Pediatric Nephrology (2023) 38:47–60

https://doi.org/10.1007/s00467-022-05514-4

REVIEW

Neonatal fluid overload—ignorance is no longer bliss

Lucinda J. Weaver1 · Colm P. Travers1 · Namasivayam Ambalavanan1 · David Askenazi1

Received: 29 November 2021 / Revised: 26 January 2022 / Accepted: 21 February 2022 / Published online: 29 March 2022
© The Author(s), under exclusive licence to International Pediatric Nephrology Association 2022

Abstract
Excessive accumulation of fluid may result in interstitial edema and multiorgan dysfunction. Over the past few decades, the
detrimental impact of fluid overload has been further defined in adult and pediatric populations. Growing evidence highlights
the importance of monitoring, preventing, managing, and treating fluid overload appropriately. Translating this knowledge
to neonates is difficult as they have different disease pathophysiologies, and because neonatal physiology changes rapidly
postnatally in many of the organ systems (i.e., skin, kidneys, and cardiovascular, pulmonary, and gastrointestinal). Thus,
evaluations of the optimal targets for fluid balance need to consider the disease state as well as the gestational and postmen-
strual age of the infant. Integration of what is known about neonatal fluid overload with individual alterations in physiology
is imperative in clinical management. This comprehensive review will address what is known about the epidemiology and
pathophysiology of neonatal fluid overload and highlight the known knowledge gaps. Finally, we provide clinical recom-
mendations for monitoring, prevention, and treatment of fluid overload.

Keywords  Infant · Newborn · Neonate · Fluid overload · Fluid · Kidney · Acute kidney injury · Preterm · Mortality ·
Dialysis · Kidney support therapy

Introduction balance to prevent dehydration, maintain adequate tissue

Fluid overload in critically ill children and adults is associ-
ated with increased mortality, need for aggressive and pro-
longed ventilatory support due to pulmonary and chest wall
edema, congestive heart failure, acute kidney injury (AKI),
and prolonged hospitalization [1–6]. Emerging data on fluid
overload in neonates suggests an increased risk of detrimen-
tal outcomes including mortality [7–10], bronchopulmonary
dysplasia (BPD) [11, 12], intraventricular hemorrhage (IVH)
[13], necrotizing enterocolitis (NEC) [14, 15], hemodynami-
cally significant patent ductus arteriosus (PDA) [14, 16, 17],
and AKI [5, 18, 19]. While evolving data about the negative
impact of fluid overload in neonates seems to mirror pediat-
ric data, it is imperative to understand these associations in
the context of distinctive neonatal physiology [10].
Neonates are dependent upon clinicians to provide par-
enteral and enteral nutrition, medications, and blood prod-
ucts. Provision of these fluids should achieve the right fluid
* Colm P. Travers
cptravers@uabmc.edu
1
University of Alabama at Birmingham, Birmingham, AL,
USA
perfusion, while also avoiding fluid overload. Management
of fluid balance homeostasis in any critically ill patient is
challenging and may be even more difficult in neonates given
the changes in fluid dynamics that evolve with developmen-
tal maturity [20–23]. The postnatal, physiologic, extracellu-
lar fluid volume (ECF) contraction is highly regulated by the
kidney [24]. Premature infant kidneys have limited ability
to strongly concentrate or dilute urine necessary to maintain
fluid homeostasis and manage serum osmolality. Conditions
such as AKI, sepsis, NEC, and cardiac dysfunction will fur-
ther complicate the ability to provide nutrition, medications,
and/or blood products without causing fluid overload.
Over the last two decades, much progress has been made
to define, track, prevent, and treat fluid overload in adult
and pediatric critical care units [25, 26]. Much of this work
has been led by the pediatric critical care nephrologists. In
2001, Goldstein et al. coined the term fluid overload after
demonstrating detrimental outcomes in critically ill pediatric
patients requiring continuous kidney replacement therapy
(CKRT) [25]. Since then, there have been multiple stud-
ies that have been summarized in a recent meta-analysis
by Alobaidi et al., who report higher rates of in-hospital
mortality with an independent odds ratio (OR) = 4.34 (95%

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48
confidence intervals (CI), 3.01–6.26) in those with fluid
overload [2]. Only a small number of neonatal patients were
included in this analysis. Since that meta-analysis, similar
research in neonatal populations have begun to show similar
outcomes.
The time has come for the neonatology and nephrology
communities to improve our understanding and enhance
strategies to prevent/treat fluid overload in critically ill neo-
nates. With improved knowledge and recognition, clinicians
will be better able to define, track, and study fluid overload.
More importantly, early prevention and appropriate treat-
ment strategies including timely kidney support therapy are
likely to improve outcomes, but well-designed neonatal stud-
ies are needed. This review will highlight areas of active
research and evolving gaps in knowledge as well as practical
clinical guidelines for the prevention and management of
fluid overload in neonates.
Postnatal fluid shifts and adaptations
After delivery, neonates undergo fluid volume contraction
and cardiovascular adaptation as they transition from intra-
to extra-uterine life. Preterm infants experience a more pro-
nounced total body water (TBW) and ECF volume contrac-
tion [21, 22, 27]. This is in part due to differences in TBW,
intracellular water (ICF), and ECF ratios that differ with
gestational age. ECF composition at 24-week gestational age
infant is ~ 60%, and it reduces to about ~ 40% in a full-term
infant and transitions to ~ 20% as a young child (Fig. 1) [21,
28]. The TBW during the first postnatal weeks is influenced
by multiple factors including gestational age, antenatal
steroid exposure, growth restriction, kidney function, and
transepidermal fluid losses [21]. Typically, full-term infants
should not lose more than 10% of their birth weight in the
first postnatal week, whereas between 10 and 20% weight
loss may be beneficial among extremely preterm neonates
[21, 27]. As a result, different targets of postnatal weight loss
have been recommended depending on gestational age. The
degree of salt and water diuresis occurring around 48–72 h
after birth is influenced by enteral and parenteral intake,
sodium supplementation, thermoregulation, and humidifi-
cation [29].
The clinician is responsible for fluid provision in preterm
infants during the first postnatal weeks until they are able to
ingest oral feeds on their own. The clinician must provide
adequate nutrition, allow ECF volume contraction while
avoiding hyponatremic fluid overload and hypernatremic
dehydration. Higher body-surface area, a thin epidermis,
dependence on caregivers, and limited ability to conserve
water put neonates at higher risk of dehydration [21]. High
humidification in modern incubators reduces insensible fluid
losses. While fluid restriction may be beneficial in the first
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Pediatric Nephrology (2023) 38:47–60
Fig. 1  The total body water shifts that occur with intracellular and
extracellular fluid throughout gestation and into infancy. Re-printed
with permission. Bell EF, Segar JL, William O (2016) Fluid and
Electrolyte Management. https://​obgyn​key.​com/​fluid-​and-​elect​rolyte-​
manag​ement/. Accessed 15 November 2021
postnatal weeks, there is concern it can predispose an infant
to a catabolic state through limited caloric intake. However,
data has shown that appropriate caloric intake can still be
achieved with lower total fluid intake [30]. Prescribed total
fluid intake goals and daily fluid advancement remain con-
troversial in practice and should be guided by serum sodium
concentrations, weight change, and urine output as surrogate
measures of fluid status [31]. Tight regulation and moderate
restriction of fluid in premature neonates have been shown
to be beneficial for long-term outcomes [13, 14, 31, 32].
Too much fluid administration affects postnatal cardiac
and pulmonary adaptation. Warburton et  al. performed
serial echocardiograms in 73 very low birth weight infants
randomized to receiving higher or lower volume mainte-
nance fluids during the first 20 postnatal days [33]. This
study showed that those randomized to higher volume fluids
had larger left ventricular end-diastolic volumes and larger
atrial to aortic root diameters [33]. These results suggest that
increased fluid provision can impact cardiovascular func-
tion and prevent appropriate adaptation from uterine envi-
ronment. In addition, fluid restriction strategies have been
evaluated in a randomized clinical trial of 64 late preterm
and full-term infants with transient tachypnea of the new-
born (TTN). Fluid restriction with approximately 20 mL/
kg/day less fluid in the first 24 postnatal hours, with a con-
trol standard of 80 mL/kg/day for premature and 60 mL/
kg/day for term infants, shortened the duration of respira-
tory support among 26 infants with severe TTN by 38 h,
but the duration of respiratory support comparing all study
participants was not statistically significant [34]. This study
Pediatric Nephrology (2023) 38:47–60
found no difference in serum sodium, creatinine, or weight
loss between groups but urine output was 0.6 mL/kg/h lower
among infants in the restricted group [34].
The association between increased fluid intake resulting
in a lack of sufficient weight loss in the first postnatal week
and the risk of hemodynamically significant PDA is well
documented [14, 16, 17, 30]. A Cochrane review by Bell
et al. included 5 randomized clinical trials comparing early
fluid restriction versus liberal fluid intake among preterm
infants in the early postnatal period. Four of the five articles
commented on reduced risk of PDA with restricted fluid
intake (relative risk (RR) 0.52, 95% CI 0.37 to 0.73; number
needed to treat (NNT), 7; 4 trials, n = 526) [14]. In three of
the trials, there was a higher percentage of postnatal weight
loss with restricted fluid intake compared with liberal fluid
intake (mean difference 1.94% of birth weight, 95% Cl 0.82
to 3.07; 3 trials, n = 326) [14]. In addition, the restricted
volume group showed potentially clinically important but
non-significant trends towards a lower risk of death (RR
0.81, 95% CI 0.54 to 1.23, 1 trial) [12], BPD (RR 0.85,
95% CI 0.63 to 1.14, 4 trials), and IVH (RR 0.74, 95% CI
0.48 to 1.14, 3 trials) [14]. This meta-analysis included rela-
tively few infants less than 750-g birth weight and most of
the studies were conducted in the era prior to surfactant,
the widespread adoption of antenatal corticosteroids, and
contemporary less invasive ventilatory support techniques
[14]. Together, these classic studies conducted in neonates
indicate improved outcomes with volume restriction to pre-
vent fluid overload in the first days following birth among
preterm infants.
Observational studies also indicate that early interven-
tion to prevent fluid overload in the first postnatal days may
help with the complex extrauterine transition and prevent
poor outcomes such as hemodynamically significant PDA or
BPD [13, 31, 32, 35]. Although there is a known association
between PDA and BPD [35–38], the exact interplay between
the two has not been fully elucidated. That being said, the
timing of fluid restriction may be important in the develop-
ment of BPD or PDA. Prolonged fluid restriction after the
establishment of full enteral feeds has not been shown to be
beneficial for prevention or long-term improvement of BPD
[39]. A randomized controlled trial involving 60 infants (less
than 1500 g and 32-week gestation) with chronic lung dis-
ease, as defined by oxygen requirement at postnatal day 28,
calorically dense volume-restricted feedings did not improve
short-term respiratory outcomes including the duration of
ventilator support or oxygen therapy [40]. However, they
did not report relevant clinical outcomes such as PDA. In
addition, a recent randomized clinical trial of 224 very pre-
term infants found no increased risk of BPD or PDA among
infants receiving higher volume enteral feedings after the
establishment of full enteral feedings [41]. However, none of
the infants enrolled in this study was less than 1000 g, who
49
are at highest risk of BPD. The effect of volume restriction
on major morbidities after the establishment of full enteral
feedings in premature infants is unclear.
Defining and quantifying fluid overload
in neonates
Calculation of fluid status relies on either a fluid bal-
ance–based approach or a weight-based approach. The fluid
balance approach (cumulative fluid balance (%) = (cumula-
tive fluid input (mL) – fluid output (mL))/weight (kg)) may
be less practical in a neonatal intensive care unit setting as
measurement of fluid balance in neonates is challenging [42,
43]. A cumulative fluid balance approach will not account
for the insensible losses which can be a significant propor-
tion of cumulative output in neonates. The degree of insen-
sible losses is influenced by external factors including total
body surface area exposure, ambient air or incubator tem-
perature and/or humidification, and respiratory support [21,
42]. Furthermore, output can be difficult to accurately assess
due to urine leakage around diapers, inaccurate measure-
ment of urine mixed with stool, and emesis [42]. Placement
of bladder catheters can be very difficult and urine collection
bags may not be ergodynamically appropriate for prema-
ture neonates. Fluid balance–based approach may be useful
in specific clinical settings such as the first postnatal week
among extremely preterm infants prior to passing stool, but
further validation of this method is needed [7]. Therefore,
a weight-based approach to assess fluid status may be more
practical in neonates.
A weight-based fluid balance formula (cumulative weight
change (%) = (daily weight (kg) − birth weight (kg))/birth
weight (kg)) has been shown in multiple studies to calcu-
late fluid status and determine fluid overload accurately in
neonates [32, 44–48]. However, the weight-based approach
has its own challenges. Small fluctuations in weight from
scale differences can have a significant impact. Critically ill
neonates may be too unstable to be weighed daily. Both fluid
balance–based and weight-based approaches may have inac-
curacies. Each method may be useful for different patients.
In addition, besides determination of the cumulative fluid
balance, the clinician must decide where the fluid is located
and whether the fluid is maldistributed. Physical examination
incorporating vital signs, evaluation of laboratory data, and
imaging should be used to determine fluid balance assess-
ment and evaluation of the location of the fluid (intravascular
space vs. extravascular). The use of ultrasound has shown
to be effective for identifying fluid overload in pediatric
patients [49, 50]. Studies in neonates to determine whether
technologies such as bioelectric impedance and ultrasound
improve the assessment of fluid balance are needed.
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Epidemiology of fluid overload in neonates:
what is known?
Critically ill neonates
The Assessment of Worldwide Acute Kidney injury Epi-
demiology in Neonates (AWAKEN) was a 24-center inter-
national retrospective cohort study developed to further
understand neonatal kidney disease [51]. The database
included 2,189 neonates who received at least 2 days of
intravenous fluids excluding infants who met preset cri-
teria including congenital heart disease requiring urgent
surgery or lethal congenital anomaly [51]. This database
has been used to evaluate the short-term outcomes of early
fluid overload in the neonatal population. Selewski et al.
showed that a positive fluid balance was associated with
mechanical ventilation on post-natal day 7 in both 645
infants ≥ 36-week gestation (OR 1.12, 95% CI 1.07 to
1.17) and in 1007 infants < 36-week gestation (OR 1.10,
95% CI 1.06 to 1.13) [45, 46]. Selewski et al. demonstrated
a graded increase in the magnitude of fluid overload in
relation to the number of neonates requiring mechanical
ventilation [45].
Extremely low birth weight (ELBW) infants
Previous work among ELBW infants after the implementa-
tion of routine steroids and surfactant administration recog-
nized that higher cumulative fluid balance early in the post-
natal period is associated with the development of chronic
lung disease [36–38]. Since that time, multiple retrospective
studies, including more recent datasets and infants below
750 g, have also indicated that preterm infants with a high
cumulative fluid balance and/or net weight gain in the first
3–10 postnatal days are at higher risk of adverse outcomes
including prolonged mechanical ventilation [7, 45], higher
rates of BPD [8, 10, 11, 35], and mortality [7–11]. Schmidt
et al. performed a retrospective analysis of the data collected
from the Trial of Indomethacin Prophylaxis in Preterm
Infants (TIPP) which evaluated the efficacy of prophylactic
indomethacin in ELBW infants. Unexpected outcomes of
the trial showed that despite decreased PDA after prophy-
lactic therapy the incidence of BPD was increased (43% vs.
30%, P = 0.015) [52]. Logistic regression analysis showed
that infants treated with indomethacin had lower weight loss
in the first week of life in comparison to those in the con-
trol group (4.8% (SD, 9.6) vs. 10.1% (SD, 7.6), P < 0.001)
[52]. The authors postulated that decreased urine output, a
known side effect of indomethacin, without any change in
fluid administration may have resulted in fluid overload and
an increased incidence of BPD [52].
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Pediatric Nephrology (2023) 38:47–60
Necrotizing enterocolitis (NEC)
Early fluid restriction may be helpful for the prevention of
NEC. The Cochrane meta-analysis by Bell et al. included 5
randomized clinical trials comparing early postnatal fluid
restriction in premature infants. Restricted fluid intake
reduced the risk of NEC (typical RR 0.43, 95% CI 0.21 to
0.87; NNT, 20; 4 trials, n = 526) [14]. A randomized, con-
trolled trial including 170 low birth weight infants from 751
to 2000 g demonstrated that increased fluid administration
in the first postnatal week was associated with increased
risk of NEC (18% vs. 0.04%, ­chi2 = 8.53, P < 0.005) as diag-
nosed by radiographic or post-surgical histologic findings
[15]. Although the exact pathophysiology remains unclear,
several mechanisms have been proposed, such as increased
intestinal wall edema, decreased perfusion due to aberrant
flow through a ductus, and/or hypoxemia from excessive
pulmonary fluid [15]. Mechanistic data on the role fluid
overload plays in the development of NEC remain limited.
Fluid overload is a common complication among infants
with a systemic inflammatory response to disease states such
as NEC or sepsis. Sonntag et al. found that the degree of
third-spaced fluid and multi-organ dysfunction were better
predictors of outcome than the Bell classifications system
[53]. Xie et al. performed a retrospective study on 172 neo-
natal patients with surgical NEC evaluating outcomes of low
(< 25.87 mL/kg/h) versus high (> 25.87 mL/kg/h) intraop-
erative fluid administration based on a median fluid adminis-
tration of 25.87 mL/kg/h [54]. Receiving more intraoperative
fluid was associated with fewer postoperative complica-
tions including surgical site infections and delayed healing
(OR = 0.54, 95% CI 0.29 to 0.99, P = 0.046) but higher mor-
tality (P = 0.005) [54]. Of note, this study included only late
preterm and term infants, and excluded neonates at highest
risk of adverse outcomes from NEC [54]. Clinicians should
monitor fluid balance in infants with NEC who are at high
risk of fluid overload.
Extracorporeal membrane oxygenation (ECMO)
Pediatric patients supported by ECMO are at high risk of
fluid overload and kidney dysfunction [55–58]. A number
of retrospective, single-center, and multicenter studies of
pediatric patients requiring ECMO have shown an asso-
ciation between the degree of fluid overload and mortality
[19, 55, 56]. Therefore, fluid overload may be targeted as an
independently modifiable risk factor for patients receiving
ECMO. In a multicenter retrospective cohort study of 446
neonates, Murphy et al. suggested that underlying patho-
physiologic processes place infants at different risks of fluid
overload [19]. Infants with congenital diaphragmatic hernia
are at particularly high risk of fluid overload [59] with higher
peak percent of fluid overload in comparison to other disease
Pediatric Nephrology (2023) 38:47–60
states (51% vs. 28% cardiac vs. 32% respiratory; P < 0.01)
[19]. Furthermore, given the high risk of concomitant kid-
ney dysfunction in these critically ill infants, earlier use of
adjunctive kidney support therapy (KST) may be benefi-
cial. Gorga et al. evaluated the impact of fluid removal on
mortality of 756 pediatric patients including 187 neonates
supported by ECMO [58]. The degree of fluid overload at
the time of initiation of KST was associated with increased
mortality (adjusted odds ratio (aOR) 1.11, 95% CI 1.00 to
1.18, P = 0.05). It is possible that early intervention strate-
gies to limit and treat fluid overload may improve outcomes
among infants on ECMO.
Pathophysiology of fluid overload
Fluid overload is defined as pathologic accumulation of
fluid. There are many potential causes of fluid overload
in neonates. Regardless of the underlying cause, intersti-
tial edema from extravasated fluid accumulates in multiple
organs, which can impede capillary blood flow [60, 61] and
cause organ dysfunction. As a result of organ congestion,
organ perfusion can become compromised which can worsen
the underlying disease process creating a positive feedback
cycle [62]. Understanding the pathophysiology of fluid
overload for each specific patient is crucial in implementing
appropriate management and treatment strategies.
The kidney is intricately involved in maintaining car-
diac and pulmonary function through regulation of preload,
afterload, pH dynamics, and osmolality [62]. The effec-
tive circulating volume (preload) is maintained by kidney
homeostatic mechanisms and erythropoietin production. The
renin and angiotensin system modifies vascular tone (after-
load). Acid–base balance is tightly controlled by the kidney
to maintain organ cellular enzymatic function and oxygen
delivery [62]. Kidney function can be compromised by fluid
overload as interstitial edema can blunt overall function.
Growing evidence shows that AKI may negatively affect
lung function through multiple mechanisms including
suboptimal fluid homeostasis, regulation of inflammation,
and maintenance of acid–base balance [62]. AKI is com-
mon in neonates, occurring in up to 48% of preterm infants
22 to < 29 weeks of gestation, 18% of preterm infants 29
to < 36 weeks, and in 37% of infants 36 weeks or older [63].
Evidence has shown that infants with AKI were more likely
to have higher fluid balance in the first week of life [45, 46,
48, 64]. Fluid overload and AKI are both independently and
synergistically associated with poor outcomes in critically
ill children [5, 18, 19, 65]. It is important to delineate the
two, as these are independently modifiable risk factors [5,
19, 48]. However among infants at risk of fluid overload,
these data stress the importance of minimizing nephrotoxic
51
insults, monitoring for signs of AKI, and preventing propa-
gation of AKI.
Vascular wall integrity plays an important role in mainte-
nance of intravascular volume. The endothelial glycocalyx
(EGL), a luminal surface-bound collection of glycoproteins
and proteoglycans, helps to maintain vascular integrity, reg-
ulate inflammation, and store non-circulating plasma volume
[66, 67]. The EGL layer supports the oncotic pressure and
attenuates plasma leak across the membrane while prevent-
ing any reabsorption from the surrounding interstitium [60,
67]. Most of the interstitial fluid resorption is facilitated by
lymphatics. Breakdown of the EGL layer can occur through
a number of processes including sepsis, hyperglycemia,
surgery, and ischemia [66, 68]. Once the EGL is damaged,
fluid efflux is dependent upon capillary hydrostatic pres-
sure, while interstitial fluid reabsorption remains relatively
constant. Fluid overload may result from third spacing in the
setting of capillary leak syndrome due to systemic inflam-
matory response including complement activation and EGL
breakdown [53]. This process leaves patients at high risk of
intravascular fluid depletion with extravasation of proteins
and accumulation of interstitial fluid [60]. A high mortality
rate has been reported among neonates and children with
capillary leak syndrome [53].
As further transvascular fluid loss occurs and intravascu-
lar volume falls, it is initially possible to restore kidney and
end-organ perfusion with volume resuscitation. However,
there is a delicate balance between intravascular volume
replacement and propagation of extravasation of fluid inter-
stitially in the setting of compromised vascular integrity and
capillary leak [60]. Therefore, careful selection of volume
replacement media is important. Continued use of isotonic
fluids such as normal saline and albumin 5% beyond the ini-
tial resuscitation may subsequently accentuate fluid overload
as these fluids leak interstitially. A number of studies have
shown that 5% albumin is not superior to normal saline as
a resuscitation fluid [69, 70]. A randomized controlled trial
comparing 5% albumin to isotonic saline in 63 hypotensive
premature infants showed that there was no difference in the
volume required, inotropic support, or mortality. However,
infants receiving the 5% albumin had significantly more
weight gain (5.9% vs. 0.9%, P = 0.05) in the first 48 h after
birth [70].
Neonates have an increased risk of hypoalbuminemia
due to slowed synthesis of albumin from immature liver
function and increased degradation. There are not clearly
defined normal ranges of albumin in neonates, but levels are
considered to be inversely proportional to gestational age.
The most widely accepted definition of moderate hypoalbu-
minemia is < 2.5 mg/dL and severe is < 2.0 mg/dL. Moderate
hypoalbuminemia has been associated with AKI [71] and
mortality in premature infants with sepsis [72]. The clinician
must weigh the risks and benefits of albumin infusions as
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there is a theoretical risk of exacerbating systemic hyper-
tension, protein extravasation, and pulmonary edema [73].
A randomized controlled trial comparing 5 mL/kg of 20%
albumin to 5 mL/kg of maintenance fluids in 40 critically ill
ventilated preterm infants (median gestational age 29 weeks)
with hypoalbuminemia (< 3.0 mg/dL) reported no difference
for reduction in weight or ventilator requirement between
the two [74].
It may be preferable to use fluids with higher oncotic
pressure such as albumin 20%, fresh frozen plasma (FFP),
or packed red blood cells (pRBC) to improve intravascu-
lar volume and decrease the requirement for isotonic fluid
boluses [75, 76]. A double-blind, randomized controlled trial
of 76 pediatric and infant patients with congenital heart dis-
ease requiring surgical management and cardio-pulmonary
bypass compared high oncotic priming with 20% albumin
versus control [77]. Patients receiving pre-treatment with
higher oncotic fluid had less hypotension (8% vs. 54%,
P = 0.02) and required fewer fluid boluses (6% vs. 54%,
P = 0.01) [77]. These data, although referring to priming
fluid instead of media for resuscitation, suggest that use of
20% albumin may be beneficial over normal saline for main-
taining intravascular volume.
There is limited data on the use of FFP as volume replace-
ment in symptomatic infants. A Cochrane review evaluated
the effect of early prophylactic volume expansion with FFP
in premature infants [78]. This meta-analysis reviewed 4
randomized trials comparing infusion of FFP versus con-
trol regardless of cardiovascular status. No improvement in
mortality (RR 1.05, 95% CI 0.81–1.36, 3 trials, N = 654) or
severe disability was noted suggesting that routine use of
FFP for volume expansion is not beneficial. Blood transfu-
sion may be preferred to maintain intravascular volume over
normal saline or 5% albumin in symptomatic patients with
anemia. A recent multicenter, double-blind, placebo-con-
trolled randomized trial of 941 extremely preterm neonates
showed that high dose erythropoietin (1000 U/kg) every 48 h
for 6 doses followed by three times weekly maintenance dos-
ing (400 U/kg) until 32 weeks post-menstrual age was safe
and reduced the number of pRBC transfusions although it
did not improve the incidence of death or severe neurode-
velopmental impairment (RR 1.03; 95% CI 0.81 to 1.32;
P = 0.80) [79]. In an ancillary project to that trial, infants
randomized to receive erythropoietin did not have a reduc-
tion in AKI [80].
Management of fluid overload
The approach to the management of the infant with fluid
overload is informed by the aforementioned pathophysiol-
ogy of fluid overload in neonates. We used evidence-based
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Pediatric Nephrology (2023) 38:47–60
potentially-better-practices to develop the management
strategy for fluid overload summarized into a mnemonic
to allow for ease of use in Table 1.
It is important to consider the differential diagnosis and
determine the most likely causes of fluid overload, includ-
ing potentially reversible causes of oliguria/anuria as dem-
onstrated in Table 2. The pathophysiology and treatment
recommendations may differ for a patient at risk of devel-
oping fluid overload depending upon the underlying etiol-
ogy. Infants with abdominal diseases, such as NEC and
spontaneous intestinal perforation, are at risk of abdominal
compartment syndrome which can present as fluid over-
load and oliguria. In an infant with a distended abdomen,
intraabdominal pressure can be assessed by transducing
a catheter placed in the bladder. Cardiac causes include a
PDA causing vascular steal, congenital heart disease, and
heart failure can be assessed with echocardiography. Most
cases of congenital anomalies of kidney and urinary tract
(CAKUT) or bladder outlet obstruction are now diagnosed
prenatally but can be suspected in infants with low urine
output and signs of pulmonary hypoplasia or pulmonary
hypertension after birth. Hypoalbuminemia can be pri-
mary or secondary and can cause or worsen fluid overload
and AKI. Hyperuricemia is a rare cause of fluid overload
and AKI that can be treated with rasburicase.
Table 3 outlines several different scenarios for at-risk
patients. The underlying pathophysiology in each may dif-
fer from another but ultimately they all result in extravas-
cular fluid accumulation and progression of cumulative
fluid overload. Importantly, there are clinical scenarios
that may not be classified into one certain scenario. For
example, an infant with NEC may develop sepsis and a
systemic inflammatory response resulting in hypotension,
oliguric kidney failure, capillary leak syndrome, low
oncotic pressure or hypoalbuminemia, and ultimately heart
failure, depending on the severity of disease.
Setting and achieving fluid balance goals
A patient is at risk of developing fluid overload when their
fluid balance is no longer in homeostasis. This can be due
to increased intake or decreased output or a combination
of both. The main ways to achieve a net negative fluid bal-
ance are through limited fluid intake and/or by increasing
fluid removal. Prevention may be the best treatment for
fluid overload. Prevention of fluid overload progression
can be achieved with vigilance, mindful fluid provision,
assuring that all fluids (including parenteral nutrition) is
concentrated and daily tracking of cumulative fluid bal-
ance in relation to clinical parameters. In patients at risk of
fluid overload, the clinician should consider the following:
Pediatric Nephrology (2023) 38:47–60 53

Table 1  A mnemonic “CAN- CAN-U-P-LOTS Mnemonic

U-P-LOTS” summarizing
evidence-based potentially-
better-practices that may be
used in clinical practice to treat
patients with fluid overload
Cause Determine underlying etiology
  - Abdominal compartment syndrome
  - Cardiac (congenital heart disease, patent ductus arteriosus, heart failure)
  - Congenital anomalies of kidney and urinary tract (CAKUT)
  - Dehydration
  - Hypoalbuminemia
  - Hyperuricemia
  - Shock (sepsis, necrotizing enterocolitis, or hypoxic ischemic injury)
Albumin Treat with 20–25% albumin:
  - 2 g/kg/dose over 4 h if albumin < 2.0 mg/dL
  - 1 g/kg/dose over 4 h if 2.0 to < 2.5 mg/dL
Nephrotoxicity Assess medications
Avoid or switch to less nephrotoxic medications
Follow levels closely if nephrotoxic medications needed
Ultrafiltration Kidney support therapy via peritoneal or extracorporeal approach
Perfusion Determine and treat cause of shock
  - Adrenal
  - Cardiac
  - Hypovolemia
  - Neurologic
  - Sepsis
Titrate mean arterial pressure (MAP) goals to achieve urine output
Lasix stress test Furosemide stress test to assess kidney response
Output Assess urine output trends
Place foley catheter
Consider bladder obstruction
Total fluid intake Determine dry weight for dosing and calculating fluid balance
Set fluid goals
Concentrate all medications and nutrition
Maintain adequate nutrition and intravascular volume
Steroids Add stress dose hydrocortisone for refractory hypotension

Table 2  A list of potentially reversible causes of oliguria/anuria in 1. Calculate and monitor the trends in the cumulative
neonates fluid balance (i.e., current weight – dry weight / dry
Potential reversible causes of oliguria/anuria weight × 100) over time.
2. Intravascular volume status should be assessed by physi-
Abdominal compartment syndrome cal examination including evaluation of perfusion and
Bladder outlet obstruction vital sign trends, as well as by investigations of electro-
Hypoalbuminemia lytes, BUN, creatinine, serum albumin, and imaging.
Inadequate kidney perfusion due to cardiac dysfunction, dehydration, 3. Develop fluid balance goals based on intravascular vol-
mineralocorticoid deficiency, shock
ume status. Re-evaluate frequently to ensure that goal is
Nephrotoxic medications
being met.
Hyperuricemia

Table 3  Clinical scenarios in which a patient is at high risk of fluid overload. The table outlines each different pathophysiologic reason for fluid
overload that must be considered when developing a treatment plan
Scenarios Intravascular Extravascular Capillary leak Oncotic pressure Systemic pressure Treatment
fluid fluid

Heart failure High Yes No Normal High, normal, or low Fluid removal
Oliguric kidney failure High Yes No Normal High Fluid removal
Sepsis Low Yes Yes Normal Low Prevention
Hypoalbuminemia Low Yes Yes Down Low Albumin

13
54
4. Evaluate all forms of fluid provision and eliminate or
concentrate all fluids (including nutrition) to achieve
lowest possible fluid intake as able.
5. Evaluate and manage reversible causes of oliguria/anuria
as demonstrated in Table 2. Different treatments should
be applied to each separate disease process.
6. Communicate with pediatric nephrologist early.
Enhanced fluid removal by improving urine output can
be achieved by optimizing kidney perfusion, diuretics, or
both. Evaluation of intravascular volume and kidney perfu-
sion will help determine therapeutic goals. It is imperative to
maintain adequate kidney perfusion through improved car-
diac output and blood pressure. While volume resuscitation
may be necessary to achieve adequate intravascular volume,
once euvolemia is achieved further volume expansion can be
harmful. Achieving effective intravascular volume requires
evaluation of volume status, determination of the appropriate
fluids for volume repletion, and knowledge of the underlying
pathophysiology. A trial of volume expansion or a “bolus”
to increase kidney perfusion may be helpful in improving
urine output. If further volume is required beyond the initial
resuscitation, consideration to give 20–25% albumin 1–2 g/
kg if hypoalbuminemic or FFP 10–20 mL/kg to increase
oncotic pressure. Our typical practice includes treatment of
moderate hypoalbuminemia (< 2.5 mg/dL) with 1 g/kg of
20% albumin, or 2 g/kg of 20% albumin over 4 h to treat per-
sistent severe hypoalbuminemia (< 2.0 mg/dL). Other blood
products can be given judiciously based on individual clini-
cal circumstances such as anemia, coagulopathy, thrombo-
cytopenia, or hypogammaglobulinemia. Once optimal intra-
vascular volume has been achieved and kidney perfusion
has been optimized, the goal for fluid balance management
should be aimed to limit fluid overload until removal of fluid
is possible.
Diuretics are one of the most prescribed medications in
the neonatal intensive care unit [81]. Despite frequent usage,
there is little evidence to support routine use of diuretic
therapy in neonates [28, 82, 83]. In the setting of progres-
sive oliguria or anuria, a trial of diuretics can be attempted
to improve or stimulate diuresis [28, 83]. Emerging data
shows a “furosemide stress test” (FST) can be very valuable
in predicting AKI progression [84]. To perform the FST,
a standard dose of diuretics (i.e., 1 mg/kg of intravenous
furosemide) is given to stimulate a diuretic response. If the
subject has a good response (i.e., > 1 mg/kg/h) over the fol-
lowing 2 h, the prognosis for recovery is good. However, if
after an FST there is not a good response, AKI progression is
likely to occur and the clinical team should begin to consider
other options such as improving perfusion and/or oncotic
pressure as well as adopting strategies to prevent further
fluid accumulation before further trials of diuretics are con-
sidered [84, 85]. Bumetanide has also been used to achieve
13
Pediatric Nephrology (2023) 38:47–60
negative fluid balance in critically ill children [86] and neo-
nates if furosemide therapy has not improved urine output
[87]. More evidence is needed for choice of therapy, optimal
dosing, administration method (bolus vs. drip), duration of
diuretic treatment, and optimization of a neonatal FST.
Aside from further volume expansion or diuretic ther-
apy, earlier use of medication to improve cardiac output that
improves kidney perfusion may be needed. Neonatal blood
pressure standards are not well defined. Several studies have
attempted to further define optimal blood pressure goals in
neonates [88–91]. Current accepted ranges are mean arte-
rial pressure (MAP) greater than gestational age [92]. In a
patient with oliguria or anuria, targeting higher MAPs may
be necessary to achieve adequate kidney perfusion, espe-
cially if there is an increase in abdominal pressure. Ongoing
data is emerging about appropriate first line vasopressor in
neonates [93–97]. Recent meta-analysis showed that dopa-
mine had the highest success of improving MAP (RR = 0.88,
95% CI: 0.76 to 0.94; 12 studies; N = 163) in neonates [93].
Dobutamine is the second most commonly used and is
thought to have less peripheral vasoconstrictive effects.
In a Cochrane review of dopamine in comparison to
dobutamine, dopamine was more effective, as shown by
reduced treatment failure (RR 0.41, 95% CI: 0.25 to 0.65),
but there was no difference in mortality outcomes [94]. In
a meta-analysis including the data from a Cochrane review
and two randomized controlled trials comparing dopamine
to epinephrine as a first-line vasopressor, there was no dif-
ference in treatment efficacy [93]. One study included in this
meta-analysis noted more significant side effects with epi-
nephrine use, including higher heart rates, elevated lactates,
and hyperglycemia [93, 98]. This review does not include
an exhaustive list of vasoactive medications useful to treat a
hypotensive neonate: a more comprehensive review can be
found via the aforementioned Cochrane review [94]. More
data are needed about the best assessment of perfusion status
and the optimal regimen and dosing of these medications to
prevent and treat fluid overload in neonates.
In addition to inotropic support, hydrocortisone is ben-
eficial in refractory hypotension [99, 100] and may improve
cardiovascular function in the setting of fluid overload.
Premature infants have a blunted adrenal response until
approximately 32 weeks gestationally (wga) and may benefit
from cortisol replacement therapy [101]. Cortisol may be
of benefit in the setting of fluid overload through improved
myocardial function, enhanced vascular responsiveness to
angiotensin II, and decreased capillary leak through effects
on luminal integrity [101]. A retrospective analysis by Tolia
et al. evaluated the effect of stress dose hydrocortisone in
the first 14 postnatal days in 1427 infants less than 30 wga
[102]. Higher dose (> 2 mg/kg) in comparison to lower dose
(≤ 2 mg/kg) hydrocortisone was associated with increased
mortality (aOR 3.27, 95% CI 2.47 to 4.34, P < 0.001) [102].
Pediatric Nephrology (2023) 38:47–60
While stress dose hydrocortisone may be helpful in hypoten-
sion and fluid overload, further data are needed to support
dosing recommendations and long term outcomes.
Kidney support therapy in neonates
If fluid restriction, diuretic trials, and optimization of hemo-
dynamics are not able to achieve the desired fluid balance
goals, kidney support therapy (KST) should be considered
[103]. Neonates can receive KST via a peritoneal dialysis
(PD) or an extracorporeal approach to treat or prevent fluid
overload refractory to diuresis. Like all other medical deci-
sions, the evaluation of the potential benefits and risk of
the procedures are needed to make clinical decisions. In a
patient with balanced electrolytes and relatively normal kid-
ney function, KST may be considered as the primary therapy
for fluid removal over diuretic therapy if the fluid accumu-
lation trend is severe and the patient is not able to achieve
the fluid goals with diuretics. The right time to start KST is
when the impending harm from the inability of the kidney to
maintain fluid, electrolytes, and toxin homeostasis outweighs
the risks of KST. In this context, it is vital to recognize the
goals, risks, and benefits of KST.
The risks associated with extracorporeal KST have been
greatly reduced with the advent of neonatal-specific kidney
support devices. Until recently, use of extracorporeal KST
in neonates had to be adapted from adult machines which
presented a number of challenges due to the large filter/tub-
ing volumes which lead to high priming volume in relation
to patient size, difficulty in maintaining adequate blood flow
for optimal circuit function, hemodynamic instability during
initiation, and challenges related to vascular access [103].
Many of the recent advances in the reduction of risk in neo-
natal KST are due to smaller tubing/filter volumes, which
allow for lower priming volumes [103, 104].
Reports of the use of KST in extremely premature
infants have mostly been limited to PD, primarily due to
patient size preventing catheter placement in small caliber
blood vessels. However, the use of PD in the setting of
fluid overload is often limited by the low, unpredictable
ultrafiltration and increased intraabdominal permeabil-
ity that predisposes them to severe hyperglycemia [105].
Although complications from PD are not very common,
the associated risks include catheter malfunction, infec-
tion, electrolyte, and blood pressure abnormalities. Cath-
eter malfunction and infection can be greatly reduced with
appropriate surgical technique and by allowing time for
the catheter insertion site to heal before use. PD is con-
traindicated in a number of patients at high risk of fluid
overload, including perforated NEC and patients with
congenital diaphragmatic hernia [106]. PD is commonly
used in neonates after cardio-pulmonary bypass surgery.
A recent review article evaluating data on early initiation
55
of PD in neonates who undergo cardio-pulmonary bypass
surgery noted a trend towards reduced fluid overload and
mortality but inconclusive evidence about the optimal tim-
ing of initiation following surgery [107].
The CARdiorenal PEDIatric Emergency Machine (CAR-
PEDIEM) (Medtronic, Minneapolis, MN) achieves fluid,
electrolyte, and waste product clearance with minimal com-
plications. Multiple studies have validated the use of this
device in the neonatal population down to infants weighing
2 kg [105, 108]. This system has very precise scales, works
in either dialysis or hemofiltration mode, must be changed
every 24 h, and has been recently approved for use in the
USA by the FDA for children between 2.0 and 9.9 kg.
The Aquadex system (Nuwellis Inc., Eden Prairie, MN)
for ultrafiltration was adapted for use in the neonatal popu-
lation after its original use in adults with congestive heart
failure. This system has an extracorporeal volume of 33 ml
(mL) and provides continuous hematocrit and mixed venous
oxygen saturation monitoring during the treatment. In com-
bination with an external fluid delivery system, Askenazi
et al. first described the ability to remove waste products,
balance electrolytes, and remove fluid in continuous veno-
venous hemofiltration mode in small children [109]. A more
recent multicenter study evaluated the ability of Aquadex to
provide effective prolonged-intermittent and slow-continu-
ous KST. Importantly, they found hemodynamic instability
in only 3% of circuit initiation, and the few episodes were
mild in nature [110].
The Newcastle Infant Dialysis and Ultrafiltration Sys-
tem (NIDUS) (Newcastle, England), another KST machine
developed for small children, has an extracorporeal volume
of 6–10 mL (depending on the stroke volume used). The
system uses a single lumen access, which may allow safe
and effective therapy in even ELBW infants. The machine
uses diffusive clearance, in contrast to the two earlier men-
tioned modalities [111]. As of 2021, the machine was not
available for commercial use, awaiting the conclusion of a
multi-center clustered wedge-shaped clinical study.
In larger children and adults, the degree of fluid overload
at the time of initiation is independently associated with
mortality [47, 55, 58, 65, 112]. Thus, it is very plausible that
this is also true in neonates. As technology has improved, the
risk of hemodynamic instability during KST in neonates has
sharply decreased. Each modality may be useful for different
patient scenarios depending upon clinical need. The benefits,
limitations, and potential complications of KST options are
displayed in Table 4. With a reduction in complications, the
risk to benefit ratio changes the equation such that early use
of early KST in neonates should be considered as a thera-
peutic option as part of a comprehensive strategy to prevent
and treat fluid overload. Further investigation on the optimal
timing of initiation and delivery of these therapies in neo-
nates is warranted.
13
56 Pediatric Nephrology (2023) 38:47–60

Table 4  A table representing the capabilities and limitations of kidney support therapies available to neonates. NEC, necrotizing enterocolitis

Kidney support modality Benefits Limitations Complications Mode of clearance

Peritoneal dialysis
Extracorporeal support
(CARPEDIEM, Nidus,
Aquadex)
- Ease of use - Limited precision of the
- No vascular access exact amount of fluid and
- Can be used if hemody- waste product removal
namically unstable - Unable to use if intraab-
dominal complications
(e.g., NEC, intrabdominal
surgery, congenital dia-
phragmatic hernia)
- Must wait until catheter
heals to use for prolonged
use
- Highly efficient waste prod- - Requires vascular access
uct clearance - May be restricted based on
- Precise fluid removal size of vessel
- Low extracorporeal volume - Requires specialized
filter/tubing enables smaller machines
catheters, and decreases - Requires higher expertise/
hemodynamic instability training
compared to traditional - Requires anti-coagulation
larger KST circuits of the circuit
- May start therapy imme-
diately after catheter
placement
- Catheter migration Diffusion
- Catheter malfunction
- Catheter infection
- Peritonitis
- Hyperglycemia
- Hyponatremia
- Hypoalbuminemia
- Catheter migration Diffusion or con-
- Catheter thrombosis vection (CAR-
- Catheter infections PEDIEM)
- Hemodynamic instabil- Diffusion (Nidus)
ity (although this is much Convection (Aqua-
lower than traditional KST dex)
machines)

Conclusions and future directions References

Increased clinician awareness of the impact of fluid over-
load will help to improve recognition and implementation
of therapies aimed at reducing fluid accumulation. Early
and targeted management of fluid overload may help pro-
viders improve outcomes. In addition, KST with machines
that have smaller extracorporeal volume can now be used to
prevent or treat fluid excess in infants who do not respond
to medical therapy. Basic, translational, and clinical stud-
ies are needed to close remaining knowledge gaps and
improve our current limited understanding of neonatal fluid
overload.
Funding  This work was supported by the National Institute of Health
(NIH) Grants (U34 KD 117128, R44 HD095225, NHLBI K23HL
157618).
Declarations  Bagshaw SM (2020) Fluid accumulation in critically ill children.
Conflict of interest  The authors declare no competing interests. For
full disclosure, we provide here an additional list of other author’s
commitments and funding sources that are not directly related to this
study:
David J Askenazi is a consultant for Baxter, Nuwellis, Medtronic Bio-
porto, Seastar and the AKI Foundation. He receives grant funding for
education and research that is not related to this project from NIH,
Baxter, Nuwellis, and Medtronic and i6. Innovations on advancements
of CKRT have been filed for patent protection.
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