ORIGINAL RESEARCH

published: 06 July 2021

doi: 10.3389/fped.2021.691721

Association Between Hyponatremia

and Maintenance Intravenous
Solutions in Critically Ill Children: A
Retrospective Observational Study
Jaime Fernández-Sarmiento 1*, Andrea Pérez 2 , Maria Alejandra Echeverri 2 ,
Paola Jimenez 3 , Maria Alejandra Joachim 3 and Andrés-Jagua 4
1
Departament of Pediatrics and Intensive Care, Fundación Cardioinfantil-Instituto de Cardiología, Universidad de La Sabana,
Bogotá, Colombia, 2 Departament of Pediatrics, Fundación Cardioinfantil-Instituto de Cardiología, Universidad El Rosario,
Bogotá, Colombia, 3 Department of Pediatrics and Intensive Care, Universidad de La Sabana, Bogotá, Colombia,
4
Departament of Research, Universidad Nacional de Colombia, Bogotá, Colombia

Objetive: We sought to determine the association between maintenance intravenous

Edited by: solutions and the presence of hyponatremia in children in pediatric intensive care (PICU).
Muralidharan Jayashree,
Post Graduate Institute of Medical Materials and Methods: An analytical observational study in children hospitalized in the
Education and Research
PICU between January 2015 and December 2018. Patients who received maintenance
(PGIMER), India
fluids within the first 48 h after admission and who had at least two serum sodium levels
Reviewed by:
Puneet Aulakh Pooni, drawn during this time were included.
Dayanand Medical College &
Hospital, India
Measurements and Main Results: A total of 1,668 patients were admitted to the
Sasidaran Kandadamy, PICU during the study period, 503 of whom met the inclusion criteria. The median age
Dr. Mehta’s Children’s Hospital, India was 24 months (IQR 8–96) and 50.9% were female. Altogether, 24.1% of the children
*Correspondence: developed hyponatremia; it was more frequent in those who received hypotonic solutions
Jaime Fernández-Sarmiento
[email protected] (63 vs. 37%; OR 1.41 95% CI 0.92, 2.15 p = 0.106), who also had a longer hospital stay
(20 vs. 14 days, difference in means 8 days, 95% CI 2.67, 13.3, p = 0.001). Children
Specialty section: who received loop diuretics and those who were post-operative had a greater risk of
This article was submitted to
Pediatric Critical Care, developing hyponatremia if they received hypotonic solutions (aOR 2.1 95% CI 1.41,
a section of the journal 3.0, p = 0.000). Those with balanced isotonic solutions had a lower risk of developing
Frontiers in Pediatrics
hyponatremia (aOR 0.59 95% CI 0.35, 0.99, p = 0.004) and hyperchloremia (aOR 0.51
Received: 06 April 2021
95% CI 0.34, 0.77, p = 0.000), adjusted for disease severity. A greater risk of death
Accepted: 03 June 2021
Published: 06 July 2021 was found in the group with severe hyponatremia < 130 mEq/L (aOR 9.75 95% CI
Citation: 1.64–58.15; p = 0.01).
Fernández-Sarmiento J, Pérez A,
Echeverri MA, Jimenez P, Joachim MA
Conclusions: Hyponatremia associated with the use of hypotonic maintenance
and Andrés-Jagua (2021) Association solutions occurs in one out of four children in intensive care. The use of these solutions
Between Hyponatremia and
is associated with a longer hospital stay, and the main risk groups are post-operative
Maintenance Intravenous Solutions in
Critically Ill Children: A Retrospective patients and those who receive loop diuretics. Clinical studies are needed to determine
Observational Study. which maintenance solutions have the greatest efficacy and safety in critically ill children.
Front. Pediatr. 9:691721.
doi: 10.3389/fped.2021.691721 Keywords: fluids, unbalanced solutions, balanced solutions, sodium, antidiuretic

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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

INTRODUCTION MATERIALS AND METHODS

Maintenance fluids are often used to sustain fluid, metabolic This was a retrospective cohort observational analytic study of
and electrolytic balance in patients who for some reason patients from 1 month to 18 years of age who were admitted to
cannot receive enteral feedings or who only receive partial the pediatric intensive care unit at the Fundación Cardioinfantil-
feedings. The traditional use of intravenous solutions is IC in Bogotá, Colombia (a reference University hospital). Patients
based on the method proposed by Malcolm Holliday and hospitalized in the PICU between January 2015 and December
William Segar in 1957, who, in an effort to approximate 2018 were included. The included children also had to have
the need for solutes and the components of breast milk, received maintenance fluids beginning within the first hour
proposed hypotonic solutions as maintenance fluids (1– after admission to the PICU, have sodium levels within normal
3). The recent American Academy of Pediatrics (AAP) limits on admission, and have had a serum sodium level drawn
guidelines do not recommend the use of these solutions within the first 6 h after admission, with at least two follow
because they are related to more serious complications up exams within the following 48 h. Only patients receiving a
which can lengthen hospital stay and cause serious single type of solution as maintenance fluids were included. The
encephalopathy (4). same institutional protocol for maintenance fluid solutions was
Hyponatremia has been defined as a serum sodium level maintained throughout the study period. Patients who received
of < 135 mEq/L. It is the most frequently described fluid two or more types of intravenous fluids were not included. This
and electrolyte complication in hospitalized children (5–8). study was approved by the institutional ethics committee, with
Various studies have reported a frequency ranging from 19– approval number SE-1176-2018. It conformed to the principles of
50% (9). Many of these cases have been associated with the the Declaration of Helsinki, and all patients had a consent form
use of excessively hypotonic maintenance fluids, with non- for signed by their parents or legal guardians on admission to
osmotic release of antidiuretic hormone (ADH), especially in the PICU.
risk groups such as patients with respiratory or neurological Patients with documented hyponatremia on blood gases
diseases and those who are post-operative (2, 10, 11). This or serum sodium drawn in the emergency room or hospital
ADH release may be related to stimuli such as pain, anxiety, wards and processed in the central lab prior to PICU admission
fever and vomiting, reducing the capacity to excrete free were excluded. Those with a diagnosis of adrenal insufficiency,
water, and increasing the risk of hyponatremia in these hypothyroidism, syndrome of inappropriate antidiuretic
patients (5, 9, 12). hormone secretion, and/or osmoregulatory readjustment prior
When the concentration of sodium drops acutely to to admission were also excluded. The PIM-2 scale was used
<125 mEq/L, ∼50% of children develop hyponatremic to evaluate disease severity on admission to the ICU, which
encephalopathy, with possible adverse neurological outcomes was measured in all cases within the first 6 h after admission.
(5, 13). Moritz and Ayus described 50 cases of hyponatremia, Likewise, those who received 3% hypertonic saline due to
26 of whom died of complications related to rapid-onset severe hyponatremia from other causes were excluded. The patients’
hyponatremia (5). admitting diagnosis was considered, and if they required any
Over the last few years, several clinical studies and surgical intervention at any point, they were included as surgical
systematic reviews have been published in which the patients for the analysis.
researchers have attempted to clarify which solution is All the data for this study were taken from the electronic
best to use as maintenance fluid. In a recent meta-analysis medical chart and supported by the clinical laboratory records.
including more than 2,000 patients, Mercier et al. found All the information was recorded in an exclusive file for this study
that the risk of developing severe hyponatremia (< 130 which had a password known only to the principal investigators.
mmol/L) was significantly lower with the use of isotonic The information obtained from the clinical charts was used
solutions compared to hypotonic solutions (RR 0.31; 95% exclusively for this study.
CI 0.19–0.50) (11). Despite this, it has been reported that, in Normal saline (NS) or dextrose in normal saline (DNS) were
78% of simulated situations, physicians, including pediatric classified as isotonic unbalanced solutions, and Ringer’s lactate or
residents, would prescribe hypotonic maintenance solutions in Plasmalyte R
were classified as balanced isotonic solutions. Two
children (14). types of hypotonic solutions were used: 80 mEq/L of sodium in
Patients in pediatric critical care have a higher risk of 5% dextrose in water (D5W) with 20 mEq of potassium, and 60
hyponatremia associated with their critical clinical condition and mEq/L in D5W with 20 mEq/L of potassium. These solutions
associated comorbidities. An up to four times greater risk of are routinely used for maintenance solutions in most middle
hyponatremia has been reported in the PICU, but it is unclear and low-income countries. Some clinicians especially prefer
if this risk changes with the use of the various isotonic solutions these hypotonic solutions for the smallest children, to limit the
available today (balanced or unbalanced) vs. hypotonic solutions amount of chloride supplied, compared with NS. The volume of
(15, 16). In this study, we sought to describe the frequency of fluids administered was calculated according to the institutional
hyponatremia in children in intensive care in a reference hospital, protocol using the Holliday-Segar formula, both for medical as
and its association with the use of maintenance fluids, as well as well as surgical patients, to cover 100% of their requirements. No
the risk factors most often related to this complication. fluid restriction was instated for those on mechanical ventilation,

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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

or for those recovering from a transplant or any other condition. all groups (IQR 8–96 months) and 51% of included patients
The only patients who received 70% of the requirement were were female (Figure 1). In addition, hyponatremia was seen
those who, according to the clinical judgement of the attending in 70 cases (25.2%) of children under the age of two, with no
physician, were in heart failure and had signs of fluid overload. differences found in the frequency of hyponatremia compared
By institutional protocol, maintenance fluids are reduced to 50% with other age groups (p = 0.57). Of these patients, 57.3%
when more than 60% of the caloric intake goals are met through received a solution with 80 mEq/L of sodium and 23.4% received
enteral feeding. 60 mEq/L of sodium, with hyponatremia found more often in
Hyponatremia was defined as a serum level < 135 mEq/L those under the age of two using these two types of hypotonic
and hypernatremia as a serum level of more than 145 mEq/L. solutions (p = 0.003) compared with children under the age of
We defined severe hyponatremia to be serum sodium below 130 two who received an isotonic solution.
mEq/L, after having been admitted with a previously normal Fifty-nine percent of cases were admitted to the PICU for
level. Potassium and chloride values were also collected, with non-surgical conditions (Table 1). There were no significant
hypokalemia being defined as potassium < 3.5 mEq/L and differences in the distribution of surgical or non-surgical cases
hyperkalemia as potassium > 5 mEq/L at any point in the by sex or age (p = 0.387), nor in disease severity evaluated
measurements during the first 48 h. Likewise, hypochloremia was using the PIM-2 scale, between the groups (p = 0.14). The most
defined as levels below 97 mEq/L and hyperchloremia as levels common causes of hospitalization were the need for pediatric
above 110 mEq/L in all age groups included in the study. surgery (11.9%), liver transplant (11.7%), and sepsis (11.1%)
Serum sodium was measured by the central laboratory, using (Supplementary Table 1). Altogether, 47.3% of the children
standard technique, and processing the sample within 1 h of its received mechanical ventilation support for more than 24 h
being drawn, according to the institutional protocol. Samples after admission, and 26.8% received vasoactive support for more
were sent via pneumatic tube from the PICU, ensuring rapid and than 24 h.
effective processing in < 60 min. The blood sample was drawn Patients hospitalized for pulmonary or gastrointestinal
from an arterial line (radial or femoral) or from venous blood conditions were significantly younger than those hospitalized for
drawn from a central venous catheter in the subclavian, jugular or other causes (p = 0.045). The age group in which hypotonic
femoral vein. Potentiometry was employed to process the plasma solutions were used was younger than the age group for whom
electrolytes, using an Abbott R
Architect i8000 system. isotonic solutions were ordered (p = 0.001).
The primary outcome was the frequency of hyponatremia Hyponatremia occurred in 121 (24.1%) of the study patients.
associated with the use of intravenous maintenance solutions. Thirty-seven percent (45 patients) of the cases occurred with
Secondary outcomes were length of hospital stay, factors isotonic solutions and 63% (76 patients) with hypotonic
associated with the presence of hyponatremia and mortality. solutions. A greater risk of hyponatremia was found with the use
A univariate analysis was performed describing quantitative of hypotonic solutions compared to isotonic solutions (OR 1.41
variables with central tendency measures, using means and 95% CI 0.92, 2.15; p = 0.106), although the difference was not
reporting standard deviations assuming normality (according statistically significant.
to the Kolmogorov-Smirnov test). For variables with non- When hyponatremia was analyzed by type of solution,
normal distribution, medians and interquartile ranges were used. balanced isotonic solutions were found to have a lower risk
Likewise, qualitative variables were reported using percentages, of hyponatremia than the other solutions (aOR 0.59 95%
and the bivariate analysis considered their relationship to CI 0.35, 0.99, p = 0.04), controlling for confounding factors
the primary outcome. Multivariate analysis was performed to (Table 2). However, there were no differences in the occurrence
attempt to control for confounding factors that could explain of hyponatremia with the use of other maintenance solutions:
hyponatremia due to another cause. The model included disease unbalanced isotonic solutions (aOR 1.51 95% CI 0.79, 2.86, p =
severity measured with the PIM-2 scale, age, and a > 10% fluid 0.21), hypotonic solution with 80 mEq/L of sodium (aOR 0.73
balance. In addition, variables which met the Hosmer-Lemeshow 95% CI 0.40, 1.33, p = 0.31), or hypotonic solution with 60 mEq/L
criteria on the bivariate analysis were considered. The model was of sodium (aOR 1.38 IC95% 0.75, 2.53, p = 0.29) Table 2.
constructed using the forward method and was adjusted with the Similarly, regardless of the type of solution used, post-
Omnibus test. A p < 0.05 was considered to be significant, and operative patients were found to have a greater risk of
STATA 14.0 software was used for the analyses. hyponatremia than non-surgical patients (27.4% in the post-
operative group vs. 17.1% in the non-surgical group; OR
1.93, 95% CI 1.23, 3.1, p = 0.001). The frequency of
RESULTS hyponatremia was even greater if these patients received loop
diuretics during the first 48 h after admission (28.3 vs. 18%;
During the study period, 1,668 patients were admitted to p = 0.007). The risk of hyponatremia in these patients
intensive care. These included 503 children who met the with the use of diuretics and in the post-operative group
inclusion criteria, 284 (56.5%) of whom received hypotonic increased if they were also receiving hypotonic solutions as
solutions and 219 isotonic solutions. Of these, 120 (23.9%) maintenance fluids (aOR 2.1 95% CI 1.41, 3.0 p = 0.000).
received balanced isotonic solutions (Ringer’s lactate or This risk increased as the concentration of sodium in the
Plasmalyte) and 99 (19.7%) received unbalanced isotonic maintenance fluid solution decreased (Table 1). We found no
solutions (NS or D5W/NS). The median age was 24 months for difference in the frequency of hyponatremia if patients received

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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

FIGURE 1 | Study population.

TABLE 1 | Characteristics of the study population.

Isotonic Hypotonic

Total patients Balanced Unbalanced Hypotonic solution: Hypotonic solution: P-value*

isotonic solution isotonic solution 80 mEq/L 60 mEq/L
(n = 503) (n = 120) (n = 99) (n = 190) (n = 94)

Female sex, n (%)** 256 (50.9) 61 (50.8) 51 (51.5) 90 (47.3) 54 (57.4) 0.954
Age in months, median (IQR) 24 (8–96) 132 (78–168) 72 (12–132) 9 (5–12)* 12 (9–36)* 0.001
Median length of hospital stay (IQR) 17 (9–34) 13 (8–25) 14 (8–31) 19 (11–36) 22 (10.47) 0.000
Surgical, n (%) 206 (41) 44 (36.7) 38 (38.4) 89 (46.8) 35 (37.2) 0.160
Reason for hospitalization, n(%)
Pulmonary 99 (19.7) 14 (11.7) 14 (14.1) 45 (23.7) 26 (27.7)* 0.001
Renal 12 (2.4) 5 (4.2) 3 (3) 1 (0.5) 3 (3.2) 0.156
Cardiac 5 (1) 2 (1.7) 0 1 (0.5) 2 (2.1) 0.347
Infectious 75 (14.9) 13 (10.8) 18 (18.2) 30 (15.8) 14 (14.9) 0.456
Neurological 24 (4.8) 9 (7.5) 4 (4) 34 (17.9) 7 (7.4) 0.756
Hematological-oncological 32 (6.4) 18 (15)* 10 (10.1)* 2 (1.1) 2 (2.1) 0.001
Gastrointestinal 100 (19.9) 10 (8.3) 11 (11.1) 65 (34.2) 14 (14.9) 0.000
Other 49 (9.7) 20 (16.7) 13 (13.1) 8 (4.2) 8 (8.5) 0.000
Other diagnoses, n(%)
Sepsis 56 (11.1) 8 (6.7) 11 (11.1) 26 (13.7) 11 (11.7) 0.124
Liver transplant 59 (11.7) 5 (4.2) 5 (5.1) 41 (21.6)* 8 (8.5) 0.001
Mechanical ventilation n (%) 238 (47.3) 47 (39.1) 42 (42.4) 98 (51.6)* 51 (54.3)* 0.030
Vasopressors n (%) 135 (26.8) 36 (30) 22 (22.2) 56 (29.5) 21 (22.3) 0.879
PIM-2 median, (IQR) 4.05 (1.3–4.1) 2.57 (1.29–8.60) 4.37 (1.41–8.86) 5.45 (1.19–13.30) 3.42 (1.62–8.35) 0.145
Use of sedatives n (%) 248 (49.3) 52 (43.3) 46 (35) 100 (52.6) 50 (53.2) 0.562

*Chi2-Test Fisher.
**The percentage expressed corresponds to the proportion of females in each group.

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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions
vasoactive support (p = 0.87), sedation (p = 0.56), mechanical
ventilation (p = 0.07), or high-flow nasal cannula support
P-value

0.07

0.96

0.03

0.05

(p = 0.6).
The frequency of hyponatremia in patients with and without
metabolic acidosis was similar (10.1 vs. 20%, OR 2.27 95% CI
0.87–5.65, p = 0.085), as well as in children with hyperlactatemia
Postoperative
aOR (95%CI)

(0.26–1.07)

(0.54–1.79)

(1.06–3.06)

(1.11–1.82)

(OR 1.32 95% CI 0.53–3.28, p = 0.536) and acute kidney injury

0.52

0.99

1.30

1.5

(OR 0.51 95% CI 0.15–1.76, p = 0.441), regardless of the type of

solution used.
Likewise, when the subgroup with severe hyponatremia (<
130 mEq/L) was analyzed, we found that there was a greater risk
P-value

of developing it when solutions with a very low sodium content

0.07

0.70

0.05

0.05

were used. Specifically, the risk of severe hyponatremia was much

greater with the 60 mEq/L solution (aOR 3.87 95% CI 1.32–18.73;
p = 0.04), and there was a greater risk of death (aOR 9.75 95% CI
1.64–58.15; p = 0.01) after adjusting for disease severity.
loop diuretics
aOR (95%CI)

(0.24–1.07)

(0.48–1.65)

(1.02–2.41)

(1.23–2.53)

Hypernatremia was found in 29 patients (5.8%) and no

Use of

0.51

0.89

1.52

1.82

association was found between the frequency of elevated sodium

and the type of solution used (p = 0.894) or age (p =
0.705), nor was it associated with the reason for hospitalization
(p = 0.621), or the group of post-operative patients (p
P-value

= 0.962). However, if the patient had hypernatremia, there

0.06

0.84

0.12

0.93

was a greater risk of unsatisfactory clinical progression and

greater mortality (25 vs. 4.8%, OR 6.6 95% CI 2.39, 18.22;
*Binary logistic regression. aOR (OR adjusted for PIM-2 disease severity, age, fluid balance, need for mechanical ventilation, vasoactives).

p = 0.001).
The use of balanced isotonic solutions was associated with
aOR (95%CI)

(0.07–1.07)

(0.35–3.68)

(0.77–9.62)

(0.27–4.04)
Mortality
TABLE 2 | Multivariate model of factors associated with presence of hyponatremia and the type of solution employed*.

a lower risk of hyperchloremia (OR 0.51 95% CI 0.34, 0.77, p

0.26

1.13

2.72

1.05

= 0.000). No association was found between chloride disorders

and the use of unbalanced and hypotonic solutions (OR 0.74
95% CI 0.47, 1.16, p = 0.234) (Supplementary Table 2). No
differences were found between the cumulative 48-h balance
P-value

and the presence of hyponatremia, according to the type of

0.01

0.72

0.17

0.78

solution employed (p = 0.58), but if the cumulative balance

was > 10% 48 h after admission, there was a greater risk
of developing hyponatremia (OR 2.54 95% CI 1.54–6.03;
Hospital stay
aOR (95%CI)

p = 0.013).
(0.19–0.82)

(0.61–2.01)

(0.85–2.43)

(0.62–1.90)

The median length of hospital stay of all the included patients

0.41

1.11

1.44

1.08

was 17 days (IQR 9–34). The group receiving hypotonic solutions

had a longer stay (20 days IQR 11–38) than the group receiving
isotonic solutions (14 days IQR 8–30) (p = 0.000). The use of
hypotonic solutions was associated with 8 more days of total
P-value

hospital stay (difference in means 8, 95% CI 2.67, 13.3, p =

0.04

0.21

0.30

0.29
0.001) (Figure 2A). Likewise, after controlling for confounding
factors, a shorter hospital stay was found with the use of balanced
solutions (aOR 0.41 95% CI 0.19–0.82; p = 0.013).
Risk of hyponatremia

The median ICU stay was 4 days (IQR 3–8) for all groups.
aOR (95%CI)

(0.793–2.86)
(0.35–0.99)

(0.40–1.33)

(0.75–2.53)
There were no differences in mortality between patients receiving
0.59

1.51

0.73

1.38
hypotonic or isotonic solutions (4.9 vs. 4.6%; p = 0.347). There
were no differences in length of ICU stay according to the type of
solution employed (p = 0.543) (Figure 2B).
Hyponatremic encephalopathy was found in four patients
(0.8%), with no subsequent neurological damage documented,

80 mEq/L hypotonic

60 mEq/L hypotonic
Type of solution and recovery with sodium correction.
Death occurred in 24 patients (4.8%) (Figure 2C). Mortality

Unbalanced
was related to other variables such as sepsis (OR 3.61 95% CI 1.42,

Balanced

solution

solution
9.42 p = 0.011), hypernatremia and lactate > 2 (OR 14.61 95% CI
1.87, 114.21, p = 0.001).
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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

FIGURE 2 | Length of stay in hospital and type of solution used. textbf(A) Distribution of length of hospital stay by solution used. (B) Distribution of length of stay in the
ICU by solution used. (C) Distribution of length of stay in the ICU in mortality cases. Navy blue: Balanced isotonic solution, Purpure: Unbalanced isotonic solution,
Dark green: Hypotonic solution type 1, and Light green: Hypotonic solution type 2.

DISCUSSION maintenance solutions (in terms of hyponatremia prevention)

has been described for more than 10 years, unfortunately,
The use of intravenous fluids as maintenance solutions is one ordering excessively hypotonic fluids for hospitalized children,
of the most common practices in hospitalized patients. There even in the PICU, is still a common practice. The AAP (4) and
is a general consensus regarding the volume administered, NICE (20) guidelines recommend always using isotonic solutions
based on the formula proposed by Holliday-Segar; however, as maintenance fluids. However, they do not specify if they should
there is controversy regarding the ideal tonicity, due to be balanced or unbalanced solutions.
reported complications like acute hyponatremia with the use In this regard, our study found that patients who received
of excessively hypotonic solutions, and the presence of adverse balanced isotonic solutions had a lower risk of hyponatremia
outcomes (13). (OR 0.59 95% CI 0.35, 0.99, p = 0.007) than those who received
This study evaluated 503 patients hospitalized in intensive unbalanced isotonic solutions as maintenance fluids. Of these,
care who received isotonic or hypotonic solutions as maintenance NS with or without 5DW was the solution used in our study.
fluids, finding that 24.1% presented acute hyponatremia within We are unaware of any studies describing this association. It has
the first 48 h after admission. Of these patients, 37% of cases recently been reported that when NS is used in adults or children
occurred with the use of isotonic solutions and 63% with as boluses for fluid resuscitation, there is a greater risk of acute
hypotonic solutions. This group had a longer hospital stay and kidney injury, hyperchloremia and metabolic acidosis (8, 18, 19).
hyponatremia was more commonly found in patients on loop However, in our study we did not find a greater incidence of this
diuretics and in post-operative recovery. type of complications, although it should be clarified that NS
The frequency of hyponatremia associated with the use of was not used in boluses but rather as a maintenance solution.
hypotonic solutions varies according to the study. Carandang et Balanced dextrose-containing solutions are not available in all
al. (9) evaluated 1,048 patients, among whom, 38.6% of those countries for exclusive maintenance fluid use, especially in small
who received hypotonic solutions developed hyponatremia while children. Prospective studies are needed to assess the safety and
27.8% of those who received isotonic solutions did so (OR 1.63; efficacy of the use of balanced solutions vs. unbalanced solutions
95% CI 1.24–2.15, p < 0.001). In a group of post-operative as maintenance fluids.
children or children with gastroenteritis, Saba et al. (17) found Furthermore, most of the studies describe the immediate post-
a 20% frequency of hyponatremia associated with the use of operative period as a risk factor for hyponatremia associated with
hypotonic solutions. However, they found no differences in the use of hypotonic solutions. Carandang et al. (9) found a
the frequency of hyponatremia between isotonic or hypotonic higher risk of hyponatremia in the subgroup of post-operative
solutions. Other researchers have had similar findings (8, 18, 19). children (RR 2.24, 95% CI 1.52–3.31). Choong et al. (21) had
The most recent meta-analysis, which included more than 2,000 similar findings in this group of patients (40.8 vs. 22.7%; RR:
children, found an overall greater relative risk of developing 1.82) (95% CI: 1.21–2.74; p = 0.004). In our cohort, a greater
severe hyponatremia with the use of hypotonic solutions (RR risk of hyponatremia was also found in the group of post-
0.31; 95% CI 0.19–0.50) (11). operative patients (OR 1.93 95% CI 1.23, 3.1, p = 0.001). The
Traditionally, the non-osmotic release of ADH has been causes could be related to the administration of anesthetic agents
related to the presence of hyponatremia associated with these or opioids and the non-osmotic secretion of ADH (22–24). In
solutions (19, 20, 22). Stimuli such as pain, stress and nausea, patients recovering from abdominal surgery, excessive interstitial
among others, may trigger this release and favor the presence fluid immediately after the procedure as well as the presence of
of hyponatremia when excessively hypotonic solutions are used. colostomies (with possible sodium loss) could also explain this
Although the superiority of isotonic over hypotonic fluids as association (16).

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Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

In addition, the use of balanced isotonic solutions was hyponatremia. Isotonic fluids in the context of ADH elevation
associated with a lower risk of hyperchloremia (OR 0.51 95% may also favor the development of hyponatremia due to free
CI 0.34, 0.77 p = 0.000), which could be related to the lower water retention. Children hospitalized in critical care tend to
supply of chloride in most balanced solutions compared with be complex, with multiple comorbidities, many of which may
unbalanced solutions. Hyperchloremia in critically ill children be non-osmotic stimuli for ADH release. Due to the design
has been associated with the use of chloride-rich solutions mainly characteristics of this study, no intervention was performed,
administered as volume expanders and maintenance fluids (OR and it was not designed to investigate the volume of fluids
1.13; 95% CI 1.04–1.23) (25). These may cause complications administered. Therefore, future clinical studies may consider that
secondary to renal and splanchnic vasoconstriction, as well as “restricted” maintenance fluids could be necessary for patients
related to increased proinflammatory cytokines, increasing the with greater ADH release, thus restricting the supply of free
risk of progressing to multiple organ failure (OR 1.9, 95% CI 1.1– water and, hypothetically, decreasing the frequency of iatrogenic
3.2, p = 0.023) and greater associated mortality (OR 3.7, 95% CI hyponatremia. This is very important, given that a significant
2.0–6.8, p < 0.001) (26). proportion of fluid overload in critically ill children is often not
Furthermore, we found that patients on loop diuretics had recognized by the attending physicians (29).
a greater risk of hyponatremia (OR 1.74 95% CI 1.11, 2.73, p
= 0.007), which was even greater if they were also receiving
CONCLUSIONS
hypotonic solutions as maintenance fluids (aOR 2.1 95% CI 1.41,
3.0 p = 0.000). Although some studies report that 73% of cases of The use of maintenance fluid solutions in critically ill
diuretic-induced hyponatremia are due to thiazide diuretics, and children is often associated with a significant incidence of
only 8% are caused by loop diuretics like furosemide, we found acute hyponatremia within the first 48 h after admission to
a greater risk of hyponatremia in this group. These diuretics intensive care. We found that one out of four children
can cause volume depletion, or the patient may receive a high receiving maintenance fluids develop acute hyponatremia. This
supply of fluids which is poorly tolerated by the children because hyponatremia is more frequent and marked in patients receiving
loop diuretics may partially alter the ability to dilute the urine. hypotonic solutions as maintenance fluids than in those receiving
These effects may be more frequent in very small children, who isotonic solutions, and this finding is associated with a more
also have difficulties in maintaining a hypertonic renal medulla prolonged hospital stay. It is more common in post-operative
(16, 27). patients, as well as in children on loop diuretics, groups which
In our cohort, we also found an average of 8 days’ longer have traditionally been considered to be at risk for this type
hospital stay with the use of hypotonic solutions compared with of complication. The use of balanced isotonic solutions as
isotonic solutions (difference in means 8, 95% CI 2.67, 13.3, p maintenance fluids is associated with a lower frequency of
= 0.001). Shein et al. found that, in patients with bronchiolitis, hyponatremia and complications. Clinical studies are needed to
hyponatremia was correlated with increased hospital stay (r = evaluate the efficacy and safety of balanced isotonic solutions as
−0.477, p < 0.0001), and thus this may be a modifiable risk maintenance fluids in critically ill children.
factor which could be mitigated by avoiding the use of hypotonic
solutions (12).
Outcomes such as death and neurological lesions have DATA AVAILABILITY STATEMENT
been reported as a result of hospital-acquired hyponatremia in
The original contributions presented in the study are included
children receiving hypotonic intravenous maintenance fluids.
in the article/Supplementary Material, further inquiries can be
Moritz and Ayus found that 9.4% of their patients who
directed to the corresponding author/s.
had iatrogenic hyponatremia during their hospital stay died,
and they suggested a direct relationship between the severity
of the hyponatremia and these unsatisfactory outcomes (28). ETHICS STATEMENT
Nevertheless, our cohort had a similar mortality between the
groups, except in children with sepsis or hypernatremia (OR The studies involving human participants were reviewed and
6.6 95% CI 2.39, 18.22, p = 0.025) and in children with severe approved by committee reference number SE-1176-2018, and the
hyponatremia (aOR 9.75 95% CI 1.64–58.15; p = 0.01). It is parents of the children agreed to participate in this study. Written
important to carry out studies to determine the risk groups for informed consent to participate in this study was provided by the
worse outcomes and their association with the type of solution participants’ legal guardian/next of kin.
used as maintenance fluids.
We consider that our study has several limitations. Due AUTHOR CONTRIBUTIONS
to its retrospective nature, the study could be susceptible to
information bias; however, the established methodology allowed JF-S, AP, ME, PJ, MJ, and A-J contributed to designing and
data capture errors to be controlled, and we used secondary performing the study. AP, ME, PJ, and MJ participated in
sources (such as nursing notes) when complete data were not data collection. JF-S supervised study development and data
available. In addition, the study reflects the experience of a single collection. All the authors contributed to drafting the manuscript
center which cares for complex patients. Thus, hospitals receiving and reviewing the final article. All authors approved the final
less complex patients might have less hyponatremia. Altogether, manuscript as submitted and agree to be accountable for all
8.9% of the children who received isotonic solutions developed aspects of the work.

Frontiers in Pediatrics | www.frontiersin.org 7 July 2021 | Volume 9 | Article 691721

Fernández-Sarmiento et al. Hyponatremia and Maintenance Intravenous Solutions

ACKNOWLEDGMENTS SUPPLEMENTARY MATERIAL

We would like to thank the PICU medical, nursing, and The Supplementary Material for this article can be found
respiratory therapy team for their kind cooperation, as well as the online at: https://www.frontiersin.org/articles/10.3389/fped.
clinical laboratory at the Fundación Cardioinfantil-IC. 2021.691721/full#supplementary-material

REFERENCES 17. Saba TG, Fairbairn J, Houghton F, Laforte D, Foster BJ. A

randomized controlled trial of isotonic versus hypotonic maintenance
1. Friedman JN, Beck CE, Degroot J, Geary DF, Sklansky DJ, Freedman intravenous fluids in hospitalized children. BMC Pediatr. (2011)
SB. Comparison of isotonic and hypotonic intravenous maintenance 11:1011. doi: 10.1186/1471-2431-11-82
fluids: a randomized clinical trial. JAMA Pediatrics. (2015) 169:445– 18. Neville KA, Sandeman DJ, Rubinstein A, Henry GM, McGlynn M, Walker
512. doi: 10.1001/jamapediatrics.2014.3809 JL. Prevention of hyponatremia during maintenance intravenous fluid
2. Wang J, Xu E, Xiao Y. Isotonic versus hypotonic maintenance iv fluids administration: a prospective randomized study of fluid type versus fluid rate.
in hospitalized children: a meta-analysis. Pediatrics. (2014) 133:105– J Pediatr. (2010) 156:313–9. doi: 10.1016/j.jpeds.2009.07.059
13. doi: 10.1542/peds.2013-2041 19. Rey C, Los-Arcos M, Hernández A, Sánchez A, Díaz J-J, López-Herce J.
3. Friedman A. Maintenance fluid therapy: what’s next. J Pediatr. (2014) 165:14– Hypotonic versus isotonic maintenance fluids in critically ill children: a
5. doi: 10.1016/j.jpeds.2014.03.014 multicenter prospective randomized study. Acta Paediatr. (2011) 100:1138–
4. Feld LG, Neuspiel DR, Foster BA, Leu MG, Garber MD, Austin K, et 43. doi: 10.1111/j.1651-2227.2011.02209.x
al. Clinical practice guideline: maintenance intravenous fluids in children. 20. Neilson J, O’Neill F, Dawoud D, Crean P. Intravenous fluids in
Pediatrics. (2018) 142:e20183083. doi: 10.1542/peds.2018-3083 children and young people : summary of NICE guidance. BMJ. (2015)
5. Moritz ML, Ayus JC. Preventing neurological complications 351:h6388. doi: 10.1136/bmj.h6388
from dysnatremias in children. Pediatr Nephrol. (2005) 20:1687– 21. Choong K, Arora S, Cheng J, Farrokhyar F, Reddy D, Thabane L,
700. doi: 10.1007/s00467-005-1933-6 et al. Hypotonic versus isotonic maintenance fluids after surgery
6. Chung CH, Zimmerman D. Hypernatremia and hyponatremia: current for children: a randomized controlled trial. Pediatrics. (2011)
understanding and management. Clin Pediatr Emerg Med. (2009) 10:272– 128:857–66. doi: 10.1542/peds.2011-0415
8. doi: 10.1016/j.cpem.2009.11.002 22. Toledo JD, Morell C, Vento M. Intravenous isotonic fluids induced a positive
7. Carcillo JA. Intravenous fluid choices in critically ill children. Curr Opin Crit trend in natremia in children admitted to a general paediatric ward. Acta
Care. (2014) 20:396–401. doi: 10.1097/MCC.0000000000000119 Paediatr Int J Paediatr. (2016) 105:e263–8. doi: 10.1111/apa.13316
8. McNab S, Duke T, South M, Babl FE, Lee KJ, Arnup SJ, et al. 140 mmol/L 23. Yang G, Jiang W, Wang X, Liu W. The efficacy of isotonic and
of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid hypotonic intravenous maintenance fluid for pediatric patients: a meta-
therapy for children in hospital (PIMS): a randomised controlled double-blind analysis of randomized controlled trials. Pediatr Emerg Care. (2015) 31:122–
trial. Lancet. (2015) 385:1190–7. doi: 10.1016/S0140-6736(14)61459-8 6. doi: 10.1097/PEC.0000000000000352
9. Carandang F, Anglemyer A, Krishnan G, Longhurst CA, Alexander 24. Grisaru S, Xie J, Samuel S, Freedman SB. Iatrogenic dysnatremias in children
SR, Kahana M et al. Association between maintenance fluid with acute gastroenteritis in high-income countries: a systematic review. Front
tonicity and hospital-acquired hyponatremia. J Pediatr. (2013) Pediatr. (2017) 5:210. doi: 10.3389/fped.2017.00210
163:1646–51. doi: 10.1016/j.jpeds.2013.07.020 25. Bulfon AF, Alomani HL, Anton N, Comrie BT, Rochwerg B, Stef SA, et al.
10. Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in hospitalized Intravenous fluid prescription practices in critically ill children: a shift in
children: a systematic review and meta-analysis. J Pediatr. (2014) 165:163– focus from natremia to chloremia? J Pediatr Intensive Care. (2019) 8:218–
9. doi: 10.1016/j.jpeds.2014.01.040 25. doi: 10.1055/s-0039-1692413
11. Mercier JC, Titomanlio L, Basmaci R, Gaschignard J. Risks of severe 26. Stenson EK, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT,
hyponatremia in children receiving hypotonic fluids. Arch Pédiatr. (2020) et al. Hyperchloremia is associated with complicated course and mortality in
27:474–9. doi: 10.1016/j.arcped.2020.08.009 pediatric patients with septic shock. Pediatr Crit Care Med. (2018) 19:155–
12. Shein SL, Slain K, Martinez Schlurmann N, Speicher R, Rotta AT. 60. doi: 10.1097/PCC.0000000000001401
Hyponatremia and hypotonic intravenous fluids are associated with 27. Schrier RW, Bansal S. Diagnosis and management of
unfavorable outcomes of bronchiolitis admissions. Hospital Pediatrics. (2017) hyponatremia in acute illness. Curr Opin Crit Care. (2008)
7:263–70. doi: 10.1542/hpeds.2016-0205 14:627–34. doi: 10.1097/MCC.0b013e32830e45e3
13. Hoorn EJ, Geary D, Robb M, Halperin ML, Bohn D. Acute 28. Moritz ML, Ayus JC. Intravenous fluid management for the acutely ill child.
hyponatremia related to intravenous fluid administration in Curr Opin Pediatr. (2011) 23:186–93. doi: 10.1097/MOP.0b013e3283440fd9
hospitalized children: an observational study. Pediatrics. (2004) 29. Al-Lawati ZH, Sur M, Kennedy CE, Akcan Arikan A. Profile of fluid exposure
113:1279–84. doi: 10.1542/peds.113.5.1279 and recognition of fluid overload in critically ill children. Ped Crit Care Med.
14. Freeman MA, Ayus JC, Moritz ML. Maintenance intravenous fluid (2020) 21:760–6. doi: 10.1097/PCC.0000000000002337
prescribing practices among paediatric residents. Acta Paediatr. (2012)
101:e465–8. doi: 10.1111/j.1651-2227.2012.02780.x Conflict of Interest: The authors declare that the research was conducted in the
15. Raksha SK, Dakshayani B, Premalatha R. Full Volume isotonic (0.9%) absence of any commercial or financial relationships that could be construed as a
vs. Two-Thirds volume hypotonic (0.18%) intravenous maintenance fluids potential conflict of interest.
in preventing hyponatremia in children admitted to pediatric intensive
care unit—a randomized controlled study. J Trop Pediatr. (2017) 63:454– Copyright © 2021 Fernández-Sarmiento, Pérez, Echeverri, Jimenez, Joachim
60. doi: 10.1093/tropej/fmx012 and Andrés-Jagua. This is an open-access article distributed under the terms of
16. Torres SF, Iolster T, Schnitzler EJ, Siaba Serrate AJ, Sticco NA, the Creative Commons Attribution License (CC BY). The use, distribution or
Rivarola MR. Hypotonic and isotonic intravenous maintenance fluids reproduction in other forums is permitted, provided the original author(s) and the
in hospitalised paediatric patients: a randomised controlled trial. copyright owner(s) are credited and that the original publication in this journal
BMJ Paediatr Open. (2019) 3:e000385. doi: 10.1136/bmjpo-2018-0 is cited, in accordance with accepted academic practice. No use, distribution or
00385 reproduction is permitted which does not comply with these terms.

Frontiers in Pediatrics | www.frontiersin.org 8 July 2021 | Volume 9 | Article 691721