Biologi molekuler:SepsisSugiharto PEuis MAndi SPrasetyo E

IDENTITAS :Nama: Tn. OUsia: 50 tahunJenis Kelamin: Laki-lakiTgl Masuk: 05-06-2007 Diagnosis: peritonitis difus ec perforasi hollow viscus

K.U: nyeri seluruh perutA.K: 3 hari smrs os mengeluh nyeri perut seluruh perut yang diawali dengan nyeri ulu hati yang tiba-tiba kemudian menebar ke seluruh perut. Keluhan disertai dengan mual, muntah (+) demam (-). BAB (-) sejak 1 hari smrs. BAK dalam batas normal

Riwayat sakit maag (+) sejak 3 thn smrsRiwayat minum jamu sendi (+) sejak 3 bln smsrsRiwayat muntah darah (-)Riwayat BAB hitam (-)

PF:status generalis:Kes: CMN: 108xT: 110/80RR: 40xS: 36,4conjungtiva: anemisstatus lokalis:abdomen: cembung, tegang, NT (+) seluruh perut, DM (+), pekak hati hilang,BU (-)RT: sfingter lemah, mukosa licin, ampulla tidak kolaps, NT (+) seluruh lingkaran.ST: faeces (+), darah (-)

Laboratorium:Hb: 9,1ureum: 114Ht: 26creatinine: 2,1L: 14.900Na: 131T: 392.000K: 4,7sgot: 58gds: 65sgpt: 27laktat: 1,3Radiologis: free air (+)

Dk: peritonitis difus ec perforasi ulkus peptikum + severe sepsisTh: LEDO:Ditemukan cairan peritoneum bercampur dengan gastric juice 1000 ccDitemukan fibrin-fibrin di subhepatik subdiafragma kiri-kanan, yang masih mudah dilepaskanDitemukan perforasi di antrum dengan diameter 1,5 cm tepi nekrotik Organ solid dan hollow viscus lain intak

Diputuskan dilakukan Grahams patch dan biopsiDiagnosis post op:Peritonitis difus ec perforasi ulkus gaster + severe sepsisTh: laparotomi eksplorasi + grahams patch + biopsi

PermasalahanApa patofisiologi perforasi gaster pasien ini? Apakah pasien ini sudah mengalami severe sepsis atau syok septik?Gangguan fungsi organ apa sajakah yang sudah terjadi?Apakah intervensi (surgical) yang dilakukan sudah tepat?Bagaimana prognosis?

Pada pasien ini terjadi perforasi gaster akibat NSAIDPada NSAID:Pengurangan pembentukan prostaglandinLapisan gel mucous rusak, dengan penurunan produksi mucous dan bicarbonat

SEPSIS Strategi Pencegahan & PenatalaksanaanDr Prasetyo EdiDr Sugiharto PDr.Andi SDr Euis M

Pathogenesis & PathophysiologyInfectionSepsisSevere Sepsis (Sepsis + MODS)Septic Shock (Severe Sepsis + Shock)Bacteremia

Correlation between Insults and Physiological Derangement with SIRS, MODS, MOF, and Death (Baue, 2000)Common Pathway to Death

Pathogenesis of Sepsis Mediated Hemodynamic DysfunctionNIDUS OF INFECTIONORGANISMSEXOGENEOUS TOXINSENDOGENOUSMEDIATORSPneumoniaPeritonitisCellulitisAbscessOther Infection SitesOrganismStructural ComponentExotoxin (TSST-1, Toxin A)EndotoxinCYTOKINES *Interleukin 1,2,.6 *Tumor Necrosis FactorPLATELET ACT FACTORARACHID ACID METABHUMORAL CASCADES *Complement *Kinins *CoagulationDEATHHYPOTENSIONMOSFHYPOTENSIONSevere Decrease SVRDepressed COMultiple Organ SystemFailureRECOVERYCARDIOVASCULARINSUFFICIENCYMYOCARDIUM *Depression *DilatationVASCULATURE *Vasodilation *Vasoconstriction *Endothelial Damage *Maldistribution of flowPhase I SequelePhase II Sequele

Hypothesis : micro circulatory arrest leading to organ failuresActivators:Injury, Bacteria, LPS Ischemia ReperfusionNecrotic tissuesInitiators :Coagulation Proteins,Platelets,Contact activating system,Mast cellsComplement proteinsvasodilationIncreased flow &premeability,EdemaChemoattractansPro-inflammatory cytokinesSystemic activationof macrophages(Phagocytosis)Margination ofNeutrophils (Phagocytosis)Microcirculatory injury& vasoconstrictionMicrocirculatory arrestFocal necrosisPhase II SequelePhase I SequeleLingkaran Setan

The Sepsis ContinuumA clinical response arising from a nonspecific insult, with 2 of the following:T >38oC or 90 beats/minRR >20/minWBC >12,000/mm3 or 10% bands

Mortality : 0 s.d 5 %SIRS = systemic inflammatory response syndrome SIRS with a presumed or confirmed infectious process

Mortality :0 s.d 10%Chest 1992;101:1644.Sepsis with organ failure

Mortality : 10 s.d 30% RefractoryHypotension

Mortality : 30 s.d 60%

ACCP / SCCM Consensus Definitions of SIRS and Allied DisordersSIRS

The systemic inflammatory response to a variety of severe clinical insults.Manifested by 2 or more of the following conditions:

Temperature>38 deg C or 90 beats/minRespiratory Rate>20 breaths/min or PaCO2

ACCP / SCCM Consensus Definitions of SIRS and Allied Disorders(Critical Care Med 1992 (20):864-874)SEVERE SEPSIS

Sepsis associated with organ dysfunction, hypoperfusion, or hypotension.Perfusion abnormalities include but are not limited to:

lactic acidosisoliguriamental status

SEPTIC SHOCK

Sepsis with hypotension (SBP

Severe Sepsis CriteriaSIRS -Plus- 1 Organ FailureCardiovascular:SBP 90 or MAP 70 despite of fluid resuscitation of at least 20 ml/kg or- continuing need for vasopressors following above fluid challengeRespiratory:PaO2/FiO2 200*Renal:UO < o.5 mL/kg despite above fluid challenge* -or- S. Creatinine > 2.0Hematologic:Platelet count < 80000 or- decrease by 50% in past 3 daysAcidosis:Lactate > 1.5 or pH < 7.30 with base deficit > 5 mmol/L*Hepatic:Acute bilirubin elevation > 3.0Brain:Acute alteration in mental status* Modified from Bone at al. Chest 1992;101:1644-1655

Septic Shock CriteriaSevere Sepsis CriteriaPlusCardiovascularSBP 90 or MAP 70 for 1 hour despite fluid resuscitation of at least 20mL/kg or continuing need of vasopressorsAnd/orSerum lactate 4.0

Pencegahan dan Penangganan Sepsis

Introduction The Management of Sepsis & TraumaSource ControlNutrition / MetabolicSupportResuscitation &Physiologic Support1. Minimize flow-dependent oxygen consumption2. Minimize flow-dependent lactate clearance3. Restore Microcirculation1. Remove / Treat Infection2. Remove / Treat Inflammation3. Remove Dead Tissue4. Stabilization Injured Tissue

Pencegahan : Diagnosis Dini dan Penangganan Tepat

A clinical response arising from a nonspecific insult, with 2 of the following:T >38oC or 90 beats/minRR >20/minWBC >12,000/mm3 or 10% bands

Mortality : 0 SIRS with a presumed or confirmed infectious process

Mortality :0 s.d 10%SIRSSepsisUpayakan Agar SIRS & Sepsis tidak menjadi Severe Sepsis & Septic Shock

BackgroundThe Surviving Sepsis Campaigns mission is to increase awareness and improve outcome in severe sepsis Guidelines developed by a group of international experts representing 11 organizationsDeveloped under unrestricted industry educational grantsPublished in March 3, 2004 issue of Critical Care MedicineDellinger, et. al. Crit Care Med 2004, 32: 858-873.

MissionTo develop guidelines that the bedside clinician can use to improve outcome in severe sepsis and septic shock

These recommendations are intended to provide guidance for the clinicians caring for a patient with severe sepsis or septic shock, but they are not applicable for all patients

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

American Association of Critical-Care NursesAmerican College of Chest PhysiciansAmerican College of Emergency PhysiciansAmerican Thoracic SocietyAustralian and New Zealand Intensive Care SocietyEuropean Society of Clinical Microbiology and Infectious DiseasesEuropean Society of Intensive Care MedicineEuropean Respiratory SocietyInternational Sepsis ForumSociety of Critical Care MedicineSurgical Infection SocietySponsoring OrganizationsDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Grading of RecommendationsSupported by at least two level I investigationsSupported by one level I investigationSupported by level II investigations onlySupported by at least one level III investigationSupport by level IV or V evidenceGrading SystemDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Large randomized trials with clear-cut results; low risk of false-positive (alpha) error or false-negative (beta) errorSmall randomized trials with uncertain results; moderate-to-high risk of false-positive (alpha) and/or false-negative (beta) errorNonrandomized, contemporaneous controlsNonrandomized, historical controls and expert opinionCase series, uncontrolled studies, and expert opinion

Grading of EvidenceGrading SystemDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Initial ResuscitationDiagnosisAntibiotic therapySource ControlFluid therapyVasopressorsInotropic TherapySteroidsRecombinant Human Activated Protein C (rhAPC) [drotrecogin alfa (activated)]

Blood Product AdministrationMechanical Ventilation Sedation, Analgesia, and Neuromuscular Blockade in SepsisGlucose ControlRenal ReplacementBicarbonate TherapyDeep Vein Thrombosis ProphylaxisStress Ulcer ProphylaxisLimitation of Support

IndexDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Central Venous Pressure 8-12 mm Hg (12-15 in ventilator pts)Mean arterial pressure > 65 mm HgUrine output > 0.5 mL/kg/hrScvO2 or SvO2 70%; if not achieved with fluid resuscitation during first 6 hours: - Transfuse PRBC to hematocrit > 30% and/or - Administer dobutamine (max 20 mcg/kg/min) to goalResuscitation should begin as soon as severe sepsis or sepsis induced tissue hypoperfusion is recognizedElevated Serum lactate identifies tissue hypoperfusion in patients at risk who are not hypotensiveGoals of therapy within first 6 hours are Grade B

Rivers E. N Engl J Med 2001;345:1368-77.Initial ResuscitationDellinger, et. al. Crit Care Med 2004, 32: 858-873.-

Early Goal-Directed Therapy Results49.2%33.3%0102030405060Standard Therapy n=133EGDTn=130P = 0.01**Key difference was in sudden CV collapse, not MODS28-day MortalityRivers E. N Engl J Med 2001;345:1368-77.

Before the initiation of antimicrobial therapy, at least two blood cultures should be obtainedAt least one drawn percutaneously At least one drawn through each vascular access device if inserted longer than 48 hoursOther cultures such as urine, cerebrospinal fluid, wounds, respiratory secretions or other body fluids should be obtained as the clinical situation dictatesOther diagnostic studies such as imaging and sampling should be performed promptly to determine the source and causative organism of the infection may be limited by patient stabilityWeinstein MP. Rev Infect Dis 1983;5:35-53 Blot F. J Clin Microbiol 1999; 36: 105-109.

Grade DGrade E

DiagnosisDellinger, et. al. Crit Care Med 2004, 32: 858-873.Grade D

Start intravenous antibiotic therapy within the first hour of recognition of severe sepsis after obtaining appropriate cultures Empirical choice of antimicrobials should include one or more drugs with activity against likely pathogens, both bacterial or fungalPenetrate presumed source of infectionGuided by susceptibility patterns in the community and hospitalContinue broad spectrum therapy until the causative organism and its susceptibilities are definedKreger BE. Am J Med 1980;68:344-355. Ibrahim EH. Chest 2000;118:146-155. Hatala R. Ann Intern Med 1996;124-717-725. Antibiotic TherapyGrade E

Grade DDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Reassess after 48-72 hours to narrow the spectrum of antibiotic therapy Duration of therapy should typically be 7-10 days and guided by clinical response Some experts prefer combination therapy for Pseudomonas infections or neutropenic patientsStop antimicrobials promptly if clinical syndrome is determined to be noninfectiousAntibiotic TherapyGrade EGrade EGrade EGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.Ali MZ. Clin Infect Dis 1997;24:796-809

Evaluate patients for focus of infection amenable to source control measures Drainage of an abscess or local focus of infectionDebridement of infected necrotic tissueRemoval of a potentially infected deviceDefinitive control of a source of ongoing microbial contaminationSource control methods must weigh benefits and risks of the specific intervention Jimenez MF. Intensive Care Med 2001;27:S49-S62.Bufalari A. Acta Chir Belg 1996;96:197-200.Source ControlGrade EGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Once a focus of infection has been identified, source control should be implemented as soon as possible following initial resuscitation Especially important for patients with necrotizing soft tissue infection or intestinal ischemiaIf intravascular access devices are suspected to be the source of infection, remove them promptly after establishing other vascular access It may be reasonable to leave access devices in place when patients develop sepsis of unknown source, until the source of infection is determinedMoss RL. J Pediatr Surg 1996;31:1142-1146.CDC. MMWR 2002;51:1-29.

Source Control (cont)Grade EGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Source Control: Examples of Potential SitesDrainageIntra-abdominal abscess - Septic arthritisThoracic empyema - Pyelonephritis, cholangitisDebridementNecrotizing fasciitis - MediastinitisInfected pancreatic necrosis - Intestinal infarctionDevice RemovalInfected vascular catheter Urinary catheter Colonized endotracheal tubeDefinitive ControlSigmoid resection for diverticulitis Amputation for clostridial myonecrosisCholecystectomy for gangrenous cholecystitis Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Fluid resuscitation may consist of natural or artificial colloids or crystalloidsNo evidenced-based support for one type of fluid over anotherCrystalloids have a much larger volume of distribution compared to colloidsCrystalloid resuscitation requires more fluid to achieve the same endpoints as colloidCrystalloids result in more edemaChoi PTL. Crit Care Med 1999;27:200-210. Cook D. Ann Intern Med 2001;135:205-208. Schierhout G. BMJ 1998;316:961-964.Fluid Therapy: Choice of FluidGrade CDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Fluid challenge in patients with suspected hypovolemia may be given500 - 1000 mL of crystalloids over 30 mins300 - 500 mL of colloids over 30 minsRepeat based on response and toleranceInput is typically greater than output due to venodilation and capillary leakMost patients require continuing aggressive fluid resuscitation during the first 24 hours of managementFluid Therapy: Fluid ChallengeGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Initiate vasopressor therapy if appropriate fluid challenge fails to restore adequate blood pressure and organ perfusionVasopressor therapy should also be used transiently in the face of life-threatening hypotension, even when fluid challenge is in progress Either norepinephrine or dopamine are first line agents to correct hypotension in septic shockNorepinephrine is more potent than dopamine and may be more effective at reversing hypotension in septic shock patients Dopamine may be particularly useful in patients with compromised systolic function but causes more tachycardia and may be more arrhythmogenic LeDoux D. Crit Care Med 2000;28:2729-2732.Regnier B. Intensive Care Med 1977;3:47-53.Martin C. Chest 1993;103:1826-1831. Martin C. Crit Care Med 2000;28:2758-2765. DeBacker D. Crit Care Med 2003;31:1659-1667. Hollenberg SM. Crit Care Med 1999; 27: 639-660.VasopressorsGrade EGrade DDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Low dose dopamine should not be used for renal protection in severe sepsisAn arterial catheter should be placed as soon as practical in all patients requiring vasopressorsArterial catheters provide more accurate and reproducible measurement of arterial pressure in shock states when compared to using a cuffVasopressin may be considered in refractory shock patients that are refractory to fluid resuscitation and high dose vasopressorsInfusion rate of 0.01-0.04 units/min in adultsMay decrease stroke volumeVasopressors (cont)Grade BGrade EGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.Hollenberg SM. Crit Care Med 1999; 27:639-660. Bellomo R. Lancet 2000; 356: 2139-2143.Kellum J. Crti Care Med 2001; 29: 1526-1531.

In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output Should be combined with vasopressor therapy in the presence of hypotension It is not recommended to increase cardiac index to target an arbitrarily predefined elevated level Patients with severe sepsis failed to benefit from increasing oxygen delivery to supranormal levels by use of dobutamineInotropic TherapyGrade EGrade AGattinoni L. N Eng J Med 1995;333:1025-1032.Hayes MA. N Eng J Med 1994;330:1717-1722. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Intravenous corticosteroids are recommended in patients with septic shock who require vasopressor therapy to maintain blood pressureAdminister intravenous hydrocortisone 200-300 mg/day for 7 days in three or four divided doses or by continuous infusionShown to reduce mortality rate in patients with relative adrenal insufficiencySteroidsGrade CAnnane, D. JAMA, 2002; 288 (7): 868Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

May use 250 mcg ACTH stimulation test to identify responders and discontinue therapy in these patientsResponders can be defined as >9 mcg/dL increase in cortisol 30-60 minutes post ACTH administrationClinicians should not wait for ACTH stimulation test results to administer corticosteroidsAfter the resolution of septic shock, may decrease dosage of steroidsConsider tapering the dose of corticosteroids at the end of therapyMay add fludrocortisone to the hydrocortisone regimenSteroidsGrade EAnnane, D. JAMA, 2002; 288 (7): 868Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Patients with Relative Adrenal Insufficiency (ACTH Test Non-responders) (77%)Patients Without Relative Adrenal Insufficiency (ACTH Test Responders) (23%)P=0.04P=0.96N=114N=36N=34N=11528-day MortalityAnnane, D. JAMA, 2002; 288 (7): 868Steroids Low-Dose Steroids: 28-day Mortality

Doses of hydrocortisone >300 mg daily should NOT be used in septic shock or severe sepsis for the purpose of treating shock In the absence of shock, corticosteroids should not be used for treatment of sepsisSteroidsGrade AGrade EBone RC. N Engl J Med 1987;653-658.VA Systemic Sepsis Cooperative Study Group. N Engl J Med 1987;317:659-665. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Recombinant human Activated Protein C [Drotrecogin alfa (activated)] is recommended in patients at a high risk of death APACHE II score 25, orSepsis-induced multiple organ failure, orSeptic shock, orSepsis induced acute respiratory distress syndromeTreatment with drotrecogin alfa (activated) should begin as soon as possible once a patient has been identified as being at high risk of deathPatients should have no absolute or relative contraindication related to bleeding risk that outweighs the potential benefit of rhAPCRecombinant human Activated Protein CGrade BBernard GR. N Eng J Med 2001;344:699-709.Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Recombinant human Activated Protein C*PlaceboDrotrecogin alfa (activated)PROWESS 28-day Mortality High Risk of Death Patients** as defined by APACHE II 25 Mortality Rate*rhAPC is drotrecogin alfa (activated)

Contraindications to use of rhAPCrhAPC (drotrecogin alfa [activated]) increases the risk of bleeding. rhAPC is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity:Active internal bleedingRecent (within 3 months) hemorrhagic strokeRecent (within 2 months) intracranial or intraspinal surgery, or severe head traumaTrauma with increased risk of life-threatening bleedingPresence of an epidural catheterIntracranial neoplasm or mass lesion or evidence of cerebral herniationSee labeling instructions for relative contraindications (i.e. warnings)The committee recommends that platelet count be maintained at 30,000 during infusion of rhAPC

Red blood transfusion should occur only when hemoglobin decreases to < 7 g/dL Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances such as significant coronary artery disease, acute hemorrhage or lactic acidosisTarget hemoglobin of 7 9 g/dLErythropoietin is not recommended for specific treatment of anemia associated with severe sepsis Unless septic patients have other accepted reasons for administration of erythropoietin Routine use of fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommendedBlood Product AdministrationGrade BGrade BGrade ECorwin HL. JAMA 2002;288:2827-2835.Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

It is NOT recommended to use antithrombin for the treatment of severe sepsis or septic shockHigh dose antithrombin in a phase III trial did not demonstrate a beneficial effect on 28-day mortality and was associated with increased risk of bleeding when administered with heparinPlatelets should be administered when platelet counts are < 5000/mm3 regardless of apparent bleeding Platelet transfusion may be considered when counts are 5000 - 30,000/mm3 and there is a significant risk of bleedingPlatelet counts 50,000/ mm3 are typically required for surgery or invasive proceduresBlood Product Administration (cont)Grade BGrade EWarren BL. JAMA 2001;286:1869-1878.Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

High tidal volumes, > 6 ml/kg, coupled with high plateau pressures, > 30 cm H2O, should be avoided Hypercapnia can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes A minimum amount of positive end expiratory pressure should be set to prevent lung collapse at end-expirationMechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDSARDSNet. N Eng J Med 2000;342:1301-1308.Grade BGrade CGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Mortality* - Low vs Traditional Tidal VolumeLow Tidal VolumeTraditional Tidal VolumeP=0.007* death before discharge home and breathing without assistanceMechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDSARDSNet. N Eng J Med 2000;342:1301-1308.

In experienced facilities, prone positioning should be considered in ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure who are not at high risk for adverse consequences to positioning changes Unless contraindicated, mechanically ventilated patients should be maintained semirecumbent with the head of the bed raised to 45 to prevent ventilator associated pneumoniaMechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDSDrakulovic M. Lancet 1999;354:1851-1858.Grade EGrade CDellinger, et. al. Crit Care Med 2004, 32: 858-873.

A weaning protocol should be in place and mechanically ventilated patients should undergo spontaneous breathing trial when they satisfy the following criteria: ArousableLow ventilatory and end expiratory pressure requirementsNo new potentially serious conditionsHemodynamically stable without vasopressorsRequiring levels of FiO2 that could be delivered with a face mask or nasal cannula Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDSEsteban A. Am J Respir Crit Care Med 1999;159:512-518.Ely EW. N Engl J Med 1996;335:1864-1869.Esteban A. Am J Respir Crit Care Med 1997;156:459-465.Grade ADellinger, et. al. Crit Care Med 2004, 32: 858-873.

Protocols should be used when sedation of critically ill mechanically ventilated patients is required The protocol should include the use of a sedation goal, measured by a standardized subjective sedation scaleIntermittent bolus or continuous infusion sedation are recommended to predetermined end points With daily interruptions/lightening of continuous infusion sedation with awakening and retitration, if necessarySedation, Analgesia, and Neuromuscular Blockade in SepsisBrook AD. Crit Care Med 1999;27:2609-2615.Grade BGrade BDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Neuromuscular blockers should be avoided in the septic patient due to the risk of prolonged neuromuscular blockadeIf needed for more than the first hour of mechanical ventilation, either intermittent bolus as required or continuous infusion with monitoring of depth of block with train of four monitoring should be used Sedation, Analgesia, and Neuromuscular Blockade in SepsisGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Following initial stabilization of patients with severe sepsis, maintain blood glucose to < 150 mg/dLBest results obtained when blood glucose was maintained between 80 and 110 mg/dLGlycemic control strategy should include a nutrition protocol with the preferential use of the enteral routeMinimize the risk of hypoglycemia by providing a continuous supply of glucose substrate Accomplished by using 5% or 10% dextrose IV infusion and followed by initiation of feeding preferably by enteral route

Glucose Controlvan den Berghe G. N Engl J Med 2001;345:1359-1367.Grade DGrade EDellinger, et. al. Crit Care Med 2004, 32: 858-873.

Mortality During Intensive CareIn-Hospital MortalityMortality (%)p = 0.01p < 0.04 (adjusted)n=783n=765ConventionalIntensive Insulinn=783n=765van den Berghe G. N Engl J Med 2001;345:1359-1367.Glucose Control Intensive Insulin

Continuous hemofiltration offers easier management of fluid balance in hemodynamically unstable septic patients Renal ReplacementMehta RL. Kidney Int 2001;60:1154-1163Kellum J. Intensive Care Med 2002;28:29-37.Grade B Continuous venovenous hemofiltration and intermittent hemodialysis are considered equivalent in acute renal failure (in the absence of hemodynamic instability) Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

No difference revealed in vasopressor requirements or hemodynamic variables between bicarbonate and normal saline for treating hypoperfusion-induced acidemiaEffects of bicarbonate therapy at pH levels < 7.13 have not been studiedBicarbonate TherapyCooper DJ. Ann Intern Med 1990;112:492-498.Mathieu D. Crit Care Med 1991;19:1352-1356.Grade C Bicarbonate is not recommended for the purpose of improving hemodynamics or reducing vasopressor requirements for the treatment of hypoperfusion induced lactic acidemia with pH 7.15Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Use a mechanical prophylactic device or intermittent compression in patients with contraindications to heparin Use a combination of pharmacological and mechanical therapy in very high risk patients (eg, severe sepsis and history of DVT)Belch JJ, Scott Med J 1981;26:115-117Samama MM, N Engl J Med 1999;341:793-800Deep Vein Thrombosis (DVT) Prophylaxis Grade A DVT prophylaxis with either low-dose unfractionated heparin or low molecular weight heparin should be used in severe sepsis patientsDellinger, et. al. Crit Care Med 2004, 32: 858-873.

H2 receptor blockers are more efficacious than sucralfate and are the preferred agents Proton pump inhibitors compared to H2 blockers have not been assessed

Stress Ulcer ProphylaxisBresalier RS et al. Am J Med 1987;83:110-116 Borrero et al. Am J Med 1985;79:62-64Grade AStress ulcer prophylaxis should be given to all patients with severe sepsis

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Decisions for less aggressive support or withdrawal of support may be in the patients best interest

Consideration for Limitation of SupportGrade EAdvance care planning, including the communication of likely outcomes and realistic goals of treatment, should be discussed with patients and families

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Keadaan Umum (KU) :KU pasien sepsis yg akan dioperasi, perlu disiapkan secara baikBila disertai syok hipovolemik, koreksi Dehidrasi, setelahnya Tetapkan Tingkatan SepsisCara Koreksi :Penilaian Tingkat KU : (R), Sedang (S), Buruk (B), Sangat Buruk (SB)Parameternya :Tingkat KesadaranTensiNadi Diuresis/menit Diketahui Tingkat KU : Ringan/Sedang/Buruk/Sangat Buruk

Prognosis Peritonitis Umum e.c Perforasi Ileum demam tifoid(Hanafi, 1979)Faktor Penentu Prognosis :Perforasi-operasi IntervalInterval < 24 jam, Mortality 4 %Interval 24-48 jam, Mortality 25%Interval 49-72 jam,Mortality 50%Interval >72 jam,Mortality > 75%

Prognosis Peritonitis Umum e.c Perforasi Ileum demam tifoid(Hanafi, 1979)Keadaan Umum Pre Op (Setelah Resusitasi)

KU baik, Mortality < 5 %KU sedang Mortality 25 %KU buruk pasca Resusitasi, Mortality mendekati 100 % Upayakan KU Baik, EGDT Pola Kita Sejak 1979

Oxygen Transport & Consumption ParameterDO2I = CI x 10 Hgb x SaO2 x 1.34 VO2I =CI x C(a-v)O2C(a-v)O2 = Hb x (SaO2 SvO2) x 1Note :VO2: global oxygen consumpton index (ml/min/m2)C(a-v)O2: extracted O2 content (ml/L)

DO2I = CI * 10 Hgb * SaO2 * 1.34

CI = SI * HRchronotropy SI @ MAP

preloadvolumecontractilityinotropyafterloadvasoactivity

Resuscitation should begin as soon as severe sepsis or sepsis induced tissue hypoperfusion is recognizedElevated Serum lactate identifies tissue hypoperfusion in patients at risk who are not hypotensiveSepsis Guideline Initial Resuscitation

TERIMA KASIHHATUR NUHUN

12Septic shock is a continuumalong this pathway of worsening of microorganisms in normally sterile host tissues and their ongoing invasion.Infection- the presence of microorganisms in normally sterile host tissue.Bacteremia- the presence of viable bacteria in bloodSepsis- The systemic response to infectionSevere sepsis- sepsis associated with organ dysfunction, hypoperfusion or hypotension.Septic shock- sepsis with hypotension despite adequate fluid resuscitation, and perfusion abnormalitites.

71% of patients with culture proven septic shock are initially identified as being in one of the milder categories, yet only 4% of patients with SIRS progress to full septick shock.Rangel-Fausto MS, Pittet D, Castigan M, Hwang T, et al., The natural history of the systemic inflammatory response syndrome. JAMA 1995; 273: 117-123.Its important to identify these patients early when they are more amenable to succsessful intervention.2034There were no industry members on the Guidelines development committee.Industry awareness or comment on the recommendations was not allowed.Each committee member completed a conflict of interest form, and individuals were not assigned to a subgroup topic if they had a potential conflict of interest.Reference p. 860

Industry sponsors for Phase II of the Surviving Sepsis Campaign (development of Guidelines) include Eli Lilly and Company, and Edwards.In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician. p. 858Document finalized and approved by the consensus committee and all sponsoring organizations in December 2003. P. 860Recommendations are graded based on a modified Delphi methodology.The goal was total consensus, which was reached in all recommendations except for 2.A grade of A, B, or C required randomized trials.In the committees deliberations, the grading of a recommendation did not establish the level of priority or importance of a specific intervention, only the degree of literature support. p. 868This index list also provides a means to quickly link to the specific slides related to the topic. Click on the subject when the slide is in the show mode and the slides automatically advances to the first slide of that specific guideline.Establishing vascular access and initiating aggressive fluid resuscitation is the first priority when managing patients with severe sepsis or septic shock. p. 860Resuscitation should begin as soon as severe sepsis or sepsis-induced tissue hypoperfusion [hypotension or lactic acidosis] is recognized and should not be delayed pending ICU admission.Elevated serum lactate concentration identifies tissue hypoperfusion in patients at risk who are not hypotensive.Lactate measurement lacks precision as a measure of tissue metabolic status.Central venous and mixed venous oxygen saturation are equivalent.In mechanically ventilated patients a higher target central venous pressure 12-15 mm Hg is recommended to account for the increased intrathoracic pressure.Decrease in pulse is a useful marker of improving intravascular filling. The consensus panel judged central venous (superior vena cava) and mixed venous oxygenation to be equivalent.Rationale for this recommendation is based on Manny Rivers protocol published in NEJM. This protocol was associated with an improvement in survival.

NOTE: The references listed in the right hand corner of the slide relate to recommendations on the slide. When the slides are viewed in the show mode, clicking on the reference will automatically take you to an abstract of the specific study (this is only if your computer is connected to the internet and has access to Pubmed.)

Cause of in-hospital death:

--Sudden Cardiovascular collapse Standard Tx= 25/119 (21%) EGDT 12/117 (10.3%)

--MODS Standard Tx 26/119(21.8%) EGDT 19/117 (16.2%) P. 1374 in New England Journal of MedicineDo not need to draw a blood culture through vascular access devices that were recently inserted (2hrs) then the PAD might be the source of infection.Volume of blood may also be important

May require additional vascular access portsAn empirical antimicrobial regimen should have coverage for all likely pathogens since there is little margin for error in critically ill patients.Failure to initiate appropriate therapy promptly has adverse consequences on outcomes.Once the organism and its susceptibilities have been defined narrowing the spectrum of antibiotics reduces the risk of resistance, superinfections and costs.Due to renal and hepatic dysfunction in severe sepsis patients and due to the altered volume of distribution, it is recommended to involve the ICU pharmacist to ensure serum concentrations are attained that maximize efficacy and minimize toxicity.Establishing vascular access and initiating aggressive fluid resuscitation is the first priority when managing patients with severe sepsis or septic shock. (p. 860) However, prompt infusion of antimicrobial agents is also a logical strategy and may require additional access ports.

This particular recommendation was one of two which the consensus panel did not reach consensus. The solution was achieved with the inclusion of sub recommendations that expressed some difference in expert opinion. P. 860For neutropenic patients, broad-spectrum therapy usually must be continued for the duration of the neutropenia. p. 861Clinicians should be cognizant that blood cultures will be negative in the majority of cases of sepsis or septic shock. Thus, the decision to continue, narrow, or stop antimicrobial therapy must be made on the basis of clinician judgment and other culture results. p. 861Clinical judgmentEngage other specialists in other disciplines such as radiology, surgery, pulmonary medicine and gastroenterology in caring for sepsis patients.Example: Percutaneous rather than surgical drainage of an abscess

Source control intervention should only take place following adequate initial resuscitation and when a focus of infection is amenable to source control measures.Case series and expert opinion support rapid correction of a source of microbial contamination to maximize survival of septic patients. See the example above at the end of the slideClinicians should consider removal and replacement of vascular access devices to be a priority, even if the device is tunneled or surgically implanted.Intravascular access devices are thought to be the source of the majority of nosocomial bloodstream infections.

No evidence-based support for one type of crystalloid over anotherNo studies that are specific to sepsis populationNote: since development of these guidelines the preliminary results of the SAFE (Fluid resuscitation with Albumin vs. Saline) study results have been reported at the Society of Critical Care Medicine National Scientific Meeting held in Feb. 2004. This randomized controlled trial of over 7,000 patients demonstrated that in the subset of severe sepsis patients there was a mortality benefit with albumin over saline (RR .087; CI 0.74-1.02). This data set was locked in late 2003; therefore, final manuscript publication is pending.

Fluid Challenge describes the initial volume expansion period in which the patients response is closely monitored. Fluid Challenge must be clearly separated from an increase in maintenance fluid administrationResponse may be measured by increase in blood pressure and urine outputTolerance may be measured by evidence of intravascular volume overloadInput/output ratio is of no utility to judge fluid resuscitation during this time periodPerfusion becomes dependent on pressure below a certain mean arterial pressure because autoregulation in various vascular beds can be lost. Supplement goal such as blood pressure with the assessment of global perfusion such as blood lactate concentrationsDopamine increases mean arterial pressure and cardiac output due to an increase in stroke volume and heart rateNorepinephrine increases mean arterial pressure due to vasoconstrictive effectsNorepinephrine causes little change in heart rate and less increase in stroke volume compared to dopamineDopamine causes more tachycardia and may be more arrhythmogenic

Arterial catheter placement in an emergency department is typically not possible or practical.Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in decreased cardiac output and hepatosplanchnic flow. Most published reports exclude patients from treatment with vasopressin if the cardiac index is < 2 or 2.5.Low doses of vasopressin may be effective in raising blood pressure in patients refractory to other vasopressors, although no outcome data are available.

Dobutamine is the first-choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure (or clinical assessment of adequate fluid resuscitation) and adequate mean arterial pressure.The goal of resuscitation should be to achieve adequate levels of oxygen delivery or avoid flow dependent tissue hypoxia.Two large prospective clinical trials that included critically ill ICU patients who had severe sepsis failed to demonstrate benefit from increasing oxygen delivery to supranormal levels by use of dobutamine. P. 863

Adrenal insufficiency is defined as post-adrencorticotropic hormone [ACTH] cortisol increase < 9 mcg/dL within 30-60 mins post ACTH administrationThis was one of two recommendations that did not achieve total consensus. The solution was achieved with the inclusion of sub recommendations that expressed some difference in expert opinion. P. 860.Adrenal insufficiency is defined as post-adrencorticotropic hormone [ACTH] cortisol increase < 9 mcg/dL within 30-60 mins post ACTH administrationThese sub recommendations were developed because the panel could not reach complete consensus on the specific recommendation for use of low dose replacement steroid therapy for adrenal insufficiency.One study added 50 mcg of fludrocortisone orally. Since hydrocortisone has intrinsic mineralocorticoid activity, there is controversy as to whether fludrocortisone should be added. P. 863ACTH Test Responders contained a total N of 70, this is 23% of the total study population (N=299). Responder placebo patients = 34 ( 18 deaths at 28 days, 53% mortality) and intervention patients = 36 ( 22 deaths at 28 days, 61% mortality).ACTH Test Non-responders contained a total N of 229 which is 77% of the total study population (N=299). Non-responder placebo patients = 115 (73 deaths at 28 days, 63% mortality), intervention patients = 114 (60 deaths at 28 days, 53% mortality)Placebo = 149 patients Intervention = 150 patientsP value for entire study population = 0.09

Notes information from p. 868.

No contraindications to continuing maintenance steroids if the patients endocrine history warrantsHigh dose corticosteroid therapy was found ineffective or harmful for treatment of severe sepsis or septic shock (based on results of two RCT studies and two meta-analyses).May maintain higher steroid doses for other medical condition other than septic shock

The inflammatory response in severe sepsis is integrally linked to procoagulant activity and endothelial activation. p. 863.The inflammatory response in sepsis is procoagulant in the early stages. P. 863rhAPC [drotrecogin alfa (activated)] has been shown, in a large, multiple center, randomized, controlled trial to improve survival in patients with sepsis-induced organ dysfunction. p. 863.At present, risk assessment is best determined by bedside clinical evaluation and judgment. Given the uncertainty of risk assessment and the potential for rapid deterioration of patients with severe sepsis and septic shock, once a patient has been identified as at high risk of death, treatment should begin as soon as possible. p. 863Inflammatory response is linked to procoagulant activity and endothelial activation.The inflammatory response in sepsis is procoagulant in the early stages.PROWESS: Phase III study evaluating the effects of drotrecogin alfa (activated) vs. placeboFrom appendix B of SSC Guidelines, p. 872.

Relative Contraindications are the listed as warnings in the drotrecogin alfa (activated) US package insert. These warnings are:

For patients with severe sepsis who have one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use drotrecogin alfa (activated) therapy: -Concurrent therapeutic heparin-Platelet count 30,000 x 106/L, even if the platelet count is increased after transfusions-Prothrombin time-INR 3.0-Recent (within 6 weeks) gastrointestinal bleeding-Recent administration (within 3 days) of thrombolytic therapy-Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors -Recent administration (within 7 days) of aspirin >650 mg/d or other platelet inhibitors -Recent (within 3 months) ischemic stroke -Intracranial arteriovenous malformation or aneurysm -Known bleeding diathesis -Chronic severe hepatic disease -Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

An additional absolute contraindication to rhAPC therapy is: Drotrecogin alfa (activated) is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of this product

The Transfusion Requirements in Critical Care trial suggested that a hemoglobin of 7-9 g/dL is adequate for most critically ill patients. A transfusion threshold of 7 g/dL was not associated with increased mortality. P. 863Red Blood Transfusion in septic patients increases oxygen delivery but does not usually increase oxygen consumptionThis transfusion threshold contrasts with the target of a hematocrit of 30% in patients with low central venous oxygen saturation during the first 6 hrs. of resuscitation of septic shock. (Rivers, NEJM, 2001, vol. 345.An example of other accepted reasons for administration of erythropoietin in severe sepsis patients is renal failure induced compromise of red blood cell production.

Phase III clinical trial of high dose antithrombin did not demonstrate any beneficial effect on 28 day all cause mortality in adults with severe sepsis or septic shock.Recommendations for platelet transfusions are based on experience with patients undergoing chemotherapy.Recommendations for platelet transfusions take into account the etiology of thrombocytopenia, platelet dysfunction, risk of bleeding, and presence of concomitant disorders. P. 864

Start a reduction in tidal volumes over 1-2 hours to a low tidal volume (6 mL per kilogram of predicted body weight) as a goal in conjunction with the goal to maintain end inspiratory plateau pressures < 30 cm H2O.The largest trial of a volume- and pressure-limited strategy showed a 9% decrease of all-cause mortality in patients ventilated with tidal volumes of 6 mL/kg of predicted body weight (as opposed to 12 mL/kg) while aiming for a plateau pressure < 30 cm H20 above two goals reduce mortality in ventilated patients. p. 864 Hypercapnia is contraindicated in patients with elevated intracranial pressure and should be limited in patients with preexisting metabolic acidosis.Sodium bicarbonate infusion may be considered in select patients to facilitate use of permissive hypercarbia. P. 864

Tidal volume of 10 to 15 mg/kg can allow lungs to reach a total lung capacity of healthy lungs.In patients with Sepsis/ARDS, this can cause disruption of alveolar walls: ventilator-induced liquid lung and alveolar rupture (VILLAR)

22% REDUCTION in deathPotentially life threatening complications to prone positioning include accidental dislodgement of the endotrachael tube and central venous catheters.Several studies have demonstrated that a majority of patients with ALI/ARDS respond to the prone position with improved oxygenation.

Spontaneous breathing trial options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-pieceThe use of protocols and daily interruption/lightening of continuous sedative infusion have shown to reduce the duration of mechanical ventilation and length of stay and tracheostomy rates.

Prolonged skeletal weakness has been reported in critically ill patients following the use of intermediate and long acting neuromuscular blockers.Intermittent assessment of the depth of neuromuscular blockade reduces the risk of prolonged paralysis.This recommendation stems from a large, single center trial of postoperative surgical patients but the panel sees no reason to think that these data are not generalizable to all severely septic patients.Glucose monitoring should be frequent every 30-60 minutes after initiation of the protocol and on a regular basis once the blood glucose concentration has stabilized (e.g., every 4 hrs).Risk of hypoglycemia.Note the glycemic goal in the clinical trial was 80-110 mg/dL but generalized to 150 mg/dL in this guideline to reduce risk of hypoglycemia. Post hoc data analysis revealed that best results were obtained when glucose was maintained at 80-110 mg/dL; however, glucose of < 150 mg/dL also showed improved outcome compared to higher glucose concentrations.The frequency of blood glucose determinations may require the use of central or arterial catheters for blood sampling. P values were determined with the use of the chi-square test. For the primary outcome variable (death during intensive care), the P value has been corrected for the repeated interim analyses, according to the method of Lan and DeMets; the unadjusted P value is 0.005. Sequential interim analyses were not performed for the other variables, and nominal (unadjusted) P values are given for these comparisons. p. 1362There is no current evidence to support the use of continuous venovenous hemofiltration for the treatment of sepsis independent of renal replacement needs. p. 865Examples of heparin contraindications: thrombocytopenia, severe coagulopathy, active bleeding, and recent intracerebral hemorrhage.Mehanical prophylactic device examples: graduated compression stockings and intermittent compression devices.Contraindication for use of mechanical prophylactic device includes the presence of peripheral vascular disease.There are no studies performed specifically in patients with severe sepsis; however, large trials confirm the benefit of DVT prophylaxis in general ICU populations that included significant numbers of septic patients.Proton pump inhibitors and H2 blockers equivalently lower gastric pH.Other conditions that benefit from stress ulcer prophylaxis that are also present in severe sepsis are coagulopathy, mechanical ventilation, hypotension. It is too frequent that inadequate physician/family communication characterizes end-of-life care in the ICU. The level of life support given to ICU patients may not be consistent with their wishes. Early and frequent caregiver discussions with patients who face death in the ICU and their loved ones may facilitate appropriate application and withdrawal of life-sustaining therapies. p. 866Establishing vascular access and initiating aggressive fluid resuscitation is the first priority when managing patients with severe sepsis or septic shock. p. 860Resuscitation should begin as soon as severe sepsis or sepsis-induced tissue hypoperfusion [hypotension or lactic acidosis] is recognized and should not be delayed pending ICU admission.Elevated serum lactate concentration identifies tissue hypoperfusion in patients at risk who are not hypotensive.Lactate measurement lacks precision as a measure of tissue metabolic status.Central venous and mixed venous oxygen saturation are equivalent.In mechanically ventilated patients a higher target central venous pressure 12-15 mm Hg is recommended to account for the increased intrathoracic pressure.Decrease in pulse is a useful marker of improving intravascular filling. The consensus panel judged central venous (superior vena cava) and mixed venous oxygenation to be equivalent.Rationale for this recommendation is based on Manny Rivers protocol published in NEJM. This protocol was associated with an improvement in survival.

NOTE: The references listed in the right hand corner of the slide relate to recommendations on the slide. When the slides are viewed in the show mode, clicking on the reference will automatically take you to an abstract of the specific study (this is only if your computer is connected to the internet and has access to Pubmed.)