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1. Original Contribution
Fluid balance in sepsis and septic shock as a determining factor
of mortality
Josep-Maria Sirvent, MD, PhD a,
⁎, Cristina Ferri, MD b
, Anna Baró, MD a
,
Cristina Murcia, MD a
, Carolina Lorencio, MD a
a
Department of Intensive Care (ICU), University Hospital of Girona Doctor Josep Trueta, IDIBGI, CIBERES, Girona, Spain
b
Department of Intensive Care (ICU), University Hospital of Tarragona Joan XXIII, Tarragona, Spain
a b s t r a c ta r t i c l e i n f o
Article history:
Received 11 October 2014
Received in revised form 25 October 2014
Accepted 7 November 2014
Objective: The objective was to assess whether fluid balance had a determinant impact on mortality rate in a
cohort of critically ill patients with severe sepsis or septic shock.
Design: A prospective and observational study was carried out on an inception cohort.
Setting: The setting was an intensive care unit of a university hospital.
Patients: Patients admitted consecutively in the intensive care unit who were diagnosed with severe sepsis or
septic shock were included.
Interventions: Demographic, laboratory, and clinical data were registered, as well as time of septic shock onset,
illness severity (Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment), and comorbidi-
ties. Daily and accumulated fluid balance was registered at 24, 48, 72, and 96 hours. Survival curves representing
28-day mortality were built according to the Kaplan-Meier method.
Results: A total of 42 patients were included in the analysis: men, 64.3%; mean age, 61.8 ± 15.9 years. Septic shock
was predominant in 69% of the cases. Positive blood cultures were obtained in 17 patients (40.5%). No age, sex,
Sepsis-related Organ Failure Assessment, creatinine, lactate, venous saturation of O2, and troponin differences
were observed upon admission between survivors and nonsurvivors. However, higher Simplified Acute Physiol-
ogy Score II was observed in nonsurvivors, P = .016. Nonsurvivors also showed higher accumulated positive fluid
balance at 48, 72, and 96 hours with statistically significant differences. Besides, significant differences (P = .02)
were observed in the survival curve with the risk of mortality at 72 hours between patients with greater than 2.5
L and less than 2.5 L of accumulated fluid balance.
Conclusions: Fluid administration at the onset of severe sepsis or septic shock is the first line of hemodynamic
treatment. However, the accumulated positive fluid balance in the first 48, 72, and 96 hours is associated with
higher mortality in these critically ill patients.
© 2014 Elsevier Inc. All rights reserved.
1. Introduction
In severe sepsis and septic shock, the main elements of treatment are
intravenous fluids, appropriate antibiotics, source control, vasopressors,
and ventilatory support [1]. For more than 10 years, the administration
of intravenous fluids has been known as a key in the initial stages of
sepsis resuscitation, as proven by a classic article on goal-based treat-
ments [2]. Anyway, it is now recognized that the administration of
excess fluid in sepsis may lead to worsened respiratory function,
increased intraabdominal pressure, worsened coagulopathy, and
increased probability of cerebral edema [3]. Some authors observed dif-
ficulty in fluid balance management in critically ill patients, and positive
fluid balance is associated with increased mortality rates in patients
with acute lung injury and septic shock [4,5]. For all these reasons, the
present observational study was designed to assess whether fluid
balance has a determinant impact on mortality in a well-defined cohort
of patients with severe sepsis or septic shock.
2. Methods
2.1. Population and data collection
Our study includes the patients admitted consecutively in the inten-
sive care unit (ICU) of a teaching hospital for 4 months (from October
2012 to January 2013) that were diagnosed with severe sepsis or septic
shock. It is a prospective and observational study on an inception cohort.
Patients with septic shock were identified by a specific team of
intensivists. Demographic, laboratory, and clinical data were registered:
age, sex, time of septic shock onset, focus of infection, presence of initial
acute kidney injury, severity of illness based on the Simplified Acute
Physiology Score (SAPS) II score [6], the Sepsis-related Organ Failure
American Journal of Emergency Medicine 33 (2015) 186–189
⁎ Corresponding author. Department of Intensive Care (ICU), University Hospital of
Girona Doctor Josep Trueta, Avda de França s/n, E-17007 Girona, Spain. Tel.: +34 972
940 288; fax: +34 972 940 296.
E-mail address: jsirvent.girona.ics@gencat.cat (J.-M. Sirvent).
http://dx.doi.org/10.1016/j.ajem.2014.11.016
0735-6757/© 2014 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine
journal homepage: www.elsevier.com/locate/ajem

2. Assessment (SOFA) score [7], and comorbidities. The kind of fluids used
in the volume resuscitation of patients was always balanced electrolyte
solution (Plamasmalyte 148) at the doses proposed by Surviving Sepsis
Campaign Guidelines [1]. Daily and accumulated fluid balance was
registered at 24, 48, 72, and 96 hours. Initial echocardiogram (within
the first 24 hours) was completed on 26 patients to evaluate percentage
ejection fraction (EF). Patients were excluded if they had developed
septic shock outside hospital requiring fluid management and vasopres-
sor drugs before their transfer to ICU. Data collection and patient inclu-
sion in the study were performed after obtaining informed consent.
2.2. Definitions
Severe sepsis was defined by the presence of acute infection and
organ dysfunction. Septic shock was defined by acute organ dysfunction
(acute renal failure, respiratory failure) in the presence of an infection
and the need of vasopressor treatment for more than 6 hours [1]. The
initial time of severe sepsis and septic shock was determined upon
ICU admission by this diagnosis. When EF was less than 45%, patients
were classified as having cardiac dysfunction.
2.3. Statistical analysis
Descriptive statistics of demographic and clinical variables included
means and standard deviations for quantitative variables and percent-
ages for qualitative variables. For unadjusted comparisons between or
among groups, continuous variables were compared by using Student
t test in case of normally distributed data or Mann-Whitney U test for
nonnormally distributed data. Categorical variables were compared by
using the χ2
test or Fisher exact test where appropriate. Comparative
variables for mortality at 28 days were studied by means of bivariate
analysis. Survival curves representing mortality at 28 days were con-
structed according to the Kaplan-Meier method and compared with
the Mantel-Haenszel log-rank test. P b .05 was considered statistically
significant for all comparisons. Statistical analyses were performed
using SPSS (version 12; SPSS Inc, Chicago, IL).
3. Results
A total of 42 patients were included in the analysis. Epidemiologic
results were as follows: predominance of men (64.3%); mean age was
61.8 ± 15.9 years; cases of septic shock were predominant (69%).
Positive blood cultures were obtained in 17 patients (40.5% of the
cases). The most frequent initial infectious focus was abdominal
(48%), followed by respiratory (17%). Infections were community
acquired in almost 70% of the cases. Severity scores upon ICU admission
were 44.6 ± 16.1 and 7.1 ± 3.4 points in SAPS II and SOFA, respectively.
Besides, 28-day mortality was observed in 15 patients (35.7%), all of
them in the septic shock group. Five out of 26 patients (19.2%) were
classified as having cardiac dysfunction by EF less than 45% (see popula-
tion characteristics in Table 1).
Table 2 presents differences in fluid balance and variables between
survivors and nonsurvivors. No age, sex, SOFA score, creatinine, lactate,
venous saturation of O2 (SatvO2), and troponin T differences were re-
ported upon admission between survivors and nonsurvivors. However,
higher SAPS II score was observed in nonsurvivors (52.5 ± 15.4 vs 40.2
± 14.9, P = .016). Nonsurvivors also showed higher accumulated posi-
tive fluid balance at 48, 72, and 96 hours with significant differences.
Fig. 1 shows a box plot with the greater daily accumulated fluid
balance in milliliters at 48, 72, and 96 hours in nonsurvivors, with statis-
tically significant differences. Fig. 2 shows the survival curve with the
risk of survival at 72 hours between patients with greater than 2.5 L
and less than 2.5 L of accumulated fluid balance, compared by log-rank
test with significant differences (P = .02).
4. Discussion
Our observational study shows that the accumulated positive fluid
balance at 48, 72, and 96 hours is associated with higher mortality in
ICU-admitted patients with sepsis or septic shock.
These results are consistent with those by Boyd et al [5], who
showed that higher positive fluid balance in resuscitation over the
first 4 days was associated with increased risk of mortality in septic
shock patients. Other factors such as creatinine, lactate, SatvO2, and
Table 1
Characteristics of the study population⁎
Variable All patients (N = 42)
Demographics
Age, y 61.8 (15.9)
Sex, male, n (%) 27 (64.3)
SAPS II upon admission, points 44.6 (16.1)
SOFA upon admission, points 7.1 (3.4)
Coexisting conditions, n (%)
Smokers 16 (38.1)
Alcohol abuse 9 (21.4)
Liver disease 4 (9.5)
Congestive heart failure 8 (19.0)
Cerebral stroke 4 (9.5)
Chronic kidney disease 2 (4.8)
Diabetes mellitus 8 (19.0)
Immunosuppression 6 (14.3)
Clinical data, n (%)
Severe sepsis 13 (31.0)
Septic shock 29 (69.0)
Bacteremia 17 (40.5)
Cardiac dysfunction†
5/26 (19.2)
Infective focus, n (%)
Abdomen 20 (47.6)
Respiratory 7 (16.7)
Soft tissues 4 (9.5)
Urinary tract 3 (7.1)
Others 8 (19.1)
Outcome
Length of ICU stay, d 11.5 (15.4)
Length of hospital stay, d 23.2 (20.7)
ICU mortality, n (%) 14 (33.3)
Mortality at 28 d, n (%) 15 (35.7)
Hospital mortality, n (%) 18 (42.9)
⁎ Data are expressed as mean (SD).
†
Echocardiogram performed in 26 out of 42 patients.
Table 2
Fluid balance and variables between survivors and nonsurvivors⁎
Variable Survivors
(n = 27)
Non-survivors
(n = 15)
P value†
Age, y 58.9 (17.6) 66.9 (11.3) .122
Sex, male, n (%) 17 (62.9) 10 (66.6) .810
SAPS II upon admission, points 40.2 (14.9) 52.5 (15.4) .016
SOFA upon admission, points 6.9 (3.2) 7.6 (3.6) .518
Initial creatinine (mg/dL) 1.5 (1.3) 1.9 (1.7) .452
Initial lactate (mg/dL) 18.9 (14.7) 28.6 (18.6) .072
Initial SatvO2 (%) 77 (9) 72 (9) .118
Troponin T hs (ng/dL) 32.5 (36.3) 115.6 (180.4) .099
Fluid balance (mL) within 24 h 1710.4 (1955.4) 3153.5 (3118.9) .096
Fluid balance (mL) within 48 h 1791.6 (2349.1) 4394.3 (3477.6) .020
Fluid balance (mL) within 72 h 1128.1 (3312.6) 5401.6 (3961.4) .002
Fluid balance (mL) within 96 h 4612.8 (4220.0) 6678.6 (4656.5) .001
Fluid balance 24 h N2.0 L 10 (37.0) 11 (73.3) .024
Fluid balance 48 h N2.5 L 12 (44.4) 11 (73.3) .071
Fluid balance 72 h N2.5 L 11 (40.7) 12 (80.0) .014
Fluid balance 96 h N2.5 L 10 (37.0) 12 (80.0) .008
Severe sepsis 13 (48.1) 0 (0.0) .001
Septic shock 14 (51.8) 15 (100.0) .980
Bacteremia 11 (40.7) 6 (40.0) .963
⁎ Data are expressed as mean (SD).
†
χ2
de Pearson or Fisher test for qualitative data and Student t or Mann-Whitney U test
for quantitative data.
187J.-M. Sirvent et al. / American Journal of Emergency Medicine 33 (2015) 186–189

3. troponin showed no statistical differences between survivors and
nonsurvivors in our study.
Micek et al [8] studied the cardiac function and accumulated fluid
balance in septic shock in a recent work and concluded that cumulative
fluid balance and cardiac dysfunction predict outcome in septic shock
patients. Cardiac function was studied only in 26 out of 42 patients in
the present work; and therefore, no conclusions could be drawn on
this issue, but these data should be taken as preliminary and analyze
in future studies.
Cordemans et al [9] observed that fluid balance and extravascular
lung water index were mortality predictors in critically ill patients
requiring mechanical ventilation. Thus, clinicians treating septic shock
patients should carefully assess the need for intravenous fluids both in
the immediate resuscitation period and over the subsequent days of
treatment. The use of more conservative fluid administration protocols
in patients with severe sepsis and septic shock needs further study to
determine their relative efficacy compared to standard care therapy [8].
Associations between increased cumulative positive fluid balance
and long-term adverse outcomes have been reported in sepsis patients
[5]. In tests of liberal vs goal-based treatments or restrictive fluid strate-
gies in patients with acute respiratory distress syndrome—particularly in
perioperative patients [3,4]—restrictive fluid strategies were associated
with reduced morbidity. However, because there is no consensus on
the definition of these strategies, high-quality tests in specific patients
populations are required [10].
The mechanisms by which positive fluid balance can adversely
influence outcomes remain unknown. However, hypervolemia or
hyperosmolarity might exacerbate capillary leak in septic shock patients,
thus contributing to pulmonary edema. Positive fluid balance could also
result in intraabdominal hypertension, thus contributing to organ hypo-
perfusion development and subsequent organ failure [11,12]. Acute
renal failure coexisting with sepsis may worsen outcomes as well as
lead to positive fluid balance [13].
Our study has important limitations. Firstly, it was performed in one
only middle-sized and university hospital and may therefore have no
external validity for other institutions. Secondly, our observational de-
sign and the lower number of studied patients tan other studies of
fluid balance, limit our ability to determine a causal relationship be-
tween fluid balance and outcomes. And thirdly, the fact that cardiac
function was only studied in 26 of the 42 patients leaves out an impor-
tant predictor of mortality. Finally, other factors such as antibiotic ther-
apy, focus control, and some other unmeasured clinical parameters may
have contributed to our findings. Recommendations in the guidelines
for sepsis treatment are well known to have recently been questioned,
specifically the early goal-directed treatment [14]. The same applies to
the recommendations of the type of fluid used for sepsis and septic
shock. For all these reasons, it is difficult to standardize a single treat-
ment protocol for these critically ill patients, as well as to draw clear
conclusions from observational studies.
Lastly, selection, timing, doses, and fluid balance in sepsis and septic
shock should also be evaluated very carefully with the aim of maximizing
efficacy and minimizing iatrogenic toxicity [15].
In conclusion, fluid administration upon the onset of severe sepsis or
septic shock is the first line of hemodynamic treatment in this clinical
situation. There is no doubt that the study of cardiac function by echo-
cardiography helps us better understand the prognosis of these
patients. However, the accumulated positive fluid balance in the first
48, 72, and 96 hours is associated with higher mortality in these critically
ill, ICU-admitted patients.
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Accumulated Fluid Balance
72h < or >2,5L
Fig. 2. Survival curve with the risk of survival at 72 hours between patients with greater
than 2.5 L and less than 2.5 L of accumulated fluid balance.
FluidBalance(mL)
Fig. 1. Comparative box plot showing accumulated fluid balance in milliliters at 24, 48, 72,
and 96 hours between survivors and nonsurvivors.
188 J-M. Sirvent et al. / American Journal of Emergency Medicine 33 (2015) 186–189

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189J.-M. Sirvent et al. / American Journal of Emergency Medicine 33 (2015) 186–189