Septic Shock

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  • Risk factors for gram + infections include vascular catheters, indwelling mechanical devices, burns, injection drug use
    Risk factors for gram- include DM, lymphoproliferative disease, cirrhosis, burns, chemo, invasive procedures
  • example: LPS and TNF-alpha promote intravascular coagulation by inducing monocytes to express tissue factor, initiating the release of plasminogen activator inhibitor type 1 and inhibiting the expression of plasminogen activator by vascular endothelial cells
  • CNS abscess/empyema and viral infections rarely cause shock
  • Septic Shock

    1. 1. SHOCKSHOCK September 6, 2005September 6, 2005 Andrew FiliatrautAndrew Filiatraut
    2. 2. In GeneralIn General  ShockShock  Clinical syndrome defined as hypoperfusionClinical syndrome defined as hypoperfusion  Hypotension and Cellular HypoxiaHypotension and Cellular Hypoxia  Elevated lactateElevated lactate  OliguriaOliguria  Hepatic/GI dysfunctionHepatic/GI dysfunction  Mental status changesMental status changes
    3. 3. In GeneralIn General  Four ClassificationsFour Classifications  HypovolemicHypovolemic  CardiogenicCardiogenic  ObstructiveObstructive  DistributiveDistributive  Septic, Addison’s, Anaphylactic, Neurogenic,Septic, Addison’s, Anaphylactic, Neurogenic, Thyrotoxicosis, Beriberi, Paget’s, Cirrhosis,Thyrotoxicosis, Beriberi, Paget’s, Cirrhosis, Chroinc Anemia, Osler-Weber-RenduChroinc Anemia, Osler-Weber-Rendu
    4. 4. Hemodynamic ProfilesHemodynamic Profiles TYPETYPE BPBP C.O.C.O. PCWPPCWP SVRSVR ↓↓ Vol.Vol. ↓↓ ↓↓ ↓↓ ↑↑ CardioCardio ↓↓ ↓↓ ↑↑ ↑↑ TmpnaTmpna dd ↓↓ or Nor N ↓↓ or Nor N ↑↑ or Nor N ↑↑ P. E.P. E. ↓↓ ↓↓ ↓↓ or Nor N ↑↑ DistribDistrib ↓↓ ↑↑ ↓↓ ↓↓
    5. 5. Septic ShockSeptic Shock
    6. 6. EpidemiologyEpidemiology  751,000 cases of severe sepsis /year751,000 cases of severe sepsis /year  Up to half develop shockUp to half develop shock  Overall mortality rate of 45%Overall mortality rate of 45%  CauseCause  Gram+ 35-40%Gram+ 35-40%  Gram- 55-60%Gram- 55-60%  Slightly higher incidence in men, olderSlightly higher incidence in men, older adults (55-60 yrs)adults (55-60 yrs)
    7. 7. DefinitionsDefinitions  InfectionInfection  Inflammation against microorganismInflammation against microorganism  BacteremiaBacteremia  Viable bacteria in bloodViable bacteria in blood
    8. 8. DefinitionsDefinitions  SIRSSIRS  Evidence of inflammationEvidence of inflammation NOTNOT necessarilynecessarily infectioninfection  2 or more of the following2 or more of the following  Temp>38 or <36Temp>38 or <36  HR >90bpmHR >90bpm  RR >20 or PaCo2 <32RR >20 or PaCo2 <32  WBC’s >12,000 or <4000 or >10% bandemiaWBC’s >12,000 or <4000 or >10% bandemia
    9. 9. DefinitionsDefinitions  SepsisSepsis  systemic inflammatory response as a result ofsystemic inflammatory response as a result of infectioninfection  Severe SepsisSevere Sepsis  sepsis associated with organ dysfunctionsepsis associated with organ dysfunction  Lactic acidosis, oliguria, mental status changeLactic acidosis, oliguria, mental status change  Septic shockSeptic shock  sepsis-induced hypotension with presence ofsepsis-induced hypotension with presence of perfusion abnormalitiesperfusion abnormalities
    10. 10. DefinitionsDefinitions  Sepsis-induced hypotensionSepsis-induced hypotension  SBP<90 or reduction of 40mm Hg fromSBP<90 or reduction of 40mm Hg from baseline without other causebaseline without other cause  Multiple Organ Dysfunction SyndromeMultiple Organ Dysfunction Syndrome  Altered organ dysfunction in acutely ill patientAltered organ dysfunction in acutely ill patient requiring intervention to maintain homeostasisrequiring intervention to maintain homeostasis
    11. 11. PathophysiologyPathophysiology
    12. 12. PathophysiologyPathophysiology  Focus of infectionFocus of infection  Pneumonia, UTI, cellulitits, abscess, indwelling devicePneumonia, UTI, cellulitits, abscess, indwelling device  ICU:ICU: catheters, sinusitis, acalculus cholecystitis,catheters, sinusitis, acalculus cholecystitis, C. diff, resistant organism, fungal infectionC. diff, resistant organism, fungal infection  Blood stream invasion or proliferation ofBlood stream invasion or proliferation of organism at siteorganism at site  Exogenous toxin releaseExogenous toxin release  Activation of endogenous mediatorsActivation of endogenous mediators
    13. 13. Molecular Mediators inMolecular Mediators in PathophysiologyPathophysiology  Three phasesThree phases  InductionInduction  Cytokine synthesis & secretionCytokine synthesis & secretion  CascadeCascade
    14. 14. Molecular Mediators inMolecular Mediators in PathophysiologyPathophysiology  InductionInduction  Interaction of microbial molecules with hostInteraction of microbial molecules with host  Mediators activated that amplify & transmit theMediators activated that amplify & transmit the microbial signal to other cellsmicrobial signal to other cells  Ex LPS binds to LPS binding protein which isEx LPS binds to LPS binding protein which is detected by CD14 releasing TNF-alphadetected by CD14 releasing TNF-alpha  Peptidoglycan & lipoteichoic acid of gram (+)Peptidoglycan & lipoteichoic acid of gram (+) induce similarlyinduce similarly
    15. 15. Molecular Mediators in PathophysMolecular Mediators in Pathophys  Cytokine cascadeCytokine cascade  Activation & release of central mediatorsActivation & release of central mediators  TNF-alpha and IL-1TNF-alpha and IL-1  Release of secondary mediatorsRelease of secondary mediators  IL-6, IL-8, PAF, PG’s, leukotrienesIL-6, IL-8, PAF, PG’s, leukotrienes  Activation of neutrophils, complement system,Activation of neutrophils, complement system, vascular endothelial cellsvascular endothelial cells  Synthesis of acute phase reactantsSynthesis of acute phase reactants
    16. 16. Molecular Mediators in PathophysMolecular Mediators in Pathophys  Parallel to SIRS is CARSParallel to SIRS is CARS  Compensatory Anti-inflammatory ResponseCompensatory Anti-inflammatory Response SystemSystem  Attempts to down regulate the SIRS responseAttempts to down regulate the SIRS response  IL-4, IL-10, transforming growth factor beta, CSF,IL-4, IL-10, transforming growth factor beta, CSF, soluble receptors to TNF, antagonists to TNF-soluble receptors to TNF, antagonists to TNF- alpha and IL-1alpha and IL-1  If CARS reaction is severe it will manifest asIf CARS reaction is severe it will manifest as anergy and infection susceptibilityanergy and infection susceptibility
    17. 17. Vasoactive Mediators in PathophysVasoactive Mediators in Pathophys  Nitric OxideNitric Oxide  Produced by endotheliumProduced by endothelium  Increased levels during shockIncreased levels during shock  Actions at high levelsActions at high levels  Mediator of vasodilation & hypotensionMediator of vasodilation & hypotension  Direct cellular toxicityDirect cellular toxicity  Myocardial depressionMyocardial depression  Increased permeabilityIncreased permeability
    18. 18. Clinical FeaturesClinical Features
    19. 19. Clinical FeaturesClinical Features  ConstitutionalConstitutional  Hyper/hypothermiaHyper/hypothermia  TachycardiaTachycardia  TachypneaTachypnea  Wide pulse pressureWide pulse pressure  Mental status changeMental status change  Most likely obtundedMost likely obtunded
    20. 20. Clinical FeaturesClinical Features  CadiovascularCadiovascular  Early, vasodilators predominateEarly, vasodilators predominate  Cardiac output is increased with tachycardiaCardiac output is increased with tachycardia  CO=SV x HRCO=SV x HR  i.e. Initially patients will have warm extremitiesi.e. Initially patients will have warm extremities  If not treated aggressively decompensationIf not treated aggressively decompensation ensuesensues  Typically hypotension is not reversible withTypically hypotension is not reversible with fluids alonefluids alone
    21. 21. Clinical FeaturesClinical Features  PulmonaryPulmonary  Sepsis is most common condition associatedSepsis is most common condition associated with ARDSwith ARDS  Lung edema from increased permeabilityLung edema from increased permeability  Alveolar edemaAlveolar edema dyspnea, hypoxemia, opacities ondyspnea, hypoxemia, opacities on CXRCXR  B/L infiltrates, wedge pressure <18B/L infiltrates, wedge pressure <18  Endotoxin, TNF-alpha, IL-1, IL-6, IL-8,Endotoxin, TNF-alpha, IL-1, IL-6, IL-8, bactericidal/permeability-increasing (BPI) proteinbactericidal/permeability-increasing (BPI) protein
    22. 22. Clinical FeaturesClinical Features  PulmonaryPulmonary  ARDSARDS  B/L pulmonary infiltratesB/L pulmonary infiltrates  PCWP <18 (non-cardiogenic pulm edema)PCWP <18 (non-cardiogenic pulm edema)  PaO2/FiO2 <200PaO2/FiO2 <200  If PaO2/FiO2 >200, but <300 then ALIIf PaO2/FiO2 >200, but <300 then ALI
    23. 23. Clinical FeaturesClinical Features  RenalRenal  Acute renal failure w/ azotemia, oliguria,Acute renal failure w/ azotemia, oliguria, active urinary sedimentactive urinary sediment  Hypotension/Dehydration, aminoglycosides,Hypotension/Dehydration, aminoglycosides, pigmenturia (e.g. myoglobinuria)pigmenturia (e.g. myoglobinuria)  Immune complex depositionImmune complex deposition  IgG, IgM,C3, bacterial antigens & antibodiesIgG, IgM,C3, bacterial antigens & antibodies  Tubulointersitial diseaseTubulointersitial disease  S. pneumoniae, S. pyogenes, Legionella, salmonellosis,S. pneumoniae, S. pyogenes, Legionella, salmonellosis, brucellosis, diptheriabrucellosis, diptheria
    24. 24. Clinical FeaturesClinical Features  GastrointestinalGastrointestinal  Accelerated apoptosis of GI epithelial cellsAccelerated apoptosis of GI epithelial cells  Can lead to blood loss anemiaCan lead to blood loss anemia  Cholestatic jaundice (most frequentCholestatic jaundice (most frequent abnormality)abnormality)  Transaminase/Alkaline phosphatase 1-3x normalTransaminase/Alkaline phosphatase 1-3x normal  Bilirubin concentrations, usually not >10mg/dLBilirubin concentrations, usually not >10mg/dL  Hemolysis of RBC’s, hepatocellular dysfunction due toHemolysis of RBC’s, hepatocellular dysfunction due to endotoxinendotoxin
    25. 25. Clinical FeaturesClinical Features  HematologicHematologic  Minor blood loss secondary to erosions inMinor blood loss secondary to erosions in mucosal layer of stomach/duodenummucosal layer of stomach/duodenum  Accelerated apoptosis of lymphocytesAccelerated apoptosis of lymphocytes  Possibly due to elevated glucocorticoidsPossibly due to elevated glucocorticoids  Most frequent changes are neutrophilia orMost frequent changes are neutrophilia or neutropenia, thrombocytopenia, DICneutropenia, thrombocytopenia, DIC
    26. 26. Clinical FeaturesClinical Features  HematologicHematologic  NeutrophiliaNeutrophilia  Most commonMost common  Left shiftLeft shift  Demargination & release of less mature granulocytesDemargination & release of less mature granulocytes from BMfrom BM  C3a causes release of neutrophil releasingC3a causes release of neutrophil releasing substancesubstance  Sustained neutrophilia is secondary to CSFsSustained neutrophilia is secondary to CSFs
    27. 27. Clinical FeaturesClinical Features  Hematologic continuedHematologic continued  NeutropeniaNeutropenia  Increases mortalityIncreases mortality  Increased peripheral use of cells, damage to cells byIncreased peripheral use of cells, damage to cells by bacterial byproducts, depression of marrow by inflammatorybacterial byproducts, depression of marrow by inflammatory mediatorsmediators  Morphological changes of WBC’s in sepsisMorphological changes of WBC’s in sepsis  Toxic granulations, Dohle bodies, vacuolizationToxic granulations, Dohle bodies, vacuolization  Functional changes of WBC’sFunctional changes of WBC’s  Increased phagocytic/cytotoxic activitiesIncreased phagocytic/cytotoxic activities
    28. 28. Clinical FeaturesClinical Features  Hematologic continuedHematologic continued  RBC production & survival are decreasedRBC production & survival are decreased  Usually does not cause anemia unless infection isUsually does not cause anemia unless infection is prolongedprolonged  Low serum Fe concentrationsLow serum Fe concentrations  Decrease by 50%Decrease by 50%  Influx into liver & other reticuloendothelial cellsInflux into liver & other reticuloendothelial cells
    29. 29. Clinical FeaturesClinical Features  Hematologic continuedHematologic continued  ThrombocytopeniaThrombocytopenia  Usual a consequence of DICUsual a consequence of DIC  May be early sign of bacteremiaMay be early sign of bacteremia  Inhibition of thrombopoiesis, increased platelet turnover,Inhibition of thrombopoiesis, increased platelet turnover, increased endothelial adherence, increased destructionincreased endothelial adherence, increased destruction
    30. 30. Clinical FeaturesClinical Features  DICDIC  Clotting & fibrinolytic systems activatedClotting & fibrinolytic systems activated  Consumption of coagulation factors & plateletsConsumption of coagulation factors & platelets  Clotting system activated through the extrinisic clottingClotting system activated through the extrinisic clotting system by bacteria, viruses, fungi, endo/exotoxinssystem by bacteria, viruses, fungi, endo/exotoxins  Gram(-) precipitate DIC more readily than gram (+)Gram(-) precipitate DIC more readily than gram (+)  Fibrinolytic system is activated by tissue type plasminogenFibrinolytic system is activated by tissue type plasminogen activatoractivator  As sepsis progresses, increase release of plasminogenAs sepsis progresses, increase release of plasminogen activator inhibitor type 1activator inhibitor type 1
    31. 31. Clinical FeaturesClinical Features  DIC continuedDIC continued  Two formsTwo forms  CompensatedCompensated  ““slower” generalized activationslower” generalized activation  Bleeding prevented by increasing coagulation factor productionBleeding prevented by increasing coagulation factor production in liver, release of platelets from reserve, synthesis of inhibitorsin liver, release of platelets from reserve, synthesis of inhibitors at accelerated rateat accelerated rate  DecompensatedDecompensated  Clinical bleeding and/or thrombosisClinical bleeding and/or thrombosis  Thrombocytopenia, prolonged PT/PTT, decreased fibrinogen &Thrombocytopenia, prolonged PT/PTT, decreased fibrinogen & antithrombin III, increased fibrin monomer/fibrin splitantithrombin III, increased fibrin monomer/fibrin split products/D-dimerproducts/D-dimer
    32. 32. Clinical FeaturesClinical Features  EndocrineEndocrine  HyperglycemiaHyperglycemia  Increased catecholamines, cortisol, glucagon, peripheralIncreased catecholamines, cortisol, glucagon, peripheral insulin resistance, impaired glucose use, decreased insulininsulin resistance, impaired glucose use, decreased insulin secretionsecretion  Significant risk for adverse outcomeSignificant risk for adverse outcome  Must maintain tight control w/insulin infusion to keep b/w 80-Must maintain tight control w/insulin infusion to keep b/w 80- 100 mg/dl100 mg/dl (NEJM Nov 8, 2001; vol 345, #19)(NEJM Nov 8, 2001; vol 345, #19)  HypoglycemiaHypoglycemia  Assoc. w/S. pneumoniae, S. aureus, S. pyogenes, Listeria,Assoc. w/S. pneumoniae, S. aureus, S. pyogenes, Listeria, Neisseria meningitidis, H. flu, EnterobacteriaceaeNeisseria meningitidis, H. flu, Enterobacteriaceae
    33. 33. Clinical FeaturesClinical Features  Acid/BaseAcid/Base  Early in sepsisEarly in sepsis  resp alkalosisresp alkalosis  Metabolic acidosis suggests inadequateMetabolic acidosis suggests inadequate perfusion, impaired hepatic clearance ofperfusion, impaired hepatic clearance of lactate/pyruvate, increased glycolysislactate/pyruvate, increased glycolysis  Hypoxemia often present due toHypoxemia often present due to vent/perfusion mismatchvent/perfusion mismatch
    34. 34. Clinical FeaturesClinical Features  CutaneousCutaneous  Direct bacterial involvementDirect bacterial involvement  Cellulitis, erysipelas, fasciitisCellulitis, erysipelas, fasciitis  Lesions as a consequence ofLesions as a consequence of sepsis/hypotension/DICsepsis/hypotension/DIC  Acrocyanosis & necrosis of peripheral tissueAcrocyanosis & necrosis of peripheral tissue  Lesions secondary to intravascular infectionLesions secondary to intravascular infection  Microemboli &/or immune complex vasculitisMicroemboli &/or immune complex vasculitis
    35. 35. DiagnosisDiagnosis
    36. 36. DiagnosisDiagnosis  Pt presents withPt presents with  Hypotension not responsive to fluid bolusHypotension not responsive to fluid bolus  Inadequate perfusionInadequate perfusion  Complaints attributable to a serious infectionComplaints attributable to a serious infection  Hot flushed skinHot flushed skin  Mental obtundation or agitationMental obtundation or agitation  Widened pulse pressureWidened pulse pressure  HyperventilationHyperventilation  DysthermiaDysthermia  **beware of the old, young, immunocompromised**beware of the old, young, immunocompromised
    37. 37. DiagnosisDiagnosis  Differential DiagnosisDifferential Diagnosis  Other causes of shockOther causes of shock  CardiogenicCardiogenic  NeurogenicNeurogenic  HypovolemicHypovolemic  AnaphylacticAnaphylactic  Obstructive (PE, tamponade)Obstructive (PE, tamponade)  Endocrine (adrenal insufficiency, thyroid storm)Endocrine (adrenal insufficiency, thyroid storm)
    38. 38. DiagnosisDiagnosis  H & PH & P  Basic lab and x-rays areBasic lab and x-rays are usuallyusually successful in identification of sourcesuccessful in identification of source  CNSCNS  Meningitis (nuchal rigidity, MS change, petechiae)Meningitis (nuchal rigidity, MS change, petechiae)  Brain abscess, sub/epi dural empyemasBrain abscess, sub/epi dural empyemas  Viral CNS infectionsViral CNS infections
    39. 39. DiagnosisDiagnosis  PulmonaryPulmonary  Acute bacterial pneumoniaAcute bacterial pneumonia  Intra-abdominal processesIntra-abdominal processes  Most common source of infection leading to sepsisMost common source of infection leading to sepsis  Acute pancreatitsAcute pancreatits  CholangitisCholangitis  Septic abortion/endometritis/myometritisSeptic abortion/endometritis/myometritis  PyelonephritisPyelonephritis  Occult AbscessOccult Abscess  SkinSkin  Cellulitis (S.aureus, S.pyogenes)Cellulitis (S.aureus, S.pyogenes)  Decubitus ulcer(s)Decubitus ulcer(s)
    40. 40. DiagnosisDiagnosis  No obvious sourceNo obvious source  EndocarditisEndocarditis  Primary bacteremiaPrimary bacteremia  S.aureus, S.pneumoniae, N.meningitidisS.aureus, S.pneumoniae, N.meningitidis  AspleniaAsplenia  Salmonella, H flu, S pneumo, N. meningitidisSalmonella, H flu, S pneumo, N. meningitidis  IVD users, Pseudomonas & gram(-) bacteriaIVD users, Pseudomonas & gram(-) bacteria  Skin abscess from “popping”Skin abscess from “popping”
    41. 41. DiagnosisDiagnosis  Ancillary StudiesAncillary Studies  CBCCBC  DIC panel (PT,PTT,fibrinogen,D-dimer, ATIII)DIC panel (PT,PTT,fibrinogen,D-dimer, ATIII)  CMP (include Mag, Ca, Phosphate)CMP (include Mag, Ca, Phosphate)  Lactate levelLactate level  ABGABG  UAUA  CXRCXR  Cultures (blood, urine)Cultures (blood, urine)  If H&P suggestIf H&P suggest  LP, CT (abd . . .)LP, CT (abd . . .)  ConsiderConsider  CRP, pro-calcitonin, IL-6 levelCRP, pro-calcitonin, IL-6 level
    42. 42. Standard TreatmentStandard Treatment
    43. 43. Standard TreatmentStandard Treatment  ABC’s!ABC’s!  Maintain O2 sat’s above 90%Maintain O2 sat’s above 90%  Hemodynamic StabilizationHemodynamic Stabilization  Rapid fluid administrationRapid fluid administration  Rate of 0.5L of NS every 5-10minRate of 0.5L of NS every 5-10min  May require 2-6L in initial stabilization phaseMay require 2-6L in initial stabilization phase  Be careful with heart failure patientsBe careful with heart failure patients  Monitor response with BP, HR, RR, mental status,Monitor response with BP, HR, RR, mental status, urine output (1cc/kg/hr), CVP, skin perfusionurine output (1cc/kg/hr), CVP, skin perfusion
    44. 44. Standard TreatmentStandard Treatment ▪▪ Inotropic supportInotropic support  If no response to fluids or signs of fluid overloadIf no response to fluids or signs of fluid overload presentpresent  Goal is to keep MAP above 65 mm HgGoal is to keep MAP above 65 mm Hg  Dopamine 5-20 micrograms/kg/minDopamine 5-20 micrograms/kg/min  Beta-1, dopaminergic and alpha adrenergic activityBeta-1, dopaminergic and alpha adrenergic activity  NorepinephrineNorepinephrine  Beta-1 and alpha adrenergic stimulationBeta-1 and alpha adrenergic stimulation  Short term vasopressin infusion (0.04 units/min for 4-Short term vasopressin infusion (0.04 units/min for 4- 16h)16h)  Vasodilatory septic shockVasodilatory septic shock
    45. 45. Standard TreatmentStandard Treatment  End pointsEnd points  Early goal directed therapy providesEarly goal directed therapy provides significant benefit & improves outcomesignificant benefit & improves outcome  Rivers et al. NEJM vol. 345:1368, 2001Rivers et al. NEJM vol. 345:1368, 2001  Maintain CVP b/w 8-12Maintain CVP b/w 8-12  Hct 30%Hct 30%  SVO2 >70%SVO2 >70%  Reduction in mortality from 44% in control group toReduction in mortality from 44% in control group to 29% in intervention group29% in intervention group
    46. 46. Standard TreatmentStandard Treatment  Empiric Antimicrobial TherapyEmpiric Antimicrobial Therapy  Start ASAPStart ASAP  TryTry to get culture samples beforeto get culture samples before  Select based on adequate coverage ofSelect based on adequate coverage of potential pathogenspotential pathogens  Should cover gram +/-Should cover gram +/-  Give maximum dose allowedGive maximum dose allowed  Give IVGive IV
    47. 47. Empiric Antibiotics in SepsisEmpiric Antibiotics in Sepsis  Table 32-3Table 32-3
    48. 48. Standard TreatmentStandard Treatment  Removal of Source of InfectionRemoval of Source of Infection  Indwelling cathetersIndwelling catheters  send tip for culturesend tip for culture  Replace Foley cathetersReplace Foley catheters  Intra-abdominal or soft tissue sites of pusIntra-abdominal or soft tissue sites of pus require urgent drainagerequire urgent drainage
    49. 49. Standard TreatmentStandard Treatment  Initial Baseline Assessment & ContinuedInitial Baseline Assessment & Continued Monitoring (again goal directed)Monitoring (again goal directed)  Some use serum lactate to monitor responseSome use serum lactate to monitor response  ABG’s to monitor ventilation & perfusionABG’s to monitor ventilation & perfusion  2 large bore IV’s2 large bore IV’s  Consider central line earlyConsider central line early  If requiring vasoactive drugs consider pulm arteryIf requiring vasoactive drugs consider pulm artery thermal-dilution catheterthermal-dilution catheter  Other monitoring gadgetsOther monitoring gadgets  Sublingual capnography, gastric pH tonometry, muscleSublingual capnography, gastric pH tonometry, muscle oximetry, bioimpedance determination of COoximetry, bioimpedance determination of CO
    50. 50. New Innovative TherapiesNew Innovative Therapies
    51. 51. Innovative TherapyInnovative Therapy  Based in premise that neutralizingBased in premise that neutralizing bacterial toxins, cytokines, & otherbacterial toxins, cytokines, & other mediators could stop or slow themediators could stop or slow the syndromesyndrome
    52. 52. Innovative TherapiesInnovative Therapies  CorticosteroidsCorticosteroids  Meta-analysis has shown physiologic dosesMeta-analysis has shown physiologic doses of hydrocortisone improves outcomesof hydrocortisone improves outcomes  (200-300mg/d) for 5-7 days(200-300mg/d) for 5-7 days  Then tapered for 5-7 daysThen tapered for 5-7 days  Early studies (proir to 1989) used high doses and hadEarly studies (proir to 1989) used high doses and had increased mortalityincreased mortality  Those published after 1997 (5)used lower doses andThose published after 1997 (5)used lower doses and reported improved survival similar to that of Activatedreported improved survival similar to that of Activated Protein CProtein C  Annal of Internal Med 2004;141:47-56Annal of Internal Med 2004;141:47-56
    53. 53. Innovative TherapyInnovative Therapy  Activated Protein C (Xigris)Activated Protein C (Xigris)  Inactivates Factors Va and VIIIaInactivates Factors Va and VIIIa  Inhibits thrombin (decreases inflammation)Inhibits thrombin (decreases inflammation)  Inhibits platelet activation, neutrophil recruitment,Inhibits platelet activation, neutrophil recruitment, and mast cell degranulationand mast cell degranulation  Blocks cytokine productionBlocks cytokine production  Inhibits cell adhesionInhibits cell adhesion  Anti-apoptotic actionsAnti-apoptotic actions  Apoptosis (i.e. GI epithelial cell) induces anergyApoptosis (i.e. GI epithelial cell) induces anergy
    54. 54. Innovative TherapyInnovative Therapy  SummarySummary  To date the only treatments shown to produceTo date the only treatments shown to produce benefitbenefit  Early goal directed hemodynamic stabilizationEarly goal directed hemodynamic stabilization  Tight control of blood glucose with insulinTight control of blood glucose with insulin  Activated protein CActivated protein C  ““Efficacy and Safety of Recombinant HumanEfficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis” NEJM 2001,Activated Protein C for Severe Sepsis” NEJM 2001, vol. 344; 699-709vol. 344; 699-709
    55. 55. Cardiogenic ShockCardiogenic Shock
    56. 56. Cardiogenic ShockCardiogenic Shock  A state of decreased cardiac output(CO)A state of decreased cardiac output(CO) producing inadequate tissue perfusionproducing inadequate tissue perfusion despite adequate or excessive circulatingdespite adequate or excessive circulating volumevolume
    57. 57. Cardiogenic shockCardiogenic shock  EtiologyEtiology  AMIAMI  Pump failure (40% of LV involved)Pump failure (40% of LV involved)  Mechanical complications (MR,VSD,free wall rupture)Mechanical complications (MR,VSD,free wall rupture)  RV infarctionRV infarction  Depression of contractilityDepression of contractility  Sepsis, myocarditis, contusionSepsis, myocarditis, contusion  Mechanical obstructionMechanical obstruction  AS, hypertrophic CM, MS, LA myxomaAS, hypertrophic CM, MS, LA myxoma  Regurgitation of LV outputRegurgitation of LV output  AI, chordal ruptureAI, chordal rupture
    58. 58. PathophysiologyPathophysiology  AMI cell death loss of contractileAMI cell death loss of contractile functionfunction  Decreased CO/SVDecreased CO/SV tachycardia/hypotension decreasedtachycardia/hypotension decreased coronary perfusion/diastolic filling timecoronary perfusion/diastolic filling time  Further ischemia SNS/Renin-AngiotensionFurther ischemia SNS/Renin-Angiotension System activationSystem activation  Increased SVR and myocardial O2 consumptionIncreased SVR and myocardial O2 consumption
    59. 59. Cardiogenic ShockCardiogenic Shock  Clinical FeaturesClinical Features  PEPE  HypoperfusionHypoperfusion  Skin mottling, obtundedSkin mottling, obtunded  +/-hypotension (SBP<90)+/-hypotension (SBP<90)  May be compensated (pulse pressure <20, ST) or pre-existingMay be compensated (pulse pressure <20, ST) or pre-existing hypertensionhypertension  Tachypnea, rales (clear if RV), JVDTachypnea, rales (clear if RV), JVD  MurmurMurmur  MR (chordae tendinea rupture): holosystolic at apex going toMR (chordae tendinea rupture): holosystolic at apex going to axillaaxilla  VSD: holosystolic at L parasternalVSD: holosystolic at L parasternal
    60. 60. Cardiogenic ShockCardiogenic Shock  Ancillary StudiesAncillary Studies  ECG: ischemia/infarction,electrolyte abnormality,drugECG: ischemia/infarction,electrolyte abnormality,drug toxicitytoxicity  CXR: helps r/o other causes (pneumonia, aorticCXR: helps r/o other causes (pneumonia, aortic dissection, pericardial effusion)dissection, pericardial effusion)  Labs: BNP, cardiac enzymes, ABG, lactate,Labs: BNP, cardiac enzymes, ABG, lactate, electrolytes, serum drug levelselectrolytes, serum drug levels  Echo: ventricular/valve dysfunctionEcho: ventricular/valve dysfunction  HD monitoring (table 33-3): invasive vs bioimpedanceHD monitoring (table 33-3): invasive vs bioimpedance
    61. 61. Cardiogenic ShockCardiogenic Shock  Differential DiagnosisDifferential Diagnosis  AMIAMI  PEPE  COPDCOPD  PneumoniaPneumonia  Aortic dissectionAortic dissection  TamponadeTamponade  Acute valvular insufficiencyAcute valvular insufficiency  HemorrhageHemorrhage  SepsisSepsis  Drug OD of negative inotropic/chronotropic agentDrug OD of negative inotropic/chronotropic agent
    62. 62. Cardiogenic ShockCardiogenic Shock  TreatmentTreatment  ABC’s firstABC’s first  IV access/cardiac monitor/art line/foleyIV access/cardiac monitor/art line/foley  Correct hypoxia/hypovolemia/rhythmCorrect hypoxia/hypovolemia/rhythm disturbance/electrolyte abnormalities/acid-basedisturbance/electrolyte abnormalities/acid-base alterationsalterations  HypotensionHypotension  Dopamine,dobutamineDopamine,dobutamine  Fluid bolus if RV involvedFluid bolus if RV involved  Acute MR consider dobutamine and nitroprussideAcute MR consider dobutamine and nitroprusside  IABPIABP
    63. 63. Cardiogenic ShockCardiogenic Shock  Treatment continuedTreatment continued  Thrombolytic therapyThrombolytic therapy  Better outcomes if followed by revascularizationBetter outcomes if followed by revascularization  Intraaortic balloon conterpulsionIntraaortic balloon conterpulsion  Decreases afterload, increases diastolic BPDecreases afterload, increases diastolic BP  Early revascularizationEarly revascularization  Most important life saving interventionMost important life saving intervention
    64. 64. Cardiogenic ShockCardiogenic Shock  Treatment continuedTreatment continued  Inotropic agentsInotropic agents  DopamineDopamine  First line agentFirst line agent  2.5-5 micrograms/kg/min beta-12.5-5 micrograms/kg/min beta-1  5-10 alpha & beta-15-10 alpha & beta-1  10-20 alpha10-20 alpha  DobutamineDobutamine  Use for signs of poor perfusion when SBP>90Use for signs of poor perfusion when SBP>90  2-20micrograms/kg/min2-20micrograms/kg/min  NorepinephrineNorepinephrine  Use only when inadequate response to other pressorsUse only when inadequate response to other pressors  2 micrograms/min and titrate to response2 micrograms/min and titrate to response  MilrinoneMilrinone  50 microgram/kg bolus followed by 0.5microgram/kg/min infusion—watch BP!50 microgram/kg bolus followed by 0.5microgram/kg/min infusion—watch BP!
    65. 65. Anaphylactic ShockAnaphylactic Shock
    66. 66. Anaphylactic ShockAnaphylactic Shock  Severe systemic hypersensitivity withSevere systemic hypersensitivity with multisystem involvementmultisystem involvement  Life-threatening release of mediators byLife-threatening release of mediators by mast cells and basophilsmast cells and basophils
    67. 67. Anaphylactic ShockAnaphylactic Shock  PathophysiologyPathophysiology  4 classic mechanisms4 classic mechanisms  1. cross-linking of 2 IgE molecules on a mast cell1. cross-linking of 2 IgE molecules on a mast cell or basophil by a multivalent antigenor basophil by a multivalent antigen  2. reaction of IgM & IgG to cell surface antigens2. reaction of IgM & IgG to cell surface antigens  3. soluble antigen-antibody complexes activating3. soluble antigen-antibody complexes activating complementcomplement  4. activation of T lymphocytes4. activation of T lymphocytes
    68. 68. Anaphylactic ShockAnaphylactic Shock  PathophysiologyPathophysiology  Classic anaphylaxisClassic anaphylaxis  2 separate exposures2 separate exposures  First the antigen or hapten-protein complex is processedFirst the antigen or hapten-protein complex is processed by macrophage & dendritic cellsby macrophage & dendritic cells  Presented externally with MHC-2Presented externally with MHC-2  T helper cells recognize and stimulate plasma cells toT helper cells recognize and stimulate plasma cells to produce IgEproduce IgE  Second exposure recognized by these IgE antibodiesSecond exposure recognized by these IgE antibodies triggers degranulation of mast cells and basophilstriggers degranulation of mast cells and basophils
    69. 69. Anaphylactic ShockAnaphylactic Shock  PathophysiologyPathophysiology  Complement mediated reactionComplement mediated reaction  Occur after administration of blood productsOccur after administration of blood products secondary to immune complexessecondary to immune complexes  C3a & C5a cause degranulationC3a & C5a cause degranulation  Non-immunologic anaphylaxis (anaphylactoid)Non-immunologic anaphylaxis (anaphylactoid)  Exogenous substances directly degranulate mastExogenous substances directly degranulate mast cellscells  Radiocontrast dye, opiates, depolarinzing drugs,Radiocontrast dye, opiates, depolarinzing drugs, dextransdextrans
    70. 70. Anaphylactic ShockAnaphylactic Shock  PathophysiologyPathophysiology  ASA/NSAIDSASA/NSAIDS  Non-mast cell processNon-mast cell process  Modulate cyclooxygenase-arachidonic acidModulate cyclooxygenase-arachidonic acid metabolismmetabolism  Idiopathic anaphylaxisIdiopathic anaphylaxis  Diagnosis of exclusionDiagnosis of exclusion
    71. 71. Anaphylactic ShockAnaphylactic Shock  Clinical FeaturesClinical Features  Diffuse urticaria & angioedemaDiffuse urticaria & angioedema  +/- abd pain or cramping, N/V, diarrhea,+/- abd pain or cramping, N/V, diarrhea, bronchospasm, rhinorrhea, conjunctivitis,bronchospasm, rhinorrhea, conjunctivitis, dysrhythmias, hypotensiondysrhythmias, hypotension  c/o “lump” in the throat heralds life-threateningc/o “lump” in the throat heralds life-threatening laryngeal edemalaryngeal edema  Usually begin w/in 60 minutes of exposureUsually begin w/in 60 minutes of exposure  Faster the onset the more severe the reactionFaster the onset the more severe the reaction  Biphasic phenomenonBiphasic phenomenon  Second release of mediators clinically evident 3-4h after theSecond release of mediators clinically evident 3-4h after the initial manifestations clearinitial manifestations clear
    72. 72. Anaphylactic ShockAnaphylactic Shock  DiagnosisDiagnosis  History and physicalHistory and physical  2 or more body systems involved2 or more body systems involved  DifferentialDifferential  Vasovagal reaction, status asthmaticus, seizure,Vasovagal reaction, status asthmaticus, seizure, epiglottitis, hereditary angioedema, FB airwayepiglottitis, hereditary angioedema, FB airway obstruction, carcinoid, mastocytosis, non-IgE drugobstruction, carcinoid, mastocytosis, non-IgE drug reactions, AMI, dysrhythmiasreactions, AMI, dysrhythmias
    73. 73. Anaphylactic ShockAnaphylactic Shock  TreatmentTreatment  First LineFirst Line  ABC’sABC’s  Epinephrine, oxygen, fluids (NS 1-2L)Epinephrine, oxygen, fluids (NS 1-2L)  Epi 0.1mg in 10cc NS over 5-10minutes IV if signs of CVEpi 0.1mg in 10cc NS over 5-10minutes IV if signs of CV collapsecollapse  If refractive start infusion: 1mg in 500ccD5W at 1-4If refractive start infusion: 1mg in 500ccD5W at 1-4 micrograms/minmicrograms/min  Less severe, give 0.3-0.5 mg IM in the thighLess severe, give 0.3-0.5 mg IM in the thigh  decontaminationdecontamination
    74. 74. Anaphylactic ShockAnaphylactic Shock  TreatmentTreatment  Second LineSecond Line  CorticosteroidsCorticosteroids  Methylprednisolone 125mg IVMethylprednisolone 125mg IV  2mg/kg in children2mg/kg in children  AntihistaminesAntihistamines  Diphenhydramine (H1) 25-50mg IVDiphenhydramine (H1) 25-50mg IV  Ranitidine or cimetidine(H2)Ranitidine or cimetidine(H2)  Avoid cimetidine in elderly, renal/hepatic failure, or ifAvoid cimetidine in elderly, renal/hepatic failure, or if patient is on beta blockerpatient is on beta blocker
    75. 75. Anaphylactic ShockAnaphylactic Shock  TreatmentTreatment  Second LineSecond Line  Agents for bronchospasmAgents for bronchospasm  AlbuterolAlbuterol  Ipratropium bromideIpratropium bromide  Magnesium 2g IV over 20-30minutesMagnesium 2g IV over 20-30minutes  25-50mg/kg in children25-50mg/kg in children  GlucagonGlucagon  1 mg IV q 5min until response followed by infusion 5-151 mg IV q 5min until response followed by infusion 5-15 micrograms/min if patient on beta blockers with refractivemicrograms/min if patient on beta blockers with refractive hypotensionhypotension
    76. 76. Anaphylactic ShockAnaphylactic Shock  DispositionDisposition  Unstable patients admit to ICUUnstable patients admit to ICU  If patient received epi-observe for 4hIf patient received epi-observe for 4h  Consider distance from care, someone to go homeConsider distance from care, someone to go home with, comorbidities, agewith, comorbidities, age  Good discharge instructions is a mustGood discharge instructions is a must  Send with epipen, short course of antihistaminesSend with epipen, short course of antihistamines and steroidsand steroids
    77. 77. Neurogenic ShockNeurogenic Shock
    78. 78. Neurogenic ShockNeurogenic Shock  Acute spinal cord injuryAcute spinal cord injury  Disruption of sympathetic outflowDisruption of sympathetic outflow  Hypotension & bradycardiaHypotension & bradycardia  Majority caused by blunt traumaMajority caused by blunt trauma  MVA, falls, sportsMVA, falls, sports  Cervical region most commonly injuredCervical region most commonly injured  Penetrating injury (10-15% of cases)Penetrating injury (10-15% of cases)  GSW’s and stab woundsGSW’s and stab wounds
    79. 79. Neurogenic ShockNeurogenic Shock  PathophysiologyPathophysiology  33 bony vertebrae33 bony vertebrae  Anterior body, posterior arch, sup/inf articular processes,Anterior body, posterior arch, sup/inf articular processes, pedicles, laminaepedicles, laminae  Spinal cord is cylindrical arising from base of brain &Spinal cord is cylindrical arising from base of brain & covered by 3 layers of meninges & CSFcovered by 3 layers of meninges & CSF  31 pairs of spinal nerves exit the canal via31 pairs of spinal nerves exit the canal via intervertebral foramenintervertebral foramen  Spinal nerves are formed by ant/post nerve rootsSpinal nerves are formed by ant/post nerve roots
    80. 80. Neurogenic ShockNeurogenic Shock  PathophysiologyPathophysiology  Spinal cord contains white & gray matterSpinal cord contains white & gray matter  White: nerve fibers running up & down in cord tractsWhite: nerve fibers running up & down in cord tracts  Gray: nerve cellsGray: nerve cells  Autonomic Nervous SystemAutonomic Nervous System  SympatheticSympathetic  Outflow tracts in lateral gray horns of 1Outflow tracts in lateral gray horns of 1stst thoracic to 2thoracic to 2ndnd lumbarlumbar  Controlled by hypothalamusControlled by hypothalamus  Lateral hornLateral hornanterior nerve rootanterior nerve rootganglia of paraspinalganglia of paraspinal sympathetic trunksympathetic trunktravel throughout the bodytravel throughout the body
    81. 81. Neurogenic ShockNeurogenic Shock  PathophysiologyPathophysiology  Autonomic Nervous SystemAutonomic Nervous System  ParasympatheticParasympathetic  Cranial Nerves & 2-4Cranial Nerves & 2-4thth sacral segments (splanchnicsacral segments (splanchnic nerves)nerves)
    82. 82. Neurogenic ShockNeurogenic Shock  Clinical featuresClinical features  Hypotensive with warm,dry skinHypotensive with warm,dry skin  Bradycardic ususallyBradycardic ususally  HypothermicHypothermic  These symptoms last 1-3 weeksThese symptoms last 1-3 weeks
    83. 83. Neurogenic ShockNeurogenic Shock  TreatmentTreatment  ABCDE’sABCDE’s  Investigate all other possible sources of hypotension &Investigate all other possible sources of hypotension & bradycardiabradycardia  Infuse crystalloids rapidlyInfuse crystalloids rapidly  Attempt to keep MAP 85-90mm Hg for the first 7 days to minimizeAttempt to keep MAP 85-90mm Hg for the first 7 days to minimize secondary cord injurysecondary cord injury  Dopamine & dobutamine may be helpfulDopamine & dobutamine may be helpful  Severe bradycardia can be treated with atropine or pacingSevere bradycardia can be treated with atropine or pacing  Steroids are not indicated in the treatment of neurogenic shockSteroids are not indicated in the treatment of neurogenic shock per seper se  Indicated in blunt injury with neuro deficits if started within 8hIndicated in blunt injury with neuro deficits if started within 8h (30mg/kg bolus then 45 mins later infuse at 5.4mg/kg/h for 23h)(30mg/kg bolus then 45 mins later infuse at 5.4mg/kg/h for 23h)
    84. 84. QuestionsQuestions  1. In cardiogenic shock the PCWP is1. In cardiogenic shock the PCWP is  A. DecreasedA. Decreased  B. IncreasedB. Increased  C. NormalC. Normal
    85. 85. QuestionsQuestions  2. SIRS is defined as inflammation2. SIRS is defined as inflammation secondary to infectionsecondary to infection  A. TrueA. True  B. FalseB. False
    86. 86.  3. Which is not a parameter used to3. Which is not a parameter used to define ARDSdefine ARDS  A. Bilateral infiltrates on CXRA. Bilateral infiltrates on CXR  B. PCWP>18B. PCWP>18  C. PaO2/FIO2 <200C. PaO2/FIO2 <200
    87. 87.  4. What is considered the first line4. What is considered the first line inotrope in cardiogenic shockinotrope in cardiogenic shock  A. DopamineA. Dopamine  B. DobutamineB. Dobutamine  C. MilrinoneC. Milrinone
    88. 88. 5.5. Which is not considered a first line agentWhich is not considered a first line agent in treatment of anaphylaxisin treatment of anaphylaxis  A. EpiA. Epi  B. OxygenB. Oxygen  C. albuterolC. albuterol
    89. 89. AnswersAnswers  1. B1. B  2. B2. B  3. B3. B  4. A4. A  5. C5. C

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