Interaction between fluid balance and disease severity on patient outcome in the critically ill.
ABSTRACT There is evidence in literature regarding the benefits of immediate aggressive fluid resuscitation together with conservative fluid management approach after initial stabilization. This retrospective study assesses the relationship between fluid balance during intensive care unit (ICU) stay and outcomes among general critically ill patients. In addition, we also aim to see the effect of fluid gain among patients with different disease severity.
A total of 639 patients admitted into ICU who stayed for 3 days or more were evaluated. Fluid balances during ICU stay were recorded. A logistic regression analysis was performed to identify significant factors associated with hospital mortality.
Acute Physiology and Chronic Health Evaluation IV predicted risk of death, fluid balance on the second plus third ICU days, and total fluid balance during ICU stay were positively associated with hospital death. Significant positive fluid balance on first ICU day, in contrast, was negatively associated with hospital mortality. The positive correlation between standardized mortality ratio (Acute Physiology and Chronic Health Evaluation IV) and fluid gain on the second plus third ICU days increases with disease severity.
Early adequate fluid resuscitation together with conservative late fluid management may provide better patient outcomes. The effect of fluid management strategy on patient outcome may depend on the underlying disease severity.
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ABSTRACT: Although several urinary biomarkers have been validated as early diagnostic markers of acute kidney injury (AKI), their usefulness as outcome predictors is not well established. This study aimed to determine the diagnostic and prognostic abilities of urinary liver-type fatty acid-binding protein (L-FABP) in heterogeneous critically ill patients. We prospectively collected data on patients admitted to medical and surgical intensive care units (ICUs) from July 2010 to June 2011. Urine neutrophil gelatinase-associated lipocalin (NGAL) and L-FABP at the time of ICU admission were quantitated. Of the 145 patients, 54 (37.2%) had AKI defined by the Acute Kidney Injury Network (AKIN) criteria. AKI patients showed significantly higher level of urinary NGAL and L-FABP and also higher mortality than non-AKI patients. The diagnostic performances, assessed by the area under the ROC curve, were 0.773 for NGAL and 0.780 for L-FABP, demonstrating their usefulness in diagnosing AKI. In multivariate Cox analysis, urinary L-FABP was an independent predictor for 90-day mortality. Urinary L-FABP seems to be promising both for the diagnosis of AKI and for the prediction of prognosis in heterogeneous ICU patients. It needs to be further validated for clinical utility.Journal of Korean medical science 01/2013; 28(1):100-5. · 0.84 Impact Factor
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ABSTRACT: Liver transplantation carries major risks during the perioperative period. Few studies focused on the hemodynamics of patients undergoing liver transplantation. The present study was aimed to evaluate the impact of the implementation of a protocol including goal-directed therapy in patients undergoing liver transplantation. Our first goal was to determine its impact on the fluid balance. Secondarily, we evaluated possible improvements in the patient outcomes. A before and after study. Fifty patients undergoing liver transplantation were included during two successive six-month periods. During the first period, the management of the patients was left at the discretion of the senior physicians (control group, n=25). During the second period, the patients were treated according to a predetermined protocol including a specific hemodynamic monitoring (protocol group, n=25). The fluid balance was negative in the protocol group and positive in the control group at 24h (-606mL vs. +3445mL, P<0.01) and 48h (-2315mL vs. +1170mL, P<0.01) after liver transplantation. The volume of the crystalloid administration was lower in the protocol group than in the control group (5000mL vs. 8000mL, P<0.01, and 1500mL vs. 6000mL, P<0.01, during surgery and 48h after liver transplantation, respectively). The duration of mechanical ventilation and postoperative ileus were significantly reduced in the protocol group, as compared with the control group, 20h vs. 94h (P<0.01) and 4days vs. 6days (P<0.01), respectively. For patients undergoing liver transplantation, the implementation of a protocol aiming to optimize hemodynamics was associated with reduced fluid balance and decreased requirement for mechanical ventilation and postoperative ileus duration.Annales francaises d'anesthesie et de reanimation 01/2014; · 0.77 Impact Factor
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ABSTRACT: There are no studies that describe the impact of the cumulative fluid balance on the outcomes of cancer patients admitted to intensive care units ICUs. The aim of our study was to evaluate the relationship between fluid balance and clinical outcomes in these patients. One hundred twenty-two cancer patients were prospectively evaluated for survival during a 30-day period. Univariate (Chi-square, t-test, Mann-Whitney) and multiple logistic regression analyses were used to identify the admission parameters associated with mortality. The mean cumulative fluid balance was significantly higher in non-survivors than in survivors [1675 ml/24 h (471-2921) vs. 887 ml/24 h (104-557), P = 0.017]. We used the area under the curve and the intersection of the sensibility and specificity curves to define a cumulative fluid balance value of 1100 ml/24 h. This value was used in the univariate model. In the multivariate model, the following variables were significantly associated with mortality in cancer patients: the Acute Physiology and Chronic Health Evaluation II score at admission [Odds ratio (OR) 1.15; 95% confidence interval (CI) (1.05-1.26), P = 0.003], the Lung Injury Score at admission [OR 2.23; 95% CI (1.29-3.87), P = 0.004] and a positive fluid balance higher than 1100 ml/24 h at ICU [OR 5.14; 95% CI (1.45-18.24), P = 0.011]. A cumulative positive fluid balance higher than 1100 ml/24 h was independently associated with mortality in patients with cancer. These findings highlight the importance of improving the evaluation of these patients' volemic state and indicate that defined goals should be used to guide fluid therapy.Acta Anaesthesiologica Scandinavica 05/2012; 56(6):712-7. · 2.36 Impact Factor
Interaction between fluid balance and disease severity on
patient outcome in the critically ill☆,☆☆,★
Hoi Ping Shum FHKCP, FHKAM (Medicine)⁎, Frank Man Hon Lee,
King Chung Chan FHKCA, FHKAM (Anaesthesiology),
Wing Wa Yan FRCP, FHKCP, FHKAM (Medicine)
Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong SAR, China
Severity of illness
Purpose: There is evidence in literature regarding the benefits of immediate aggressive fluid
resuscitation together with conservative fluid management approach after initial stabilization. This
retrospective study assesses the relationship between fluid balance during intensive care unit (ICU) stay
and outcomes among general critically ill patients. In addition, we also aim to see the effect of fluid gain
among patients with different disease severity.
Methods: A total of 639 patients admitted into ICU who stayed for 3 days or more were evaluated. Fluid
balances during ICU stay were recorded. A logistic regression analysis was performed to identify
significant factors associated with hospital mortality.
Results: Acute Physiology and Chronic Health Evaluation IV predicted risk of death, fluid balance on the
second plus third ICU days, and total fluidbalance during ICU stay were positivelyassociated withhospital
mortality. The positive correlation between standardized mortality ratio (Acute Physiology and Chronic
Health Evaluation IV) and fluid gain on the second plus third ICU days increases with disease severity.
Conclusion: Early adequate fluid resuscitation together with conservative late fluid management may
the underlying disease severity.
© 2011 Elsevier Inc. All rights reserved.
Fluid therapy is a fundamental component of treatment in
critically ill patients. Interestingly, fluid balance has recently
emerged as a potential biomarker for survival in critically ill
patients . Appropriate initial fluid administration is vital
for those critically ill. In patient with severe sepsis and septic
shock, early goal–directed therapy (EGDT) with aggressive
initial fluid resuscitation clearly improved clinical outcomes
. A similar study published in 2009 also reported the
☆Financial support/ funding: None.
☆☆Declaration of interests: Nil for all authors.
★Trial registration: HKU clinical trial register (www.HKClinical
Trials.com, Ref: HKCTR-1135).
⁎Corresponding author. Tel.: +1 852 64600117/852 25956111.
E-mail addresses: firstname.lastname@example.org, email@example.com (H.P. Shum).
0883-9441/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
Journal of Critical Care (2011) 26, 613–619
significant benefits of adequate initial fluid resuscitation
within 6 hours after the onset of therapy with vasopressors
and vice versa for groups receiving conservative late fluid
treatment . The Protocolized Care for Early Septic Shock
study (NCT00510835) is a multicenter study currently being
conducted in the United Status with its purpose to confirm
the beneficial effects of EGDT.
However, over the last decade, multiple clinical studies
documented an association of a positive fluid balance with
morbidity and mortality. There is clear evidence suggesting
that fluid overload may be detrimental in many conditions.
Brandstrup and colleagues  found that restricted perio-
perative intravenous fluid regimen aiming at unchanged
body weight reduced postoperative complications after
elective colorectal resection. In acute lung injury (ALI) or
acute respiratory distress syndrome (ARDS), Sakr et al 
found that positive fluid balance was associated with worse
intensive care unit (ICU) outcome, whereas Wiedemann 
showed that conservative strategy of fluid management
improved lung function and shortened the duration of
mechanical ventilation and intensive care. In severe sepsis,
fluid gain was among the strongest prognostic factors for
patient's mortality . Upadya and colleagues  also found
that positive fluid balance (in 24, 48, and 72 hours and
cumulatively from the onset of hospital admission) was
associated with ventilator weaning failure. It seems that a
threshold in time may exist where aggressive fluid therapy
would be detrimental to a patient's survival.
The main purpose of this retrospective cohort study is to
assess the relationship between fluid balance during ICU stay
and outcomes among general critically ill patients. In
addition, this study also aims to see the effect of fluid gain
among patients with different disease severity.
This study was approved by the hospital ethics
committee and registered with Hong Kong University
Clinical Trial Register (ref: HKCTR-1135). Written in-
formed consent was waived.
This study was a retrospective, single-centered, cohort
study conducted at the ICU of Pamela Youde Nethersole
Eastern Hospital, a 2300-bed acute care tertiary hospital that
provides comprehensive care except cardiothoracic surgery,
transplant surgery, and burns. The ICU is a 20-bed closed
mixed medical-surgical unit with an average admission of
1300 patients per year. Patient's mean Acute Physiology and
Chronic Health Evaluation IV (APACHE IV) score was
71.9 ± 36.7, and the standardized mortality ratio (SMR) is
0.65. Their median length of stay was 1.9 days (interquartile
range, 1.0-4.2). Patients admitted into our ICU during 2009
were evaluated. However, those whose APACHE IV data
were not available for analysis, were younger than 16 years,
or stayed in ICU for less than 4 hours were excluded from
this study. For recurrent ICU admission during the same
hospitalization episode, only the first admission episode was
analyzed. For admissions involving the same patient in
different hospitalization episodes, they were treated inde-
pendently. Based on Alsous and colleagues , who found
of a significant difference in fluid balance between hospital
survivors and nonsurvivors who experienced fluid gain on
either 1 of the first 3 days of ICU stay, our study focused on
patients who stayed in ICU for 3 days or more.
The following data were collected: demographics,
comorbidities, admissiondiagnosis, ICUorhigh-dependence
unit cases, emergency or elective cases, ICU and hospital
length of stay, and ICU and hospital outcomes. Clinical and
laboratory data required for calculation of APACHE IV were
reported as the worst value within the first 24 hours of
ICU admission. For fluid status data, daily fluid balances up
We defined each day to be 24 hours after midnight. Because
of a variance in ICU admission time for the patients in our
study, the mean duration of stay during the first ICU day was
13.44 ± 6.88 hours. All patient data were collected from the
central clinical management system and the IntelliVue
Clinical Information Portfolio from Philips (Royal Philips
Electronics, Amsterdam, the Netherlands). Patients were
followed until death or hospital discharge.
2.1. Statistical analysis
A univariate analysis was performed using a χ2test, Fisher
exact test for categorical data or the 2-tailedt test, and a Mann-
Whitney U test for continuous data to compare hospital
survivors and nonsurvivors. Appropriate parameters (P ≤ .20)
were entered into a logistic regression model using a forward
stepwise entry(likelihood ratio) to identifyindependent factors
associated with hospital mortality. Values of P b .05 were
considered significant. The Hosmer-Lemeshow goodness-of-
fit test was used to assess the overall validity of the logistic
regression model. The hospital mortality prediction perfor-
mance of APACHE IV predicted risk of death (ROD), fluid
balance on first ICU day, fluid balance on second plus third
ICU days, and total fluid balance during ICU stay were
evaluated using calibration and discriminatory statistical
analyses. Calibration analysis was performed using the
Hosmer-Lemeshow goodness-of-fit test. The areas under the
receiver operating characteristic curve were obtained to assess
the discriminatory capability of the model. Values are given as
mean ± SD or median and interquartile range if appropriate.
Data analysis was performed by the Statistical Package for
Among 1386 patients admitted into our ICU in 2009, only
639 patients stayed in ICU for 3 or more days. Table 1 shows
614H.P. Shum et al.
the baseline characteristics of patients stratified based on
their hospital outcome. Hospital nonsurvivors were older,
more likely to be emergency cases on admission to ICU, had
higher APACHE IV scores, had longer ICU length of stay
(LOS), and had significantly more fluid gain. In the logistic
regression analysis (Table 2; Hosmer and Lemeshow
goodness-of-fit test χ2= 4.67, df = 8, P = .792), 4 factors
were significantly associated with hospital mortality. The
predicted ROD of APACHE IV, fluid balance on the second
plus third ICU days, and total fluid balance during ICU stay
were positively associated with hospital death. Significant
positive fluid balance on first ICU day, in contrast, was
negatively associated with hospital mortality. Daily average
fluid gain and fluid gain after third ICU day were not
associated with poor hospital outcome. The receiver
operating characteristic curve (Fig. 1) indicated that
cumulative fluid balance had the best discriminatory
capability on hospital mortality in comparison with
APACHE IV–predicted ROD and fluid balance on the
second plus third ICU days, although it was not statistically
significant. The discriminatory capability of fluid balance on
the first ICU day was poor. A cumulative fluid gain of 3.5 L
during the second plus third ICU days combined was 99%
predictive of hospital mortality. Patients were stratified into 3
groups (b0.13, 0.13-0.42, and N0.42) according to their
APACHE IV–predicted ROD (Fig. 2 and Table3). The SMR
of those in the lower APACHE IV predicted ROD tertile
showed no significant correlation with fluid gain on the
second plus third ICU days (P = .39). For those in the middle
tertile, the correlation is positive and of borderline
Baseline characteristics of hospital survivors and nonsurvivors
VariablesAll patients stay for ≥3 d
(n = 639)
(n = 505)
(n = 134)
Age (y), mean ± SD
Source of consultation
ICU vs HDU
Emergency vs elective
Postoperative vs nonoperative
ICU LOS (d), mean ± SD
APACHE IV score, mean ± SD
Fluid balance of 1st ICU day (L)
Fluid balance of 2ndICU day (L)
Fluid balance of 3rdICU day (L)
Fluid balance of 4thICU day (L)
Fluid balance of 5th ICU day (L)
Total fluid balance during ICU stay (L)
Daily average fluid balance during ICU stay (L)
ICU mortality (%)
65.5 ± 15.8
64.8 ± 16.0
68.3 ± 14.4
5.8 ± 6.4
79.8 ± 34.4
0.73 ± 1.13
0.49 ± 1.17
0.18 ± 0.82
0.08 ± 0.80
0.00 ± 0.67
1.83 ± 3.60
0.48 ± 1.98
5.1 ± 5.4
73.1 ± 31.5
0.61 ± 0.95
0.21 ± 0.68
0.02 ± 0.57
-0.07 ± 0.61
-0.06 ± 0.51
0.88 ± 2.32
0.29 ± 2.03
8.3 ± 8.8
105.3 ± 33.2
1.15 ± 1.59
1.53 ± 1.87
0.77 ± 1.25
0.50 ± 1.08
0.18 ± 0.95
5.41 ± 5.05
1.19 ± 1.58
A&ED indicates accident and emergency department; OT, operation theater; HDU, high-dependency unit; GI, gastrointestinal; CVS, cardiovascular system;
LOS, length of stay.
aCompares hospital survivors with nonsurvivors.
615Fluid balance and ICU outcome
significance (P = .07), whereas those in the upper tertile, the
correlation becomes statistically significant (P = .04).
The findings from this observational study demonstrate
the impact of fluid gain on the survival of critically ill
patients. Fluid balance on the second plus third ICU days
and total fluid gain during ICU stay were positively
associated with hospital mortality, whereas positive fluid
balance on the first ICU day gave reversed findings. Also,
the importance of fluid gain on patient's outcome correlated
with disease severity.
Rivers and colleagues  evidently showed the importance
of initial aggressive volume administration. Although the total
amount of volume administered within the first 72 hours was
approximately the same in both groups, patients who were
randomizedto EGDTreceived37% oftotal volumewithin the
first 6 hours, whereas patients on standard therapy received
more fluidbetween7and72hours after admission.Hence,the
critical difference was the timing of fluid administration, not
improved survival, but late and excessive fluid administration
was associated with increased mortality. In fact, Murphy and
septic shock and ALI, adequate initial fluid resuscitation
(defined as the administration of an initial fluid bolus of ≥20
mL/kg before and achievement of a central venous pressure of
≥8 mmHg within 6 hours after the onset of therapy with
vasopressors) coupled with conservative late fluid manage-
ment (defined as even-to-negative fluid balance measured on
at least 2 consecutive days during the first 7 days after septic
shock onset) were associated with better hospital survival. So
far, there is no clear-cut definition between “early” and “late”
in terms of fluid management strategy. More than 6 hours was
considered to be “late” in both previously mentioned studies
[2,3]. Our study demonstrated that significant positive fluid
balance on the first ICU day (13.44 ± 6.88 hours) was
negatively associated with hospital mortality. Fluid gain on
subsequent ICU days correlated with poorer hospital
outcome. Whether 13 hours could be taken as “late” is
debatable. It may be beneficial to further investigate into
what defines the boundary between “early” and “late”
Along with previous findings, our study showed that
cumulative fluid gain correlated with poorer outcomes.
factors associated with hospital mortality
Logistic regression analysis to identify individual
VariablesP Odds ratio95% CI
APACHE IV–predicted ROD
Fluid gain on 2nd plus 3rd
Total fluid balance during
Fluid balance on 1stICU day
CI indicates confidence interval.
Receiver operating characteristic curve to compare different variables associated with hospital mortality.
616H.P. Shum et al.
Several pediatric and adult observational studies focused on
patients with acute kidney injury consistently identified fluid
overload as an independent factor associated with mortality
[10-13]. In our cohort, 29.9% of patients were diagnosed to
have acute kidney injury, defined as “injury” stage or more
based on Risk, Injury, Failure, Loss and End stage (RIFLE)
criteria . The use of renal replacement therapy or diuretic
therapy to achieve better fluid balance to improve patient's
outcome was less well established. However, for patients
with acute kidney injury who required renal replacement
therapy, continuous renal replacement therapy may be better
as compared with intermittent hemodialysis . Acute lung
injury and ARDS are other commonly encountered clinical
diagnoses in an ICU setting. Simmons and colleagues 
found significant differences in cumulative fluid balance
between survivors and nonsurvivors with ARDS. Patients
who lost 3 kg or more weight had a much higher survival
than did those who gained 3 kg or more weight. In a
randomized control trial conducted by Wiedemann  in
patients with ALI, although there was no significant
difference in the primary outcome of 60-day mortality, the
conservative strategy of fluid management improved lung
function and shortened the duration of mechanical ventila-
tion and ICU stay without increasing nonpulmonary organ
failures. These results support the use of a conservative
strategy of fluid management in patients with ALI.
An interesting finding of our study is that a higher fluid
balance on the second plus third days of ICU stay is
associated with an increase in hospital mortality. Fluid gain
after the third ICU day was not correlated with poorer
outcome. A previous study involved the retrospective
analysis of 36 patients with septic shock, which also reported
that throughout a 7-day analysis period, the differences in
fluid balance between patients who had survived and who
had died were greatest on days 2 and 3 . The author
offered no explanation regarding this finding. Greater fluid
gain on the second plus third ICU days may simply imply a
more severe condition that requires longer duration for
stabilization, or continued deterioration of clinical condition.
However, this factor still stands out as an independent
determinant for hospital mortality after correction for case
severity based on APACHE IV score. It is possible that those
patients received suboptimal care during the first ICU da y
required more fluid loading during subsequent days of ICU
stay. Because our SMR remained relatively low, insufficient
fluid resuscitation on first ICU day should be less likely.
Fluid balance on the second plus third ICU day can be
obtained with ease. Incorporation of this factor into model
like APACHE IV system may be beneficial to provide better
prognoses in critically ill patients.
This study also demonstrated a positive correlation
between SMR (APACHE IV) and fluid gain on the second
plus third ICU days in the sickest patients. For those with less
severe illness, fluid gain may not have any significant impact
on patient's outcome because their disease status improves
much more rapidly. However, for those with more severe
illnesses, excessive initial fluid gain may contribute to gut
edema, poor adsorption capacity, intra-abdominal hyperten-
sion with impaired kidney function, bowel perfusion, and
worsening of cardiac condition . The deteriorating renal
function further augments fluid accumulation that likely
establishes a vicious cycle ultimately leading to mortality.
It is possible that severe fluid overload indicates a very
sick patient who requires large volumes of fluid to
maintain hemodynamic stability in the context of pro-
nounced critical illness. On the other hand, increasing
evidence shows that fluid overload itself could be seen as a
“biomarker” that contributes independently to the elevated
mortality in critically ill patients . Early adequate fluid
resuscitation together with conservative late fluid manage-
ment may provide better patient outcomes. Volume status
assessment should be a key focus for appropriate fluid
management. In view of the difficulties in assessment of
volume status with routine static measures of preload,
Lower tertile of APACHE IV predicted Risk of Death (0-13%)
Gain 0-1LGain 1-2LGain 2-3LGain >=3L
Middle tertile of APACHE IV predicted Risk of Death (13-42%)
Gain 0-1L Gain 1-2LGain 2-3L Gain >=3L
Upper tertile of APACHE IV predicted Risk of Death (>42%)
Gain 0-1LGain 1-2LGain 2-3LGain >=3L
plus third ICU days and fluid balance in patients with severity
stratified based on APACHE IV–predicted ROD.
Association between hospital mortality and the second
617Fluid balance and ICU outcome
dynamic techniques like leg elevation or pulse pressure
variation should be used [17,18].
The main limitation of this study was its retrospective
nature and the absence of a standardized protocol on fluid
administration. Hence, the cause-effect relationship between
positive fluid balance on the second plus third ICU days and
observed hospital mortality could not be ascertained. The
positive fluid balance might be the cause of the higher
hospital morality, but might very well be the result of
“sicker” patients who had higher hospital mortality because
they were not responding to intensive treatment, including
fluid resuscitation provided in the ICU. The second
limitation of this study was the calculation of fluid balance
using calendar days as a cutoff, not the actual ICU
admission time. This introduced some ambiguity in the
so-called day 1 fluid balance. However, the effect should be
minimal for the fluid balance on days 2 and 3. Another
limitation was the relatively small number of subjects
included in this single-centered study. We have not studied
the association of hospital mortality and fluid balance in
special subgroups of patients, such as surgical patients,
ARDS, sepsis, head injury, or polytrauma. Also, the
association observed in this study may not be generalizable
to other ICUs.
In conclusion, there was no high-quality study on the
optimal fluid management strategy after initial stabilization
of critically ill patient. Multiple retrospective studies,
including the present one, only demonstrated an associa-
tion between subsequent fluid gain and mortality. There-
fore, a prospective study to identify a clear strategy in fluid
management is required to see if patient outcome's can
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Association between hospital mortality and day 2 plus day 3 fluid balances in patients with severity stratified based on
Fluid gain during ICU days 2 and 3
Negative0-1 L1-2 L2-3 L
Lower APACHE IV–predicted ROD tertile (0-13%)
Actual mortality rate
Expected mortality rate
Rank correlation coefficient for SMR = 0.4, P = .39
Middle APACHE IV–predicted ROD tertile (13%-42%)
Actual mortality rate
Expected mortality rate
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619 Fluid balance and ICU outcome