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Objectives:. Define SIRS, Sepsis, and Septic ShockEpidemiology, PathophysiologyHistory of EGDTRefining EGDTSurviving Sepsis CampaignImplementing EGDT in the EDFocus on AbxGOAL: Clinically Useful, Evidence-Based Guidelines for treating your Septic pts. Definitions. SIRS? HR > 90, Temp > 38 C, RR > 20, WBC > 12Sepsis? SIRS Suspected InfxnSevere Sepsis? End Organ DysfunctionSeptic Shock Hypotension (not responsive to IVF).
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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; 29:13031310)
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 didnt 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 (well talk about this later)
17. Protocol Contd 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 Dont 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 Contd Dont 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 Contd 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 Contd 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; Wont 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, Id 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 patients 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 ß-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. Whats 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