High Impact Concepts in the Management of Severe Sepsis

Transcription

1 High Impact Concepts in the Management of Severe Sepsis Rolando Berger M.D., FACP, FCCP Professor of Medicine Director of MICU University of Kentucky Medical Center

2 Five Learning Objectives The nature and the scope of the problem Antimicrobials and Source Control: timing is all! Hemodynamic management: what, when, and how Does it matter? The role of corticosteroids in severe sepsis. New therapies to prevent late death : the coagulation and inflammation cascades preventing ATP-depletion and cell death.

3 SEPSIS: THE NATURE AND THE SCOPE OF THE PROBLEM

4 Sepsis: A Complex Disease This Venn diagram provides a conceptual framework to view the relationships between various clinical septic syndromes. The inflammatory changes of sepsis and SIRS are tightly linked to a disturbed coagulation and fibrinolysis process. severe shock severe Adapted from: Bone RC et al. Chest. 1992;101: Opal SM et al. Crit Care Med. 2000;28:S81-S82

5 Sepsis: A Clinical Continuum focal HR, WBC oxygenation BP oxygenation symptoms fever, BP coagulopathy urine output BUN/cr, LFTs CNS INFECTION SEPSIS SEVERE SEPSIS MODS DEATH supportive care fluids supplemental O 2 vasopressors mechanical ventilation dialysis HIGH RISK antimicrobials source control drotrecogin alfa cytoprotective interventions

6 Severe Sepsis Concept So, in plain English, severe sepsis simply means that clinically significant dysfunction of one or more organs and/or systems has resulted as a consequence of the SIRS process, and not as a direct result of the infection per se.

7 The Impact of Sepsis Major cause of morbidity and mortality worldwide Leading cause of death in noncoronary ICU (USA) * 11 th leading cause of death overall (USA) More than 750,000 annual cases in the USA In the USA, more than 500 patients die of severe sepsis each day (1 every 3 minutes) * Sands KE et al. JAMA. 1997;278: Based on data for septicemia. Murphy SL. National Vital Statistics Reports. Angus DC et al. Crit Care Med 2001;29:

8 Cases/100,000 Severe Sepsis: Comparison Deaths/Year With Other Major Diseases Incidence of Severe Sepsis Mortality of Severe Sepsis , , , AIDS Colon Cancer Breast Cancer CHF * Severe Sepsis 100,000 50,000 0 AIDS Breast Cancer AMI * Severe Sepsis National Center for Health Statistics, American Cancer Society, * American Heart Association Angus DC et al. Crit Care Med 2001;29:

9 Sepsis Cases Total US Population/1,000 Severe Sepsis: A Growing Challenge Today Future 1,800,000 Severe Sepsis Cases 600,000 1,600,000 US Population 500,000 > 750,000 cases of severe sepsis/year in the US * 1,400,000 1,200,000 1,000, , , , , , , , , Year * Angus DC. Crit Care Med 2001;29:

10 Treat infection; block toxins; source control!! Block mediators and/or receptor sites Restore coagulation and fibrinolytic homeostasis IN FE C T ION: e ndo/e x o-toxins, peptidogly c a ns C E LLU LAR R E S PON S E : release of throm boxanes, leukotriens, PAF, oxidases (N O, spla2 ), kinins, and the cytokines(t N F, IL1, IL6, IL8) IN FLAM M AT ION AN D E N D OT H E LIAL IN JU R Y: these e ve nts in turn a c tiva te c oagula tion a nd inhibit fibrinoly sis C OAG U LOPAT H Y: c e ll a poptosis a nd ongoing infla m m a tion Cytoprotective interventions (phenanthridinone, Mg-adenosine triphosphate, and others). E N D R E S U LT : shock, M OF, death

11 Treat infection; block toxins; source control!! Block mediators and/or receptor sites Restore coagulation and fibrinolytic homeostasis IN FE C T ION: e ndo/e x o-toxins, peptidogly c a ns C E LLU LAR R E S PON S E : release of throm boxanes, leukotriens, PAF, oxidases (N O, spla2 ), kinins, and the cytokines(t N F, IL1, IL6, IL8) IN FLAM M AT ION AN D E N D OT H E LIAL IN JU R Y: these e ve nts in turn a c tiva te c oagula tion a nd inhibit fibrinoly sis C OAG U LOPAT H Y: c e ll a poptosis a nd ongoing infla m m a tion Cytoprotective interventions (phenanthridinone, Mg-adenosine triphosphate, and others). E N D R E S U LT : shock, M OF, death

12 Treating the Underlying Cause of Severe Sepsis Means Adequate Antimicrobials and SourCE Control.. but Timing is All!!

13 Choice and Timing of Antimicrobials Prompt and correct antimicrobial therapy is essential to improve outcome. As far as timing is concerned, any delay translates into worse outcome for any severe infection. For severe sepsis the recommended maximal interval between diagnosis and initiation of antimicrobial therapy is < 60 minutes!! Surviving Sepsis Campaign Management Guidelines Crit Care Med 2004; 32: Revised International Guidelines Crit Care Med 2008;36:

14 timing IS All.or At least Half Of It!! A large (2,154 ICU patients), multicenter (10 hospitals, 14 ICUs), and multinational (US and Canada), cohort study of ICU patients with severe sepsis. By multivariable analysis, for every hour delay (from the onset of hypotension) in administering antimicrobials there was a 7.6% decrease in survival rate, for an adjusted odds ratio for death of 1.12 per hour of delay (up to 6 hours) (95% CI of 1.10 to 1.13, p < 0.001). Kumar A et al: Crit Care Med 2006;34:

15 Survival Rate (%) Time Kills!!! Graphic depiction of the slope of expected decrease in survival for every hour of delay in starting antimicrobials after the onset of hypotension (7.6% per hour) in a theoretical scenario that assumes an initial survival rate of 76% Hours From Onset of Hypotension

16 AnD more DAtA A single-center cohort study of 261 patients with severe sepsis or septic shock. All treated with EGD by medical team in the ER. Timing from EGD to antimicrobial administration was a main determinant of mortality: 25% vs. 38.5% when treated in < 1 hour vs. in > 1 hour. Odds ratio for death if treated in < 1 hour was 0.50 (95% CI of 0.27 to 0.92) Crit Care Med 2010;38:

17 But It HAS to BE FASt and It Has To Be Right There Never Is A Second Chance To Make A First Impression! The Only Antibiotic Dose That Saves Your Life Is The First One.

18 Antimicrobials: A Very Serious Problem! The cumulative evidence for the harmful effect of inadequate initial antimicrobial therapy for all serious infections (not only septic shock) is overwhelming and beyond discussion. Correcting antimicrobial therapy after hrs is not adequate. Wrong initial therapy translates into a major increase in the risk of death: the best mortality odds-ratio reported so far is 1.6; that is a 60% increase in the mortality risk.. and this is the best result!

19 Inappropriate Antibiotics And Mortality Study of 5,715 patients with sepsis by SCCM/ACCP criteria (in 83% bacterial sepsis confirmed in 17% the diagnosis was suspected). Initial inappropriate antimicrobials (48 to 72 hours) yielded on average a 5-fold reduction in survival rates: range 2.3 to 17 depending on site and type of infection. The p value was , and the 95% CIs were narrow and far away from 1. From the University of Manitoba Presented at the SCCM annual meeting- Feb 2008 Honolulu, Hawaii

20 The New Clinical Paradigm Escalation is Dead! Long Live De-Escalation!

21 remember.. The Only Antibiotic Dose That Saves Your Life Is The First One.

22 HEMODYNAMIC MANAGEMENT IN SEPSIS

23 What Have We Learned? Time to correction of shock is crucial! Strictly timed goal-directed therapy has the best outcome. Volume resuscitation must be done first. Add transfusion of RBCs if SvO2 remains low and/or if there is persistent lactic acidosis. Myocardial depression is common in sepsis, and significant RV failure may occur. Inotropes are often needed to maintain adequate CO. In septic shock alpha-pressors increase splanchnic perfusion if used correctly, with the possible exception of dopamine (CCM 2003;31: CCM 1997;25: ). Stress-dose corticosteroids may help

24 Percent Survival Shock, Survival, and Cumulative O 2 Deficit n = 100 dogs Adapted from: JW Crowell & EE Smith Am J Physiol 1964; 206: Oxygen Debt in ml/kg/min

25 Percent Survival Shock, Survival, and Serum Lactic Acid Modified from: MH Weil & AA Afifi Circulation 1970; 41: n = 142 patients > 17 Plasma Lactate Level in mmol/l

26 The Goal of Treating Shock It is to achieve and maintain proper oxygenation and function of vital organs. It is not to achieve any magical value of systemic blood pressure, pulmonary wedge pressure, SVR, and/or cardiac index!

27 HoW to tell IF the GoAl is Being Achieved End-organ function: urine, CNS, heart, liver Acid-Base Balance: Gastric tonometry (research tool value?) ph, lactic acid levels, AG, serum HCO 3 - Perfusion markers: color, warmth, capillary filling of skin, fingers, and toes. Blood Pressure: traditionally MAP > 60 mm Hg SvO 2 : 60% (in PA) or 70% (in SVC).

28 Bad! SvO Good! O 2 demands O 2 delivery

29 Goal-Directed Therapy Martin, Saux and colleagues in 1990 (Marseilles Medical School, France) Acta Anesthesiol Scand 1990; 34: Rivers, Nguyen and colleagues in 2001 (The Early Goal-Directed Therapy Collaborative Group Detroit, MI) N Engl J Med 2001; 345:

30 A Recipe For Septic Shock Reduce oxygen needs: cool down, mechanical ventilation, sedation, analgesia, paralysis, etc. Volume resuscitation to CVP > 10 or PWP > 12 mm Hg. Usually 4 6 liters of cristalloids in first 1-2 hours. Use RBCs if Hgb < 10 g/dl. If SvO 2 still low (< 70%), add dobutamine at increments of 5 mcg/kg/min q mins. May give RBCs if SvO 2 remains < 60%-70% on maximal dobutamine, regardless of Hgb. If MAP < 60 mm Hg, start levarterenol (Levophed ) at increments of 5 mcg/min q mins. Consider vasopressin at fixed dose of units/min. Consider hydrocortisone 100 mg IV q 8 hours x 7 days.

31 Is There A Role For Steroids In Severe Sepsis and Septic Shock?

32 How Did This Get Started? Aren t steroids great? High-dose steroids for septic shock became popular in the late 1970 s and early 1980 s after William Schumer s paper was published Schumer W: "Steroids in the Treatment of Septic Shock". Ann Surgery 1976; 1845:

33 AnD then the BuBBlE BurSt. Five large prospective, controlled studies (and 2 meta-analysis) killed this practice: Sprung et al: NEJM 1984; 311: Bone et al: NEJM 1987; 317: VA Cooperative Study: NEJM 1987; 317: Luce et al: ARRD 1988; 138: Slotman et al: CCM 1993; 21: Lefering & Neugebauer: "Steroid Controversy in Sepsis and Septic Shock: A Meta-Analysis". CCM 1995; 23: Cronin et al: "Corticosteroid Therapy for Sepsis: A Critical Appraisal and Meta-Analysis of the Literature". CCM 1995; 23:

34 But. In the mid 1990 s clear evidence of adrenal insufficiency occurring in patients with severe sepsis was published Anita Soni et al: "Adrenal Insufficiency Occurring During Septic Shock: Incidence, Outcome, and Relationship to Peripheral Cytokine Levels". Am J Med 1995; 98:

35 A new BEGInnInG.? Thus, in the late 1990 s two studies reported benefit from stress-dose steroids in severe refractory septic shock Briegel J et al: "Effect of Hydrocortisone on Reversal of Hyperdynamic Septic Shock: A Randomized, Double-Blind, Placebo- Controlled Single-Center Study". Shock 1997; 7:165 (Abstract). Then Crit Care Med 1999; 27: Bollaert P-E et al: "Reversal of Late Septic Shock with Supraphysiologic Doses of Hydrocortisone". Crit Care Med 1998; 26:

36 Two More Recent StuDIES A study by Annane and colleagues (Paris University) confirmed this finding (JAMA 2002; 288: ), using fludrocortisone (50 mcg/d) and hydrocortisone (50 mg IV q 6 h). However, the multi-center trial Corticus yielded conflicting results and showed no clear benefit, although it did not show any harm either (N Engl J Med 2008;358(2): ).

37 So the DEBAtE ContInuES There is no agreement on how to define or test for clinically significant adrenal insufficiency in severe sepsis. The current recommendation is to NOT do any kind of testing but to treat everyone who does not rapidly improve and stabilize with conventional therapy (within 6 hours or less). Treatment should be 200 to 300 mg of hydrocortisone a day. Treatment should be for 7 days based on a metaanalysis that showed that the survival benefit was only seen in patients treated for at least one week (Annane et al; British Medical Journal, August 2004 ).

38 THE NEW THERAPIES: PREVENTING MORBIDITY AnD late DEAtH

39 Treat infection; block toxins; source control!! Block mediators and/or receptor sites Restore coagulation and fibrinolytic homeostasis IN FE C T ION: e ndo/e x o-toxins, peptidogly c a ns C E LLU LAR R E S PON S E : release of throm boxanes, leukotriens, PAF, oxidases (N O, spla2 ), kinins, and the cytokines(t N F, IL1, IL6, IL8) IN FLAM M AT ION AN D E N D OT H E LIAL IN JU R Y: these e ve nts in turn a c tiva te c oagula tion a nd inhibit fibrinoly sis C OAG U LOPAT H Y: c e ll a poptosis a nd ongoing infla m m a tion Cytoprotective interventions (phenanthridinone, Mg-adenosine triphosphate, and others). E N D R E S U LT : shock, M OF, death

40 Severe Sepsis: A Truly Vicious Cycle SEPSIS ACUTE ORGAN DYSFUNCTION (Severe Sepsis) DEATH

41 Sepsis: A Network of Cascading Events ATIII= antithrombin 3 TFPI= antithrombin tissue factor 3 pathway inhibitor TFPI= Tissue factor pathway inhibitor Activated Protein C AT-III Protein C Activated Protein C TFPI Courtesy of Eli Lilly and Co.

42 Homeostasis Of Coagulation Is Unbalanced in Severe Sepsis Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5: ; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

43 Modulating Coagulation, Fibrinolysis, and Inflammation Activated APC, ATIII, Protein TFPIC Activated APC, ATIII, Protein TFPIC Coagulation Inflammation Fibrinolysis Homeostasis Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5: ; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44

44 three main rct S (Advances in Sepsis 2001;1(4): ) PROWESS TRIAL: recombinant human activated protein C or drotrecogin alpha (Xigris ) (NEJM 2001;344:699). KYBERSEPT TRIAL: human antithrombin, formerly antithrombin III (JAMA 2001; 286:1869). OPTIMIST TRIAL: Tifacogin or Tissue Factor Pathway Inhibitor (JAMA 2003; 290: ).

45 prowess results % Placebo Drotrecogin alfa 2-sided p value: Absolute risk reduction: 6.1% Adjusted relative risk reduction: 19.4% Increase in survival odds: 38.1% 24.7%

46 Apache II Score and Mortality Patient Group Mortality APC group Mortality Placebo Group Relative Absolute Risk Ratio Difference (RRR) 95% CI for RRR All 24.7% 30.8% - 6.1% to 0.93 Apache II 0 to 24 Apache II > 25 19% 19% 0% % 44% - 13% to to 0.85

47 Treat infection; block toxins; source control!! Block mediators and/or receptor sites Restore coagulation and fibrinolytic homeostasis IN FE C T ION: e ndo/e x o-toxins, peptidogly c a ns C E LLU LAR R E S PON S E : release of throm boxanes, leukotriens, PAF, oxidases (N O, spla2 ), kinins, and the cytokines(t N F, IL1, IL6, IL8) IN FLAM M AT ION AN D E N D OT H E LIAL IN JU R Y: these e ve nts in turn a c tiva te c oagula tion a nd inhibit fibrinoly sis C OAG U LOPAT H Y: c e ll a poptosis a nd ongoing infla m m a tion Cytoprotective interventions (phenanthridinone, Mg-adenosine triphosphate, and others). E N D R E S U LT : shock, M OF, death

48 Cytoprotection: Phenanthridinone Shock/reperfusion states cause cellular DNA injury, which in turn induces the release of poly(adenosine 5 -diphosphate-ribose) synthetase (known as PARS or PARP) to repair the damage. This repair-enzyme can rapidly deplete NAD and ATP stores through its energy-costly cycle of transferring ADP-ribose units to nuclear proteins. NAD and ATP depletion results in decreased glycolysis and mithocondrial respiration, eventually culminating in cell death. Phenanthridinone inhibits PARS in animals. Crit Care Med 2002; 30:

49 Cytoprotection: Adenosine Tri-Phosphate MgCl 2 Septic states lead to decrease intracellular production of ATP, which coupled with the increased use also associated to severe sepsis, can result in cell death. In animal studies adenosine triphosphate-magnesium dichloride (ATP-MgCl 2 ) restored cell function in severely endotoxemic pigs. Crit Care Med 2002; 30:

50 TIME IS UP! ANY QUESTIONS?

51 The Prowess Trial Randomized, double-blind, placebo-controlled, multi-center (164 hospitals), and multi-national (11 countries) study. 1,728 patients recruited the study was prematurely terminated because of achieved benefit at pre-determined level of significance for second interim review (June 2000): p < There were 857 patients in the placebo arm, and 840 completed the study. There were 871 patients in the drotrecogin-alfa arm, and 850 completed the study: thus, 1690 of 1,728 patients (97.8%) completed the study as per protocol.

52 The KYBERSEPT Trial From March 1977 to January 2000 a multicenter prospective, randomized, controlled, and blinded clinical trial of antithrombin III in severe sepsis was conducted in 211 hospitals in 19 countries, eventually including a total of 2,314 adult patients. No overall benefit in 28-day mortality found. Increased risk of hemorrhage in patients receiving concomitant heparin: 23.8% vs. 13.5%, p < Trend toward possible survival benefit in those not on heparin was noted post-hoc, but p = 0.08 for mortality at 28 days and survival difference did not reach significance until day 90 (p = 0.03). JAMA 2001; 286:1869

53 The TFPI OPTIMIST Trial Recombinant Tissue Factor Pathway Inhibitor (TFPI) or Tifacogin was developed in partnership by Pharmacia Corp. and Chiron and appeared promising in an initial clinical trial (CCM 2001;29:2081). A much larger phase III trial ( OPTIMIST trial ) was carried out in slightly over 2,000 patients, enrolled in about 16 different countries. The reported data from this study indicated that no mortality advantage at 28 days was found in the group as a whole (JAMA 2003; 290: ).

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