Redefining sepsis and sepsis treatment

Transcription

1 Redefining sepsis and sepsis treatment What should we change in the treatment algorithm? Ricard Ferrer Critical Care Department Mutua Terrassa University Hospital Barcelona. SPAIN

2 Time dependency Microorganism Host

3 Bacterial Load

4 Bacterial Load DMID 2010 In vivo

5 Bacterial Load and Severity Rello J et al. CHEST 2009; 136: CV dysfunction Respiratory dysfunction

6 Bacterial Load and Severity Rello J et al. CHEST 2009; 136:

7 SEVERE ANTI-INFLAMMATORY RESPONSE: HARMFUL MODERATED ANTI-INFLAMMATORY RESPONSE:BENEFITIAL Immuno-paralysis Apoptosis ANTI-INFLAMMATORY CYTOKINES IL-10, IL-11 MACROPHAGE ENDOTOXIN (PAMP) TLR-4 (PRR) LYMPHOCYTES Treg % PAF LIPID MEDIATOR FACTORS PG, LEUCOTRIENS TISSUE FACTOR PRO-INFLAMMATORY CYTOKINES (IL-1, IL-6, TNFα) HMGB1 COMPLEMENT ACTIVATION CORTISOL CATECHOLAMINES VASOPRESSIN GLUCAGON VO 2 DO 2 PLATELET AGGREGATION PAI-1 FIBRINOLISIS DIC COAGULOPATHY MICROVASCULAR DYSFUNCTION THROMBIN COAGULATION NITRIC OXIDE ENDOTHELIUM CAPILARY LEAK INTERSTICIAL EDEMA NEUTROPHILS ANTINFECTIOUS RESPONSE VASODILATATION HYPOTENSION MYOCARDIAL DYSFUNCTION DO 2 VO 2, Cell Death, Multi-organ failure MODERATED PRO-INFLAMMATORY RESPONSE: BENEFICIAL SEVERE PRO-INFLAMMATORY RESPONSE: SEPTIC SHOCK

8 Pillars of Sepsis Treatment ABX Source Control HMDC Resusc. Radiology Lactate YOUR speed is LIFE!

9 Tissue dysoxia Oxygen Consumption (VO 2 ): O 2 extracted by the tissues. The rate (ml/min) at which O 2 dissociates from hemoglobin in the microcirculation and moves into the tissues.

10 O2 extraction needed to maintain VO2

11 CCM 1999

12 The biphasic VO 2 DO 2 model VO2 Critical point: DO 2 crit VO 2 and impaired OER Dependence zone: Max O 2 ER Independence zone: Variable O 2 Extraction Ratio Sepsis Normal 10 ml/min kg 15 ml/min kg DO2

13 VO 2 DO 2 model: O 2 Debt VO 2 O 2 Debt= O 2 Deficit x Time Dependence zone Independence zone Sepsis O 2 Deficit & Anaerobic Metabolism Lactate DO 2

14 28-Day Mortality (%) Serum Lactate and Mortality in Severe Sepsis Initial serum lactate evaluated in 839 adults admitted with severe High sepsis. initial serum lactate associated with mortality regardless of presence of shock (hypotension despite fluid resuscitation) p < p = Low Int High p = p = Low Int High Non-Shock Shock Mikkelsen ME, Miltiades AN, Gaieski DF et al. Crit Care Med. 2009;37:

15 VO 2 and alteration of microvascular flow Principal mechanisms implicated in the development of microcirculatory alterations Capillary density number of stopped-flow and intermittent-flow capillaries surface for O 2 exchange De Backer et al. Annals of Intensive Care 2011

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17 Treatment strategies: balanced DO2/VO2

18 Decrease VO 2 VO 2 1 Septic Shock 2 Balanced DO 2 /VO 2 1 Sepsis O 2 Deficit & Anaerobic Metabolism 2 Lactate DO 2

19 Decrease VO 2 Normotermia (or hipotermia) Analgesia Mechanical Ventilation. Infection control: Adequate empirical antibiotics and Source Control. Titrate minimun dose of Termogenic drugs like inotropes.

20 Increase DO 2 VO2 1 Septic Shock 2 Resuscitated Shock Restored VO 2 3 Supranormal Resuscitation DO 2 > 600 ml/min m Sepsis 1 Lactate DO2

21 DO 2 = CO x CaO 2 TREATMENTS Fluids Inotropes Vasopressors CaO 2 Hb x 1.34 x SaO 2 /100 O 2 PRBC

22 End-Points of Resuscitation Treatments Fluids Vasopressors Inotropes PRBC Transfusion Protocol with Goals Outcomes Mortality Morbidity Other TTMs not included

23 n= 263; 1 ED First 6 hours Control: Usual care ED + ICU TTM: Protocol in the ED, later transfer to ICU. Continuous ScvO 2 ScvO 2 goal Rivers et al. N Engl J Med 2001; 345:

24 Early goal directed therapy EGDT involves: Identification of high risk patients. Monitoring: central venous catheter with continuous oxymetry. 6h of protocolized resuscitation with fluids and vasopressors. Additional protocol for ScvO 2 : inotropes and PRBC.

25 EGDT: Treatments PROTOCOL GOAL GOAL

26 Early goal-directed therapy EGDT in patients with septic shock or lactate > 4 T C RRR NNT p Hospital mortality 31% 47% 34% d mortality 44% 57% 22% EGDT in patients with lactate >4 and no hypotension (cryptic shock) T C RRR NNT p Hospital mortality 20% 60,9% 67%

27 Quantitative Resuscitation in sepsis: Meta analysis Early quantitative resuscitation with different Goals Jones A et al. Crit Care Med 2008; 36:

28 Quantitative Resuscitation in sepsis: Meta analysis Jones A et al. Crit Care Med 2008; 36:

29 n= 300; 3 ED Early Septic Shock Different Goals. In both arms: All patients treated in ED. ICU was blinded. Same catheter inserted. Same protocol. Same treatments: Fluids Vasopressors Inotropes PRBC Jones A et al. JAMA 2010;303(8):739-46

30 Different Goals, same administered treatments Jones A et al. JAMA 2010;303(8):739-46

31 Different Goals, same morbidity and mortality Jones A et al. JAMA 2010;303(8):739-46

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33 NEJM 2014 First 6H RCT, 450 patients/group Early Septic Shock Protocol Based EGDT: Requires Continous Central Venous Monitoring Indications to DO 2 if ScvO 2 < 70% Protocol similar to Rivers Protocol Based Standard Therapy: Protocolized resuscitation without CV monitoring No special indications to DO 2 Usual care

34 If Hgb < 7.5, transfuse PRBC Lactate > 4, oliguria, mottled skin

35 Monitorization

36 Treatments

37 Outcome

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41 Impact of Molecular Weight on Volume Effect Crystalloid Colloid Gelatin Albumin Starchs Molecular weight: Volume effect: 60 da kda 69 kda 130 kda mins 1-2 hrs 2 4 hrs 100% 4-6 hrs Adapted with kind permission of P. Gosling 2003

42 Adverse effects of IV fluids Vincet JL et al. Minerva Anestesiologica 2011

43 26 Scandinavian ICUs 6S TRIAL

44 Time to death 6S TRIAL Kaplan Meier curves of survival censored at 90 days Survival Distribution Function Ringers Starch Days

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46 6S TRIAL

47 6S TRIAL

48 6S TRIAL

49 6S TRIAL

50 6S TRIAL

51 Pillars of Sepsis Treatment ABX Source Control HMDC Resusc. Radiology Lactate YOUR speed is LIFE!

52 PRINCIPLES OF SOURCE CONTROL Source control: all physical measures undertaken to eliminate a source of infection, to control ongoing contamination, and to restore premorbid anatomy and function. CORE ELEMENTS OF SOURCE CONTROL Drainage Debridement Device removal Definitve measures John C.Marshall, MD, Abdullah al Naqbi, MD. Principles of Source Control in the Management of Sepsis. Crit Care Clin 25 (2009)

53 TIMING OF SOURCE CONTROL 154 patients with GI perforation and septic shock Takeo Azuhata, et al. Time from admission to initiation of surgery for source control is a critical determinant of survival in patients with gastrointestinal perforation with associated septic shock. Critical Care 2014, 18:R87.

54 TIMING OF SOURCE CONTROL 2,668 patients treated surgically for PPU Shock on admission 16.1% D. L. Buck, et al. Surgical delay is a critical determinant of survival in perforated peptic ulcer. British Journal of Surgery 2013; 100:

55 TIMING OF SOURCE CONTROL 89 patients with NSTI Hypotension 18% Chin-Ho Wong, et al. Necrotizing Fasciitis: Clinical Presentation, Microbiology, and Determinants of Mortality. The Journal of Bone & Joint Surgery

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57 Pillars of Sepsis Treatment ABX Source Control HMDC Resusc. Radiology Lactate YOUR speed is LIFE!

58 SSC 2013 Guidelines The administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) should be the goal of therapy. Remark: Although the weight of the evidence supports prompt administration of antibiotics following the recognition of severe sepsis and septic shock, the feasibility with which clinicians may achieve this ideal state has not been scientifically evaluated.

59 Selection of Antibiotic We recommend that initial empiric antiinfective therapy include one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into the tissues presumed to be the source of sepsis (grade 1B).

60 Severe Sepsis and Septic Shock Empirical antibiotics after sepsis recognition CCM 2014;42:

61 Predicted hospital mortality and 95% CIs for time to first antibiotic administration Results adjusted by the sepsis severity score, ICU admission source ([ED], ward, vs ICU), and geographic region (Europe, United States, and South America)

62 26.3% 51.8% 68.6% 78.2% 84.0% 87.5% 100% Median time to empiric antibiotics

63 Adequate empirical antibiotics en less than 1H Not so easy!

64 Selection of Antibiotics in Sepsis Pathogen Source Setting: Community vs Nosocomial. Biofilms Local susceptibility patterns. Outbreak? Clinical syndrome: Shock Initial microbiological information Host Drug intolerances Previous colonization or infection. Recent antibiotics Comorbidities Immune Status Antibiotic Broad spectrum Bactericidal Activity Post-Antibiotic effect PK/PD. Tissue penetration Elimination by CRRT Toxicity Availability Cost

65 Corticosteroids 2012 Recommendations 1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C). 2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone (grade 2B). 3. In treated patients hydrocortisone tapered when vasopressors are no longer required (grade 2D). 4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock (grade 1D). 5. When hydrocortisone is given, use continuous flow (grade 2D).

66 Observational study using the SSC database

67 Retrospective Observational study CCM 2014

68 Retrospective Observational study Subgroup Analysis CCM 2014

69 Anticoagulants Antithrombin Thrombomodulin No relevant additional information in other anticoagulants: heparin, apc, tifacogin.

70 No major safety concerns

71 CCM 2013 p= 0.17 No major safety concerns

72 Clinical Haemostasis and Thrombosis 2015 RCT OBS

73 serious bleeding complications Clinical Haemostasis and Thrombosis 2015

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75 Immunoglobulins 2012 Recommendations 1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock (grade 2B).

76 2013

77 All studies

78 All studies

79 Specific Antibodies CCM 2013 Ventilator-fee days: No difference

80 Renal Replacement Therapy 2012 Recommendations 1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure (grade 2B). 2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D).

81 Dose of Hemofiltration: HVHF Two previous negative trials in critically ill: The VA/NIH Acute Renal Failure Trial Network: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359:7 20 The RENAL Replacement Therapy Study Investigators: Intensity of continuous renalreplacement therapy in critically ill patients. N Engl J Med 2009; 361:

82 Intensive Care Med (2013) 39:

83 Hemabsorption technologies 2012 Recommendations No recommendation

84 Crit Care Med 2013; 41:00 00

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86 SSC Guidelines 2016 Timeline: October 2016 Scope: Early management of severe sepsis and septic shock. Early is defined as within the first 24 hours. Target audience: Any healthcare worker in any healthcare setting who is caring for adult patients with sepsis. Independent Pediatric Guidelines and limited-resource countries.

87 Living Guideline Concept Living guidelines are systematically developed, evidence based, and continually updated. Rigorous monitoring of published literature. Electronic format vs Paper format. Evaluation of the current state of the recommendation: no revision needed, revision possible, revision imperative.

88 Take Home Messages Sepsis is time dependent: TEMPUS FUGIT

89 Take Home Messages Early Treatment based on: Three pillars of sepsis treatments. Bundles and guidelines. Acute care support in the ICU. Organizational changes to make early care possible. Expert decission for advanced care.

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