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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