not identified in up to
50 percent of patients who present with sepsis nor is a
positive culture required to make a decision regarding
treatment with empiric antibiotics.

DIAGNOSIS
• Its a constellation of clinical, laboratory, radiologic, physiologic, and
microbiologic data is typically required for the diagnosis of sepsis and
septic shock.
• The diagnosis is often made empirically at the bedside upon
presentation, or retrospectively when followup data returns (eg, positive
blood cultures in a patient with endocarditis) or a response to antibiotics
is evident.
• The identification of a culprit organism, although preferred, is not always
feasible since in many patients no organism is ever identified.
• In some patients this may be because they have been partially treated
with antibiotics before cultures are obtained.
• PACs are difficult to interpret and rarely placed in patients with
suspected sepsis.

Management of sepsis
• The early administration of fluids and antibiotics is the
cornerstone of management for patients with sepsis and
septic shock.
• Therapeutic priorities for patients with sepsis or septic
shock include:
●Early initiation of supportive care to correct physiologic
abnormalities, such as hypoxemia and hypotension .
●Distinguishing sepsis from systemic inflammatory
response syndrome (SIRS) because, if an infection exists, it
must be identified and treated as soon as possible .
• This may require appropriate antibiotics as well as a
surgical procedure (eg, drainage).

Management of sepsis
• EARLY MANAGEMENT — The first priority is stabilization of their airway
and breathing. Next, perfusion to the peripheral tissues should be
restored and antibiotics administered .
• Stabilize respiration — Supplemental oxygen should be supplied to all
patients with sepsis and oxygenation should be monitored continuously
with pulse oximetry.
• Intubation and mechanical ventilation may be required to support the
increased work of breathing that typically accompanies sepsis, or for
airway protection since encephalopathy and a depressed level of
consciousness frequently complicate sepsis .
• Chest radiographs and arterial blood gas analysis should be obtained
following initial stabilization. These studies are used in combination with
other clinical parameters to diagnose acute respiratory distress syndrome
(ARDS), which frequently complicates sepsis.

Assess perfusion
• Clinical signs of impaired perfusion include the following:
• ●Hypotension – Hypotension is the most common
indicator that perfusion is inadequate ( [SBP] <90 mmHg,
mean arterial pressure <70 mmHg, decrease in SBP >40
mmHg)., an arterial catheter may be inserted if blood
pressure is labile or restoration of arterial perfusion
pressures is expected to be a protracted process .
• Attempts to insert an arterial line should not delay the
prompt management of shock.
• ●Signs of poor end-organ perfusion
• ●Elevated lactate .

Restore perfusion
• Establish venous access — Venous access should be established as
soon as possible in patients with suspected sepsis.
• pulmonary artery catheters (PACs) should not be used in the
routine management of patients with severe sepsis or septic shock.
• PACs increase complications and have not been shown to improve
outcome .
• Interventions to restore perfusion — The rapid restoration of
perfusion is predominantly achieved by the administration of
intravenous fluids, usually crystalloids.
• Modalities such as vasopressor therapy, inotropic therapy, and
blood transfusion are added, depending on the response to fluid
resuscitation, evidence for MI, and presence of anemia.

Goals of initial resuscitation
• The goal of fluid resuscitation is early restoration of
perfusion to prevent or limit multiple organ
dysfunction, as well as to reduce mortality.
• The term "early goal-directed therapy" (EGDT) refers to
the administration of intravenous fluids within the first
six hours of presentationusing physiologic targets to
guide fluid management.
• EGDT has gained widespread acceptance in clinical
practice but the optimal targets are unknown.

• Early goal-directed therapy targets :
• Mean arterial pressure (MAP) ≥65 mmHg (MAP = [(2 x diastolic)
+ systolic]/3)
• Urine output ≥0.5 mL/kg/hour
• Static or dynamic predictors of fluid responsiveness, eg, CVP 8 to 12
mmHg or the radial artery pulse pressure (dynamic measurement).
• Central venous (superior vena cava) oxyhemoglobin saturation
(ScvO2) ≥70 percent (when central access is available) or mixed
venous oxyhemoglobin saturation (SvO2) ≥65 percent (if a
pulmonary artery catheter is being used).

• Lactate clearance should be followed as a target in
patients with sepsis to ensure a trend that
demonstrates adequate clearance with therapy.
• The lactate clearance is defined by the equation [(initial
lactate - lactate >2 hours later)/initial lactate] x 100.
• The lactate clearance and interval change in lactate
over the first 12 hours of resuscitation has been
evaluated as a potential marker for effective
resuscitation.

• ●Other – Dynamic indices have been studied as a
potential target to guide fluid management in sepsis.
• Respiratory changes in the vena caval diameter, radial
artery pulse pressure, aortic blood flow peak velocity, and
brachial artery blood flow velocity are considered
dynamic hemodynamic measures.
• Dynamic measures are more accurate predictors of fluid
responsiveness than static measures, as long as the
patients are in sinus rhythm and passively ventilated with
a sufficient tidal volume.

• For actively breathing patients or those with
irregular cardiac rhythms, an increase in the
cardiac output in response to a passive leg-
raising maneuver (measured by
echocardiography, arterial pulse waveform
analysis, or pulmonary artery catheterization) is
a sensitive and specific predictor of fluid
responsiveness .
• Large randomized studies will be needed its
routine recommendation.

Intravenous fluids
• Fluid therapy should be administered in well-defined (eg,
500 mL), rapidly infused boluses .
• Volume status, tissue perfusion, blood pressure, and the
presence or absence of pulmonary edema must be
assessed before and after each bolus.
• Intravenous fluid challenges can be repeated until blood
pressure and tissue perfusion are acceptable, pulmonary
edema ensues, or fluid fails to augment perfusion.
• Careful monitoring is essential because patients with sepsis
may develop noncardiogenic pulmonary edema ( [ARDS]).

Intravenous fluids
• Fluid overload is common in patients with sepsis and is
associated with the increased performance of medical
interventions (eg, diuresis, thoracentesis).
• The effect of fluid overload and such interventions on
mortality and functional recovery is unclear .
• while the early, aggressive fluid therapy is appropriate
in sepsis and septic shock, fluids may be unhelpful or
harmful when the circulation is no longer fluid-
responsive.

Intravenous fluids
• In patients with sepsis, intravascular hypovolemia is typical and
may be severe, requiring rapid fluid resuscitation.
• Volume — The optimal volume of resuscitative fluid is unknown.
• Several studies of early goal directed therapy reported
intravenous fluid infusions targeted to physiologic endpoints and
resulted in volumes ranging from 3 to 5 liters.
• Initial bolus : (20-30 ML/KG)
• Rapid, large volume infusions of intravenous fluids are indicated
as initial therapy for severe sepsis or septic shock, unless there is
coexisting clinical or radiographic evidence of heart failure.

Choice of fluid
• Evidence from randomized trials and meta-analyses have found no
convincing difference between using albumin solutions and
crystalloid solutions (eg, normal saline, Ringer’s lactate) in the
treatment of sepsis or septic shock, but they have identified
potential harm from using pentastarch or hydroxyethyl starch
rather than a crystalloid solution .
• Its recommended to use a crystalloid solution instead of albumin
solution because of the lack of clear benefit and higher cost of
albumin.
• Giving a sufficient quantity of intravenous fluids rapidly and
targeting appropriate goals is more important than the type of
fluid chosen.

Vasopressors
• Vasopressors are second line agents in the treatment of sepsis and
septic shock; we prefer intravenous fluids as long as they increase
perfusion without seriously impairing gas exchange .
• Intravenous vasopressors are useful in patients who remain
hypotensive despite adequate fluid resuscitation or who develop
cardiogenic pulmonary edema.
• In most patients with septic shock,Its prefer to
use norepinephrine
• phenylephrine (a pure alpha-adrenergic agonist) is useful when
tachycardia or arrhythmias preclude the use of agents with beta-
adrenergic activity (eg, norepinephrine).

Initial resuscitation
• There is conflicting evidence on the use of additional
therapies, such as inotropic therapy or red blood cell
transfusion.
• These are targeted at increasing the cardiac output to
improve tissue perfusion and thereby raise the central
venous (superior vena cava) oxyhemoglobin saturation
toward normal (ScvO2 ≥70 percent).
• Their use should be limited to those with refractory
shock in whom the ScvO2 remains <70 percent after
optimization of intravenous fluid and vasopressor
therapy.

• Inotropic therapy — A trial of inotropic therapy may be
warranted in patients who have refractory shock who also
have diminished cardiac output .
• Inotropic therapy should not be used to increase the
cardiac index to supranormal levels .
• Dobutamine is the usual inotropic agent . At low doses,
dobutamine may cause the blood pressure to decrease
because its peripheral effects can dilate the systemic
arteries.
• However, as the dose is increased, blood pressure usually
rises because cardiac output increases out of proportion to
the fall in peripheral vascular resistance.

• Red blood cell transfusions — red blood cell transfusion is
reserved for patients with a hemoglobin level ≤7 g /dl. Exceptions
include suspicion of concurrent hemorrhagic shock or active
myocardial ischemia.
• No differences in the outcomes and adverse effects between the
restrictive transfusion strategy (goal HB >7 g/dL) and the liberal
strategy (the HB ≤9 g/dL ).
• Data from randomized studies of EGDT that use RBC transfusion as
part of the protocol for treating patients with sepsis are conflicting.
While one trial initially reported a mortality benefit from EGDT that
included transfusing patients to a goal hematocrit >30 (hemoglobin
level 10 g/dL) , two similarly designed studies published since then
reported no benefit to this strategy .

CONTROL OF THE SEPTIC FOCUS
• Prompt identification and treatment of the primary site or sites of
infection are essential .
• This is the primary therapeutic intervention, with most other
interventions being purely supportive. Antibiotics should be
administered within the first six hours of presentation or earlier.
• Identification of the septic focus — A careful history and physical
examination may yield clues to the source of sepsis and help guide
microbiologic evaluation . As an example, sepsis arising after
trauma or surgery is often due to infection at the site of injury or
surgery.
• The presence of a urinary or vascular catheter increases the
chances that these are the source of sepsis.

CONTROL OF THE SEPTIC FOCUS
• Gram stain of material from sites of possible infection may give early clues to the
etiology of infection while cultures are incubating.
• Urine should be routinely analyzed via dipstick for leukocyte esterase, Gram
stained, and cultured; sputum should be examined in a patient with a productive
cough; and an intra-abdominal collection in a postoperative patient should be
percutaneously sampled under ultrasound or other radiologic guidance.
• Blood should be drawn from two distinct venipuncture sites and inoculated into
standard blood culture media (aerobic and anaerobic). For patients with a
vascular catheter, blood should be obtained both through the catheter and from
another site .
• If invasive candida or aspergillus infection is suspected, serologic assays for 1,3
beta-D-glucan, galactomannan, and anti-mannan antibodies, if available, may
provide early evidence of these fungal infections.

Antimicrobial regimen
• Intravenous antibiotic therapy should be
initiated within the first six hours or earlier (eg,
within one hour), after obtaining appropriate
cultures, since early initiation of antibiotic
therapy is associated with lower mortality .
• The choice of antibiotics can be complex and
should consider the patient's history (eg, recent
antibiotics received , comorbidities, clinical
context (eg, community- or hospital-acquired),
Gram stain data, and local resistance patterns .

• Poor outcomes are associated with inadequate or
inappropriate antimicrobial therapy (ie, treatment with
antibiotics to which the pathogen was later shown to be
resistant in vitro) .
• They are also associated with delays in initiating
antimicrobial therapy, even short delays (eg, an hour).
• When the potential pathogen or infection source is not
immediately obvious, broad-spectrum antibiotic coverage
directed against both gram-positive and gram-negative
bacteria (eg, Staphlococcus aureus, Klebsiella
pneumoniae, Streptocuccus pneumoniae).

• Staphylococcus aureus is associated with significant morbidity if
not treated early in the course of infection . There is growing
recognition that (MRSA) is a cause of sepsis not only in
hospitalized patients, but also in community dwelling individuals
without recent hospitalization.
• It is recommend that severely ill patients presenting with sepsis of
unclear etiology be treated with
intravenous vancomycin (adjusted for renal function) until the
possibility of MRSA sepsis has been excluded.
• Potential alternative agents to vancomycin (eg, daptomycin for
non-pulmonary MRSA, linezolid, ceftaroline) should be considered
for patients with refractory or virulent MRSA, or a
contraindication to vancomycin.

• If Pseudomonas is an unlikely pathogen: combining vancomycin with one of the
following:
• ●Cephalosporin, 3rd generation (eg, ceftriaxone or cefotaxime) or 4th generation
(cefepime ), or
• ●Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-
clavulanate), or
• ●Carbapenem (eg, imipenem or meropenem)
• If Pseudomonas is a possible pathogen :combining vancomycin with two of:
• ●Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or
• ●Antipseudomonal carbapenem (eg, imipenem, meropenem), or
• ●Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-
tazobactam, ticarcillin-clavulanate), or
• ●Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or
• ●Aminoglycoside (eg, gentamicin, amikacin), or
• ●Monobactam (eg, aztreonam)

• Selection of two agents from the same class, for example,
two beta-lactams, should be avoided.
• local susceptibility patterns.
• After culture results and antimicrobial susceptibility data
return:therapy be pathogen- and susceptibility-directed,
even if there has been clinical improvement while on the
initial antimicrobial regimen.
• In patients with gram negative pathogens, its recommend
use a single agent with proven efficacy and the least
possible toxicity, except in patients who are either
neutropenic or whose sepsis is due to a known or
suspected Pseudomonas infection .

• The duration of therapy is typically 7 to 10 days, although
longer courses may be appropriate in patients who have a
slow clinical response, an undrainable focus of infection, or
immunologic deficiencies .
• In patients who are neutropenic, antibiotic treatment
should continue until the neutropenia has resolved or the
planned antibiotic course is complete, whichever is longer.
• In non-neutropenic patients in whom infection is
thoroughly excluded, antibiotics should be discontinued to
minimize colonization or infection with drug-resistant
microorganisms and superinfection with other pathogens.

Anti-fungal regimens
• Invasive fungal infections occasionally complicate the course of
critical illness in non-neutropenic patients, especially when the
risk factors are present: surgery, parenteral nutrition, prolonged
antimicrobial treatment, septic shock or multisite colonization
with Candida spp.
• However, studies do not support the routine use of empiric
antifungals in this population.
• Several empirical anti-fungal treatments have been studied:
• Untargeted empiric antifungal therapy possibly reduced fungal
colonization and the risk of invasive fungal infection but did not
reduce all-cause mortality.
• The routine administration of empirical antifungal therapy is not
generally warranted in non-neutropenic critically-ill patients.

ADDITIONAL THERAPIES
• Glucocorticoids : most likely to be beneficial in patients who have severe
septic shock (defined as a systolic blood pressure <90 mmHg) that is
unresponsive to adequate fluid resuscitation and vasopressor
administration.
• Nutrition :
• Nutritional support improves nutritional outcomes in critically ill
patients, such as body weight and mid-arm muscle mass.
• However, it is uncertain whether nutritional support improves important
clinical outcomes (eg, duration of mechanical ventilation, length of stay,
mortality), or whether there is a validated role for specific supplements.
• Venous thromboembolism prophylaxis
• Intensive insulin therapy : The targeted blood glucose levels between
140 and 180 mg/dL (7.7 to 10 mmol/L).
• External cooling or antipyretics — Controlling fever during sepsis and
septic shock has potential benefits and adverse effects, the net effects of
which are uncertain.

Potential therapy
• A number of potential therapies for sepsis appear promising in animal
models, but have not yet been adequately studied in humans.
• These include toll-like receptor antagonists and neutralizing antibodies,
talactoferrin, interferon gamma, macrophage migration inhibition factor
neutralizing antibody, and a synthetic peptide that inhibits bacterial
superantigen-induced expression of certain proinflammatory genes.
• Other potential therapies for sepsis have been studied in humans, but
have provided conflicting results and require additional investigations to
clarify their effects.
• These include polyclonal intravenous (IVIG), hemoperfusion through
adsorptive materials or membranes, plasma exchange, whole blood
exchange, coupled plasma filtration adsorption, (GM-CSF), hemofiltration,
anticoagulants, naloxone, pentoxifylline, and statins.
• Potential therapies that require further validation of benefit in patients
with septic shock include therapy with the short-acting beta
blocker,esmolol.

In-hospital morbidity and mortality
• Sepsis has a high mortality rate. Rates depend upon how the data are
collected but estimates range from 10 to 52 percent
• Sepsis is responsible for 6 percent of all deaths but may be higher.
Mortality rates increase linearly according to the disease severity of sepsis
.
• In one study, the mortality rates of SIRS, sepsis, and septic shock were 7,
16, and 46 percent, respectively . In another study, the mortality
associated with sepsis was ≥10 percent while that associated with septic
shock was ≥40 percent .
• Mortality appears to be lower in younger patients (<44 years) without
comorbidities (<10 %)
• Several studies have reported decreasing mortality rates over time.
• Patients admitted with sepsis also developed more ICU-acquired
infections including infection with opportunistic pathogens, hinting at
possible immune suppression.

Long-term prognosis
• Following discharge from the hospital, sepsis carries an increased risk of death (up
to 20 percent) as well as an increased risk of further sepsis and recurrent hospital
admissions (up to 10 percent are readmitted).
• Most deaths occur within the first six months but the risk remains elevated at two
years . Patients who survive sepsis are more likely to be admitted to acute
care and/or long term care facilities in the first year after the initial hospitalization,
and also appear to have a persistent decrement in their quality of life .
• The most common diagnoses associated with readmission at 90 days are heart
failure, pneumonia, acute exacerbations of chronic obstructive pulmonary disease,
and urinary tract infections
• Higher rates of readmission with subsequent infection and sepsis may be
associated with previous hospitalization for an infection, particularly infection
with clostridium difficile
• Another database analysis reported that a previous diagnosis of sepsis was a
leading cause of readmissions when compared with myocardial infarction, chronic
obstructive pulmonary disease, heart failure, and pneumonia [.
• Sepsis survivors may also be at increased risk of major cardiovascular events and
stroke when compared with patients hospitalized with nonsepsis diagnosis

Prognostic factors
• Clinical characteristics that impact the severity of sepsis and, therefore, the
outcome include the host's response to infection, the site and type of infection,
and the timing and type of antimicrobial therapy.
• Host-related — Anomalies in the host's inflammatory response may indicate
increased susceptibility to severe disease and mortality. As examples, the failure to
develop a fever (or hypothermia) and the development of leukopenia,
thrombocytopenia, hyperchloremia, a patient's comorbidities, age, hyperglycemia,
and hypocoagulability have all been associated with poor outcomes .
• Failure to develop a fever (defined as a temperature below 35.5ºC) was more
common among non-survivors of sepsis than survivors (17 versus 5 percent)
.Leukopenia (WBC < 4000/mm3) was similarly more frequent among non-survivors
than survivors (15 versus 7 percent) in a Gram negative sepsis and a platelet
count<100,000/mm3 was found to be an early prognostic marker of 28-day
mortality patients with septic shock. In another retrospective analysis of critically
ill septic patients, hyperchloremia (Cl ≥110 mEq/L) at 72 hours after ICU admission
was independently associated with an increase in all-cause hospital mortality .

Prognostic factors
• A patient's comorbidities and functional health status are also important
determinants of outcome in sepsis .
• Risk factors for mortality include new-onset atrial fibrillation , an age
above 40 years , and comorbidities such as AIDS , liver disease , cancer ,
alcohol dependence , and/or immune suppression.
• Age is probably a risk factor for mortality because of its association with
comorbid illnesses, impaired immunologic responses, malnutrition,
increased exposure to potentially resistant pathogens in nursing homes,
and increased utilization of medical devices, such as indwelling catheters
and central venous lines .
• Admission hyperglycemia, was found in one prospective observational
study of 987 patients with sepsis to be associated with an increased risk of
death (hazard ratio 1.66) that was unrelated to the presence of diabetes .
• Inability to clot has also been associated with increased mortality. In one
prospective study of 260 patients with sepsis, indicators of
hypocoagulability using standard and functional levels of fibrinogen, were
associated with a six-fold increase in the risk of death.

Site of infection
• The site of infection in patients with sepsis may be an important
determinant of outcome, with sepsis from a urinary tract infection
generally being associated with the lowest mortality rates .
• One study found that mortality from sepsis was 50 to 55 percent
when the source of infection was unknown, gastrointestinal, or
pulmonary, compared with only 30 percent when the source of
infection was the urinary tract . Another retrospective, multicenter
cohort study of nearly 8000 patients with septic shock reported
similar results with the highest mortality in those with sepsis from
ischemic bowel (78 percent) and the lowest rates in those with
obstructive uropathy-associated urinary tract infection (26 percent)
.
• Approximately 50 percent of patients with sepsis are bacteremic at
the time of diagnosis according to one study.

Type of infection
• Sepsis due to nosocomial pathogens has a higher
mortality than sepsis due to community-acquired
pathogens.
• Increased mortality is associated with bloodstream
infections due to methicillin-resistant staphylococcus
aureus , non-candidal fungus , candida , methicillin-
sensitive staphylococcus aureus , and pseudomonas ,
as well as polymicrobial infections .
• When bloodstream infections become severe (eg,
septic shock), regardless of whether the pathogens are
Gram-negative or Gram-positive bacteria ,the outcome
is similar.

Prognostic factors
• Antimicrobial therapy — The early administration of appropriate
antibiotic therapy (ie, antibiotics to which the pathogen is sensitive)
has a beneficial impact on bacteremic sepsis .
• Adequate antibiotic therapy was associated with a 50 percent
reduction in the mortality rate compared to antibiotic therapy to
which the infecting organisms were resistant .
• Prior antibiotic therapy (ie, antibiotics within the past 90 days) may
be associated with increased mortality, at least among patients with
Gram negative sepsis .
• Restoration of perfusion — Failure to aggressively try to restore
perfusion early (ie, failure to initiate early goal-directed therapy)
may also be associated with mortality . A severely elevated lactate
(>4 mmol/L) is associated with a poor prognosis in patients with
sepsis with one study reporting a mortality of 78 percent in a
population of critically ill patients, a third of whom had sepsis.

• During hospital admission, sepsis may increase the risk of acquiring
a subsequent hospital-related infection. One prospective
observational study of 3329 admissions to the ICU reported that
ICU-acquired infections occurred in 13.5 percent admissions of
patients with sepsis compared with 15 percent of non-sepsis ICU
admissions [73]. In patients with a sepsis admission diagnosis,
secondary infections were mostly catheter-related blood stream
infections (26 percent), pneumonia (25 percent), or abdominal
infections (16 percent), compared with patients with non-sepsis
admission where pneumonia was the most common ICU-acquired
infection (48 percent). In both groups, patients who developed ICU-
acquired infection were more severely ill on admission (eg, higher
Acute Physiologic and Chronic Health Evaluation [APACHE] IV and
Sequential Organ Failure Assessment scores and more shock on
admission) and had higher mortality at day 60. However, the
contribution of developing a secondary infection was small.

•Timing and duration — The early administration of fluid appears to be more important than volume or type of
fluid in reducing mortality associated with sepsis. Based upon evidence from randomized studies and meta-
analyses, we favor the initiation of fluid resuscitation within sixhours of presentation. Once the targets of
resuscitation are met and perfusion is restored, fluids can be reduced or stopped, and occasionally patients can be
diuresed, when necessary. Resolution of sepsis and septic shock can take as little as a few hours or can be
protracted to days or weeks.
•A 2008 meta-analysis of randomized trials that initiated resuscitation targeting specific physiologic endpoints
reported that compared to standard care, only trials that initiated resuscitation within 24 hours of the onset of
sepsis showed a mortality benefit (39 versus 57 percent, odds ratio 0.50, 95% CI 0.37-0.69) [66]. In contrast,
analysis of randomized trials that initiated therapy more than 24 hours after the onset of sepsis found no
difference in mortality (64 versus 58 percent for standard resuscitation, odds ratio 1.16, 95% CI 0.60-2.22).
•There are two possible outcomes following the interventions described above:
•●Inadequate perfusion – Despite aggressive therapy, the patient may have persistent hypoperfusion and
progressive organ failure. This should prompt reassessment of the adequacy of the above therapies, antimicrobial
regimen, and control of the septic focus, as well as the accuracy of the diagnosis and the possibility that
unexpected complications or coexisting problems have intervened (eg, pneumothorax following CVC insertion).
•●Adequate perfusion – Patients who respond to therapy should have the rate of fluid administration reduced or
stopped, and vasopressor support weaned. Patients should also continue to have their clinical and laboratory
parameters followed closely. These include blood pressure, arterial lactate, urine output, creatinine, platelet
count, Glasgow coma scale score, serum bilirubin, liver enzymes, oxygenation (ie, arterial oxygen tension or
oxyhemoglobin saturation), and gut function (table 4). Reevaluation is indicated if any of these parameters worsen
or fail to improve.

•Protocol-directed therapy — Protocols targeted
at the use of a combination of physiologic
endpoints to guide fluid management in patients
with sepsis and septic shock are common practice
[17-19,49,50,61-63]. Typically, they combine the
EGDT targets (ScvO2, CVP, MAP (calculator 1) and
urine output, lactate) for fluid management with
early administration of antibiotics, both within
the first six hours of presentation.
•There is conflicting evidence regarding the value
of protocol-based therapy for sepsis

Sepsis 2017

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