ARISE in the PROMISE of the PROCESS

Squeeze your face in, like you’ve sucked a lemon, then say the following ‘Early Goal Directed Therapy doesn’t work’  We’ve had three massive, well run RCTs published in the last 6 months which compared “usual care” to “EGDT” for severe sepsis.  They all show no difference between EGDT and “Usual Care”.

Headline figures

ARISE PROCESS PROMISE RIVERS 2001
n 1600

796 EGDT

804 “Usual”

1341

439 EGDT

446 Protocol Standard

456 Usual

1260

630 EGDT

630 Usual

263

130 EGDT

133 Usual

Outcome

Mortality

147/792 18.6% EGDT

150/796 18.8% Usual

 

[90 day mortality]

129/405  31.9% EGDT

128/415 30.8% Protocol

139/412 33.7 % Usual

[90 day mortality]

184/623 29.5% EGDT

181/620 29.2% Usual

 

[90 day mortality]

50/130 44.3%EGDT

70/133 56.9% Usual

 

[60 day mortality]

 

All of the recent MCT RCT’s showed no significant difference between EGDT (the River’s protocol) and “Usual” care.

Pooling Results EGDT Vs “Usual”

n 4201

1865 EGDT

1890 Usual

Outcome Mortality 90 days 460/1865 24.66% EGDT

470/1890 24.86% Usual

 

So if there is no difference between EGDT and ‘normal’ care, can we just ditch the sepsis six, buffalo, or whatever acronym reminder is used in your department to manage sepsis early?  Some trusts are creating sepsis nurses, or sepsis champions who go around helping fight sepsis on the wards.  Is all this expenditure, time, and effort (for god sakes think of the sheer number of blood cultures alone).  Not worth it?

Well you could collapse down into a nihilistic funk if you want, but if you take a slightly longer view things are looking up for sepsis mortality, and this is probably because “Usual Care” now in 2015 is different to “Usual Care” in 2001.

I found a prospective meta-analysis looking at sepsis mortality between 1958 and 1997 (n= 10 694).  This gives a headline overall mortality of 49.7% but there was a trend to improving mortality.  So if we take 49% as a historical mortality, something has happened to drop mortality between 1997 and 2015 by almost half.

Mortality from Sepsis pre 1997 49.7%, mortality from Sepsis in 2015 25%.

In fact the news has got even better (at least in Australasia), a retrospective observational study from 2000 to 2012 in 171 ICUs in Australasia showed an absolute mortality decrease from 35% to 18.4%.  This at least agrees with ARISE’s slightly better numbers than PROCESS or PROMISE.  It might be interesting to find out why outcomes in Australasia are better than in the US and UK.

There are massive caveats to this, the 3 big RCTs excluded lots of patients for logistical and clinical issues.  Do we DNAR more people now than we used to?  A lot patients got excluded from all 3 trials because the treating physician felt ‘aggressive care was unsuitable’.  That’s going to skew the results slightly.

What do we do differently now?  What’s making the difference?  Antibiotics haven’t changed, if anything our ability to treat systemic bacterial infections has got a little less impressive given the rise of resistant organisms.  The widespread implementation of early warning scores, awareness raising, and early fluid resuscitation and early antibiotics are probably the biggest difference. Certainly the main component of the EGDT that’s been adopted (at least where I have worked) is the ‘E’.  In terms of critical care the same tools are used, just as they always were, the actual targets or ‘goals’ might be different, but intensivitists are still aiming to perfuse tissues and organs, and it’s entirely probable that they are keeping similar numbers in their heads as Emanuel Rivers did 15 years ago.  What we may have here is the biggest contamination confounding variable ever.

Maybe we can tentatively conclude that sepsis treatment has improved in the US, UK and Australasia.  The surviving sepsis campaign must surely take the lion’s share of the credit here, at least for giving hospitals implementation and treatment strategies, as well as raising the awareness of systemic infection.

There is much we still don’t understand, exactly how much fluid to give remains elusive, and the pathogenesis of septic shock on biochemical level is still poorly understood.  The FEAST trial suggested that we still don’t understand fully the effects of giving simple intravenous fluid boluses to people in shock.

In conclusion ARISE, PROMISE and PROCESS probably don’t show a benefit because EGDT is now very similar to “usual care”.

References

  • Rivers, Emanuel, et al. “Early goal-directed therapy in the treatment of severe sepsis and septic shock.”New England Journal of Medicine 19 (2001): 1368-1377.
  • Peake, Sandra L., et al. “Goal-directed resuscitation for patients with early septic shock.”The New England journal of medicine 16 (2014): 1496.
  •   Trial of Early, Goal-Directed Resuscitation for Septic Shock. (ProMISe Trial). N Engl J Med 2015;epublished March 17th
  • Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time? Crit Care Med 26:2078–2086
  • Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis. N Engl J Med 2015;epublished March 17th
  • Yealy, Donald M., et al. “A randomized trial of protocol-based care for early septic shock.”The New England journal of medicine 18 (2014): 1683-1693.

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