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sepsis update


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  • 1. Sepsis and Septic Shock Therapy in 2012 Dr Masood ur Rahman. FCCP. Senior Consultant Intensive careDeputy Chairman Department of Critical Care Medicine, Tawam Hospital Al Ain, United Arab Emirates.
  • 2. Objectives• Incidence• End point of resuscitation – CVP and ScVo2? Or ?• Update on role of – Early Goal directed therapy – Antibiotics – Glycemic control – Steroid – Activated protien c
  • 3. Severe Sepsis: Comparison With Other Major Diseases Incidence of Severe Sepsis Mortality of Severe Sepsis 300 250,000 250 200,000Cases/100,000 Deaths/Year 200 150,000 150 100,000 100 50,000 50 0 0 AIDS* Colon Breast CHF† Severe AIDS* Breast AMI† Severe Cancer Sepsis‡ Cancer Sepsis‡†NationalCenter for Health Statistics, 2001. American Cancer Society, 2001. *American HeartAssociation. 2000. ‡Angus DC et al. Crit Care Med 2001
  • 4. Severe Sepsis: Comparison With Other Major Diseases Incidence of Severe Sepsis Mortality of Severe Sepsis 300 250,000 250 200,000Cases/100,000 Deaths/Year 200 150,000 150 100,000 100 50,000 50 0 0 AIDS* Colon Breast CHF† Severe AIDS* Breast AMI† Severe Cancer Sepsis‡ Cancer Sepsis‡†NationalCenter for Health Statistics, 2001. American Cancer Society, 2001. *American HeartAssociation. 2000. ‡Angus DC et al. Crit Care Med 2001
  • 5. Severe Sepsis: A Growing Healthcare Challenge Today Future 1,800,000 600,000 Severe Sepsis Cases Total US Population/1,000 1,600,000 US Population 500,000 1,400,000 >750,000 Sepsis Cases 1,200,000 400,000 cases of severe 1,000,000 sepsis/year 800,000 300,000 in the US* 600,000 200,000 400,000 100,000 200,000 2001 2025 2050 Year*Angus DC. Crit Care Med 2001;29:1303-10
  • 6. Goals of Treatment• ABCDE • Airway • control work of Breathing • optimize Circulation • assure adequate oxygen Delivery • achieve End points of resuscitation
  • 7. SIRS- It All Starts Out So Innocent • Clinical Response to nonspecific insult • Temperature > 380 C or < 360 C • Heart Rate > 90 per minute • Respirations > 20 per minute • WBC > 12,000 or < 4,000 or > 10% bands • PaCO2 < 32Members of the American College of Chest Physicians/Society of Crit CareMed Consensus Conference Committee: American College of ChestPhysicians/Society of Crit Care Med Consensus Conference: Definitions forsepsis and organ failure and guidelines for the use of innovative therapies insepsis. Crit Care Med 1992; 20: 864–874
  • 8. Definition• Sepsis- 2 or more SIRS criteria with infection• Severe Sepsis- Sepsis with evidence of organ dysfunction• Septic Shock- Sepsis with refractory hypotension• Multiple Organ Dysfunction Syndrome (MODS)
  • 9. Down a Slippery Slope
  • 10. How to prevent this?
  • 11. EGDT • 263 patients randomized to goal directed or standard therapy • In hospital mortality for EGDT patients 30.5% versus 46.5% for standard therapy • Longer length of stay and consumption of resources for standard therapy patientsRivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis andseptic shock. N Engl J Med 345. 1368-1377.2001;
  • 12. The Importance of Early Goal-Directed Therapy for Sepsis Induced Hypoperfusion NNT to prevent 1 event (death) = 6-8 60 Standard therapy EGDT 50 Mortality (%) 40 30 20 10 0 In-hospital 28-day 60-day mortality mortality mortality (all patients)Adapted 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; 345:1368-1377
  • 13. EGDT is Liberal? • Average of 5 Liters of crystalloid in 6 hours • After 72 hours no difference between standard and EGDT group • Timing is the key • Less intubation in EGDT group after 6 hours • Dialysis patients less intubation in EGDTOtero, RM, Nguyen, B, Huang, DT, et al (2006) Early goal-directed therapy in severesepsis and septic shock revisited. Chest 130,1579-1595Wiedemann, HP, Wheeler, AP, Bernard, GR, et al Comparison of two fluid-managementstrategies in acute lung injury. N Engl J Med 2006;354,2564-2575Jones A, et al, The effect of a quantitative resuscitation strategy on mortality in patientswith sepsis: A meta-analysis. Critical Care Medicine: October 2008 - Volume 36 - Issue10 - pp 2734-2739Boyd J, et al, Fluid resuscitation in septic shock: A positive fluid balance and elevatedcentral venous pressure are associated with increased mortality. Critical Care Medicine:February 2011 - Volume 39 - Issue 2 - pp 259-265
  • 14. Guidelines 2008
  • 15. Guidelines 2008
  • 16. • There is poor relationship between CVP and blood volume as well as the inability of CVP/ΔCVP to predict the hemodynamic response to a fluid challenge. CVP should not be used to make clinical decisions regarding fluid management.
  • 17. Conclusion:Applying an early quantitative resuscitation strategy to patients with sepsis impartsa significant reduction in mortality
  • 18. Retrospective review of use of IV fluid used duringfirst 4 days.VASST ( vasopressin in shock trial).? Positive fluid balance and CVP are associated withmortality.
  • 19. Cox survival curves, adjusted for Age, (APACHE) II score. severity of shock (dose of norepinephrine),
  • 20. • limitation of study • Conclusion – A more positive fluid balance – Retrospective both early in resuscitation and – Type of IV fluid not cumulatively over 4 days is associated with an increased risk documented of mortality in septic shock. – Unable to determine if – Central venous pressure may be CVP and fluid balance used to gauge fluid balance <12 hrs into septic shock but are independetly effect becomes an unreliable marker the out come. of fluid balance thereafter.
  • 21. How to decide end point of resucitation?• Static hemodynamic measure – CVP , PAOP• Dynamic hemodynamic measure – Respiratory changes in the radial artery pulse pressure( pulse pressure variation), – Aortic blood flow peak velocity, – Brachial artery blood flow velocity – Stroke volume variation• Mixed venous saturation (SvO2)• Central venous saturation (ScvO2)• Lactic acidosis
  • 22. Which is better measure dynamic versus static?• Increasing evidence that dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and controlled ventilated with a sufficient tidal volume Intensive Care Med. 2003;29(3):476. Am J Respir Crit Care Med. 2000;162(1):134. Intensive Care Med. 2005;31(9):1195
  • 23. Get a Leg Up!• Passive leg raise (PLR) increased radial arterial pulse pressure.• Pulse pressure = Systolic BP- Diastolic BP.• PP= 9% correlates with fluid response.• Change with PLR correlated with an increase in stroke volume.• PLR changes correlated with stroke volume changes when same patients received a fluid bolus. , Crit Care Med 2010; 38:819–825.
  • 24. How accurate are they?
  • 25. PPV better than CVP Crit Care Med 2009 Vol. 37, No. 9
  • 26. Got Ultrasound ?  IVC diameter changes with volume  IVC diameter will decrease during inspiration Diameter will increase with expiration  Caval Index = 100 x (IVC expiration-IVC inspiration)/IVC expiration.  caval index is greater than 50% it suggests low central venous pressure (CVP less than 8 mmHg) and high probability of fluid responsiveness  Limitations need to be considered Blehar DJ, et al, Identification of congestive heart failure via respiratory variation of inferior vena cava diameter, Am J Emerg Med - 01-JAN-2009; 27(1): 71-5 Nagdev, et al, Emergency Department Bedside Ultrasonographic Measurement of the Caval Index for Noninvasive Determination of Low Central Venous Pressure, Volume 55, Issue 3 March 2010, 290- 295
  • 27. Got Alternative Technology ? The placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate hemodynamic parameters Impedance cardiography Napoli A, Machan J, et al, The Use of Impedance Cardiography in Predicting Mortality in Emergency Department Patients With Severe Sepsis and Septic Shock, Academic Emergency Medicine 2010; 17:452–455
  • 28. Esophageal Doppler-Minimally Invasive Option• Deltex CardioQ• Placement of flexible orogastric or nasogastric probe• Doppler technology• Measures blood flow velocity in descending aorta• Able to derive values for cardiac output, preload and contractility
  • 29. New guideline 2012?• Dynamic measures such as delta pulse pressure or stroke volume variation to determine the adequacy of fluid resuscitation, rather than such static measures as central venous pressure. Annual meeting of the Society for Academic Emergency Medicine (SAEM) 2012
  • 30. ScVO2 Revisited• Lactate vs ScVO2
  • 31. Venous Oxygen Saturation• Measure of global oxygen extraction• Central versus mixed• Compromised by cirrhosis or shunt
  • 32. ScVo2• Svo2 ≥has significant impact on mortality than rest of the components of resuscitation bundle. CCM 2010• Failure to achieve ScVo2≥ 70 within first 6 hours is associated with significantly high mortality( 14%). Pope et al:Annal of emergency medicine 2010
  • 33. Lactate? Serum lactate identifies hypoperfusionShapiro N, et al, Serum Lactate as a Predictor of Mortality in Emergency Department Patients withInfection, Annals of Emergency Medicine, Volume 45, Issue 5 (May 2005), 524-528
  • 34. Got Lactate ?• Recent prospective study reveals utility of lactate clearance• Potential use as resuscitation endpoint Nguyen HB, et al, Early lactate clearance is associated with improved outcome in severe sepsis and septic shock Critical Care Medicine - Volume 32, Issue 8 (August 2004) Arnold R, et al, Multicenter Study Of Early Lactate Clearance as a Determinant Of Survival in Patients With Presumed Sepsis, SHOCK Vol. 32, No. 1, pp. 35-39, 2009 Jones A, et al, Lactate Clearance Versus Central Venous Oxygenation as Endpoints of Early Sepsis Therapy: A Randomized Clinical Trial. (49), Critical Care Medicine. 37(12), December 2009 Adams BD, Bonzani TA, Hunter CJ. The anion gap does not accurately screen for lactic acidosis in emergency department patients. Emerg Med J 2006;23:179–8
  • 35. Colloids• Option in addition to crystalloids• Albumin is SAFE• Subset analysis suggests mortality decrease• Possible anti-inflammatory component The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-2256. Brunkhorst F , et al, Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis, NEJM 2008;358:125-139. Kirschenbaum L, Effect Of Resuscitative Fluids On Cell Activation In Septic Shock (439), Critical Care Medicine. 37(12):A1-A542, December 2009 Mullen M, Use of Concentrated Albumin in the Emergency Department May Improve Morbidity in Severe Sepsis and Septic Shock (482), Critical Care Medicine. 37(12):A1-A542, December 2009 Delaney A, et al, The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis, Crit Care Med. 2011 Feb;39(2):386-91
  • 36. The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis*Conclusionuse of albumin-containingsolutions for the resuscitation of patients with sepsis was associated with lower mortality comparedwith other fluid resuscitation regimens. Until the results of ongoing randomized controlled trials are known, clinicians shouldconsider the use of albumin-containing solutions for the resuscitation of patient swith sepsis. Delaney A, et al,, Crit Care Med. 2011 Feb;39(2):386-9 1
  • 37. Better than crystalloids in septic patient ?
  • 38. New Twist on Pressors• Epinephrine and norepinephrine plus dobutamine compared in 330 patients• No difference in mortality at 28 days• No statistical difference in adverse effects Annane D, Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial . The Lancet , Volume 370 , Issue 9588, Pages 676 - 684 D, 2007
  • 39. Vasopressin versus norepinephrine?• Results of a multi-center trial of septic shock patients receiving 0.03 units/min of vasopressin versus norepinephrine• 776 patients• No difference in mortality• Trend toward improved outcome with vasopressin in less severe shock• Higher doses may be future interventionRussell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl JMed 2008;358:877-887.Luckner G , Comparison of two dose regimens of arginine vasopressin in advanced vasodilatory shock. Crit Care Med OCT-2007; 35(10): 2280-5
  • 40. Low dose vasopressin plus steroid better than Norepinephrine plus steroids • Post hoc analysis of patients in VAAST • Review of patients with norepinephrine (293) and steroids and vasopressin (295) and steroids • 28 day mortality difference 44.7% versus 35.9% (p=0.03) • ? Increased responsiveness to catecholamines • ? Increased vasopressin levels • ? Decreased inflammationRussell J, et al, Interaction of vasopressin infusion, corticosteroid treatment, andmortality of septic shock, Crit Care Med 2009 Vol. 37, 811-8
  • 41. Blood?!!• Hebert did not address severe sepsis/tissue hypoxia• 79% EGDT patients did show improvement in ScVO2• Need to consider infection issues/ALI/age of PRBC’s• Vincent-Observational study (n=1040) did not show increased mortality with transfusion• Napolitano- Transfusion needs on individual basis Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care: Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409–417T Friedlander M, et al, The relationship of packed cell transfusion to red blood cell deformability in systemic inflammatory response syndrome patients, SHOCK 1998 Feb;9(2):84-8. Vincent JL, Sakr Y, et al, Are blood transfusions associated with greater mortality rates? Results of the Sepsis Occurrence in Acutely Ill Patients study. Anesthesiology. 2008 Jan;108(1):31-9. Napolitano L, et al, Clinical Practice Guideline: Red Blood Cell Transfusion in Adult Trauma and Critical Care, Crit Care Med 2009, Vol 37 (12), 3124-3157
  • 42. Early Antibiotics:• Kumar (2009)- 5000 patient study• 20 % patients received inappropriate antibiotics• Increased mortality by factor of 5• Combination therapy needs to be considered• Rise of Extended Spectrum Beta Lactam (ESBL) Gram Negative infectionKumar A, et al, Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survivalin human septic shock. Chest 2009 Nov;136(5):1237-48.Kumar A, Early combination antibiotic therapy yields improved survival compared with monotherapy inseptic shock: A propensity-matched analysis. Critical Care Medicine: September 2010 - Volume 38 -Issue 9 - pp 1773-1785Quinn JP, Clinical significance of extended-spectrum beta-lactamases. European Journal of ClinicalMicrobiology & Infectious Diseases, Volume 13, Supplement 1 1994 , S39-S42
  • 43. Early Antibiotics (Even in the ED) • ED based retrospective study • 231 patients • Time to appropriate antibiotics mortality factor • Less than 1hour - 19% mortality • Greater than 1 hour - 33.2 % mortalityGaieski D, et al, Impact of time to antibiotics on survival in patients with severe sepsis or septic shockin whom early goal-directed therapy was initiated in the emergency department, Crit Care Med 2010;38:1045–1053.
  • 44. Got Glucose ? • Glycemic control impacts critical illness • Maintenance of blood glucose between 80-110 mg/dl • Absolute reduction in ICU mortality • Reduction of in-hospital mortality by 34% • Reduction in morbidity as well • Mixed support in follow-up studiesVan den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy incritically ill patients. N Engl J Med 2001;345:1359-1367Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy inthe medical ICU. N Engl J Med 2006;354:449-461.Krinsley JS, Effect of an intensive glucose management protocol on themortality of critically ill adult patients. Mayo Clin Proc. 2004 Aug;79(8):992-1000Carr J, Sellke F, et al, Implementing Tight Glucose Control After CoronaryArtery Bypass Surgery Ann. Thorac. Surg., Sep 2005; 80: 902 - 909.
  • 45. Not So Nice, Sugar…. • Intensive versus Conventional Glucose Control in Critically Ill Patients, NEJM, March 26, 2009 • 6104 randomized patients • Intensive (80-108) versus conventional (less than 180) • Increase 90 day mortality 27.5% versus 24.9% with tight control • Expect a possible wider range (?140-180)Nice-Sugar Investigators, Intensive versus Conventional Glucose Controlin Critically Ill Patients, N Engl J Med 2009;360:1283-97
  • 46. Still important……• Retrospective cohort 259,040 patients• Review risk adjusted mortality in this cohort• Hyperglycemia does affect mortality• Risk varies with admission diagnosis• Adjusted mortality lowest with glucose 111 to 145 mg/dL Falciglia M, et al, Hyperglycemia-related Mortality in Critically Ill patients Varies with Admission Diagnosis, Critical Care Medicine. 37(12):3001-3009, December 2009
  • 47. CORTICUS • CORTICUS- Randomized, controlled study hydrocortisone vs placebo in septic shock. • 500 patients multi-center, multinational study • No difference in the overall 28-day mortality rate • Cosyntropin responsiveness made no difference • Tapered steroids • Cosyntropin test called into question • Shock resolution faster with steroidsSprung CL, Annane D, et al, Hydrocortisone therapy for patients with septic shock. N Engl J Med.2008 Jan 10;358(2):111-24
  • 48. Update • Most recent literature-comprehensive meta-analysis Review of 17 studies • Overall steroids do not affect 28 day mortality • 12 studies of low dose prolonged steroids did suggest improved outcome • Recommended for vasopressor refractory shockAnnane D, et al, Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in AdultsA SystematicReview, JAMA. 2009;301(22):2362-2375.
  • 49. Activated protien C? • Activated Protein C- Anti-inflammatory, anti-thrombotic, profibrinolytic properties • 28 day mortality study/1690 randomized patients • Mortality decrease and relative risk reduction statistically significant • Mortality decrease from 30.8% to 24.7% • First agent in 20 years to modify course of severe sepsis • Increased bleeding risk (3.5% vs 2.0%) • Exclusion criteria extensiveBernard GR, Vincent J-L, Laterre P-F, et al.Efficacy and safety of recombinant humanactivated protein C for severe sepsis. N Engl JMed 2001;344:699-709
  • 50. Low Tidal Volume Mechanical Ventilation• Multicenter, randomized trial of over 800 patients• Comparison of 12 ml/kg versus 6ml/kg tidal volume• Lower volumes to keep plateau pressure 30 mm H2O or less• More recent smaller trial 6 ml/kg vs 10 ml/ kg• Less inflammatory markers• Less incidence of ALI/ Stopped early The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308 Determann R, Ventilation with lower tidal volumes as compared to conventional tidal volumes for patients without acute lung injury - a preventive randomized controlled trial, Critical Care 2010, 14:R1 (7 January 2010)
  • 51. Putting It All Together• Early goal directed therapy still valid/ Likely to change• Early aggressive antibiotics remain key/ Resistance emerging• Glycemic control still has benefit• Consider adrenal insufficiency in fluid resuscitated shock• Low tidal volume remains the best practice• Exciting new therapies/ monitoring on horizon• Activated protien C is History
  • 52. What Should We Do
  • 53. Impact of order sets
  • 54. What are We Doing At Tawam• Implementing sepsis clinical pathway.• Sepsis care set
  • 55. Establishing Measure• SEPSIS RESUCITATION BUNDLE – Serum Lactate measured – Blood culture obtained before antibiotics administered. – Timing of antibiotics – CVP goal – Central venous saturation
  • 56. • SEPSIS MANAGEMENT BUNDLE – Glycemic control – Plateau pressure – Low dose steroids administered
  • 57. THANK YOU