Therapy
Early goal-directed therapy in the treatment of severe sepsis and septic shock.
This review may be edited
Summary
Posted By: Gordon S. Doig
E-Mail: gdoig@med.usyd.edu.au
Posted Date: July 2, 2003
Title: Early goal-directed therapy in the treatment of severe sepsis and septic shock.
Authors: Rivers E, Nguyen B, Havstad S et al.
Reference: N Engl J Med. 2001 Nov 8;345(19):1368-77.
Link: Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract: BACKGROUND: Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.
METHODS: We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups.
RESULTS: Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. 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). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001).
CONCLUSIONS: Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.
 
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
Yes. The authors report the use of 'sealed, opaque randomly assorted envelopes.' This is a very practical way to maintain allocation concealment.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Uncertain. There is controversy surrounding this issue.
The first line of the Results section of the paper states "We evaluated 288 patients; 8.7 percent were excluded or did not consent to participate. The 263 patients enrolled were randomly assigned",
The Wall Street Journal reports: "Dr. Rivers, in an April interview describing how he proceeded, said "all 288 are randomized" -- that is, placed into either the standard-therapy group or the other group -- "and then some are excluded because they're not considered severe septic shock."."
No outcomes or groups are reported for these 25 missing patients. A failure to report outcomes on 8.7% of all randomised patients represents a serious deficiency. These patient's outcomes could significantly influence the results and change the overall conclusions.
2b. Were patients analyzed in the groups to which they were randomized?
Yes. There were no cross-overs.
3. Were patients, health workers, and study personnel blind to treatment?
No. It would be extremely difficult to blind this study during the intervention however the authors do report that clinicians who subsequently treated the patients in the ICU were unaware of the patients' study group assignments.
4. Were the groups similar at the start of the trial?
Yes. The authors report there were no significant differences in baseline balance (see Table 1 on the paper).
5. Aside from the experimental intervention, were the groups treated equally?
The authors do not explicitly report interventions other than those that were part of the resuscitation protocol. There is no reason to suspect that there was a systematic difference in how the patients were treated, however complete reporting of other treatments would address this concern.
What are the Results?
1. How large was the treatment effect?
Early goal directed resuscitation significantly reduced:
  • hospital discharge mortality from 44% to 29% (ARR 15.1%, NNT 6.6, p=0.009).
  • 28 day mortality from 45.8% to 30.7% (ARR 15.1%, NNT 6.6, p=0.01)
  • 60 day mortality from 52.6% to 38.5% (ARR 14.2, NNT 7.0, p=0.03)
  • 2. How precise was the estimate of the treatment effect?
    The 95% CI for the Absolute Risk Reduction for:
  • hospital discharge mortality was 0.04 to 0.27.
  • for 28 day mortality was 0.03 to 0.27.
  • for 60 day mortality was 0.02 to 0.26.
  • Will the Results Help Me In Caring For My Patients?
    1. Can the results be applied to my patient care?
    Yes. It is likely that the patients entered into this trial are representative of patients presenting to most emergency departments. The intervention is well described and could be implemented in most hospitals.
    2. Were all clinically important outcomes considered?
    Yes. Mortality was reported at hospital discharge, 28 days and 60 days.
    3. Are the likely treatment benefits worth the potential harms and costs?
    For the benefit of an absolute mortality reduction of 15% (NNT 6.6), the costs associated with the protocol are likely reasonable.

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