Part of the ProCESS

A BLOG BY DR olusegun olusanya (Follow @iceman_ex) FOR OXICM

The following article contains minor spoilers for the Star Wars franchise

EPISODE IV: A NEW HOPE

A long time ago, in a galaxy far, far away

The late 1990s seem like a dark time for critically ill patients with sepsis. 28 day mortality approached 50%, with demonstrable delays in time to receive critical interventions such as antibiotics and fluids. Despite increased awareness, new definitions to help, and cool devices and ideas to maximise- and even supramaximise- oxygen delivery, mortality had not changed from severe sepsis and septic shock in nearly 40 years.

Enter Emmanuel Rivers, MD and Early Goal Directed Therapy.

You refer to the prophecy of the one who will bring balance to the force.
You believe it is this…

His team, from Detroit, Michigan, postulated that treating these severely ill patients early and aggressively, aiming to maximize certain resuscitation end points (CVP, MAP, urine output, central venous oxygen saturation, and haematocrit) within 6 hours with continuous monitoring and liberal use of fluids, blood, and vasopressors to achieve the targets.

The results were astounding- a reduction in in-hospital mortality from 46.5% to 30%. (15% ARR reduction, NNT 6). Published in the New England Journal of Medicine in 2001, this landmark paper transformed sepsis care around the world. So much so, that the 2008 Surviving Sepsis guidelines used the Detroit protocol essentially verbatim.

However, dark times were to come. Critics pointed out the rapid adoption of a single-centre unblended RCT with significants risk of bias. Undisclosed conflicts of interest were discovered. And, despite multiple attempts, no one was able to replicate the impressive results of Rivers’ trial (except for this one study from China).

Begun, the clone wars now has

The ProCESS study is the latest published attempt to verify the effects of EGDT. Conducted across 31 hospitals in the USA between 2007 and 2013, 1351 patients were enrolled in a 3 arm trial comparing EGDT as per Rivers’ protocol, a “protocolised” arm using less aggressive targets, and a “usual care arm”.

Mortality rates at 90 days were 21% EGDT, 18% “protocolised” and 19% “usual care”. The difference was not found to be statistically significant.

YOU WERE THE CHOSEN ONE!

Looking in closer at the trial, it’s difficult to see any major flaws. There was tight adherence to the protocols in all groups. The patients were similar to the ones in Detroit (APACHE scores etc).

It could be argued that there wasn’t enough difference between the groups. Each of them were resuscitated to some targets within 6 hours and had early antibiotics (indeed- fluid balance was quite similar between groups at 6 hours and 72 hours, except blood and inotropes which were higher in the Rivers group). It could also be argued that there was a “Hawthorne effect” of being in the trial, and that it may be underpowered to detect small mortality benefits.

The trial also shows some amazing stuff- the mortality from severe sepsis has been reduced in these American units by nearly 25% in the last 13 years. They’re doing similarly well down under, too.

No, I am your father…search your feelings, you know this to be true…
NOOOOOOOOO!!

It would seem that despite the controversy, EGDT ended up improving sepsis care throughout the USA by promoting early recognition and aggressive treatment. Dr Rivers did bring balance to the Force after all- perhaps not the way he initially intended.

There is still good in him…I can feel it.

So what does this mean for us ICM trainees in the UK? Based on fairly recent data, our severe sepsis mortality is hovering around 30% (as is most of Europe)… it would seem that there is room for improvement.

Use the Force, Luke…

I see a number of things we can do:

1.       Help to answer the question locally. The UK Protocolised management in Sepsis (ProMISE) trial is currently recruiting, and is our own version of ProCESS. Help recruit and spread the word! (If you’re down under, the ARISE study is your local equivalent)
2.       Improve local sepsis care. Give early antibiotics and fluids (use the sepsis six if you’re not already). Help out with audit and research- ask your local ED and ICU consultants how you can help.
3.       Join the larger conversation. Read the paper, the editorial, and the excellent online commentaries (Like this one http://academiclifeinem.com/process-study-identify-sepsis-early-treat-aggressively/) . Discuss it at your local journal club. Get online and blog about it. Join Twitter and Google + and continue debating how we can further improve sepsis care. Listen to podcasts- Scott Weingart of emcrit.org has interviewed Derek Angus  (one of the key players in the study) -listen to it here http://emcrit.org/podcasts/process-trial/

Should we change practice based on this paper? I think that’s more for your local teams to decide. It would certainly seem that oximetric CVCs and optimising haematocrit doesn’t offer much over simpler targets (lactate clearance and MAP).

I suspect that many teams would like to see the results of ProMISE before making any big decisions. Interestingly, the plan is to combine the results of ProCESS, ARISE and ProMISE into a “supertrial” and do lots of clever analysis. The saga of EGDT is far from over…

You’re all clear kid! Now let’s blow this thing and go home!

REFERENCES

1.       Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med 1998 Dec; 26(12): 2078-86  (http://www.ncbi.nlm.nih.gov/pubmed/9875924 )
2.       Rivers E, Nguyen B, et al. Early Goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001 Nov 8; 345(19): 1386-77  (http://www.ncbi.nlm.nih.gov/pubmed/11794169)
3.       Dellinger RP et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008 Jan; 36(1): 296-327 (http://www.ncbi.nlm.nih.gov/pubmed/18158437 )
4.       Early Goal-Directed Therapy Collaborative Group of Zheijang Province. The effect of early goal directed therapy on treatment of critical patients with severe sepsis/septic shock: A multi-center prospective randomized control study. Zhonggue Wei Zhong Bing Ji Jiu Yi Xue 2010 Jun; 22(6): 331-4  (http://www.ncbi.nlm.nih.gov/pubmed/20594464 )- article in Chinese
5.       The ProCESS investigators. A randomised trial of protocol-based care for Early Septic Shock. NEJM 2014 Mar 18. (Epub ahead of print) (http://www.ncbi.nlm.nih.gov/pubmed/24635773 )
6.       Kaukonen KM et al. Mortality related to severe sepsis and Septic Shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014 March 18 (online first). (https://jama.jamanetwork.com/article.aspx?articleid=1850096 )

USEFUL TWITTER LINKS

@theARISEstudy (twitter feed of Anthony Delaney, key investigator. He’s also a fountain of EGDT knowledge and will answer lots of questions related to ProCESS, ProMISE and ARISE!)

FURTHER LISTENING

Great podcast from 2012 by Anthony Holley on goal-directed therapy here http://intensivecarenetwork.com/index.php/icn-activities/icn-podcasts/247-goal-directed-therapy-by-anthony-holley-with-presentation

Segun is an anaesthetic and ICU registrar in the Oxford deanery, Coeditor of JICScast, prolific twitterer and firm believer in / contributor to #FOAMed