1. Surviving sepsis Balraj APPADU M.D., FRCA, FFICM Consultant in Anaesthesia & Intensive Care Medicine

2. Agenda Understand the scope of the sepsis epidemic 1 Become familiar with the Surviving Sepsis Campaign and the IHI defined sepsis bundles 2 Recognize how time-critical therapies can save lives in the emergency departments and ICUs 3

3. What's the problem? Severe sepsis affects over 120,000 patients each year in the U.K. (increasing at a rate of 1.5% per annum) Last year 78,000 of these patients admitted to ITU Mortality for these 30 – 80 %

4. Comparable Global Epidemiology 95 cases per 100,000 2 week surveillance 206 French ICUs 95 cases per 100,000 3 month survey 23 Australian/New Zealand ICUs 51 cases per 100,000 England, Wales and Northern Ireland.

5. Severe Sepsis: Comparison With Other Major Diseases AIDS* Colon Breast Cancer § CHF † Severe Sepsis ‡ Cases/100,000 Incidence of Severe SepsisMortality of Severe Sepsis AIDS* Severe Sepsis ‡ AMI † Breast Cancer § Deaths/Year † National Center for Health Statistics, 2001. § American Cancer Society, 2001. *American Heart Association. 2000. ‡ Angus DC et al. Crit Care Med. 2001

6. Sepsis Epidemiology: Effect of the Aging Population

7. Economics of Sepsis  Severe Sepsis  $22,000 per case  US annual cost $16.7 Billion  Nosocomial Sepsis  increased LOS - ICU 8 days, Hosp 24 days  $40,890 per case Angus CCM, 2001 Pittet JAMA, 1994

8. T ime S ensitive I nterventions AMI Stroke “Time is Brain” The sooner that treatment begins, the better are one’s chances of survival without disability. Trauma “The Golden Hour” Requires immediate response and medical care “on the scene.” Patients typically transferred to a qualified trauma center for care. “Door to PCI” Focus on the timely return of blood flow to the affected areas of the heart.

9. Severe Sepsis vs. Current Care Priorities Care Priorities U.S. Incidence # of DeathsMortality Rate AMI (1) 900,000225,00025% Stroke (2) 700,000163,50023% Trauma (3) (Motor Vehicle) 2.9 million (injuries) 42,6431.5% Severe Sepsis (4) 751,000215,00029% Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: 1328-1428. (2) American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Available at: www.americanheart.org. (3) National Highway Traffic Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting System and the General Estimates System. Available at http://www.nhtsa.dot.gov/. (4) Angus DC et al. Crit Care Med 2001;29(7): 1303- 1310.http://www.nhtsa.dot.gov/

10. Surviving Sepsis Campaign Launched in Autumn 2002 as a collaborative effort of European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine Goal: reduce sepsis mortality by 25% in the next 5 years Guidelines revealed at SCCM in Feb 2004, REVISED 2008 Critical Care Medicine March 2004 32(3):858-87. Website: survivingsepsis. org

11. What is sepsis? Sepsis, Septic Shock, SIRS (systemic inflammatory response syndrome), SSI (signs and symptoms of infection), Septicaemia, Bacteraemia, Toxic Shock Syndrome, Bloodstream infection etc, etc….

12. n Infection –Inflammatory response to microorganisms, or –Invasion of normally sterile tissues n Systemic Inflammatory Response Syndrome (SIRS) –Systemic response to a variety of processes n Sepsis –Infection plus –  2 SIRS criteria n Severe Sepsis –Sepsis –Organ dysfunction n Septic shock –Sepsis –Hypotension despite fluid resuscitation Bone RC et al. Chest. 1992;101:1644-55. ACCP/SCCM Consensus Definitions

13. A systemic response to a nonspecific insult Infection, trauma, surgery, massive transfusion, etc Defined as  2 of the following : Temperature >38.3 or <36 0 C Heart rate>90 min-1 Respiratory rate >20 min-1 White cells 12 Acutely altered mental state Hyperglycaemia (BM>7.7) in absence of DM SIRS SEVERE SEPSIS What is SIRS?

14. Pneumonia 50% Urinary Tract infection Meningitis Endocarditis Device related Central line Cannula Abdominal 25% Pain Diarrhoea Distension Urgent laparotomy Soft tissue/ musculoskeletal Cellulitis Septic arthritis Fasciitis Wound infection What counts as an infection?

15. SIRS due to an infection what is Sepsis?

16. Sepsis with organ dysfunction, hypoperfusion or hypotension CNS:Acutely altered mental status CVS: Syst < 90 or mean < 65 mmHg Resp: SpO 2 >90% only with new/ more O 2 Renal: Creatinine >177 μmol/l or UO <0.5 ml/kg/hr for 2 hrs Hepatic:Bilirubin >34 μmol/l Bone marrow: Platelets <100 Hypoperfusion:Lactate >2 mmol/l Coagulopathy:INR>1.5 or aPTT>60secs What is Severe Sepsis?

17. Tissue perfusion is not adequate for the tissues’ metabolic requirements What is shock? Septic Shock Shock secondary to systemic inflammatory response to a new infection Types of Shock Cardiogenic Neurogenic Hypovolaemic Anaphylactic and…

18. Tissue perfusion is not adequate for the tissues’ metabolic requirements For sepsis, shock is one of: SBP < 90 mmHg MBP < 65 mmHg after IV fluids Drop of < 40 mmHg Lactate > 4 mmol/l What is shock?

19. The Sepsis Continuum  A clinical response arising from a nonspecific insult, with  2 of the following:  T >38 o C or <36 o C  HR >90 beats/min  RR >20/min  WBC >12,000/mm 3 or 10% bands SIRS = systemic inflammatory response syndrome SIRS with a presumed or confirmed infectious process Chest 1992;101:1644. SepsisSIRS Severe Sepsis Septic Shock Sepsis with organ failure Refractory hypotension

20. Are any 2 of the following SIRS criteria present and new to your patient? Obs: Temperature >38.3 or 20 min -1 Heart rate >90 bpmAcutely altered mental state Bloods:White cells 12x10 9 /lGlucose>7.7mmol/l (if patient is not diabetic) If yes, patient has SIRS Severe Sepsis Screening Tool

21. Is this likely to be due to an infection? For example Cough/ sputum/ chest pain Dysuria Abdo pain/ diarrhoea/ distension Headache with neck stiffness Line infection Cellulitis/wound infection/septic arthritis Endocarditis If yes, patient has SEPSIS Start SEPSIS BUNDLE

22. Severe Sepsis: Ensure Senior Doctor/ITU to attend NOW! Check for SEVERE SEPSIS BP Syst < 90 / Mean < 65 mmHg (after initial fluid challenge) Lactate > 4 mmol/l Urine output< 0.5 ml/kg/hr for 2 hrs INR > 1.5 aPTT > 60 s Bilirubin > 34 μmol/l O 2 Needed to keep SpO 2 > 90% Platelets < 100 x 10 9 /l Creatinine > 177 μmol/l or UO < 0.5 ml/kg/hr

23. What is a Bundle? Specifically selected care elements From evidence based guidelines Implemented together provide improved outcomes compared to individual elements alone

24. 6 Hour Resuscitation Bundle Early Identification Early Antibiotics and Cultures Early Goal Directed Therapy

25. 6 - hour Severe Sepsis/ Septic Shock Bundle Early Detection: Obtain serum lactate level. Early Blood Cx/Antibiotics: within 3 hours of presentation. Early EGDT: Hypotension (SBP 4 mmol/L : initial fluid bolus 20-40 ml of crystalloid (or colloid equivalent) per kg of body weight. Vasopressors: –Hypotension not responding to fluid –Titrate to MAP > 65 mmHg. Septic shock or lactate > 4 mmol/L: –CVP and ScvO 2 measured. –CVP maintained >8 mmHg. –MAP maintain > 65 mmHg. ScvO2 8 mmHg, MAP > 65 mmHg: –PRBCs if hematocrit < 30%. –Inotropes.

26. Why does it matter?

28. Perspective

29. The Sepsis Six 1. Give high-flow oxygen via non-rebreath bag 2. Take blood culturesand consider source control 3. Give IV antibioticsaccording to local protocol 4. Start IV fluid resuscitation Hartmann’s or equivalent 5. Check lactate 6. Monitor hourly urine output consider catheterisation within one hour..plus Critical Care support to complete EGDT

30. Start therapy as soon as possible and certainly in the first hour......preferably after taking blood cultures!! Choice should include one or more with activity against likely pathogen Penetration of presumed source Guided by local pathogens Give broad spectrum till defined Give Antibiotics

31. SSC- antibiotics Begin IV antibiotics as early as possible, and always within the first hour of recognising severe sepsis (1D) and septic shock. (1B) Broad-spectrum: one or more agents active against likely bacterial/ fungal pathogens and with good penetration into presumed source. (1B) Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs. (1C)

32. Begin IV antibiotics as early as possible, and always within the first hour of recognising severe sepsis (1D) and septic shock. (1B) Citation: Kumar A et al. Crit Care Med 2006: 34(6) Retrospective, 15 years, 14 sites n = 2,154 median 6 h, 50% administered in 6h Only 5% first 30 minutes- survival 87% 12% first hour- survival 84%

33. Kumar et al. CCM. 2006:34:1589-96. time from hypotension onset (hrs) 0-0.50.5-1 1-22-33-44-55-66-9 9-12 12-2424-36 36+ fraction of total patients 0.0 0.2 0.4 0.6 0.8 1.0 survival fraction cumulative antibiotic initiation Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock

34. Funk and Kumar Critical Care Clinics 2012(in press) Running average survival in septic shock based on antibiotic delay (n=4195)

35. Funk and Kumar Critical Care Clinics 2011 (in press) Running average survival in septic shock based on antibiotic delay (n=2154) For each hour’s delay in administering antibiotics in septic shock, mortality increases by 7.6%

36. AuthornSettingMedian time (mins) Odds Ratio for death Gaieski Crit Care Med 2010; 38:1045-53 261ED, USA (Shock) 1190.30 (first hour vs all times) Daniels Emerg Med J 2010; doi:10.1136 567Whole hospital, UK 1210.62 (first hour vs all times) Kumar Crit Care Med 2006; 34(6):1589-1596 2154ED, Canada (Shock) 3600.59 (first hour vs second hour) Appelboam Critical Care 2010; 14(Suppl 1): 50 375Whole hospital, UK 2400.74 (first 3 hours vs delayed) Levy Crit Care Med 2010; 38 (2): 1-8 15022Multi-centre0.86 (first 3 hours vs delayed) Early antibiotics are good...

37. Retrospective, 22 hospitals, n= 4532 64.4% septic shock patients developed early AKI 64.4% septic shock patients developed early AKI Median time shock to antibiotic = 5.5 h Median time shock to antibiotic = 5.5 h OR for AKI 1.14 (1.10-1.20) P < 0.001 per hour’s delay OR for AKI 1.14 (1.10-1.20) P < 0.001 per hour’s delay Bagshaw SM et al Intensive Care Med. 2009;35(5):871-81

38. SSC Results: Critical Care Medicine 2010; 38(2): 1-8

40. Citation: Ibrahim et al. Chest 2000;118:146–155 BSI, n = 492 59.1% HAI 29.9% inadequate 8.3% fungal VREs Pseudomonas Coag-neg Staph MONARCS trial OR 0.65 for death with adequate cover (n=2634) Mortality (%) 0 50 70 10 30 Appropriate initial antibiotic Inappropriate initial antibiotic p<0.001 40 60 20 MacArthur RD et al. Clin Infect Dis 2004; 38:284-288 Appropriate antibiotics

41. Fluids Why? To reduce organ dysfunction and multi-organ failure By optimising tissue oxygen delivery By increasing organ perfusion

42. DO 2 = Oxygen delivery to the tissue CaO 2 = Amount of O 2 in arterial blood Fluid therapy improves cardiac output by increasing venous return to the heart CaO 2 = ([Hb] x SaO 2 x 1.34) + (PaO 2 x 0.0225) CaO 2 = ([Hb] x SaO 2 x 1.34) + (PaO 2 x 0.0225) DO 2 = CaO 2 x CO Optimising oxygen delivery

43. Judicious fluid challenges Up to 60ml/kg in divided boluses (min. 20ml/kg in shock) Crystalloid (500ml boluses) Colloid (250-300ml boluses) Reassess for effect after each challenge HR, BP, capillary refill, urine output, RR In patients with cardiac disease Use smaller volumes More frequent assessment Early CVC How to fluid resuscitate

44. Lactate High lactate identifies tissue hypoperfusion in patients at risk who are not hypotensive ‘Cryptic shock’ Gives an overview of current tissue oxygen delivery The Goal Lactate to improve as resuscitation progresses

45. Trzeciak, S et al, Acad Emerg Med; 13, 1150-1151. n-=1613 Risk stratification by lactate

46. Accurate hourly urine output monitoring (for many, this will mean catheterisation) The Goal > 0.5 ml/kg/hr > 40 ml/hour in the average adult Urine Output

47. Urine output is a direct measure of GFR GFR= Glomerular Filtration Rate GFR is directly proportional to CO Kidneys receive 1/5 cardiac output (1 L/min) CO falls UO falls Therefore urine output in the early stages is a useful assessment of cardiac output Urine Output

48. In health, kidneys autoregulate, so UO is independent of BP over a wide range In sepsis, this is lost and UO will fall as BP falls Renal Blood Flow & Urine Output

49. Early Goal Directed Therapy

50. Rivers et al 2001, NEJM; 345, 1368-1377 EGDT Call for specialist support Crystalloid Colloid CVP line < 8mmHg < 65 or <90 mmHg MAP Vasoactive Drugs >8 mmHg ScvO 2 Transfuse red cells until Hb > 10 g/dl YES Goals Achieved ScvO 2 >70% < 70% Inotropic agents NO >65 & >90mmHg >70%

51. 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 Med 2001; 345:1368-1377 Standard therapy EGDT NNT to prevent 1 event (death) = 6-8 ARR 16% In-hospital mortality (all patients) 0 10 20 30 40 50 60 28-day mortality 60-day mortality Mortality (%) The Importance of Early Goal-Directed Therapy for Sepsis Induced Hypoperfusion

52. Mortality by Sepsis Six Cohort size (%) Mortality %RRR % (NNT) Total 567 (100)34.7- Sepsis Six  347 (61.2)44.0 Sepsis Six  220 (38.8)20.046.6 (4.16)

53. Cohort sizeMortality %RRR % (NNT) Total 567 (100%)34.7- Delayed Antibiotics 217 (38.4%)45.4 Antibiotics within 1 h 350 (61.6%)28.138.1 (5.77) Mortality by antibiotics

54. Cohort sizeMortality %RRR % (NNT) Total 567 (100%)34.7- No fluids in 1h 183 (32.3%)44.8 Fluids in 1h 384 (67.7%)30.033.0 (6.73) Mortality by fluid challenges

55. 2.0 fewer Critical Care bed days 3.4 fewer hospital bed days Compared with other survivors Equates to c. £5,000 cost ‘saving’ For patients receiving the Sepsis Six

56. The clincher

57. For each year, for every 500 beds.. 62 lives saved 883 fewer bed days 520 fewer CC bed days Direct costs for survivors reduced by £0.78M Achieving 80% reliability

58. Summary Improve recognition/diagnosis Alter attitude – treat sepsis like MI Early aggressive treatment Use EGDT Collaborate with ITU early

59. Sepsis is a life-threatening condition that arises when the body's response to an infection injures its own tissues and organs. Sepsis leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Sepsis remains the primary cause of death from infection despite advances in modern medicine, including vaccines, antibiotics and acute care. Millions of people die of sepsis every year worldwide

60. Comments and Questions