Paul R. Mouncey, M.Sc., Tiffany M. Osborn, M.D., G. Sarah
Power, M.Sc., David A. Harrison, Ph.D., M. Zia Sadique, Ph.D., Richard D.
Grieve, Ph.D., Rahi Jahan, B.A., Sheila E. Harvey, Ph.D., Derek Bell, M.D.,
Julian F. Bion, M.D., Timothy J. Coats, M.D., Mervyn Singer, M.D., J. Duncan
Young, D.M., and Kathryn M. Rowan, Ph.D. for the ProMISe Trial Investigators
The New England Journal of Medicine
March 17, 2015
BACKGROUND
The incidence of severe sepsis and septic shock in adults is
estimated to range from 56 to 91 per 100,000 population per year.1 Affected
patients have high rates of death, complications, and resource utilization. 2-5
Since 2002, the Surviving Sepsis Campaign (SSC) has promoted
best practice, including early recognition, source control, appropriate and
timely antibiotic administration, and resuscitation with intravenous fluids and
vasoactive drugs.6-8 Resuscitation guidance is largely based on a 2001
single-center, proof-of-concept study by Rivers et al., which indicated that
protocolized delivery of 6 hours of early, goal-directed therapy (EGDT) to
patients presenting to the emergency department with early septic shock reduced
hospital mortality and hospital stay.9 Such therapy aims to optimize tissue
oxygen transport with the use of continuous monitoring of prespecified
physiological targets — central venous pressure, mean arterial pressure, and
central venous oxygen saturation (ScvO2) — to guide delivery of intravenous
fluids, vasoactive drugs, and red-cell transfusions.
However, despite the SSC recommendations, the adoption of
EGDT has been limited, with concern about the external validity of results from
a single center, the complexity of delivery, the potential risks of the
components, and resources required for implementation.10,11
To address these concerns, multicenter trials of EGDT were
conducted in the United States (Protocolized Care for Early Septic Shock
[ProCESS] trial),12 Australasia (Australasian Resuscitation in Sepsis
Evaluation [ARISE] trial),13 and England (Protocolised Management in Sepsis
[ProMISe] trial). In all three trials, harmonized methods14 were used to permit
subsequent meta-analysis of data from individual patients.15 The two published
studies12,13 reported no benefit for EGDT. However, both reported
lower-than-anticipated mortality, with a 60-day in-hospital mortality of 18.9%
(as compared with an anticipated rate of 30 to 46%) in the ProCESS trial and
90-day mortality of 18.8% (as compared with an anticipated rate of 38%) in the
ARISE trial. Consequently, neither trial could rule out the potential for a 20%
relative reduction in 90-day mortality for EGDT, as compared with usual care,
with a relative risk of 0.94 (95% confidence interval [CI], 0.77 to 1.15) in
the ProCESS trial and a relative risk of 0.98 (95% CI, 0.80 to 1.21) in the
ARISE trial. We based sample-size calculations for the ProMISe study on a
relative risk reduction of 20%.
The ProMISe study, which was conducted in a setting in which
the reported mortality for septic shock is high and was designed with an
integrated economic evaluation, tested the hypothesis that the 6-hour EGDT
resuscitation protocol is superior, in terms of clinical and cost-effectiveness
measures, to usual care in patients presenting with early septic shock to
National Health Service (NHS) emergency departments in England.
METHODS
Study Design and Oversight
Our study was a pragmatic, open, multicenter,
parallel-group, randomized, controlled trial. The North West London Research
Ethics Committee approved the study protocol, which is available with the full
text of this article at NEJM.org. The United Kingdom National Institute for
Health Research (NIHR) funded the study and convened a trial steering committee
and independent data monitoring and ethics committee. The Clinical Trials Unit
at the United Kingdom Intensive Care National Audit and Research Centre
(ICNARC) managed the study (for details, see the Supplementary Appendix,
available at NEJM.org). Edwards Lifesciences loaned monitors and provided training
and technical support but had no other role in the study.
Sites and Patients
The study was conducted in English NHS hospitals that did
not routinely use EGDT that included continuous ScvO2 monitoring. Adults (≥18
years of age) were eligible if within 6 hours after presentation to the
emergency department they had a known or presumed infection, two or more
criteria of the systemic inflammatory response syndrome,16 and either
refractory hypotension (systolic blood pressure, <90 mm Hg; or mean arterial
pressure, <65 mm Hg, despite resuscitation with at least 1 liter of
intravenous fluids within 60 minutes) or hyperlactatemia (blood lactate level,
≥4 mmol per liter) and did not meet any exclusion criteria (see the Methods
section in the Supplementary Appendix).
Randomization had to be completed within 2 hours after the
patient met the inclusion criteria. All patients provided written informed
consent, or consent was granted through an agreement with a personal or
professional consultee or independent clinician.17 Patients were assigned in a
1:1 ratio by means of 24-hour telephone randomization to receive either EGDT or
usual care. Study-group assignment was performed by means of randomized
permuted blocks, with variable block lengths of 4, 6, and 8, and stratified
according to site. In all study patients, antimicrobial drugs were initiated
before randomization.
Study Interventions
After randomization, the usual-care group continued to
receive monitoring, investigations, and treatment as determined by the treating
clinicians, whereas the EGDT group started the resuscitation protocol (Fig. S1
in the Supplementary Appendix). For the latter, during the first hour, which
was defined as the next whole hour (e.g., if randomization was performed at
9:24, then by 11 o'clock), a central venous catheter capable of continuous
ScvO2 monitoring was placed. The resuscitation protocol was followed for 6
hours (intervention period) with personnel involved and treatment location
decided according to the site. At least one trained staff member was available
throughout the intervention period. Key staff members were trained before the
initiation of recruitment at each site. All other treatment, during the
intervention period and after, was at the discretion of the treating clinicians.
Blinding to study-group assignment was not possible. During the intervention
period, data were collected prospectively for the EGDT group and
retrospectively for the usual-care group to avoid the influence of data
collection on treatment delivery.
Outcome Measures
The primary clinical outcome was all-cause mortality at 90
days. Secondary outcomes were the score on the Sequential Organ Failure
Assessment (SOFA)18 at 6 hours and 72 hours; receipt of advanced
cardiovascular, advanced respiratory, or renal support and the number of days
in the first 28 days after randomization that were free from such support19;
length of stay in the emergency department, intensive care unit (ICU), and
hospital; duration of survival; all-cause mortality at 28 days, at hospital discharge,
and at 1 year; and health-related quality of life (as measured on the European
Quality of Life–5 Dimensions [EQ-5D] five-level questionnaire), resource use,
and costs at 90 days and 1 year. Adverse events were monitored up to 30 days.
All definitions are provided in the Supplementary Appendix.
Statistical Analysis
Using the ICNARC Case Mix Program Database,20 we estimated
that 90-day mortality would be 40% in the usual-care group. On the basis of
this estimation, we calculated that an enrollment of 1260 patients would have a
power of 80% to detect a relative reduction of 20% in risk (absolute risk
reduction, 8 percentage points) in the EGDT group, allowing for a loss to
follow-up or withdrawal of 6%. 21
All analyses were performed according to the intention-to-treat
principle and were prespecified in the statistical analysis plan.22 A P value
of less than 0.05 was considered to indicate statistical significance. All
tests were two-sided with no adjustment for multiple comparisons. Continuous
variables are reported as means and standard deviations or medians and
interquartile ranges. Categorical variables are reported as proportions.
We used Fisher's exact test to compare between-group
differences in the primary outcome. Relative and absolute reductions in risk
are reported with 95% confidence intervals without adjustment. Secondary
analyses of the primary outcome included odds ratio with adjustment for
Mortality in Emergency Department Sepsis (MEDS) score components, sensitivity
analyses for missing data, learning-curve analysis, and adherence-adjusted
analysis. We conducted prespecified subgroup analyses by testing interactions
between the effect of EGDT and the degree of protocolized care (in the
usual-care group), age, MEDS score,23 SOFA score, and the time from
presentation at the emergency department to randomization.
In the cost-effectiveness analysis, we reported
quality-adjusted life-years (QALYs) by combining survival data with
quality-of-life scores at 90 days and estimated incremental net benefits by
valuing incremental QALYs at the recommended threshold for a QALY gain (£20,000
[U.S. $28,430]) and then subtracting the incremental costs from this value.24
Stata/SE software, version 13.0, was used for all analyses. (Details about
methods are provided in the Statistical Analysis section in the Supplementary
Appendix.)
RESULTS
Study Patients
From February 16, 2011, to July 24, 2014, we screened 6192
patients at 56 sites (including 29% that are teaching hospitals), which
resulted in the enrollment of 1260 patients (Tables S1 and S2 and Fig. S2 and
S3 in the Supplementary Appendix). Four patients requested complete withdrawal
and five were ineligible, which left 1251 patients in the initial analysis (625
in the EGDT group and 626 in the usual-care group). Eight patients withdrew
before 90 days, which left 1243 patients in the analysis of outcomes (623 in
the EGDT group and 620 in the usual-care group) (Figure 1, and Table S3 in the Supplementary Appendix). The two study
groups were well matched at baseline (Table 1, and Table S4 in the Supplementary Appendix).
The criterion for refractory hypotension was met in 338
patients (54.1%) in the EGDT group and 348 patients (55.6%) in the usual-care
group, and the criterion for hyperlactatemia was met in 409 patients (65.4%)
and 399 patients (63.7%), respectively. The intravenous-fluid volume before
randomization was similar in the two groups, as were median times from
presentation at the emergency department until inclusion criteria were met and
until randomization. Only about two thirds of patients in either group were
deemed likely to be admitted to the ICU from the emergency department if they
were not enrolled in the study; those deemed unlikely to be admitted were less
severely ill. The sites of infection (most commonly lung) were well balanced in
the two groups. All patients received antimicrobial drugs before randomization.
Adherence to the Protocol
Most patients in the EGDT group underwent timely insertion
of a central venous catheter capable of continuous ScvO2 monitoring. Two
catheters that were inserted in error in the usual-care group were not used for
monitoring ScvO2 (Table 2, and Table S5 in the Supplementary Appendix). In the EGDT
group, reasons for failure of insertion were as follows: patient no longer met
inclusion criteria or met exclusion criteria (22 patients), there was a lapse
in the process of care (lack of equipment, staff, beds, communication, or
error) (20 patients), there were technical difficulties or problems with a
patient (18 patients), there was a decision by a clinician (9 patients), or the
patient declined to have a catheter inserted but did not withdraw from the
trial (5 patients); in 4 patients, no reason was provided, and 2 patients died
before catheter insertion. The mean (±SD) first ScvO2 value recorded (at hour
1) was 70±12% (Fig. S4 in the Supplementary Appendix). Standard central venous
catheters were not mandated but were placed in 50.9% of the patients in the
usual-care group, and ScvO2 was measured from aspirated blood samples in 6
patients. Arterial catheters were also not mandated but were placed in most
patients.
EGDT was stopped prematurely in 21 patients (median time to
cessation, 3 hours) because active treatment was withdrawn (9 patients), the patient
was no longer considered to have sepsis (5 patients), or EGDT was terminated in
error (3 patients); in addition, 1 patient was transferred to an operating
room, 1 patient declined treatment, and no reason was provided for 2 patients.
Among the 35 patients who died within 6 hours (17 in the EGDT group and 18 in
the usual-care group), 5 in the EGDT group and 6 in the usual-care group had
withdrawal of active treatment. Adherence to EGDT ranged from 86 to 95%,
depending on the method of assessment (Fig. S5 in the Supplementary Appendix).
Intervention Period
During the 6-hour intervention period, patients in the EGDT
group received more intravenous fluids than did patients in the usual-care
group (Table 2). Hourly fluid volume decreased over the 6 hours, but patients
in the usual-care group received a larger initial volume (Fig. S6 in the
Supplementary Appendix). Crystalloids were administered more frequently than
colloids in the two groups. More patients in the EGDT group than in the
usual-care group received vasopressors and dobutamine. Although more patients
in the EGDT group received red-cell transfusions, larger volumes were
transfused in the usual-care group. During the 6-hour intervention period,
administration of platelets and fresh-frozen plasma was similar in the two
groups, although the volume of each was higher in the EGDT group (Table 2). At
6 hours, values for central venous pressure, mean arterial pressure, systolic
blood pressure, and hemoglobin were similar in the two groups among patients in
whom they were measured, which happened with greater frequency in the EGDT
group (Table S6 in the Supplementary Appendix).
After the Intervention Period
Between 6 and 72 hours, the numbers of patients in the two
groups receiving intravenous fluids were similar, but patients in the
usual-care group received larger volumes. More patients in the EGDT group
received intravenous colloids, but overall volumes were similar in the two
groups. The number of patients receiving intravenous crystalloids was similar in
the two groups, but volumes were larger in the usual-care group. The number of
patients receiving red-cell transfusions was higher in the EGDT group, but
volumes were larger in the usual-care group. The use of vasopressors and
dobutamine remained higher in the EGDT group. Although the numbers of patients
receiving platelets and fresh-frozen plasma were similar in the two groups, the
volume of platelets was larger in the EGDT group, whereas the volume of
fresh-frozen plasma was higher in the usual-care group (Table 2, and Table S7
in the Supplementary Appendix). At 72 hours, physiological, biochemical, and
SOFA values were similar in the two groups (Table S8 in the Supplementary
Appendix).
Primary Outcome
Mortality at 90 days was not significantly different in the
two groups, with deaths reported in 184 of 623 patients (29.5%) in the EGDT
group versus 181 of 620 patients (29.2%) in the usual-care group, with an
unadjusted relative risk in the EGDT group of 1.01 (95% CI, 0.85 to 1.20;
P=0.90), for an absolute risk reduction of −0.3 percentage points (95% CI, −5.4
to 4.7). After adjustment for baseline characteristics, the odds ratio was 0.95
(95% CI, 0.74 to 1.24; P=0.73) (Table 3). Sensitivity analyses for patients with a missing primary
outcome (2 in the EGDT group and 6 in the usual-care group) showed relative
risks ranging from 0.99 to 1.03. There was no evidence of a learning-curve
effect (P=0.56). In the adherence-adjusted analysis, the relative risk was 1.02
(95% CI, 0.78 to 1.32; P=0.90) (Table S9 and Fig. S7 in the Supplementary
Appendix).
Secondary Outcomes
The mean SOFA score at 6 hours, the proportion of patients
receiving advanced cardiovascular support, and the median length of stay in the
ICU were significantly greater in the EGDT group than in the usual-care group.
No other secondary outcomes were significantly different (Table 3, and Table
S10 in the Supplementary Appendix). There was no significant difference in the
duration of survival between the two groups (P=0.63 by the log-rank test;
adjusted hazard ratio, 0.94, 95% CI, 0.79 to 1.11; P=0.46) (Figure 2). Mean EQ-5D scores and QALYs were similar in the two
groups. The average cost was higher in the EGDT group (£12,414 [U.S. $17,647])
than in the usual-care group (£11,424 [U.S. $16,239]), but the difference was
not significant (P=0.26) (Table 3, and Tables S11 through S16 and Fig. S8 in
the Supplementary Appendix). The incremental net benefit for EGDT as compared
with usual care was negative and similar across prespecified subgroups and
alternative scenarios that were considered in sensitivity analyses (Tables S17
and S18 and Fig. S9 in the Supplementary Appendix). The probability that EGDT
was cost-effective was below 20% (Fig. S10 in the Supplementary Appendix).
Subgroup Analyses
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 (P=0.39 to
0.72 for interaction) (Table S9 and Fig. S11 in the Supplementary Appendix).
Serious Adverse Events
At least one serious adverse event was reported in 30
patients (4.8%) in the EGDT group and 26 patients (4.2%) in the usual-care
group (P=0.58) (Table 3, and Table S19 in the Supplementary Appendix). Four
serious adverse events were reported as being related to EGDT (two cases of
pulmonary edema and one of arrhythmia, which were deemed to be probably
related, and one case of myocardial ischemia, which was deemed to be definitely
related), as compared with four events (in three patients) related to usual
care (two cases of pneumothorax and one case of pulmonary edema, which were
deemed to be probably related, and one case of ventricular fibrillation, which
was deemed to be definitely related).
DISCUSSION
In our study involving adults with early signs of septic
shock who presented to emergency departments in England, there was no
significant difference in mortality at 90 days among those receiving 6 hours of
EGDT and those receiving usual resuscitation. Although the overall rate of
death in the usual-care group was lower than anticipated (29% rather than 40%),
it is unlikely that patients in the EGDT group would have a relative reduction
of more than 15% in risk. The effect of EGDT was not significantly different in
prespecified subgroups. More patients receiving EGDT were admitted to and spent
more days in the ICU. Treatment intensity was greater in the EGDT group, driven
by adherence to the protocol and indicated by the increased use of central
venous catheters, intravenous fluids, vasoactive drugs, and red-cell
transfusions. Increased intensity was reflected by significantly higher SOFA
scores and more days of receiving advanced cardiovascular support. There were
no significant differences in any other secondary outcomes, including
health-related quality of life, which was substantially poorer in this severely
ill group of patients (0.60) than in the general population matched for age and
sex (0.80).25 On average, the use of EGDT increased costs, and given similar
QALYs in the two groups, the probability that EGDT was cost-effective was below
20%.
Our study was set in a real-world context and in a large,
representative, mixed sample of approximately one quarter of NHS hospitals in
England. Site setup was rapid, and the study recruited the full 1260 patients
over a shorter time period than those of the two similar studies in the United
States12 and Australasia.13 This factor minimized the potential for other
changes in clinical practice to affect outcomes. Unlike previous studies, our
study reports on quality of life and cost-effectiveness at 90 days. Loss to
follow-up was low, and all analyses were conducted according to a prespecified
statistical analysis plan and included adjusted analyses to address the degree
of adherence to EGDT and the possibility of the existence of a learning curve
for its delivery.
Our study has several limitations. As in all studies that
enroll patients presenting to emergency departments, recruitment was more
challenging on weekends and during out-of-office hours; overall, only one third
of eligible patients were recruited, although exclusion from the study by a
clinician was rare. The intervention could not be blinded, but the risk of bias
was minimized through central randomization to ensure the concealment of
study-group assignments and the use of a primary outcome that was not subject
to observer bias. Since the rate of death was lower than anticipated, our study
data may not apply to settings with higher mortality.
Unlike Rivers et al., in their 2001 study, we did not
observe a significant reduction in hospital mortality with the use of EGDT.
Many aspects of initial sepsis management have changed during the past 15
years, as can be seen in comparing the usual-care groups. In our study, as
compared with the study by Rivers et al., mortality was substantially reduced,
randomization occurred later, patients appeared to be less sick at baseline
(with lower blood lactate levels and Acute Physiology and Chronic Health
Evaluation [APACHE] II scores), and all patients received antibiotics before
randomization. In addition, our patients received much lower volumes of
intravenous fluids and more vasoactive drugs (Table S20 in the Supplementary
Appendix).
The level of adherence to EGDT was good and was equivalent
to adherence levels in the ProCESS12 and ARISE13 trials and higher than
reported rates of compliance with the SSC guidelines.26 Most outcomes were
similar to those reported in the ProCESS and ARISE trials, although the rate of
death at 90 days that was reported in our study was lower than that in the
ProCESS trial but higher than that in the ARISE trial. Of note, a higher
proportion of patients in our study than in the ProCESS and ARISE trials met both
of the two inclusion criteria — refractory hypotension and hyperlactatemia
(Table S21 in the Supplementary Appendix) — a factor that is associated in our
national ICU database with a doubling of hospital mortality (Table S22 in the
Supplementary Appendix).
In conclusion, our results suggest that techniques used in
usual resuscitation have evolved over the 15 years since the landmark study by
Rivers et al.9 In our study, NHS hospitals achieved levels of in-hospital
survival in patients receiving usual care that were similar to those achieved
with EGDT in the earlier study for patients with septic shock who were
identified early and received intravenous antibiotics and adequate fluid
resuscitation. The addition of continuous ScvO2 monitoring and strict protocolization
did not improve outcomes in the EGDT group. Our results complete the planned
trio of studies of EGDT, all of which showed that EGDT was not superior to
usual care.
Supplementary Appendix: http://www.nejm.org/doi/suppl/10.1056/NEJMoa1500896/suppl_file/nejmoa1500896_appendix.pdf
The views expressed in this article are those of the authors
and do not necessarily reflect those of the National Institute for Health
Research, the Health Technology Assessment Programme, the National Health
Service, or the Department of Health.
Supported by a grant from the United Kingdom National
Institute for Health Research Health Technology Assessment Programme (project
number 07/37/47).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
This article was published on March 17, 2015, at NEJM.org.
SOURCE INFORMATION
From the Clinical Trials Unit, Intensive Care National Audit
and Research Centre (P.R.M., G.S.P., D.A.H., R.J., S.E.H., K.M.R.), Department
of Health Services Research and Policy, London School of Hygiene and Tropical
Medicine (M.Z.S., R.D.G.), and Faculty of Medicine, Imperial College London
(D.B.), Department of Acute Medicine, Chelsea and Westminster Hospital NHS
Foundation Trust (D.B.), and Bloomsbury Institute of Intensive Care Medicine,
University College London (M.S.), London, the Department of Intensive Care Medicine,
University of Birmingham, Birmingham (J.F.B.), Department of Cardiovascular
Sciences, University of Leicester, Leicester (T.J.C.), and Nuffield Division of
Anaesthetics, University of Oxford, Oxford (J.D.Y.) — all in the United
Kingdom; and the Departments of Surgery and Emergency Medicine, Washington
University at St. Louis, St. Louis (T.M.O.).
Address reprint requests to Dr. Rowan at the Intensive Care
National Audit and Research Centre, Napier House, 24 High Holborn, London WC1V
6AZ, United Kingdom, or at kathy.rowan@icnarc.org.
A complete list of investigators in the Protocolised
Management in Sepsis (ProMISe) trial is provided in the Supplementary Appendix,
available at NEJM.org.
http://www.nejm.org/doi/full/10.1056/NEJMoa1500896
CME Questions:
http://www.nejm.org/doi/full/10.1056/NEJMoa1500896
CME Questions:
1. True or False:
Since
2002, the Surviving Sepsis Campaign (SSC) has promoted Early Goal Directed
Therapy; a heavy protocolized therapy which aimed to optimize tissue oxygen
transport with the use of continuous monitoring of prespecified physiological
targets.
2. Based
on a 2002 study by Rivers, early goal-directed therapy (EGDT) recommended the
utilization of central venous pressure, mean arterial pressure, and central
venous oxygen saturation (ScvO2) — to guide the following:
a.
delivery of intravenous fluids
b.
delivery of vasoactive drugs
c.
delivery of red-cell transfusions.
d.
All of the Above
3. The following
study(studies) have evaluated the benefits of Early Goal Directed Therapy?
a. Arise
b. Process
c. Promise
d. All of the above
4. True or False
The Promise trial (and other trials) achieved levels of in-hospital survival in patients
receiving usual care that were similar to those achieved with EGDT.
5.
The key to improving survival in sepsis relates mostly to:
a.
early identification of sepis
b.
early intravenous antibiotics
c.
adequate fluid resuscitation.
d.
ScvO2 monitoring
e.
Strict protocolization
f.
a, b, c
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