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
Background Goal-directed therapy has
been used for severe sepsisand septic shock in the intensive care
unit. This approach involvesadjustments of cardiac preload,
afterload, and contractilityto balance oxygen delivery with oxygen
demand. The purpose ofthis study was to evaluate the efficacy of
early goal-directedtherapy before admission to the intensive care
unit.
Methods We randomly assigned patients who arrived at an urbanemergency department with severe sepsis or septic shock to receiveeither six hours of early goal-directed therapy or standardtherapy (as a control) before admission to the intensive careunit. Clinicians who subsequently assumed the care of the patientswere 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
betweenthe study groups.
Results Of the 263 enrolled patients, 130 were randomly assignedto early goal-directed therapy and 133 to standard therapy;there were no significant differences between the groups withrespect to base-line characteristics. In-hospital mortalitywas
30.5 percent in the group assigned to early goal-directedtherapy, as
compared with 46.5 percent in the group assignedto standard therapy
(P=0.009). During the interval from 7 to72 hours, the patients
assigned to early goal-directed therapyhad a significantly higher
mean (±SD) central venousoxygen saturation (70.4±10.7 percent vs.
65.3±11.4percent), a lower lactate concentration (3.0±4.4 vs.3.9±4.4 mmol per liter), a lower base deficit (2.0±6.6vs.
5.1±6.7 mmol per liter), and a higher pH (7.40±0.12vs. 7.36±0.12)
than the patients assigned to standardtherapy (P0.02 for all comparisons). During the same period,mean
APACHE II scores were significantly lower, indicating lesssevere
organ dysfunction, in the patients assigned to earlygoal-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 significantbenefits with respect to outcome in patients with severe sepsisand septic shock.
The systemic inflammatory response syndrome can be self-limitedor
can progress to severe sepsis and septic shock.1
Along thiscontinuum, circulatory abnormalities (intravascular volume
depletion,peripheral vasodilatation, myocardial depression, and
increasedmetabolism) lead to an imbalance between systemic oxygen
deliveryand oxygen demand, resulting in global tissue hypoxia or
shock.2An indicator of serious illness, global tissue hypoxia is akey
development preceding multiorgan failure and death.2
Thetransition to serious illness occurs during the critical
"goldenhours," when definitive recognition and treatment provide
maximalbenefit in terms of outcome. These golden hours may elapse
inthe emergency department,3
hospital ward,4
or the intensivecare unit.5
Early hemodynamic assessment on the basis of physical findings,vital signs, central venous pressure,6
and urinary output7
failsto detect persistent global tissue hypoxia. A more
definitiveresuscitation strategy involves goal-oriented manipulation
ofcardiac preload, afterload, and contractility to achieve a
balancebetween systemic oxygen delivery and oxygen demand.2
End pointsused to confirm the achievement of such a balance
(hereaftercalled resuscitation end points) include normalized values
formixed venous oxygen saturation, arterial lactate
concentration,base deficit, and pH.8
Mixed venous oxygen saturation has beenshown to be a surrogate for
the cardiac index as a target forhemodynamic therapy.9
In cases in which the insertion of a pulmonary-arterycatheter is
impractical, venous oxygen saturation can be measuredin the central
circulation.10
Whereas the incidence of septic shock has steadily increasedduring the past several decades, the associated mortality rateshave remained constant or have decreased only slightly.11
Studiesof interventions such as immunotherapy,12
hemodynamic optimization,9,13or pulmonary-artery catheterization14
enrolled patients up to72 hours after admission to the intensive
care unit. The negativeresults of studies of the use of hemodynamic
variables as endpoints ("hemodynamic optimization"), in particular,
promptedsuggestions that future studies involve patients with
similarcauses of disease13
or with global tissue hypoxia (as reflectedby elevated lactate
concentrations)15
and that they examineinterventions begun at an earlier stage of
disease.16,17
We examined whether early goal-directed therapy before admissionto the intensive care unit effectively reduces the incidenceof
multiorgan dysfunction, mortality, and the use of healthcare
resources among patients with severe sepsis or septic shock.
Methods
Approval of Study Design
This prospective, randomized study was approved by the institutionalreview board for human research and was conducted under theauspices of an independent safety, efficacy, and data monitoringcommittee.
Eligibility
Eligible adult patients who presented to the emergency departmentof an 850-bed academic tertiary care hospital with severe sepsis,septic shock, or the sepsis syndrome from March 1997 throughMarch 2000 were assessed for possible enrollment according tothe inclusion18,19
and exclusion criteria (Figure 1).
The criteriafor inclusion were fulfillment of two of four criteria
for thesystemic inflammatory response syndrome and a systolic
bloodpressure no higher than 90 mm Hg (after a
crystalloid-fluidchallenge of 20 to 30 ml per kilogram of body
weight over a30-minute period) or a blood lactate concentration of 4
mmolper liter or more. The criteria for exclusion from the
studywere an age of less than 18 years, pregnancy, or the
presenceof an acute cerebral vascular event, acute coronary
syndrome,acute pulmonary edema, status asthmaticus, cardiac
dysrhythmias(as a primary diagnosis), contraindication to central
venouscatheterization, active gastrointestinal hemorrhage,
seizure,drug overdose, burn injury, trauma, a requirement for
immediatesurgery, uncured cancer (during chemotherapy),
immunosuppression(because of organ transplantation or systemic
disease), do-not-resuscitatestatus, or advanced directives
restricting implementation ofthe protocol.
Figure 1.Overview
of Patient Enrollment and Hemodynamic Support.
SIRS denotes systemic inflammatory response syndrome, CVP central
venous pressure, MAP mean arterial pressure, ScvO2
central venous oxygen saturation, SaO2 arterial oxygen
saturation, and VO2 systemic oxygen consumption. The
criteria for a diagnosis of SIRS were temperature greater than or
equal to 38°C or less than 36°C, heart rate greater than 90 beats
per minute, respiratory rate greater than 20 breaths per minute or
partial pressure of arterial carbon dioxide less than 32 mm Hg, and
white-cell count greater than 12,000 per cubic millimeter or less
than 4000 per cubic millimeter or the presence of more than 10
percent immature band forms.
The
clinicians who assessed the patients at this stage wereunaware of
the patients' treatment assignments. After writteninformed consent
was obtained (in compliance with the HelsinkiDeclaration20),
the patients were randomly assigned either toearly goal-directed
therapy or to standard (control) therapyin computer-generated blocks
of two to eight. The study-groupassignments were placed in sealed,
opaque, randomly assortedenvelopes, which were opened by a hospital
staff member whowas not one of the study investigators.
Treatment
The patients were treated in a nine-bed unit in the emergencydepartment by an emergency physician, two residents, and threenurses.3
The study was conducted during the routine treatmentof other
patients in the emergency department. After arterialand central
venous catheterization, patients in the standard-therapygroup were
treated at the clinicians' discretion according toa protocol for
hemodynamic support21
(Figure
1), with critical-careconsultation, and were admitted for
inpatient care as soon aspossible. Blood, urine, and other relevant
specimens for culturewere obtained in the emergency department
before the administrationof antibiotics. Antibiotics were given at
the discretion ofthe treating clinicians. Antimicrobial therapy was
deemed adequateif the in vitro sensitivities of the identified
microorganismsmatched the particular antibiotic ordered in the
emergency department.22
The patients assigned to early goal-directed therapy receiveda
central venous catheter capable of measuring central venousoxygen
saturation (Edwards Lifesciences, Irvine, Calif.); itwas connected
to a computerized spectrophotometer for continuousmonitoring.
Patients were treated in the emergency departmentaccording to a
protocol for early goal-directed therapy (Figure
2)for at least six hours and were transferred to the firstavailable inpatient beds. Monitoring of central venous oxygensaturation 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
wereunaware of the patients' study-group assignments. The studyinvestigators did not influence patient care in the intensivecare unit.
Figure 2.Protocol
for Early Goal-Directed Therapy.
CVP denotes central venous pressure, MAP mean arterial pressure,
and ScvO2 central venous oxygen saturation.
The
protocol was as follows. A 500-ml bolus of crystalloid wasgiven
every 30 minutes to achieve a central venous pressureof 8 to 12 mm
Hg. If the mean arterial pressure was less than65 mm Hg,
vasopressors were given to maintain a mean arterialpressure of at
least 65 mm Hg. If the mean arterial pressurewas greater than 90 mm
Hg, vasodilators were given until itwas 90 mm Hg or below. If the
central venous oxygen saturationwas less than 70 percent, red cells
were transfused to achievea hematocrit of at least 30 percent. After
the central venouspressure, 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 µgper kilogram of body weight per minute, a dose that was
increasedby 2.5 µg per kilogram per minute every 30 minutes
untilthe central venous oxygen saturation was 70 percent or
higheror until a maximal dose of 20 µg per kilogram per minutewas given. Dobutamine was decreased in dose or discontinuedif
the mean arterial pressure was less than 65 mm Hg or if theheart
rate was above 120 beats per minute. To decrease oxygenconsumption,
patients in whom hemodynamic optimization couldnot 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 thefirst 6 hours of treatment and assessed every 12 hours for 72hours. Arterial and venous blood gas values (including centralvenous oxygen saturation measured by in vitro co-oximetry; NovaBiomedical, Waltham, Mass.), lactate concentrations, and
coagulation-relatedvariables and clinical variables required for
determinationof the Acute Physiology and Chronic Health Evaluation
(APACHEII) score (on a scale from 0 to 71, with higher scores
indicatingmore severe organ dysfunction),23
the Simplified Acute PhysiologyScore II (SAPS II, on a scale from 0
to 174, with higher scoresindicating more severe organ
dysfunction),24
and the MultipleOrgan Dysfunction Score (MODS, on a scale from 0 to
24, withhigher scores indicating more severe organ dysfunction)25
wereobtained at base line (0 hours) and at 3, 6, 12, 24, 36,
48,60, and 72 hours.2,26
The results of laboratory tests requiredonly for purposes of the
study were made known only to the studyinvestigators. Patients were
followed for 60 days or until death.The consumption of health care
resources (indicated by the durationof vasopressor therapy and
mechanical ventilation and the lengthof the hospital stay) was also
examined.
Statistical Analysis
In-hospital mortality was the primary efficacy end point. Secondaryend points were the resuscitation end points, organ-dysfunctionscores, coagulation-related variables, administered treatments,and the consumption of health care resources. Assuming a rateof refusal or exclusion of 10 percent, a two-sided type I errorrate of 5 percent, and a power of 80 percent, we calculatedthat a sample size of 260 patients was required to permit thedetection of a 15 percent reduction in in-hospital mortality.Kaplan–Meier estimates of mortality, along with risk ratiosand
95 percent confidence intervals, were used to describe therelative
risk of death. Differences between the two groups atbase line were
tested with the use of Student's t-test, thechi-square test, or
Wilcoxon's rank-sum test. Incremental analysesof the area under the
curve were performed to quantify differencesduring the interval from
base line to six hours after the startof treatment. For the data at
six hours, analysis of covariancewas used with the base-line values
as the covariates. Mixedmodels were used to assess the effect of
treatment on prespecifiedsecondary variables during the interval
from 7 to 72 hours afterthe start of treatment.27
An independent, 12-member externalsafety, efficacy, and data
monitoring committee reviewed interimanalyses of the data after one
third and two thirds of the patientshad been enrolled and at both
times recommended that the trialbe continued. To adjust for the two
interim analyses, the alphaspending function of DeMets and Lan28
was used to determinethat a P value of 0.04 or less would be
considered to indicatestatistical significance.
Results
Base-Line Characteristics
We evaluated 288 patients; 8.7 percent were excluded or didnot
consent to participate. The 263 patients enrolled were randomlyassigned to undergo either standard therapy or early goal-directedtherapy; 236 patients completed the initial six-hour study period.All 263 were included in the intention-to-treat analyses. Thepatients assigned to standard therapy stayed a significantlyshorter time in the emergency department than those assignedto
early goal-directed therapy (mean [±SD], 6.3±3.2vs. 8.0±2.1 hours;
P<0.001). There was no significantdifference 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-dysfunctionscores, and coagulation-related variables were also similarin
the two study groups at base line (Table
2).
Table 2.Vital
Signs, Resuscitation End Points, Organ-Dysfunction Scores, and
Coagulation Variables.
Twenty-seven
patients did not complete the initial six-hourstudy period (14
assigned to standard therapy and 13 assignedto early goal-directed
therapy), for the following reasons:discontinuation of aggressive
medical treatment (in 5 patientsin 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 assignedto early goal-directed therapy), a need for
interventional urologic,cardiologic, or angiographic procedures (in
2 patients in eachgroup), and refusal to continue participation (in
1 patientin each group) (P=0.99 for all comparisons). There were no
significantdifferences between the patients who completed the
initial six-hourstudy period and those who did not in any of the
base-line characteristicsor base-line vital signs, resuscitation end
points, organ-dysfunctionscores, or coagulation-related variables
(data not shown).
Vital Signs and Resuscitation End Points
During the initial six hours after the start of therapy, therewas
no significant difference between the two study groups inthe mean
heart rate (P=0.25) or central venous pressure (P=0.22)(Table 2).
During this period, the mean arterial pressure wassignificantly
lower in the group assigned to standard therapythan 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 byall the patients.
The goal of 70 percent or higher for centralvenous oxygen saturation
was met by 60.2 percent of the patientsin the standard-therapy
group, as compared with 94.9 percentof those in the early-therapy
group (P<0.001). The combinedhemodynamic goals for central venous
pressure, mean arterialpressure, and urine output (with adjustment
for patients withend-stage renal failure) were achieved in 86.1
percent of thestandard-therapy group, as compared with 99.2 percent
of theearly-therapy group (P<0.001). During this period, the
patientsassigned to standard therapy had a significantly lower
centralvenous 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)
andsimilar 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 significantlyhigher heart rate (P=0.04) and a significantly lower mean arterialpressure (P<0.001) than the patients assigned to early
goal-directedtherapy; the two groups had a similar central venous
pressure(P=0.68). During this period, those assigned to standard
therapyalso had a significantly lower central venous oxygen
saturationthan those assigned to early goal-directed therapy
(P<0.001),as well as a higher lactate concentration (P=0.02), a
greaterbase 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, SAPSII, and MODS were significantly higher in the patients assignedto standard therapy than in the patients assigned to early
goal-directedtherapy (P<0.001 for all comparisons) (Table 2).
During thisperiod, the prothrombin time was significantly greater in
thepatients assigned to standard therapy than in those assignedto early goal-directed therapy (P=0.001), as was the concentrationof fibrin-split products (P<0.001) and the concentrationof
D-dimer (P=0.006). The two groups had a similar partial-thromboplastintime (P=0.06), fibrinogen concentration (P=0.21), and plateletcount (P=0.51) (Table
2).
Mortality
In-hospital mortality rates were significantly higher in thestandard-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 at60 days
primarily reflected the difference in in-hospital mortality.Similar
results were obtained after data from the 27 patientswho did not
complete the initial six-hour study period wereexcluded from the
analysis (data not shown). The rate of in-hospitaldeath due to
sudden cardiovascular collapse was significantlyhigher in the
standard-therapy group than in the early-therapygroup (P=0.02); the
rate of death due to multiorgan failurewas similar in the two groups
(P=0.27).
Table 3.Kaplan–Meier Estimates of Mortality and Causes of
In-Hospital Death.
Administered
Treatments
During the initial six hours, the patients assigned to earlygoal-directed therapy received significantly more fluid thanthose assigned to standard therapy (P<0.001) and more frequentlyreceived red-cell transfusion (P<0.001) and inotropic support(P<0.001), whereas similar proportions of patients in thetwo 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 significantlymore 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 lineto 72 hours after the start
of treatment, there was no significantdifference between the two
groups in the total volume of fluidadministered (P=0.73) or the rate
of use of inotropic agents(P=0.15), although a greater proportion of
the patients assignedto standard therapy than of those assigned to
early goal-directedtherapy 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), themean hematocrit during this 72-hour period was
significantlylower in the standard-therapy group than in the
early-therapygroup (P<0.001). Despite the transfusion of red
cells, itwas significantly lower than the value obtained at base
linein each group (P<0.001 for both comparisons) (Table
2).
There were no significant differences between the two groupsin
the mean duration of vasopressor therapy (2.4±4.2vs. 1.9±3.1 days,
P=0.49), the mean duration of mechanicalventilation (9.0±13.1 vs.
9.0±11.4 days, P=0.38),or the mean length of stay in the hospital
(13.0±13.7vs. 13.2±13.8 days, P=0.54). However, of the patientswho survived to hospital discharge, those assigned to standardtherapy had stayed a significantly longer time in the hospitalthan those assigned to early goal-directed therapy (18.4±15.0vs. 14.6±14.5 days, P=0.04).
Discussion
Severe sepsis and septic shock are common and are associatedwith
substantial mortality and substantial consumption of healthcare
resources. There are an estimated 751,000 cases (3.0 casesper 1000
population) of sepsis or septic shock in the UnitedStates each year,
and they are responsible for as many deathseach year as acute
myocardial infarction (215,000, or 9.3 percentof all deaths).29
In elderly persons, the incidence of sepsisor septic shock and the
related mortality rates are substantiallyhigher than those in
younger persons. The projected growth ofthe elderly population in
the United States will contributeto an increase in incidence of 1.5
percent per year, yieldingan estimated 934,000 and 1,110,000 cases
by the years 2010 and2020, respectively.29
The present annual cost of this diseaseis estimated to be $16.7
billion.29
The transition from the systemic inflammatory response syndrometo
severe sepsis and septic shock involves a myriad of pathogenicchanges, including circulatory abnormalities that result inglobal tissue hypoxia.1,2
These pathogenic changes have beenthe therapeutic target of previous
outcome studies.12
Althoughthis transition occurs over time, both out of the hospital
andin the hospital, in outcome studies interventions have
usuallybeen initiated after admission to the intensive care unit.12In studies of goal-directed hemodynamic optimization, in particular,there was no benefit in terms of outcome with respect to normaland supranormal hemodynamic end points, as well as those guidedby mixed venous oxygen saturation.9,13
In contrast, even thoughwe enrolled patients with lower central
venous oxygen saturationand lower central venous pressure than those
studied by Gattinoniet al.9
and with a higher lactate concentration than those studiedby Hayes
et al.,13
we found significant benefits with respectto outcome when
goal-directed therapy was applied at an earlierstage of disease. In
patients with septic shock, for example,Hayes et al. observed a
higher in-hospital mortality rate withaggressive hemodynamic
optimization in the intensive care unit(71 percent) than with
control therapy (52 percent), whereaswe observed a lower mortality
rate in patients with septic shockassigned to early goal-directed
therapy (42.3 percent) thanin those assigned to standard therapy
(56.8 percent).
The benefits of early goal-directed therapy in terms of outcomeare multifactorial. The incidence of death due to sudden
cardiovascularcollapse in the standard-therapy group was
approximately doublethat in the group assigned to early
goal-directed therapy, suggestingthat an abrupt transition to severe
disease is an importantcause of early death. The early
identification of patients withinsidious illness (global tissue
hypoxia accompanied by stablevital signs) makes possible the early
implementation of goal-directedtherapy. 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 systemicinflammatory response syndrome, global tissue hypoxia
independentlycontributes to endothelial activation and disruption of
thehomeostatic balance among coagulation, vascular
permeability,and vascular tone.30
These are key mechanisms leading to microcirculatoryfailure,
refractory tissue hypoxia, and organ dysfunction.2,30When early therapy is not comprehensive, the progression tosevere disease may be well under way at the time of admissionto the intensive care unit.16
Aggressive hemodynamic optimizationand other therapy12
undertaken thereafter may be incompletelyeffective or even
deleterious.13
The value of measurements of venous oxygen saturation at theright
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 areabove 65 percent. In
patients in the intensive care unit whohave hyperdynamic septic
shock, the mixed venous oxygen saturationis rarely below 65
percent.32
In contrast, our patients wereexamined during the phase of
resuscitation in which the deliveryof supplemental oxygen is
required (characterized by a decreasedmixed venous oxygen saturation
and an increased lactate concentration),when the central venous
oxygen saturation generally exceedsthe mixed venous oxygen
saturation.33,34
The initial centralvenous oxygen saturation was less than 50 percent
in both studygroups. The mixed venous oxygen saturation is estimated
to be5 to 13 percent lower in the pulmonary artery33
and 15 percentlower in the splanchnic bed.35
Though not numerically equivalent,these ranges of values are
pathologically equivalent and areassociated with high mortality.32,36
Among all the patientsin the current study in whom the goals with
respect to centralvenous pressure, mean arterial pressure, and urine
output duringthe first six hours were met, 39.8 percent of those
assignedto standard therapy were still in this oxygen-dependent
phaseof resuscitation at six hours, as compared with 5.1
percentof those assigned to early goal-directed therapy. The
combined56.5 percent in-hospital mortality of this 39.8 percent of
patients,who were at high risk for hemodynamic compromise, is
consistentwith the results of previous studies in the intensive care
unit.32,36
In an open, randomized, partially blinded trial, there are unavoidableinteractions during the initial period of the study. As thestudy progressed, the patients in the standard-therapy groupmay have received some form of goal-directed therapy, reducingthe treatment effect. This reduction may have been offset bythe slight but inherent bias resulting from the direct influenceof the investigators on the care of the patients in the treatmentgroup. The potential period of bias was 9.9±19.5 percentof the
overall hospital stay in the standard-therapy group and7.2±12.0
percent of that in the group assigned to earlygoal-directed therapy
(P=0.20). This interval was minimal incomparison with those in
previous studies9,13
because the clinicianswho assumed responsibility for the remainder
of hospitalizationwere completely blinded to the randomization
order.
We conclude that goal-directed therapy provided at the earlieststages of severe sepsis and septic shock, though accountingfor
only a brief period in comparison with the overall hospitalstay, has
significant short-term and long-term benefits. Thesebenefits arise
from the early identification of patients athigh risk for
cardiovascular collapse and from early therapeuticintervention to
restore a balance between oxygen delivery andoxygen demand. In the
future, investigators conducting outcometrials in patients with
sepsis should consider the quality andtiming of the resuscitation
before enrollment as an importantoutcome 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
NovaBiomedical (which provided equipment for laboratory
assays).
We are indebted to the nurses, residents, senior staff attendingphysicians, pharmacists, patient advocates, technicians, andbilling and administrative personnel of the Department of EmergencyMedicine; to the nurses and technicians of the medical and surgicalintensive care units; and to the staff members of the Departmentof Respiratory Therapy, Department of Pathology, Departmentof
Medical Records, and Department of Admitting and Dischargefor their
patience and their cooperation in making this studypossible.
* The members of
the Early Goal-Directed Therapy CollaborativeGroup 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 erivers1{at}hfhs.org
.
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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-TherapyCollaborative 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,
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