Septic shock. Outline. Spoiler alert. History Early Goal Directed Therapy EGDT

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1 Outline Septic shock Early Goal Directed Therapy Kim Engelen, MD Voortgezette Opleiding Urgentiegeneeskunde Anesthesia, Critical Care Medicine, 24 November 2015 Emergency Medicine Leuven Ziekenhuis Oost-Limburg, Genk EGDT -History - Surviving Sepsis Campaign Guidelines - Improving outcome - Criticism Latest evidence - ProCESS - ARISE - ALBIOS - SEPSISPAM - TRISS - ProMISe Spoiler alert History This will NOT be a Cinderella story Early is maybe more important than goal Early antibiotic treatment is maybe more important than CVP, S cv O 2, hematocrit The largest effect of EGDT in sepsis over the past decade appears to be increasing awareness and thus turning usual care into good clinical practice by early diagnosis and intervention. 1

2 It all started with EGDT - Protocol - 2 SIRS criteria - Fluid bolus ml/kg over 30 min. - BDsyst < 90 mmhg or lactate > 4 mmol/l Rivers et al. N Engl J Med 2001; 345: EGDT - Hemodynamic support EGDT - Outcome - EGDT for 6 hours - Crystalloid bolus 30 ml/kg every 30 min. - Dobutamine 2.5 μg/kg/min., increased by 2.5 μg/kg/min. every 30 min. (max. dose of 20 μg/kg/min.) 2

3 EGDT - Outcome EGDT therapeutic interventions Rivers et al. N Engl J Med 2001; 345 Rivers conclusion Barcelona Declaration

4 Barcelona Declaration 2002 SSC Guidelines Barcelona Declaration, October 2 nd 2002 ESICM, SCCM, International Sepsis Forum To tackle the 10 th most common cause of death and to reduce mortality by 25% over next 5 years JL Vincent. Crit Care 2003; 7: 1-2 SSC Guidelines Definitions Bone et al. The ACCP/SSCCM Consensus Conference Committee. Chest 1992; 101:

5 SSC - Care bundles Initial resuscitation and infection issues 5

6 Hemodynamic support 6

7 Other supportive therapies 7

8 Improving outcome? Hopping on the bandwagon Rivers E. Chest 2010; 136:

9 A meta-analysis And another one 9 studies (1001 patients) Gu et al. Crit Care 2014; 18: 570 Jones et al. Crit Care Med. 2008; ): Overall mortality 13 RCT s, 2525 patients, 17% RR reduction on overall mortality Gu et al. Crit Care 2014; 18: 570 Gu et al. Crit Care 2014; 18: 570 9

10 Timing of intervention Some criticism Gu et al. Crit Care 2014; 18: 570 Cry me a Rivers Single center trial Low number of patients Bias in small, single-center trials may lead to inflated effect-sizes that cannot be replicated in larger multicenter studies Representation of all septic patients? Detroit Metro ED (poor, minority population, poor health status, high incidence of chronic disease) US citizens without insurance are sicker when seeking care Extremely low ScvO2 values (and low C.O.?!) caused by comorbidities/hypovolemia due to late ED arrival Real clinical value of CVP and S cv O 2? 10

11 Are all septic patients the same? Later sepsis studies: S cv O 2 values higher than in the Rivers trial But also lower lactate, higher CVP, lower mortality! Patients in the Rivers trial were much sicker, and with more comorbidities Kortgen et al. Crit Care Med 2006; 34: Shapiro et al. Crit Care Med 2006; 34: Danis et al. Crit Care Med 2006; 34: Esper et al. Crit Care Med 2006; 34: Ho et al. Crit Care 2006; 10: R80 Dombrovskiy et al. Crit Care Med 2007; 35: Van Beest et al. Crit Care 2008; 12: R33 Sprung et al. N Engl J Med 2008; 358: Rivers et al. N Engl J Med 2001; 345: What about hemodynamic goals? CVP 8-12 mmhg? Packman et al. Crit Care Med 1983; 11: Filling pressure does not reliably predict fluid responsiveness! Risk for iatrogenic fluid overload Michard et al. Chest 2002; 121: Vincent et al. Crit Care Med 2006; 34: Antonelli et al. Intensive Care Med 2007; 33: Osman et al. Crit Care Med 2007; 35: Martin et al. Crit Care 2005; 9: R74 Singer M. Crit Care Resusc 2006; 8: Marik PE et al. Chest. 2008;134: Boyd et al. Crit Care Med 2011; 39: Micek et al. Crit Care 2013; 17: R246 Azriel Perel. Crit Care 2008; 12:

12 What about hemodynamic goals? S cv O 2 70%? A low S cv O 2 value is an important warning sign of the inadequacy of systemic oxygen delivery to meet oxygen demands But it does not provide information about the reason for this inadequacy, nor does it provide guidance to the optimal therapeutic approach. Kortgen et al. Crit Care Med 2006; 34: Shapiro et al. Crit Care Med 2006; 34: Rivers et al. Crit Care Med 2007; 35: Perel et al. Crit Care 2008; 12 (suppl 2) Van Beest et al. Crit Care 2008; 12: R33 Jones et al. JAMA 2010; 303 (8): Non inferiority (lower limit C.I. above - 10% predefined threshold) Latest evidence 12

13 Latest evidence in sepsis management ALBIOS Trial (Albumin) Caironi et al. N Engl J Med 2014; 370: ALBIOS SEPSISPAM Trial (MAP) Asfar et al. N Engl J Med 2014; 370: ProCESS Trial (EGDT) The ProCESS Investigators. N Engl J Med 2014; 370: TRISS Trial (Transfusion) Holst et al. N Engl J Med 2014; 371: ARISE Trial (EGDT) The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014; 371: Caironi et al. N Engl J Med 2014; 370: ProMISE Trial (EGDT) The ProMISE Investigators. N Engl J Med 2015; 372: ALBIOS 100 ICU s in Italy, 1818 patients severe sepsis Fluid resuscitation according to EGDT Albumin 20% + crystalloid vs. crystalloid alone Albumin 20% 300 ml 30 g/l serum level from day 1 to 28 (or ICU discharge) - Lower daily net fluid balance in Albumin group - Lower median cumulative net fluid balance in Albumin group Primary outcome: 28-day all-cause mortality Secondary outcomes: 90-day mortality Number of patients with organ dysfunction, degree of organ dysfunction ICU stay, hospital stay 13

14 Outcome ALBIOS conclusion Albumin in addition to crystalloids is safe in severe sepsis, but does not alter survival. Albumin improves hemodynamic variables Targeted MAP reached within 6 hours in greater proportion of patients Higher MAP, lower heart rate, lower net fluid balance Lower average cardiovascular SOFA-score Shorter time to suspension of vasopressor or inotropic support SEPSISPAM SEPSISPAM 29 centers in France, 776 patients Septic shock Refractory to fluid resuscitation (30 ml/kg) Vasopressors 0.1 μg/kg/min. Within 6 hours after initiation of vasopressor MAP mmhg vs mmhg At least 5 days or when weaned from vasopressor Primary outcome: 28 all-cause mortality Asfar et al. N Engl J Med 2014; 370: Secondary outcomes: 90-day mortality Days alive and free from organ dysfunction by day 28 14

15 But Values of MAP exceeded the target values in both groups Lower-than-expected rate of death underpowered study for detection of (rare) adverse effects SEPSISPAM Conclusion ProCESS No survival benefit for MAP mmhg vs mmhg More A-fib in higher target group More RRT in lower target group with chronic hypertension patients The ProCESS Investigators. N Engl J Med 2014; 370:

16 ProCESS ProCESS 31 ED s in USA, 1341 patients 3 Study arms: protocol-based EGDT, protocol-based standard therapy (without CVC, inotropes or blood transfusion), usual care. Resuscitation - processes of care from baseline to 72h Primary end point: 60-day in-hospital mortality Superiority of protocol-based care (EGDT and standard) to usual care and of EGDT to protocol-based standard therapy Antibiotics within 2 hours of sepsis with circulatory failure Secondary end points: longer-term mortality, need for organ support ProCESS conclusion Protocol-based care (either by EGDT or standard-type) - Does not improve outcome in septic shock patients. - Resulted in an increased use of IV fluids, vasoactive agents and blood transfusions. - Had a higher requirement for intensive care and renal replacement therapy. 16

17 TRISS TRISS 32 ICU s in Scandinavia, 998 patients with septic shock Red cells transfusion when Hb 7 g/dl (low threshold) vs. Hb 9 g/dl (high threshold) Primary outcome: 90-day mortality Holst et al. N Engl J Med 2014; 371: Secondary outcome: Use of vasopressor/inotropes Mechanical ventilation Renal replacement therapy Ischemic events TRISS TRISS 17

18 TRISS conclusions ARISE In septic shock patients, leukoreduced transfusion at threshold Hb 7 did not improve outcome compared with threshold Hb 9. There was no difference in ischemic events, however power was limited and myocardial infarction was not a prespecified outcome measure Excess transfusion (median of 3U) showed no harm The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014; 371: ARISE 51 hospitals (Australia, NZ, Finland, Hong Kong, R. of Ireland), 1600 patients with septic shock EGDT (for 6 hours) vs. usual care (S cv O 2 not permitted) Primary outcome: 90-day all-cause mortality Secondary outcome: ICU mortality, mortality at 28 days and 60 days Hospital stay, ICU stay Organ support (vasopressor, mechanical ventilation, renal replacement therapy) 18

19 ARISE - outcome ARISE - outcome All-cause mortality at 90 days: EGDT 18.6% vs. Usual 18.8% (P=0.90) Absolute difference in risk of death EGDT compared to Usual: -0.3% (95% confidence interval {CI}; ) Survival time NS Between-group mortality in subgroups NS ICU and hospital stay NS More vasopressors in EGDT (no difference in duration) Mechanical ventilation, RRT NS ARISE - outcome ProMISe NEJM 2015; 372 (14):

20 ProMISE ProMISe Phase III, open, multicenter RCT (pragmatic, ITT) ED s in the UK (56 NHS hospitals), 2160 patients EGDT vs usual care Primary outcome = all-cause mortality at 90 days Secondary outcomes: SOFA, organ support, LOS, mortality at 28d/1y IV antimicrobials and fluid challenge initiated before randomisation NEJM 2015; 372 (14): ProMISe ProMISe NEJM 2015; 372 (14): NEJM 2015; 372 (14):

21 ProMISe But survival in sepsis did increase over the last decade, right? Because of early recognition Because of early antibiotic treatment! (besides fluid resuscitation and vasopressors) Kumar et al. Crit Care Med 2006; 34: Kumar et al. Chest 2009; 136: Kumar et al. Crit Care Med 2010; 38: Puskarich et al. Crit Care Med 2011; 39: Hutchinson et al. Dimens Crit Care Nurs 2011; 30: K Rowan. ISICEM 2015 Brussels. One common denominator in the later sepsis trials was early administration of AB s Kumar et al. Crit Care Med 2006; 34: Each hour that antimicrobial therapy is deferred has been associated with a 7.6% decrease in survival for patients in septic shock! Kumar et al. Crit Care Med 2006; 34:

22 Take home messages Remaining challenges Make the diagnosis early! SIRS, severe sepsis, septic shock Rapid fluid resuscitation (20-30 ml/kg) Balanced crystalloids Avoid fluid overload! (PLR-test, PiCCO...) Norepinephrine to maintain MAP 65 mmhg MAP 85 mmhg if chronic hypertension? Early AB treatment (and source control) De-escalate accordingly. Refractory shock: Solucortef (200 mg/day) Vasopressine? Albumin? (maintain 30 g/l) Transfusion: PRBC to maintain Hb 7 mg/dl Hb 9 mg/dl if ACS... How to accurately assess preload conditions? How to predict fluid responsiveness and perform adequate volume resuscitation? Multimodal therapy? (i.e. statins, β-blockers,...) Defining individualized care! Male, 65y, caucasian Medical history: Diabetes, obesity (90 kg, BMI 31) Liver steatosis, kidney stones Ischemic heart disease, PCI (stable condition, LVEF 55%) Admitted 1 month ago with Pseudomonas-pneumonia Elective cholecystectomy (laparoscopic open procedure) POD 2 transfer from surgical ward to ED: Fever (T 38.8) HR 100 bpm, BP 95/50 (MAP 65 mmhg) RR 28/min. S p O 2 95% (mask 10L/min.) Urinary output over last 4 hours: 120 ml 22

23 Chest X-ray: So, what are we talking about? SIRS Sepsis Severe sepsis Septic shock On the ward: WBC 25, GFR 38 ml/min., Troponin nl., Alb 28, Hb 7.3 Condition worsens SpO2 drops to 88% (on 100% O 2 ), RR 30/min. BP 80/40 (MAP 53 mmhg), HR 120 bpm - >2 SIRS criteria - Documented infection: pneumonia - Organ dysfunction (AKI Rifle failure) - Yes, there is hypotension, but no fluid bolus given yet What do you do? - Call someone from respiratory care - Order a bronchoscopy to identify the culprit germ - Start vasopressor therapy - Administer fluids Which fluid? - Volulyte 6% 30 ml/kg - Plasmalyte 30 ml/kg - Albumin 20% 200 ml - NaCl 0.9% 30 ml/kg - Packed cells 23

24 After fluid administration: BP 85/42 (MAP 56 mmhg) = SEPTIC SHOCK! What do you do? (besides titrated fluid resuscitation) - Start inotropes - Start vasopressors - Start glucocorticoids Which vasopressor? - Adrenaline - Noradrenaline - Vasopressin Noradrenaline to maintain MAP 65 mmhg Via peripheral IV line if necessary Do not wait for extended period of time in order to place central venous line! Ventilatory support NIV If responsive to low levels of pressure support and PEEP: proceed If non-responsive or worsening : low threshold for intubation Which antibiotic? Augmentin Biclar Tazocin Meanwhile: Place arterial line Obtain cultures (sputum culture if possible, hemocultures) Start antibiotic therapy Glazidim Glazidim + Ciproxine 2 days in hospital, so still community acquired, BUT history of recent Pseudomonas-pneumonia! Ceftazidim + Ciproxin (Aminoglycoside?? AKI-F) First 24-48h full dose! (keep it above the MIC!) 24

25 MAP still below 60 mmhg with Noradrenaline 0.2 μg/kg/min. Hb 8.0 Lactate 7.5 mmol/l - Increase NA-dose - Place central venous line (if not already done) Persistent hypoxemia on NIV, respiratoiry fatigue Intubate! Which hypnotic? - Propofol - Hypnomidate - Valium - Ketalar - Thiopenthal Titrate accordingly! (age, kidney function, hemodynamic state, comorbidities...) ABG (FiO2 0.8): PO2 80, PCO2 48, ph 7.3, Bic 17, B.E. -4 Which ventilator settings? Lung protective ventilation (TV 6 ml/kg, PEEP +12 cmh2o) Minimal FiO2 to maintain PO2 70 Avoid prolonged hyperoxic state Plateau pressure < 35 cmh2o MAP still below 60 mmhg with repeated fluid boluses and NE 0.65 μg/kg/min. -Consider Solucortef 100 mg IV (+ repeat doses 50 mg every 6 hours) - Vasopressin 2-3 U/hour IV-drip If refractory hypoxemia Prone/supine Percussion ventilation? (HFOV?) ECMO... MAP 67 mmhg but lactate 4.5 mmol/l Hb 7.2 g/dl So, what s next? 25

26 Should we use inotropic support? Should we continue fluid boluses? Why not use PICCO? PICCO: Cardiac output Preload (SVV, PVV) ELWI But be careful with interpretation of parameters! -Arythmias - Severe heart valve disease - Tidal volume < 8 ml/kg (LPV) - TEE PICCO: C.I. 2.2 SVV 12% ELWI 8% Is this patient fluid responsive? Passive leg raising test: if positive give fluids, if negative start inotropic support (Dobutamine 4-10 μg/kg/min.) If possible, perform echocardiography to assess global ventricular performance and SWMA s (regional function) 3D-TEE: global severe hypokinesia, septal dyskinesia 26

27 Are we concerned about CVP? S cv O 2? Hematocrit? But what if: Hb is 5.9 g/dl? Family mentions chronic use of Amlodipin? Serum albumin is 20 g/l? Not really for now. Transfusion of PRBC s (4 ml/kg increases Hb by 1 g/dl) Maintain higher MAP s (85-90 mmhg) Administer Albumin to maintain serum levels of 30 g/l Septic shock is a dynamic state! Thank you & kind regards from Genk! MAP 68 mmhg, HR 110 bpm C.I. 3.7 P a O 2 81 mmhg (F i O 2 0.5), PCO 2 45 mmhg, ph 7.29 Lactate 2.1 Urinary output 90 ml over last hour Let s chestbump and have a coffee Oh yeah, and call ICU 27