ProMISe

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Mouncey PR, et al. "Trial of early, goal-directed resuscitation for septic shock". The New England Journal of Medicine. 2015. 372(14):1301-1311.
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Clinical Question

In patients with severe sepsis and septic shock, does early goal-directed therapy reduce mortality compared to standard therapy in a multicenter trial?

Bottom Line

In this multicenter trial of patients with severe sepsis and septic shock, EGDT did not improve mortality at 90 days compared to standard therapy including IV fluids and vasopressors.

Major Points

The Rivers Trial (2001) demonstrated a 16% absolute mortality reduction in severe sepsis and septic shock with the implementation of a specific goal-oriented resuscitation protocol which subsequently became known as early goal-directed therapy (EGDT). At its most basic, EGDT dictates a series of CVP, MAP and ScvO2 thresholds to target with the use of fluid boluses, vasopressors and inotropes, and transfusions. As a result of the survival benefit seen in the Rivers study, EGDT quickly became implemented into the Surviving Sepsis Guidelines and thus became standard of care in the treatment of sepsis. Given the study's limited sample size (N=263) and single-center design, physicians and investigators called into question the reproducibility of the findings. Thus, three concurrent randomized trials were undertaken to verify the results of the Rivers trial and confirm the benefits of EGDT in a broader patient population. Two of these trials, ProCESS in the United States, and ARISE in Australia failed to reproduce the findings of the Rivers Trial, showing no benefit to EGDT over the standard of care. The major criticism of these trials was a lower-than-expected baseline mortality rate of ~20% at 60 to 90 days which limited power to detect a benefit of EGDT in these patients. Investigators called for additional randomized studies on the basis of these and other concerns.

The UK-based Protocolised Management in Sepsis (ProMISe) study randomized 1,260 patients with severe sepsis or septic shock to EGDT or standard care. With a primary endpoint of 90-day overall mortality, ProMISe demonstrated no significant difference between treatment groups, even though EGDT patients received more vasopressors, dobutamine, and blood transfusions. A cost-effectiveness analysis showed a trend toward higher cost with EGDT primarily attributed to more aggressive therapy and increased length of ICU stay with no improvement in quality of life. As seen in PROCESS and ARISE, the observed mortality rate of 29% in the control arm was slightly lower than expected, nevertheless given these findings a clinically meaningful benefit of EGDT in this population is deemed highly unlikely.

Taken together, the results of these three trials strongly suggest that stringent adherence to EGDT is likely not associated with improved outcomes despite more intensive therapy. In particular, it does not appear useful to aggressively target a ScvO2 >70% or CVP 8-12 mmHg in the early resuscitation period. The contrast between these three studies and the 2001 Rivers Trial are likely attributable to limitations of the Rivers Trial such as small sample size and single-center design, as well as improvements over time in standard sepsis care such as early recognition and prompt use of antimicrobial agents, as evidenced by significantly lower overall mortality in the more contemporary studies.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[1]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence)
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=1,260 patients with severe sepsis or septic shock
    • EGDT (n=630)
    • Standard (n=630)
  • Setting: 56 sites in the United Kingdom
  • Enrollment: 2011-2014
  • Follow-up: 90 days for primary endpoint, 1 year of follow-up thereafter
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality at 90 days

Population

Inclusion Criteria

  • Age ≥18 years
  • Within 6 hours of presentation to ED met all of the following:
    • Known or presumed infection
    • Two or more SIRS criteria
    • Either of:
      • Refractory hypotension (SBP <90 mmHg or MAP <65 mmHg despite at least 1 liter of IV fluids)
      • Lactate >4 mmol/L

Exclusion Criteria

  • Known pregnancy
  • Primary diagnosis of stroke, coronary syndrome, pulmonary edema, asthma, arrhythmia, seizure, drug overdose, injury from burn or trauma
  • GI bleed with hemodynamic instability
  • Requirement for immediate surgery
  • History of AIDS
  • DNR status, advanced directives restricting resuscitation protocol, or deemed that aggressive resuscitation inappropriate
  • Unable to commence resuscitation protocol within one hour or complete six hour protocol
  • Contraindications to central venous catheterization or blood transfusion
  • Transfer from another in-hospital setting

Baseline Characteristics

From the EGDT arm.

  • Demographics: Mean age 66, male 67%
  • Shock parameters: Refractory hypotension 54%, elevated lactate 65%, mean lactate 7 mmol/L, supplemental O2 74%, ICU need 67%, APACHE II score 18.7, MEDS score 8.0, SOFA score 4.2
  • Resuscitation: Median IVF administered prior to randomization 1950cc
  • Median time to randomization 2.5 h
  • Severe condition in PMH 29.1%
  • Sites of infection: lungs 37%, abdomen 6%, blood 16%, CNS 2%, soft tissue 6%, urinary 17%, other 3%, unknown 12%

Interventions

  • 1:1 randomization to EGDT or standard therapy
    • EGDT targets
      • Prompt placement of central access with ScvO2 monitoring
      • CVP 8-12 mmHg, achieved with fluid boluses
      • MAP >65 mmHg, achieved with vasopressors
      • ScvO2 >70%, achieved with packed RBC transfusions and dobutamine
    • Standard therapy
      • Monitoring, investigations, and treatment as determined by treating clinicians
  • Resuscitation protocol followed for 6 hours, after which all treatments at discretion of treating clinicians
  • Following intervention period, data collected prospectively for EGDT group and retrospectively for usual care group
  • Followed for 1 year

Outcomes

Comparisons are EGDT versus standard therapy.

Primary Outcomes

All-cause mortality at 90 days
29.5% vs. 29.2% (unadjusted HR 1.01; 95% CI 0.85-1.20; P=0.90 / adjusted HR 0.95; 95% CI 0.74-1.24; P=0.73)

Secondary Outcomes

SOFA score (6 hr)
6.4 vs. 5.6 (Incremental Effect +0.8; 95% CI 0.5-1.1; P<0.001)
SOFA score (72 hr)
4.0 vs. 3.7 (Incremental Effect +0.4; 95% CI 0-0.8; P=0.056)
Receipt of advanced cardiovascular support
37.0% vs. 30.9% (HR 1.19; 95% CI 1.02-1.40; P=0.026)
Median ICU length of stay (days)
2.6 vs. 2.2 (P=0.005)
Health-related quality of life on EQ-5D at 90 days
0.609 vs. 0.613 (Incremental Effect -0.004; 95% CI -0.051-0.044; P=0.88)
Costs up to 90 days
$17,647 vs. $16,239 (Incremental Effect +1406; 95% CI -1032-3845; P=0.26)

Incremental net benefit up to 90 days

Incremental Effect -1422; 95% CI -3866-1023; P=0.25)

Subgroup Analysis

There was no significant difference regarding the effect of EGDT according to prespecified subgroups as defined by the degree of protocolized care used in the usual-care group, age, MEDS score, SOFA score, or time from presentation at the emergency department to randomization.

Adverse Events

Serious adverse events
4.8% vs. 4.2% (HR 1.16; 95% CI 0.69-1.93; P=0.58)

Criticisms

  • Blinding to study group assignment was not performed, potentially introducing bias in outcome evaluation.
  • Mortality rate in the usual care group of 29% lower than than anticipated (40%), limiting power to detect a large difference in survival between EGDT and standard therapy. A benefit from EGDT in patients who are more critically ill cannot be ruled out.

Funding

Study supported by a grant from the UK National Institute for Health Research Technology Assessment Programme.

Further Reading

  1. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.