Early Goal-Directed Therapy

Transcription

1 Early Goal-Directed Therapy Where do we stand? Jean-Daniel Chiche, MD PhD MICU & Dept of Host-Pathogen Interaction Hôpital Cochin & Institut Cochin, Paris-F

2 Resuscitation targets in septic shock 1 The physiological evidence

3 Hemodynamics of Septic Shock Decreased vascular tone Hyperdynamic shock Myocardial depression Capillary leak syndrome Altered microcirculation Impaired O 2 extraction Ideal resuscitation targets?

4 Septic Shock Bundle (To be started immediately & completed within 6 hours) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg. In the event of persistent arterial hypotension despite volume resuscitation (septic shock) and/or initial lactate > 4 mmol/l (36 mg/dl): Insert central line Achieve central venous pressure (CVP)>8 mmhg. Achieve central venous oxygen saturation (ScvO 2 ) of > 70%.*

5 CVP MAP CO SvO 2 DO 2 Lactacte clearance Microcirculation

6 CONSUMPTION DELIVERY SvO 2 CONSUMPTION OUTPUT C(a-v)O 2 Lactate CONSUMPTION DEMAND

7 The biphasic VO 2 - DO 2 concept

8 Tested whether increasing cardiac index to a supranormal level (CI group) or increasing mixed venous oxygen saturation to a normal level (SvO 2 group) would decrease morbidity and mortality in ICU patients, as compared with a control group (normal cardiac index) PCRT with 762 patients randomized CTL group 252 pts target reached 94.3 % CI group 253 pts target reached 44.9 % SvO pts target reached 66.7 %

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10 N Engl J Med 2001;345:

11 EGDT protocol N Engl J Med 2001;345:

12 N Engl J Med 2001;345:

13 Total fluids (ml) N Engl J Med 2001;345:

14 Mortality (%) 16% absolute mortality reduction; NNT to prevent 1 event (death) = Usual care EGDT Hospital mortality 28-day mortality 60-day mortality N Engl J Med 2001;345:

15 What happened next Endorsement in SSC guidelines Several single centre reports of benefit with decrease in mortality Small studies with historical controls or before/after design Publication bias? Slow adoption! Strength of evidence base? Logistical burden to initiate change? Knowledge transfer? Skepticism? Which goal?

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19 Resuscitation targets in septic shock 1 The physiological evidence 2 Next generation trials: what s new?

20 Are Rivers results generalisable? Single US centre, not blinded study Conducted, analysed & reported by the protagonist What made it work? Physiology-based interventions & therapies Rivers is really a good doctor All elements of the protocol necessary? Early central venous catheterization in all patients ScvO 2 monitoring, with instructions for PRBC and dobutamine Is so much fluid safe and valuable? Why is the control group mortality so high?

21 DESIGN Region Design Blinded N o sites Hospitals First patient N o pts Population N 0 groups Intervention Control NCT NCT ISRCTN Australia, NZ, Hong Kong, Finland Multi-centre RCT No 47 Uni, metro, rural October Severe sepsis in ED Two-arm 6-hr EGDT NA Usual care USA Multi-centre RCT No 27 Uni, teaching, 3 0 referral March Severe sepsis in ED Three-arm 6-hr EGDT Protocolised standard Usual care UK (not Scotland) Multi-centre RCT No 46 Uni, non-uni February (completed!) Severe sepsis in ED Two-arm 6-hr EGDT NA Usual care Prospectively-defined individual patient meta-analysis PRISM

22 Early septic shock in the ED Randomization to 3 arms for 6 h of resuscitation Protocol-based Early Goal-directed Therapy Protocol-based standard therapy Usual care Two sequential hypotheses 1. Protocol-based resuscitation better than usual care? Comparing the 2 protocol arms combined to usual care 2. EGDT superior to protocol-based standard therapy? Where standard therapy does NOT include Central venous pressure and oxygen monitoring Instructions to give blood or dobutamine

23 Inclusion criteria Adults with early septic shock >18 years of age Suspected infection & >2 SIRS criteria Refractory hypotension OR serum lactate >4mmol/L Refractory hypotension SBP <90 mmhg or need for vasopressors despite fluid challenge (initially >20cc/kg but later changed to 1L) Timing & location Randomization while still in ED Within 2h of meeting shock criteria Within 12h of arriving in the hospital Written consent from patient or legallyauthorized representative

24 Protocol-based EGDT Early insertion of CVC for ScvO 2 Potential use of dobutamine & PRBC Titrate to CVP, MAP & ScvO 2

25 Protocol-based standard therapy Consensus process All participating sites No mandated central line Time-based prompts Blood pressure Shock index Clinical signs Fluid overload Hypoperfusion Treatments Intravenous fluids Vasopressors

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28 Intravenous fluids Vasoactive agents & blood Pressors Blood Dobutamine Intravenous fluids EGDT protocol 2.8 L P<0.001 Std Rx protocol 3.3 L Usual care 2.3 L Intravenous antibiotics EGDT protocol 97.5% P=0.90 Std Rx protocol 97.1% Usual care 96.9%

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30 Conclusions For patients presenting with early septic shock In the setting of Prompt recognition Prompt intravenous fluid bolus for hypotension Prompt intravenous antibiotics There is no apparent additional benefit of Protocol-based resuscitation Mandatory central line placement in all patients ScvO2 monitoring, with triggers for blood transfusion and dobutamine

31 Study treatments Randomisation 1:1 to receive either usual care or EGDT for 6 hours (stratified by site) Usual care group Investigations, monitoring and all treatments determined by treating clinicians ScvO 2 measurement NOT permitted during the 6-hour intervention period EGDT group Dedicated study team (doctor, nurse, coordinator) trained in EGDT delivery Care providers and location of delivery dependent on local resources ED-based, ICU-based and ED/ICU hybrid models

32 EGDT arm Arterial catheter and ScvO 2 -CVC inserted within 1h randomisation SpO 2 93% O 2 & respiratory support CVP 8 (SV) or 12 (MV) mmhg 500 ml i.v. fluid bolus MAP mm Hg Vasoactive agent ScvO2 70% PRBC transfusion (Hct <30%) Dobutamine

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34 Baseline characteristics

35 SpO 2 CVP MAP ScvO 2 (EGDT only) At 6 hours EGDT 76.5 ± 10.8 vs. usual care 75.3 ± 11.4, P = 0.04

36 % patients Intravenous fluids EGDT Usual care P value 0 to 6 hours 1964 ± 1415 ml 1713 ± 1401 ml < ,6 57,8 P < for all ,6 15,4 7,0 2,6 Vasopressor RBC Dobutamine EGDT Usual care

37 EGDT 18.6 % vs. usual care 18.8% (P = 0.90) Absolute risk difference -0.3% (95% CI -4.1% to 3.6%) Relative risk 0.98 (95% CI 0.80 to 1.21)

38 Conclusions Large randomized trial of EGDT for patients with early septic shock presenting to ED in multiple countries and across a variety of healthcare settings Delivery of the resuscitation algorithm associated with a high degree of compliance EGDT associated with increased use of iv. fluids, vasopressors, RBC and dobutamine between 0 and 6 hours compared to usual resuscitation practice EGDT was associated with decreased mortality, time spent in ICU or hospital or duration of organ support

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42 Are we looking at the same patients? Rivers et al. Angus et al. Peake et al. Mouncey et al. Time from ED to randomization (Median& IQR, hr) C ±97* 2.7 ( ) 2.5 ( ) EGDT ±116* 2.8 ( ) 2.5 ( ) Systolic blood pressure (mmhg) C 109± ± ± ±10.2 EGDT 106± ± ± ±11.0 Lactate (mmol/l) C 6.9± ± ± ±3.2 EGDT 7.7± ± ± ±3.5 * Mean ± SD, min

43 So what s left? None of these studies are a repeat of the Rivers study Single vs. multicenter The fidelity of protocols may have diminished Late 1990s vs Tight glucose control, low tidal volumes, SSC guidelines

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45 So what s left? None of these studies are a repeat of the Rivers study Single vs. multicenter The fidelity of protocols may have diminished Late 1990s vs Tight glucose control, low tidal volumes, Patient selection Probably mandate revision of the SSC guidelines but how? Targets for MAP & CVP may still be right though It all depends on control group mortality

46 So what s left? Usual care was usual care when septic shock was recognized These studies do not undermine efforts to promote sepsis awareness, early diagnosis and prompt treatment Not well-powered to explore subgroups Combined individual patient-level meta-analysis

47 Study Events, Events, % ID OR (95% CI) EGDT control Weight Rivers et al. (2001) 0.52 (0.31, 0.86) 38/130 59/ Jones et al. (2010) 1.47 (0.82, 2.60) 34/150 25/ ProCESS Investigators (2014) 1.17 (0.88, 1.55) 92/ / ARISE Investigators (2014) 0.98 (0.76, 1.26) 147/ / ProMISe Investigators (2015) 1.02 (0.80, 1.30) 184/ / Overall (I-squared = 56.7%, p = 0.055) 1.01 (0.88, 1.16) 495/ / Favours EGDT Favours control

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