Sepsis, EGDT, and Source Control

Perioperative and Acute Care Surgery Course

BITDEC, APRIL 2012

Objectives

• 15 minutes for definition and clinical aspect of sepsis– Patophysiology of sepsis

– Intervention in septic patients SSC

• 10 minutes to explain about Early Goals Directed therapy– Algorithm of EGDT

– Clinical implication of EGDT

• 10 minute for source control in sepsis • 10 minutes Discussion

Stages of SepsisConsensus Conference Definition

• Systemic Inflammatory Response Syndrome (SIRS)Two or more of the following:

– Temperature of >38oC or <360C

– Heart rate of >90

– Respiratory rate of >20

– WBC count >12 x 109/L or <4 x 109/L or 10% immature forms (bands)

• SepsisSIRS plus a culture-documented infection

• Severe SepsisSepsis plus organ dysfunction, hypotension, or hypoperfusion(including but not limited to lactic acidosis, oliguria, or acute mental status changes)

• Septic ShockHypotension (despite fluid resuscitation) plus hypoperfusion

*Severe SIRS/Sepsis includes some evidence of organ failureBone RS, 1997

SIRS / Sepsis

SIRSInfection

Other

Trauma

Burns

Pancreatitis

Bacteremia (septicemia)

Fungal

Parasit.

OtherVir.

Sepsis

Microbial product, trauma, ischemia

reperfusion injury, ect

Rapid activation of the innate immune response and release of a

variety of humoral mediator

Human Immune Response to Sepsis caused by Injury/ Infection is

orchestrated by complex interactions of soluble mediator and cellular

elements

Process of The Inflammatory Response to Sepsis, 5 phases :

1. Recognition of microbial contamination or tissue injury

2. Release of Signaling Molecules

3. Recruitment of Cellular Effectors

4. Destruction of Invading Microbes and Metabolism of Injured Tissue

5. Restoration of Tissue Integrity

Sepsis Mediator

Signal transduction Chemo taxisPhagocytosis

Cytokine receptor up regulation

Shed cytokine receptor Adherens Shed adhesion

molecule

Released enzyme

Secreted mediator

receptor

recognition

Immunoglobulin, LPS, LBP, CD14,

complement systemPhase 1

Phase 2

Phase 3

Phase 4

General cellular response in sepsis

Rapid activation of host defenses expressed by the activation of :

• Plasma Protein System / Humoral system ( coagulation cascade, complement cascade,

kallikrein kinin system)

• Cellular defense system ( phagocytes, endothelium, lymphocytes, neutrophils )

• Uncontrolled activation of this protein cascades and release of inflammatory mediators result in

systemic inflammation

Endothelium

Neutrophil

Monocyte

IL-6IL-1TNF-

IL-6

Inflammatory Response

Thrombotic Response

Fibrinolytic Response

TAFI

PAI-1

Suppressedfibrinolysis

Factor VIIIaTissue Factor

COAGULATION CASCADE

Factor Va

THROMBIN

Fibrin

Fibrin clotTissue Factor

Organisms

(Shock, Trauma, Operations, Pulmonary insufficiency, Anesthesia, Infections,

MOF)

cytokines

Impaired of anticoagulant

pathway

Generation thrombin mediated

by tissue factor

Suppression of fibrinolysis by PAI - 1

Formation of fibrin Attenuation of AT III, Protein C,

TFPI

Inadequate removal of fibrin

Anti-coagulant tendencyprocoagulant

Attenuate cellular Immune defense

lead to poor healing or prolonged infection

Robust Response may precipitate shock and MOF

Proper balance to regulate systemic & local immune function

Primary circulating cells that participate in septic response : mononuclear phagocyte & neutrophils

Support the role of T cell, B cell, and Natural

Killer ( NK) cells

Produced :

Pro inflammatory mediators

Anti inflammatory mediators

Growth factors

Initial insultLocal Pro

inflammatory response

Local Anti inflammatory

response

Systemic reaction

SIRS

CARS

Cardiovascular compromised

Homeostasis CARS and

SIRS balance

Apoptosis death with minimal

inflammation

Organ Dysfunction

SIRS predominate

Suppression of immune system

CARS predominate

Systemic spill over of pro

inflammatory mediators

Systemic spill over of anti

inflammatory mediator

Host Response to Injury

Inflammation Complement activation Endothelial activation injury Vasodilatation Microcirculatory leakage forming protein rich edema Expression of Adhesion Molecules, cytokines, growth factor Extravasations of PMN cells and monocytes Respiratory burst and phagocytosis Removal of debris

Coagulation

Activation of Coagulation Inhibition of fibrinolysis Systemic enhancement of fibrinolysis

1

2

Host Response to Injury

Systemic Inflammatory System

Fever Induction of acute phase protein Stimulation leukocyte proliferation in bone marrow Activation and / or proliferation of B and T lymphocyte depending on stimuli

Metabolic Response

Increased cortisol production Activation of sympathetic nervous system Reduction of active thyroid hormone

Repair Apoptosis of inflammatory cell Regeneration of parenchyma cell Angiogenesis Proliferation of epithelia and fibroblasts

3

4

5

Stress Response ( neuroendocrine response )

A. Afferent stimuli (Shock, Trauma, Operations, Pulmonary

insufficiency, Anesthesia, Infections, MOF)

B. Transmitters ( Blood and lymphatics, peripheral

nerves, CNS)

C. Effector site

Sympathetic nerv syst Hypothalamus Kidney Pancr islets

Adrenal medula Ant pituitary Post pituitary

Epinephrn

norepinephr

Adr cortex

Cortison, aldostr, G.H

ADH

Renin, angiotens Glukagon

InsulinAldostrn

Approach to Management

Therapy Across the Sepsis Continuum

Chest 1992;101:1644.

SepsisSIRSSevere

SepsisSeptic

Shock

Antibiotics and Source ControlChest 2000;118(1):146

62%

28%

Drainage

Debridement

Device removal

Definitive control

• resection

• amputation

Therapy Across the Sepsis Continuum

Chest 1992;101:1644..

SepsisSIRSSevere

SepsisSeptic

Shock

Early Goal Directed Therapy

Antibiotics and Source ControlEarly Goal-Directed Therapy (EGDT): involves adjustments of cardiac preload, afterload, and contractility to balance O2 delivery with O2 demand

SepsisSIRSSevere

SepsisSeptic

Shock

Xigris (Drotrecogin)

Insulin and tight glucose control – DVT prophylactic

Early Goal Directed Therapy

Antibiotics and Source Control

Therapy Across the Sepsis Continuum

SepsisSIRSSevere

SepsisSeptic

Shock

Drotrecogin

Insulin and tight glucose control – DVT prophylactic

Early Goal Directed Therapy

Steroids

Antibiotics and Source Control

Chest 1992;101:1644..

Therapy Across the Sepsis Continuum

• Initial resuscitation and Infections Issues

• Indicates a strong recommendation “we recommend”

• Indicates a weak recommendation “we suggest”

• Initial resuscitation (first 6 hrs)

Initial Resuscitation

• Begin resuscitation immediately in patients with hypotension or elevated serum lactate 4 mmol/L; do not delay pending ICU admission (1C)

• Resuscitation goals (1C) – CVP 8–12 mm Hg – MAP≥ 65 mm Hg – Urine output 0.5 – 1 mL/kg/hr

• Central venous (superior vena cava) oxygen saturation 70% or mixed venous 65%

• If venous oxygen saturation target is not achieved (2C) – Consider further fluid – Transfuse packed red blood cells if required to hematocrit of 30% and/or– Start dobutamine infusion, maximum 20μg/kg/min

PROTOCOL OF EARLY GOAL-DIRECTED THERAPY

Diagnosis

• Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C)– Obtain two or more BCs

– One or more BCs should be percutaneous

– One BC from each vascular access device in place > 48 hrs

– Culture other sites as clinically indicated

• Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)

Antibiotic therapy• Begin intravenous antibiotics as early as possible and always

within the first hour of recognizing severe sepsis (1D) and septic shock (1B)

• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source (1B)

• Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs (1C)– Consider combination therapy in Pseudomonas infections (2D)– Consider combination empiric therapy in neutropenic patients (2D)– Combination therapy 3–5 days and de-escalation following

susceptibilities (2D)• Duration of therapy typically limited to 7–10 days; longer if

response is slow or there are undrainable foci of infection or immunologic deficiencies (1D)

• Stop antimicrobial therapy if cause is found to be noninfectious (1D)

Source identification and control

• A specific anatomic site of infection should be established as rapidly as possible (1C) and within first 6 hrs of presentation (1D)

• Formally evaluate patient for a focus of infection amenable to source control measures (e.g. abscess drainage, tissue debridement) (1C)

• Implement source control measures as soon as possible following successful initial resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is best delayed) (2B)

• Choose source control measure with maximum efficacy and minimal physiologic upset (1D)

• Remove intravascular access devices if potentially infected (1C)

Fluid Therapy

• Fluid-resuscitation using crystalloids or colloids (1B)• Target a CVP of 8 mm Hg (12 mm Hg if mechanically

ventilated) (1C)• Use a fluid challenge technique while associated with a

hemodynamic improvement (1D)• Give fluid challenges of 1000 mL of crystalloids or 300–500

mL of colloids over 30 mins • More rapid and larger volumes may be required in sepsis-

induced tissue hypoperfusion (1D)• Rate of fluid administration should be reduced if cardiac

filling pressures increase without concurrent hemodynamic improvement (1D)

Vasopressor

• Maintain MAP 65 mm Hg (1C)• Norepinephrine and dopamine centrally administered are the

initial vasopressors of choice (1C)• Epinephrine, phenylephrine, or vasopressin should not be

administered as the initial vasopressor in septic shock (2C) • Vasopressin 0.03 units/min may be subsequently added to

norepinephrine with anticipation of an effect equivalent to norepinephrine alone

• Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly responsive to norepinephrine or dopamine (2B)

• Do not use low-dose dopamine for renal protection (1A)• In patients requiring vasopressors, insert an arterial catheter as

soon as practical (1D)

Inotropic

• Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output (1C)

• Do not increase cardiac index to predetermined supranormal levels (1B)

Steroid • Consider intravenous hydrocortisone for adult septic shock when

hypotension responds poorly to adequate fluid resuscitation and vasopressors (2C)

• ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone (2B)

• Hydrocortisone is preferred to dexamethasone (2B)• Fludrocortisone (50 g orally once a day) may be included if an

alternative to hydrocortisone is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional if hydrocortisone is used (2C)

• Steroid therapy may be weaned once vasopressors are no longer required (2D)

• Hydrocortisone dose should be 300 mg/day (1A)• Do not use corticosteroids to treat sepsis in the absence of shock

unless the patient’s endocrine or corticosteroid history warrants it (1D)

Recombinant activated protein C

• Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II 25 or multiple organ failure) if there are no contraindications (2B, 2C for postoperative patients).

• Adult patients with severe sepsis and low risk of death (typically, APACHE II 20 or one organ failure) should not receive rhAPC (1A)

OTHERS

Blood product administration

Mechanical ventilation of sepsis-induced ALI/ARDS

Sedation, analgesia, and neuromuscular blockade in sepsis

Glucose control

Renal replacement

Bicarbonate therapy

Deep vein thrombosis prophylaxis

Stress ulcer prophylaxis

Consideration for limitation of support

Source ControlSource Control

Historical Perspective

• Alfred Blalock (early 20th century)shock – intravascular volume deficit

• Fleming (1920s) – penicillin

• Surgical management of infection– Trephination – 10,000yr old skull

– Egyptians, Babylonians, Greeks, Romans

– Ambroise Pare (15th century) drainage of abcess

– Appendiceal abcess incision & drainage (1530)

– First appendectomy by Groves 1883 Canada

Scientific Basis• Rationale for surgical intervention: unlikely randomized controlled trial intervention vs nonintervention is undertaken

• Source control should be individualized based on:– Diagnostic uncertainty

– Physiologic stability

– Premorbid health status

– Previous surgical interventions

– Surgeon’s experience & skill

– Available surgical facilities

What is Source Control?

• All those physical measures that are undertaken– To eliminate a focus of infection– To control ongoing contamination– To restore premorbid anatomy &

function

What is Source Control?

• Not always surgical procedures, also include– Radiologically directed drainage of

intracavitary abscess– Removal of colonized urinary or vascular

catheter– Removal of devitalized tissue by frequent

dressing changes

Definitions of termsTerm Definition

Source control All physical measures undertaken to eliminate a source of infection, control ongoing contamination, and restore premorbid anatomy and function

Sinus Abnormal communication to an epithelial cell-lined surface

Fistula Abnormal communication between two epithelial cell-lined surfaces

Abcess Fluid-filled collection of tissue fluid, tissue debris, neutrophis, and bacteria contained within a fibrous capsule

Drainage Creation of a controlled sinus or fistula

Debridement Removal of devitalized tissue, foreign bodies, or other areas advantageous to bacterial growth

Principles of Source Control

• Drainage of abscess

• Debridement of nonviable of infected tissue

• Definitive management of the anatomic abnormality responsible for ongoing microbial contamination restoring normal function and anatomy

Drainage

• Converting a contained collection to a controlled fistula (to exterior) or sinus

• Drain must permit free flow of the abscess• Minimum risk and physiologic derangement:

percutaneous drainage• Modern imaging: all collections can be

visualized preoperatively• In unstable and ill patient – surgery for

controlled sinus/fistula & removal of dead tissue only

Debridement

• The process of removing nonviable tissue

• Directed against solid components that promote bacterial growth

• Demarcation between viable and nonviable tissue maybe not absolute at early stage

• Gentle debridement use wet to dry saline dressing

Debridement

• Remove all necrotic tissue but minimize the resulting defects for easier reconstruction

• Bleeding from viable tissue is better than fail to debride necrotic material

DebridementNecrotic bowel

• Excision for necrotic bowel is more complex

• The benefits of resection must be weighed against the consequences of loss of bowel length

• The dilemma is usually best resolved by a planned second-look laparotomy

DebridementForeign body

• Risks are minimal when urinary or vascular catheter is infected

• Risks are high when aortic graft or heart valve is infected

Definitive management

• The ultimate aim of therapy: – to restore function with the least risk– To correct the abnormality that created the

infection

Biologic Rationale

• Host defenses are occasionally incapable of combating the introduction of microbes and establishment of infection– When large number of microbes are present– When host defenses are diminished– Ongoing source of microbial contamination

• Inadequate source control increases morbidity and mortality up to 7 folds

Drainage

• Percutaneous abscess drainage (PD) is preferred

• Indication of operative intervention– When PD has failed– When absolute contraindications to PD

• PD can temporize, permitting delayed definitive management

Debridement & Peritoneal Toilet

• The degree of peritoneal contamination correlates with the severity of infection & outcome

• The goal of peritoneal toilet to remove mechanically as many contaminants as possible reducing infection severity

Device Removal

• Make sure the diagnosis of infection is secure

• Determine whether device removal would pose a significant risk

• Assess complicating factors (virulence, immunosuppression) and the history (previous therapy failed)

• When in doubt, take it out

Definitive vs Temporizing

• The judgement to select a temporizing vs definitive requires an integrated assessment of– The surgeon’s knowledge about the

underlying disease– Systemic host factors– Severity of the local inflammatory

response

Extent of Surgical Therapy

• The more extensive the initial intervention, the greater is the challenge of subsequent reconstruction

• The optimal intervention is that which accomplishes the source control objectives in the simplest manner

Failed Source Control

• Failure of source control is more important than antibiotic failure

• Cause of failure:– Poor choice of operation– Correct operation performed poorly– Poor timing

• Consequences of failure:– Nosocomial infections– Nutritional and metabolic disorders– Multiple organ dysfunction syndrome

Diffuse Peritonitis

• Aggressive initial surgical source control : intraoperative lavage

• If source control not possible– Continuous lavage– Laparostomy– Planned reexploration– Or combination of above

Timing of Intervention

• As general principle: as soon as possible

• Rapid, minimally invasive, temporizing or palliative measures may be superior to definitive but lengthy, more traumatizing procedures

Complications of Source Control

• Complications from– Technical error– Local factors that impair healing

Reconstructive Surgery after Source Control

• Reoperation should be delayed for several months following resolution of all complications from the source control operation

• Timing is very important

• Enter peritoneal cavity through a “virgin area” of the abdominal wall

Evaluating Adequacy of Source Control

• No single test can measure whether adequate source control has been achieved

• If ongoing intraabdominal infection is suspected CT scan before surgery

Empiric Reexploration:Is there a role?

• The need for relaparotomy significantly worsens the outcome

Conclusion

• The key to success when treating surgical infections is timely intervention to stop the delivery of bacteria and adjuvants of inflamation/infection into the peritoneal cavity

• All others are useless if source control failed

Thank you