Current Medical Research and Opinion

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Use of intravenous fluids/solutions: a narrative

review

N. El Gkotmi, C. Kosmeri, T. D. Filippatos & M. S. Elisaf

To cite this article: N. El Gkotmi, C. Kosmeri, T. D. Filippatos & M. S. Elisaf (2017) Use of
intravenous fluids/solutions: a narrative review, Current Medical Research and Opinion, 33:3,
459-471, DOI: 10.1080/03007995.2016.1261819

To link to this article: https://doi.org/10.1080/03007995.2016.1261819

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Nov 2016.
Published online: 14 Dec 2016.

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CURRENT MEDICAL RESEARCH AND OPINION, 2017
VOL. 33, NO. 3, 459–471
http://dx.doi.org/10.1080/03007995.2016.1261819
Article ST-0403.R1/1261819
All rights reserved: reproduction in whole or part not permitted

REVIEW

Use of intravenous fluids/solutions: a narrative review

N. El Gkotmi, C. Kosmeri, T. D. Filippatos and M. S. Elisaf
Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece

ABSTRACT ARTICLE HISTORY

Objective: Intravenous fluids are broadly categorized into colloids and crystalloids. The aim of this Received 11 August 2016
review is to present under a clinical point of view the characteristics of intravenous fluids that make Revised 18 October 2016
them more or less appropriate either for maintaining hydration when enteral intake is contraindicated Accepted 10 November 2016
or for treating hypovolemia.
Methods: We considered randomized trials and meta-analyses as well as narrative reviews evaluating KEYWORDS
the effects of colloids or crystalloids in patients with hypovolemia or as maintenance fluids published Albumin; balanced
in the PubMed and Cochrane databases. solutions; bicarbonate;
Results: Clinical studies have not shown a greater clinical benefit of albumin solutions compared with colloids; crystalloids;
crystalloid solutions. Furthermore, albumin and colloid solutions may impair renal function, while there hyperchloremia; mortality;
is no evidence that the administration of colloids reduces the risk of death compared with resuscitation metabolic acidosis;
with crystalloids in patients with trauma, burns or following surgery. Among crystalloids, normal saline potassium
is associated with the development of hyperchloremia-induced impairment of kidney function and
metabolic acidosis. On the other hand, the other commonly used crystalloid solution, the Ringer’s
Lactate, has certain indications and contraindications. These matters, along with the basic principles of
the administration of potassium chloride and bicarbonate, are meticulously discussed in the review.
Conclusions: Intravenous fluids should be dealt with as drugs, as they have specific clinical indications,
contraindications and adverse effects.

Introduction crystalloids in patients with hypovolemia or as maintenance

Administration of intravenous fluids, which are broadly cate-
gorized into colloids and crystalloids, is an everyday practice
in hospitalized patients either for maintaining hydration when
enteral intake is contraindicated or for treating hypovolemia.
No intravenous solution covers all needs in everyday medical
practice and the selection is mostly based on clinician prefer-
ence relying on the knowledge of physiological principles, the
patient’s profile and tolerance as well as on the cost.
Recently, there has been wide discussion concerning the
most appropriate intravenous crystalloid solution, given that
each type of fluid has certain advantages but also disadvan-
tages. Thus, the current idea recently proposed is that any
type of fluid should be considered as a drug followed by
indications, contraindications and adverse effects1.
The aim of this review is to present under a clinical point
of view the characteristics of intravenous fluids that make
them more or less appropriate either for maintaining hydra-
tion when enteral intake is contraindicated or for treating
hypovolemia.
Methods
We considered randomized trials and meta-analyses, as well
as narrative reviews, evaluating the effects of colloids or
fluids. We searched for eligible published manuscripts in
PubMed and the Cochrane Central Register of Controlled
Trials (last search September 2016) using the search algo-
rithm: (hypovol
OR dehydrat
OR hydrat
) AND (colloids OR
albumin OR hydroxyethyl starch solutions OR starch OR dex-
tran OR gelatin OR crystalloid OR normal saline OR hyper-
tonic saline OR balanced intravenous fluids OR balanced
crystalloids OR Ringer OR Plasmalyte OR Hartmann) AND
(mortality OR death OR renal OR kidney OR acidosis OR
hyperchlor
OR acid-base OR electrolytes OR chloride OR
potassium OR bicarbonate OR tonicity) limited to English lan-
guage. Moreover, we screened systematic and narrative
reviews that pertained to eligible topics.
The role of colloid solutions in fluid resuscitation
The use of colloid solutions has been implemented in clinical
practice because they increase oncotic pressure in the blood
vessels and they can reduce the total amount of fluids
needed to improve hemodynamics and systemic perfusion in
comparison with crystalloid fluids. Proponents of colloid solu-
tions suggest a ratio of 1:3 of colloids to crystalloids regard-
ing the volume of solution needed to preserve the
intravascular volume2,3. However, this ratio is much smaller

CONTACT Professor Moses S. Elisaf melisaf54@gmail.com, egepi@cc.uoi.gr Department of Internal Medicine, School of Medicine, University of Ioannina,
45 110 Ioannina, Greece
ß 2016 Informa UK Limited, trading as Taylor & Francis Group
www.cmrojournal.com
460 N. EL GKOTMI ET AL.
in clinical studies4–6. A meta-analysis showed that greater
fluid volumes are required to meet the same targets with
crystalloids than with colloids, with an estimated ratio of
1:1.5 (95% confidence interval [CI] 1.36–1.65), but there is
marked heterogeneity among studies7. Fluid overload has
been associated with increased mortality especially in critic-
ally ill patients8,9. This may be a potential benefit of colloids
as they do not expand the total volume so much compared
with crystalloids.
In the CRISTAL (Colloids Versus Crystalloids for the
Resuscitation of the Critically Ill) trial the use of colloids com-
pared with crystalloids was associated with similar mortality
at 28 days (primary endpoint, relative risk [RR] 0.96, 95% CI
0.88–1.04, p ¼ 0.26), but a lower mortality at 90 days (second-
ary endpoint, RR 0.92, 95% CI 0.86–0.99, p ¼ 0.03) in intensive
care unit (ICU) patients with hypovolemic shock (Table 1).
Renal replacement therapy (RRT) did not significantly differ
between colloids and crystalloids (RR 0.93, 95% CI 0.83–1.03,
p ¼ 0.19). Additionally, at 28 days colloids were associated
with more days alive without mechanical ventilation (mean
14.6 vs. 13.5 days; mean difference 1.10, 95% CI 0.14–2.06
days; p ¼ 0.01) and alive without vasopressor therapy (mean
16.2 vs. 15.2 days; mean difference 1.04, 95% CI -0.04 to 2.10
days, p ¼ 0.03). The study concluded that colloids may have
an advantage when used for primary resuscitation in critically
ill patients since those who received colloid fluids were in
less need of vasopressor therapy and mechanical ventilation
and had lower mortality at 90 days (Table 1)10. However, the
CRISTAL trial has received scientific criticism, such as that it
was un-blinded, the method of allocation of patients did not
ensure allocation concealment, and the use of a secondary
endpoint as a marker of benefit (taking into account the
non-significant primary endpoint) should be tested by stricter
statistical methods16,17. Additionally, as shown below, most
other studies and meta-analyses have shown non-beneficial
or even harmful effects of colloids in terms of mortality, renal
failure and transfusion needs.
Human albumin has been used in many trials and in
many circumstances in patients with hypovolemia, burns or
hypoalbuminemia. For example, the SAFE (Saline versus
Albumin Fluid Evaluation) study examined the safety of albu-
min administration in ICU patients (Table 1)4. It showed no
significant difference in mortality rate, no significant differ-
ence in hemodynamic parameters and it had no significant
impact on organ function compared with normal saline (NS)
solution (0.9% NaCl). However, a potential decrease in mor-
tality among patients with severe sepsis irrespective of the
presence of hypoalbuminemia was shown4. Hence, albumin
may be beneficial in early resuscitation in patients with
severe sepsis, but future suitable randomized controlled trials
are needed to definitely assess this matter. The ALBIOS
(Albumin Italian Outcome Sepsis) trial tested the hypothesis
that the combined use of 20% albumin with crystalloids may
be beneficial in patients with severe sepsis compared with
crystalloid solution alone (Table 1)11. Despite inducing a
higher mean arterial pressure (p ¼ 0.03) and a lower net fluid
balance (p < 0.001) during the first 7 days, the combined
administration of albumin with crystalloids did not improve
the rate of survival compared with crystalloids alone at
28 days (RR 1.00, 95% CI 0.87–1.14, p ¼ 0.94) and 90 days
(RR 0.94, 95% CI 0.85–1.05, p ¼ 0.29)11.
Albumin has been associated with increased mortality in
patients with brain trauma due to increased intracranial pres-
sure4,18. The last Cochrane Systematic review that compared
albumin with crystalloid solutions published in 2011 showed
that the pooled RR of death with albumin administration was
1.05 (95% CI 0.95–1.16), for cases of hypovolemia RR was
1.02 (95% CI 0.92–1.13), for patients with burns RR was 2.93
(95% CI 1.28 to 6.72) and for patients with hypoalbuminemia
it was 1.26 (95% CI 0.84–1.88)19. These non-beneficial effects
even in patients with hypoalbuminemia have been attributed
to increased vascular permeability due to underlying inflam-
mation, which leads to extravasation of albumin to the
interstitium.
In 2014, a network meta-analysis showed a beneficial
effect of mortality with albumin compared with other fluids
in patients with sepsis20. However, it should be mentioned
that this type of meta-analysis (network meta-analysis) is
potentially more subject to error than a routine meta-
analysis, since it provides a global estimate of comparative
treatment effectiveness combining both direct and indirect
evidence21. Another meta-analysis based on 15 randomized
controlled trials evaluated whether the use of albumin-
containing fluids for resuscitation in patients with sepsis was
associated with a decreased mortality rate and concluded
that there was no significant advantage of using albumin-
containing fluids for resuscitation in patients with sepsis of
any severity (RR 0.94, 95% CI 0.87–1.02)22.
A meta-analysis of prospective randomized clinical trials of
adults with sepsis of any severity (16 primary clinical trials
that included 4190 adults) showed that compared with con-
trol fluids (crystalloids or colloids) the administration of a
median of 70 g/day of pooled human albumin over a median
of 3 days as part of fluid volume expansion and resuscitation
did not improve the relative risk of death (RR 0.94, 95% CI
0.87–1.01, p ¼ 0.11)23. In a predefined subgroup analysis in
which studies at high risk of bias were excluded, no signifi-
cant difference in mortality was found23. These observations
point to the fact that albumin solutions as part of fluid vol-
ume expansion and resuscitation for critically ill adults with
sepsis of any severity do not significantly reduce mortality.
Additionally, it should be acknowledged that a human prod-
uct is not devoid of the danger of transmitting viruses,
although various laboratory techniques can substantially
reduce this possibility24–26. Based on the above evidence,
and taking into account the cost-effectiveness of albumin
use, crystalloids should be the first choice for fluid resuscita-
tion in septic patients.
Currently used hydroxyethyl starch solutions (HES) exhibit
low concentration (6%), low molecular weight (130 kD) and
molar substitution ratio (0.38–0.45). The CRYSTMAS (Effects of
Voluven on Hemodynamics and Tolerability of Enteral
Nutrition in Patients with Severe Sepsis) study showed that
HES 130/0.4 solution was significantly better than NS in rela-
tion to the amount of solution required to achieve initial
hemodynamic stability in patients with severe sepsis
(Table 1)5. However, the use of HES has not been associated
with benefit in terms of mortality rates; in fact there is
Table 1. Main studies that have compared the use of albumin or colloids with crystalloid solutions
.
Study Design and population Solutions Primary outcome Secondary outcome
CRISTAL trial10  RCT Colloids (gelatins, dextrans, hydrox- Mortality at 28 days: 359 deaths (25.4%) vs. Mortality at 90 days: 434 deaths (30.7%) vs.
 Mixed ICU population yethyl starches, or 4% or 20% of albu- 390 deaths (27.0%), RR 0.96 (95% CI 493 deaths (34.2%), RR 0.92 (95% CI
min; n ¼ 1414) vs. crystalloids 0.88–1.04), p ¼ 0.26. 0.86–0.99), p ¼ 0.03).
(isotonic or hypertonic saline or RRT: 156 (11.0%) vs. 181 (12.5%), RR 0.93
Ringer lactate solution; n ¼ 1443) (95% CI 0.83–1.03), p ¼ 0.19).
SAFE trial4  RCT Albumin 4% (n ¼ 3497) vs. NS Mortality at 28 days: 726 (20.9%) vs. 729 Remained in ICU at 28 days: 111 (3.2%) vs.
 Mixed ICU population (n ¼ 3500) (21.1%), RR 0.99 (95% CI 0.91–1.09), 87 (2.5%), RR 1.27, p ¼ 0.09.
p ¼ 0.87. Remained in hospital at 28 days: 793
(22.8%) vs. 848 (24.5%), RR 0.93 (95% CI
0.86–1.01), p ¼ 0.10.
Similar survival times, new organ failure,
mean length of stay in the hospital, days
of RRT (all p ¼ ns).
Death in trauma patients with cranial injury:
59/241 (24.5%) vs. 38/251 (15.1%), RR
1.62 (95% CI 1.12–2.34), p ¼ 0.009).
Death in patients with severe sepsis: 185/
603 (30.7%) vs. 217/615 (35.3%), RR 0.87
(95% CI 0.74–1.02), p ¼ 0.09.
ALBIOS trial11  RCT Albumin 20% plus crystalloid solution Mortality at 28 days: 285 (31.8%) vs. 288 Mortality at 90 days: 365 (41.1%) vs. 389
(n ¼ 910) vs. crystalloid solution alone (32.0%), RR 1.00 (95% CI 0.87–1.14), (43.6%), RR 0.94 (95% CI 0.85–1.05),
(n ¼ 908) p ¼ 0.94. p ¼ 0.29.
SOFA score: median 6 (IQR 4.0–8.5) vs. 5.62
(IQR 3.92–8.28), p ¼ 0.23.
Post hoc subgroup analysis in 1121 patients
with septic shock at baseline: 243 (43.6%)
vs. 281 (49.9%), RR 0.87 (95% CI
0.77–0.99), p ¼ 0.03 for heterogeneity vs.
patients without septic shock.
FEAST trial12  RCT Albumin 5% (n ¼ 1050) vs. NS Death at 48 hours: 111 (10.6%) vs. 110 Death at 4 weeks: 128 (12.2%) vs. 126 (12%)
 Children with severe (n ¼ 1047) (10.5%) vs. 76 (7.3%), RR of saline bolus vs. 91 (8.7%), RR of saline bolus vs. no
febrile illness (poor (20 to 40 ml/kg of body weight) vs. vs. no bolus 1.44 (95% CI 1.09–1.90), bolus 1.38 (95% CI 1.07–1.78), p ¼ 0.01;
resource setting, Africa) no bolus control therapy (n ¼ 1044) p ¼ 0.01; RR of albumin bolus vs. saline RR of bolus albumin vs. no bolus 1.40
bolus 1.00 (95% CI 0.78–1.29), p ¼ 0.96; (95% CI 1.08–1.80), p ¼ 0.01; RR of com-
RR of bolus combined therapy vs. no bined bolus vs. no bolus 1.39 (95% CI
bolus 1.45 (95% CI 1.13–1.86), p ¼ 0.003. 1.11–1.74), p ¼ 0.004.
CRYSTMAS trial5  RCT HES (n ¼ 100) vs. NS (n ¼ 96) Amount of study drug (ml) required to Time to achieve initial HDS (hours):
 ICU patients with severe achieve initial hemodynamic stability: 11.8 ± 10.1 vs. 14.3 ± 11.1, p ¼ ns.
sepsis 1379 ± 876 vs. 1709 ± 1164 ml, p ¼ 0.0185. Length of stay in ICU (days): 15.4 ± 11.1 days
vs. 20.2 ± 22.2, p ¼ ns.
Length of stay in the hospital (days):
37.7 ± 26.5 vs. 42.7 ± 31.6, p ¼ ns.
Mortality rate at day 28: was 31/100 (31.0%)
vs. 24/95 (25.3%), p ¼ 0.37.
VISEP trial13  RCT HES 200/0.5 (n ¼ 262) vs. Ringer’s lac- Death at 28 days: 70 (26.7%) vs. 66 (24.1%), Deaths at 90 days: 107 (41.0%) vs. 93
 Patients with severe tate (n ¼ 275) p ¼ 0.48. (33.9%), p ¼ 0.09.
sepsis Morbidity (mean SOFA score): 8 (95% CI Acute renal failure: 91 (34.9%) vs. 62
7.5–8.5) vs. 7.5 (7.1–8.0), p ¼ 0.16. (22.8%), p ¼ 0.002.
RRT: 81 (31%) vs. 51 (18.8%), p ¼ 0.001.
Red cell transfusion: 199 (76%) vs. 189
USE OF INTRAVENOUS FLUIDS/SOLUTIONS: A NARRATIVE REVIEW

(68.7%), p ¼ 0.06.
Number of red cell units: median 6 (IQR
4–12) vs. 4 (2–8), p < 0.001.
(continued)
461
 462 N. EL GKOTMI ET AL.

evidence that HES may increase mortality. The VISEP (Efficacy

Abbreviations. RCT, randomized controlled trial; ICU, intensive care unit; RR, relative risk; RRT, renal replacement therapy; ICU, intensive care unit; IQR, interquartile range; RIFLE, Risk, Injury, Failure, Loss of kidney function,
(54.0%) vs. 1912 (57.3%), RR 0.94 (95% CI

RRT: 235 (7.0%) vs. 196 (5.8%), RR 1.21 (95%

RRT: 87 (22%) vs. 65 (16%), RR 1.35 (95% CI

New hepatic failure: 55 (1.9%) vs. 36 (1.2%),

(36.5%) vs. 722 (39.9%), RR 0.91 (95% CI
Death at 28 days: 154 (39%) vs. 144 (36%),

and End-stage kidney disease classification; AKI, acute kidney injury; SOFA, Sepsis-related Organ Failure Assessment; NS, normal saline; ns, non-significant; HDS, hemodynamic stability; HES, hydroxyethyl starch solutions.
RIFLE – renal dysfunction at 90 days: 1788
Severe bleeding: 38 (10%) vs. 25 (6%), RR
of Volume Substitution and Insulin Therapy in Severe Sepsis)

Severe allergic reactions: 1 (0.25%) vs. 0

RR 1.08 (95% CI 0.90–1.28), p ¼ 0.43.

RR 1.56 (95% CI 1.03–2.36), p ¼ 0.03.

trial compared the use of 10% HES 200/0.5 to Ringer’s lactate

New cardiovascular organ failure: 663

SOFA score at day 5: median 6 vs. 6,
1.52 (95% CI 0.94–2.48), p ¼ 0.09.
(RL) for volume replacement therapy in 537 septic patients
Secondary outcome

(Table 1). Patients receiving colloids exhibited a similar group

rate of death at 28 days to RL (26.7% and 24.1%, respectively,

CI 1.00–1.45), p ¼ 0.04.
0.90–0.98), p ¼ 0.007.
p ¼ 0.48) and a trend toward a higher rate of death at 90

1.01–1.80), p ¼ 0.04.

0.84–0.99), p ¼ 0.03.
days (41.0% vs. 33.9%, p ¼ 0.09)13. Another randomized trial,
(0%), p ¼ 0.32.

the 6S (Scandinavian Starch for Severe Sepsis/Septic Shock)

p ¼ 0.64.

study, which was conducted in an ICU population, also

showed an increased 90 day mortality with the use of HES
compared with Ringer’s acetate solution (RR 1.17, 95% CI
1.01–1.36, Table 1)14.
The results of randomized controlled trials have also
related HES with increased renal adverse effects. In the VISEP
trial patients receiving HES compared with those in the RL
Death at 90 days: 201 (51%) vs. 172 (43%),
after randomization: 202 (51%) vs. 173
Death or dependence on dialysis 90 days

group exhibited increased rates of acute renal failure (34.9%

RR 1.17 (95% CI 1.01–1.36), p ¼ 0.03.

(17.0%), RR 1.06 (95% CI 0.96–1.18),

Death at 90 days: 597 (18.0%) vs. 566

vs. 22.8%, p ¼ 0.002) and more days on which RRT was

(43%), RR 1.17 (95% CI 1.01–1.36),

required (18.3% vs. 9.2%)13. The 6S trial also showed an

Primary outcome

increased 90 day need of RRT with the use of HES compared

with Ringer’s acetate solution (RR 1.1.35, 95% CI 1.01–1.80)14.
The CHEST (Crystalloid versus Hydroxyethyl Starch Trial) trial
did not associate HES with increased mortality in ICU
patients, not even in patients with sepsis, but a 21% increase
p ¼ 0.03.

p ¼ 0.26.

in the rate of RRT was noticed (Table 1)15. The adverse

effects of HES on renal function have been attributed to vari-
ous mechanisms, such as an acute increase in oncotic pres-
sure and/or to osmotic nephrosis27,28.
A meta-analysis of 13 studies in patients undergoing non-
cardiac surgery showed a shorter length of hospital stay with
HES compared with crystalloids (mean difference -1.52 days;
HES 130/0.42 (n ¼ 398) vs. Ringer’s

95% CI -2.87 to -0.18), but a trend to increased mortality

HES (130/0.42; n ¼ 3500) vs. NS

within 90 days (risk ratio 2.97, 95% CI 0.96–9.19), no differ-

ence in acute kidney injury (AKI) and RRT (risk ratio 1.11, 95%
Solutions

CI 0.26–4.69), and no difference in the rate of major infec-

tious complications (risk ratio 1.19, 95% CI 0.59–2.39)29.
acetate (n ¼ 400)

Another meta-analysis of 38 trials showed that the risk ratio

for death with HES compared to other solutions in studies
(n ¼ 3500)

reporting mortality data (n ¼ 10,880) was 1.07 (95% CI

1.00–1.14)30. Moreover, when seven trials that involved 590
patients were excluded (due to suspicion of scientific miscon-
duct), HES was correlated with increased mortality in a sam-
ple of 10,290 patients (risk ratio 1.09, 95% CI 1.02–1.17),

Values indicate number of patients, unless otherwise stated.

increased renal failure in a sample of 8725 patients (risk ratio

 ICU patients with severe

1.27, 95% CI 1.09–1.47) and increased use of RRT in a sample

Design and population

 Mixed ICU patients

of 9258 patients (risk ratio 1.32, 95% CI 1.15–1.50)30.

Moreover, HES has been correlated with harmful effects
on bleeding and hemostasis. In the VISEP study, patients
receiving HES had a lower median platelet count (179,600/
sepsis
 RCT

 RCT

cm3) compared with patients in the RL group (224,000/cm3,

p < 0.001) and received more units of packed red cells
(median number 6 vs. 4, p < 0.001)13. In the 6S trial 10% of
patients in HES group had severe bleeding compared with
6% of patients in the Ringer’s acetate group (RR 1.52, 95% CI
Table 1. Continued

0.94–2.48, p ¼ 0.09)14. A meta-analysis regarding postopera-

tive blood loss in randomized clinical trials involving adult
CHEST trial15

cardiopulmonary bypass surgery (18 studies, n ¼ 970) showed

6S trial14

that, compared with albumin, HES increased postoperative

Study

blood loss by 33.3% (95% CI 18.2–48.3, p < 0.001).


Additionally, the risk of reoperation for bleeding was more
than doubled (RR 2.24, 95% CI 1.14–4.40, p ¼ 0.020), whereas
an increased transfusion of red blood cells by 28.4% (95% CI
12.2–44.6, p < 0.001), fresh-frozen plasma by 30.6% (95% CI
8.0–53.1, p ¼ 0.008) and platelets by 29.8% (95% CI 3.4–56.2,
p ¼ 0.027) was shown31. An older meta-analysis has shown
similar harmful effects of HES compared with albumin in
patients undergoing cardiopulmonary bypass surgery32.
However, a meta-analysis on the effect of 6% HES versus
other fluids for non-septic ICU patients (22 studies, n ¼ 6064)
showed that HES was not associated with decreased overall
mortality (RR 1.03, 95% CI 0.09–1.17, p ¼ 0.67), RRT incidence,
bleeding volume and red blood cell transfusion33.
HES is eliminated through urinary excretion, but also
undergoes tissue uptake34. A meta-analysis (25 studies,
n ¼ 287) showed that tissue uptake of low-molecular-weight
HES (200 kD) was significantly greater compared with high-
molecular-weight HES (42.3%, 95% CI 39.6–45.0 vs. 24.6%,
95% CI 17.8–31.4, p < 0.001)35. Regarding single HES solu-
tions, 130/0.4 and HES 200/0.5 had a similar tissue uptake
(42.6%, 95% CI 35.0–50.2 and 43.3%, 95% CI 39.4–47.2),
which was significantly lower compared with HES 450/0.7
(22.2%, 95% CI 14.8–29.6, both p < 0.01)35. A major site of
HES uptake and storage is the skin, which is related to occur-
rence of severe prolonged (can persist for up to 12–24
months) refractory pruritus36–38. In a retrospective study of
70 patients with electron microscopy-proven HES-induced
pruritus the median latency between HES exposure and
onset of pruritus was 3 weeks, with a median duration of
pruritus of 6 months. Indeed, pruritus was characterized as
severe or very severe from 80% of patients39. In a meta-ana-
lysis of the CHEST and CHRYSTMAS trials, compared with NS,
pruritus was significantly increased with HES 130/0.4 (RR
1.81, 95% CI 1.37–2.38)40. The mechanisms of HES-induced
pruritus are not fully understood, although HES storage to
HES-laden vacuoles in skin macrophages and in small cutane-
ous nerves may play a central role36.
In 2013 the US Food and Drug Administration, based
on evidence from randomized controlled trials and meta-
analyses, issued a “black box” warning regarding increased
mortality and severe renal injury associated with the use of
HES in critically ill patients (including those with sepsis), sug-
gesting that it should not be administered in this population
or in patients with pre-existing renal dysfunction41. A com-
mittee of the European Medicines Agency (EMA) initially sug-
gested a total ban for HES, a suggestion which was
subsequently partially reversed by a second committee,
which proposed that HES solutions can be used in patients
with hypovolemia due to acute blood loss within the first
24 hours after elective surgery or trauma, but they must not
be used in critically ill patients or those with sepsis and burn
injuries. However, the permission to use HES even in limited
circumstances has been criticized, because it has been
argued that this decision was based on inadequate (or unreli-
able) data42.
The effects of HES have been presented in detail because
large well designed randomized controlled trials are available.
However, available data shows similar non-beneficial effects
with other colloids, such as gelatins or dextrans43–49. A recent
USE OF INTRAVENOUS FLUIDS/SOLUTIONS: A NARRATIVE REVIEW 463
meta-analysis including 30 randomized controlled trials
(n ¼ 3629), 8 non-randomized studies and 22 animal studies
showed that gelatin administration was associated with
increased mortality (RR 1.15, 95% CI 0.96–1.38), requirement
of allogeneic blood transfusion (RR 1.10, 95% CI 0.86–1.41),
AKI (RR 1.35, 95% CI 0.58–3.14) and anaphylaxis (RR 3.01,
95% CI 1.27–7.14)6. Furthermore, evidence from non-random-
ized trials pointed to increased risk of hospital mortality and
AKI or renal replacement therapy with gelatin administration.
Additionally, a large proportion (17–31%) of administered
gelatin was located extravascularly6.
Hypertonic salt solution has been also examined as vol-
ume expander, since it expands intravascular volume with
less volume compared with isotonic salt solutions50.
Generally, large randomized controlled trials are absent. A
meta-analysis of 18 studies in people undergoing surgery
(n ¼ 1087; none with >3 days duration) a less positive fluid
balance postoperatively (mean difference 1.92 L, 95% CI
2.61 to 1.22 L, p < 0.00001), but a higher maximum serum
sodium concentration (mean difference 7.73 mEq/L, 95% CI
5.84–9.62, p < 0.00001), was shown in patients receiving
hypertonic saline compared with isotonic saline51. Hypertonic
saline compared with any other solution did not decrease
mortality (RR 0.96, 95% CI 0.83–1.11) and did not improve
intracranial pressure control (weighted mean difference
-1.25 mmHg, 95% CI -4.18 to 1.68) in a meta-analysis of 11
studies in people with severe traumatic brain injury (n ¼ 1820
patients)52.
According to a meta-analysis, there is no evidence that
the administration of colloids reduces the risk of death com-
pared with resuscitation with crystalloids in patients with
trauma, burns or following surgery. In contrast, there is evi-
dence that the use of HES might increase mortality rates53.
Currently available data regarding the non-beneficial or even
harmful effects of colloids, along with the high cost of albu-
min, point to the preferential use of crystalloid solutions in
everyday clinical practice in patients who need intravenous
fluids.
The role of crystalloids in fluid resuscitation
The purpose of fluid therapy is not only to increase intravas-
cular volume, but also to improve perfusion and oxygenation
of vital organs and maintain hydration. Crystalloids are cate-
gorized into several types such as dextrose 5% and saline
solutions. There are plenty of types of fluids available, such
as NS, RL, Ringer’s acetate, Hartmann’s solution and Plasma-
Lyte 148. In this review only NS and RL will be discussed
since they are most frequently prescribed. The main charac-
teristics of NS and RL are shown in Figure 1. These two solu-
tions differ in composition and tonicity54. Tonicity is the
effective osmolality and is equal to the sum of the concentra-
tions of the solutes which have the capacity to exert an
osmotic force across the membrane. In medical science, an
isotonic solution is the solution that contains the same num-
ber of milliosmoles/L with the number of milliosmoles that is
contained in 1 L of blood plasma. A hypotonic solution given
intravenously lowers plasma osmolality and leads to water
464 N. EL GKOTMI ET AL.
Figure 1. Main characteristics of the most commonly used crystalloid solutions.
movement from intravascular to extravascular space in order
to maintain the osmotic balance.
Crystalloid solutions, when given intravenously, are distrib-
uted among intravascular and extracellular space as they
contain osmotically active substances. In healthy subjects,
after administration of 1 L of each solution, approximately
220 ml of NS and 200 ml of RL remain in the intravascular
space, rendering these solutions appropriate for maintaining
intravascular and extracellular volume55. In contrast, after
administering dextrose 5% only an amount <100 ml remains
in the intravascular space, so this solution is more useful
for maintaining daily fluid needs rather than treating
hypovolemia55.
Characteristics and adverse effects of normal saline
NS is an isotonic with plasma solution useful for maintaining
intravascular and extracellular volume, but it has been associ-
ated with certain adverse effects (Figure 2). NS contains a
concentration of chloride which is about 1.5 times higher
than in plasma (Figure 1), which is associated with the devel-
opment of hyperchloremia and metabolic acidosis.
Hyperchloremic metabolic acidosis following NS administra-
tion occurs due to a dilutional effect but also due to a
decrease in renal excretion of Hþ56. Hyperchloremia results in
an increased concentration of Cl in the macula densa. The
increased concentration of Cl in the macula densa leads to
a decreased secretion of renin and aldosterone, which results
in a decreased excretion of Hþ and promotes metabolic acid-
osis. Even though the NS-induced metabolic acidosis was ini-
tially considered to be a transient metabolic abnormality
without any consequences, it has been recently suggested
that metabolic acidosis can adversely affect immune system
function and also lead to impaired coagulation resulting in
prolonged hospital stays and increased postoperative
mortality57,58.
Additionally, the hyperchloremia-induced increased con-
centration of Cl- in the macula densa via tubuloglomerular
feedback leads to renal vasoconstriction and in turn
decreases the restoration of glomerular filtration rate.
Therefore, the development of hyperchloremia with the
administration of NS is associated with an increased risk of
AKI and utilization of RRT59.
Furthermore, administration of NS increases the interstitial
fluid volume, which further affects organs that are sur-
rounded by a capsule, such as the kidney. Interstitial edema
in the kidney leads to intracapsular hypertension and there-
fore to impaired tissue perfusion and to organ dysfunction.
Interstitial edema is also manifested as peripheral edema,
ascites, splanchnic edema, abdominal compartment syn-
drome and gastrointestinal dysfunction60.
Further attention should also be paid when NS solutions
are infused in patients with loss of renal diluting capacity
because this increases the risk of developing hyponatremia61.
On the other hand, the impaired concentrating ability of the
kidney in patients with sickle cell disease, obstructive urop-
athy, congenital nephrogenic diabetes insipidus, reflux nephr-
opathy, renal dysplasia, tubulointerstitial nephritis and use of
lithium pose a risk of developing hypernatremia after admin-
istration of NS61.
Characteristics and adverse effects of Ringer’s lactate
Balanced saline solutions, such as RL, exhibit an electrolyte
composition similar to that of extracellular fluid. However, RL
is slightly hypotonic (osmolality 254 mOsm/kg) and is chlor-
ide restricted as its chloride concentration is less than 110
mEq/L (Figure 1). As opposed to NS, it is quickly excreted
from the body, causes less frequently interstitial edema and
it has been shown to be associated with decreased hospital
mortality in septic patients62. In contrast with NS, it does not
promote metabolic acidosis and it is not associated with
deterioration of kidney function resulting in less need of
renal replacement therapy63,64. Because of these advantages
balanced solutions (and especially RL that is the most used
balanced solution) are preferred in certain situations, as they
are beneficial in surgical patients, in patients with trauma, in
patients with burns as well as in patients with diabetic ketoa-
cidosis (Table 2)2. In fact, in cases of diabetic ketoacidosis the
administration of RL leads to a faster improvement of acid-
base disturbances65. Nevertheless, RL is not free from adverse
effects (Table 2). Taking into account the small potassium

Figure 2. Adverse effects of normal saline. GFR: glomerular filtration rate; AKI: acute kidney injury.
Table 2. When to use and when to avoid Ringer’s lactate.
Indications
 Surgical patients
 Patients with trauma
 Septic patients
 Patients with diabetic ketoacidosis
 Patients with burns
 Patients with acute pancreatitis
content of this solution, administration of RL is associated
with increased serum potassium levels in patients with
decreased renal function and in individuals with potassium
homeostasis abnormalities. It is also associated with the
development of metabolic alkalosis (as the lactate metabo-
lizes to CO2), which can be noticed in patients with pre-exist-
ing alkalemia or in those with inability to excrete a
bicarbonate loading. When administering RL, which contains
calcium, with sodium bicarbonate solutions, the insoluble salt
CaCO3 may be formed, thus this combination should be
avoided54. It is worth mentioning that hypotonic saline solu-
tions should be avoided in patients at risk of developing
hyponatremia66–69. Such patients are those with nausea and
vomiting, pain, stress, central nervous system disease, inflam-
mation, hypoxemia, as well as those in the perioperative
state, since these conditions are associated with antidiuretic
hormone excess. Importantly, the occurrence of hypotonicity
sets a risk of developing brain edema; therefore in patients
at risk for brain disease (meningitis, encephalitis, head injury,
brain surgery, brain tumors, etc.) isotonic fluids and not RL
should be used70. In addition, calcium and other electrolytes
that are included in RL may induce clot formation when co-
administered with blood products which contains citrate1.
Finally, RL contains lactate and its administration is contrain-
dicated in patients with lactic acidosis in the case that lactate
clearance is simultaneously impaired.
USE OF INTRAVENOUS FLUIDS/SOLUTIONS: A NARRATIVE REVIEW 465
Contraindications
 Severe metabolic alkalosis
 Lactic acidosis with impaired lactate clearance
 Severe hyperkalemia
 Co-administration with citrated blood products
 Patients at risk of developing brain edema (traumatic brain disease,
neurosurgical patients or conditions associated with increased secretion
of antidiuretic hormone)
 Co-administration of NaHCO3
Studies comparing normal saline and balanced solutions
There are many studies that have compared balanced and
unbalanced crystalloid solutions in ICU patients, in patients
undergoing kidney transplantation, abdominal or aortic sur-
gery, and patients with diabetic ketoacidosis (Table 3)63,71–81.
Generally, with the exception of the SPLIT (0.9% Saline vs.
Plasma-Lyte 148 (PL-148) for ICU fluid Therapy) trial (see
below for details), most studies are small and only a few
have compared the effects of NS and balanced crystalloids
on renal function or hard outcomes (Table 3); thus, they do
not permit robust conclusions. Many studies investigated
whether NS would result in hyperchloremic metabolic acid-
osis. Most of them concluded that NS is associated with
hyperchloremic metabolic acidosis72,73,78,82–84. It should be
mentioned that two randomized controlled trials showed
that none of the solutions (NS, Plasma-Lyte 148 or RL) pro-
duced metabolic acidosis in the populations investigated
(patients with dehydration in the emergency department or
children with acute diarrhea)80,85.
The development of metabolic acidosis and other short-
comings of NS are directly dependent on the amount admin-
istered. In fact, the administration of small amount of NS,
used in maintenance rates for a short time, is not associated
with significant adverse consequences61. A very interesting
study was the double-blind, cluster randomized, double-
Table 3. Studies with >50 patients that have compared balanced solutions with normal saline (arranged by study population)
.
Study Design and study population Solutions Primary outcome(s) Secondary outcome(s)
466

71
SPLIT trial  Cluster randomized, double- NS (n ¼ 1110) vs. Plasma-Lyte 148 AKI at 90 days: 94 (9.2%) vs. 102 (9.6%), RR RRT: 38 (3.4%) vs. 38 (3.3%), RR 0.96
crossover trial (n ¼ 1152) 1.04 (95% CI 0.80–1.36), p ¼ 0.77. (95% CI 0.62–1.50), p ¼ 0.91.
 ICU patients In-hospital mortality: 95 (8.6%), 87
(7.6%), RR 0.88 (95% CI 0.67–1.17),
p ¼ 0.40.
Yunos et al.63  Prospective, open-label, Chloride-restrictive (n ¼ 760) vs. Serum creatinine concentration: 22.6 (95% RRT: 49 (6.3%, 95% CI 4.6%–8.1%) vs.
sequential period (duration of chloride-liberal intravenous fluid CI 17.5–27.7) vs. 14.8 (95% CI 9.8–19.9) 78 (10%, 95% CI 8.1%–12%),
each period 6 months) study strategy (n ¼ 773) lmol/L, p ¼ 0.03). p ¼ 0.005.
 ICU patients RIFLE-defined AKI: 65 (8.4%, 95% CI No differences in hospital mortality, hos-
6.4%–10%) vs. 105 (14%, 95% CI pital or ICU length of stay, or need
N. EL GKOTMI ET AL.

11%–16%), p < 0.001. for RRT after hospital discharge.

Hadimioglu et al.72
Kim et al.73
Khajavi et al.74
Modi et al.75
O’Malley et al.76
Shaw et al.77
Waters et al.78
Zunini et al.79
 RCT (duration 7 days)
 Adults undergoing living-
related kidney transplantation
 RCT
 Patients undergoing kidney
transplantation
 RCT
 Patients undergoing kidney
transplantation
 RCT
 Patients undergoing live-
related renal transplantation
 RCT
 Patients undergoing kidney
transplantation
 Observational study
 Patients undergoing major
open abdominal surgery
 RCT
 Patients undergoing aortic
reconstructive surgery
 Retrospective study
 Children aged <5 years who
had craniofacial surgery
NS (n ¼ 30) vs. RL (n ¼ 30) vs.
Plasma-Lyte 148 (n ¼ 30)
NS (n ¼ 30) vs. Plasma-Lyte (n ¼ 30)
NS (n ¼ 26) vs. RL (n ¼ 26) during
surgery
NS (n ¼ 37) vs. RL (n ¼ 37) during
surgery
NS (n ¼ 26) vs. RL (n ¼ 25) during
surgery
NS (n ¼ 30,994) vs. balanced crystal-
loid solution (Plasma-Lyte A or
Plasma-Lyte 148; n ¼ 926) on the
day of surgery
NS (n ¼ 33) vs. RL (n ¼ 33)
NS group received significantly more blood
NS (n ¼ 63) vs. RL (n ¼ 59)
Severe acidosis: 39% vs. 8% (p ¼ 0.003).
Compared with baseline, NS decreased pH
(7.44 ± 0.50 vs. 7.36 ± 0.05) and base
excess (0.4 ± 3.1 vs. -4.3 ± 2.1), and
increased serum chloride (104 ± 2 vs.
125 ± 3 mM/L).
NS group developed significantly lower val-
ues of pH, base-excess, and effective
strong ion differences compared with
Plasma-Lyte group during surgery.
Mean serum Kþ levels: 4.88 ± 0.7 vs.
4.03 ± 0.8 mEq/L, p < 0.001. Mean
changes in serum Kþ: þ0.5 ± 0.6 vs.
-0.5 ± 0.9 mEq/L, p < 0.001. Mean
changes in pH: -0.06 ± 0.05 vs.
-0.005 ± 0.07, p < 0.001.
pH: decrease from 7.43 to 7.33 vs. no
change (p not shown).
HCO3: from 20.87 ± 3.89 to 19.47 ± 3.02 vs.
from 21.88 ± 4.63 to 21.62 ± 3.56,
p < 0.05 between groups.
Postoperative (day 3) serum creatinine
concentration: 2.3 ± 1.8 vs. 2.1 ± 1.7 mg/
dL, p ¼ 0.70.
Major morbidity: 33.7% vs. 23%, p < 0.001.
In-hospital mortality: 5.6% vs. 2.9%,
p < 0.001.
Fewer complications with balanced solu-
tion in the 3:1 propensity-matched sam-
ple (odds ratio 0.79, 95% CI 0.66–0.97).
NS patients developed hyperchloremic acid-
osis and received more bicarbonate ther-
apy compared with RL group (30 ± 62 ml
vs. 4 ± 16 ml).
products (p ¼ 0.02).
Metabolic acidosis: 66% vs. 26% (p ¼ 0.015)
in the first 2 hours and 80% vs. 37%
(p ¼ 0.027) in the next 2 hours.
Compared with baseline, RL increased
lactate levels (0.48 ± 0.29 vs.
1.95 ± 0.48).
No significant changes with Plasma-Lyte
148.
Graft failure requiring dialysis: 1 vs. 3
episodes (p ¼ 0.30) during the first 7
postoperative days.
Thrombotic events: 0% vs. 7.7%,
p ¼ 0.49.
Kþ: from 3.94 ± 0.45 to 4.31 ± 0.59 vs.
3.76 ± 0.75 to 3.99 ± 0.71, p < 0.05
between groups.
Urine output: similar between groups.
Episodes of biopsy-proven rejection: 4
vs. 2 patients.
Peak intraoperative serum Kþ: 5.1 ± 0.6
vs. 5.1 ± 1.1 mEq/L. Serum Kþ >6.0
mEq/L: 19% vs. 0% (p ¼ 0.05).
Use of dialysis in the 3:1 matched
cohort: 1.0% (95% CI 0.05–1.8) vs.
4.8% (95% CI 4.1–5.7), p < 0.001.
Transfusion: 11.5% (95% CI 10.3–12.7)
vs. 1.8% (95% CI 1.2–2.9), p < 0.001.
Tests to evaluate acidosis: arterial blood
gases 22.3% (95% CI 21.3–24.5) vs.
13.7% (95% CI 11.7–16.1) and lactic
acid levels 8.0% (95% CI 7.0–9.1) vs.
3.3% (95% CI 2.4–4.7), p < 0.001
No difference in the postoperative com-
plications and death.
Hyponatremia: 40% vs. 26% in the first
2 hours and 52% vs. 50% in the next
2 hours (both p ¼ ns).
Hypokalemia: 13% vs. 5% (p ¼ 0.30) in
the first 2 hours and 19.5% vs. 3%
(p ¼ 0.03) in the next 2 hours.
(continued)
 USE OF INTRAVENOUS FLUIDS/SOLUTIONS: A NARRATIVE REVIEW 467

crossover SPLIT trial, which aimed to identify the adverse

NS: normal saline; RL: Ringer’s lactate; RCT: randomized controlled trial; RRT: renal replacement therapy; ICU: intensive care unit; IQR, interquartile range; RIFLE: Risk, Injury, Failure, Loss of kidney function, and End-stage
Time to resolution of diabetic ketoacido-
Unadjusted time to lower blood glucose

vs. 300 min (IQR 235–420), p ¼ 0.044.

to 14 mmol/l: 410 min (IQR 240–540)
effects of NS or balanced crystalloid solutions on renal func-

No significant changes in potassium,

tion in 2278 ICU patients without established AKI requiring

Secondary outcome(s)
RRT71. Participating ICUs were assigned a masked study fluid,

sis: no difference (adjusted

either NS (n ¼ 1025) or a buffered crystalloid (Plasma-Lyte

sodium, or chloride levels.

148, n ¼ 1067), for alternating 7 week treatment blocks, so
that each ICU used each fluid twice during the 28 weeks of
the study. The total volume of administered fluids, which

p ¼ 0.758).
was mainly given in the first day, was not different between
buffered crystalloid and NS groups (median 2000 ml [inter-
quartile range 1000–3500 ml] vs. 2000 ml [1000–3250 ml]). At
90 days, similar proportions of patients developed AKI (pri-
mary endpoint, defined as a rise in serum creatinine level at
least two-fold or a serum creatinine level of 3.96 mg/dL
Median time to reach a pH of 7.32: 540 min
In all groups pH values were in the physio-
logical range (7.35–7.45) throughout the

NS group: significant tendency to lower pH

with an increase of 0.5 mg/dL) in the buffered crystalloid

(95% CI 184–896) vs. 683 min (95% CI

group (9.6%) and in the NS group (9.2%; RR 1.04, 95% CI

Time to venous pH normalization (pH
¼7.32): hazard ratio 1.863 (95% CI

0.80–1.36, p ¼ 0.77). Similarly, the secondary endpoints of RRT

Primary outcome(s)

(3.3% vs. 3.4%, RR 0.96, 95% CI 0.62–1.50, p ¼ 0.91) and death

values (from 7.40 to 7.36).

in the hospital (7.6% vs. 8.6%, RR 0.88, 95% CI 0.67–1.17,

0.937–3.705), p ¼ 0.076.

378–988), p ¼ 0.251).

p ¼ 0.40) were non-significantly different between the buf-

fered crystalloid group and the NS group71. Thus, these
2-hour period.

results point to the fact that no solution is hazardous when

the total volume of intravenous crystalloid fluids is about 2 L.

Characteristics and adverse effects of dextrose 5%

solution
Dextrose 5% is isotonic with plasma (osmolality 277 mOsm/
kg) and contains a small amount of glucose (50 g/L) provid-
(n ¼ 30) vs. RL (n ¼ 30) (all at

ing little energy. The glucose administered is rapidly metabo-

NS (n ¼ 30) vs. Plasma-Lyte 148

lized in the liver and the remaining water is distributed in all

RL (n ¼ 28) vs. NS (n ¼ 29)
20 ml/kg/h for 2 hours)

fluid compartments and thus only a small volume (approxi-

Solutions

mately 100 ml) remains in the intravascular space after

administering 1 L of dextrose 5% solution. Therefore, this
solution is useful for maintaining hydration but not for treat-
ing hypovolemia. Certain adverse effects of dextrose 5% solu-
tion are the development of hypotonicity and the reduction
of serum potassium concentration, as dextrose administration
induces insulin secretion that promotes potassium movement
kidney disease classification; AKI: acute kidney injury; ns: non-significant.

from extracellular to intracellular space. The occurrence of

hyponatremia with the use of hypotonic fluids, such as dex-

Values indicate number of patients, except otherwise mentioned.
Patients with dehydration in

trose solutions, is a significant problem in hospitalized

the emergency department
Design and study population

patients, especially in children, and is correlated with serious

Patients with diabetic

adverse effects (for example hyponatremic encephalop-

athy)86,87. Thus, hypotonic fluids should be avoided in hospi-
talized patients and the administration of dextrose 5% in
ketoacidosis

isotonic solutions is preferable in order to avoid endogenous

catabolism61.
RCT

RCT






Practical concepts of using intravenous fluids

Based on the current evidence, colloid solutions should be
avoided in most clinical situations due to their increased cost
Table 3. Continued

and certain adverse effects. Most hospitalized patients can be

80

Van Zyl et al.81

Hasman et al.

managed with crystalloid solutions to deal with hypovolemia

or as maintenance fluids.
In everyday clinical practice, each patient should be indi-
Study

vidually treated with crystalloid solutions based on the

468 N. EL GKOTMI ET AL.
Table 4. Conditions associated with increased antidiuretic hormone levels,
which predispose to the development of hyponatremia.
 Hypovolemia
 Congestive heart failure
 Cirrhosis with ascites
 Central nervous system diseases
 Post-obstructive condition
 Cancer
 Pulmonary diseases, especially associated with hypoxemia and
hypercapnia
 Administration of drugs such as selective serotonin reabsorption inhibi-
tors, carbamazepine, thiazides
Table 5. Basic principles of potassium chloride (KCl) administration.
 In patients with normal potassium balance administration of 60–80 mEq
Kþ/day in the infusates (2–3 L/day) to cover daily potassium needs is
indicated.
 In patients with a negative potassium balance:
 KCl should be added only to saline (and not to dextrose) solutions
 No more than 60 mEq Kþ/L can be given; preferably Kþ should be
administrated in a large vein
 Potassium-rich infusates should be given slowly to avoid
hyperkalemia
 KCl should be added preferably to hypotonic saline solutions to avoid
circulatory overload (since KCl contains osmotically active ions, e.g.
1 L 0.45% saline solution þ 54 [4 amp] mEq KCl is nearly isotonic to
plasma)
 Frequent determination of serum potassium levels are necessary dur-
ing treatment
underlying volume status, renal function, comorbidities, and
acid-base and electrolyte homeostasis.
Hence, in hypovolemic patients with metabolic acidosis,
RL (which promotes metabolic alkalosis) should be preferred.
RL is also preferable in patients with hyperchloremia. On the
other hand, when the patient with hypovolemia also has
metabolic alkalosis and/or hypochloremia, or he/she has
hyperkalemia, NS or hypotonic saline fluids should be pre-
scribed. In cases of hypokalemia a more useful intravenous
solution is RL or hypotonic saline solutions with the addition
of KCl. In patients with traumatic brain injury or neurosurgi-
cal patients NS should be administered to avoid cerebral
edema54.
In patients without hypovolemia who cannot receive
adequate fluids by mouth dextrose 5% in isotonic solutions
can be used as maintenance fluid (with caution in patients at
risk of hypokalemia).
The danger of hypotonicity is widely discussed in the lit-
erature in relation to the use of isotonic or hypotonic solu-
tions as maintenance fluids in critically ill patients. The usual
standard of care, especially in hospitalized children, was to
prescribe hypotonic fluids for maintaining hydration. In hos-
pitalized patients there are many stimuli, both hemodynamic
and non-hemodynamic, that can cause excess antidiuretic
hormone secretion (Table 4). This antidiuretic hormone
excess in combination with hypotonic fluid administration
can cause acute hyponatremia and hyponatremic encephal-
opathy, as shown in recent publications86,88,89. Therefore, iso-
tonic fluids should be preferred in acutely ill children but
also in adults, especially in patients who may exhibit
increased antidiuretic hormone levels and are at risk for
developing hyponatremia. On the other hand, hypotonic
saline solutions are very useful when potassium or
Table 6. Basic principles of NaHCO3 solution administration.
 NaHCO3 should not be given with Ringer’s lactate solutions
 NaHCO3 should not be administered in patients with lactic acidosis or
diabetic ketoacidosis, unless pH is <7.10
 NaHCO3 should not be given in an isotonic saline solution to avoid cir-
culatory overload, but with hypotonic solutions (e.g. 1 L 0.45% saline
solution þ45 mEq NaHCO3 þ 30 mEq KCl is nearly isotonic to plasma)
magnesium needs to be replaced. In these cases, the add-
ition of potassium should be taken into account when esti-
mating the tonicity of the final infusate. For example, the
addition of 4 amp KCl to a half-isotonic saline solution ren-
ders the solution almost isotonic. The addition of KCl to NS
should be avoided because it renders the solution hypertonic
compared with plasma and increases the risk of volume over-
load. Certain directions for the use of KCl are given in
Table 5. Additionally, hypotonic solutions are also useful for
the administration of bicarbonate (Table 6). Similar to potas-
sium administration, bicarbonate should be added in hypo-
tonic and not isotonic solutions in order to avoid the use of
(finally) hypertonic solutions that are prone to circulatory
overload.
The appropriate volume of the chosen infusate should
be carefully estimated so as to avoid over-hydration, since
recent data strongly suggest that it is harmful and should
be avoided. A large number of adverse effects are attrib-
uted to fluid overload either from colloids or crystalloid sol-
utions, such as interstitial edema, cardiac, pulmonary and
bowel dysfunction, dilutional coagulopathy, impaired water
and sodium regulation and also impaired wound heal-
ing90,91. A positive fluid balance was found to be an inde-
pendent risk factor for 60-day mortality in patients with
acute kidney failure in the SOAP (Sepsis Occurrence in
Acutely Ill Patients) study and also in patients with sep-
sis92,93. Additionally, the FEAST (Fluid Expansion As
Supportive Therapy) trial pointed to the importance of
avoiding rapid resuscitation via fluid boluses in children
who live in resource-limited settings (Uganda, Kenya, or
Tanzania) because this procedure has been associated with
increased mortality due to cardiovascular collapse
(Table 1)12,94. Thus, the rate of administration needs to be
individualized, and close monitoring with frequent physical
examination and assessment of vital signs, measurement of
fluid intake and output, and daily measurement of body
weight and serum electrolyte levels is required54,61.
Conclusions
The selection of intravenous fluids should be based on their
indications and contraindications, in relation to the volume
status, cardiovascular status, renal function, electrolyte and
acid base status of the patient. Studies have shown that
albumin and colloids do not significantly reduce mortality
compared with crystalloid fluids in patients with trauma,
burns or following surgery. Among crystalloids, the adminis-
tration of NS is associated with hyperchloremia-induced
impairment of kidney function and metabolic acidosis. On
the other hand, the other usually used crystalloid solution,

RL, has certain indications as well as contraindications, such
as severe metabolic alkalosis or severe hyperkalemia.
Intravenous fluids should be used in the same way as drugs,
as they have specific clinical indications, contraindications
and adverse effects.
Key messages
 Based on the evidence from randomized controlled trials,
and taking into account its cost-effectiveness, the use of
albumin is not preferable to the use of crystalloid fluids
and should be avoided in patients with traumatic brain
injury.
 Most studies have shown a non-significant effect or harm
in terms of mortality or renal replacement therapy with
hydroxyethyl starch solution (HES) compared with crystal-
loids, thus currently HES has only a few indications. Its
use is contraindicated in patients with sepsis or in those
at risk of acute renal failure.
 The available data regarding gelatins, dextrans and hyper-
tonic saline solutions does not point to a beneficial effect
compared with crystalloids.
 Balanced crystalloids are preferred in most conditions to
avoid hyperchloremia and metabolic acidosis associated
with the use of normal saline. However, an individual
approach is strongly recommended taking into account
serum sodium and potassium levels as well as acid-base
abnormalities.
 In patients with central nervous system disorders isotonic
crystalloid solutions should be given to avoid hyponatre-
mia and hyponatremic encephalopathy.
 Isotonic solutions should be given as a maintenance fluid
in acutely ill patients (mainly in children) especially when
conditions associated with increased antidiuretic hormone
secretion are also present.
 In any case, avoiding hypervolemia with its devastating
consequences is suggested; thus, fluid balance and body
weight should be carefully assessed during treatment and
monitoring for peripheral edema is mandatory.
Transparency
Declaration of funding
No funding was received for the writing of this review.
Declaration of financial/other relationships
N.E.G., C.K., T.D.F., and M.S.E. have disclosed that they have no significant
relationships with or financial interests in any commercial companies
related to this study or article.
CMRO peer reviewers on this manuscript have no relevant financial
or other relationships to disclose.
ORCID
T. D. Filippatos http://orcid.org/0000-0002-1713-0923
M. S. Elisaf http://orcid.org/0000-0003-0505-078X
USE OF INTRAVENOUS FLUIDS/SOLUTIONS: A NARRATIVE REVIEW 469
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