American Journal of Emergency Medicine 33 (2015) 186–189

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American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

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 r t i c l e i n f o a b s t r a c t

Article history: Objective: The objective was to assess whether fluid balance had a determinant impact on mortality rate in a
Received 11 October 2014 cohort of critically ill patients with severe sepsis or septic shock.
Received in revised form 25 October 2014 Design: A prospective and observational study was carried out on an inception cohort.
Accepted 7 November 2014 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
⁎ 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).
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

http://dx.doi.org/10.1016/j.ajem.2014.11.016
0735-6757/© 2014 Elsevier Inc. All rights reserved.
 J.-M. Sirvent et al. / American Journal of Emergency Medicine 33 (2015) 186–189 187

Assessment (SOFA) score [7], and comorbidities. The kind of fluids used Table 2
in the volume resuscitation of patients was always balanced electrolyte Fluid balance and variables between survivors and nonsurvivors⁎

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