Sepsis, EGDT, and Source ControlPerioperative and Acute Care Surgery Course

Objectives 10 minutes for definition and clinical aspect of sepsisPatophysiology of sepsis Intervention in septic patients SSC 15 minutes to explain about Early Goals Directed therapyAlgorithm of EGDTClinical implication of EGDT20 minute for source control in sepsis

Stages of SepsisConsensus Conference DefinitionSystemic Inflammatory Response Syndrome (SIRS) Two or more of the following:Temperature of >38oC or 90Respiratory rate of >20WBC count >12 x 109/L or

*Severe SIRS/Sepsis includes some evidence of organ failureSIRS / Sepsis

Microbial product, trauma, ischemia reperfusion injury, ectRapid 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 : Recognition of microbial contamination or tissue injury Release of Signaling Molecules Recruitment of Cellular Effectors Destruction of Invading Microbes and Metabolism of Injured Tissue Restoration of Tissue Integrity

Sepsis MediatorSignal transductionChemo taxisPhagocytosisCytokine receptor up regulationShed cytokine receptorAdherensShed adhesion moleculeReleased enzymeSecreted mediatorreceptorrecognitionImmunoglobulin, LPS, LBP, CD14, complement systemPhase 1Phase 2Phase 3Phase 4General 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

EndotheliumOrganisms(Shock, Trauma, Operations, Pulmonary insufficiency, Anesthesia, Infections, MOF)

cytokinesImpaired of anticoagulant pathwayGeneration thrombin mediated by tissue factorSuppression of fibrinolysis by PAI - 1Formation of fibrinAttenuation of AT III, Protein C, TFPI Inadequate removal of fibrinAnti-coagulant tendencyprocoagulant

Attenuate cellular Immune defense lead to poor healing or prolonged infection

Robust Response may precipitate shock and MOFProper balance to regulate systemic & local immune function

Primary circulating cells that participate in septic response : mononuclear phagocyte & neutrophilsSupport the role of T cell, B cell, and Natural Killer ( NK) cellsProduced : Pro inflammatory mediators Anti inflammatory mediatorsGrowth factors

Initial insultPro inflammatory responseAnti inflammatory responseSystemic reactionSIRS CARSCardiovascular compromisedHomeostasis CARS and SIRS balanceApoptosis death with minimal inflammationOrgan Dysfunction SIRS predominateSuppression of immune system CARS predominateSystemic spill over of pro inflammatory mediatorsSystemic spill over of anti inflammatory mediator

Host Response to InjuryInflammation 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 debrisCoagulation Activation of Coagulation Inhibition of fibrinolysis Systemic enhancement of fibrinolysis12

Host Response to InjurySystemic 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 ResponseIncreased cortisol production Activation of sympathetic nervous system Reduction of active thyroid hormoneRepair Apoptosis of inflammatory cell Regeneration of parenchyma cell Angiogenesis Proliferation of epithelia and fibroblasts345

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 siteSympathetic nerv syst Hypothalamus Kidney Pancr islets Adrenal medulaAnt pituitaryPost pituitaryEpinephrnnorepinephrAdr cortexCortison, aldostr, G.HADHRenin, angiotensGlukagonInsulinAldostrn

Approach to Management

Therapy Across the Sepsis ContinuumChest 1992;101:1644.Antibiotics and Source ControlChest 2000;118(1):14662%28%DrainageDebridementDevice removalDefinitive controlresectionamputation

Therapy Across the Sepsis Continuum Chest 1992;101:1644.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

Xigris (Drotrecogin)Insulin and tight glucose control DVT prophylactic - FASTHUG Early Goal Directed Therapy Antibiotics and Source ControlTherapy Across the Sepsis Continuum

Drotrecogin

Insulin and tight glucose control DVT prophylactic - FASTHUG

Early Goal Directed Therapy SteroidsAntibiotics and Source ControlChest 1992;101:1644.Therapy Across the Sepsis Continuum

Initial resuscitation and Infections Issues Indicates a strong recommendation we recommend Indicates a weak recommendation we suggestInitial resuscitation (first 6 hrs)

Initial ResuscitationBegin resuscitation immediately in patients with hypotension or elevated serum lactate 4 mmol/L; do not delay pending ICU admission (1C)Resuscitation goals (1C) CVP 812 mm Hg MAP 65 mm Hg Urine output 0.5 1 mL/kg/hrCentral 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/orStart dobutamine infusion, maximum 20g/kg/min

Diagnosis Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C)Obtain two or more BCsOne or more BCs should be percutaneousOne BC from each vascular access device in place > 48 hrsCulture other sites as clinically indicatedPerform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)

Antibiotic therapyBegin 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 35 days and de-escalation following susceptibilities (2D)Duration of therapy typically limited to 710 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 controlA 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 TherapyFluid-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 300500 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 aloneUse 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 patients endocrine or corticosteroid history warrants it (1D)

Recombinant activated protein CConsider 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)

Source ControlReno Rudiman

Historical PerspectiveAlfred Blalock (early 20th century) shock intravascular volume deficitFleming (1920s) penicillinSurgical management of infectionTrephination 10,000yr old skullEgyptians, Babylonians, Greeks, RomansAmbroise Pare (15th century) drainage of abcessAppendiceal abcess incision & drainage (1530)First appendectomy by Groves 1883 Canada

Scientific BasisRationale for surgical intervention: unlikely randomized controlled trial intervention vs nonintervention is undertakenSource control should be individualized based on:Diagnostic uncertaintyPhysiologic stabilityPremorbid health statusPrevious surgical interventionsSurgeons experience & skillAvailable surgical facilities

What is Source Control?All those physical measures that are undertakenTo eliminate a focus of infectionTo control ongoing contaminationTo restore premorbid anatomy & function

What is Source Control?Not always surgical procedures, also includeRadiologically directed drainage of intracavitary abscessRemoval of colonized urinary or vascular catheterRemoval of devitalized tissue by frequent dressing changes

Definitions of terms

TermDefinitionSource controlAll physical measures undertaken to eliminate a source of infection, control ongoing contamination, and restore premorbid anatomy and functionSinusAbnormal communication to an epithelial cell-lined surfaceFistulaAbnormal communication between two epithelial cell-lined surfacesAbcessFluid-filled collection of tissue fluid, tissue debris, neutrophis, and bacteria contained within a fibrous capsuleDrainageCreation of a controlled sinus or fistulaDebridementRemoval of devitalized tissue, foreign bodies, or other areas advantageous to bacterial growth

Principles of Source ControlDrainage of abscessDebridement of nonviable of infected tissueDefinitive management of the anatomic abnormality responsible for ongoing microbial contamination restoring normal function and anatomy

DrainageConverting a contained collection to a controlled fistula (to exterior) or sinusDrain must permit free flow of the abscessMinimum risk and physiologic derangement: percutaneous drainageModern imaging: all collections can be visualized preoperativelyIn unstable and ill patient surgery for controlled sinus/fistula & removal of dead tissue only

DebridementThe process of removing nonviable tissueDirected against solid components that promote bacterial growthDemarcation between viable and nonviable tissue maybe not absolute at early stageGentle debridement use wet to dry saline dressing

DebridementRemove all necrotic tissue but minimize the resulting defects for easier reconstructionBleeding from viable tissue is better than fail to debride necrotic material

DebridementNecrotic bowelExcision for necrotic bowel is more complexThe benefits of resection must be weighed against the consequences of loss of bowel lengthThe dilemma is usually best resolved by a planned second-look laparotomy

DebridementRetroperitoneumPeripancreatic retroperitoneal necrosis is well toleratedBlind exploration of retroperitoneum risk of uncontrollable hemorrhageDelayed debridement is preferred for suspected infected necrosis

DebridementForeign bodyRisks are minimal when urinary or vascular catheter is infectedRisks are high when aortic graft or heart valve is infected

Definitive managementThe ultimate aim of therapy: to restore function with the least riskTo correct the abnormality that created the infection

Biologic RationaleHost defenses are occasionally incapable of combating the introduction of microbes and establishment of infectionWhen large number of microbes are presentWhen host defenses are diminishedOngoing source of microbial contaminationInadequate source control increases morbidity and mortality up to 7 folds

DrainagePercutaneous abscess drainage (PD) is preferredIndication of operative interventionWhen PD has failedWhen absolute contraindications to PD

PD can temporize, permitting delayed definitive management

Debridement & Peritoneal ToiletThe degree of peritoneal contamination correlates with the severity of infection & outcomeThe host responds to peritoneal infection by absorbing pathogens into the bloodstream & by mounting a local peritoneal inflammatory reaction kill bacteria but affect the hostThe goal of peritoneal toilet to remove mechanically as many contaminants as possible reducing infection severity

Device RemovalMake sure the diagnosis of infection is secureDetermine whether device removal would pose a significant riskAssess complicating factors (virulence, immunosuppression) and the history (previous therapy failed)When in doubt, take it out

Definitive vs TemporizingThe judgement to select a temporizing vs definitive requires an integrated assessment ofThe surgeons knowledge about the underlying diseaseSystemic host factorsSeverity of the local inflammatory response

Extent of Surgical TherapyThe more extensive the initial intervention, the greater is the challenge of subsequent reconstructionThe optimal intervention is that which accomplishes the source control objectives in the simplest manner

Failed Source ControlFailure of source control is more important than antibiotic failureCause of failure:Poor choice of operationCorrect operation performed poorlyPoor timingConsequences of failure:Nosocomial infectionsNutritional and metabolic disordersMultiple organ dysfunction syndrome

Diffuse PeritonitisAggressive initial surgical source control : intraoperative lavageIf source control not possibleContinuous lavageLaparostomyPlanned reexplorationOr combination of above

Timing of InterventionAs general principle: as soon as possibleRapid, minimally invasive, temporizing or palliative measures may be superior to definitive but lengthy, more traumatizing procedures

Complications of Source ControlComplications fromTechnical errorLocal factors that impair healing

Reconstructive Surgery after Source ControlReoperation should be delayed for several months following resolution of all complications from the source control operationTiming is very importantEnter peritoneal cavity through a virgin area of the abdominal wall

Evaluating Adequacy of Source ControlNo single test can measure whether adequate source control has been achievedIf ongoing intraabdominal infection is suspected CT scan before surgery

Empiric Reexploration:Is there a role?The need for relaparotomy significantly worsens the outcome

ConclusionThe key to success when treating surgical infections is timely intervention to stop the delivery of bacteria and adjuvants of inflamation/infection into the peritoneal cavityAll others are useless if source control failed

Thank you

**Endogenous Activated Protein C has multiple mechanisms of action. The diverse effects of the endogenous protein include:Modulation of the inflammatory response to infection by:Inhibiting TNF- production by monocytesBlocking leukocyte adhesion to selectinsLimiting the thrombin-induced inflammatory response within the microvasculatureAntithrombosis by:Inhibition of coagulation Factors Va and VIIIaPreventing amplification of the coagulation process by downregulating thrombin generationProfibrinolysis by:Inhibiting plasminogen activator inhibitor-1 (PAI-1)Limiting the generation of activated thrombin-activatable-fibrinolysis-inhibitor (TAFI)

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