Critically evaluate the role of Early Goal Directed Therapy (EGDT) in septic patients.

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College Answer

Definition of EGDT –This is a protocolised approach to sepsis that refers to sequentially targeting a series of haemodynamic targets with the use of fluids, vasopressors/dilators, inotropes and blood within the first six hours of presentation. This follows early appropriate antibiotic therapy and source control where appropriate.

The 3 major trials:

Rivers (NEJM 2001) – single centre, randomised trial of 263 patients with severe sepsis or septic shock compared a protocol – including targeting ScVO2 > 70%, CVP 8-12 mmHg, MAP > 65 mmHg and urine output > 0.5mL/kg/hour – to conventional therapy that targeted CVP, MAP and urine output only. Both groups initiated therapy (including antibiotics) within 6 hours of presentation. Mortality was lower in the group where all 4 targets were used (31% Vs 47%), suggesting that targeting SCVo2, CVP, MAP and urine output was a superior strategy.

Critique – There was an emphasis on use of blood transfusion (haematocrit>30) and dobutamine in order to reach the ScVO2 target, which is controversial. Results may not be generalisable due to inclusion of significant number of sick patients/late presentations with liver and heart disease that may have potentially biased the outcome favourably (resulting in very high mortality in control group as well as treatment group – higher than that seen in other settings). “Hawthorne effect” in intervention group patients who were managed by a senior, experienced clinician.

ProCESS (NEJM 2014) – multicentre, randomised trial of 1341 patients (U.S. based) with septic shock reported no mortality benefit with protocol-based therapies. The study had 3 arms – a protocol-based therapy that used all of the EGDT targets (ScvO2, CVP, MAP, urine output, central access required), a protocol-based standard therapy arm (MAP, urine output, central access not required) and a ‘’usual care’’ (no protocol) arm.

ARISE (NEJM 2014) – multicentre, randomised trial of 1600 patients conducted in Australia and New Zealand. The study had 2 arms – the EGDT group and the usual-care group. Patients in the EGDT group received a larger mean volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group and were more likely to receive vasopressor infusions, red-cell transfusions, and dobutamine. There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay between the 2 groups.

Critique for ProCESS and ARISE – There are a number of proposed explanations for the negative results from ProCESS and ARISE. Antibiotics were administered early (70 to 100% before randomisation) in all randomisation groups. The trials were conducted in academic centres during an era of education and training regarding sepsis management. Central line placement was common in patients receiving protocol-based and usual care (>50%).

ProMISe due out soon

Conclusion

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:

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.

References

References

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Peake, Sandra L., et al. "Goal-directed resuscitation for patients with early septic shock." The New England journal of medicine 371.16 (2014): 1496.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Mouncey, Paul R., et al. "Trial of early, goal-directed resuscitation for septic shock." New England Journal of Medicine 372.14 (2015): 1301-1311.

Angus, D. C., et al. "A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators." Intensive care medicine (2015): 1-12.

Jones, Alan E., et al. "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial." Jama 303.8 (2010): 739-746.