Surviving Sepsis Campaign The Pathophysiology Of Sepsis .
Surviving Sepsis CampaignGuidelines for Management ofSevere Sepsis/Septic ShockThe Pathophysiology ofSepsis / SIRS and MOFAn OverviewObjectives The Definitions of Sepsis and the SepsisSyndromes. The Factors that precipitate andperpetuate the Sepsis Cascade.What is Sepsis? The Pathogenesis of Multiple OrganDysfunction in Sepsis. Treatment options in SepsisSepsis Criteria (SCCM, ESICM,ACCP, ATS, SIS, 2001):Sepsis Criteria (SCCM, ESICM,ACCP, ATS, SIS, 2001):1
Definitions (ACCP/SCCM,1991) Systemic Inflammatory ResponseSyndrome (SIRS):The systemicinflammatory response to a variety ofsevere clinical insults (For example,infection). Sepsis:The systemic inflammatorySIRS is manifested by two or more of thefollowing conditions: Temperature 38 degrees Celsius or 36 degrees Celsius. Heart rate 90 beats per minute. Respiratory rate 20 breaths per minuteor PaCO2 32mmHg. White blood cell count 12,000/cu mm, 4,000/ cu mm, or 10% band forms.response to infection.SurvivingSepsisCampaign2008Definitions (ACCP/SCCM): Infection: A microbial phenomenoncharacterized by an inflammatory responseto the presence of microorganisms or theinvasion of normally sterile host tissue bythose organisms. Bacteremia: The presence of viable bacteriain the blood.Relationship Between Sepsisand Definitions (ACCP/SCCM) Sepsis: Known or suspected infection, plus 2 SIRS Criteria. Severe Sepsis: Sepsis plus 1 organ dysfunction. MODS. Septic Shock.PANCREATITIS2
Definitions (ACCP/SCCM): Septic Shock: Sepsis induced withhypotension despite adequateresuscitation along with the presenceof perfusion abnormalities which mayinclude, but are not limited to lacticacidosis, oliguria, or an acute alterationin mental status.Surviving Sepsis Campaign2008Definitions (ACCP/SCCM): Multiple Organ Dysfunction Syndrome(MODS): The presence of altered organfunction in an acutely ill patient suchthat homeostasis cannot be maintainedwithout intervention.Clinical Signs of Sepsis Fever. Leukocytosis. Tachypnea. Tachycardia. Reduced Vascular Tone. Organ Dysfunction.Clinical Signs of Septic ShockClinical Signs of Septic Shock Hemodynamic Alterations Hyperdynamic State (“Warm Shock”) Myocardial Depression. Tachycardia. Elevated or normal cardiac output. Decreased systemic vascular resistance. Hypodynamic State (“Cold Shock”) Altered Vasculature. Altered Organ Perfusion. Imbalance of O2 delivery andConsumption. Metabolic (Lactic) Acidosis. Low cardiac output.3
Levels of Clinical Infection Level I Locally Controlled. Level II Locally Controlled,Leukocytosis. Level III Systemic HyperdynamicResponse. Level IV Oxygen metabolism becomesuncoupled. Level V Shock, Organ Failure.Stages In the Development ofSIRS (Bone, 1996) Stage 1. In response to injury / infection, thelocal environment produces cytokines. Stage 2. Small amounts of cytokines arereleased into the circulation: Recruitment of inflammatory cells. Acute Phase Response. Normally kept in check by endogenous antiinflammatory mediators (IL-10, PGE2, Antibodies,Cytokine receptor antagonists).Stages In the Development ofSIRS Stage 3.Failure to controlinflammatory cascade: Loss of capillary integrity. Stimulation of Nitric Oxide Production. Maldistribution of microvascular bloodflow. Organ injury and dysfunction.Severe Sepsis Major cause of morbidity andmortality worldwide. Leading cause of death in noncoronaryICU. 11th leading cause of death overall. More than 750,000 cases of severesepsis in US annually. In the US, more than 500 patients dieof severe sepsis daily.Why is Sepsis Important?Severe Sepsis is alitySands,et al Zeni, et al. Angus,et al4
Severe Sepsis is CommonSevere Sepsis is increasing inincidenceSevere Sepsis cases300250200US stCA600LungCA250200120252050Severe Sepsis is a SignificantHealthcare Burden Sepsis consumes significant healthcareresources.Mediators of SepticResponse In a study of Patients who contract nosocomialinfections, develop sepsis and survive: ICU stay prolonged an additional 8 days. Additional costs incurred were 40,890/ patient. Estimated annual healthcare costs due to severesepsis in U.S. exceed 16 billion.Pro-inflammatory Mediators Bacterial in-8Platelet Activating Factor ric OxideAnti-inflammatory Mediators Interleukin-10PGE2Protein M-CSFTGFIL-1RA5
Question: Why do SepticPatients Die?Mechanisms of Sepsis Induced Organ Injury andOrgan Failure Answer: Organ FailureOrgan Failure and Mortality Knaus, et al. (1986): Multiple Organ Dysfunction (MODS) andMultiple Organ Failure (MOF) result fromdiffuse cell injury / death resulting incompromised organ function. Direct correlation between number of organsystems failed and mortality. Mortality Data:#OSF123Pathophysiology of SepsisInduced Organ y of SepsisInduced Ischemic OrganInjury Cytokine production leads to massive productionof endogenous vasodilators. Structural changes in the endothelium result in Mechanisms of cell injury / death: Cellular Necrosis (ischemic injury).Apoptosis.Leukocyte-mediated tissue injury.Cytopathic ndothelialDysfunctionHypotension Microvascular Plugging VasoconstrictionEdemaMaldistribution of Microvascular Blood Flowextravasation of intravascular fluid intointerstitium and subsequent tissue edema.Ischemia Plugging of select microvascular beds withneutrophils, fibrin aggregates, and microthrombiimpair microvascular perfusion. Organ-specific vasoconstriction.Cell DeathOrgan Dysfunction6
Pathogenesis of Vasodilationin Sepsis Loss of Sympathetic Responsiveness: Down-regulation of adrenergic receptornumber and sensitivity, possible altered signaltransduction.Vasodilatory InflammatoryMediators Vasoactive Intestinal Peptide Bradykinin Platelet Activating Factor Prostanoids Vasodilatory Inflammatory Mediators. Cytokines Leukotrienes Endotoxin has direct vasodilatory effects. Histamine NO Increased Nitric Oxide Production.Microvascular Plugging inSepsis Decreased red cell deformability in inflammatory states. Microvascular sequestration of activated leukocytes andplatelets. Sepsis is a Procoagulant State. The extrinsic pathway may be activated in sepsis byupregulation of Tissue Factor on monocytes orendothelial cells. Fibrinolysis appears to be inhibited in sepsis byupregulation of Plasminogen Activator Inhibitor.Endothelial Dysfunction inSepsis Endothelial cell expression of Selectinsand ICAM / ELAM is upregulated in Sepsisdue to inflammatory activation. Selectins bind carbohydrate ligands on thesurfaces of PMN’s. ICAM bind Integrins on the surfaces of PMN’s. The Selectins initiate a weak bond between thePMN and the endothelial cell causing PMN’s totumble along the vessel wall. A variety of pathways result in reduced Protein Cactivity in sepsis.Pathogenesis of EndothelialCell Dysfunction in SepsisEndothelial Cell Dysfunction in Sepsis Binding of leukocytes to ICAM leads totransmigration of PMN’s into interstitium. Transmigration disrupts normal cell-celladhesions resulting in increased vascularpermeability and tissue edema. Vascular permeability is also increased byseveral types of inflammatory cytokines.7
Apoptosis in Sepsis A physiologic process of homeostatically-regulated programmed cell death to eliminatedysfunctional or excessive cells. A number of inflammatory cytokines, NO, lowtissue perfusion, oxidative injury, LPS, andglucocorticoids all are known to increaseapoptosis in endothelial and parenchymal cells. Levels of circulating sfas (circulating apoptoticreceptor) and nuclear matrix protein (general celldeath marker) are both elevated in MODS.Leukocyte-Mediated TissueInjury Transmigration and release ofelastase and other degradativeenzymes can disrupt normal cell-cellconnections and normal tissuearchitecture required for organfunction. Reactive oxygen species cause directcellular DNA and membrane damageand induce apoptosis.Cytopathic Hypoxia A defect of cellular oxygen utilization. May be due to activation of PARP (poly-Therapy For SepsisADP-ribosylpolymerase-1). Oxidative DNA damage activates PARPwhich consumes intracellular andmitochondrial NAD . NAD depletion leads to impairedrespiration and a shift to anaerobicmetabolism.Therapeutic Strategies inSepsis Optimize Organ Perfusion Expand effective blood volume. Hemodynamic monitoring. Early goal-directed therapy. 16% reduction in absolute risk of in-house mortality.39% reduction in relative risk of in-house mortality.Decreased 28 day and 60 day mortality.Less fluid volume, less blood transfusion, lessvasopressor support, less hospital length of stay.Therapeutic Strategies inSepsis Optimize Organ Perfusion Pressors may be necessary. Compensated Septic Shock: PhenylephrineNorepinephrineDopamineVasopressin Uncompensated Septic Shock: Epinephrine Dobutamine Phenylephrine / Norepinephrine8
Therapeutic Strategies inSepsisTherapeutic Strategies inSepsis Control Infection Source Support Dysfunctional Organ Systems Drainage Surgical Radiologically-guided Renal replacement therapies (CVVHD, HD). Culture-directed antimicrobial therapy Mechanical ventilation. Cardiovascular support (pressors, inotropes). Transfusion for hematologic dysfunction. Support of reticuloendothelial system Enteral / parenteral nutritional support Minimize immunosuppressive therapies Minimize exposure to hepatotoxic and nephrotoxictherapies.Experimental Therapies inSepsisExperimental Therapies inSepsis Modulation of Host Response Modulation of Host Response Targeting Endotoxin Anti-endotoxin monoclonal antibody failed toreduce mortality in gram negative sepsis. IL-1 Antagonism Three randomized trials: Only 5% mortalityimprovement. Neutralizing TNF Excellent animal data. Large clinical trials of anti-TNF monoclonalantibodies showed a very small reduction inmortality (3.5%). PAF-degrading enzyme Great phase II trial. Phase III trial stopped due to no demonstrable efficacy.Experimental Therapies inSepsis Modulation of Host Response Antithrombin III No therapeutic effect. Subset of patients with effect when concomitantheparin not given. Activated Protein C (Drotrecogin alpha /Xigris) Statistically significant 6% reduction in mortality. Well-conducted multicenter trial (PROWESS). FDA-approved for use in reduction of mortality insevere sepsis (sepsis with organ failure). NO Antagonist (LNMA) Increased mortality (? Pulmonary Hypertension).Mediator-Directed TherapiesCoagulation System Xigris (Drotrecogin alpha/activatedProtein C PROWESS Study#MODMortality ReductionAbsoluteRelative 411%22%38%24%25%20%12%8%9
Experimental Therapies inSepsis Modulation of Host Response CorticosteroidsEvidence-Based SepsisGuidelines Incorporation of data from the existing medicalliterature in the design of guidelines for thecare of patients with severe sepsis and septicshock. Multiple studies from 1960’s – 1980’s:Not helpful, possibly harmful. Guideline development strongly advocated bymultiple critical care societies. Annane, et al. (2002): 10% mortalityreduction in vasopressor-dependentseptic shock (relative adrenalinsufficiency, ACTH nonresponders). Guideline development for the reduction ofmortality in sepsis is part of the 100K livesCampaign of IHI and is likely to soon become aJCAHCO requirement.Evidence-Based SepsisGuidelinesEvidence-Based Sepsis Guidelines Components: Early Recognition Early Goal-Directed Therapy Monitoring Resuscitation Pressor / Inotropic Support Steroid Replacement Recombinant Activated Protein C Source Control Glycemic Control Nutritional Support Adjuncts: Stress Ulcer Prophylaxis, DVT Prophylaxis,Transfusion, Sedation, Analgesia, OrganReplacementEvidence-Based Sepsis GuidelinesSurviving SepsisA global program to:Reduce mortality rates in severe sepsis10
Surviving SepsisSurviving SepsisPhase 1 Barcelona declarationPhase 2 Evidence based guidelinesPhase 3 Implementation and educationPhase 1 Barcelona declarationPhase 2 Evidence based guidelinesPhase 3 Implementation and educationSponsoring Organizations 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 InfectiousDiseasesEuropean Society of Intensive Care MedicineEuropean Respiratory SocietyInternational Sepsis ForumSociety of Critical Care MedicineSurgical Infection SocietyGuidelines Committee*Dellinger tenBrun-BuissonCarcilloCordonnierDellinger rphyNitsunSzokolTrzeciakVisonneau*Primary investigators from recently performed positive trials with implications for septicpatients excluded from committee selection.Surviving Sepsis Campaign (SSC)Guidelines for Management of SevereSepsis and Septic ShockDellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM,Ramsay G, Zimmerman JL, Vincent JL, Levy MM and theSSC Management Guidelines CommitteeCrit Care Med 2004;32:858-873Intensive Care Med 2004;30:536-555available online comCrit Care Med 2008;36:296-327Sackett DL. Chest 1989; 95:2S–4SSprung CL, Bernard GR, Dellinger RP. Intensive Care Medicine 2001; 27(Suppl):S1-S211
ClarificationsSurvivingSepsisCampaign2008 Recommendations grouped by categoryand not by hierarchy Grading of recommendation impliesliterature support and not priority ofimportanceInitial ResuscitationFigure B, page 948, reproduced with permission from Dellinger RP. Cardiovascularmanagement of septic shock. Crit Care Med 2003;31:946-955.The Importance of Early Goal-DirectedTherapy for Sepsis Induced HypoperfusionNNT to prevent 1 event (death) 6-8Mortality (%)6050Standard therapyEGDTInitial Resuscitation In the presence of sepsis-inducedhypoperfusion40 Hypotension Lactic acidosis3020100In-hospitalmortality(all patients)28-daymortality60-daymortalityAdapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al.Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med2001; 345:1368-137712
MAP65 mm Hg75 mm Hg85 mm HgF/LTUrinaryoutput (mL)49 1856 2143 13.60/.71Capillary blood flow(mL/min/100 g)6.0 1.65.8 115.3 0.9.59/.550.42 0.060.44 0160.42 0.06.74/.97Pico2 (mm Hg)41 247 246 2.11/.12Pa-Pico2 (mm Hg)13 317 316 3.27/.40Red CellVelocity (au)Initial ResuscitationGoals during first 6 hours: Central venous pressure: 8–12 mm Hg Mean arterial pressure 65 mm Hg Urine output 0.5 mL kg-1/hr- -1 Central venous (superior vena cava) ormixed venous oxygen [SvO2] saturation 70% Central venous 70% or Mixed venous 65%Grade BAdapted from Table 4, page 2731, with permission from LeDoux, Astiz ME, Carpati CM,Rackow ED. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med2000; 28:2729-2732DiagnosisInitial Resuscitation Appropriate cultures Minimum 2 blood culturesGoals during first 6 hours: Central venous or mixed venous O2 sat 70% after CVP of 8–12 mm Hg Packed RBCs to Hct 30% and/or Dobutamine to max 20 g/kg/min 1 percutaneous 1 from each vascular access 48hrsCulture other sites as clinically indicatedGrade DGrade BAntibiotic TherapyAntibiotic Therapy Begin intravenous antibiotics withinfirst hour of recognition of severesepsis. and in septic shock.As early as possibleGrade E One or more drugs active against likelybacterial or fungal pathogens. Broad-spectrum Consider microorganism susceptibilitypatterns in the community and hospital.Grade D13
Source ControlAntibiotic TherapyReassess antimicrobial regimenat 48-72 hrs Microbiologic and clinical dataNarrow-spectrum antibioticsNon-infectious cause identifiedPrevent resistance, reduce toxicity,reduce costsPseudomonasCombined therapy in neutropenic patientsCombination 3-5 days and de-escalatingDuration typically limted to 7-10 days Evaluate patient for a focused infectionamendable to source control measuresincluding abscess drainage or tissuedebridement. Move rapidly Consider physiologic upset of measure Intravascular access devicesGrade EGrade EPhotograph used with permission from Janice L. Zimmerman, MDEKG tracing reproduced with permission from Janice L. Zimmerman, paign2008Fluid Therapy Fluid resuscitation may consist of natural orartificial colloids or crystalloids.Grade C14
Fluid Therapy Fluid challenge over 30 min 500–1000 ml crystalloid 300–500 ml colloid Repeat based on response andtoleranceTarget a CVP 8 mmHg ( 12 mmHg if MV)Use a fluid challenge techniqueGradeReduce rate if cardiac filling pressuresincrease without concurrent hemodynamicimprovementEFigure 2, page 206, reproduced with permission from Choi PT, Yip G, Quinonez L, Cook DJ.Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27:200–210Effects of Dopamine, Norepinephrine,and Epinephrine on the SplanchnicCirculation in Septic ShockVasopressors Either norepinephrine or dopamineadministered through a centralcatheter is the initial vasopressor ofchoice. Failure of fluid resuscitationDuring fluid resuscitationAvoid epinephrine, phenylephrineo or vasopressinas the initial vasopressors of choiceUse epinephrine as the first alternative when poorlyresponsive to norepinephrineGrade DVasopressorsFigure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, VincentJL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septicshock: Which is best? Crit Care Med 2003; 31:1659-1667Vasopressors Do not use low-dose dopamine forrenal protection. In patients requiring vasopressors,place an arterial catheter as soon aspossible.Grade BGrade EBellomo R, et al. Lancet 2000; 356:2139-214315
Circulating Vasopressin Levels in Septic ShockVasopressin and Septic Shock Versus cardiogenic shock Decreases or eliminatesrequirements of traditionalpressors As a pure vasopressor expectedto decrease cardiac outputFigure 2, page 1755 reproduced with permission from Sharshar T, Blanchard A, Paillard M,et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31:1752-1758During Septic ShockVasopressorsVasopressinDiastole Not a replacement for norepinephrine ordopamine as a first-line agent Consider in refractory shock despite highdose conventional vasopressors If used, administer at 0.01-0.04 units/minute0.03 units/minutein adultsSystole10 Days Post ShockDiastoleSystoleGrade EImages used with permission from Joseph E. Parrillo, MDInotropic TherapyInotropic Therapy Consider dobutamine in patients withmeasured low cardiac output despitefluid resuscitation. Do not increase cardiac index to achievean arbitrarily predefined elevated level ofoxygen delivery.Grade A Continue to titrate vasopressor to meanarterial pressure of 65 mm Hg or greater.Grade EYu, et al. CCM 1993; 21:830-838Hayes, et al. NEJM 1994; 330-1717-1722Gattinoni, et al. NEJM 1995; 333:1025-103216
Steroid TherapyP .045P .007Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al.Effect of treatment with low doses of hydrocortisone and
Pathophysiology of Sepsis-Induced Organ Injury Multiple Organ Dysfunction (MODS) and Multiple Organ Failure (MOF) result from diffuse cell injury / death resulting in compromised organ function. Mechanisms of cell injury / death: Cellular Necrosis (ischemic injury). Apoptosis. Leukocyte-mediated tissue injury. Cytopathic .
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
associated with a greater risk of . (2015) ‘Neutropenic Sepsis: Assessment, pathophysiology & nursing care’. British Journal of Neuroscience Nursing. Vol 11 (2) pp79-87 Surviving Sepsis Campaign (2016) International Guidelines and Management od Sepsis and Septic Shock. JAMA Vol 315 (8) pp801-810. .
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have
sepsis and septic shock: the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (Fig. 2).10 Sepsis is now defined as life-threatening or-gan dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in the total Sequential (Sepsis-
mass black holes, no credible formation process is known, and indeed no indications have been found that black holes much lighter than this \Chandrasekhar limit" exist anywhere in the Universe. Does this mean that much lighter black holes cannot exist? It is here that one could wonder about all those fundamental assumptions that underly the theory of quantum mechanics, which is the basic .
