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Early Goal-Directed Therapy in the Treatment of
Severe Sepsis and Septic Shock
Emanuel Rivers, M.D., M.P.H., Bryant Nguyen, M.D., Suzanne
Havstad, M.A., Julie Ressler, B.S., Alexandria Muzzin, B.S., Bernhard Knoblich,
M.D., Edward Peterson, Ph.D., Michael Tomlanovich, M.D., for the Early
Goal-Directed Therapy Collaborative Group
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 (P0.02 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.
The systemic inflammatory response
syndrome can be self-limited or can progress to severe sepsis and
septic shock.1
Along this continuum, circulatory abnormalities (intravascular volume
depletion, peripheral vasodilatation, myocardial depression, and
increased metabolism) lead to an imbalance between systemic oxygen
delivery and oxygen demand, resulting in global tissue hypoxia or
shock.2
An indicator of serious illness, global tissue hypoxia is a key
development preceding multiorgan failure and death.2 The
transition to serious illness occurs during the critical "golden
hours," when definitive recognition and treatment provide maximal
benefit in terms of outcome. These golden hours may elapse in the
emergency department,3
hospital ward,4
or the intensive care unit.5
Early hemodynamic assessment on the basis of physical findings,
vital signs, central venous pressure,6 and
urinary output7
fails to detect persistent global tissue hypoxia. A more definitive
resuscitation strategy involves goal-oriented manipulation of cardiac
preload, afterload, and contractility to achieve a balance between
systemic oxygen delivery and oxygen demand.2 End
points used to confirm the achievement of such a balance (hereafter
called resuscitation end points) include normalized values for mixed
venous oxygen saturation, arterial lactate concentration, base
deficit, and pH.8
Mixed venous oxygen saturation has been shown to be a surrogate for
the cardiac index as a target for hemodynamic therapy.9 In
cases in which the insertion of a pulmonary-artery catheter is
impractical, venous oxygen saturation can be measured in the central
circulation.10
Whereas the incidence of septic shock has steadily increased during
the past several decades, the associated mortality rates have
remained constant or have decreased only slightly.11
Studies of interventions such as immunotherapy,12
hemodynamic optimization,9,13
or pulmonary-artery catheterization14
enrolled patients up to 72 hours after admission to the intensive
care unit. The negative results of studies of the use of hemodynamic
variables as end points ("hemodynamic optimization"), in
particular, prompted suggestions that future studies involve
patients with similar causes of disease13 or
with global tissue hypoxia (as reflected by elevated lactate
concentrations)15
and that they examine interventions begun at an earlier stage of
disease.16,17
We examined whether early goal-directed therapy before admission
to the intensive care unit effectively reduces the incidence of
multiorgan dysfunction, mortality, and the use of health care
resources among patients with severe sepsis or septic shock.
Methods
Approval of Study Design
This prospective, randomized study was approved by the
institutional review board for human research and was conducted
under the auspices of an independent safety, efficacy, and data
monitoring committee.
Eligibility
Eligible adult patients who presented to the emergency department
of an 850-bed academic tertiary care hospital with severe sepsis, septic
shock, or the sepsis syndrome from March 1997 through March 2000
were assessed for possible enrollment according to the inclusion18,19
and exclusion criteria (Figure 1). The
criteria for inclusion were fulfillment of two of four criteria for
the systemic inflammatory response syndrome and a systolic blood
pressure no higher than 90 mm Hg (after a crystalloid-fluid challenge
of 20 to 30 ml per kilogram of body weight over a 30-minute period)
or a blood lactate concentration of 4 mmol per liter or more. The
criteria for exclusion from the study were an age of less than 18
years, pregnancy, or the presence of an acute cerebral vascular
event, acute coronary syndrome, acute pulmonary edema, status
asthmaticus, cardiac dysrhythmias (as a primary diagnosis),
contraindication to central venous catheterization, active
gastrointestinal hemorrhage, seizure, drug overdose, burn injury,
trauma, a requirement for immediate surgery, uncured cancer (during
chemotherapy), immunosuppression (because of organ transplantation
or systemic disease), do-not-resuscitate status, or advanced
directives restricting implementation of the protocol.
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The clinicians who assessed the patients at this stage were unaware
of the patients' treatment assignments. After written informed
consent was obtained (in compliance with the Helsinki Declaration20),
the patients were randomly assigned either to early goal-directed
therapy or to standard (control) therapy in computer-generated
blocks of two to eight. The study-group assignments were placed in
sealed, opaque, randomly assorted envelopes, which were opened by a
hospital staff member who was not one of the study investigators.
Treatment
The patients were treated in a nine-bed unit in the emergency
department by an emergency physician, two residents, and three nurses.3 The
study was conducted during the routine treatment of other patients
in the emergency department. After arterial and central venous
catheterization, patients in the standard-therapy group were treated
at the clinicians' discretion according to a protocol for
hemodynamic support21 (Figure 1), with
critical-care consultation, and were admitted for inpatient care as
soon as possible. Blood, urine, and other relevant specimens for
culture were obtained in the emergency department before the administration
of antibiotics. Antibiotics were given at the discretion of the
treating clinicians. Antimicrobial therapy was deemed adequate if
the in vitro sensitivities of the identified microorganisms matched
the particular antibiotic ordered in the emergency department.22
The patients assigned to early goal-directed therapy received
a central venous catheter capable of measuring central venous oxygen
saturation (Edwards Lifesciences, Irvine, Calif.); it was connected
to a computerized spectrophotometer for continuous monitoring.
Patients were treated in the emergency department according to a
protocol for early goal-directed therapy (Figure 2) for
at least six hours and were transferred to the first available
inpatient beds. Monitoring of central venous oxygen saturation was
then discontinued. Critical-care clinicians (intensivists, fellows,
and residents providing 24-hour in-house coverage) assumed the care
of all the patients; these physicians were unaware of the patients'
study-group assignments. The study investigators did not influence
patient care in the intensive care unit.
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The protocol was as follows. A 500-ml bolus of crystalloid was given
every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg.
If the mean arterial pressure was less than 65 mm Hg, vasopressors
were given to maintain a mean arterial pressure of at least 65 mm
Hg. If the mean arterial pressure was greater than 90 mm Hg,
vasodilators were given until it was 90 mm Hg or below. If the
central venous oxygen saturation was less than 70 percent, red cells
were transfused to achieve a hematocrit of at least 30 percent.
After the central venous pressure, mean arterial pressure, and
hematocrit were thus optimized, if the central venous oxygen
saturation was less than 70 percent, dobutamine administration was
started at a dose of 2.5 µg per kilogram of body weight per minute,
a dose that was increased by 2.5 µg per kilogram per minute every 30
minutes until the central venous oxygen saturation was 70 percent or
higher or until a maximal dose of 20 µg per kilogram per minute
was given. Dobutamine was decreased in dose or discontinued if
the mean arterial pressure was less than 65 mm Hg or if the heart
rate was above 120 beats per minute. To decrease oxygen consumption,
patients in whom hemodynamic optimization could not be achieved
received mechanical ventilation and sedatives.
Outcome Measures
The patients' temperature, heart rate, urine output, blood
pressure, and central venous pressure were measured continuously for
the first 6 hours of treatment and assessed every 12 hours for 72
hours. Arterial and venous blood gas values (including central venous
oxygen saturation measured by in vitro co-oximetry; Nova Biomedical,
Waltham, Mass.), lactate concentrations, and coagulation-related variables
and clinical variables required for determination of the Acute
Physiology and Chronic Health Evaluation (APACHE II) score (on a
scale from 0 to 71, with higher scores indicating more severe organ
dysfunction),23
the Simplified Acute Physiology Score II (SAPS II, on a scale from 0
to 174, with higher scores indicating more severe organ
dysfunction),24
and the Multiple Organ Dysfunction Score (MODS, on a scale from 0 to
24, with higher scores indicating more severe organ dysfunction)25
were obtained at base line (0 hours) and at 3, 6, 12, 24, 36, 48,
60, and 72 hours.2,26
The results of laboratory tests required only for purposes of the
study were made known only to the study investigators. Patients were
followed for 60 days or until death. The consumption of health care
resources (indicated by the duration of vasopressor therapy and
mechanical ventilation and the length of the hospital stay) was also
examined.
Statistical Analysis
In-hospital mortality was the primary efficacy end point.
Secondary end points were the resuscitation end points,
organ-dysfunction scores, coagulation-related variables,
administered treatments, and the consumption of health care
resources. Assuming a rate of refusal or exclusion of 10 percent, a
two-sided type I error rate of 5 percent, and a power of 80 percent,
we calculated that a sample size of 260 patients was required to
permit the detection of a 15 percent reduction in in-hospital
mortality. Kaplan–Meier estimates of mortality, along with risk
ratios and 95 percent confidence intervals, were used to describe
the relative risk of death. Differences between the two groups at
base line were tested with the use of Student's t-test, the chi-square
test, or Wilcoxon's rank-sum test. Incremental analyses of the area
under the curve were performed to quantify differences during the
interval from base line to six hours after the start of treatment.
For the data at six hours, analysis of covariance was used with the
base-line values as the covariates. Mixed models were used to assess
the effect of treatment on prespecified secondary variables during
the interval from 7 to 72 hours after the start of treatment.27
An independent, 12-member external safety, efficacy, and data
monitoring committee reviewed interim analyses of the data after one
third and two thirds of the patients had been enrolled and at both
times recommended that the trial be continued. To adjust for the two
interim analyses, the alpha spending function of DeMets and Lan28
was used to determine that a P value of 0.04 or less would be
considered to indicate statistical significance.
Results
Base-Line Characteristics
We evaluated 288 patients; 8.7 percent were excluded or did not
consent to participate. The 263 patients enrolled were randomly assigned
to undergo either standard therapy or early goal-directed therapy;
236 patients completed the initial six-hour study period. All 263
were included in the intention-to-treat analyses. The patients
assigned to standard therapy stayed a significantly shorter time in
the emergency department than those assigned to early goal-directed
therapy (mean [±SD], 6.3±3.2 vs. 8.0±2.1 hours; P<0.001). There
was no significant difference between the groups in any of the
base-line characteristics, including the adequacy and duration of
antibiotic therapy (Table 1). Vital
signs, resuscitation end points, organ-dysfunction scores, and
coagulation-related variables were also similar in the two study
groups at base line (Table 2).
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Twenty-seven patients did not complete the initial six-hour study
period (14 assigned to standard therapy and 13 assigned to early
goal-directed therapy), for the following reasons: discontinuation
of aggressive medical treatment (in 5 patients in each group),
discontinuation of aggressive surgical treatment (in 2 patients in
each group), a need for immediate surgery (in 4 patients assigned to
standard therapy and in 3 assigned to early goal-directed therapy),
a need for interventional urologic, cardiologic, or angiographic
procedures (in 2 patients in each group), and refusal to continue
participation (in 1 patient in each group) (P=0.99 for all comparisons).
There were no significant differences between the patients who
completed the initial six-hour study period and those who did not in
any of the base-line characteristics or base-line vital signs,
resuscitation end points, organ-dysfunction scores, or
coagulation-related variables (data not shown).
Vital Signs and Resuscitation End Points
During the initial six hours after the start of therapy, there
was no significant difference between the two study groups in the
mean heart rate (P=0.25) or central venous pressure (P=0.22) (Table 2). During
this period, the mean arterial pressure was significantly lower in
the group assigned to standard therapy than in the group assigned to
early goal-directed therapy (P<0.001), but in both groups the
goal of 65 mm Hg or higher was met by all the patients. The goal of
70 percent or higher for central venous oxygen saturation was met by
60.2 percent of the patients in the standard-therapy group, as
compared with 94.9 percent of those in the early-therapy group
(P<0.001). The combined hemodynamic goals for central venous
pressure, mean arterial pressure, and urine output (with adjustment
for patients with end-stage renal failure) were achieved in 86.1
percent of the standard-therapy group, as compared with 99.2 percent
of the early-therapy group (P<0.001). During this period, the
patients assigned to standard therapy had a significantly lower
central venous oxygen saturation (P<0.001) and a greater base
deficit (P=0.006) than those assigned to early goal-directed
therapy; the two groups had similar lactate concentrations (P=0.62)
and similar pH values (P=0.26).
During the period from 7 to 72 hours after the start of treatment,
the patients assigned to standard therapy had a significantly higher
heart rate (P=0.04) and a significantly lower mean arterial pressure
(P<0.001) than the patients assigned to early goal-directed therapy;
the two groups had a similar central venous pressure (P=0.68). During
this period, those assigned to standard therapy also had a
significantly lower central venous oxygen saturation than those
assigned to early goal-directed therapy (P<0.001), as well as a
higher lactate concentration (P=0.02), a greater base deficit (P<0.001),
and a lower pH (P<0.001).
Organ Dysfunction and Coagulation
Variables
During the period from 7 to 72 hours, the APACHE II score, SAPS
II, and MODS were significantly higher in the patients assigned to
standard therapy than in the patients assigned to early goal-directed therapy
(P<0.001 for all comparisons) (Table 2). During
this period, the prothrombin time was significantly greater in the
patients assigned to standard therapy than in those assigned to
early goal-directed therapy (P=0.001), as was the concentration of
fibrin-split products (P<0.001) and the concentration of D-dimer
(P=0.006). The two groups had a similar partial-thromboplastin time
(P=0.06), fibrinogen concentration (P=0.21), and platelet count
(P=0.51) (Table 2).
Mortality
In-hospital mortality rates were significantly higher in the standard-therapy
group than in the early-therapy group (P=0.009), as was the
mortality at 28 days (P=0.01) and 60 days (P=0.03) (Table 3). The
difference between the groups in mortality at 60 days primarily
reflected the difference in in-hospital mortality. Similar results
were obtained after data from the 27 patients who did not complete
the initial six-hour study period were excluded from the analysis
(data not shown). The rate of in-hospital death due to sudden
cardiovascular collapse was significantly higher in the
standard-therapy group than in the early-therapy group (P=0.02); the
rate of death due to multiorgan failure was similar in the two
groups (P=0.27).
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Administered Treatments
During the initial six hours, the patients assigned to early goal-directed
therapy received significantly more fluid than those assigned to
standard therapy (P<0.001) and more frequently received red-cell
transfusion (P<0.001) and inotropic support (P<0.001), whereas
similar proportions of patients in the two groups required
vasopressors (P=0.62) and mechanical ventilation (P=0.90) (Table 4). During
the period from 7 to 72 hours, however, the patients assigned to
standard therapy received significantly more fluid than those
assigned to early goal-directed therapy (P=0.01) and more often
received red-cell transfusion (P<0.001) and vasopressors (P=0.03)
and underwent mechanical ventilation (P<0.001) and
pulmonary-artery catheterization (P=0.04); the rate of use of
inotropic agents was similar in the two groups (P=0.14) (Table 4). During
the overall period from base line to 72 hours after the start of
treatment, there was no significant difference between the two
groups in the total volume of fluid administered (P=0.73) or the
rate of use of inotropic agents (P=0.15), although a greater
proportion of the patients assigned to standard therapy than of
those assigned to early goal-directed therapy received vasopressors
(P=0.02) and mechanical ventilation (P=0.02) and underwent
pulmonary-artery catheterization (P=0.01), and a smaller proportion
required red-cell transfusion (P<0.001). Though similar between
the groups at base line (P=0.91), the mean hematocrit during this
72-hour period was significantly lower in the standard-therapy group
than in the early-therapy group (P<0.001). Despite the
transfusion of red cells, it was significantly lower than the value
obtained at base line in each group (P<0.001 for both
comparisons) (Table
2).
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Consumption of Health Care Resources
There were no significant differences between the two groups in
the mean duration of vasopressor therapy (2.4±4.2 vs. 1.9±3.1 days,
P=0.49), the mean duration of mechanical ventilation (9.0±13.1 vs.
9.0±11.4 days, P=0.38), or the mean length of stay in the hospital
(13.0±13.7 vs. 13.2±13.8 days, P=0.54). However, of the patients
who survived to hospital discharge, those assigned to standard therapy
had stayed a significantly longer time in the hospital than those assigned
to early goal-directed therapy (18.4±15.0 vs. 14.6±14.5 days,
P=0.04).
Discussion
Severe sepsis and septic shock are common and are associated with
substantial mortality and substantial consumption of health care
resources. There are an estimated 751,000 cases (3.0 cases per 1000
population) of sepsis or septic shock in the United States each
year, and they are responsible for as many deaths each year as acute
myocardial infarction (215,000, or 9.3 percent of all deaths).29
In elderly persons, the incidence of sepsis or septic shock and the
related mortality rates are substantially higher than those in
younger persons. The projected growth of the elderly population in
the United States will contribute to an increase in incidence of 1.5
percent per year, yielding an estimated 934,000 and 1,110,000 cases
by the years 2010 and 2020, respectively.29
The present annual cost of this disease is estimated to be $16.7
billion.29
The transition from the systemic inflammatory response syndrome
to severe sepsis and septic shock involves a myriad of pathogenic changes,
including circulatory abnormalities that result in global tissue
hypoxia.1,2 These
pathogenic changes have been the therapeutic target of previous
outcome studies.12
Although this transition occurs over time, both out of the hospital
and in the hospital, in outcome studies interventions have usually
been initiated after admission to the intensive care unit.12
In studies of goal-directed hemodynamic optimization, in particular,
there was no benefit in terms of outcome with respect to normal and
supranormal hemodynamic end points, as well as those guided by mixed
venous oxygen saturation.9,13
In contrast, even though we enrolled patients with lower central
venous oxygen saturation and lower central venous pressure than
those studied by Gattinoni et al.9 and
with a higher lactate concentration than those studied by Hayes et
al.,13
we found significant benefits with respect to outcome when
goal-directed therapy was applied at an earlier stage of disease. In
patients with septic shock, for example, Hayes et al. observed a
higher in-hospital mortality rate with aggressive hemodynamic
optimization in the intensive care unit (71 percent) than with
control therapy (52 percent), whereas we observed a lower mortality
rate in patients with septic shock assigned to early goal-directed
therapy (42.3 percent) than in those assigned to standard therapy
(56.8 percent).
The benefits of early goal-directed therapy in terms of outcome
are multifactorial. The incidence of death due to sudden cardiovascular
collapse in the standard-therapy group was approximately double that
in the group assigned to early goal-directed therapy, suggesting that
an abrupt transition to severe disease is an important cause of
early death. The early identification of patients with insidious
illness (global tissue hypoxia accompanied by stable vital signs)
makes possible the early implementation of goal-directed therapy. If
sudden cardiovascular collapse can be prevented, the subsequent need
for vasopressors, mechanical ventilation, and pulmonary-artery
catheterization (and their associated risks) diminishes. In addition
to being a stimulus of the systemic inflammatory response syndrome,
global tissue hypoxia independently contributes to endothelial
activation and disruption of the homeostatic balance among
coagulation, vascular permeability, and vascular tone.30
These are key mechanisms leading to microcirculatory failure,
refractory tissue hypoxia, and organ dysfunction.2,30
When early therapy is not comprehensive, the progression to severe
disease may be well under way at the time of admission to the
intensive care unit.16
Aggressive hemodynamic optimization and other therapy12
undertaken thereafter may be incompletely effective or even
deleterious.13
The value of measurements of venous oxygen saturation at the right
atrium or superior vena cava (central venous oxygen saturation) instead
of at the pulmonary artery (mixed venous oxygen saturation) has been
debated,31
in particular, when saturation values are above 65 percent. In
patients in the intensive care unit who have hyperdynamic septic
shock, the mixed venous oxygen saturation is rarely below 65
percent.32
In contrast, our patients were examined during the phase of
resuscitation in which the delivery of supplemental oxygen is
required (characterized by a decreased mixed venous oxygen
saturation and an increased lactate concentration), when the central
venous oxygen saturation generally exceeds the mixed venous oxygen
saturation.33,34
The initial central venous oxygen saturation was less than 50
percent in both study groups. The mixed venous oxygen saturation is
estimated to be 5 to 13 percent lower in the pulmonary artery33
and 15 percent lower in the splanchnic bed.35
Though not numerically equivalent, these ranges of values are
pathologically equivalent and are associated with high mortality.32,36
Among all the patients in the current study in whom the goals with
respect to central venous pressure, mean arterial pressure, and
urine output during the first six hours were met, 39.8 percent of
those assigned to standard therapy were still in this
oxygen-dependent phase of resuscitation at six hours, as compared
with 5.1 percent of those assigned to early goal-directed therapy.
The combined 56.5 percent in-hospital mortality of this 39.8 percent
of patients, who were at high risk for hemodynamic compromise, is
consistent with the results of previous studies in the intensive
care unit.32,36
In an open, randomized, partially blinded trial, there are
unavoidable interactions during the initial period of the study. As
the study progressed, the patients in the standard-therapy group
may have received some form of goal-directed therapy, reducing the
treatment effect. This reduction may have been offset by the slight
but inherent bias resulting from the direct influence of the
investigators on the care of the patients in the treatment group.
The potential period of bias was 9.9±19.5 percent of the overall
hospital stay in the standard-therapy group and 7.2±12.0 percent of
that in the group assigned to early goal-directed therapy (P=0.20).
This interval was minimal in comparison with those in previous
studies9,13
because the clinicians who assumed responsibility for the remainder
of hospitalization were completely blinded to the randomization
order.
We conclude that goal-directed therapy provided at the earliest
stages of severe sepsis and septic shock, though accounting for
only a brief period in comparison with the overall hospital stay,
has significant short-term and long-term benefits. These benefits
arise from the early identification of patients at high risk for
cardiovascular collapse and from early therapeutic intervention to
restore a balance between oxygen delivery and oxygen demand. In the
future, investigators conducting outcome trials in patients with
sepsis should consider the quality and timing of the resuscitation
before enrollment as an important outcome variable.
Supported by the Henry Ford Health Systems Fund for Research,
a Weatherby Healthcare Resuscitation Fellowship, Edwards Lifesciences
(which provided oximetry equipment and catheters), and Nova Biomedical
(which provided equipment for laboratory assays).
We are indebted to the nurses, residents, senior staff attending
physicians, pharmacists, patient advocates, technicians, and billing
and administrative personnel of the Department of Emergency Medicine;
to the nurses and technicians of the medical and surgical intensive
care units; and to the staff members of the Department of
Respiratory Therapy, Department of Pathology, Department of Medical
Records, and Department of Admitting and Discharge for their
patience and their cooperation in making this study possible.
* The members of the Early Goal-Directed
Therapy Collaborative Group are listed in the Appendix.
Source Information
From the Departments of Emergency Medicine (E.R., B.N., J.R.,
A.M., B.K., M.T.), Surgery (E.R.), Internal Medicine (B.N.), and Biostatistics
and Epidemiology (S.H., E.P.), Henry Ford Health Systems, Case Western Reserve
University, Detroit.
Address reprint requests to Dr. Rivers at the Department of
Emergency Medicine, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI
48202, or at [log in to unmask].
References
Appendix
The following persons participated in the study: External Safety, Efficacy, and Data
Monitoring Committee: A. Connors (Charlottesville, Va.),
S. Conrad (Shreveport, La.), L. Dunbar (New Orleans), S. Fagan
(Atlanta), M. Haupt (Portland, Oreg.), R. Ivatury (Richmond, Va.),
G. Martin (Detroit), D. Milzman (Washington, D.C.), E. Panacek (Palo
Alto, Calif.), M. Rady (Scottsdale, Ariz.), M. Rudis (Los Angeles),
and S. Stern (Ann Arbor, Mich.); the
Early-Goal-Directed-Therapy Collaborative Group: B.
Derechyk, W. Rittinger, G. Hayes, K. Ward, M. Mullen, V. Karriem, J.
Urrunaga, M. Gryzbowski, A. Tuttle, W. Chung, P. Uppal, R. Nowak, D.
Powell, T. Tyson, T. Wadley, G. Galletta, K. Rader, A. Goldberg, D.
Amponsah, D. Morris, K. Kumasi-Rivers, B. Thompson, D. Ander, C.
Lewandowski, J. Kahler, K. Kralovich, H. Horst, S. Harpatoolian, A.
Latimer, M. Schubert, M. Fallone, B. Fasbinder, L. Defoe, J. Hanlon,
A. Okunsanya, B. Sheridan, Q. Rivers, H. Johnson, B. Sessa-Boji, K.
Gunnerson, D. Fritz, K. Rivers, S. Moore, D. Huang, and J. Farrerer
(Henry Ford Hospital, Detroit).
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.