Early Goal Directed Therapy Fondazione Ospedale Maggiore Last nail in the coffin? Antonio Pesenti MD Fondazione Ospedale Maggiore University of Milano Italy antonio.pesenti@unimi.it Kuwait 2018

RCTs EGDT LAST NAIL IN THE COFFIN

Rivers E et al. N Engl J Med 2001;345:1368-1377.

Rivers E et al. N Engl J Med 2001;345:1368-1377.

2014-2015 challenges to EGDT: PROCESS, ARISE, PROMISE Along 2 years, 3 studies from different regions of the world challenged the EGDT protocol 3 large (>4000 pts enrolled) multicenter international randomized trials comparing EGDT vs. standard of care

Patients assigned to EGDT followed the protocol used by Rivers et al. Placement of a CVC to monitor pressure and Scvo2 and to administer intravenous fluids, vasopressors, dobutamine, or packed red-cell transfusions. Patients in the usual-care group, the bedside providers directed all care, with the study coordinator collecting data but not prompting any actions

NEJM 2014

Intravenous Antibiotics NEJM 2014 Intravenous Fluids EGDT 2.8 L Usual Care 2.3 L Intravenous Antibiotics EGDT 97.5% Usual Care 96.9%

…Although our study had entry criteria similar to those in the original EGDT trial, it is possible that the patients in our study had a reduced risk of death because of low rates of chronic disease and better functional status…

ProMIse

ProMIse

N Engl J Med 2017;376:2223.

N Engl J Med 2017;376:2223. Even though….. measurement of CVP and SatO2cv in all patients with sepsis did not improve outcomes, clinical judgment should always be applied because, in specific circumstances, there may be a role for these measurements. The future of sepsis therapy may yet lie with protocols that permit a more individualized approach .. based on a greater understanding of the complex interplay among host genetics, individual pathophysiological features, and the infective agent.

Caveats / Limitations of ProCESS, ARISE & Promise The overall management of sepsis has changed… In all three studies patients had early antibiotics, > 30ml/kg of intravenous fluid prior to randomization. We need therefore to be very careful about over interpreting the results in areas where this paradgim is not valid.

Same population? EGDT ProCESS ARISE ProMISe LACTATE at incl. mEq/L 7 5 4 SCVO2 % (EGDT group) 49 71 73 70 Mortality % Control/EGDT 50/33 19/21 19/19 29/29

Why did EGDT fail? Head, LW Coopersmith, CM: Advances in Surgery 50 (2016) 221 Changes in septic management in time (Surviving Sepsis Campaign!) Efficacy of individual elements of EGDT CVP MAP SCVO2 ( high vs low) Transfusion ( TRISS)

Study Albios SEPSISPAM TRISS ProCESS ARISE Patients enrolled (N) 1,810 776 998 1,341 1,591 Death at 90 days (%) 42.2 % 43% 44% 32% 18.7% Mech Vent 79.8% 76.5% 69% 14% 15.2% Expected Mortality 41% 60-62% 48-51% 38.1-41.6% 22.9-25.6%

Initial Resuscitation We recommend that in the resuscitation from sepsis-induced hypoperfusion, at least 30ml/kg of intravenous crystalloid fluid be given within the first 3 hours. (Strong recommendation; low quality of evidence) We recommend that following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status. (Best Practice Statement)

Fluid Therapy  We recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock (Strong recommendation, moderate quality of evidence).   We suggest using albumin in addition to crystalloids when patients require substantial amounts of crystalloids (weak recommendation, low quality of evidence).

Caironi et al : NEJM 370:15:1412 Supplement Material

CRT= capillarey refilling time in seconds

NEJM :376;23:2235

The River’s work was useful…. As it provided us a construct on how to understand resuscitation: Start early- (give antibiotics) Correct hypovolaemia Restore perfusion pressure And in some cases a little more may be required..! These concepts are as important today as they ever were.

EGDT