medical

1. The Importance of Fluid Management in
Acute Lung Injury Secondary to Septic
Shock
Claire V. Murphy, PharmD; Garrett E. Schramm, PharmD;
Joshua A. Doherty, BS; Richard M. Reichley, RPh; Ognjen Gajic, MD, FCCP;
Bekele Afessa, MD, FCCP; Scott T. Micek, PharmD; and
Marin H. Kollef, MD, FCCP
Background: Recent studies have suggested that early goal-directed resuscitation of patients with
septic shock and conservative fluid management of patients with acute lung injury (ALI) can
improve outcomes. Because these may be seen as potentially conflicting practices, we set out to
determine the influence of fluid management on the outcomes of patients with septic shock
complicated by ALI.
Methods: A retrospective analysis was performed at Barnes-Jewish Hospital (St. Louis, MO)
and in the medical ICU of Mayo Medical Center (Rochester, MN). Patients hospitalized with
septic shock were enrolled into the study if they met the American-European Consensus
definition of ALI within 72 h of septic shock onset. Adequate initial fluid resuscitation (AIFR)
was defined as the administration of an initial fluid bolus of > 20 mL/kg prior to and
achievement of a central venous pressure of > 8 mm Hg within 6 h after the onset of therapy
with vasopressors. Conservative late fluid management (CLFM) was defined as even-to-
negative fluid balance measured on at least 2 consecutive days during the first 7 days after
septic shock onset.
Results: The study cohort was made up of 212 patients with ALI complicating septic shock.
Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and
higher for those achieving only CLFM, those achieving only AIFR, and those achieving
neither (17 of 93 patients [18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53 patients [56.6%] vs
27 of 35 [77.1%], respectively; p < 0.001).
Conclusions: Both early and late fluid management of septic shock complicated by ALI can
influence patient outcomes. (CHEST 2009; 136:102–109)
Abbreviations: AIFR ⫽ adequate initial fluid resuscitation; ALI ⫽ acute lung injury; ANOVA ⫽ analysis of
variance; APACHE ⫽ acute physiology and chronic health evaluation; BMI ⫽ body mass index; CLFM ⫽
conservative late fluid management; Fio2 ⫽ fraction of inspired oxygen; IQR ⫽ interquartile range; ScvO2 ⫽
central venous oxygen saturation; SOFA ⫽sepsis-related organ failure assessment
Despite advances in medical practice, severe sep-
sis and septic shock remain responsible for
significant morbidity and mortality.1,2 Early goal-
directed cardiovascular resuscitation decreases mor-
tality in patients with septic shock.3–5 Acute lung
injury (ALI) is a frequent complication of septic
shock that is a risk factor for its occurrence.6 Several
studies7–10 have demonstrated that conservative fluid
management in patients with ALI can improve pa-
tient outcomes including reduced mortality and
fewer days of mechanical ventilation. The most
recent Surviving Sepsis Campaign11 addressed the
initial phase of fluid resuscitation in patients with
septic shock, providing goals for resuscitation and a
conservative fluid strategy for patients with estab-
lished ALI who do not have evidence of tissue
hypoperfusion. The adoption of best practices for the
management of septic shock and ALI should result
in improved patient outcomes.12–18 Therefore, we set
out to perform a study with two main goals. The first
goal was to determine the relationship of both
adequate initial fluid resuscitation (AIFR) of patients
with septic shock and conservative late fluid man-
agement (CLFM) of patients with ALI to hospital
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CRITICAL CARE MEDICINE
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2. mortality. The second study goal was to establish
whether AIFR and CLFM had additive effects on
patient outcomes.
Materials and Methods
Study Location and Patients
The study was conducted at the following two academic
medical centers: Barnes-Jewish Hospital/Washington University
Medical Center (1,300 beds) in St. Louis, MO, and the medical
ICU of Mayo Medical Center (1,951 beds) in Rochester, MN.
The study was approved by the institutional review boards of both
institutions. Hospitalized patients with septic shock who had
been admitted between January 1, 2005, and December 31, 2006
(to Barnes-Jewish Hospital), and between March 1, 2004, and
April 1, 2007 (to Mayo Medical Center), requiring mechanical
ventilation in an ICU for ⬎ 24 h were eligible for this investiga-
tion. All patients had to meet the American-European Consensus
definition of ALI within 72 h of the onset of septic shock. Patients
were excluded if they had been hospitalized for ⬍ 7 days after the
onset of septic shock; had evidence of non–sepsis-related cardio-
vascular compromise as defined by acute myocardial infarction,
cardiogenic shock, or a history of congestive heart failure with an
ejection fraction ⬍ 40%; had a requirement for extracorporeal
membrane oxygenation or the use of a ventricular assist device; or
developed septic shock at an outside hospital requiring vasopres-
sor and fluid management prior to transfer. If a patient met the
inclusion criteria on multiple occasions within the study period,
only the first episode of septic shock complicated by ALI was
reviewed.
Study Design
A retrospective cohort study was performed with hospital
mortality as the primary outcome parameter. Secondary out-
comes included ICU and hospital length of stay, duration of
mechanical ventilation, total quantity of IV and enteral fluids
administered, and the prescription of appropriate initial antimi-
crobial treatment. For the purposes of determining compliance
with early goal-directed treatment guidelines and the timing of
antibiotic administration, the time of septic shock onset was
defined as the time that a vasopressor agent, either norepineph-
rine or dopamine, was first administered. All pertinent data were
then collected relative to this time.
Data Collection
Patients with septic shock were identified electronically by
International Classification of Diseases, ninth revision, codes for
acute organ dysfunction and acute infection, and by an active
order for a vasopressor through the pharmacy database at
Barnes-Jewish Hospital or prospective surveillance at Mayo
Medical Center. For the purpose of this study, septic shock was
further limited to patients requiring vasopressor support for ⬎ 1 h.
From this electronic list, patients with ALI were also identified
using chest radiograph reports, Pao2/fraction of inspired oxygen
(Fio2) ratio, the requirement for mechanical ventilation, and
medical record and available echocardiographic data indicating
the absence of acute cardiac disease as the etiology for the
pulmonary infiltrates. Data were collected retrospectively from
automated patient medical records and pharmacy databases at
both Barnes-Jewish Hospital and Mayo Medical Center by the
investigators (C.V.M., G.E.S., J.A.D., R.M.R., and O.G.). Patient
identifiers were removed from any aggregated data and were
coded with a numbered assignment. A master list of the coding,
which contained the number assignment and corresponding
patient name, and the raw encoded data, was maintained in a
password-locked folder on a password-protected computer.
Pertinent demographic, laboratory, and clinical data were
gathered and recorded on a structured data collection form,
including age, gender, race, patient location at the time of septic
shock and ALI onset, severity of illness based on the acute
physiology and chronic health evaluation (APACHE) II score19
and the sepsis-related organ failure assessment (SOFA) score,20
comorbidities, site of the infection, and positive cultures with
sensitivities. Patient-specific factors starting at the time of septic
shock onset were also collected, including vital signs, hemody-
namic measurements, and laboratory data. Information regarding
the management of septic shock and ALI was recorded, including
achievement of early goal-directed resuscitation, time to appro-
priate antimicrobial agent administration, steroid administration,
mechanical ventilator settings, and daily fluid balances (including
both IV and enteral fluid intake).
Definitions
Septic shock was defined as noted earlier by an International
Classification of Diseases, ninth revision, code for acute organ
dysfunction (eg, acute renal failure and respiratory failure) in the
presence of an acute infection and by an active order for a
vasopressor that was administered for ⬎ 1 h. The onset of septic
shock was defined as the time of vasopressor initiation. The
definition for ALI for this investigation21 was based on the
American-European Consensus definition and defined as bilat-
eral infiltrates on the chest radiograph, acute onset of respiratory
failure requiring mechanical ventilation, Pao2/Fio2 ratio ⬍ 300
mm Hg, and a pulmonary artery occlusion pressure ⱕ 18 mm
Hg, or no evidence of left atrial hypertension. Pulmonary artery
catheters were not routinely used, and the assessment of left
atrial hypertension was at the discretion of the treating clinician.
The etiology of ALI was deemed to be septic shock if the patient
met the criteria for ALI within 72 h of the onset of septic shock.11
The APACHE II and SOFA scores were calculated from clinical
data available from the first 24-h period surrounding the onset of
septic shock. Obesity was defined as a body mass index (BMI)
ⱖ 40 kg/m2
.
Appropriate empiric antimicrobial therapy was defined as
antimicrobial agents administered within 24 h of the onset of
septic shock that were active against the pathogen associated with
septic shock, based on susceptibility testing.22 AIFR was defined
as the administration of an initial fluid bolus of ⱖ 20 mL/kg prior
to vasopressor therapy initiation and the achievement of a central
From the Department of Pharmacy (Drs. Murphy and Micek),
Barnes-Jewish Hospital, St. Louis, MO; Hospital Pharmacy Ser-
vices (Dr. Schramm), and the Division of Pulmonary and Critical
Care Medicine (Drs. Gajic and Afessa), Mayo Clinic, Rochester,
MN; Medical Informatics (Mr. Doherty and Mr. Reichley), BJC
Healthcare, St. Louis, MO; and the Division of Pulmonary and
Critical Care Medicine (Dr. Kollef), Washington University
School of Medicine, St. Louis, MO.
The authors have reported to the ACCP that no significant
conflicts of interest exist with any companies/organizations whose
products or services may be discussed in this article.
Manuscript received November 19, 2008; revision accepted
January 28, 2009.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/site/misc/reprints.xhtml).
Correspondence to: Marin H. Kollef, MD, FCCP, Division of
Pulmonary and Critical Care Medicine, Washington University
School of Medicine, 660 S Euclid Ave, Campus Box 8052, St.
Louis, MO 63110; e-mail: mkollef@im.wustl.edu
DOI: 10.1378/chest.08-2706
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3. venous pressure of ⱖ 8 mm Hg within 6 h after vasopressor
therapy initiation.11 CLFM was defined as even-to-negative fluid
balance on at least 2 consecutive days during the first 7 days after
septic shock onset.
Statistical Analysis
The primary data analysis compared hospital survivors to
hospital nonsurvivors. Continuous data were reported as the
mean ⫾ SD for parametric data and the median with interquar-
tile ranges (IQRs) for nonparametric data. The Student t test was
used when comparing parametric data, and the Mann-Whitney U
test was employed to analyze nonparametric data. Categorical
data were expressed as frequency distributions, and the ␹2
test
was used to determine whether differences existed between
groups. After univariate analysis, stepwise multivariable logistic
regression was undertaken to determine the independent risk
factors for hospital mortality. Risk factors significant at the 0.20
level in the univariate analysis were included in the models. The
values are reported as adjusted odds ratios and corresponding
95% confidence intervals. Analysis of variance (ANOVA) for
repeated measures was used for pairwise comparisons of fluid
balance between groups (survivors and nonsurvivors) and be-
tween time points within each group. All tests were two-tailed,
and a p value ⬍ 0.05 was determined to represent statistical
significance. Analyses were performed using a statistical soft-
ware package (SPSS, version 11.0.1 for Windows; SPSS, Inc;
Chicago, IL).
Results
Patients
Of the 212 patients included in the study, 125
(59%) survived and 87 (41%) died during hospital-
ization. Echocardiograms were employed in 82% of
the patients (174 of 212 patients) to exclude the
presence of pulmonary hypertension. Hospital non-
survivors were statistically more likely to be medical
ICU patients, had a lower incidence of obesity, and
were more likely to have been admitted to the
hospital from a health-care setting (Table 1). Hospi-
tal nonsurvivors were also more severely ill at base-
line compared to survivors, as indicated by higher
mean APACHE II and mean SOFA scores.
Process-of-Care Variables
Table 2 outlines the process-of-care variables for
survivors and nonsurvivors. Survivors received a
larger median fluid volume within the 6-h window of
septic shock onset (3,500 mL [IQR, 1,825 to 6,000]
vs 3,000 mL [IQR, 1,000 to 4,500], respectively;
p ⫽ 0.076). Survivors were also more likely to have
central venous pressure measured (92.0% vs 70.1%,
respectively; p ⬍ 0.001) and to have a documented
central venous pressure ⱖ 8 mm Hg (79.2% vs
54.0%, respectively; p ⬍ 0.001) within the 6-h win-
dow of septic shock onset. There was no difference
in central venous oxygen saturation (ScvO2) mea-
surement or attainment of an ScvO2 of ⱖ 70%.
Those patients who received colloids (albumin or
hetastarch) or packed RBCs as part of their fluid
resuscitation were noted to have a statistically higher
rate of hospital death. Figure 1 depicts the average
daily fluid balance between nonsurvivors and survi-
vors from the onset of septic shock through hospital
day 7. Significant differences in average fluid balance
for both groups were observed when compared to
the previous 24-h time frame (days 2 to 5). When
average daily fluid balances were compared, there
were statistically significant differences on days 3 to
7 after the onset of septic shock for nonsurvivors and
survivors. Figure 2 shows a similar pattern when
Table 1—Baseline Characteristics
Variables
Survivors
(n ⫽ 125)
Nonsurvivors
(n ⫽ 87) p Value
Age, yr 58.5 ⫾ 15.8 60.7 ⫾ 14.9 0.296
Male gender 62 (49.6) 47 (54.0) 0.526
Race 0.830
White 94 (75.2) 65 (74.7)
African-American 26 (20.8) 17 (19.5)
Other 5 (4.0) 5 (5.7)
BMI ⱖ 40 kg/m2
23 (18.4) 6 (6.9) 0.024
Charlson comorbidity
score
3.7 ⫾ 3.6 4.8 ⫾ 4.0 0.041
Coexisting conditions
Coronary artery
disease
24 (19.2) 16 (18.4) 0.882
COPD 30 (24.0) 21 (24.1) 0.982
Cirrhosis 15 (12.0) 14 (16.1) 0.394
Chronic kidney
disease
18 (14.4) 19 (21.8) 0.198
Long-term
hemodialysis
2 (1.6) 5 (5.7) 0.126
Diabetes 46 (36.8) 22 (25.3) 0.100
Active malignancy 14 (11.2) 12 (13.8) 0.671
HIV positive 1 (0.8) 3 (3.4) 0.308
Solid organ transplant 13 (10.4) 9 (10.3) 0.990
Other
immunosuppression
23 (18.4) 17 (19.5) 0.860
Location prior to ICU
admission
0.003
Home 81 (64.8) 43 (49.4)
Extended-care facility/
nursing home
8 (6.4) 19 (21.8)
Hospital 36 (28.8) 25 (28.7)
Medical ICU 72 (57.6) 62 (71.3) 0.042
APACHE II score 23.9 ⫾ 6.0 26.7 ⫾ 7.3 0.003
SOFA score 9.5 ⫾ 2.5 11.0 ⫾ 3.3 ⬍ 0.001
Respiratory variables
Tidal volume, mL/kg
IBW
7.6 ⫾ 1.5 7.6 ⫾ 1.6 0.889
Pao2/Fio2 ratio 168.3 ⫾ 65.7 155 ⫾ 66.0 0.157
PEEP 6.7 ⫾ 2.6 7.0 ⫾ 2.7 0.360
Neuromuscular
blockade
28 (22.4) 16 (18.4) 0.497
Values are expressed as the mean ⫾ SD or No. (%), unless otherwise
indicated. IBW ⫽ ideal body weight; PEEP ⫽ positive end-expiratory
pressure.
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4. average cumulative fluid balances were compared to
the previous time frames and between study groups.
In comparison to nonsurvivors, survivors had lower
cumulative fluid balances for days 3 to 7.
There were no significant differences for vaso-
pressor selection between the two groups; however,
those patients who required vasopressor support at
day 7 after septic shock onset had higher mortality
rates. The majority of patients received norepineph-
rine and had low rates of dobutamine usage (Table
2). The median vasopressor infusion duration for
nonsurvivors was double that of survivors (4 days
[IQR, 2 to 6.5 days] vs 2 days [IQR, 1 to 3.5 days,
respectively; p ⬍ 0.001).
Outcomes and Multivariate Analysis
Patients achieving AIFR had a lower hospital
mortality compared to those not achieving AIFR (47
of 146 patients [32.2%] vs 40 of 66 patients [60.6%],
respectively; p ⬍ 0.001). Patients achieving CLFM
also had a lower hospital mortality compared to those
not achieving CLFM (30 of 121 patients [24.8%] vs
57 of 91 patients [62.6%], respectively; p ⬍ 0.001).
Hospital mortality was lowest for those patients
achieving both AIFR and CLFM and was higher for
those achieving only CLFM, those achieving only
AIFR, and those achieving neither (17 of 93 patients
[18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53
patients [56.6%] vs 27 of 35 patients [77.1%], respec-
tively; p ⬍ 0.001) [Fig 3]. Multivariate analysis iden-
tified not achieving either AIFR or CLFM, duration
of vasopressor administration, increasing Charlson
comorbidity score, increasing APACHE II score,
renal replacement therapy, and colloid administra-
tion as independent risk factors for hospital mortality
(Table 3).
Discussion
Our study demonstrated that both early and late
fluid management of septic shock complicated by
ALI may influence patient outcomes. We found that
achievement of AIFR and CLFM was associated
with statistically greater rates of hospital survival.
Our data also suggest that there may be an additive
effect of these fluid management strategies on
patient outcomes. Patients whose management at-
tained both AIFR and CLFM had the lowest risk of
hospital mortality, whereas patients who achieved
only one of these goals had intermediate hospital
Table 2—Process of Care Variables
Variables Survivors (n ⫽ 125) Nonsurvivors (n ⫽ 87) p Value
Initial IV fluid resuscitation
Volume within 6 h of septic shock onset
mL 3,500 (1,825–6,000) 3,000 (1,000–4,500) 0.076
mL/kg 45.5 (20.5–89.5) 42.9 (13.4–64.6) 0.132
CVP measured 115 (92.0) 61 (70.1) ⬍ 0.001
AIFR 99 (79.2) 47 (54.0) ⬍ 0.001
ScvO2 measured 57 (45.6) 34 (39.1) 0.345
ScvO2 ⱖ 70% 40 (32.0) 30 (34.5) 0.705
Colloids administered 59 (47.2) 53 (60.9) 0.049
PRBCs administered 87 (69.6) 71 (81.6) 0.048
Vasopressor and inotrope usage
Norepinephrine 117 (93.6) 86 (98.9) 0.062
Dopamine 20 (16.0) 18 (20.7) 0.467
Phenylephrine 17 (13.6) 5 (5.7) 0.071
Vasopressin 38 (30.4) 22 (25.3) 0.442
Epinephrine 1 (0.8) 3 (3.4) 0.308
Dobutamine 8 (6.4) 11 (12.6) 0.144
Requiring vasopressor support at day 7
after septic shock onset
11 (8.8) 25 (28.7) ⬍ 0.001
Late fluid management
Cumulative 7-day fluid balance, mL 8,062 (2,412–13,833) 13,694 (7,113–20,249) ⬍ 0.001
CLFM 91 (72.8) 30 (34.5) ⬍ 0.001
ICU fluid balance, mL 8,037 (2,487–13,575) 19,335 (9,765–27,274) ⬍ 0.001
Hospital fluid balance, mL 6,603 (⫺547–14,026) 22,231 (11,643–30,682) ⬍ 0.001
Appropriate initial antimicrobial therapy in
patients with positive cultures
43 (70.5) 24 (61.5) 0.353
Corticosteroids 70 (56.0) 50 (57.5) 0.832
Drotrecogin alfa activated 9 (7.2) 7 (8.0) 0.799
Values are expressed as the median (IQR) or No. (%), unless otherwise indicated. CVP ⫽ central venous pressure; PRBC ⫽ packed RBC.
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5. mortality, and those achieving neither had the great-
est risk of hospital mortality.
Septic shock and ALI are disease states requiring
timely and directed interventions.6,11 Appropriate fluid
management of septic shock appears to be an impor-
tant determinant of patient outcomes.3–5 Unfortu-
nately, despite the recommendations of the Surviving
Sepsis Campaign, there appears to be variation in the
management of this important parameter. Gao et al13
studied 101 patients with severe sepsis initially evalu-
ated outside of a critical care unit. They found that only
52% of these patients were treated in compliance with
their 6-h sepsis bundle. When they compared mortality
rates for patients receiving care based on the 6-h
bundle, the noncompliant group had a significantly
greater hospital mortality rate (49% vs 23%, respec-
tively; p ⫽ 0.01) despite similar severities of illness for
the two groups.
Fluid management in patients with ALI also ap-
pears to be an important determinant of hospital
mortality. Sakr et al8 showed that patients with
ARDS who survived their ICU stay achieved a net
negative fluid balance compared to nonsurvivors. A
positive mean fluid balance was also shown to be an
independent predictor of ICU mortality in their
investigation. Simmons et al23 found similar results
in their study of fluid balance in ARDS; Humphrey
et al24 demonstrated that patients with ARDS who
achieved goal-directed fluid removal had a statisti-
cally greater hospital survival compared to those not
attaining this therapeutic end point. Wiedemann et
al7 performed a large multicenter study to determine
whether conservative fluid management in ARDS
patients impacted survival. Although they demon-
strated no difference in hospital mortality, patients
assigned to the conservative fluid management group
had more ventilator-free and ICU-free days during
their hospital stay compared to patients in the liberal
fluid management group. It is important to note that
many of our patients were treated before these study
results were available. Additionally, we required that
patients achieve the negative fluid balance goals in
order to be classified as attaining CLFM, whereas in
the study by Wiedemann et al7 it was the application
of the process and not necessarily achieving the fluid
management goals that separated their study groups.
This difference may explain the lack of mortality
benefit in this earlier study.
The studies examining fluid balance in septic
shock and ALI patients individually, as well as our
Figure 1. Mean (⫾ SE) daily fluid balance (in milliliters) for days 1 through 7 following the onset of
septic shock. Nonsurvivors are depicted by squares, and survivors by circles. * ⫽ p ⬍ 0.05 pairwise
compared between survivors and nonsurvivors (ANOVA for repeated measures); † ⫽ p ⬍ 0.05
compared with the previous time point (ANOVA for repeated measures).
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6. data assessing fluid management in patients with
both syndromes, suggest that improvements in pa-
tient survival can be attained if patients improve to
the point where optimal fluid management practices
are able to be applied. The standardization of
evidence-based practices in the care of critically ill
patients with septic shock has become accepted as
the optimal method for their management.11 By
standardizing care, clinicians ensure that necessary
procedures and therapies are carried out in a timely
manner. They also allow practice changes to be more
accurately monitored in terms of their impact on
patient outcomes. The management of septic shock
easily lends itself to standardization because of the
importance of achieving early goal-directed resusci-
tation and administration of appropriate antimicro-
bial treatment.25 Similar arguments6,10,11,26 have
been made to standardize the treatment of ARDS/
ALI, given the complexity of this syndrome and
emerging evidence that specific practices are associ-
ated with improved patient outcomes. Although
there are expenses associated with implementing
treatment bundles for complex disorders like septic
shock and ALI, a cost analysis by Shorr et al27
suggests that optimizing the care of patients with
septic shock will reduce overall hospital costs.
Our study has several important limitations. First,
it was performed within two large teaching hospitals,
so the results may not be generalizable to other types
of institutions. However, the results are consistent with
those demonstrated by other investigations,3–5,7–10 sug-
gesting that these findings are more generalizable.
Second, the retrospective study design limits our
ability to determine a causal relationship between
the fluid management strategies examined and the
outcomes we evaluated. Despite the large odds
ratios, AIFR and CLFM may simply represent mark-
ers of disease severity and not determinants of
outcome. Third, because this was not a randomized
clinical trial we cannot distinguish between provider
actions and severity of illness. For example, we
cannot exclude the presence of potential interaction
between fluid therapy for septic shock and CLFM.
Patients with more persistent shock requiring ther-
apy with vasopressors, and thus more likely to die,
were unlikely to achieve negative fluid balance (ie,
CLFM). Fourth, we had few patients treated with
drotrecogin alfa activated and thus could not assess
the effect of this therapy on patient outcomes. Fifth,
it is important to note that in our study, AIFR
specifically refers to the initial fluid bolus adminis-
tered and corresponded to the positive fluid balance
Figure 2. Mean (⫾ SE) cumulative daily fluid balance (in milliliters) for days 1 through 7 following
the onset of septic shock. Nonsurvivors are depicted by squares, and survivors by circles. * ⫽ p ⬍ 0.05
pairwise compared between survivors and nonsurvivors (ANOVA for repeated measures); † ⫽ p ⬍ 0.05
compared with the previous time point (ANOVA for repeated measures).
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7. reported by Rivers et al3 in the first 6 h of their early
goal-directed therapy strategy. However, it is impor-
tant to note that other therapies such as the optimi-
zation of myocardial contractility and oxygen delivery
to tissues, manipulated by nonfluid approaches,
likely influenced patient outcomes as well.
Another potential limitation of our study, as well as
of other analyses of shock resuscitation, is defining
the timing of fluid resuscitation. Several studies28–31
have suggested that the prevention of tissue injury
and inflammation requires adequate fluid resuscita-
tion within 2 to 3 h and not ⬎ 6 h after shock onset.
Therefore, our definition of AIFR may not have
been specific enough to differentiate between pa-
tients achieving a beneficial effect from their initial
fluid resuscitation and those who did not. We also
included patients from two different hospitals with
different but overlapping enrollment periods. How-
ever, one of the authors (G.E.S.) worked at both
hospitals, and examination of the individual hospital
data showed the trends for both AIFR and CLFM to
be in the same direction as for the combined cohort,
suggesting that similar fluid resuscitation protocols
were followed at both sites. Finally, our study results
may not be applicable to patients with extremes of
illness because we excluded patients who did not
survive 24 h and those hospitalized for ⬍ 7 days. This
was done purposely to evaluate a more homogeneous
patient population.
In summary, the fluid management of patients
with septic shock complicated by ALI appears to be
an important determinant of hospital mortality. Both
early goal-directed fluid resuscitation and CLFM
seem to be independent aspects of fluid manage-
ment that affect patient outcomes.
References
1 Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiol-
ogy of severe sepsis in the United States: analysis of incidence
outcome and associated costs of care. Crit Care Med 2001;
29:1303–1310
2 Martin GS, Mannino DM, Eaton S, et al. The epidemiology
of sepsis in the United States from 1979 through 2000.
N Engl J Med 2003; 348:1546–1554
Figure 3. Hospital mortality according to whether or not patients achieved AIFR, CLFM, both, or
neither.
Table 3—Multivariate Analyses of Independent Risk
Factors for Hospital Mortality
Variables
Adjusted
OR 95% CI p Value
APACHE II score, 1-point
increments
1.07 1.01–1.14 0.030
Charlson comorbidity score,
1-point increments
1.11 1.01–1.23 0.040
Renal replacement therapy 3.15 1.51–4.79 0.020
Colloid administration 2.94 1.41–4.47 0.011
AIFR not achieved 4.94 2.07–11.79 ⬍ 0.001
Duration of vasopressors,
1-day increments
1.24 1.04–1.47 0.017
CLFM not achieved 6.13 2.77–13.57 ⬍ 0.001
Other covariates not in the table had a p value ⬍ 0.5, including BMI
ⱖ 40 kg/m2
, patient location prior to ICU admission, medical ICU
patients, and transfusion of packed RBCs (p ⫽ 0.588 关Hosmer-
Lemeshow goodness-of-fit test兴). CI ⫽ confidence interval; OR ⫽
odds ratio.
108 Original Research
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