Question 16

College Answer

EGDT definition:

Within 6 hours of presentation to the Emergency Department intensive monitoring of specific circulatory parameters with the aggressive management of these parameters to specified targets:

Parameters

• CVP ³ 8-12 mmHg
• MAP 65 – 90 mmHg

• Urine output ³ 0.5 ml/kg/hr
• Mixed venous oxygen saturation ³ 65% / ScvO2 ³ 70%

• Haematocrit ³ 30%

Interventions

• Reduce work of breathing by early use of mechanical ventilation
• Fluid resuscitation
• Use of vasoactive medication
• Transfusion

Rationale:

The principle of applying EGDT for septic shock is based on the observations that:

• Early treatment for Myocardial Infarction, Acute Ischaemic Stroke and
• Trauma improves patient outcomes.
• Patients presenting to ED with sepsis have measurable O2 deficit
• Evidenced by high lactate and high ScvO2.
• For septic shock the hypothesis is that early optimization of the compromised
• Septic circulation may reduce mortality.

Evidence:

The evidence for the intervention is based on an American, single-centre RCT (Rivers 2001) and a recent Chinese multicenter study supporting EGDT -

Surviving Sepsis Guidelines: Grade 1C (inconsistent results, well done observational studies/control RCTs) recommendation

Limitations of Rivers study include the following:

Study population limited to ED presentations and did not include ward patients Single centre

Non-blinded 
Control group had an above-average mortality rate

Unclear which interventions are most important – whole EGDT protocol or one single component

Target parameters are restrictive

Use of ScvO2 and pressure monitoring has not been tested in the target population Transfusion target to improve DO2 contradicts restrictive transfusion practice and may be associated with increased mortality in the critically ill

Results of ANZ ARISE and related international studies (ProCESS and ProMISE) Awaited

Adverse effects:

Protocols for implementing EGDT usually result in more fluid being administered, more use of vasoactive medication and more use of blood transfusion.

Therefore potential adverse effects relate to:

• Fluid overload
• Arrhythmias
• Adverse effects of blood transfusion

Proscriptive targets may not suit all (eg higher MAP needed for elderly patients, lower MAP and Hct targets for young, fit patients).

Statement of Candidate’s Own Practice:

Summary statement including any reasonable strategy.

Discussion

Also LITFL have an excellent autopsy of this technique. Additonally, Paul Marik recently published an opinion piece in CHEST which is an excellent summary of modern approaches to the acute management of sepsis. Lastly, the ProCESS and ARISE studies have now added damning empirical evidence to the theoretical objections.

Upon my initial inspection, the college answer seemed extremely detailed, and seemed unlikely to be reproduced by the time-starved exam candidate.

A succinct version would be better... but, in an attempt to create one, my version also became hideously bloated. There is simply no way to approach this answer without a vast amount of detail.

Such was the extent of this bloat, that the original answer to this question has mutated into a whole chapter on the merits and demerits of early goal-directed therapy.

An then was re-summarised again.

Thus:

• Introduction / definition:
  • Goals of early goal-directed therapy:
    • CVP  8-12 mmHg
    • MAP 65 – 90 mmHg
    • Urine output >0.5 ml/kg/hr
    • Mixed venous oxygen saturation >65%,
      • or ScvO2 >70%
    • Haematocrit >30%
• Rationale:
  • Septic patients present with shock and evidence of poor tissue oxygen delivery
  • Poor tissue oxygwen delivery results in organ system failure
  • Duration and magnitude of poor oxygen delivery correlates with severity of organ injury
  • Organ system failure correlates with increased mortality
  • Thus, early correction of the tissue oxygen delivery deficit should improve mortality by decreasing the incidence and severity of organ system failure.
• Criticism of early goal-directed therapy, and specifically of the trial rationale and methodology:
  • Single centre study
  • Non-blinded
  • Only enrolled ED patients
  • Control group had an above-average mortality rate
  • This mortality rate - a reduction from 46.5% to 30.5% - was still higher than the average rate in Australian ICUs (which do not practice early goal-directed therapy)
  • The whole protocol was the test intervention, and it is unclear which particular goals should be prioritised.
  • The use of ScvO₂ is controversial - it is not validated as an endpoint of management in sepsis, and it may not be a good surrogate for mixed venous saturation
  • Lactate monitoring is non-inferior to ScvO₂
  • The only independently validated time-critical intervention is early antibiotic administration
  • Transfusion target to improve DO₂ contradicts restrictive transfusion practice and may be associated with increased mortality in the critically ill
  • Hemodynamic end-points used in this trial do not address sepsis-induced microvascular hemodynamic changes
• Support for early goal-directed therapy:
  • A multi-centre study from 2010 duplicated Rivers' results (15.7% improvement in mortality)
  • EGDT has been incorporated into the Surviving Sepsis guidelines
• Contradictory studies in the literature:
  • The 2014 ProCESS trial used the same goals in a multi-centre setting, and found no mortality difference.
  • The Australian ARISE trial (2014) confirmed that EGDT has no significant mortality benefit over the (already awesome) local routine practice.
• Advantages of using this approach in one's own practice
  • The hemodynamic goals are laudable - at least MAP is a physiological parameter worth pursuing.
  • If one is comfortable with the methodology of the trial, the improvement in survival (16%) is substantial
  • Individual use of the EGDT strategy is validated by its incorporation into the Surviving Sepsis guidelines
• Disadvantages of using this approach in one's own practice
  • You end up using more fluids and blood products
  • You end up resorting to more vasopressors and inotropes.
  • The use of EGDT was trialled in the ED population only.
  • There does not appear to be any benefit in the ICU setting (ProCESS, ARISE).
• Summary: the key points for one's practice
  • Early aggressive resuscitation of shock is important, no matter the cause
  • Though individual components of EGDT have been criticised, MAP and perhaps oter hemodynamic goals can be incorporated into practice which also involves other parameters (such as lactate).

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.

Jones, Alan E., et al. "The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis." Critical care medicine 36.10 (2008): 2734.

Kumar, Anand, et al. "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*." Critical care medicine 34.6 (2006): 1589-1596.

Early Goal-Directed Therapy Collaborative Group of Zhejiang Province. "The effect of early goal-directed therapy on treatment of critical patients with severe sepsis/septic shock: A multi-center, prospective, randomized, controlled study." Zhongguo wei zhong bing ji jiu yi xue= Chinese critical care medicine= Zhongguo weizhongbing jijiuyixue 22.6 (2010): 331.

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.

Power, GSarah, et al. "The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan." Critical Care and Resuscitation 15.4 (2013): 311.

Delaney, Anthony P., et al. "The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan." Critical Care and Resuscitation 15.3 (2013): 162.

Marik, Paul E. "Early Management of Severe Sepsis: Concepts and Controversies." CHEST Journal 145.6 (2014): 1407-1418.

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.