Adapted from The New England Journal

Of Medicine
335:16 October 2006

MANAGEMENT OF SEPSIS

A Better Understanding :

Inflammatory
Progcoagulant

Rational theurapeutic plans from which

Sepsis

Several important themes emerge

Immunosupressive aspects

1.

Rapid diagnosis ( 6 hours) and expeditious treatment are critical

2.

Multiple approaches are necessary in the treatment of sepsis

3.

It is important to select patients for each give therapy with great care

The Spectrum Of Sepsis

Suspected or proven infection plus a SIRS
(Fever, tachicardya, tachypnea, and leukocytosis
Severe Sepsis : Sepsis with organ dysfunction
(hypotension, hypoxemia, oliguria, metabolic acidosis,

SEPSIS

Thrombocytopenia, or obtudantion)
Septic shock : Severe Sepsis with hypotension, despite
adequate fluid resuscitation
Septic Shock and multiorgan dysfunction most common
causes of death in patients with sepsis
Mortality Rate : Severe Sepsis 25-30 %
Septic Shock : 40-70 %
USA : 750.000 cases of sepsis a year
Aging population : Numbers of patients infected with treatment
resistant organisms
Patients with compromised immune systems
Patients who undergo prolonged

PATHOPHYSIOLOGY
Sepsis : The culmination complex
interaction
Microorganism and the host immune
Inflammatory
coagulation responses
Rationale therapeutic targets
Progressive : Charateristic of the
microorganism
High burden of Infection
opsonization

Resistance to

Table 1 Pathway and Mediator of Sepsis ,

Potential Treatment, and Results of
Randomized, Controlled Trials (RCTs)

INNATE IMMUNITY AND INFLAMMATION IN

EARLY SEPSIS
Host defenses : - innate
- Adaptive immune system
Innate immune system responds : TLRs (Toll-likereceptors) Highly conserved molecules
microorganism
TLR-2
a peptidoglycan of gram + bacteria
TLR- 4
a lipopolysaccharide of gram bacteria
Binding-TLRs Pro inflammatory : TNF-, IL-1, ILWith epitopes 10
Antiinflammatory : IL-10
Up-regulate adhesion : molecules in
Pro
Inflammatory neutrophils and endothelial cells injure
endothelium (mediators) vascular
permeability, protein rich edema fluid ,

Figure 1. Inflammatory Responses to

Sepsis

SPECIFICITY AND AMPLIFICATION OF

THE IMMUNE RESPONES BY
ADAPTIVE IMMUNITY

Microorganisms spesific humoral and CMI Ig

APC
Type I helper

Type 2 helper

Proinflammatory
cytokines
TNF and IL-1

Antiinflammatory
cytokines
IL-4 and IL 10

Disturbance of Procoagulant Anticoagulant Balance

Alteration of the procoagulant ( )
anticoagulant ( ) balance

Lipopolysaccharide : endothelial cells tissue factor, activating

coagulation. Fibrinogen fibrin formation of microvascular thrombi
amplifying injury
Anticoagulant factors (Protein C, Protein S, antithrombin III, and
Tissue factor pathway) : Activated Protein C inactivated factors
Va and VIIIa inhibits the synthesis of PAI -1 apoptosis, adhesions
Of leukocytes and cytokine production
Sepsis : Protein C, Protein S and AT III and Tissue factor inhibitors
Lipoplysaccharide and TNF impairing the activation protein C , PAI-1
Fibinolysis
Key to and understanding of sepsis : shock and Hypoxia

Figure 2. Procoagulant in Sepsis

Immunosuppression and apoptosis in

late sepsis

Host immunosuppresions late death

Anergy
Lymphopenia
Hypothermia
Nosocomial infection
Monocytes (Sepsis) : proinflammatory citokines

Multi Organ Dysfunction

Shift to an antiinflammatory phenotype

Apoptosis of key immune, epithelial, endothelial cells
Apoptosis B cells and CD4+ T cells immunosupression
Increased levels of TNF- and lypopolysaccharide apoptosis of lung and intestinal
epithelial cells

Sepsis and Widespread Organ

Dysfunction
The altered signaling pathways tissue injury and
multiorgan dysfunction

Cardiovascula
r
dysfunction

Circulatory shock and the redistribution of

blood flow, decreased vascular resistance,
hypovolemia.
Myocardial contractility NO, TNF ,
IL-6

Respiratory
dysfunction

Increased microvascular permeability

acute lung injury

Renal
dysfunction

Morbidity and Mortality

Treatment According to the early and

later stages of sepsis
Emergency care : early stage ( 0 to 6 hours)
Critical care
: later stages
Emergency management in early stage goal
directed therapy, lung protective ventilation, broad
spectrum antibiotics and possibly activated protein
C.
Rivers and collegaues Randomized, controlled
trial patients Severe sepsis and Septic shock
Group receiving early : Goal directed therapy,
central venous oxygen saturation was monitored
continously with the use of a central venous
cathether

Figure 3. Therapeutic Plan Based on

the Early and Later stages of Sepsis

Table 2 Results of Positive Randomized,

Control Trialis

The protocol

Cristalloids : Maintain CVP at 8 to 12 mm Hg

Vasopressor : MAP < 65 mm Hg
Central venous oxygen saturation < 70 % : Erythrocytes
Transfusion Ht : 30 %
Dobutamine : CVP, MAP , Ht and venous oxygen saturation
< 70 %
Early goal directed therapy : mortality at 28 and 60 days
Of hospitalization
Mechanisms ( 7- 72 hours) : Reversal of tissue hypoxia,
inflammation and coagulation defects

Ventilation
Lung protective ventilation ( acute lung injury)
Goal directed therapy
Mortality
Beneficial in septic acute lung injury
Tidal volume 6 cc/kg of Ideal Body weight
( 4cc/Kg ideal body weight / plateau pressure >
30 cmH2O : Organ
dysfunction and lower levels of cytokines
Caution / Avoided with sedation and
Neuromuscular blocking agents nosocomial
pneumonia and prolonged neuromuscular
dysfunction

Broad Spectrum Antibiotics

Intravenous broad spectrum antibiotics administred expeditiously :

The Site of infection and responsible microorganisms are usually
not known initially in patient with sepsis.
Prevalence of fungi, gram positive bacteria, hyghly resistant gram
negative bacilli, MRSA, VRE and PRP
Observational studies : Sepsis and septic shock are worse if the
causative microorganisms are not sensitive to the initial antibiotic
regimen

Activated Protein C
Therapy Activated Protein C (goal-directed
therapy) :
24 g/Kg/hour for 96 hour) mortality rate (13
%) and to ameliorate organ dysfunction in
patients with severe sepsis
Activated protein C : Lack of effectiveness with
low risk patient
PROWESS (Protein C Worldwide Evaluation in
Severe Sepsis) trial : serious bleeding among
patients receiving activated protein C than
among patients in the placebo group
ENHANCE U.S (Extended Evaluation of
Recombinant Human Activated Protein C United
States) : Intracranial hemorraghe 0.6 % of
patients given activated protein C.
Meningitis and severe thrombocytopenia : risk
factors for

 Activated protein C : Cost effective for patients

with severe sepsis and a high risk of death.
The mechanism of action by which activated
protein C : clinical outcome is unknown.
Activated protein C : protein C and marker
of thrombin generation ( D dimer), prevent
hypotension, it has little effect on coagulation in
human intravenous endotoxin model of sepsis
Anticoagulant therapies (AT III, Tissue pathway
inhibitor)
was effective complex antiinflammatory,
antiapoptotic and anticoagulant actions

Treatment of Anemia in Sepsis

Anemia in sepsis : TNF , IL 1 : the expression
of the
erythropoietin gene and protein
Rivers et al : hematoctrit of 30 % as a threshold for
transfusion in early sepsis as part of a- 6-hour
protocol improved outcome
Hebert et al compared Hb values of 70 and 100 g
/dl as a threshold for transfusion in the course of
critical care There was no significant in mortality
Transfusion is worthwhile if needed during the
emergency
stage of sepsis (mantaining hb levels at 70-90 g/dl)
after the first 6 hours to decrease transfusion
requirements

Corticosteroids in patients who require critical

care
Corticosteroid in sepsis ?
Randomized, controlled trials : Early short
/shortcourse (48 hours) of high dose
corticosteroid doesnot improve survival in severe
sepsis
Severe controversies :
1. The concept of adrenal insufficiency in sepsis
2. Only two (of five) small randomized controlled
trials
low dose hydrocortisone the need for
vasopressor support in patients with sepsis
3. Only one adequately powered trial reported a
survival
benefit of such treatment in patients who had
no

 Anna and colleagues : Evaluated oliguric patients with

vasopressor-dependent septic shock who required
ventilation

Patient underwent 250 g corticotropin stimulation test : classified as

having adrenal insufficiency (no responses) when the serum total cortisol
level rose by less than 10 g/dl)
Randomly assigned to receive placebo
Hydrocortisone + fludrocortisone for 7 days

Improved survival both in the overall cohort and the prospectively sub group
Of patients who had no response to corticotropin (Over a 28 day period,
the differece in mortality was not significant (p = 0.09)
Patietns without respon corticotropin (corticosteroid) had significantly lower morta
lity than patients who received placebo.

 Observational studies : No data that indicate how patients respond to cortico

steroids and thus provide limited guidance as compared with randomized,
controlled trials
Marik and Zaloga : 95 % of patients in septic shock cortisol level < 25 g/dl
/ < 15 g/dl relative adrenal insufficiency
Hamrahian and colleagues reported : critically ill patients with hypoalbuminemia
Corticotropin-stimulated serum total cortisol levels subnormal but corticotropin stimu
lated serum free cortisol levels were higher than normal 6 -10 weeks after
discharge : CSS free cortisol levels had declined to the normal range.
Corticosteroid : Treatment of persisten ARDS
Mortality was lower among those given placebo in one small trial
Randomized clinical trial : No difference between groups 60-day
mortality
Adverse effects in patients with sepsis: neuromyopathy, hyperglicemia, numbers
of lymphocytes, immunosupression and loss of epithelial cells through apoptosis
The immunosuppresion corticosteroid : Nosocomial infection and impaired
wound healing
Randomized, controlled trials early use of short course, high dose corticosteroid
doesnot improve survival in severe sepsis

Evaluation and Control of The Source of

Sepsis
Succesful management of critical care
stage
of sepsis Affected Organ (20 % of
patients
have negative cultures)

Antibiotic Regimen Antibiotic

Resistance
Imaging to search of Sepsis (USG, CT
Scan,
Thoracocentesis)

Vasopressin
Vasopressin : Septic shock

Vasopressin Therapy : (0.03-0.04 U/mnt

Dilates renal, pulmonary, cerebral

Blood pressure, urinary output, and

Creatinine clearence,

And coronary arteries

SE : intestinal ischemia, cardiac output,
Skin necrosis, cardiac arrest (>0.04 U/mnt

Small studies : Inhibition of nitric oxide synthase with NG

Methyl arginine hydrochloride mortality

HYPERGLYCEMIA AND INTENSIVE INSULIN

THERAPY
Pro Coagulant
HYPERGLYCEMIA

Apoptosis
Impairs neutrophil function
Increased The risk of infection
Impairs wound healing
Increased risk of death

Insulin Therapy : Antiinflammatory, Anticoagulant and

Antiapoptotic actions
DECREASE

The rate of death in the ICU

Van den Berghe : Insulin infusion maintain

(< 5 days)

Blood glucose level :

Prevalence of prolonged ventilaory support

4.4 -6.1 mmol (intensive insulin dose)

Renal replacement therapy

10.0-11.1mmol (conventional insulin dose)

Peripheral neuromuscular dysfunction

Bacteriemi

Mortality : No significant difference in mortality with the use of Intensive or

Conventional insulin therapy

Intensive insulin therapy decreased the rate of date among patients who
remained in the ICU for 3 or more days but increased the rate
Of death among patients whose stay lasted fewer than 3 days

The Mechanism intensive insulin therapy ?

Induction of euglycemia
Antiinflammatory
Protects endothelial and mitochondrial function

Intensive insulin therapy : Beneficial in surgical patients

The lack of efficacy in medical patients Risk factor patient who have a short stay in the ICU
Equipose

 Renal Dysfunction and Dialysis

Acute Renal Failure

Morbidity
Mortality

Low Dose Dopamine (2-4 g /kg/minute)

Neither decreases the need for renal
Support nor improves survival
Sodium bicarbonate : Improves neither hemodynamics
Nor the response to vasopressor medications

CRRT

SUPPORT AND GENERAL CARE

The goal of cardiovascular support

Central Venous oxygen saturation > 70 % (first 6 hours ?)

Adequate perfusion
Respiratory support : Tidal volume of 6 ml per kilogram

Deep Vein thrombosis : Prophylatic heparin Activated protein C

Recommended for patients who do not have active bleeding or coagulopathy
Enteral Nutrition : Safer and more effective than parenteral nutrition
Parenteral Nutrition : Abdominal Sepsis, surgery, or trauma
Sepsis with mechanical ventilation : Stress ulcer prophylaxis with the use of histamine
H2-receptor antagonist gastrointestinal hemorrhage
Sedation, neuromuscular-blocking agents and corticosteroids should be minimized Exacerbate the
Septic encephalopathy,polyneuropathy, and myopathy of sepsis.
Decreased risk of nosocomial Infection : Narrow spectrum antibiotics, weaning patients from
ventilation, avoiding immunosupression and removing catheters

Ineffective therapies

Several types of therapy have proven ineffective :

Antilipopolysaccharide : It was applied late (after the polysaccharide

peak in sepsis / the antibodies used lacked the ability to neutralize
Lypopalysaccharide)
Numerous therapy (block proinflammatory cytokines) : immunosuppressiv e,
Ibuprofen, Platelet activating factor aceylhydrolase, bradykinin antagonists
(-) improved survival among patients with sepsis

Potential New Therapies

Potential theurapeutic targets :Superantigens and mannose

Inhibition of tissue factor ( a proximal target) : mitigate

Excessive procoagulant activity.
Strategies to boost immunity :Improve the outcome
Of sepsis
Interferon gama : Imporved macrohage function and
Increased survival in one study of sepsis
Anticaspases : Improved survival in an animal model
Of sepsis
Lipid emulsion (Phase 3 trial) : Binds and neutralizes
Lippolysaccharide, and modulate innate immunity
by inhibiting lipopolysaccaride

SUMMARY
Optimal Management Of Sepsis

Goal directed therapy

Lung protective ventilation
Antibiotics
Possibly activated protein C

Further Study : Corticosteroid, vasopressin and intensive insulin therapy

Sepsis : Appropiate management necessitates : Organ support and prevention of nosocomial
Infection
Studies focused : Novel Target, Mechanisms of action and combination therapy
may improve current treatment