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Critical Care Department

RECENT CONCEPTS OF SEPTIC

SHOCK IN INTENSIVE CARE UNIT

Essay

Submitted in Partial Fulfillment Master Degree M.SC. IN Critical care Medicine

BY

Mariam "Mohammed Salah Eldin" "Mohammed Alafify"Wahdan

M.B.B.Ch Benha Faculty of Medicine

Benha University

Under supervision of

Prof. Dr. Ehab Ahmed Abdel Rahman Hanafi

Professor of Anesthesia and Intensive Care Faculty of Medicine

Benha University

Dr.Ahmed Hamdy Abdel Rahman Ali

Lecturer of Anesthesia and Intensive care Faculty of Medicine

Benha University

Faculty of Medicine Benha University

2015

Acknowledgement

First of all, thanks to God who granted me the ability to finish

this work.

Words can never express my deepest gratitude and sincere

appreciation to Prof. Dr. Ehab Abdel Rahman Professor of

Anesthesia and Intensive care Dept., Benha University for his

continuous encouragement , powerful support , extreme patient and

faithful advice .

My deepest thanks and appreciation and sincere gratitude to

Dr. Ahmed Hamdy Lecturer of Anesthesia and Intensive care

Dept., Benha University , who spared no time and effort to provide

me with his valuable instructions and expert touches .

My truthful love to my family who were and will always be by

my side, all my life.

Mariam Mohammed Salah Wahdan

List of Contents

Items Page No.

List of Abbreviation I

List of Table V

Introduction 1

Aim of the work 5

Chapter (I):

Definitions and pathophysiology

6

Chapter (II)

Microbiology of sepsis

22

Chapter (III)

Diagnosis of sepsis and septic shock

30

Chapter (IV)

Management of severe sepsis and septic shock

50

Summary 77

References 83

Arabic Summary 1

List of Abbreviations

APPT

Activated Partial Thromboplastin Time

AKI

Acute Kidney Injury.

ALI

Acute Lung Injury.

ARDS

Acute Respiratory Distress Syndrome

ATP

Adenosine Tri Phosphate.

ACTH

AdrenoCorticotropic Hormone

ALB

Albumin

ALBIOS

Albumin Italian Outcome Sepsis Study .

ACCP

American College of Chest Physicians

ATS

American Thoracic Society

ARISE

Australasian Resuscitation In Sepsis Evaluation

ARISE

Australasian Resuscitation of Sepsis Evaluation .

BUN

Blood Urea Nitrogen.

CRP

C Reactive Protein .

CNS

Central Nervous System.

CVC

Central Venous Catheters.

ScVO2

Central Venous Oxyhemoglobin Saturation.

CVP

Central Venous Pressure.

CSF

Cerebrospinal fluid .

CAMRS

Community Acquired Methicillin Resistent Staphylococcus Aureus

COMRS

Community Onset Methicillin Resistent nStaphylococcus Aureus.

CAPs

Community-acquired pneumonias.

-I-

-II-

CT

Computed Tomography

CVVH

Continous venovenous hemofiltration

CORTIC

Corticosteroid Therapy of Septic Shock Study

DM

Diabetes Mellitus

DIC

Dissiminated Intravascular Coagulopathy.

EGDT

Early Goal Directed Therapy.

EEG

Electroencephalogram.

ERCP

Endoscopic Retrograde Cholangio Pancreatography

E.COLI:

Escherichia Coli.

ESICM

European Society of Intensive Care Medicine.

EVLW

Extravascular lung water

FEAST

Fluid Expansion as Supportive Therapy

GCS

Glasco Coma Score.

GNBs

Gram Negative Bacillis

GM

Granulocyte-macrophage colony stimulating factor

HAP

Hospital Acquired Pneumonia .

ICU

Intensive Care Unit.

IL6

Interleukin 6

IL8

Interleukin 8.

IV

Intra Venous

IVIG

Intravenous immunoglobulin

LPS

Lipopolysaccharides.

LFTs

Liver Function Tests.

LP

Lumber Puncture

-III-

MAP

Mean Arterial Pressure

MRSA

Methicillin Resistant Staphylococcus Aureus

MIF

Migration Inhibition factor

MODS

Multi organ Dysfunction Syndrone.

NO

Nitric Oxide.

NS

Normal Saline

NP

Nosocomial Pneumonia.

PAF

Platelet Activating Factor.

PMNLs :

Polymorphnuclear leukocytes.

PBFC

Polymyxin B fiber column

PARs

Protease Activated Receptors.

PT

Prothrombin Time

ProMISe

Protocolised Management In Sepsis.

ProCES

Protocolized Care for Early Septic Shock.

PCWP

Pulmonary Capillary Wedge Pressure.

PDH

Pyruvate dehydrogenase

RL

Ringer Lactate

SAFE

Saline vs Albumin Fluid Evaluation.

SOFA

Sequential Organ Failure Assesment

SCCM

Society of Critical Care Medicine

SCCM

Society of Critical Care Medicine.

SIS

Surgical Infection Society.

SIRS

Systemic inflammatory response syndrome.

TH2

T Helper Cell Type 2

-IV-

ACCCM

The American College of Critical Care Medicine.

TLR

Toll Like Receptors

TNF

Tumor Necrosing Factor.

USCOM

Ultrasonic Cardiac Output Monitor

UTI

Urinary tract infection

VRE

Vancomycin Resistent Enterococci.

VSE

Vancomycin Sensitive Enterococci.

VASST

Vasopressin in Septic Shock Trial

VAP

Ventillator Associated Pneumonia.

WBCs

White Blood Cells.

-V-

List of Tables

Table No. Title Page

Table (1) : Diagnostic criteria of sepsis. 34

Table (2) : Severe sepsis. 35

Table (3) : Sequential Organ Failure Assesment Score. 48-49

Table (4) : Clinical features that shoud alert the physician to

the diagnosis of severe sepsis.

52

Introduction

-1-

Introduction

Sepsis refers to the systesmic inflammtory response following

microbial infection, sepsis may be best defined as the systemic response

to infection with the presence of some degree of organ dysfunction.

(Vincet, et al., 2013)

Severe sepsis and septic shock is the leading cause of hospital

death. An enormous economic burden is attributed to severe sepsis and

the general consensus is that early identification and early appropriate

evidence-based medical care will impact this burden. (Hall, et al., 2011)

As the concept of the host theory emerged, it was first assumed

that the clinical features of sepsis were the result of inflammation ,later

on it was found that the initial inflammatory response give way to

compensatory anti inflammatory response syndrome. (Bone, et al., 2008)

Knowledge of pathogen recognition has increased in the past

decade. Pathogens activate immune cells through an interaction with

pattern-recognition receptors, of which four main classes: toll-like

receptors,C-type lectin receptors, retinoic acid inducible gene 1–like

receptors, and nucleotide-binding oligomerization domain–like receptors

— have been identified . (Takeuchi, et al ., 2010)

Severe sepsis is almost invariably associated with altered

coagulation, frequently leading to disseminated intravascular coagulation

(DIC) . (Levi, et al., 2010)

The immune system harbors humoral, cellular, and neural

mechanisms that attenuate the potentially harmful effects of the

proinflammatory response. (Opal, et al ., 2008)

Introduction

-2-

Although the mechanisms that underlie organ failure in sepsis have

been only partially elucidated, impaired tissue oxygenation plays a key

role . (Goldenberg, et al., 2011)

Physician need to have high index of suspicion for the presence of

sepsis ,clinical features that shoud alert the physician to diagnose severe

sepsis and septic shock include : heart rate >100/min ,systolic BP<90,

respiratory rate >20/min ,temperature >38.5 or <36 c ,confusion, oliguria,

chills, rigors, tachypnea. (Westphal, et al., 2011)

Acute lung injury (ALI)—mild Acute respiratory distress

syndrome (ARDS), by the Berlin Definition-leading to moderate or

severe ARDS is a major complication of severe sepsis and septic shock.

The incidence of ARDS is approximately 18% in patients with septic

shock, and mortality approaches 50%. (Ranieri, et al., 2012)

Sepsis is the most common cause of Acute kidney injury (AKI)

which affects 40-70% of all critically ill patients.(Hall, et al., 2011)

The Sequential Organ Failure Assesment (SOFA) score was

developed to quantify the severity of patient illness based on the degree

of organ dysfunction. The score is based on six different scores, one each

for the respiratory, cardiovascular, hepatic, coagulation, renal and

neurological systems (Vincent, et al., 1997)

Workup and investigative studies include laboratory tests and

imaging modalities to detect clinically suspected focal infection, they

include blood chemistries, coagulation studies, complete blood with

differential ,blood cultures , plain radiography , ultrasonograohy , CT and

MRI. (Dellinger, et al., 2013)

Introduction

-3-

The management of patients with sepsis centers on the

administration of antibiotics, IV fluids, and vasoactive agents, followed

by source control. However, it is likely that the early detection of sepsis

with the early administration of appropriate antibiotics is the single most

important factor in sepsis. (Barochia, et al., 2010)

Empirical IV antibiotic therapy should be started as soon as

possible and within the first hour of recognition of severe sepsis, after

appropriate cultures have been obtained. (Kumar, et al., 2006 )

Current teaching suggests that aggressive fluid resuscitation is the

best initial approach for the cardiovascular instability of sepsis.

(Hilton, et al., 2012 )

A low MAP is a reliable predictor for the development of organ

dysfunction. (Bellomo, et al., 2001)

In patients with sepsis, norepinephrine increases BP as well as

cardiac output and renal, splanchnic, cerebral, and microvascular blood

flow, while minimally increasing heart rate. (Silva, et al., 2012 )

A large number of hemodynamic, perfusion, oxygenation, and

echocardiographic targets have been proposed as resuscitation goals in

patients with severe sepsis and septic shock .(Dellinger, et al., 2012)

The 2012 Surviving Sepsis Campaign guidelines state that ―during

the first 6 hours of resuscitation, if Scvo2 is less than 70%, dobutamine

infusion or transfusion packed red blood cells to achieve a hematocrit of

greater than or equal to 30% in attempts to achieve the Scvo2 goal are

options. (Dellinger, et al., 2012 )

Introduction

-4-

The use of low dose corticosteroids in patients with severe sepsis

remains controversial. (Marik, et al., 2011)

It has been known for centuries that, unless the source of the

infection is controlled, the patient cannot be cured of his/her infective

process and death will eventually ensue. (Dellinger, et al., 2012 )

Although considered an important body of knowledge for

physician education and a reference source for optimal treatment,

guidelines do not have high impact on bedside healthcare practitioner

performance. Simply put, guidelines are not enough. In order to change

bedside behavior, protocols and performance improvement programs with

audit and feedback are needed. Early screening and hospital-based

performance improvement programs are now recommended by the

Campaign. ( Levi, et al., 2010)

.

-5-

Aim of the work

Aim Of The Work

The aim of this work is to discuss the causes and pathogenesis of

sepsis and septic shock for early detection and initiation of recent trends

of management and its impact on reducing morbidity and mortality.

-6-

Chapter (I) Definitions and Pathophysiology

Chapter (I)

Definitions and pathophysiology

Systemic inflammatory response syndrome (SIRS), sepsis, severe

sepsis, and septic shock were initially defined in 1991 by a consensus

panel convened by the American College of Chest Physicians (ACCP)

and Society of Critical Care Medicine (SCCM), then they were

reconsidered in 2001 during an International Sepsis Definitions

Conference that included representatives from the ACCP, SCCM,

American Thoracic Society (ATS), European Society of Intensive Care

Medicine (ESICM), and Surgical Infection Society (SIS).

(Levi, et al., 2003)

A practical modification of the definitions has since been

published, which provides exact hemodynamic definitions for septic

shock . (Annane, et al., 2005)

The definitions presented in a way that highlights the notion that

both SIRS and sepsis exist on a continuum of severity that ends with

multiple organ dysfunction syndrome (MODS).

SIRS is defined as 2 or more of the following variables:

Fever of more than 38°C (100.4°F) or less than 36°C (96.8°F) , Heart rate

of more than 90 beats per minute , Respiratory rate of more than 20

breaths per minute or arterial carbon dioxide tension (PaCO 2) of less than

32 mm Hg , Abnormal white blood cell count (>12,000/µL or < 4,000/µL

or >10%immature [band] forms) , Increased C reactive protein, Increased

cardiac output, low systemic vascular resistance, Increased oxygen

consumption, Increased procalcitonine concentration, Increased

interleukin 6 (IL6), IL8, Otherwise unexplained alternation in coagulation

-7-


parameter, alternation in mental status, hyperbilirubinemia , Increased

insulin requirement. (Fink, et al., 2004)

Infection is defined as "a microbial phenomenon characterized

by an inflammatory response to the microorganisms or the invasion of

normally sterile tissue by those organisms."

Bacteremia is the presence of viable bacteria within the

bloodstream, but this condition does not always lead to SIRS or sepsis.

(Bae, et al., 2012)

Sepsis is the systemic response to infection and is defined as the

presence of SIRS in addition to a documented or presumed infection.

Sepsis-induced hypotension is defined as the presence of a systolic

blood pressure of less than 90 mm Hg or a reduction of more than 40 mm

Hg from baseline in absence of any other cause of hypotension.

(Heffiner, et al., 2010)

Severe sepsis is defined as sepsis plus at least one of the following

signs of hypoperfusion or organ dysfunction:

Areas of mottled skin, Capillary refilling requires three seconds or longer,

Urine output <0.5 mL/kg for at least one hour, or renal replacement

therapy, Lactate >2 mmol/L, Abrupt change in mental status, Abnormal

electroencephalographic (EEG) findings, Platelet count <100,000

platelets/mL, Disseminated intravascular coagulation, Acute lung injury

or acute respiratory distress syndrome (ARDS), Cardiac dysfunction (i.e.,

left ventricular systolic dysfunction), as defined by echocardiography or

direct measurement of the cardiac index. (Fink, et al., 2003)

Septic shock Septic shock exists if there is severe sepsis plus one or

both of the following:

-8-


. Systemic mean blood pressure is <60 mmHg (or <80 mmHg if the

patient has baseline hypertension) despite adequate fluid resuscitation

(Adequate fluid resuscitation is defined as infusion of 20 to 30 mL/kg of

starch, infusion of 40 to 60 mL/kg of saline solution, or a measured

pulmonary capillary wedge pressure (PCWP), also known as (the

pulmonary artery occlusion pressure) of 12 to 20 mmHg. For patients

who have a central venous catheter rather than a pulmonary arterial

catheter, a central venous pressure (CVP) of 8 to 12 mmHg is a

reasonable substitute).

. Maintaining the systemic mean blood pressure >60 mmHg (or >80

mmHg if the patient has baseline hypertension) requires dopamine >5

mcg/kg per min, norepinephrine <0.25 mcg/kg per min, or epinephrine

<0.25 mcg/kg per min despite adequate fluid resuscitation.


Refractory septic shock Refractory septic shock exists if maintaining

the systemic mean blood pressure >60 mmHg (or >80 mmHg if the

patient has baseline hypertension) requires dopamine >15 mcg/kg per

min, norepinephrine >0.25 mcg/kg per min, or epinephrine >0.25 mcg/kg

per min despite adequate fluid resuscitation.

Multiple organ dysfunction syndromes multiple organ dysfunction

syndromes refer 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 SIRS and sepsis.

-9-


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 (e.g., 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 (e.g.,

acute respiratory distress syndrome in patients with pancreatitis).

(Martin, et al., 2006)

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 correlated with increased ICU mortality:

PO2/FiO2 ratio, Serum creatinine, Platelet count, Glasgow coma score,

Serum bilirubin, Pressure-adjusted heart rate (defined by heart rate

multiplied by the ratio of central venous pressure and mean arterial

pressure). ( Cook, et al., 2007)

Pathophysiology

Host response

As the concept of host theory emerged , it was first assumed that

the clinical features of sepsis were the result of inflammation , later on it

was found that the initial inflammatory response gave way to

compensatory anti inflammatory response syndrome. However, it has

become apparent that infection triggers a much more complex, variable,

and prolonged host response, in which both proinflammatory and

antiinflammatory mechanisms can contribute to clearance of infection

and tissue recovery on the one hand and organ injury and secondary

infections on the other (Van der poll , et al., 2010)


-10-

The specific response in any patient depends on the causative

pathogen (load and virulence) and the host (genetic characteristics and

coexisting illnesses), with differential responses at local, regional, and

systemic levels, The composition and direction of the host response

probably change over time in parallel with the clinical course. In general,

proinflammatory reactions (directed at eliminating invading pathogens)

are thought to be responsible for collateral tissue damage in severe sepsis,

whereas antiinflammatory responses (important for limiting local and

systemic tissue injury) are implicated in the enhanced susceptibility to

secondary infections. (Opal, et al., 2008)

Innate Immunity

Knowledge of pathogen recognition has increased tremendously in

the past decade. Pathogens activate immune cells through an interaction

with pattern-recognition receptors, of which four main classes : toll-like

receptors, C-type lectin receptors, retinoic acid inducible gene 1–like

receptors, and nucleotide-binding oligomerization domain–like receptors

— have been identified, with the last group partially acting in protein

complexes called inflammasommes. (Takeuchi, et al., 2010)

These receptors recognize structures that are conserved among

microbial species, so-called pathogen-associated molecular patterns,

resulting in the up-regulation of inflammatory gene transcription and

initiation of innate immunity. The same receptors also sense endogenous

molecules released from injured cells, so-called damage-associated

molecular patterns, or alarmins, such as high-mobility group protein B1,

S100 proteins, and extracellular RNA, DNA, and histones.

(Chan, et al., 2012)


-11-

Alarmins are also released during sterile injury such as trauma,

giving rise to the concept that the pathogenesis of multiple organ failure

in sepsis is not fundamentally different from that in noninfectious critical

illness. (Roth, et al., 2012)

Coagulation Abnormalities

Severe sepsis is almost invariably associated with altered

coagulation, frequently leading to disseminated intravascular coagulation,

Excess fibrin deposition is driven by coagulation through the action of

tissue factor, a transmembrane glycoprotein expressed by various cell

types; by impaired anticoagulant mechanisms, including the protein C

system and antithrombin; and by compromised fibrin removal owing to

depression of the fibrinolytic system (Van der poll, et al., 2010) .

Protease-activated receptors (PARs) form the molecular link

between coagulation and inflammation. Among the four subtypes that

have been identified, PAR1 in particular is implicated in sepsis.


PAR1 exerts cytoprotective effects when stimulated by activated

protein C or low-dose thrombin but exerts disruptive effects on

endothelial-cell barrier function when activated by high-dose

thrombin.The protective effect of activated protein C in animal models of

sepsis is dependent on its capacity to activate PAR1 and not on its

anticoagulant properties (Ruf, et al ., 2010)

Antiinflammatory mechanisms and Immunosuppression

The immune system harbors humoral, cellular, and neural

mechanisms that attenuate the potentially harmful effects of the

proinflammatory response (Opal, et al., 2010).


-12-

Phagocytes can switch to an antiinflammatory phenotype that

promotes tissue repair, and regulatory T cells and myeloid-derived

suppressor cells further reduce inflammation. In addition, neural

mechanisms can inhibit inflammation. (Andersson, et al ., 2012) .

In the so-called neuroinflammatory reflex, sensory input is relayed

through the afferent vagus nerve to the brain stem, from which the

efferent vagus nerve activates the splenic nerve in the celiac plexus,

resulting in norepinephrine release in the spleen and acetylcholine

secretion by a subset of CD4+ T cells.The acetylcholine release targets α7

cholinergic receptors on macrophages, suppressing the release of

proinflammatory cytokines. (Rosas, et al., 2011)

In animal models of sepsis, disruption of this neural-based system

by vagotomy increases susceptibility to endotoxin shock, whereas

stimulation of the efferent vagus nerve or α7 cholinergic receptors

attenuates systemic inflammation. (Tracey, et al., 2012)

Patients who survive early sepsis but remain dependent on

intensive care have evidence of immunosuppression, in part reflected by

reduced expression of HLA-DR on myeloid cells. (Boomer, et al ., 2011)

These patients frequently have ongoing infectious foci, despite

antimicrobial therapy, or reactivation of latent viral infection.

(Torgersen, et al., 2009)

Multiple studies have documented responsiveness in blood

leukocytes to pathogens in patients with sepsis.

(Van Der Poll, et al., 2008)

Findings that were recently corroborated by postmortem studies

revealing strong functional impairments of splenocytes obtained from

patients who had died of sepsis in the ICU. (Boomer, et al., 2011).


-13-

Besides the spleen, the lungs also showed evidence of

immunosuppression; both organs had enhanced expression of ligands for

T-cell inhibitory receptors on parenchymal cells. (Boomer, et al., 2011)

Enhanced apoptosis, especially of B cells, CD4+ T cells, and

follicular dendritic cells, has been implicated in sepsis-associated

immunosuppression and death (Hotchkiss, et al., 2005)

Epigenetic regulation of gene expression may also contribute to

sepsis-associated immunosuppression (Carson, et al., 2011)

Organ Dysfunction

Although the mechanisms that underlie organ failure in sepsis have

been only partially elucidated, impaired tissue oxygenation plays a key

role .Several factors:including hypotension, reduced red cell

deformability, and microvascular thrombosis contribute to diminished

oxygen delivery in septic shock. Inflammation can cause dysfunction of

the vascular endothelium, accompanied by cell death and loss of barrier

integrity, giving rise to subcutaneous and body cavity edema.

(Goldenberg, et al., 2011)

In addition, mitochondrial damage caused by oxidative stress and

other mechanisms impairs cellular oxygen use. (Galley, et al., 2011)

Moreover, injured mitochondria release alarmins into the

extracellular environment, including mitochondrial DNA and formyl

peptides, which can activate neutrophils and cause further tissue injury.

(Zhang, et al., 2010)

Systemic Effects of Sepsis

Widespread cellular injury may occur when the immune response

becomes generalized, cellular injury is the precursor to organ

dysfunction. The precise mechanism of cellular injury is not understood,


-14-

but its occurrence is indisputable as autopsy studies have shown

widespread endothelial and parenchymal cell injury. Mechanisms

proposed to explain the cellular injury include: tissue ischemia

(insufficient oxygen relative to oxygen need), cytopathic injury (direct

cell injury by proinflammatory mediators and/or other products of

inflammation), and an altered rate of apoptosis (programmed cell death).

(Brealey, et al., 2008)

Tissue ischemia

Significant derangement in metabolic autoregulation, the process

that matches oxygen availability to changing tissue oxygen needs, is

typical of sepsis.In addition, microcirculatory and endothelial lesions

frequently develop during sepsis. These lesions reduce the cross-sectional

area available for tissue oxygen exchange, disrupting tissue oxygenation

and causing tissue ischemia and cellular injury:

Microcirculatory lesions – The microcirculatory lesions may be the

result of imbalances in the coagulation and fibrinolytic systems,

both of which are activated during sepsis.

Endothelial lesions – The endothelial lesions may be a

consequence of interactions between endothelial cells and activated

polymorphonuclear leukocytes (PMNs). The increase in receptor-

mediated neutrophil-endothelial cell adherence induces the

secretion of reactive oxygen species, lytic enzymes, and vasoactive

substances (nitric oxide, endothelin, platelet-derived growth factor,

and platelet activating factor) into the extracellular milieu, which

may injure the endothelial cells.


-15-

Another factor contributing to tissue ischemia in sepsis is that

erythrocytes lose their normal ability to deform within the systemic

microcirculation. (Boudjeltia, et al., 2003)

Cytopathic injury

Proinflammatory mediators and/or other products of inflammation

may cause sepsis-induced mitochondrial dysfunction (e.g., impaired

mitochondrial electron transport) via a variety of mechanisms, including

direct inhibition of respiratory enzyme complexes, oxidative stress

damage, and mitochondrial DNA breakdown. Such mitochondrial injury

leads to cytotoxicity. There are several lines of evidence that support this

belief. (Harrois, et al., 2009)

The clinical relevance of mitochondrial dysfunction in septic shock

was suggested by a study of 28 critically ill septic patients who

underwent skeletal muscle biopsy within 24 hours of admission to the

ICU . Skeletal muscle ATP concentrations, a marker of mitochondrial

oxidative phosphorylation, were significantly lower in the 12 patients

who died of sepsis than in 16 survivors. In addition, there was an

association between nitric oxide overproduction, antioxidant depletion,

and severity of clinical outcome. Thus, cell injury and death in sepsis may

be explained by cytopathic (or histotoxic) anoxia, which is an inability to

utilize oxygen even when present. (Brand, et al., 2002)

Mitochondria can be repaired or regenerated by a process called

biogenesis. Mitochondrial biogenesis may prove to be an important

therapeutic target, potentially accelerating organ dysfunction and

recovery from sepsis. (Carraway, et al., 2007)


-16-

Apoptosis

Apoptosis (also called programmed cell death) describes a set of

regulated physiologic and morphologic cellular changes leading to cell

death. This is the principal mechanism by which dysfunctional cells are

normally eliminated and the dominant process by which inflammation is

terminated once an infection has subsided. (Gray, et al., 2003)

During sepsis, proinflammatory cytokines may delay apoptosis in

activated macrophages and neutrophils, thereby prolonging or

augmenting the inflammatory response and contributing to the

development of multiple organ failure. Sepsis also induces extensive

lymphocyte and dendritic cell apoptosis, which alters the immune

response efficacy and results in decreased clearance of invading

microorganisms. The extent of lymphocyte apoptosis correlates with and

the severity of the septic syndrome and the level of immunosuppression.

Apoptosis has been also observed in parenchymal cells, endothelial, and

epithelial cells. Several experiments studies show that inhibiting

apoptosis protect animal from organ dysfunction and lethality.

(Sharshar, et al., 2003)

Immunosuppression

Clinical observations and animal studies suggest that the excess

inflammation of sepsis may be followed by immunosuppression. Among

the evidence supporting this hypothesis, an observational study removed

the spleens and lungs from 40 patients who died with active severe sepsis

and then compared them with the spleens from 29 control patients and the

lungs from 30 control patients. The median duration of sepsis was four

days. The secretion of proinflammatory cytokines (i.e., tumor necrosis

factor, interferon gamma, interleukin-6, and interleukin-10) from the

splenocytes of patients with severe sepsis was generally less than 10


-17-

percent that of controls, following stimulation with either anti-CD3/anti-

CD28 or lipopolysaccharide. Moreover, the cells from the lungs and

spleens of patients with severe sepsis exhibited increased expression of

inhibitory receptors and ligands, as well as expansion of suppressor cell

populations, compared with cells from control patients. The inability to

secrete proinflammatory cytokines combined with enhanced expression

of inhibitory receptors and ligands suggests clinically relevant

immunosuppression. (Hasper, et al., 2008)

Organ-Specific Effects of Sepsis

The cellular injury accompanied by the release of proinflammatory

and anti-inflammatory mediators, often progresses to organ dysfunction.

No organ system is protected.

Circulation

Hypotension due to diffuse vasodilatation is the most severe expression

of circulatory dysfunction in sepsis. It is probably an unintended

consequence of the release of vasoactive mediators, whose purpose is to

improve metabolic auto regulation (the process that matches oxygen

availability to changing tissue oxygen needs) by inducing appropriate

vasodilatation. Mediators include the vasodilators prostacyclin and nitric

oxide (NO), which are produced by endothelial cells.

(Vincet, et al., 2008)

NO is believed to play a central role in the vasodilatation

accompanying septic shock, since NO synthase can be induced by

incubating vascular endothelium and smooth muscle with endotoxin .

When NO reaches the systemic circulation, it depresses metabolic auto

regulation at all of the central, regional, and microregional levels of the

circulation. (Gray, et al., 2003)


-18-

Another factor that may contribute to the persistence of

vasodilatation during sepsis is impaired compensatory secretion of

antidiuretic hormone (vasopressin). This hypothesis is supported by a

study that found that plasma vasopressin levels were lower in patients

with septic shock than in patients with cardiogenic shock (3.1 versus 22.7

pg/mL), even though the groups had similar systemic blood pressures. It

is also supported by numerous small studies that demonstrated that

vasopressin improves hemodynamics and allows other pressors to be

withdrawn. (Carsin, et al., 2008)

Vasodilatation is not the only cause of hypotension during sepsis,

Hypotension may also be due to redistribution of intravascular fluid. This

is a consequence of both increased endothelial permeability and reduced

arterial vascular tone leading to increased capillary pressure.

In addition to these diffuse effects of sepsis on the circulation, there are

also localized effects:

In the central circulation (i.e., heart and large vessels), decreased

systolic and diastolic ventricular performance due to the release of

myocardial depressant substances is an early manifestation of

sepsis. Despite this, ventricular function may still be able to use the

Frank Starling mechanism to increase cardiac output, which is

necessary to maintain the blood pressure in the presence of

systemic vasodilatation. Patients with preexisting cardiac disease

(e.g., elderly patients) are often unable to increase their cardiac

output appropriately. (Price, et al., 1999)

In the regional circulation (i.e., small vessels leading to and within

the organs), vascular hyporesponsiveness leads to an inability to

appropriately distribute systemic blood flow among organ systems.

As an example, sepsis interferes with the redistribution of blood


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flow from the splanchnic organs to the core organs (heart and

brain) when oxygen delivery is depressed. (Nevier, et al., 2008)

The microcirculation (i.e., capillaries) may be the most important

target in sepsis. Sepsis is associated with a decrease in the number

of functional capillaries, which causes an inability to extract

oxygen maximally. This may be due to extrinsic compression of

the capillaries by tissue edema, endothelial swelling, and/or

plugging of the capillary lumen by leukocytes or red blood cells

(which lose their normal deformability properties in sepsis).

(De Backer, et al., 2008)

At the level of the endothelium, sepsis induces phenotypic changes

to endothelial cells. This occurs through direct and indirect

interactions between the endothelial cells and components of the

bacterial wall. These phenotypic changes may cause endothelial

dysfunction, which is associated with coagulation abnormalities

reduced leukocytes, decreased red blood cell deformability,

upregulation of adhesion molecules, adherence of platelets and

leukocytes, and degradation of the glycocalyx structure.

(Donadello, et al., 2009)

Microparticles from circulating and vascular cells also participate

in the deleterious effects of sepsis-induced intravascular

inflammation (Favory, et al., 2009)

Lung

Endothelial injury in the pulmonary vasculature during sepsis

disturbs capillary blood flow and enhances microvascular permeability,

resulting in interstitial and alveolar pulmonary edema. Neutrophil

entrapment within the lung's microcirculation initiates and/or amplifies

the injury in the alveolocapillary membrane. The result is pulmonary


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edema, which creates ventilation-perfusion mismatch and leads to

hypoxemia . Acute respiratory distress syndrome is a manifestation of

these effects. (Ghosh, et al., 2003)

Gastrointestinal tract

The circulatory abnormalities typical of sepsis may depress the

gut's normal barrier function, allowing translocation of bacteria and

endotoxin into the systemic circulation (possibly via lymphatics, rather

than the portal vein) and extending the septic response.

(Arid, et al., 2003)

Liver

The reticuloendothelial system of the liver normally acts as the first

line of defense in clearing bacteria and bacteria-derived products that

have entered the portal system from the gut. Liver dysfunction can

prevent the elimination of enteric-derived endotoxin and bacteria-derived

products . (Luce, et al., 2008)

Kidney

Sepsis is often accompanied by acute renal failure. The

mechanisms by which sepsis and endotoxemia lead to acute renal failure

are incompletely understood. Acute tubular necrosis due to hypoperfusion

and/or hypoxemia is one mechanism. However, systemic hypotension,

direct renal vasoconstriction, release of cytokines (e.g., tumor necrosis

factor), and activation of neutrophils by endotoxin may also contribute to

renal injury. (Auch, et al., 2003)

The likelihood of death is increased in patients with sepsis who

develop renal failure. It is not well understood why this occurs. One

factor may be the release of proinflammatory mediators as a result of

leukocyte-dialysis membrane interactions when hemodialysis is


-21-

necessary. Use of biocompatible membranes can prevent these

interactions and may improve survival and the recovery of renal function.

(Hakim, et al., 2007)

Nervous system

Central nervous system (CNS) complications occur frequently in

septic patients, often before the failure of other organs. The most

common CNS complications are an altered sensorium (encephalopathy).

The pathogenesis of the encephalopathy is poorly defind.

(Hecht, et al., 2007)

CNS dysfunction has been attributed to changes in metabolism and

alterations in cell signaling due to inflammatory mediators. Dysfunction

of the blood brain barrier probably contributes, allowing increased

leukocyte infiltration, exposure to toxic mediators, and active transport of

cytokines across the barrier . (Fleshner, et al., 1998)

-22-

Chapter (II) Microbiology of sepsis

Chapter (II)

Microbiology of sepsis

Until the beginning of the 20th century, reports describing

infections other than those due to Salmonella enterica serovar Typhi

(typhoid fever) and Yersinia pestis(plague) were rare. Sepsis and septic

shock, caused by gram-negative and gram-positive bacteria, fungi,

viruses, and parasites, have become increasingly important over the past

decades (Glauser, et al., 1991)

In the United States, the septicemia rates more than doubled

between 1979 and 1987 causing up to 250,000 deaths annually . In three

distinct studies, the proportion of infections due to gram-negative bacteria

varied between 30 and 80% and that of infections due to gram-positive

bacteria varied between 6 and 24% of the total number of cases of sepsis,

with the remainder being accounted for by other pathogenic organisms

(Opal, et al., 1999)

However, the contribution of gram-positive bacteria to sepsis has

increased, and in the early 1990s it accounted for more than 50% of all

cases of septicemia ,with Staphylococcus aureus and S. epidermidis being

responsible for more than half of the cases of sepsis due to gram-positive

bacteria (Bates, et al., 1995)

The increasing septicemia rates are probably caused by the

increasing use of catheters and other invasive equipment, by

chemotherapy, and by immunosuppression in patients with organ

transplants or inflammatory diseases. Furthermore, improvements in

medical care have resulted in longer life spans for the elderly and patients

with metabolic, neoplastic, or immunodeficiency disorders. These groups

remain at increased risk for infection (Bone, et al., 1994)

-23-


Due to differences in interpretation of the clinical condition ―septic

shock,‖ reported mortality rates in patients with septic shock vary from

20 to 80% . The mortality is related to both the severity of sepsis and the

underlying disease that is nearly always present. In many cases of sepsis,

the presence of microorganisms (bacteremia) or Lipopolysaccharide

(Lps) in the blood (endotoxemia) cannot be established.

(Bone, et al., 1994)

There are marked differences in the responses to gram-positive and

gram-negative bacteria. Where as gram-negative bacteria all contain LPS

as their major pathogenic determinant, gram-positive bacteria contain a

number of immunogenic cell wall components besides the highly

deleterious exotoxins.The immunological response to gram-negative

bacteria mainly involves leukocytes and the production of cytokines such

as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6.

The release of exotoxins, many of which are superantigens, by gram-

positive bacteria activates T cells, resulting in a different cellular

response and different cytokine profile, with relatively low levels of TNF-

α, IL-1, and IL-6 and increased levels of IL-8 (Opal, et al.,1999)

Bacterial infections are the commonest aetiological agents of both

community-acquired and hospital related sepsis, but a causative organism

is confirmed in only 60% cases. Disease progression is similar regardless

of organism. However, there has been a rise in multiply resistant bacteria

such as Acinobacter species, Enterococci and methicillin resistant

Staphylococcus aureus (MRSA) .The microbiology and primary sources

of infection have undergone a remarkable transition over the past 30

years. The predominant pathogen responsible for sepsis in the 1960s and

1970s were Gram-negative bacilli; however, over the past few decades

there has been a progressive increase in the incidence of sepsis caused by

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Gram-positive and opportunistic fungal pathogens. Although the

abdomen was the major source of infection in sepsis from 1970 to 1990,

in the past decade pulmonary infections have emerged as the most

frequent site of infection (Eaton, et al., 2003)

The most common organisms identified in community acquired

Infection requiring intensive care hospitalization are S. pneumoniae,

Legionella, and Haemophilus influenzae, with S. aureus, Early-onset

nosocomial Infection (< 4–7 days) in patients who have not received prior

antibiotic therapy is typically caused by Enterobacteriaceae, Haemophilus

species, S. aureus, and pneumococci E coli. Patients who develop late-

onset Infection (> 4–7 days) and who have received prior antibiotic

therapy are at risk for infection with P. aeruginosa,MRSA,

Enterobacteriaceae, including Citrobacter, Klebsiella, Enterobacter,

Serratia, Proteus, Morganella, and Providencia spp. Approximately 20–

40% of nosocomial Infection are polymicrobial in etiology.

(Dillinger, et al., 2008)

Infection has been and remains a leading cause of death in patients

with leukemia and lymphoma and a major cause of morbidity and

mortality in patients with solid tumors or transplants .Rapid progression

of fungal, bacterial, and mycobacterial infections occurs in patients given

monoclonal antibodies to treat Crohn's disease and autoimmune diseases

such as rheumatoid arthritis. (Robin, et al., 2005)

Although a great variety of microorganisms have been noted to

cause severe, life-threatening infections in immunocompromised hosts,

the clinician can formulate a diagnostic plan and decide on empiric

therapy by giving careful consideration to the nature, duration, and

severity of the immunosuppression that is causing the patient's

predisposition to infection. Additionally, immunocompromised patients

-25-


and Elderly patients, uremic patients, and patients with end-stage liver

disease or those receiving corticosteroids often will fail to mount a

significant febrile response even to serious infection.

(Darmon, et al., 2005)

Overwhelming pneumococcal sepsis occurs in patients with

asplenia or diminished splenic function. Such patients usually present

with overwhelming pneumococcal sepsis rather than pneumococcal

pneumonia even if the initial site of infection is the lungs or upper

respiratory tract. Patients who have overwhelming pneumococcal sepsis,

unlike those who have other pneumonias, present with a diffuse petechial

or ecchymotic rash and shock. (Cunha, et al., 2006)

Polymicrobial diseases, caused by combinations of viruses,

bacteria, fungi, and parasites, are being recognized with increasing

frequency. In these infections, the presence of one micro-organism

generates a niche for other pathogenic micro-organisms to colonize; one

micro-organism predisposes the host to colonization by other

microorganisms, or two or more non-pathogenic micro-organisms

together cause disease. The medical community is recognizing the

significance of Polymicrobial diseases and the major types of microbial

community interactions associated with human health and disease. Many

traditional therapies are just starting to take into account the

polymicrobial cause of diseases and the repercussions of treatment and

prevention .Polymicrobial episodes were significantly more likely to be

hospital-acquired, to emanate from bowel or multiple foci, and to occur in

immunocompromised patients, especially those with terminal

malignancies, nonhematologic malignancies or multiple underlying

diseases (Bakaletz, et al., 2004)

-26-


Deaths directly related to sepsis were two fold higher in

polymicrobial versus unimicrobial bacteremia. Factors associated with

increased mortality in polymicrobial sepsis included age greater than 40

years, absent or diminished febrile response to sepsis, absolute

granulocytopenia, inadequate antimicrobial therapy for all

microorganisms isolated and a primary focus of infection in the bowel,

the respiratory tract, an abscess, or an occult site . (Brogden, et al., 2002)

Enterobacteriaceae, non group A streptococci, anaerobic bacteria,

and pseudomonads were disproportionately common in polymicrobial

bacteremia. The occurrence and type of polymicrobial bacteremia can

suggest a source of sepsis as well as additional diagnostic and therapeutic

maneuvers .Polymicrobial sepsis is associated with immunosuppression

caused by the predominance of anti-inflammatory mediators and

profound loss of lymphocytes through apoptosis. (Lipsky, et al., 2004)

Common sources of sepsis

Gastrointestinal tract

Very important source of sepsis is the distal gastrointestinal tract.

The colon contains more bacteria than any other organ. The fecal flora is

predominantly 75% Bacteroides fragilis. Most of the remaining anaerobic

fecal flora are common coliforms 20% and less common aerobic gram

negative bacilli(GNBs), excluding Pseudomonas aeruginosa. The

remaining portion of fecal flora 5% is comprised of group D enterococci.

Of this, about 95% are E faecalis and about 5% are Enterococcus

faecium, which are virtually all vancomycin resistant (VRE). Because

group D enterococci are „„permissive‟‟ pathogens in the gastrointestinal

tract (excluding the biliary tract), specific anti vancomycin sensitive

enterococcus (VSE) coverage is unnecessary in intra-abdominal

infections. The predominant organism in the colonic flora is B fragilis.

-27-


Making up the other component of the fecal flora are aerobic GNBs,

which are the organisms that cause bacteremia and peritonitis.

(Cruz, et al., 2002)

B fragilis is the predominant pathogen in lower intra-abdominal

and pelvic abscesses. When the integrity of the colon is breached and

high numbers of GNBs are released into the peritoneum or bloodstream

by infection (e.g., diverticulitis) or trauma (e.g., surgery or colitis), sepsis

is predictably frequent .Biliary tract sepsis is usually due to Escherichia

coli, Klebsiella pneumoniae, or VSE. Optimal empiric monotherapy is

with meropenem, piperacillin- tazobactam, levofloxacin, or tigecycline

(Marshall , et al., 2002)

Central venous catheters

For CVC sepsis infection mainly caused by Staphylococcus

aureus. If methicillin-sensitive Staph aureus (MSSA) strains predominate

in an institution, anti–methicillin-resistant S aureus (anti-MRSA) is not

necessary after catheter removal .CVC breaches the normal skin barrier to

infection and bacteria may be directly introduced into the bloodstream

and if present in sufficient numbers will result in clinical sepsis.

(Gill, et al., 1999)

Genitourinary tract

Urosepsis is sepsis originating from the urinary tract, where the

organism cultured from the urine is the same as the organism cultured

from the blood. The urinary tract, like other organ systems, is designed to

prevent infection .Urosepsis occurs only in the setting of pre-existing

renal disease, abnormal urinary tract anatomy, foreign bodies (stents),

renal or bladder stones, or genitourinary instrumentation with infected

urine. Uropathogens causing urosepsis originate from the gastrointestinal

-28-


tract and expectedly are aerobic GNBs or group D enterococci, usually

Enteroccoccus faecalis (i.e., vancomycin- sensitive enterococci [VSE]

(Cunha, et al., 2007)

Pulmonary

Pneumonias may be classified in many ways by causative organism

or by site of acquisition (ie, community-acquired pneumonias [CAPs] or

nosocomial pneumonia [NP]. A subset of hospital-acquired pneumonia

(HAP) or NP is ventilator-associated pneumonia (VAP) . From the

infectious disease perspective, NP, HAP, and VAP are caused by the

same pathogens. Occasionally, patients with HAP, NP, or VAP may be

complicated by septic shock. There are three NP, HAP, and VAP

pathogens that have the potential to cause sepsis and septic shock. These

are Klebsiella pneumoniae, Staph aureus, and Pseudomonas aeruginosa.

CAPs are not associated with sepsis or septic shock except in three

circumstances. Firstly, K pneumoniae is seen virtually only in chronic

alcoholics. (Cunha, et al., 2007)

K pneumoniae CAP is similar to K pneumoniae NP in terms of its

clinical characteristics and radiograph appearance. Nosocomial K

pneumoniae is more likely to present with sepsis and shock than its

community-acquired counterpart. P aeruginosa is not a cause of CAP

except in patients with cystic fibrosis or chronic bronchiectasis and even

in these patients does not present with sepsis or septic shock. Patients

who have febrile neutropenia who are predisposed to Pseudomonas

bacteremia do not present with Pseudomonas pneumonia with sepsis or

septic shock.CAP due to MSSA or MRSA, either community-onset

MRSA (COMRSA) or community-acquired MRSA (CA-MRSA), may

present with sepsis and shock in patients with viral influenza or an

influenza like illness. (Routsi, et al., 2007)

-29-


Most staphylococcal pneumonias seen in the hospital are

community acquired and superimposed upon viral influenza. In the

absence of influenza, S aureus is rarely, if ever, a CAP pathogen. Viral

influenza with associated tracheo-bronchial damage predispose to

necrotizing hemorrhagic MSSA and MRSA CAP. Viral influenza alone is

associated with a high mortality and morbidity even in young healthy

adults. Certainly patients with viral influenza and superimposed MSSA or

MRSA pneumonia are critically ill. However, it is difficult to factor out

the relative contributions of the bacterial versus the viral component in

terms of its virulence potential which, if not synergistic, is certainly

additive. (Lipsky, et al., 2007)

Chapter (III) Diagnosis of sepsis and septic shock

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Chapter (III)

Diagnosis of sepsis and septic shock

Sepsis is one of the oldest and most elusive syndromes in

medicine. Hippocrates claimed that sepsis was the process by which flesh

rots, swamps generate foul airs, and wounds fester.

(Majino, et al., 1991)

With the confirmation of germ theory by Semmelweis, Pasteur,

and others, sepsis was recast as a systemic infection, often described as

―blood poisoning,‖ and assumed to be the result of the host's invasion by

pathogenic organisms that then spread in the bloodstream. However, with

the advent of modern antibiotics, germ theory did not fully explain the

pathogenesis of sepsis: many patients with sepsis died despite successful

eradication of the inciting pathogen.Thus, researchers suggested that it

was the host, not the germ, that drove the pathogenesis of sepsis.

(Cerra, et al., 1985)

In 1992, an international consensus panel defined sepsis as a

systemic inflammatory response to infection, noting that sepsis could

arise in response to multiple infectious causes and that septicemia was

neither a necessary condition nor a helpful term. Instead, the panel

proposed the term ―severe sepsis‖ to describe instances in which sepsis is

complicated by acute organ dysfunction, and they codified ―septic shock‖

as sepsis complicated by either hypotension that is refractory to fluid

resuscitation or by hyperlactatemia . (Bone, et al., 1992)


-31-

In 2003, a second consensus panel endorsed most of these

concepts, with the caveat that signs of a systemic inflammatory response,

such as tachycardia or an elevated white-cell count, occur in many

infectious and noninfectious conditions and therefore are not helpful in

distinguishing sepsis from other conditions. Thus, ―severe sepsis‖ and

―sepsis‖ are sometimes used interchangeably to describe the syndrome of

infection complicated by acute organ dysfunction (Fink, et al., 2003)

Incidence and Causes

The incidence of severe sepsis depends on how acute organ

dysfunction is defined and on whether that dysfunction is attributed to an

underlying infection. Organ dysfunction is often defined by the provision

of supportive therapy (e.g., mechanical ventilation), and epidemiologic

studies thus count the ―treated incidence‖ rather than the actual incidence.

In the United States, severe sepsis is recorded in 2% of patients admitted

to the hospital. Of these patients, half are treated in the intensive care unit

(ICU), representing 10% of all ICU admissions. (Lidicker , et al., 2001)

The number of cases in the United States exceeds 750,000 per

year and was recently reported to be rising. (Lago, et al.,2012)

The true incidence is presumably far higher. Severe sepsis occurs

as a result of both community-acquired and health care–associated

infections. Pneumonia is the most common cause, accounting for about

half of all cases, followed by intraabdominal and urinary tract

infections. (Barie, et al., 2012)

Blood cultures are typically positive in only one third of cases, and

in up to a third of cases, cultures from all sites are negative.

Staphylococcus aureus and Streptococcus pneumoniae are the most

common gram-positive isolates, whereas Escherichia coli, klebsiella


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species, and Pseudomonas aeruginosa predominate among gram-negative

isolates. An epidemiologic study of sepsis showed that during the period

from 1979 to 2000, gram-positive infections overtook gram-negative

infections. (Thompson, et al., 2012)

However, in another study involving 14,000 ICU patients in 75

countries, gram-negative bacteria were isolated in 62% of patients with

severe sepsis who had positive cultures, gram-positive bacteria in 47%,

and fungi in 19%. (Marshall, et al., 2009)

Risk factors

Risk factors for severe sepsis are related both to a patient's

predisposition for infection and to the likelihood of acute organ

dysfunction if infection develops. There are many well-known risk

factors for the infections that most commonly precipitate severe sepsis

and septic shock, including chronic diseases (e.g., the acquired

immunodeficiency syndrome, chronic obstructive pulmonary disease, and

many cancers) and the use of immunosuppressive agents.

(Pinsky, et al., 2001)

Among patients with such infections, however, the risk factors for

organ dysfunction are less well studied but probably include the causative

organism and the patient's genetic composition, underlying health status,

and preexisting organ function, along with the timeliness of therapeutic

intervention. Age, sex, and race or ethnic group all influence the

incidence of severe sepsis, which is higher in infants and elderly persons

than in other age groups, higher in males than in females, and higher in

blacks than in whites. (Mayr, et al., 2010)

There is considerable interest in the contribution of host genetic

characteristics to the incidence and outcome of sepsis, in part because of

strong evidence of inherited risk factors. Many studies have focused on


-33-

polymorphisms in genes encoding proteins implicated in the pathogenesis

of sepsis, including cytokines and other mediators involved in innate

immunity, coagulation, and fibrinolysis. However, findings are often

inconsistent, owing at least in part to the heterogeneity of the patient

populations studies. (Namath, et al., 2011)

Although a recent genomewide association study explored drug

responsiveness in sepsis, no such large-scale studies of susceptibility to or

outcome of sepsis have been performed (Man, et al., 2012)

Clinical Features

The clinical manifestations of sepsis are highly variable, depending

on the initial site of infection, the causative organism, the pattern of acute

organ dysfunction, the underlying health status of the patient, and the

interval before initiation of treatment.The signs of both infection and

organ dysfunction may be subtle, and thus the most recent international

consensus guidelines provide a long list of warning signs of incipient

sepsis. (Levi, et al., 2003)


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Table (1): Diagnostic criteria for sepsis:

Infection, documented, or suspected, and some of the following:

General variables

Fever, >38.3 °C

Hypothermia (core temperature <36 °C)

Heart rate >90/min−1

or more than two SD above the normal value for age

Tachypnea

Altered mental status

Significant edema or positive fluid balance (>20 mL/kg over 24 h)

Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of

diabetes

Inflammatory variables

Leukocytosis (WBC >12 000 μL−1

)

Leukopenia (WBC count <4000 μL−1

)

Normal WBC count with greater than 10% immature forms

Plasma C-reactive protein more than two SD above the normal value

Plasma procalcitonin more than 2 SD above the normal value

Hemodynamic variables

Arterial hypotension (SBP <90 mmHg, MAP <70 mmHG, or an SBP decrease

>40 mmHg in adults or less than 2 SD below normal for age )

Organ dysfunction variables

Arterial hypoxemia (PaO2/FiO2 <300)

Acute oliguria (urine output <0.5 mL/kg/h for at least 2 h despite adequate fluid

resuscitation)

Creatinine increase >0.5 mg/dL or 44.2 μmol/L

Coagulation abnormalities (INR >1.5 or aPTT >60 s)

Ileus (absent bowel sound)

Thrombocytopenia (platelet count <100 000 μL−1

)

Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 μmol/L)

Tissue perfusion variables

Hyperlactatemia (>1 mmol/L)

Decreased capillary refill or mottling

(Sunderram, et al., 2007)


-35-

Table (2): Severe sepsis:

Severe sepsis definition = sepsis-induced tissue hypoperfusion or organ

dysfunction (any of the following thought to be due to the infection)

Sepsis-induced hypotension

Lactate above upper limits laboratory normal

Urine output <0.5 mL/kg/h for more than 2 h despite adequate fluid

resuscitation

Acute lung injury with PaO2/FiO2 <250 in the absence of pneumonia as

infection source

Acute lung injury with PaO2/FiO2 <200 in the presence of pneumonia as

infection source

Creatinine >2.0 mg/dL (176.8 μmol/L)

Bilirubin >2 mg/dL (34.2 μmol/L)

Platelet count <100 000 μL

Coagulopathy (international normalized ratio >1.5)


Acute organ dysfunction most commonly affects the respiratory

and cardiovascular systems. Respiratory compromise is classically

manifested as the acute respiratory distress syndrome (ARDS), which is

defined as hypoxemia with bilateral infiltrates of noncardiac origin .

(Rubenfeld, et al., 2012)

Cardiovascular compromise is manifested primarily as

hypotension or an elevated serum lactate level. After adequate volume

expansion, hypotension frequently persists, requiring the use of

vasopressors, and myocardial dysfunction may occur.

(Dellinger, et al., 2013)


-36-

The brain and kidneys are also often affected. Central nervous

system dysfunction is typically manifested as obtundation or delirium.

Imaging studies generally show no focal lesions, and findings on

electroencephalography are usually consistent with nonfocal

encephalopathy. Critical illness polyneuropathy and myopathy are also

common, especially in patients with a prolonged ICU stay.

(Sharshar, et al., 2002)

Acute kidney injury is manifested as decreasing urine output and

an increasing serum creatinine level and frequently requires treatment

with renal-replacement therapy. Paralytic ileus, elevated aminotransferase

levels, altered glycemic control, thrombocytopenia and disseminated

intravascular coagulation, adrenal dysfunction, and the euthyroid sick

syndrome are all common in patients with severe sepsis.

(Fink, et al ., 2003)

Outcome

Before the introduction of modern intensive care with the ability to

provide vital organ support, severe sepsis and septic shock were typically

lethal. Even with intensive care, rates of in-hospital death from septic

shock were often in excess of 80% as recently as 30 years ago.

(Silva, et al., 1998)

However, with advances in training, better surveillance and

monitoring, and prompt initiation of therapy to treat the underlying

infection and support failing organs, mortality is now closer to 20 to 30%

in many series. (Kumar, et al., 2011)

With decreasing death rates, attention has focused on the trajectory

of recovery among survivors. Numerous studies have suggested that

patients who survive to hospital discharge after sepsis remain at increased

risk for death in the following months and years. Those who survive often


-37-

have impaired physical or neurocognitive functioning, mood disorders,

and a low quality of life. (Carlet, et al., 2003)

In most studies, determining the causal role of sepsis in such

subsequent disorders has been difficult. However, a recent analysis of the

Health and Retirement Study, involving a large, longitudinal cohort of

aging Americans, suggested that severe sepsis significantly accelerated

physical and neurocognitive decline. (Balk, et al., 1997)

Complications

End organ failure is a major contributor to mortality in sepsis and

septic shock. The complications with the greatest adverse effect on

survival are Acute respiratory distress syndrome (ARDS),DIC,and acute

kidney injury (AKI ) previously termed acute renal failure (ARF).Acute

lung injury (ALI)—mild ARDS, by the Berlin Definition —leading to

moderate or severe ARDS is a major complication of severe sepsis and

septic shock. The incidence of ARDS is approximately 18% in patients

with septic shock, and mortality approaches 50% . (Ranieri, et al., 2012)

ARDS also leads to prolonged intensive care unit (ICU) stays and

an increased incidence of ventilator-associated pneumonia. ARDS

secondary to severe sepsis demonstrates the manifestations of underlying

sepsis and the associated multiple organ dysfunction. Pulmonary

manifestations include acute respiratory distress and acute respiratory

failure resulting from severe hypoxemia caused by intrapulmonary

shunting. Fever and leukocytosis may be present secondary to the lung

inflammation.

The severity of ARDS may range from mild lung injury to severe

respiratory failure. The onset of ARDS usually is within 12-48 hours of

the inciting event. The patients demonstrate severe dyspnea at rest,


-38-

tachypnea, and hypoxemia; anxiety and agitation are also present. The

frequency of ARDS in sepsis has been reported to range from 18% to

38% (with gram-negative sepsis, 18-25%). Sepsis and multiorgan failure

are the most common cause of death in ARDS patients. Approximately

16% of patients with ARDS die of irreversible respiratory failure. Most

patients who show improvement achieve maximal recovery by 6 months,

with lung function improving to 80-90% of predicted values.

(Thompson, et al., 2012)

Acute kidney injury

Sepsis is the most common cause of AKI (ARF), which affects 40-

70% of all critically ill patients, depending on how AKI is defined (eg,

according to the RIFLE [risk, injury, failure, loss, and end stage] or

AKIN [Acute Kidney Injury Network] classifications]). AKI complicates

therapy and worsens the overall outcome. (Dennen, et al., 2010)

There is an increased risk of mortality when urosepsis is present

with severe sepsis and septic shock ; however, the global prognosis for

patients with urosepsis is better than that for those with sepsis from other

infectious sites. (Grabe, et al., 2011)

Other complications

Other complications of septic shock include the following: DIC (also occurring in 40% of patients with septic shock),Chronic renal

dysfunction, Mesenteric ischemia, Myocardial ischemia and dysfunction,

Liver failure, Other complications related to prolonged hypotension and

organ dysfunction.

http://emedicine.medscape.com/article/758674-overview


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Diagnostic Considerations

A clinical continuum of severity exists, from sepsis to severe sepsis

to septic shock and multiple organ dysfunction syndrome (MODS). In a

study that evaluated 2527 intensive care unit (ICU) patients with systemic

inflammatory response syndrome (SIRS), 26% developed sepsis, 18%

developed severe sepsis, and 4% developed septic shock. The incidence

of positive results on blood culture was 17% in patients with sepsis and

69% in patients with septic shock. (Wenzel, et al., 1998)

The diagnosis of septic shock requires features of SIRS (eg, mental

changes, hyperventilation, distributive hemodynamics, hyperthermia or

hypothermia, or reduced, elevated, or left-shifted white blood cells

[WBCs]) in addition to a potential source of infection.

Whenever a patient presents with shock, an early working diagnosis

must be formulated, an approach to urgent resuscitation must be

established, and steps must be taken to confirm the working diagnosis.

The following points should be considered for early diagnosis of sepsis:

Patients with sepsis may present in a myriad of ways, and high clinical

suspicion is necessary to identify subtle presentations .

Patients in a septic state should be screened for evidence of tissue

hypoperfusion, such as cool or clammy skin, mottling, and elevated

shock index (heart rate−to−systolic blood pressure >0.9)

A lactic acid level higher than 4 mmol/dL has been used as an entry

criterion for early goal-directed therapy (EGDT) and an indicator of

severe tissue hypoperfusion. (Annane, et al., 2003)

Important to note, three large prospective multicenter randomized

clinical trials of EGDT in the management of septic shock (ProCESS

[Protocolized Care for Early Septic Shock] ARISE [Australasian


-40-

Resuscitation In Sepsis Evaluation], and ProMISe [Protocolised

Management In Sepsis] ) have all yielded the same negative results,

namely that the use of strict protocolized monitoring (central venous

catheterization, lactate and ScvO2 measures) and management (targeting

a hemoglobin >8 g/dL, ScvO2 >70%) were no better than usual care as

long as patients were managed closely . (Yealy, et al., 2014)

Initial laboratory studies

Complete blood count with differential

The white blood cell (WBC) count and the WBC differential can

be somewhat helpful in predicting bacterial infection, though an elevated

WBC count is not specific to infection. In the setting of fever without

localizing signs of infection, a WBC count higher than 15,000/µL or a

neutrophil band count higher than 1500/µL has about a 50% correlation

with bacterial infection. WBC counts higher than 50,000/µL or lower

than 300/µL are associated with significantly decreased survival rates.

Hemoglobin concentration dictates oxygen-carrying capacity in blood,

which is crucial in shock to maintain adequate tissue perfusion. Although

there is no specific hematocrit or hemoglobin target, keeping the

hemoglobin concentration above 7 g/dL is usually practiced, and studies

comparing this versus 9 g/dL have shown no increased survival benefit

from either arm.Platelets, as acute-phase reactants, usually increase at the

onset of any serious stress and are typically elevated in the setting of

inflammation. However, the platelet count will fall with persistent sepsis,

and disseminated intravascular coagulation (DIC) may develop.

( Levi, et al.,2009)


-41-

Coagulation studies

Coagulation status should be assessed by measuring the

prothrombin time (PT) and the activated partial thromboplastin time

(aPTT). Patients with clinical evidence of a coagulopathy require

additional tests to detect the presence of DIC. The PT and the aPTT are

elevated in DIC, fibrinogen levels are decreased, and fibrin split products

are increased. (Carlet, et al., 2008)

Blood chemistries

At regular intervals, metabolic assessment should be carried out by

measuring serum levels of electrolytes, including magnesium, calcium,

phosphate, and glucose. Sodium and chloride levels are abnormal in

severe dehydration.Decreased bicarbonate can point to acute acidosis,

however sodium bicarbonate therapy is not recommended to improve

hemodynamics or replace vasopressor requirements in patients with

metabolic acidemia from hypoperfusion whose pH level is 7.15 or greater

(Levi, et al ., 2005)

Serum lactate is perhaps the best serum marker for tissue perfusion,

in that it is elevated under conditions of anaerobic metabolism, which

occurs when tissue oxygen demand exceeds supply. This can result from

decreased arterial oxygen content (hypoxemia), decreased perfusion

pressure (hypotension), maldistribution of flow, and decreased diffusion

of oxygen across capillary membranes to target tissues, as well as

decreased oxygen utilization on a cellular level.There is also evidence

that lactate can be elevated in sepsis in the absence of tissue hypoxia, as a

consequence of mitochondrial dysfunction and down regulation of

pyruvate dehydrogenase, which is the first step in oxidative

phosphorylation . (Levy, et al ., 2005)


-42-

Lactate levels higher than 2.5 mmol/L are associated with an

increase in mortality. The higher the serum lactate, the worse the degree

of shock and the higher the mortality. Lactate levels higher than 4

mmol/L in patients with suspected infection have been shown to yield a

5-fold increase in the risk of death and are associated with a mortality

approaching 30% . (Howell, et al., 2005)

It has been hypothesized that lactate clearance is a measure of

tissue reperfusion and an indication of adequate therapy.

(Jones, et al., 2010)

Liver function tests (LFTs) and levels of bilirubin, alkaline

phosphatase, and lipase are important in evaluating multiorgan

dysfunction or a potential causative source (eg, biliary disease,

pancreatitis, or hepatitis). Increased BUN and creatinine levels can point

to severe dehydration or renal failure.In severely ill patients suspected of

having adrenal insufficiency, a delta cortisol level below 9 µg/dL (after

administration of 250 µg of cosyntropin) or a random total cortisol level

below 10 µg/dL is diagnostic. (Marik, et al., 2003)

It should be kept in mind that the adrenocorticotropic hormone

(ACTH) stimulation test is not recommended for identifying the subset of

patients with septic shock or acute respiratory distress syndrome (ARDS)

who should receive corticosteroid therapy. (Pastores, et al., 2008)

The American College of Critical Care Medicine (ACCCM) does

not recommend the routine use of free cortisol measurements in critically

ill patients. There are no clear parameters for the normal range of free

cortisol in such patients, and the free cortisol assay is not widely

available, despite its advantages over the total serum cortisol level .

(Arlt, et al., 2008)


-43-

Microbiology Studies

Blood cultures

Blood cultures should be obtained in patients with suspected sepsis

to facilitate isolation of a specific organism and tailoring of antibiotic

therapy. These cultures are the primary means of diagnosing intravascular

infections (eg, endocarditis) and infections of indwelling intravascular

devices. Individuals at high risk for endocarditis are intravenous (IV)

drug abusers and patients with prosthetic heart valves.

(Wood, et al., 2006)

The Surviving Sepsis Campaign recommends obtaining at least 2

blood cultures before antibiotics are administered, with 1 percutaneously

drawn and the other(s) obtained through each vascular access (unless the

device was inserted < 48 hours beforehand). (Rhodes, et al., 2013)

Again, however, it must be remembered that blood cultures are

positive in fewer than 50% of cases of sepsis. (Kumar, et al., 2006)

To optimize recovery of aerobic bacteria from patients with

suspected intra-abdominal infection, 1-10 mL of fluid can be directly

inoculated into an aerobic blood culture; an additional 0.5 mL of fluid

should be sent for Gram staining and, if indicated, fungal cultures.

(Solomkin, et al., 2010)

For anaerobic bacteria, 1-10 mL of fluid can also be directly

inoculated into an anaerobic blood culture bottle. Susceptibility testing

for organisms that have a high risk for resistance (eg,Pseudomonas,

Proteus, Acinetobacter, Staphylococcus aureus, and predominant

[moderate to heavy growth] Enterobacteriaceae) should be performed.

(Bradley, et al., 2010)


-44-

Urine analysis and urine culture

Urine analysis and urine culture are indicated for every patient who

is in a septic state. Urinary tract infection (UTI) is a common source for

sepsis, especially in elderly individuals. Adults who are febrile without

localizing symptoms or signs have a 10-15% incidence of occult UTI.

Obtaining a culture is important for isolating a specified organism and

tailoring antibiotic therapy. (Mazuski, et al., 2010)

Gram stain and culture of secretions and tissue

The Gram stain is the only immediately available test that can

document the presence of bacterial infection and guide the choice of

initial antibiotic therapy. Secretions or tissue for Gram stain and culture

from the sites of potential infection (eg, cerebrospinal fluid [CSF],

wounds, respiratory secretions, or other body fluids) may be are obtained

as they are identified, preferably before administering antibiotic therapy.

(Opal, et al., 2012)

At least 1 mL of fluid or tissue is needed for cultures. For aerobic

or anaerobic cultures, 0.5 mL of fluid or 0.5 g of tissue should be

transported to the laboratory in the appropriate aerobic or anaerobic

transport medium . (Goldstein, et al., 2010)

If pneumonia is suspected, a sputum specimen should be obtained

for Gram stain and culture, provided that the patient has a productive

cough and that a good quality specimen can be obtained.

(Mandell, et al ., 2007)

Dranaige

Any abscess should be drained promptly and purulent material sent

to the microbiology laboratory for analysis. If meningitis is suspected, a

CSF specimen should be obtained. (Dean, et al., 2007)


-45-

Routine culture and susceptibility studies should be obtained in the

following cases:

Perforated appendicitis and other community acquired intraabdominal

infections in which there is significant resistance of a common

community isolate to an antimicrobial regimen in widespread use

locally. (Solomkin, et al., 2010)

Higher risk patients who have a greater risk of harboring resistant

pathogens, such as those with previous antibiotic exposure.

(Baron, et al., 2010)

Although Gram staining may be helpful for identifying healthcare-

related infections (eg, presence of yeast), it has not proved to be of

clinical value in community-acquired intra-abdominal infections.

Anaerobic cultures are not necessary for community-acquired intra-

abdominal infections if empiric antimicrobial therapy against common

anaerobic pathogens is administered (Rodovold, et al., 2010)

Plain Radiography

Chest

Because most patients who present with sepsis have pneumonia,

and because the clinical examination is unreliable for the detection of

pneumonia (especially in elderly patients), a chest radiograph is

warranted. Chest radiography detects infiltrates in about 5% of febrile

adults without localizing signs of infection; accordingly, it should be

routine in adults who are febrile without localizing symptoms or signs

and in patients who are febrile with neutropenia and without pulmonary

symptoms (Solomkin, et al., 2010)

Chest radiography is useful in detecting radiographic evidence of

ARDS which carries a high mortality. The discovery of such evidence on


-46-

a chest radiograph should prompt consideration of early intubation and

mechanical ventilation, even if the patient has not yet shown signs of

overt respiratory distress. (Thompson, et al., 2012)

Abdomen

Supine and upright or lateral decubitus abdominal radiographs

should be obtained; these may be useful when an intra-abdominal source

of sepsis is suspected. Abdominal plain films should be obtained if

clinical evidence of bowel obstruction or perforation exists. However, if

obvious signs of diffuse peritonitis are present and immediate surgical

intervention is planned, further diagnostic imaging is not require.

(Mazuski, et al., 2010)

In adult patients with suspected intra-abdominal infection who are

not undergoing immediate laparotomy, computed tomography (CT) of the

abdomen is preferable to abdominal radiography. (Baron, et al., 2010)

Ultrasonography

Abdominal ultrasonography is indicated when patients have

evidence of acute cholecystitis or ascending cholangitis exists (eg, right

upper quadrant abdominal tenderness, fever, vomiting, elevated LFT

results, elevated bilirubin level, or elevated alkaline phosphatase level).

(Goldstein, et al., 2010)

Surgery or endoscopic retrograde cholangiopancreatography

(ERCP) may be urgently necessary in the setting of sepsis with acute

cholecystitis or ascending cholangitis . (Baron, et al., 2010)

Echocardiography

Has a number of uses in assessing patients with septic shock and

may be considered. This imaging modality can provide a comprehensive

cardiac evaluation in patients with hemodynamic instability and can be





-47-

helpful for guiding fluid therapy and monitoring treatment effects. Other

conditions that can be assessed include sepsis-induced myocardial

dysfunction, right heart failure, dynamic left ventricular obstruction, and

tamponade. (Merkel, et al., 2010)

Lumbar Puncture

An LP is indicated when there is clinical evidence or suspicion of

meningitis or encephalitis. If the opening pressure is elevated, only as

much CSF as is needed for culture should be obtained . Broad spectrum

antibiotics to cover meningitis should be administered before the start of

the procedure. In patients with an acute fulminant presentation, rapid

onset of septic shock, and severely impaired mental status, this procedure

is used to rule out bacterial meningitis. (Janoo, et al., 2007)

The Sequential Organ Failure Assessment score

The SOFA score is a scoring system to determine the extent of a

person's organ function or rate of failure. The score is based on six

different scores, one each for the respiratory, cardiovascular, hepatic,

coagulation, renal and neurological system Both the mean and highest

SOFA scores being predictors of outcome. (Ferreira, et al., 2001)

An increase in SOFA score during the first 24 to 48 hours in the

ICU predicts a mortality rate of at least 50% up to 95%. Scores less than

9 give predictive mortality at 33% while above 11 can be close to or

above 50% (Vincent JL, et al., 2000).

The score tables below only describe points-giving conditions. In

cases where the physiological parameters do not match any row, zero

points are given. In cases where the physiological parameters match more

than one row, the row with most points is picked.


https://en.wikipedia.org/wiki/Coagulation

https://en.wikipedia.org/wiki/Renal


-48-

1- Respiratory System

2 -Nervous System

3-Cardio Vascular System

4 -Liver

5 -Coagulation

6- Renal System

Table (3): The Sequential Organ Failure Assessment score

Respiratory system

PaO2/FiO2 (mmHg) SOFA score

< 400 1

< 300 2

< 200 and mechanically ventilated 3

< 100 and mechanically ventilated 4

Nervous system

Glasgow coma scale SOFA score

13–14 1

10–12 2

6–9 3

< 6 4

Cardio Vascular system

Mean Arterial Pressure OR administration of

vasopressors required (doses are in µg/kg/min)

SOFA score

MAP < 70 mm/Hg 1

dopamine<= 5 or dobutamine (any dose) 2

dopamine> 5 OR epinephrine<= 0.1 OR 3

norepinephrine <= 0.1

dopamine > 15 OR epinephrine > 0.1 OR 4

norepinephrine.> 0.1

Liver

Bilirubin (mg/dl) [μmol/L] SOFA score

1.2–1.9 [> 20-32] 1

https://en.wikipedia.org/wiki/SOFA_score#Respiratory_System

https://en.wikipedia.org/wiki/SOFA_score#Nervous_System

https://en.wikipedia.org/wiki/SOFA_score#Cardio_Vascular_System

https://en.wikipedia.org/wiki/SOFA_score#Liver

https://en.wikipedia.org/wiki/SOFA_score#Coagulation

https://en.wikipedia.org/wiki/SOFA_score#Renal_System

https://en.wikipedia.org/wiki/Glasgow_coma_scale

https://en.wikipedia.org/wiki/Dopamine

https://en.wikipedia.org/wiki/Dobutamine


https://en.wikipedia.org/wiki/Epinephrine

https://en.wikipedia.org/wiki/Norepinephrine


https://en.wikipedia.org/wiki/Epinephrine

https://en.wikipedia.org/wiki/Norepinephrine


-49-

2.0–5.9 [33-101] 2

6.0–11.9 [102-204] 3

> 12.0 [> 204] 4

Coagulation

Platelets×103/µl SOFA score

< 150 1

< 100 2

< 50 3

< 20 4

Renal System

Creatinine (mg/dl) [μmol/L] (or urine output) SOFA score

1.2–1.9 [110-170] 1

2.0–3.4 [171-299] 2

3.5–4.9 [300-440] (or < 500 ml/d) 3

> 5.0 [> 440] (or < 200 ml/d) 4

(Vincent JL, et al., 2000).

Chapter (IV) Management of severe sepsis and septic shock

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Chapter (IV)

Management of severe sepsis and septic shock

Sepsis refers to the systemic inflammatory response following

microbial infection. Although the clinical criteria that defines sepsis

remain controversial, sepsis may best be defined as the ―systemic

response to infection with the presence of some degree of organ

dysfunction‖ (Angus, et al., 2013)

Sepsis is among the most common reasons for admission to ICUs

throughout the world, and it is believed to be the third most common

cause of death in the United States. Although the exact incidence of

sepsis in the United States is unclear, the annualized incidence has been

reported to have increased by 8.7% to 13% over the past 30 years.

(Edwards, et al., 2013)

The aging of the population in developed countries is believed to be

largely responsible for the increasing incidence of sepsis.


Sepsis is an exceedingly complex condition. Exposure of human

macrophages to bacterial antigens has been demonstrated to result in a

significant change in the expression of over 950 genes. These include

genes for proinflammatory and antiinflammatory cytokines, chemokines,

adhesion molecules, transcription factors, enzymes, clotting factors, stress

proteins, and antiapoptotic molecules. These gene products alter the

function of every cell and tissue in the body. Furthermore, these

mediators interact in complex positive and negative feedback loops and

result in epigenetic modifications that further alter the expression of this

network of mediators. (Leentjens, et al., 2013)


-51-

The early phase of sepsis is generally believed to result from the

uncontrolled production of proinflammatory mediators, the so-called

―cytokine storm.‖ However, some data suggest that both a

proinflammatory and an opposing antiinflammatory response occur

concurrently in patients with sepsis. In general, following a variable time

course, patients transition from a predominantly proinflammatory to an

antiinflammatory immunosuppressive state. (Boomer, et al., 2011)

The pathogenetic mechanism and physiologic changes associated

with sepsis are exceedingly complex, The major pathophysiologic

changes in patients with severe sepsis and septic shock include vasoplegic

shock (distributive shock), myocardial depression, altered microvascular

flow, and a diffuse endothelial injury. (Slutsky, et al., 2010)

These pathophysiologic changes play a central role in the early

management of patients with sepsis. The widespread endothelial injury

results in a microvascular leak, with tissue and organ edema,hypotension,

and shock. Increased endothelial permeability is caused by shedding of

the endothelial glycocalyx and the development of gaps between

endothelial cells (paracellular leak). (Goldenberg, et al., 2011)

Vasoplegic shock due to the failure of the vascular smooth muscle to

constrict, results in arterial and venodilatation. Venodilatation decreases

venous return and compounds the intravascular volume deficit caused by

the vascular leak . (Oliver, et al., 2001)

Management

The early management of patients with severe sepsis and septic

shock centers on the administration of antibiotics, IV fluids, and

vasoactive agents, followed by source control. However, the specific

approach to the resuscitation of patients with septic shock remains highly


-52-

controversial. However, it is likely that the early detection of sepsis with

the timely administration of appropriate antibiotics is the single most

important factor in reducing morbidity and mortality from sepsis. It has

become increasingly apparent that in many patients there is a long delay

in both the recognition of sepsis and the initiation of appropriate therapy.

This has been demonstrated to translate into an increased incidence of

progressive organ failure and a higher mortality. (Westphal , et al., 2011)

Physicians, therefore, need to have a high index of suspicion for

the presence of sepsis. The clinical features that should heighten the index

of suspicion for the diagnosis of sepsis are listed in table (4)

Table (4) Clinical Features That Should Alert the Physician to the

Diagnosis of Severe Sepsis

Clinical Feature

Heart rate > 120/min

Systolic BP < 90 mm Hg

Respiratory rate > 20/min

Temperature > 38.5° or < 36° C

Confusion

Lactate > 2 mmol/L

Procalcitonin > 0.5 ng/mL

WBC count > 12,000 or < 4,000 cells/μL

Band count > 5%

Lymphocytopenia < 0.5 × 103

μL

Thrombocytopenia < 150 × 103

μL

Oliguria

Chills and rigors

(Westphal , et al., 2011)

Antibiotic Therapy




-53-

appropriate cultures have been obtained. In a retrospective analysis of

2,600 patients demonstrated that the risk of dying increased progressively

with an increase in the time to receipt of the first dose of antibiotic from

the onset of sepsis-induced hypotension.

(Kumar, et al., 2008)

Furthermore, there was a 5% to 15% decrease in survival with

every hour of delay over the first 6 h. The choice of antibiotics is largely

determined by the source or focus of infection, the patient’s immunologic

status, whether the infection is nosocomial or community acquired, and

knowledge of the local microbiology and sensitivity patterns.

(Dickinson, et al., 2011)

Initial empirical antiinfective therapy should include one or more

drugs act against the likely pathogens and that penetrate into the

presumed source of sepsis. Because the identity of the infecting

pathogen(s) and its sensitivity pattern(s) are unknown at the time of

initiation of antibiotics, the initial regimen in patients with severe sepsis

and septic shock should include two or more antibiotics or an extended

spectrum β-lactam antibiotic with the aim of treating all realistically

possible microbial causes. A number of studies have demonstrated that

appropriate initial antimicrobial therapy, defined as the use of at least one

antibiotic active in vitro against the causative bacteria, reduced mortality

when compared with the inappropriate therapy other patients received .

(Kollef, et al., 2011)

Once a pathogen is isolated, monotherapy is adequate for most

infections; this strategy of initiating broad-spectrum cover with two or

more antibiotics, and then narrowing the spectrum to a single agent when

a pathogen is identified, is known as ―antimicrobial de-escalation.

(Joung, et al., 2011)


-54-

The indications for continuation of double-antimicrobial therapy

include enterococcal infections and severe intraabdominal infections. In

addition, double antimicrobial therapy (third-generation cephalosporin

and macrolide) is recommended for patients with severe community-

acquired pneumonia and those with pneumococcal bacteremia.

(Asadi, et al., 2014)

To rapidly achieve adequate blood and tissue concentrations,

antibiotics should be given via IV, at least initially. Dosing regimens

should take into account whether the antibiotic ―kills‖ by time-dependent

kinetics (eg, β-lactam antibiotics, vancomycin) or by concentration-

dependent kinetics (eg, aminoglycoside). The clinical effectiveness of β-

lactam antibiotics and vancomycin is optimal when the concentration of

the antimicrobial agent in the serum exceeds the minimum inhibitory

concentration of the infecting organism for at least 40% of the dosing

interval. In addition, antibiotic dosing should take into account the

patient’s hepatic and renal function. (Dickinson, et al., 2011)

Fluid Therapy

Beyond the early administration of antibiotics, aggressive

―supportive measures‖ may be harmful and the ―less is more‖ paradigm

appears applicable for the management of patients with severe sepsis. In

these highly vulnerable patients, more intensive treatment may promote

the chance of unwanted adverse effects and, hence, iatrogenic injury.

(Kox, et al., 2013).

Current teaching suggests that aggressive fluid resuscitation is the

best initial approach for the cardiovascular instability of sepsis.

Consequently, large volumes of fluid (5-10 L) are often infused in the

early stages of sepsis. There is, however, no human data that substantial


-55-

(> 30 mL/kg) fluid resuscitation reliably improves BP or end-organ

perfusion. (Hilton, et al., 2013)

From a pathophysiologic point of view, large-volume fluid

resuscitation in patients with sepsis is illogical and may worsen the

hemodynamic derangements of sepsis. In patients with septic shock who

are fluid responders (an increase in cardiac output with fluid boluses),

vasodilatation with a fall in systematic vascular resistance has been

observed. (Pierrakos, et al., 2012)

A similar finding has been noted in an experimental sepsis model.

(Rehberg, et al., 2012)

Hence, although the cardiac output increases, vasodilatation occurs

and the BP may remain unchanged. Increased shear stress increases the

expression of nitric oxide synthetase with increased release of nitric

oxide. In addition, increased cardiac filling pressures increase the release

of natriuretic peptides, which act synergistically with nitric oxide, causing

cyclic guanosine monophosphate-mediated vasodilatation. Endotoxin

enhances this vasodilatory response. As cardiac filling pressures increase,

extravascular lung water (EVLW) and tissue edema increase.

(Marik , et al., 2012)

Furthermore, increased cardiac filling pressures consequent to

large volume resuscitation increase the release of natriuretic

peptides. Natriuretic peptides cleave membrane-bound proteoglycans and

glycoproteins (most notably syndecan-1 and hyaluronic acid) off the

endothelial glycocalyx. The endothelial glycocalyx plays a major role in

regulating endothelial permeability, and damage to the glycocalyx plays a

major role in increasing tissue edema. Because of the endothelial injury,

capillary leak, and increased hydrostatic pressures, < 5% of infused


-56-

crystalloid remains intravascular within 3 h after infusion, resulting in an

increase in EVLW and further tissue edema. Increased EVLW has been

demonstrated to be a strong independent predictor of death.

(Slva , et al., 2013)

In patients with pneumonia, large-volume fluid resuscitation may

result in severe pulmonary edema. Myocardial edema due to excess fluid

administration compounds the myocardial dysfunction. Evidence of the

harmful effects of aggressive fluid resuscitation on the outcome of sepsis

is supported by experimental studies as well as by data accumulated from

clinical trials. (Sousse, et al., 2012)

Multiple clinical studies have demonstrated an independent

association between an increasingly positive fluid balance and increased

mortality in patient with sepsis. (Murphy, et al., 2010)

In a secondary analysis of the Vasopressin in Septic Shock Trial

(VASST) demonstrated that a greater positive fluid balance and a higher

central venous pressure (CVP) at both 12 h and 4 days were independent

predictors of death. (Boyd, et al., 2011)

In a recent study, demonstrated that a positive fluid balance at 8

days was the strongest independent predictor of hospital mortality. In this

study, the 24-h fluid balance was 37.5 mL/kg (about 2.5 L) in the

survivors compared with 55.3 mL/kg (3.9 L) in those who died.

(Hampton, et al., 2013)

In a recent study demonstrated a strong correlation among the net

fluid balance, the increase in brain natriuretic peptide, and death in

patients with sepsis. The most compelling data that fluid loading in sepsis

is harmful come from the Fluid Expansion as Supportive Therapy

(FEAST) study performed in 3,141 children with severe sepsis. In this

study, aggressive fluid loading was associated with a significantly


-57-

increased risk of death. Furthermore, there was no subgroup of patients

that benefited from aggressive fluid resuscitation. (Boyd, et al., 2011)

In the Australasian Resuscitation of Sepsis Evaluation (ARISE)

study, which used the same entry criteria as the EGDT study, 2.2 ± 1.9 L

of fluid were given in the first 6 h. The hospital mortality was 23% in the

ARISE study compared with 30% in the intervention arm of the EGDT

study. In the VASST, optimal survival occurred with a positive fluid

balance of approximately 3 L at 12 h. (Bellomo, et al., 2009)

In some patients, hypotension and tachycardia do resolve with

limited fluid resuscitation. However, fluids alone will not reverse the

hemodynamic instability of patients with more severe sepsis; in these

patients, fluids alone are likely to exacerbate the vasodilatory shock and

increase the capillary leak and tissue edema. Based on these data, its

better limiting the initial fluid resuscitation to approximately 20 to 30

mL/kg . It is important to emphasize that this conservative approach to

fluid management in patients with sepsis is based on indirect evidence

and not on a randomized controlled trial specifically designed to answer

this question. Furthermore, this recommendation differs somewhat from

that of the most recent Surviving Sepsis Campaign guidelines, which

suggest ―a minimum fluid challenge of 30ml/kg‖ and that ―greater

amounts of fluid may be needed in some patients (Levi, et al., 2013)

The optimal time to start a vasopressor agent in patients with sepsis

has not been well studied. However, after receiving 20 to 30 mL/kg of

crystalloid, it seems unlikely that additional fluid boluses will increase

the mean arterial pressure (MAP) in patients who remain hypotensive.

(Hilton, et al., 2012)

Therefore, its recommended the initiation of a vasopressor agent

(norepinephrine) in patients who remain hypotensive (MAP < 65 mm Hg)


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after receiving 20 to 30 mL/kg of crystalloid solution. Additional fluid

boluses (500 mL) may be given once the ―target‖ norepinephrine dose is

achieved (about 0.1-0.2 μg/kg/min), and this should be based on a

dynamic assessment of volume responsiveness and ventricular function .

Its suggested using the passive leg-raising maneuver coupled with

minimally invasive cardiac output monitoring to assess volume

responsiveness. Calibrated pulse contour analysis, bioreactance, the

ultrasonic cardiac output monitor (USCOM), carotid Doppler flow,

Doppler echocardiography, or esophageal Doppler techniques can be

used to dynamically follow the cardiac output in real time.

(Funk, et al., 2013)

Bioreactance, USCOM, and carotid Doppler flow are truly

noninvasive and are suitable for guiding fluid resuscitation in the

Emergency Department(ED).In cases of life-threatening hypotension

(diastolic BP < 40 mm Hg), treatment with vasopressors should be started

concurrently with fluid administration. (Marik ,et al., 2013)

Recent data suggest that the choice of resuscitation fluid may have

an effect on outcome.Balanced salt solutions (Lactated Ringers solution,

Hartmann’s solution, Plasmalyte 148) are the preferred resuscitation

fluids. Normal saline (0.9% NaCl) is associated with an increased risk of

renal dysfunction, a hyperchloremic metabolic acidosis, and an increased

risk of death. (Shaw, et al., 2013)

Similarly, hydroxyethyl starch solutions are associated with an

increased risk of renal failure and death and are considered

contraindicated in patients with sepsis. (Perner, et al., 2012)

Albumin has a number of theoretical benefits in patients with

sepsis, including its antioxidant and antiinflammatory effects as well as


-59-

its ability to stabilize the endothelial glycocalyx.However, the use of

albumin in patients with sepsis is controversial. (Kozar, et al., 2011)

The multicenter randomized Albumin Italian Outcome Sepsis

Study (ALBIOS) demonstrated that a 25% albumin infusion decreased

the mortality of patients with septic shock (and a serum albumin of

< 3g/dL) once hemodynamic stability had been achieved. The use of

albumin is patients with sepsis is supported by the Saline vs Albumin

Fluid Evaluation (SAFE) study, as well as by a metaanalysis on this topic.

Because a 25% albumin infusion may restore the damaged endothelial

glycocalyx, this would appear to be a reasonable intervention in patients

with severe septic shock. (Dan, et al., 2011)

Vasopressors and Inotropic Agents

A low MAP is a reliable predictor for the development of organ

dysfunction. When the MAP falls below an organ’s autoregulatory

threshold, organ blood flow decreases in an almost linear fashion.

Because the autoregulatory ranges of the heart, brain, and kidney are > 60

mm Hg, a MAP below this level will likely result in organ ischemia.

(Bellomo, et al., 2001)

An analysis of a large ICU database demonstrated that the risk of

kidney injury and death increased sharply as the MAP fell below 60 mm

Hg. Varpula and colleagues studied the hemodynamic variables

associated with mortality in patients with septic shock. These researchers

calculated the area under the curve (AUC) of various MAP thresholds

over a 48-h time period. The highest AUC values were found for a MAP

< 65 mm Hg . Because of the shift in the autoregulatory range (to the

right) in patients with chronic hypertension, a higher MAP may be

required in these patients. (Bailey, et al., 2009)


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The Assessment Of Two Levels Of Arterial Pressure On Survival In

Patients With Septic Shock (SEPSISPAM) is a multicenter, randomized

controlled trial completed in France. In this study, patients with septic

shock were randomized to achieve a target MAP of 65 to 70 or 80 to 85

mm Hg. The primary outcome was 28-day mortality. Secondary

outcomes included 90-day mortality and organ failures. A priori, a

secondary analysis was planned in patients with and without a history of

hypertension. Overall, there was no difference in either primary or

secondary end point between the two treatment groups. However the

incidence of organ failures (particularly renal dysfunction) was higher in

the subgroup of patients with chronic hypertension in the lower MAP

group.

Based on these data, an initial MAP of 65 mm Hg in patients with

septic shock is atarget and in patients with a history of chronic

hypertension, targeting a slightly higher MAP (75-80 mm Hg).(Panwar,

et al., 2013)

In patients with sepsis, norepinephrine increases BP as well as

cardiac output and renal, splanchnic, cerebral, and microvascular blood

flow, while minimally increasing heart rate. Although not widely

appreciated, norepinephrine causes α1 adrenergic receptor-mediated

venoconstriction; this increases the mean systemic pressure with a

significant increase in venous return and cardiac preload.

(Silva, et al., 2012)

The early use of norepinephrine restores BP and organ blood flow

with a significant fluid sparing effect. The early administration of

norepinephrine largely reverses the hemodynamic abnormalities of severe

vasodilatory shock. Abid and colleagues demonstrated the early use of

norepinephrine in patients with septic shock was a strong predictor of


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survival. In situations in which norepinephrine is not available,

epinephrine is a suitable alternative agent. In patients with septic shock,

dopamine is associated with an increased mortality when compared with

norepinephrine, and is best avoided. (Vasu, et al., 2012)

Similarly, phenylephrine is not recommended, because in

experimental models it decreases cardiac output as well as renal and

splanchnic blood flow. Furthermore, phenylephrine has not been well

studied in patients with sepsis. (Malay, et al., 2004)

In patients who remain hypotensive or have evidence of inadequate

organ perfusion despite fluid optimization and an adequate dose of

norepinephrine (approximately 0.1-0.2 μg/kg/min), further hemodynamic

assessment to exclude ventricular dysfunction is recommended. Global

biventricular dysfunction has been reported in up to 60% of patients with

septic shock . (Page, et al., 2008)

Dobutamine at a starting dose of 2.5 μg/kg/min is recommended in

patients with significant ventricular dysfunction (milrinone is an

alternative agent). The dose of dobutamine should be titrated to the

hemodynamic response as determined by minimally invasive cardiac

output monitoring. (Chimot, et al., 2011)

This recommendation is in keeping with the updated Surviving

Sepsis Campaign guidelines, which suggest ―a trial of dobutamine

infusion up to 20 micrograms/kg/min be administered or added to

vasopressor (if in use) in the presence of (a) myocardial dysfunction as

suggested by elevated cardiac filling pressures and low cardiac output, or

(b) ongoing signs of hypoperfusion, despite achieving adequate

intravascular volume and adequate MAP . (Levi, et al., 2012)

These recommendations, however, differ from the EGDT study

protocol, which suggests the use of an inotropic agent based on the CVP


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(> 8-12 mm Hg) and a central venous oxygen saturation (ScvO2) of < 70%

(without an evaluation of ventricular function or cardiac output).

(Chimot, et al., 2011)

The Surviving Sepsis Campaign guidelines suggest that

―vasopressin 0.03 units/min can be added to norepinephrine with the

intent of either raising MAP or decreasing norepinephrine dosage

(ungraded).‖ Vasopressin reverses the ―relative vasopressin deficiency‖

seen in patients with septic shock and increases adrenergic sensitivity.

(Oliver, et al., 2001)

Terlipressin is an alternative agent should vasopressin not be

available (terlipressin is not Food and Drug Administration-approved in

the United States). (Ertmer, et al., 2009)

Vasopressin may be effective in raising BP in patients with

refractory hypotension; however, the optimal time to initiate this drug is

not clear. The VASST randomized patients with septic shock to

norepinephrine alone or norepinephrine plus vasopressin at 0.03

units/min. By intention-to-treat analysis there was no difference in

outcome between the groups. However, an a priori-defined subgroup

analysis demonstrated that survival among patients receiving < 0.2

μg/kg/min norepinephrine at the time of randomization was better with

the addition of vasopressin than that of those receiving norepinephrine at

a dose > 0.2 μg/kg/min. , therefore, the addition of vasopressin at a dose

of norepinephrine between 0.1 and 0.2 μg/kg/min is preferred.

(Singer, et al., 2008)

Thereafter the dose of norepinephrine should be titrated to achieve

a MAP of at least 65 mm Hg. It is important to emphasize that

vasopressin is administered as a fixed dose of 0.03 units/min and should

not be uptitrated. (Paul, et al., 2014)


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Resuscitation End Points



patients with severe sepsis and septic shock. (Avwzedo, et al., 2010)

Most of these targets, however, are controversial and are not

supported by outcome data. The Surviving Sepsis Campaign guidelines

recommend a CVP of 8 to 12 mm Hg (12-15 mm Hg if mechanically

ventilated), an Scvo2 > 70%, and a urine output > 0.5 mL/kg/h as targets

for resuscitation. (Rhodes, et al., 2012)

It has been well established that there is no relationship between

the CVP and intravascular volume and no relationship between the CVP

and fluid responsiveness. Consequently, the CVP should not be used to

guide fluid therapy. (Marik, et al., 2013)

The use of ScvO2 to guide the resuscitation of patients who are

septic is equally problematic. Patients who are septic usually have a

normal or increased ScvO2 caused by reduced oxygen extraction. Indeed,

recently , a ScvO2 > 70% was considered a diagnostic criterion for severe

sepsis. In a large, multicenter, goal-directed study, a high (> 90%) but not

a low (< 70%) initial ScvO2 was an independent predictor of death.

(Pope, et al., 2010)

Furthermore, Nee and collegues conclude that the ―attainment of

a CVP of > 8 mm Hg and Scvo2 of > 70% did not influence survival in

patients with septic shock.‖ (Nee, et al., 2011)

The Surviving Sepsis Campaign guidelines recommend ―targeting

resuscitation to normalize lactate in patients with elevated lactate levels

as a marker of tissue hypoperfusion.‖ This recommendation is based on

the notion that an elevated lactate is a consequence of tissue hypoxia and


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inadequate oxygen delivery, and is ―supported‖ by two studies that used

lactate clearance as the target of resuscitation. (Jones, et al ., 2010)

Multiple studies have demonstrated that the increased blood lactate

concentration in sepsis is not caused by tissue hypoxia but is rather

produced aerobically as part of the metabolic stress response. Increasing

oxygen delivery in these patients does not increase oxygen consumption.

(Bellomo, et al., 2013)

Previous studies have demonstrated that targeting supramaximal

oxygen delivery does not improve outcome and may be harmful.

In the setting of septic shock, an infusion of a short-acting β-

blocker reduced cardiac output and oxygen delivery; paradoxically, this

intervention reduced blood lactate levels and improved patient survival as

compared with the control group .(Westphal, et al., 2013)

These data would suggest that achieving a MAP of at least 65 mm

Hg should be the primary target in the resuscitation of patients with septic

shock. Furthermore, although attempts to achieve a supranormal cardiac

index may be potentially harmful, normal cardiac index (> 2.5 L/min/m2)

is a target. Although a falling arterial lactate concentration is a sign that

the patient is responding to therapy (attenuation of the stress response),

titrating therapy to a lactate concentration is devoid of scientific evidence.

(Garcia, et al., 2014)

Blood Transfusion

The 2012 Surviving Sepsis Campaign guidelines state that ―during

the first 6 hours of resuscitation, if ScvO2 is less than 70%...then

dobutamine infusion…or transfusion of packed red blood cells to achieve

a hematocrit of greater than or equal to 30% in attempts to achieve the

ScvO2 goal are options . (Rhodes, et al., 2013)


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In patients who are septic, RBC transfusions do not acutely

increase tissue oxygen uptake; paradoxically, they have been

demonstrated to impair microcapillary flow and tissue oxygenation. In

addition, the release of cell-free hemoglobin from banked blood may be

particularly deleterious in patients who are septic. (Janz, et al ., 2013)

One study demonstrated that "transfusion of PRBCs was associated

with worsened clinical outcomes in patients with septic shock treated

with EGDT". (Fuller, et al., 2010)

Blood transfusions are associated with an increased risk of

secondary infections, multiorgan dysfunction syndrome, and death and

should be considered only in patients with a hemoglobin < 7 g/dL.

(Fink, et al., 2011)

Corticosteroids

The use of low-dose corticosteroids in patients with severe sepsis

remains controversial. (Marik, et al ., 2011)

It has been proposed that inadequate cellular glucocorticoid

activity (critical illness-related corticosteroid insufficiency) due to either

adrenal suppression or glucocorticoid tissue resistance results in an

exaggerated and protracted proinflammatory response. In addition to

down-regulating the proinflammatory response, corticosteroids may have

additional beneficial effects, including increasing adrenergic

responsiveness and preserving the endothelial glycocalyx.

(Chappell, et al., 2007)

It was found that corticosteroids were only of benefit if given

within 6 h after the onset of septic shock-related hypotension.

(Park, et al., 2012)


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In the Corticosteroid Therapy of Septic Shock Study

(CORTICUS), the initial time frame for the initiation of corticosteroids

was 24 h, which was then increased to 72 h. (Flemmer, et al., 2012)

It is also important to recognize that in the CORTICUS, > 60% of

the patients were surgical patients. It has now been well established that

surgery induces an immunosuppressive state and that this occurs within

hours of surgery. It would, therefore, appear counterproductive to give

postsurgical patients who are septic corticosteroids because this is only

likely to compound the immunosuppressive state and increase the risk of

secondary infections (as was demonstrated in the CORTICUS).

(Marik, et al ., 2012)

Although the mortality benefit of corticosteroids in septic shock is

controversial, low-dose hydrocortisone has been demonstrated to

significantly reduce vasopressor dependency, with a favorable side effect

profile. (Annane, et al., 2009)

Furthermore, the combination of low dose corticosteroids and

vasopressin has been associated with decreased mortality and organ

dysfunction in patients with septic shock. (Luckner, at al., 2011)

Based on these data, treatment with hydrocortisone concomitant

with the initiation of vasopressin for the management of severe

vasodilatory septic shock is preferred, however, this approach has not

been tested prospectively. Two large randomized controlled trials are

currently underway, and it is hoped that they will resolve this ongoing

controversy about the use of corticosteroids in septic shock.

(Oyen, et al., 2012)

Source Control

It has been known for centuries that, unless the source of the

infection is controlled, the patient cannot be cured of his/her infective


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process and death will eventually ensue. It is important that specific

diagnoses of infection that require emergent source control be made in a

timely manner (eg, necrotizing soft tissue infection, peritonitis,

cholangitis, intestinal infarction) and surgical consultation be obtained

immediatelY . ( Boyer, et al., 2009)

When source control in a patient who is severely septic is required,

the effective intervention associated with the least physiologic insult

should be used (eg, percutaneous rather than surgical drainage of an

abscess). If intravascular access devices are a possible source of severe

sepsis or septic shock, they should be removed promptly after other

vascular access has been established . (Mermel, et al., 2001)

Therapies Being Investigated:

A number of potential therapies for sepsis appear promising in

animal models, but have not yet been adequately studied in humans.

Other potential therapies have been studied in humans, but have given

conflicting results and require additional investigations to clarify their

effects.

Inhibition of innate immunity

Infecting microbes display highly conserved macromolecules (e.g.,

lipopolysaccharides, peptidoglycans) on their surface. When these

macromolecules are recognized by pattern-recognition receptors (called

Toll-like receptors [TLRs]) on the surface of immune cells, the host’s

immune response is initiated. This may contribute to the excess systemic

inflammatory response that characterizes sepsis. Inhibition of several

TLRs is being evaluated as a potential therapy for sepsis :

Inhibition of TLR-4 with the antagonist, E5564 (Eritoran), is

currently being tested in humans. The ACCESS (AControlled


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Comparison of Eritoran Tetrasodium and Placebo in Patients with

Severe Sepsis) trial has finished enrolling patients, but its results have

not been reported. An earlier clinical trial that evaluated the inhibition

of TLR-4 with another antagonist, TAK 242 (Resatorvid), found a

non-statistically significant reduction in 28-day mortality.

Inhibition of TLR-2 with a neutralizing antibody (anti-TLR-2)

successfully prevented lethal septic shock in an experimental mouse

model, even if the antibody was given three hours after the initiation

of systemic inflammation. Anti-TLR-2 has not been tested in humans.

(Delaney, et al., 2007)

Restoration of the gastrointestinal barrier

Talactoferrin is a glycoprotein that has anti-infective and anti-

inflammatory properties, possibly by restoring the barrier properties of

the gastrointestinal mucosa. In unpublished studies conducted using

animal models, talactoferrin reduced mortality when given enterally up to

12 hours following the onset of sepsis. A randomized trial has been

completed in humans with severe sepsis and another randomized trial in

humans with severe sepsis is planned.

Intravenous immunoglobulin

It has been hypothesized that polyclonal intravenous

immunoglobulin (IVIG) may benefit patients with sepsis by binding

endotoxin. However, the data are conflicting:

Suggesting that polyclonal IVIG has no benefit, a randomized

trial of 653 patients with sepsis found that IVIG did not reduce

28-day mortality compared to placebo .

Suggesting that polyclonal IVIG has a benefit, meta-analyses of

randomized trials found that polyclonal IVIG decreased


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mortality compared to either placebo or no IVIG. The mortality

benefit was greatest when IgA- or IgM-enriched IVIG was used.

(Delaney, et al., 2007)

Taken together,the evidence is insufficient to recommend the

administration of polyclonal IVIG to patients with sepsis. However, well-

designed randomized trials are warranted to evaluate the impact of IgA-

and IgM-enriched IVIG. (Laupland, et al., 2007)

Endotoxin inactivation or removal

Strategies to improve sepsis by either inactivating or removing

endotoxin have been investigated and some of the preliminary data

appear promising :

Hemoperfusion through an endotoxin-avid column-Polymyxin B is

an antibiotic with a high affinity for endotoxin. Several studies have

found that hemoperfusion through a column that contains polymyxin

B may be beneficial to patients with sepsis. The largest was a

multicenter trial that randomly assigned 64 patients with severe

sepsis or septic shock to receive conventional therapy alone or

conventional therapy plus hemoperfusion through a polymyxin B

fiber column (PBFC). All of the patients had undergone emergency

surgery for intraabdominal infection. The group that received

hemoperfusion through a PBFC had lower 28-day mortality than the

group that received conventional therapy alone (32 versus 53

percent). In addition, only the group that received hemoperfusion

through a PBFC had increased mean arterial pressure, decreased

vasopressor requirement, and decreased severity of illness at 72

hours. (Vincent, et al., 2005)


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Plasma or whole blood exchange Case series and observational

studies with historical controls reported favorable outcomes when

endotoxin was removed by plasma or whole blood exchange,

including lower plasma endotoxin concentrations and, possibly,

lower mortality. (Reeves, et al., 2002)

Interferon-gamma

A decrease in monocyte function has been observed late in the

course of sepsis, which may predispose patients to life-threatening

secondary infections. This observation prompted a study in which

patients with sepsis were administered interferon-gamma. The study

found that interferon-gamma restored monocytic cell function. Controlled

clinical trials measuring patient-important outcomes in patients with

sepsis have not been reported, although a trial evaluating the impact of

interferon-gamma in candidemia is underway. (Randow, et al., 1997)

Granulocyte-macrophage colony stimulating factor

Granulocyte-macrophage colony stimulating factor (GM-CSF,

sargramostim, molgramostim) is a cytokine that promotes maturation of

the progenitor cells of granulocytes, erythrocytes, megakaryocytes, and

macrophages, as well as mature neutrophils, monocytes, macrophages,

dendritic cells, T-lymphocytes, and plasma cells. Its use in sepsis has

been studied in several controlled clinical trials. (Meisel, et al., 2009)

Augmentation of immunomodulation

Antibodies directed against macrophage migration inhibition

factor (MIF) prevented death in a study that used a cecal puncture animal

model of sepsis, even when administered up to eight hours after the onset

of peritonitis . The mechanism of action is uncertain, but MIF inhibition

might restore or augment the immunomodulatory actions of endogenous

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glucocorticoids. While it is known that elevated MIF levels correlate with

poor outcomes in humans with sepsis, the impact of MIF inhibition has

not been studied in humans. (Sehefold, et al., 2009)

Hemofiltration

It has been proposed that hemofiltration may remove

proinflammatory molecules that induce hemodynamic collapse in septic

shock, improving outcomes. However, the data in humans are

inconsistent . (Mateo, et al., 2009)

Case series suggest that high-volume hemofiltration may benefit

patients with sepsis

In a representative series, 20 patients with refractory hyperdynamic

septic shock underwent a single, 12 hour session of high-volume

hemofiltration. Eleven patients improved following hemofiltration

(i.e., improved perfusion and decreased vasopressor requirement)

and nine patients did not. ICU mortality was only 18 percent among

those who improved, compared to 67 percent among those who did

not.

In contrast, a randomized trial that evaluated continuous venovenous

hemofiltration (CVVH) in patients with sepsis did not demonstrate

any improvement in the clearance of inflammatory mediators or

clinical outcomes , while another trial was discontinued after an

interim analysis showed more frequent and more severe organ

failure in the hemofiltration group. (Payen, et al., 2009)

Heparin

Heparin has anti-thrombotic and immunomodulating effects,

both of which have the potential to be beneficial in sepsis. In a

retrospective cohort study of patients with septic shock, intravenous


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therapeutic heparin was associated with decreased mortality,

discontinuation of vasoactive drug infusions, and liberation from

mechanical ventilation. The risk of major hemorrhage or the need for

transfusion was not increased . (Morales, et al., 2009)

Naloxone

A meta-analysis of three randomized trials (61 patients) comparing

naloxone to either placebo or no naloxone found that naloxone therapy

led to hemodynamic improvement, but did not improve the case-fatality

rate. Adverse effects that have been associated with naloxone therapy

include pulmonary edema, hypertension, and seizures. Given the

limitations of the meta-analysis that found a physiological benefit, the

absence of patient-important benefits, and the potential for adverse

effects, we believe that naloxone therapy is not warranted for patients

with septic shock. (Gauvin, et al., 2000)

Pentoxifylline

Sepsis results in decreased red cell deformability and increased

erythrocyte aggregation, effects that may be mitigated by pentoxifylline.

Pentoxifylline also inhibits neutrophil adhesion and activation, and

modulates endotoxin-induced expression of proinflammatory cytokines.

In a trial of 51 surgical patients with severe sepsis who were randomly

assigned to receive pentoxifylline or placebo, pentoxifylline improved the

multiple organ dysfunction score and the arterial oxygen tension to

fraction of inspired oxygen (PaO2/FIO2), but there was no improvement

in the 28-day mortality. (Rock, et al., 2011)

Statins

HMG CoA reductase inhibitors (statins) are in wide clinical use

and have an established role in the management of hyperlipidemia and

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cardiovascular disease. Statins also appear to have beneficial anti-

inflammatory properties, such as suppression of endotoxin-induced up-

regulation of TLR-4 and TLR-2. Several observational studies have

suggested that statins are beneficial in patients with sepsis.

(Plump, et al., 2011)

Recombinant human activated protein C

Activated protein C, a component of the natural anticoagulant

system, is a potent antithrombotic serine protease with substantial

antiinflammatory properties. What has the efficacy of this treatment

taught us about the pathogenesis of sepsis, and what are the strengths and

limitations of this important clinical trial. (Bernard, et al., 2001)

In the initial response to a localized infection, as in pneumonia or

an intraabdominal abscess, the release of endotoxins or exotoxins by a

bacterial infection induces tissue macrophages to generate inflammatory

cytokines, including tumor necrosis factor α, interleukin-1β, and

interleukin-8 Although these early-response cytokines play an important

part in host defense by attracting activated neutrophils to the site of

infection, the entry of these cytokines and bacterial products into the

systemic circulation can bring about widespread microvascular injury,

leading to multiorgan failure. Most prior clinical trials evaluated

pharmacologic agents designed to attenuate these early inflammatory

events in sepsis, including glucocorticoids and drugs designed to

neutralize endotoxin, tumor necrosis factor α, or interleukin-1β. None of

these treatments were effective, perhaps in part because the importance of

the coagulation cascade in sepsis was not recognized.

(Daniei, et al., 2011)

There are a number of compelling reasons why activated protein C

might be an effective therapy in patients with sepsis. First, most patients


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with severe sepsis have diminished levels of activated protein C, in part

because the inflammatory cytokines generated in sepsis down-regulate

thrombomodulin and the endothelial-cell protein C receptor, components

of the coagulation system that are necessary for the conversion of inactive

protein C to activated protein C. Second, activated protein C inhibits

activated factors V and VIII, thereby decreasing the formation of

thrombin. Third, activated protein C stimulates fibrinolysis by reducing

the concentration of plasminogen-activator inhibitor type 1. Fourth, the

administration of activated protein C to baboons with gram-negative

sepsis reverses the procoagulant and inflammatory effects of sepsis and

increases survival. Finally, there is recent evidence that treatment with

protein C may improve clinical outcomes in patients with severe

meningococcemia. (Grubers,et al., 2012)

Activated protein C should be given to patients who meet all the

inclusion criteria, including evidence of end-organ dysfunction with

shock, acidosis, oliguria, or hypoxemia. The drug should not be given to

patients with clinical signs of mild-to-moderate sepsis who do not have

evidence of end-organ injury, unless a future trial shows a clear benefit in

these patients. Furthermore, the risks and benefits of the agent must be

studied in patients at a higher risk of bleeding, in children, and in

immunosuppressed patients, especially those with thrombocytopenia or

neutropenia. Because the cost of this new therapy will be substantial,

ways to make this drug affordable throughout the world should be

identified. (Bernard, et al., 2001)

Recombinant human activated protein C, an anticoagulant is the

first anti-inflammatory agent that has proved effective in the treatment of

sepsis. In patients with sepsis, the administration of activated protein C in


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a dose of 24Mic/kg/hr resulted in a 19.4 percent reduction in the relative

risk of death and an absolute risk reduction of 6.1 percent.

(Bernard, et al., 2001)

Dosing: (Adult)

Severe sepsis: I.V.: 24 mcg/kg/hour for a total of 96 hours; stop

infusion immediately if clinically-important bleeding is identified. Note:

Use actual body weight for dosing.There is no specific adjustment

recomended in patients with renal impairment. (Bernard, et al., 2001)

Administration

Infuse separately from all other medications. Only dextrose,

normal saline, dextrose/saline combinations, and lactated Ringer's

solution may be infused through the same line. May administer via

infusion pump. Administration of prepared solution must be completed

within 12 hours of preparation. Suspend administration for 2 hours prior

to invasive procedures or other procedure with significant bleeding risk;

may continue treatment immediately following uncomplicated,

minimally-invasive procedures, but delay for 12 hours after major

invasive procedures/surgery. (Levy, et al., 2005)

Compatibility

Stable in NS(normal saline); only NS, dextrose, LR(lactate

Ringer), or dextrose/saline mixtures may Activated protein C inactivates

factors Va and VIIIa, thereby preventing the generation of thrombin.

(Matthay, et al., 2001).

The efficacy of an anticoagulant agent in patients with sepsis has

been attributed to feedback between the coagulation system and the

inflammatory cascade . Inhibition of thrombin generation by activated

protein C decreases inflammation by inhibiting platelet activation,

neutrophil recruitment, and mast-cell degranulation. Activated protein C


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has direct anti-inflammatory properties, including blocking of the

production of cytokines by monocytes and blocking cell adhesion. Also,

activated protein C has antiapoptotic actions that may contribute to its

efficacy. (Joyce, et al., 2001)

The debate regarding the appropriate use of activated protein C, as

well as its potential adverse effects, particularly bleeding, has been

discussed in many articles. A major risk associated with activated protein

C is hemorrhage; in a study of activated protein C, 3.5 percent of patients

had serious bleeding (intracranial hemorrhage, a life-threatening bleeding

episode, or a requirement for 3 or more units of blood), as compared with

2 percent of patients who received placebo (P < 0.06).

(Warren, et al., 2002)

Activated protein C is compatible with Cisatracurium, fluconazole,

nitroglycerin, potassium chloride, vasopressin. Incompatible with

Amiodarone, ciprofloxacin, cyclosporine, gentamicin, imipenem/

cilastatin sodium, insulin (regular), levofloxacin, magnesium sulfate,

metronidazole, midazolam, nitroprusside, norepinephrine, piperacillin/

tazobactam, ticarcillin/ clavulanate, tobramycin, vancomycin. Variable

compatible with Albumin, ampicillin/sulbactam sodium, ceftazidime,

ceftriaxone, clindamycin, dobutamine, dopamine, epinephrine,

fosphenytoin, furosemide, heparin, potassium phosphate, ranitidine.

(Sweeny, et al., 2009)

Contraindications

Hypersensitivity to activated protein c or any component of the

formulation., active internal bleeding., recent hemorrhagic stroke (within

3 months).,severe head trauma (within 2 months). ,recent intracranial or

intraspinal surgery (within 2 months). intracranial neoplasm or mass

lesion. ,evidence of cerebral herniation., presence of an epidural catheter.,

trauma with an increased risk of life-threatening bleeding.

(Sweeny, et al., 2009)

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Summary

Summary

Systemic inflammatory response syndrome (SIRS), sepsis, severe

sepsis, and septic shock were initially defined in 1991 by a consensus

panel convened by the American College of Chest Physicians (ACCP)

and Society of Critical Care Medicine (SCCM), then they were

reconsidered in 2001 during an International Sepsis Definitions

Conference that included representatives from the ACCP, SCCM,

American Thoracic Society (ATS), European Society of Intensive Care

Medicine (ESICM), and Surgical Infection Society (SIS).


A practical modification of the definitions has since been

published, which provides exact hemodynamic definitions for septic

shock . (Annane , et al., 2005)

The definitions presented in a way that highlights the notion that

both SIRS and sepsis exist on a continuum of severity that ends with

multiple organ dysfunction syndrome (MODS).

SIRS is defined as 2 or more of the following variables:

Fever of more than 38°C (100.4°F) or less than 36°C (96.8°F) , Heart rate

of more than 90 beats per minute , Respiratory rate of more than 20

breaths per minute or arterial carbon dioxide tension (PaCO 2) of less than

32 mm Hg , Abnormal white blood cell count (>12,000/µL or < 4,000/µL

or >10%immature [band] forms) , Increased C reactive protein, Increased

cardiac output, low systemic vascular resistance , Increased oxygen

consumption, Increased procalcitonine concentration, Increased

interleukin 6 (IL6), IL8 , Otherwise unexplained alternation in

coagulation parameter, alternation in mental status, hyperbilirubinemia ,

Increased insulin requirement. (Fink, et al., 2004)

Summary

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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 correlated with increased ICU mortality:

PO2/FiO2 ratio, Serum creatinine, Platelet count, Glasgow coma score,

Serum bilirubin, Pressure-adjusted heart rate (defined by heart rate

multiplied by the ratio of central venous pressure and mean arterial

pressure). ( Cook, et al., 2007)

Bacterial infections are the commonest aetiological agents of both

community-acquired and hospital related sepsis, but a causative organism

is confirmed in only 60% cases. Disease progression is similar regardless

of organism. However, there has been a rise in multiply resistant bacteria

such as Acinobacter species, Enterococci and methicillin resistant

Staphylococcus aureus (MRSA) .The microbiology and primary sources

of infection have undergone a remarkable transition over the past 30

years. The predominant pathogen responsible for sepsis in the 1960s and

1970s were Gram-negative bacilli; however, over the past few decades

there has been a progressive increase in the incidence of sepsis caused by

Gram-positive and opportunistic fungal pathogens. Although the

abdomen was the major source of infection in sepsis from 1970 to 1990,

in the past decade pulmonary infections have emerged as the most

frequent site of infection. (Eaton, et al., 2003)

Polymicrobial diseases, caused by combinations of viruses,

bacteria, fungi, and parasites, are being recognized with increasing

frequency. In these infections, the presence of one micro-organism

generates a niche for other pathogenic micro-organisms to colonize; one

micro-organism predisposes the host to colonization by other

microorganisms, or two or more non-pathogenic micro-organisms

Summary

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together cause disease. The medical community is recognizing the

significance of Polymicrobial diseases and the major types of microbial

community interactions associated with human health and disease. Many

traditional therapies are just starting to take into account the

polymicrobial cause of diseases and the repercussions of treatment and

prevention .Polymicrobial episodes were significantly more likely to be

hospital-acquired, to emanate from bowel or multiple foci, and to occur in

immunocompromised patients, especially those with terminal

malignancies, nonhematologic malignancies or multiple underlying

diseases (Bakaletz, et .,2004)

Sepsis is one of the oldest and most elusive syndromes in

medicine. Hippocrates claimed that sepsis was the process by which

flesh rots, swamps generate foul airs, and wounds fester.

(Majino, et al., 1991)

Galen later considered sepsis a laudable event, necessary for

wound healing (Funk, et al., 2009)

With the confirmation of germ theory by Semmelweis, Pasteur,

and others, sepsis was recast as a systemic infection, often described as

―blood poisoning,‖ and assumed to be the result of the host's invasion by

pathogenic organisms that then spread in the bloodstream. However, with

the advent of modern antibiotics, germ theory did not fully explain the

pathogenesis of sepsis: many patients with sepsis died despite successful

eradication of the inciting pathogen.Thus, researchers suggested that it

was the host, not the germ, that drove the pathogenesis of sepsis.

(Cerra, et al., 1985)

In 1992, an international consensus panel defined sepsis as a

systemic inflammatory response to infection, noting that sepsis could

Summary

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arise in response to multiple infectious causes and that septicemia was

neither a necessary condition nor a helpful term. (Bone, et al., 1992)

The incidence of severe sepsis depends on how acute organ

dysfunction is defined and on whether that dysfunction is attributed to an

underlying infection.Organ dysfunction is often defined by the provision

of supportive therapy (e.g., mechanical ventilation), and epidemiologic

studies thus count the ―treated incidence‖ rather than the actual incidence.

In the United States, severe sepsis is recorded in 2% of patients admitted

to the hospital. Of these patients, half are treated in the intensive care unit

(ICU), representing 10% of all ICU admissions. (Lidicker , et al., 2001)

Risk factors for severe sepsis are related both to a patient's

predisposition for infection and to the likelihood of acute organ

dysfunction if infection develops. There are many well-known risk

factors for the infections that most commonly precipitate severe sepsis

and septic shock, including chronic diseases (e.g., the acquired

immunodeficiency syndrome, chronic obstructive pulmonary disease, and

many cancers) and the use of immunosuppressive agents.

(Pinsky, et al., 2001)

The clinical manifestations of sepsis are highly variable, depending

on the initial site of infection, the causative organism, the pattern of acute

organ dysfunction, the underlying health status of the patient, and the

interval before initiation of treatment.The signs of both infection and

organ dysfunction may be subtle, and thus the most recent international

consensus guidelines provide a long list of warning signs of incipient

sepsis. (Levi, et al., 2003)

Acute organ dysfunction most commonly affects the respiratory

and cardiovascular systems. Respiratory compromise is classically

Summary

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manifested as the acute respiratory distress syndrome (ARDS), which is

defined as hypoxemia with bilateral infiltrates of noncardiac origin .

(Rubenfeld, et al., 2012)

Cardiovascular compromise is manifested primarily as

hypotension or an elevated serum lactate level. After adequate volume

expansion, hypotension frequently persists, requiring the use of

vasopressors, and myocardial dysfunction may occur.

(Dellinger, et al., 2013)

Before the introduction of modern intensive care with the ability to

provide vital organ support, severe sepsis and septic shock were typically

lethal. Even with intensive care, rates of in-hospital death from septic

shock were often in excess of 80% as recently as 30 years ago.

(Silva,et al., 1998)

The early management of patients with severe sepsis and septic

shock centers on the administration of antibiotics, IV fluids, and

vasoactive agents, followed by source control. However, the specific

approach to the resuscitation of patients with septic shock remains highly

controversial. However, it is likely that the early detection of sepsis with

the timely administration of appropriate antibiotics is the single most

important factor in reducing morbidity and mortality from sepsis. It has

become increasingly apparent that in many patients there is a long delay

in both the recognition of sepsis and the initiation of appropriate therapy.

This has been demonstrated to translate into an increased incidence of

progressive organ failure and a higher mortality. (Westphal , et al., 2011)



appropriate cultures have been obtained. In a retrospective analysis of

2,600 patients demonstrated that the risk of dying increased progressively

Summary

-82-

with an increase in the time to receipt of the first dose of antibiotic from

the onset of sepsis-induced hypotension.(Kumar, et al., 2008)

Beyond the early administration of antibiotics, aggressive

―supportive measures‖ may be harmful and the ―less is more‖ paradigm

appears applicable for the management of patients with severe sepsis. In

these highly vulnerable patients, more intensive treatment may promote

the chance of unwanted adverse effects and, hence, iatrogenic injury.

(Kox , et al., 2013).

In some patients, hypotension and tachycardia do resolve with

limited fluid resuscitation. However, fluids alone will not reverse the

hemodynamic instability of patients with more severe sepsis; in these

patients, fluids alone are likely to exacerbate the vasodilatory shock and

increase the capillary leak and tissue edema. Based on these data, its

better limiting the initial fluid resuscitation to approximately 20 to 30

mL/kg . It is important to emphasize that this conservative approach to

fluid management in patients with sepsis is based on indirect evidence

and not on a randomized controlled trial specifically designed to answer

this question. Furthermore, this recommendation differs somewhat from

that of the most recent Surviving Sepsis Campaign guidelines, which

suggest ―a minimum fluid challenge of 30ml/kg‖ and that ―greater

amounts of fluid may be needed in some patients. (Levi, et al., 2013)



patients with severe sepsis and septic shock. (Avwzedo, et al., 2010)

Most of these targets, however, are controversial and are not

supported by outcome data. The Surviving Sepsis Campaign guidelines

recommend a CVP of 8 to 12 mm Hg (12-15 mm Hg if mechanically

ventilated), an Scvo2 > 70%, and a urine output > 0.5 mL/kg/h as targets

for resuscitation. (Rhodes, et al., 2012)

-83-

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الملخص العربى

يعرف تسمم الدم انو استجابة الجسم لوجود عدوى ميكروبيو مع وجود درجو معينو عمى اجيزة الجسم , ويعتبرتسمم الدم الشديد والصدمو التسمميو من االسباب من التاثير

الرئيسيو لموفاه فى العنايو .وبعد ظيور نظرية المضيف )الجسم( وجد ان التسمم يحدث نتيجة التياب وىذا

االلتياب يتسبب فى رد فعل فى الجسم لمقاومة ىذا االلتياب بطرق مختمفو .مراض تقوم بتنشيط خاليا مناعيو من خالل التفاعل مع وقد وجد ان مسببات اال

مستقبالت معينو .يسبب تسمم الدم الشديد حدوث تغيرات فى تجمط الدم مما يؤدى الى حدوث تخثر الدم , ويقوم جياز المناعو بآليات مختمفو لمقاومة العدوى واالتياب , ويمعب نقص

االكسجين دورا ميما فى التسمم الشديد والصدمو التسمميو . :زيادة ضربات القمب ووجود ىذه العالمات يزيد من احتمالية وجود تسمم فى الدم

,ارتفاع درجة الحراره اكثر من 01فى الدقيقو ,انخفاض ضغط الدم اقل من 011اكثر من فى الدقيقو , نقص كمية البول , اضطراب فى 01درجو ,زيادة معدل التنفس اكثر من 83

درجة الوعى .ويتسبب التسمم الشديد والصدمو التسمميو فى حدوث فشل كموى حاد وفشل فى

تنفس )متالزمة الضائقو التنفسيو الحاده(.الوقد وضع نظام لتحديد شدة المرض يعتمد عمى مدى تأثيره عمى االجيزه المختمفو ويستند ىذا النظام عمى ستة نقاط واحده لكل من الجياز التنفسى ,القمب واالوعية

الدموية,تجمط الدم ,الكمى ,الجياز العصبى والكبد .عات لمتاكد من وجود تسمم بالدم مثل :وظائف الكمى والكبد وتوجد عدة تحاليل وأش

,صورة دم كاممو ,مزرعة دم ,اشعو عاديو ,اشعو تميفزيونيو , اشعو مقطعيو وأشعة رنين مغناطيسى وذلك لمعرفة مكان العدوى .

عالج التسمم والتسمم الشديد والصدمو التسمميو يبدأ بالمضادات الحيويو والمحاليل قابضو .واألدويو ال

ويعتبر سرعة بدء المضادات الحيويو فى العالج ىى اىم عامل فى العالج ,ولكن يجب سحب مززارع الدم قبميا.

ويعتبر دواء النورأدرينالين من اىم االدويو فى عالج الصدمو التسمميو حيث يقوم بزيادة ضغط الدم فى الجسم .

يو محل جدال .واليزال استخدام الكورتيزون فى عالج الصدمو التسممويعتبر نقل كرات دم مكدسة أو استخدام دواء الدوبيوتامين طريقة لتحسين نسبة

األكسجين فى الدم . ويعتبر اىم ىدف فى عالج تسمم الدم الشديد والصدمة التسممية ىو عالج مصدر

العدوى ولو لم يتم التحكم فيو سيؤدى ذلك إلى حدوث الوفاة .

أسباب وكيفية حدوث تسمم الدم والصدمة التسممية وييدف ىذا العمل لمعرفة والتعرف عمى الطرق الحديثة لمعالج وتأثير ذلك عمى تقميل معدل الوفاة.

الجديد فً الصدمت التسمميت فً وحدة

العنايه المركزة

رسالة

للحصول على درجة الماجستير فى طب ورعاية الحاالت الحرجه

من ةمقدم الطبيبة / مريم "محمد صالح الدين" "محمد العفيفى" وهدان

جامعة بنها -بكالوريوس الطب والجراحه

تحت إشراف

حنفً إيهاب أحمد عبد الرحمن/ أستاذ دكتىر أستاذ التخدير والعناية المركزه

جامعة بنها -كلية الطب

أحمد حمدي عبد الرحمن علً/ دكتىر والعناية المركزهمدرس التخدير جامعة بنها -كلية الطب

كلية الطب جامعة بنها

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