Question 28

Conflicting evidence regarding the value of protocol-based therapy for sepsis with larger multi- centre trials not demonstrating the originally reported benefit.

Results of the ProMISe (UK) trial awaited.

Surviving Sepsis Guidelines still recommend central venous access for CVP/ScvO2 measurement together with MAP and urine output in all patients with severe sepsis. The Guidelines were created before the publication of ARISE and ProCESS.

The optimal target to guide fluid management is unknown. However, it may be reasonable to aim for certain physiological targets when resuscitating patients with severe sepsis, rather than have no therapeutic targets.

OR any reasonable conclusion.

Additional comments:

Candidates were not expected to provide specific details of the trials, such as patient numbers.
(Note: ProMISe trial findings subsequently published in NEJM April 2015: 1260 patients with early septic shock randomised to EGDT or usual care did not show improved outcome in EGDT protocol group)

Discussion

The previous incarnation of this SAQ (Question 16 from the second paper of 2013) focused on deconstructing the original protocol as published by Rivers et al. (2001). The locally available critique has much material on that subject. In 2015, more evidence became available (in fact about 4200 patients worth of EGDT-related trial material was published) and so the model answer expected by the college has also changed. The last time this came up in the exam only 9% of the candidates passed; the encouragingly high pass rate in 2015 suggests that everybody has done the past papers several times over.

The following resources are required for answering this question:

• Rivers et al. (2001)
• ProCESS trial (2013)
• ARISE trial (2014)
• ProMISE trial (2015)
• A meta-analysis of all of the above (2015)
• One LITFL page to rule them all

In summary:

Goals of goal-directed therapy:

• CVP  8-12 mmHg
• MAP 65 – 90 mmHg
• Urine output >0.5 ml/kg/hr
• Mixed venous oxygen saturation >65% / ScvO2 >70%
• Haematocrit >30%

Rationale for early goal-directed therapy

• Poor oxygen delivery to organs (another words, shock) leads to multi-organ system failure.
• Duration of shock correlates with severity of organ dysfunction.
• Severity of organ dysfunction
• Patients with sepsis frequently have shock- they present with a high lactate, deranged oxygen extraction and suboptimal hemodynamic parameters.
• Ergo, early normalisation of oxygen delivery should improve survival in septic shock, by decreasing the incidence of multi-organ system failure.

Trials mentioned by the college:

ProCESS trial (2013): n=1341; multicentre RCT (31 US hospitals)

• 3 arms: protocol-based therapy (full EGDT), protocol-based standard care, and some sort of  "anything goes" non-protocol therapy
• The primary end point was 60-day in-hospital mortality.
• Mean APACHE II score was about 20.8
• Outcome for this were 21.0% mortality (EGDT), 18.2% (standard protocol) and 18.9% (anything goes).
• There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.

ARISE trial (2014): n=1600; multicentre RCT (50 Australian hospitals)

• 2 arms: protocol-based therapy (full EGDT), and "anything goes" non-protocol therapy.
• The primary outcome was all-cause mortality within 90 days.
• Mean APACHE II score was about 15.8
• Rates of death were 18.6% (EGDT) and 18.8% (standard)
• Again, there was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.

 ProMISE trial (2015): n=1260; multicentre RCT (56 UK hospitals)

• 2 arms: protocol-based therapy (full EGDT), and "anything goes" non-protocol therapy.
• The primary outcome was all-cause mortality at 90 days.
• Mean APACHE II score was about 18.0
• Rates of death were  29.5% (EGDT) and 29.2% (standard)

Meta-analysis (2015) - Angus, Barnato, Bell, Bellomo et al...

• The authors of the ProCESS, ProMISE and ARISE trials scraped the databases for abstracts. Of 2395 eligible abstracts, only five RCTs met the inclusion criteria, totalling 4735 patients. Of these, the ProCESS, ProMISE and ARISE trials contributed 4201. The remaining 532 patients came from the Rivers trial and the lesser-known Jones trial (2010) which actually had more patients than Rivers.
• In summary, EGDT was not associated with decreased mortality, but it was associated with increased admission to ICU.
• Did this increase in ICU admissions improve the organ system function of admitted patients? No it did not. The same organ system support requirements were the same, except for the fact that the EGDT group got more vasopressors.

Since the publication of these trials, and since the first paper of 2015 was sat in March, the Surviving Sepsis Guidelines have changed slightly, and they no longer insist on CVP or ScvO₂ targets. These previously mandatory goals have become reduced to suggestions; one may serially assess the patient with a "focused exam", or one may choose to look at CVP, ScvO₂ , bedside TTE, or passive leg raise.