Early Goal Directed Therapy and Antibiotics for Sepsis

1. Early Goal Directed Therapy and Antibiotics for Sepsis Faheem Guirgis MD

2. Objectives: Define SIRS, Sepsis, and Septic Shock Epidemiology, Pathophysiology History of EGDT Refining EGDT Surviving Sepsis Campaign Implementing EGDT in the ED Focus on Abx GOAL: Clinically Useful, Evidence-Based Guidelines for treating your Septic pts

3. Definitions SIRS? HR > 90, Temp > 38 C, RR > 20, WBC > 12 Sepsis? SIRS + Suspected Infxn Severe Sepsis? + End Organ Dysfunction Septic Shock Hypotension (not responsive to IVF)

4. Severe Sepsis and Shock The Problem � Mortality of Severe Sepsis - 28.6%, or 215,000 pts nationally (Angus et al, Crit Care Med 2001; 29:1303�1310) Septic Shock has lower survival rate of 43.7% (Kumar et al, Chest. 2009 Nov;136(5):1237-48.) and mortality of 40 to 70% Okay�So we know the mortality is high�

5. What do Septic Patients Die from?

6. MODS Multi-Organ Dysfunction Syndrome

7. Our Goal = Prevention of MODS

8. When does MODS occur? Upstairs in the ICU Death usually occurs later in the course of disease even if they present in septic shock Septic patients rarely die in the ED, but if they do�they CRASH

9. CRASH Syndrome - Death from Sepsis in the ED Asplenic pneumonia: At risk for life-threatening S. pneumoniae pneumonia Liver failure and anything Meningiococcemia MRSA pneumonia: Consider adding Vancomycin Necrotizing fasciitis � LOOK AT THE EXTREMITIES! Neutropenic fever

10. Trying to Reduce Mortality from Severe Sepsis and Septic Shock Shoemaker WC � surgical intensivist from California Focused on hemodynamic resuscitation in the critically ill Theorized that adjustment of physiologic parameters predicted oxygenation and would affect mortality

11. Published over 40 Papers on Hemodynamic Resuscitation in Septic Patients Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988;94:1176-1186. Shoemaker WC, Kram HB, Appel PL, Fleming AW. The efficacy of central venous and pulmonary artery catheters and therapy based upon them in reducing mortality and morbidity. Arch Surg 1990;125:1332-1339. Velmahos GC, Demetriades D, Shoemaker WC, et al. Endpoints of resuscitation of critically injured patients: normal or supranormal? A prospective randomized trial. Ann Surg. 2000 Sep;232(3):409-18. Shoemaker WC, et al. Hemodynamic and oxygen transport monitoring to titrate therapy in septic shock. New Horiz. 1993 Feb;1(1):145-59. Shoemaker WC, et al.Sequence of physiologic patterns in surgical septic shock. Crit Care Med. 1993 Dec;21(12):1876-89. Shoemaker WC, et al. Temporal hemodynamic and oxygen transport patterns in medical patients. Septic shock. Chest. 1993 Nov;104(5):1529-36.

12. Goal Directed Therapy? �the prompt attainment of optimal goals (DO2, VO2, Cardiac index) improved outcome in postoperative shock with and without sepsis, as well as in medical sepsis� especially when �attained in 8 to 12 hrs, there was marked and significant reduction in mortality and morbidity rates� - 1993 But Shoemaker didn�t get it completely right�

14. Rivers, et al�2001 EM/IM/Critical Care from Detroit Theorized that �the transition to serious illness occurs during the critical golden hours� Knew that attempts at �immunotherapy, hemodynamic optimization, and pulmonary artery catheterization� were unsuccessful Focused on indicators of global tissue hypoxia = lactate

15. Rivers, et al�2001 SIRS criteria (2 of 4) plus lactate > 4 and/or Systolic BP < 90 (after 20 to 30 mL/kg IV Bolus over 30 min) Early Goal Directed Therapy � Attain Goals within 6 hrs CVP 8-12 MAP > 65 UO > 0.5ml/kg/hr SVO2 > 70%

16. How Did They Do it? Meet Criteria Central Line and A-line placed Pan-cultured Antibiotics per physician discretion (we�ll talk about this later)

17. Protocol Cont�d 500-mL Bolus given q30min to CVP 8-12 If MAP <65 give pressors, if MAP >90 give BP lowering agents If SVO2 < 70%, give PRBCs to Hct of 30 If SVO2 still <70%, give Dobutamine starting at 2.5 mcg/kg/min to max of 20mcg/kg/min Dobutamine stopped if HR > 120 or MAP <65 If Hemodynamic optimization could not be achieved � intubated and sedated Pts stayed in ED for full 6 hrs

18. RCT - 263 Pts � 130 EGDT, 133 Standard Tx Baseline Characteristics -HR, CVP, MAP, SVO2, Lactate, Base Deficit, Arterial pH

19. Differences In Treatment First 6 hrs - EGDT group received increased IVF, PRBCs, and Inotropes. Use of Pressors and Mech Vent were equal. Over 72 hrs � no difference in total IVF or Inotropes; Standard Tx group received more Pressors, Mech. Vent., PA Cath but less PRBCs.

20. Differences During Treatment Goals? SVO2 > 70 � 94.9% for EGDT, 60.2% Standard Tx (p<.001) CVP, MAP, UO goals � 99.2% EGDT, 86.1% Standard Tx (p<.001)

21. Affect on Mortality In-hospital Mortality � 30.5% in EGDT group compared to 46.5% in Standard Tx group

22. The Data seems pretty clear, so why is there so much controversy surrounding Rivers� original study?

23. Criticisms Rebuttals *Henry Ford Health System. Letter to the Editor, WSJ. 2008. **Huang DT, Clermont G, Dremsizov TT, et al. Implementation of early goal-directed therapy for severe sepsis and septic shock: A decision analysis. Crit Care Med. Sep 2007;35(9):2090-2100. **Talmor D, Greenberg D, Howell MD, et al. The costs and cost-effectiveness of an integrated sepsis treatment protocol. Crit Care Med. Apr 2008;36(4):1168-1174. **Shorr AF, Micek ST, Jackson WL, Jr., et al. Economic implications of an evidence-based sepsis protocol: can we improve outcomes and lower costs? Crit Care Med. May 2007;35(5):1257-1262.

24. Criticisms 27 Excluded Pts Would Have Changed Results? 14 from Standard Group, 13 from EGDT group Pt refused aggressive tx (5 in each grp) Pt refused aggressive surgical tx (2 in each grp) Need for immediate surgery (4 in Standard grp, 3 in EGDT grp) Need for interventional Uro, Cardio, Angio Procedure (1 in each group)

25. EGDT Validation 2008 � 1001 pts � overall mortality � EGDT 39%, Standard Tx 64%.* 2008 � 5998 pts (US, Switzerland, Poland, Finland, Canada, Spain, the UK, Germany, Italy and Brazil) � absolute risk reduction of 9% across all studies**

26. To Come�Prospective RCTs ProCESS (Protocolized Care for Early Septic Shock) � 1935 pts at 24 institutions British Protocolised Management in Sepsis (ProMISe) Australia (and New Zealand) Resuscitation in Sepsis Evaluation (ARISE)

27. ProCESS The ProCESS protocol � 3 arms: Standard therapy for severe sepsis Rivers EGDT � using Edwards catheter EGDT w/o catheter � still using IVF, PRBCs, Pressors

28. Surviving Sepsis Campaign International Guidelines started in 2001, revised in 2004 and again in 2008 GRADE system used to evaluate quality of evidence � A is very high quality evidence to D which is very low 1 = Strong Recommendation � Risks clearly outweigh Benefits 2 = Weak Recommendation � Risk vs Benefit less clear

29. How Do We Do It? Recognize early - > 2 SIRS criteria + suspected infxn and lactate >4 But Don�t Forget !

30. Did Somebody Say End-Organ? Renal - Creatinine or decreased UO Cardiac � Troponins Hepatic � elevated bili, LFTs Heme � Platelets Pulm - CXR = ARDS GI � ileus Neuro - AMS

31. How Do We Do It? Board to ICU immediately Obtain Blood Cultures (1C) and culture indwelling catheters (48 hrs) Antibiotics within the 1st hour for severe sepsis (1D) and septic shock (1B)

32. How Do We Do It Cont�d Don�t need to be hypotensive to place Central line � Place Central line early! Attain goals of EGDT � CVP 8-12, MAP > 65, UO > 0.5 mL/kg/hr, SvO2 >70% Pressors if MAP <65 � Norepinephrine and Dopamine (1C) are initial pressors of choice Some evidence that Norepinephrine may be superior

33. How Do We Do It Cont�d Add fixed dose Vasopressin at .03 U/min if persistently hypotensive (2B) If SVO2 < 70, transfuse PRBCs to Hct of 30 (2C) If SVO2 still < 70, add Dobutamine to max of 20 mcg/kg/min Foley catheter to measure UO

34. How Do We Do It Cont�d Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly to adequate fluid resuscitation and vasopressors (2C) ACTH stimulation test is NOT recommended to identify the subset of adults with septic shock who should receive hydrocortisone (2B) Hydrocortisone is preferred to dexamethasone (2B)

35. Surviving Sepsis Campaign Funding from Eli Lilly ? � Yes; Won�t discuss APC Guidelines accepted by ACEP and SCCM

36. Antibiotics for SepsisAvoiding Pitfalls

37. West Side at Montefiore� 62 yo NH pt w/ multiple medical problems, alert but demented � NH note says �r/o sepsis� T102F, HR 115, R 24, BP 90/50, Sat 94% on 2L NC 2 Peripheral IVs placed, IVF boluses started, Tylenol given

38. West Side at Montefiore� Lactate = 6 Chemistry still pending CXR Pending Foley placed � minimal urine

39. Pitfall No. 1 �I SHOULD WAIT FOR A SOURCE BEFORE STARTING ANTIBIOTICS�

40. How to Kill Your Patient Withhold the Antibiotics for a while Surviving Sepsis 2008� �Begin IV antibiotics as early as possible and always within the first hour of recognizing severe sepsis (1D) and septic shock (1B).� Kumar et al, CCM 2006 � 2100 pts - Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. Kumar et al, Intens Care Med 2009 - 4,532 pts - A longer duration to antimicrobial therapy was also associated an increase in incidence of AKI AND AKI was associated with significantly higher odds of death

41. What Causes this Delay? �Excuse me ID, I�d like approval for Zosyn please��

42. Pitfall No. 2 �I MUST KNOW THE CREATININE BEFORE GIVING THE FIRST DOSE OF ABX�

43. Does Kidney Function Matter for Initial Antibiotic Dosing? Surviving Sepsis 2008 � �All patients should receive a full loading dose of each antimicrobial.�

44. Kidney Function Pea, et al � Retrospective Study in which therapeutic drug monitoring (TDM) results were analyzed in critically ill patients over a 7-year period �the percentage of patients receiving appropriate loading was inversely correlated with their degree of renal function, decreasing from 60.4% in the case of normal renal function to 26.8% and 5.5%, respectively, in cases of moderately or totally impaired renal function.� According to Pea, et al �the need for appropriate loading at the commencement of therapy is independent of the patient�s renal function� and that �in the absence of loading, several days may be required to achieve therapeutically effective concentrations� These patients had suboptimal concentrations persisting at Day 4 of treatment

45. Kidney Function Zimmerman, et al � Retrospective review of kidney function and Vanc levels - No statistically significant correlation between nephrotoxicity and initial serum creatinine, days of hospital stay, or days of vancomycin therapy.

46. Pitfall No. 3� UNDERESTIMATING THE IMPORTANCE OF THE LOADING DOSE

47. Hydrophilic vs Lipophilic

48. Hydrophilic Abx =PCNs, Aminoglycosides, Cephalosporins Diffuse more slowly into deep-seated sites of infxn (PNA, intra-abdominal, etc) = Loading Dose is MORE Important!

49. Hydrophilic Abx Affected by Volume of Distribution Target plasma concentration (Ct) that is achieved with the first dose - loading dose (LD) - depends solely on the volume of distribution (Vd) of the drug Ct = LD/Vd So if you increase your Vd, you decrease the chance of achieving the optimal Ct

50. Pts in Septic Shock have high Vd because of third spacing (capillary permeability) and IV hydration!

51. Hydrophilic Abx This means that�Target plasma conc (Ct) may be reduced when using the standard LD = �Third Spacing Phenomenon� Joukhadar and company showed that the peak levels of piperacillin after a single standard 4 g IV dose were several fold lower, either in plasma or in the interstitium of soft tissues, in patients with septic shock than in correctly matched healthy volunteers.* Initial peak plasma concentrations of gentamycin and tobramycin following a 3 mg/kg LD in critically ill surgical patients with life-threatening Gram negative infections were found to be lower than desired (<8.3 mg/l) in about half of the patients and greater LDs - by at least 20% to 25% - were advocated.**

52. The Full LDs of �-lactams, aminoglycosides or glycopeptides (Vanc, Teicoplanin) should be administered to ensure optimal exposure at the infection site whenever treatment is begun in patients with severe sepsis or septic shock.

53. Lipophilic Abx = Macrolides, Quinolones, Rifampin, Linezolid Less affected by Vd, act on intracellular pathogens, hepatically metabolized Consider adding one of these in deep tissue infection (eg Moxi for PNA, Cipro for abdominal infxns)

54. Pitfall No. 4� �NARROWER COVERAGE IS FINE IF I HAVE A SUSPECTED SOURCE�

55. Inadequate Antibiotics � A Clean Kill �Restriction of antibiotics as a strategy to reduce the development of antimicrobial resistance or to reduce cost is not an appropriate initial strategy in this patient population.� Surviving Sepsis Guidelines 2008 Ibrahim, et al, Chest 2000 � 147 pts w/ inadequate antibiotics (29.9%) for bloodstream infections. Hospital mortality 61.9% versus 28.4% in group with adequate antibiotics. Fraser et al, AJM 2006 - Inappropriate initial antibiotic treatment was prescribed in 36% of patients (N=319). All-cause 30-day mortality rates were 20.1% (N=64) and 11.8% (N=68) in patients who received inappropriate and appropriate treatment, respectively. Kumar et al, Chest 2009 - 5,715 patients with septic shock in three countries. Overall mortality 43.7%. The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001)

56. Pitfall No. 5� INAPPROPRIATE SELECTION OF ANTIBIOTICS FOR PNEUMONIA

57. Pneumonia � Break it down! CAP � Not hospitalized or in ECF for 14 days prior and Does not meet the criteria for HCAP HCAP � Hospitalization for 2 days or longer w/in last 90 days From ECF Anyone who received IV Abx, chemotherapy, or wound care within last 30 days Anyone on HD HAP � new infection occurring 48 hours after hospital admission VAP - pneumonia occurring 48 to 72 hours after endotracheal intubation

58. CAP � IDSA, ATS Guidelines

59. Pneumonia � IDSA, ATS Guidelines

60. Treat HCAP, HAP and VAP the same IDSA 2005 guidelines � pts admitted after recent hospitalization or from NH, Dialysis etc should be treated for MDR pathogens MDR Pathogens - P. aeruginosa, E. coli, Klebsiella pneumoniae and Acinetobacter, MRSA

61. Empiric Coverage for HCAP, HAP and VAP Anti-Pseudomonal + Vanc/Linezolid Also, cover Legionella w/ a Macrolide or a Quinolone if suspected

62. Abx Dosing *Taken from 2005 IDSA/ATS Guidelines

63. Double Gram Negative Coverage? Safdar, et al � Meta-analysis of 3077 pts across 17 studies � 2 out 17 studies found benefit, 1 found increased mortality, 14 showed no benefit* Prospective Studies were separated out and still no benefit Cochrane Review of 7586 pts comparing PCN + AG to PCN alone for Gram neg sepsis � No mortality benefit**

64. Why No Benefit? Likely due to increased potency of newer antibiotics Studies that showed benefit were older studies comparing older drugs Surviving Sepsis Guidelines � No evidence for double coverage but�

65. What about Pseudomonas? Recently hospitalized patients NH patients Vent dependent patients Indwelling tubes/lines

66. Double Pseudomonas Coverage? Safdar, et al � Same study in 3077 pts � found benefit to double coverage when Pseudomonas was isolated Surviving Sepsis Guidelines � double cover if suspecting Pseudomonas (2D)

67. Neutropenic Patients IDSA � double gram neg coverage is recommended* Surviving Sepsis Guidelines � double gram neg coverage is recommended (2D)

68. In Summary�The Evidence Says Recognize Severe Sepsis and Septic Shock Get Appropriate Antibiotics on board early Broad coverage recommended Full LD regardless of kidney function Double coverage if suspected pseudomonas or neutropenic pts

69. In Summary�The Evidence Says Place the Central Line early! Believe in EGDT � Achieve your goals R/O CRASH Diagnoses � Asplenic PNA, Liver dz, Meningiococcemia, Nec Fasc, Neutropenic fever, MRSA PNA Source control and R/O Surgical Problems

70. SAVE A LIFE!

74. What�s With this 4 Hour Time to Abx? Houck, et al � retrospective study of 13,771 pts w/ CAP � decreased 30 day mortality, in-hospital mortality, and Hospital LOS in pts Tx in < 4 hrs Weaknesses � post-hoc 4 hr cut-off chosen; More pts in 4 hr cut-off grp received appropriate abx; Same mortality in any of the pts treated between 3 and 8 hrs* This does not apply to sepsis � in which case pts should receive prompt Abx w/in 1 hr