Early goal directed therapy: unbundling the resuscitation bundle

Recall that a few days ago I gave you a heads up that results of three new sepsis trials evaluating EGDT were about to be released. The first of those, the ProCESS trial, was just published, on line ahead of print in NEJM. You can access the full text here. Let's get straight to the findings:

We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.

The social media are full of comments like “EGDT is dead” and “EGDT is of no benefit.” Before reaching such a simplistic conclusion consider the following:

The original Rivers study in 2001 showed---

In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P=0.009).

That means a 35% relative risk mortality reduction, 16% absolute risk reduction and NNT of 6 attributable to EGDT.

The mortality was much lower in all three groups in the ProCESS trial, on the order of 18-20%.

That reflects an overall trend of reduced mortality in severe sepsis as illustrated by this recent paper:

DESIGN, SETTING, AND PARTICIPANTS 

Retrospective, observational study from 2000 to 2012 including 101 064 patients with severe sepsis from 171 ICUs with various patient case mix in Australia and New Zealand.

MAIN OUTCOMES AND MEASURES 

Hospital outcome (mortality and discharge to home, to other hospital, or to rehabilitation).

RESULTS 

Absolute mortality in severe sepsis decreased from 35.0% (95% CI, 33.2%-36.8%; 949/2708) to 18.4% (95% CI, 17.8%-19.0%; 2300/12 512; P less than .001), representing an overall decrease of 16.7% (95% CI, 14.8%-18.6%), an annual rate of absolute decrease of 1.3%, and a relative risk reduction of 47.5% (95% CI, 44.1%-50.8%). After adjusted analysis mortality decreased throughout the study period with an odds ratio (OR) of 0.49 (95% CI, 0.46-0.52) in 2012, using the year 2000 as the reference (P less than .001).

Although differences in the use of various resuscitation modalities reached statistical significance among the treatment groups in ProCESS, these differences were not large with the exception of transfusion and dobutamine administration, which were much more frequent in the EGDT group.

Patients in the protocolized non-EGDT group had to undergo a clinical hemodynamic assessment at least once an hour.

What does this all mean?

“Usual care” for sepsis has, over the past decade, incorporated evidence based process improvements, including the principles of EGDT. This is attributable in large part to the Surviving SepsisCampaign, which was once criticized as a marketing campaign disguised as evidencebased medicine.

“Usual care” has now improved to the point where system improvements in the form of bundles may no longer be important. This comment form one of the other blogs says it well:

Lastly, we need to be cautious about contamination here. The principles of EGDT are well known and widely applied even if they are not part of a strict protocol. The differences between a strict regime and what has now become common knowledge and practice since 2001 are unlikely to be as dramatic as they were back in 2001. We must ask ourselves whether this is a failure of a protocol to be different or rather the success of it’s dissemination to a wider clinical practice.

The real questions addressed by this study concerned which specific components of the resuscitation bundle (EGDT) need to be preserved and which can be dispensed with. It appears now that dobutamine and aggressive transfusion will take a back seat.

That leaves us with the question of the central line. From the ProCESS trial we can conclude that clinical volume assessment is an acceptable alternative to CVP monitoring in many patients. Central venous oxygen saturation is not essential (lactate measurements and clinical parameters are reasonable surrogates).

What about the need for a central line (or IO access) for administration of pressors? Is the use of norepinephrine via a peripheral IV contraindicated? According to this post and literaturereview at the EM Crit blog that may be an urban legend, but you can read the post and go to the primary sources and decide for yourself.