64 Original Article

Adverse Outcomes due to Aggressive Fluid

Resuscitation in Children: A Prospective
Observational Study
Anand Muttath1 Lalitha Annayappa Venkatesh1 Joe Jose1 Anil Vasudevan2 Santu Ghosh3

1 Department of Paediatrics, St John’s Medical College and Hospital, Address for correspondence Lalitha Annayappa Venkatesh, MBBS,
Bangalore, Karnataka, India MD Pediatrics, DNB, FNB Pediatric Critical Care FACEE, Department of
2 Department of Paediatric Nephrology, St John’s Medical College and Paediatrics, St John’s Medical College and Hospital, Sarjapur Road,
Hospital, Bangalore, Karnataka, India Bangalore 560034, Karnataka, India
3 Department of Biostatistics, St John’s Medical College, Bangalore, (e-mail: Drlalitha03@gmail.Com).
Karnataka, India

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J Pediatr Intensive Care 2019;8:64–70.

Abstract Fluid management has a major impact on the duration, severity, and outcome of critically ill
children. The aim of this study was to examine the relationship between cumulative fluid
overload (CFO) with mortality and morbidity in critically ill children. This was a prospective
observational study wherein children (1 month–16 years) who were critically ill (with shock
requiring inotropes and/or mechanically ventilated) were enrolled. CFO was defined as the
sum of daily fluid balances. Daily fluid balance was calculated as a difference between fluid
intake (oral and intravenous) and output (urine output, discharge from nasogastric tube) in
24 hours. Percentage of fluid overload (FO) (PFO) was calculated as the ratio of CFO with
weight at admission in kilogram. The CFO and PFO at 24, 48, 72 hours and at 7 days or end of
PICU stay were calculated. A total of 291 children (244 survivors and 47 non-survivors; 47%
males) were included in the final analysis. A higher mortality was observed in children with
higher PFO (>20% FO: 45.8% mortality vs. 14.5% < 10% FO, p < 0.01) and CFO
(10.97 ! 6.4 mL/kg in survivors vs. 13.95 ! 9.6 mL/kg in non-survivors; p ¼ 0.022) at
72 hours. A 1% increase in fluid overload was associated with 6% and 4% increase in mortality
at 72 hours and 7 days, respectively. Similarly, the impact of every 1% increase in fluid
overload on both ventilation (yes/no) and acute kidney injury (AKI; yes/no) were found to be
Keywords significant for both parameters at 72 hours, but only AKI had significant correlation on
► critically ill seventh day. In the multivariate stepwise Cox’s proportional hazard model for PICU stay and
► intensive care units hospital stay, 3% (p < 0.05) and 2% (p > 0.05) increase were found for every 1% increase in
► pediatric fluid overload, respectively. Oxygenation index is also associated with fluid overload with
► critical care the adjusted model estimated 0.27 units (95% confidence interval: 0.18–0.36) increase per
► fluid 1% increase in fluid overload. FO was associated with increased mortality and morbidity in
► therapy critically ill children.

Introduction
been associated with dramatic improvements in outcome.
Fluid management plays a major role in resuscitation of Recent data suggest that the cost–benefit of aggressive fluid
critically ill. Aggressive volume expansion to support tissue resuscitation is more complex than previously thought and may
oxygen delivery as part of early management of septic shock has depend on clinical scenario and the availability of intensive

received Copyright © 2019 by Georg Thieme DOI https://doi.org/

February 27, 2018 Verlag KG, Stuttgart · New York 10.1055/s-0038-1667009.
accepted after revision ISSN 2146-4618.
June 3, 2018
published online
July 12, 2018
 Aggressive Fluid Resuscitation in Children Muttath et al. 65

care.1 After the resuscitation phase, critically ill children tend to esis, discharge from nasogastric tube). CFO was defined as the
retain free water while having reduced insensible losses. sum of daily fluid balances until the given day and calculated at
A dose–response relationship between cardiopulmonary com- 24, 48, 72 hours, and at 7 days or end of PICU stay. The
plications and increasing degrees of fluid overload (FO) has percentage of FO (PFO) is calculated as the ratio of CFO with
been demonstrated in adult critical care patients; those with weight at admission in kilogram (CFO # weight at admission
less fluid gain and lower lung water had more ventilator free [kg]) $ 100 at the given day.5 Based on previous studies,
days and shorter intensive care unit and hospital length of stays < 10% is considered as mild FO, 10 to 20% as moderate, and
which indicates lesser morbitity.1,2 Retrospective studies have above 20% as severe FO. OI was calculated according to
looked at positive fluid balance and morbidity in pediatric standard formula (mean airway pressure $ FiO2 $ 100/
population.3 However, only few studies have evaluated PaO2) and the worst recorded OI was used for analysis.6 AKI
the degree of daily positive fluid balance and its relation to was defined according to KDIGO criteria.7
morbidity and mortality prospectively.4
The aim of this study was to examine the association Sample Size Calculation
of degree of cumulative FO (CFO) with the morbidity and Assuming 5% level of significance and 80% power, our

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mortality in critically ill children. required sample size was a minimum of 42 each of survivors
and non-survivors. This calculation was done using “n.for.2p
()” o\for “epi Display” package of R.
Materials and Methods
Setting and Participants Statistical Analysis
This prospective observational single-center study was con- Data were entered into Microsoft Excel 2013. All quantitative
ducted in the pediatric intensive care unit (PICU) of a tertiary variables are summarized by mean and standard deviation
care hospital. Children were enrolled between October 2016 classified by group indicator. Independent t test or Mann–
and September 2017. Children aged between 1 month and Whitney’s test8 was applied for statistical significance
16 years who were critically ill (with shock requiring ino- depending on shape of the data. The qualitative variables
tropes and/or mechanically ventilated) were included. Chil- are summarized in terms of count and percentage stratified
dren with chronic kidney disease, nephrotic syndrome, by group indicator. Chi-square test of independence was
congestive cardiac failure, and those with PICU stay less applied for statistical significance. The FOs at different
than 24 hours were excluded. The study was approved by days stratified by survivor and non-survivor were compared
the Institutional Ethics and Research Board Committee. by box–whisker plot. A stepwise multivariate logistic regres-
Informed written consent was obtained from the parent sion9 for all dichotomous outcome on exposure adjusted for
(s)/guardian(s) of each patient before enrollment. potential risk factors and a stepwise multivariate linear
regression model for continuous outcome on exposure
Objectives and Outcome Measures adjusted for potential risk factor were applied to estimate
The objective was to determine the association between the impact of FO on different outcomes. For PICU and hospital
positive fluid balance with clinically important outcome stay, a stepwise Cox’s proportional hazard model was
measures, such as duration of ventilation, oxygenation index applied. Finally, impact of FO on all outcomes with their
(OI), incidence and severity of acute kidney injury (AKI), PICU 95% confidence intervals (CIs) is presented in terms percen-
and hospital length of stay (LOS) and death. tage increase or unit increase per unit increase of FO by an
error bar plot. The data have been analyzed by statistical
Methodology Software R version 3.4.3.
Data recorded prospectively at admission included age,
gender, severity of illness (Pediatric Risk of Mortality
Results
[PRISM] III score) score and the diagnosis. The PRISM III
score is based on clinical and laboratory parameters assessed A total of 291 cases were enrolled during the study period
during the first 12 hours. Additional information recorded (►Fig. 1). Among them were 244 survivors and 47 non-
during the PICU stay included duration of inotropes and survivors. Median age of the study children was 47 months
mechanical ventilation, OI, presence or absence of AKI, need (interquartile range [IQR]: 6, 171) and 47% were males.
for renal replacement therapy, and duration of stay in the Median PRISM III score at admission was 9 (IQR: 0, 28).
PICU and the hospital. Routine and specific investigations Median duration of PICU stay was 6 days (IQR: 2, 24) and
including cultures done in all cases were also recorded. The hospital stay was 10 days (IQR: 3, 28); 15.1% of study
children were treated as per standard protocol guidelines. population required mechanical ventilation with a median
duration of 96 hours (IQR: 24, 483). Most common diagnosis
Estimating Cumulative and Percent Fluid Overload at admission was related to respiratory system (66%). AKI
Fluid balance was calculated based on total fluid intake and was seen in 17.2% of the study population and 74.9% had one
urine output every day for the first 7 days of PICU stay. The or more organ dysfunction detected as per standard guide-
patients were followed up until death, hospital discharge, or lines, while 17% had anemia. One in five children required
for 28 days. Daily fluid balance was calculated as a difference inotropes. Coagulopathy was found in 20%. Overall mortality
between fluid intake (oral and intravenous) and output (diur- rate was 16% among those recruited for the study. Other key

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66 Aggressive Fluid Resuscitation in Children Muttath et al.

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Fig. 1 Study design.

baseline characteristics of the study population are vs. 13.95 ! 9.6 mL/kg in non-survivors; p ¼ 0.022) at 72 hours.
described in ►Table 1. Similar observations were seen for data at 7 days; PFO (>20%
PFO of 24, 48, 72 hours and 7 days among survivors and FO: 7% in survivor group vs. 22% in non-survivor group;
non-survivors were assessed (►Fig. 2). Further analysis was p < 0.01) and CFO (122.9 ! 88.6 mL/kg in survivors vs.
done on CFO and PFO at 72 hours and 7 days. Based on the 172.6 ! 112.6 mL/kg in non-survivors; p ¼ 0.024).
above analyses, mortality was increased significantly among Higher PFO was associated with increased PICU LOS in 10 to
children with higher PFO (>20% FO: 45.8% mortality vs. 14.5% 20% FO group compared with <10% FO group (10.1 ! 6.3 vs.
<10% FO, p < 0.01) and CFO (10.97 ! 6.4 mL/kg in survivors 5.7 ! 2.7 days; p ¼ 0.001). Likewise, higher degree of PFO was

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 Aggressive Fluid Resuscitation in Children Muttath et al. 67

Table 1 Baseline characteristics of the study population

Parameter Overall (n ¼ 291) Survivor (n ¼ 244) Non-survivor (n ¼ 47) p-Value

(n ¼ 244) (n ¼ 47)
Age (mo) 48 (3,172) 48 (3,154) 46 (5,172) 0.9
Weight (kg) 13.9 (3.1,48.4) 14.24 (3.2,36.8) 13.42(3.1,48.4) 0.8
Gender (males %) 47.1 43.4 56.6 0.4
Number of children receiving fluid bolus 273 229 44 0.6
Number of children ventilated 116 69 47 0.04%%
PaO2/FiO2 181.5 (48,361) 182.6 (72,361) 142.2 (48,278) 0.814
Number of children requiring RRT (%) 14.43 7.6 24.16 0.001%%
Labs at admission

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Hemoglobin (g/dL) 10 ! 2.5 10.2 ! 1.9 9.7 ! 2.3 0.09
Lactate (mmol/L) 2.5 (0.8, 6.8) 2.26 (0.4, 5.1) 3.7 (0.8, 6.8) 0.07
Creatinine (mg/dL) 0.42 (IQR 0.25, 0.68) 0.2 (IQR 0.1, 0.6) 0.3 (IQR 0.2, 0.8) 0.069
Admission diagnosis—organ system primarily involved
Respiratory 192 (66%) 161 31
Cardiac 6 (2%) 5 1
Neurology 23 (8%) 20 3
Hematology 9 (3%) 7 2
Trauma 20 (7%) 17 3
GI 12 (3.6%) 9 3
Others 29 (10.7%) 25 4

Abbreviations: GI, gastrointestinal system; RRT, renal replacement therapy.

%%
p-Value < 0.05.

also associated with increased hospital LOS among the same found between the two groups for the levels of PFO at 72 hours,
groups (10.8 ! 8.3 vs. 15.8 ! 9.4 days; p ¼ 0.04). described above. The OI in >20% FO group was 8.1 ! 3.4 as
Fluid overload at 72 hours was analyzed to look for possible compared with 12.8 ! 8.1 in <10% FO group (p ¼ 0.018).
association with duration of ventilation and OI. There was A higher incidence of AKI was also seen when the 10 to
significant difference observed in duration of ventilation 20% FO group was compared with the <10% FO group (21.8
across the levels of PFO at 72 hours. The mean ventilation vs. 5.5%; p ¼ 0.018). Also, the PFO was greater in AKI children
duration in the 10 to 20% FO group was found to be versus those children who did not have AKI (9.0 ! 7.1 vs.
83.6 ! 52.3 hours compared with 162.7 ! 122.4 hours for 11.9 ! 9.2, p ¼ 0.009).
<10% FO group (p ¼ 0.001). A significant difference in OI was A multivariate stepwise logistic regression (►Fig. 3) of
mortality at 72 hours and 7 days was performed. CFO was
adjusted for PRISM III score, organ dysfunction, infection, and
comorbidities (►Table 2) (best subset selected by Akaike
Information Criterion). The model showed odds ratios (ORs)
of 1.06 (95% CI: 1.01–1.11) and 1.04 (95% CI: 1.01–1.08), which
implies 6 and 4% increase in mortality for every 1% (p < 0.05)
increase in FO at 72 hours and 7 days, respectively. Similarly,
the impact of every 1% increase in 72 hours FO on both
ventilation (yes/no) and AKI (yes/no) were found to be sig-
nificant but only for AKI for FO at seventh day. The ORs with
their 95% CIs were estimated as 1.07 (95% CI: 1.01–1.13) and
1.09 (95% CI: 1.03–1.14) for 72 hours and 7 days FO, respec-
tively, after adjusting for sex, age, PRISM III score, infection,
comorbidity, organ dysfunction, and the need for inotrope(s).
A multivariate stepwise Cox’s proportional hazard model
(►Fig. 3) of PICU stay and hospital stay considering mortality
Fig. 2 Comparison of daily fluid balance between the two study as the censoring, estimated hazard ratio as 0.97 (95% CI:
groups. 0.95–0.99) and 0.98 (95% CI: 0.96–1.001) due to 72 hours FO,

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68 Aggressive Fluid Resuscitation in Children Muttath et al.

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Fig. 3 Increase in outcome per 1% increase in fluid overload (multivariate analysis).

respectively. This latter finding implies a 3% (p < 0.05) and to be associated with significantly increased mortality and
2% (p > 0.05) increase in PICU stay and hospital stay, respec- morbidity. Children with >20% FO had higher risk of mortality
tively, for every 1% increase in 72 hours FO. Similarly, the in the initial 72 hours of admission as compared with children
7 days FO also estimated a significant increase in both PICU with <20% FO. However, on comparing the length of PICU and
(2.9%) and hospital stay (3.7%). Similarly, the adjusted model hospital stay between survivors and non-survivors, a signifi-
for OI estimated that for a 0.27 unit (95% CI: 0.18–0.36) cant correlation to FO was found only among <10% versus 10 to
increase in OI per 1% increase in 72 hours FO. 20% PFO groups. This latter result could be because children
with higher FO did not survive long enough to reveal a
significant correlation. The same bias can be considered to be
Discussion
present for the >20% group for the duration of mechanical
This was a prospective observational study to assess the ventilation. Comparable to previous studies,10 this study also
effects of FO on mortality and morbidity in critically ill reports that positive fluid balance increased the duration of
children. FO at 72 hours and 7 days was used for analysis, mechanical ventilation, PICU, and hospital stay.
and it was found that in multivariate analysis with age, sex, In pediatric patients with acute lung injury, OI at admis-
PRISM III score, organ dysfunction, and comorbid conditions sion predicted death and length of mechanical ventilation,
being controlled, FO independently increased the morbidity with high specificity and sensitivity11–13 as well as predict-
and mortality. ing the development of chronic lung disease in neonates.14
We also evaluated the degree of FO and risk of morbidity and Our study showed statistically significant correlation
mortality. It was observed that children with higher degree of between positive fluid balance and OI, both at the end of
FO had higher risk of mortality, longer PICU and hospital LOS, 72 hours and 7 days, thereby again showing the increased
higher incidence of mechanical ventilation, longer duration of respiratory morbidity associated with FO.
ventilation, and higher OI. This once again shows that not just This study also investigated the association between FO
the presence but also degree of FO affects the eventual outcome and AKI. It has been previously reported that children with a
of these patients. A percentage FO of more than 20% was found higher degree of FO were found to have higher rate of AKI, as

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 Aggressive Fluid Resuscitation in Children Muttath et al. 69

Table 2 Univariate analysis by outcome among survivors and nonsurvivors at 72 hours

Factor Subgroup Survivors (%) Non-survivor (%) Odds ratio, p-Value

Fluid overload group <10% 106 (85.5%) 18 (14.5%) 0.368 (95% CI ¼ 0.14–0.91)
p < 0.001%%
10–20% 112 (94.1%) 7 (5.9%)
>20% 26 (54.2) 22 (45.8)
Age <1 110 (86.6) 17 (13.4) 1.50 (95% CI ¼ 0.68–3.31)
p ¼ 0.522
1–5 56 (81.2) 13 (18.8)
6–16 78 (82.1) 17 (17.9)
PRISM III 0–10 142 (91) 14 (9) 3.54 (95% CI ¼ 1.70–737)
p < 0.001%%
11–16 63 (74.1) 22 (25.9)
16–21 30 (85.7) 5 (14.3)

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>21 9 (60) 6 (40)
Organ dysfunction No 68 (93.2) 5 (6.8) 3.24 (95% CI ¼ 1.23–8.54)
p ¼ 0.021%%
Yes 176 (80.7) 42 (19.3)
Infection No 31 (81.6) 7 (18.4) 0.83 (95% CI ¼ 0.34–2.01)
p ¼ 0.864
Yes 213 (84.2) 40 (15.8)
Comorbidities No 234 (86.3) 37 (13.7) 6.23 (95% CI ¼ 2.46–16.23)
p < 0.001%%
Yes 10 (50) 10 (50)
Anemia No 201 (83.4) 40 (16.6) 0.81 (95% CI ¼ 0.34–1.94)
p ¼ 0.808
Yes 43 (86) 7 (14)
Coagulopathy No 204 (87.6) 29 (12.4) 2.99 (95% CI ¼ 1.50–5.98)
p ¼ 0.003%%
Yes 40 (70.2) 17 (29.8)
Inotrope requirement No 200 (84.7) 36(15.3) 1.38 (95% CI ¼ 0.65–2.94)
p ¼ 0.511
Yes 44 (80) 11 (20)

Abbreviations: CI, confidence interval; PRISM, Pediatric Risk of Mortality.

%%
p-Value < 0.05.

compared with children with lesser FO.15 A similar finding of Conflict of Interest
increased frequency and higher grade of AKI was seen in this None declared.
study (p ¼ 0.04). However, whether FO causes increased risk
of AKI or FO was caused by the renal injury could not be Acknowledgments
ascertained. All patients, their parents, relatives, and the staff members
Our study has several limitations. The sample size used of the department of PICU helped us to conduct the study.
in this particular study is small and a larger study involving
multiple centers is required to confirm our findings in this
study. Fluid status prior to admission was not accounted for References
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