Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

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 (2016): Use of
intravenous fluids/solutions: A narrative review, Current Medical Research and Opinion, DOI:
10.1080/03007995.2016.1261819

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

Accepted author version posted online: 16

Nov 2016.

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Use of intravenous fluids/solutions: A
narrative review

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

Department of Internal Medicine, School of Medicine, University of Ioannina,

Ioannina, Greece

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Correspondence to:

Professor Moses S. Elisaf

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Department of Internal Medicine, School of Medicine, University of Ioannina
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45 110 Ioannina, Greece

Phone: +302651007509, Fax: +302651007016

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E-mail: melisaf54@gmail.com; egepi@cc.uoi.gr

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Abstract
Objective: Intravenous fluids are broadly categorized into colloids and crystalloids.

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

hydration 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 crystalloids in patients with hypovolemia

or as maintenance fluids published in PubMed and Cochrane databases.

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Results: Clinical studies have not shown a greater clinical benefit of albumin

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solutions compared with crystalloid solutions. Furthermore, albumin and colloid

solutions may impair renal function, while there is no evidence that the
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administration of colloids reduces the risk of death compared with resuscitation with

crystalloids in patients with trauma, burns or following surgery. Among crystalloids,

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normal saline 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
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contraindications. These matters, along with the basic principles of the

administration of potassium chloride and bicarbonate, are meticulously discussed in

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the review.

Conclusions: Intravenous fluids should be dealt with as drugs, as they have specific

clinical indications, contraindications and adverse effects.

Key words: colloids, albumin, crystalloids, balanced solutions, potassium,

bicarbonate, mortality, metabolic acidosis, hyperchloremia

Introduction
Administration of intravenous fluids, which are broadly categorized 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

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is mostly based on clinician preference relied on the knowledge of physiological

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principles, the patient’s profile and tolerance as well as on the cost.
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Recently, there is a wide discussion concerning the most appropriate intravenous

crystalloid solution, given that each type of fluid has certain advantages but also
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disadvantages. Thus, the current idea recently proposed is that any type of fluid
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should be considered as a drug followed by indications, contraindications and

adverse effects[1].
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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
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hydration 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 crystalloids in patients with hypovolemia or as

maintenance fluids. We searched for eligible published manuscripts in PubMed and

the Cochrane Central Register of Controlled Trials (last search September 2016) using

the search algorithm: (hypovol* OR dehydrat* OR hydrat*) AND (colloids OR albumin

OR hydroxyethyl starch solutions OR starch OR dextran OR gelatin OR crystalloid OR

normal saline OR hypertonic saline OR balanced intravenous fluids OR balanced

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crystalloids OR Ringer OR Plasmalyte OR Hartmann) AND (mortality OR death OR

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renal OR kidney OR acidosis OR hyperchlor* OR acid-base OR electrolytes OR

chloride OR potassium OR bicarbonate OR tonicity) limited to English language.

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Moreover, we screened systematic and narrative reviews that pertained to eligible

topics.
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The role of colloid solutions in fluid

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resuscitation
The use of colloid solutions has been implemented in clinical practice
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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 solutions suggest a ratio of

1:3 of colloids to crystalloids regarding with the volume of solution needed to

preserve the intravascular volume[2, 3]. However, this ratio is much smaller in
clinical studies[4-6]. 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 studies[7]. Fluid overload has been associated with increased mortality

especially in critically ill patients[8, 9]. This may be a potential benefit of colloids as

they do not expand so much the total volume compared with crystalloids.

In the CRISTAL (Colloids Versus Crystalloids for the Resuscitation of the

Critically Ill) trial the use of colloids compared with crystalloids was associated with

similar mortality at 28 days [primary endpoint, relative risk (RR) 0.96, 95% CI 0.88-

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1.04, p = 0.26), but a lower mortality at 90 days (secondary endpoint, RR 0.92, 95% CI

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0.86-0.99, p = 0.03) in intensive care unit (ICU) patients with hypovolemic shock

(Table 1). Renal replacement therapy (RRT) did not significantly differ between
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colloids and crystalloids (RR 0.93, 95% CI 0.83-1.03, p = 0.19). Additionally, at 28 days

colloids were associated with more days alive without mechanical ventilation (mean
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14.6 vs 13.5 days; mean difference 1.10, 95% CI 0.14-2.06 days; p = 0.01) and alive
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without vasopressor therapy (mean 16.2 vs 15.2 days; mean difference 1.04, 95% CI

−0.04 to 2.10 days, p = 0.03). The study concluded that colloids may have an
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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
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ventilation and had lower mortality at 90 days (Table 1)[10]. However, the CRISTAL

trial has been received scientific critique, such as 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 (taken into account the non-significant

primary endpoint) should be tested by stricter statistical methods[11, 12].

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 albumin

administration in ICU patients (Table 1)[4]. It showed no significant difference in

mortality rate, no significant difference in hemodynamic parameters and it had no

significant impact on organ function compared with normal saline (NS) solution

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(0.9% NaCl). However, a potential decrease in mortality among patients with severe

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sepsis irrespective of the presence of hypoalbuminemia was shown[4]. Hence,

albumin may be beneficial in the early resuscitation in patients with severe sepsis,
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but future suitable randomized controlled trials are needed to definitely assess this

matter. The ALBIOS (Albumin Italian Outcome Sepsis) trial tested the hypothesis that
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the combined use of 20% albumin with crystalloids may be beneficial in patients with
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severe sepsis compared with crystalloid solution alone (Table 1)[13]. Despite

inducing a higher mean arterial pressure (p=0.03) and a lower net fluid balance
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(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
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28 days (RR 1.00, 95% confidence interval (CI) 0.87-1.14, p=0.94) and 90 days (RR

0.94, 95% CI 0.85-1.05, p=0.29)[13]. Albumin has been associated with increased

mortality in patients with brain trauma due to increased intracranial pressure[4, 14].

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% confidence interval (CI) 0.95 to 1.16], for cases of

hypovolemia RR was 1.02 (95% CI 0.92 to 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 to 1.88)[15]. These non-beneficial effects even in patients with

hypoalbuminemia have been attributed to increased vascular permeability due to

underlying inflammation, 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 sepsis[16]. However, it

should be mentioned that this type of meta-analysis (network meta-analysis) is

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potentially more subject to error than a routine meta-analysis, since it provides a

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global estimate of comparative treatment effectiveness combining both direct and

indirect evidence[17]. Another meta-analysis based on 15 randomized controlled

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trials evaluated whether the use of albumin-containing fluids for resuscitation in

patients with sepsis was associated with a decreased mortality rate and concluded
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that there was no significant advantage of using albumin-containing fluids for

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resuscitation in patients with sepsis of any severity (RR 0.94, 95% CI 0.87-1.02][18]. A

meta-analysis of prospective randomized clinical trials of adults with sepsis of any

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severity (16 primary clinical trials that included 4,190 adults) showed that compared

with control fluids (crystalloids or colloids) the administration of a median of 70

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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=0.11)[19]. In a predefined subgroup analysis in which studies at high

risk of bias were excluded, no significant difference on mortality was also found[19].

These observations point to the fact that albumin solutions as part of fluid volume
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

product is not devoid of the danger of transmitting viruses, although various

laboratory techniques can substantially reduce this possibility[20-22]. Based on the

above evidence, and taking into account the cost-effectiveness of albumin use,

crystalloids should be the first choice for fluid resuscitation 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

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Nutrition in Patients With Severe Sepsis) study showed that HES 130/0.4 solution

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was significantly better to NS in relation with the amount of solution required to

achieve initial hemodynamic stability in patients with severe sepsis (Table 1)[5].
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However, the use of HES has not been associated with a benefit in terms of mortality

rates; in contrast there is evidence that HES may increase mortality. The VISEP
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(Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis) trial compared
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the use of 10% HES 200/0.5 to Ringer’s Lactate (RL) for volume replacement therapy

in 537 septic patients (Table 1). Patients receiving colloids exhibited a similar with RL
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group rate of death at 28 days (26.7% and 24.1%, respectively, p=0.48) and a trend

toward a higher rate of death at 90 days (41.0% vs. 33.9%, p=0.09)[23]. Another
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randomized trial, the 6S (Scandinavian Starch for Severe Sepsis/Septic Shock) study,

which was conducted in 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)[24].

 The results of randomized controlled trials have also been related HES with

increased renal adverse effects. In the VISEP trial patients receiving HES compared

with those on RL group exhibited increased rates of acute renal failure (34.9% vs.

22.8%, p=0.002) and more days on which RRT was required (18.3% vs. 9.2%)[23]. The

6S trial also showed an 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)[24]. 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 in the rate of RRT was also noticed (Table 1)[25]. The adverse effect of HES

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on renal function have been attributed to various mechanisms, such as an acute

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increase in oncotic pressure and/or to osmotic nephrosis[26, 27].

A meta-analysis of 13 studies in patients undergoing non-cardiac surgery

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showed a shorter length of hospital stay with HES compared with crystalloids (mean

difference -1.52 days; 95% CI -2.87 to -0.18), but a trend to increased mortality
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within 90 days (risk ratio 2.97, 95% CI 0.96-9.19), no difference in acute kidney injury
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(AKI) and RRT (risk ratio 1.11, 95% CI 0.26-4.69), and no difference in the rate of

major infectious complications (risk ratio 1.19, 95% CI 0.59-2.39)[28]. Another meta-
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analysis of 38 trials showed that the risk ratio for death with HES compared to other

solutions in studies reporting mortality data (n=10,880) was 1.07 (95% CI 1.00-
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1.14)[29]. Moreover, when 7 trials that involved 590 patients were excluded (due to

suspicion of scientific misconduct), HES was related with increased mortality in a

sample of 10,290 patients (risk ratio 1.09, 95% CI 1.02-1.17), increased renal failure

in a sample of 8,725 patients (risk ratio 1.27, 95% CI 1.09-1.47) and increased use of

RRT in a sample of 9,258 patients (risk ratio 1.32, 95% CI 1.15-1.50)[29].

 Moreover, HES have been related with harmful effects on bleeding and

hemostasis. In the VISEP study, patients receiving HES had a lower median platelet

count (179,600/cm3) compared with patients in the Ringer's lactate group

(224,000/cm3, p<0.001) and received more units of packed red cells (median number

6 vs. 4, p<0.001)[23]. 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 0.94-

2.48, p=0.09)[24]. A meta-analysis regarding postoperative blood loss in randomized

clinical trials involving adult cardiopulmonary bypass surgery (18 studies, n=970)

showed that compared with albumin, HES increased postoperative blood loss by

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33.3% (95% CI 18.2-48.3, p<0.001). Additionally, the risk of reoperation for bleeding

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was more than doubled (RR 2.24, 95% CI 1.14-4.40, p= 0.020), whereas an increased

transfusion of red blood cells by 28.4% (95% CI 12.2-44.6, p<0.001), fresh-frozen

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plasma by 30.6% (95% CI 8.0-53.1, p=0.008) and platelets by 29.8% (95% CI 3.4-56.2,

p=0.027)[30]. An older meta-analysis has shown similar harmful effects of HES

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compared with albumin in patients undergoing cardiopulmonary bypass surgery[31].

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However, a meta-analysis on the effect of 6% HES versus other fluids for non-septic

ICU patients (22 studies, n=6,064) showed that HES was not associated with
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decreased overall mortality (RR 1.03, 95% CI 0.09-1.17, p=0.67), RRT incidence,

bleeding volume and red blood cell transfusion[32].

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HES is eliminated through urinary excretion, but also undergoes tissue

uptake[33]. A meta-analysis (25 studies, n=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)[34]. Regarding single HES solutions, 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)[34]. A major site of HES uptake and storage is the skin, which is related to

occurrence of severe prolonged (can persist for up to 12-24 months) refractory

pruritus[35-37]. 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 patients[38]. In a

meta-analysis of CHEST and CHRYSTMAS trials, compared with NS, pruritus was

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significantly increased with HES 130/0.4 (RR 1.81, 95% CI 1.37-2.38)[39]. The

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mechanisms of HES-induced pruritus are not fully understood, although HES storage

to HES-laden vacuoles in skin macrophages and in small cutaneous nerves may play a
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central role[35].

In 2013 the U.S. Food and Drug Administration, based on evidence from
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randomized controlled trials and meta-analyses, issued a “black box” warning

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regarding increased mortality and severe renal injury associated with the use of HES

in critically ill patients (including those with sepsis), suggesting that it should not be
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administered in this population or in patients with pre-existing renal dysfunction[40].

A committee of the European Medicines Agency (EMA) suggested initially a total ban
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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 of using HES even in limited circumstances
has been criticized, because it has been argued that this decision was based on non-

adequate (or non-reliable) data[41].

The effects of HES have been presented in detail because large well-designed

randomized controlled trials are available. However, available data show similar non-

beneficial effects with other colloids, such as gelatins or dextrans[42-48]. A recent

meta-analysis including 30 randomized controlled trials (n=3,629), 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

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anaphylaxis (RR 3.01, 95% CI 1.27-7.14)[6]. Furthermore, evidence from non-

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randomized trials pointed to increased risk of hospital mortality and AKI or renal

replacement therapy with gelatin administration. Additionally, a large proportion

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(17-31%) of administered gelatin was located extravascularly[6].
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Hypertonic salt solution has been also examined as volume expander, since it
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expands intravascular volume with less volume compared with isotonic salt

solutions[49]. Generally, large randomized controlled trials are missing. A meta-

analysis of 18 studies in people undergoing surgery (n=1,087; none with >3 days
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duration) a less positive fluid balance postoperatively (mean difference -1.92 L, 95%
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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 saline[50]. 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 mm Hg, 95% CI -4.18 to 1.68) in a meta-analysis of 11 studies in people with

severe traumatic brain injury (n=1,820 patients)[51].

According to a meta-analysis, there is no evidence that the administration of

colloids reduces the risk of death compared with resuscitation with crystalloids in

patients with trauma, burns or following surgery. In contrast, there is evidence that

the use of HES might increase mortality rates[52]. Currently available data regarding

the non-beneficial or even harmful effects of colloids, along with the high cost of

albumin, point to the preferential use of crystalloid solutions in the everyday clinical

practice in patients who need intravenous fluids.

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The role of crystalloids in fluid
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resuscitation
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The purpose of fluid therapy is not only to increase intravascular volume, but
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also to improve perfusion and oxygenation of vital organs and maintain hydration.

Crystalloids are categorized in several types such as dextrose 5% and saline

solutions. There are plenty types of fluids available, such as NS, RL, Ringer’s Acetate,
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Hartmann’s solution and Plasma-Lyte 148. In this review only NS and RL will be
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discussed since they are most frequently prescribed. The main characteristics of NS

and RL are shown in Figure 1. These two solutions differ in composition and

tonicity[53]. Tonicity is the effective osmolality and is equal to the sum of the

concentrations 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 number of milliosmoles/L with the number of milliosmoles that is
contained in 1L of blood plasma. A hypotonic solution given intravenously lowers

plasma osmolarity and leads to water movement from intravascular to extravascular

space in order to maintain the osmotic balance.

Crystalloid solutions, when given intravenously, are distributed among

intravascular and extracellular space as they contain osmotically active substances.

In healthy subjects, after administration of 1L 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 volume[54]. In contrast,

after administering Dextrose 5% only an amount <100 ml remains in the

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intravascular space, so this solution is more useful for maintaining daily fluid needs

rather than treating hypovolemia[54].

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a) Characteristics and adverse effects of NS

NS is an isotonic with plasma solution useful for maintaining intravascular

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and extracellular volume, but it has been associated with certain adverse effects
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(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 development of

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hyperchloremia and metabolic acidosis. Hyperchloremic metabolic acidosis following

NS administration occurs due to a dilutional effect but also due to a decrease in renal
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excretion of H+[55]. Hyperchloremia results in an increased concentration of Cl- in

macula densa. The increased concentration of Cl- in macula densa leads to a

decreased secretion of renin and aldosterone, which results in a decreased excretion

of H+ and promotes metabolic acidosis. Even though the NS-induced metabolic

acidosis was initially considered to be a transient metabolic abnormality without any

consequences, it has been recently suggested that metabolic acidosis can adversely

affect the immunity system function and also lead to impaired coagulation resulting

in prolonged hospital stay and increased postoperative mortality[56, 57].

Additionally, the hyperchloremia-induced increased concentration of Cl- in

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 RRT[58].

Furthermore, administration of NS increases the interstitial fluid volume,

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which further affects organs that are surrounded by a capsule, such as the kidney.

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Interstitial edema in the kidney leads to intracapsular hypertension and therefore to

impaired tissue perfusion and to organ dysfunction. Interstitial edema is also

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manifested as peripheral edema, ascites, splachnic edema, abdominal compartment

syndrome and gastrointestinal dysfunction[59].

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Further attention should also be paid when NS solutions are infused in

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patients with loss of renal diluting capacity because this increases the risk of

developing hyponatremia[60]. On the other hand, impaired concentrating ability of

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the kidney in patients with sickle cell disease, obstructive uropathy, congenital

nephrogenic diabetes insipidus, reflux nephropathy, renal dysplasia,

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tubulointerstitial nephritis and use of lithium pose a risk of developing

hypernatremia after administration of NS[60].

b) Characteristics and adverse effects of RL

Balanced saline solutions, such as RL, exhibit an electrolyte composition similar to

that of extracellular fluid. However, RL is slightly hypotonic (osmolarity 254

mOsm/kg) and is chloride 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 patients[61]. In contrast with normal saline, it does not

promote metabolic acidosis and it is not associated with deterioration of kidney

function resulting in less need of renal replacement therapy[62, 63]. Because of

these advantages balanced solutions (and especially RL that is the most used

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balanced solution) are preferred in certain situations, as they are beneficial in

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surgical patients, in patients with trauma, in patients with burns as well as in patients

with diabetic ketoacidosis (Table 2)[2]. In fact, in cases of diabetic ketoacidosis the
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administration of RL leads to a faster improvement of acid-base disturbances[64].

Nevertheless, RL is not free from adverse effects (Table 2). Taken into account the
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small potassium content of this solution, administration of RL is associated with

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increased serum potassium levels in patients with decreased renal function and in

individuals with potassium homeostasis abnormalities. It is also associated with the

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development of metabolic alkalosis (as the lactate metabolizes to CO2), which can be

noticed in patients with preexisting alkalemia or in those with inability to excrete a

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bicarbonate loading. When administering RL, which contains calcium, with sodium

bicarbonate solutions, the insoluble salt CaCO3 may be formed, thus this

combination should be avoided[53]. It is worth mentioning that hypotonic saline

solutions should be avoided in patients at risk of developing hyponatremia[65-68].

Such patients are those with nausea and vomiting, pain, stress, central nervous
system disease, inflammation, 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;

thereby in patients at risk for brain disease (meningitis, encephalitis, head injury,

brain surgery, brain tumors, etc.), isotonic fluids and not RL should be used[69]. In

addition, calcium and other electrolytes that are included in RL may induce clot

formation when co-administered with blood products which contains citrate[1].

Finally, RL contains lactate and its administration is contraindicated in patients with

lactic acidosis in the case that lactate clearance is simultaneously impaired.

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c) Studies comparing NS and balanced solutions
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There are many studies that have compared balanced and unbalanced crystalloid
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solutions in ICU patients, in patients undergoing kidney transplantation, abdominal

or aortic surgery, and patients with diabetic acidosis (Table 3)[62, 70-80]. Generally,
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with the exception of the SPLIT (0.9% Saline vs Plasma-Lyte 148 (PL-148) for ICU fluid
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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

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outcomes (Table 3); thus, they do not permit robust conclusions. Many studies

investigated whether NS would result in hyperchloremic metabolic acidosis. Most of

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them concluded that NS is associated with hyperchloremic metabolic acidosis[71, 72,

77, 81-83]. It should be mentioned that two randomized controlled trials showed

that neither solution (NS, Plasmalyte 148 or RL) could produce metabolic acidosis in

the populations investigated (patients with dehydration in the emergency

department or children with acute diarrhea)[79, 84].

The development of metabolic acidosis and other shortcomings of NS are directly

depended on the amount administered. In fact, the administration of small amount

of NS, used in maintenance rates for a short time, is not associated with significant

adverse consequences[60]. A very interesting study was the double-blind, cluster

randomized, double-crossover SPLIT (0.9% Saline vs Plasma-Lyte 148 (PL-148) for ICU

fluid Therapy) trial, which aimed to identify the adverse effects of NS or balanced

crystalloid solutions on renal function in 2,278 ICU patients without established AKI

requiring RRT[70]. Participating ICUs were assigned a masked study fluid, either NS

(n=1025) or a buffered crystalloid (Plasma-Lyte 148, n=1067), for alternating 7-week

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treatment blocks, so that each ICU used each fluid twice during the 28 weeks of the

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study. The total volume of administered fluids, which was mainly given in the first

day, was not different between buffered crystalloid and NS groups (median 2,000 mL
EP
(interquartile range 1,000-3,500 mL vs. 2,000 mL (1,000-3,250 mL). At 90 days,

similar proportion of patients developed AKI (primary endpoint, defined as a rise in

C

serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL
AC

with an increase of ≥0.5 mg/dL) in the buffered crystalloid group (9.6%) and in NS

group (9.2%; RR 1.04, 95% CI 0.80-1.36, p=0.77). Similarly, the secondary endpoints
ST

of RRT (3.3% vs. 3.4%, RR 0.96, 95% CI 0.62-1.50, p=0.91) and death in the hospital

(7.6% vs. 8.6%, RR 0.88, 95% CI 0.67-1.17, p=0.40) were non-significantly different
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between the buffered crystalloid group and the NS group[70]. Thus, these results

point to the fact that no solution is hazardous when the total volume of intravenous

crystalloid fluids is about 2L.

d) Characteristics and adverse effects of dextrose 5% solution

Dextrose 5% is isotonic with plasma (osmolarity 277mosm/kg) and contains a small

amount of glucose (50g/L) providing little energy. The glucose administered is rapidly

metabolized in the liver and the remaining water is distributed in all fluid

compartments and thus only a small volume (approximately 100 ml) remains in the

intravascular space after administering 1L of Dextrose 5% solution. Therefore, this

solution is useful for maintaining hydration but not for treating hypovolemia. Certain

adverse effects of dextrose 5% solution are the development of hypotonicity and the

reduction of serum potassium concentration, as dextrose administration induces

insulin secretion that promotes potassium movement from extracellular to

D
intracellular space. The occurrence of hyponatremia with the use of hypotonic fluids,

TE
such as dextrose solutions, is a significant problem in hospitalized patients, especially

in children, and is related to serious adverse effects (for example hyponatremic

EP
encephalopathy)[85, 86]. Thus, hypotonic fluids should be avoided in hospitalized

patients and the administration of dextrose 5% in isotonic solutions is preferable in

C

order to avoid endogenous catabolism[60].

AC
ST

Practical concepts of using intravenous

fluids
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Based on the current evidence, colloid solutions should be avoided in most clinical

situations due to their increased cost and certain adverse effects. Most hospitalized

patients can be managed with crystalloid solutions to deal with hypovolemia or as

maintenance fluids.
In everyday clinical practice, each patient should be individually treated with

crystalloid solutions based on the underlying volume status, the renal function, the

comorbidities, as well as the 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 contrary, when the patient with hypovolemia has also

metabolic alkalosis and/or hypochloremia, or he/she has hyperkalemia, NS or

hypotonic saline fluids should be prescribed. In cases of hypokalemia the ideal type

of more useful intravenous solution is RL or hypotonic saline solutions with the

D
addition of KCl. In patients with traumatic brain injury or neurosurgical patients NS

should be administered to avoid cerebral edema[53].

TE
In patients without hypovolemia who cannot receive adequate fluids by mouth
EP
dextrose 5% in isotonic solutions can be used as maintenance fluid (with caution in

patients at risk of hypokalemia).

C

The danger of hypotonicity is widely discussed in the literature in relation with the
AC

use of isotonic or hypotonic solutions as maintenance fluids in critically ill patients.

The usual standard of care, especially in hospitalized children, was to prescribe

ST

hypotonic fluids for maintaining hydration. In hospitalized patients there are many

stimuli, both hemodynamic and non-hemodynamic, that can cause excess

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antidiuretic hormone secretion (Table 4). This antidiuretic hormone excess in

combination with hypotonic fluid administration can cause acute hyponatremia and

hyponatremic encephalopathy, as shown in recent publications[87-89]. Therefore,

isotonic 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 magnesium needs to be replaced. In these cases, the

addition of potassium should be taken into account when estimating the tonicity of

the final infusate. For example, the addition of 4 amp KCl to a half-isotonic saline

solution renders 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 overload. 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 with potassium administration, bicarbonate should be

D
added in hypotonic and not isotonic solutions in order to avoid the use of (finally)

TE
hypertonic solutions that prone to circulatory overload.

The appropriate volume of the chosen infusate should be carefully estimated

EP
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 attributed to fluid
C

overload either from colloids or crystalloid solutions, such as interstitial edema,

AC

cardiac, pulmonary and bowel dysfunction, dilutional coagulopathy, impaired water

and sodium regulation and also impaired wound healing [90, 91]. A positive fluid
ST

balance was found to be an independent risk factor for 60-day mortality in patients

with acute kidney failure in the SOAP (Sepsis Occurrence in Acutely Ill Patients) study
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and also in patients with sepsis[92, 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)[94, 95]. 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 required[53, 60].

Conclusions
The selection of intravenous fluids should be based on their indications and

contraindications, in relation with the volume status, cardiovascular status, renal

function, electrolyte and acid base status of the patient. Studies have shown that

D
albumin and colloids do not significantly reduce mortality compared with crystalloid

TE
fluids in patients with trauma, burns or following surgery. Among crystalloids, the

administration of NS is associated with hyperchloremia-induced impairment of

EP
kidney function and metabolic acidosis. In contrast, the other usually used crystalloid

solution, the RL, has certain indications as well as contraindications, such as severe
C

metabolic alkalosis or severe hyperkalemia. Intravenous fluids should be used as

AC

drugs, as they have specific clinical indications, contraindications and adverse

effects.
ST
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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 solutions

(HES) compared with crystalloids, thus currently HES has only a few

D
indications. Their use is contraindicated in patients with sepsis or in those at


risk of acute renal failure.

TE
The available data regarding gelatins, dextrans and hypertonic saline
EP
solutions do not point to a beneficial effect compared with crystalloids.

 Balanced crystalloids are preferred in most conditions to avoid

C

hyperchloremia and metabolic acidosis associated with the use of normal

AC

saline. However, an individual approach is strongly recommended taking into

account serum sodium and potassium levels as well as acid-base

ST

abnormalities.

 In patients with central nervous system disorders isotonic crystalloid

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solutions should be given to avoid hyponatremia 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, it is suggested to avoid hypervolemia with its devastating

consequences; 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.

D
Declaration of financial or other interest:
TE
EP
The authors on this manuscript have no relevant financial relationships to disclose.

The CMRO Peer Reviewers on this manuscript have no relevant financial

C

relationships to disclose.
AC
ST
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Figure legends
Figure 1: Main characteristics of the most commonly used crystalloid solutions.

Figure 2: Adverse effects of normal saline.

GFR = glomerular filtration rate; AKI = acute kidney injury

D
TE
EP
C
AC
ST
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JU
ST
AC
C
EP
TE
D
Table 1: Main studies that have compared the use of albumin or colloids with

solutions*.

Study Design and Solutions Primary Secondary

population outcome outcome

CRISTAL  RCT Colloids Mortality at 28 Mortality at 90

trial[10]  Mixed ICU (gelatins, days: 359 days: 434 deaths

population dextrans, deaths (25.4%) (30.7%) vs. 493

hydroxyethyl vs. 390 deaths deaths (34.2%),

starches, or (27.0%), RR RR 0.92 (95% CI

D
4% or 20% 0.96 (95% CI 0.86-0.99),

n=1,414) vs. p=0.26.

TE
of albumin; 0.88-1.04), p=0.03).

RRT: 156 (11.0%)

EP
crystalloids vs. 181 (12.5%),

(isotonic or RR 0.93 (95% CI

C
AC

hypertonic 0.83-1.03),

saline or p=0.19).

Ringer
ST

lactate

solution;
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n=1,443)

SAFE  RCT Albumin 4% Mortality at 28 Remained in ICU

trial[4]  Mixed ICU (n=3,497) vs. days: 726 at 28 days: 111

population NS (n=3,500) (20.9%) vs. 729 (3.2%) vs. 87

 (21.1%), RR (2.5%), RR 1.27,

0.99 (95% CI p=0.09.

0.91-1.09), Remained in

p=0.87. hospital at 28

days: 793 (22.8%)

vs. 848 (24.5%),

RR 0.93 (95% CI

0.86-1.01),

p=0.10.

D
Similar survival

TE times, new organ

failure, mean
EP
length of stay in

the hospital, days

C

of RRT (all p=NS).

AC

Death in trauma

patients with
ST

cranial injury:

59/241 (24.5%)
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vs. 38/251

(15.1%), RR 1.62

(95% CI 1.12-

2.34), p=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=0.09.

ALBIOS  RCT Albumin Mortality at 28 Mortality at 90

D
trial[13] 20% plus days: 285 days: 365 (41.1%)

crystalloid

solution
TE
(31.8%) vs. 288 vs. 389 (43.6%),

(32.0%), RR RR 0.94 (95% CI

EP
(n=910) vs. 1.00 (95% CI 0.85-1.05),

crystalloid 0.87-1.14), p=0.29.

C
AC

solution p=0.94). SOFA score:

alone median 6 (IQR

(n=908) 4.0-8.5) vs. 5.62

ST

(IQR 3.92-8.28),

p=0.23.
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Post hoc

subgroup

analysis in 1,121

patients with
 septic shock at

baseline: 243

(43,6%) vs. 281

(49.9%), RR 0.87

(95% CI 0.77-

0.99), p=0.03 for

heterogeneity vs.

patients without

septic shock.

D
FEAST  RCT Albumin 5% Death at 48 Death at 4

trial[94]  Children (n=1050) vs. hours:

with severe NS (n=1047)

TE 111 weeks:

(10.6%) vs. 110 (12.2%) vs. 126

128
EP
febrile (20 to 40 (10.5%) vs. 76 (12%) vs. 91

ml/kg of (7.3%), RR of (8.7%), RR of

C

illness
AC

(poor body saline bolus vs. saline bolus vs.

resource weight) vs. no bolus 1.44 no bolus 1.38

setting, no bolus (95% CI 1.09- (95% CI 1.07-

ST

Africa) control 1.90), p=0.01; 1.78), p=0.01; RR

therapy RR of albumin of bolus albumin

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(n=1,044) bolus vs. saline vs. no bolus 1.40

bolus 1.00 (95% CI 1.08-

(95% CI 0.78- 1.80), p=0.01; RR

1.29), p=0.96; of combined

 RR of bolus bolus vs no bolus

combined 1.39 (95% CI

therapy vs. no 1.11-1.74),

bolus 1.45 p=0.004.

(95% CI 1.13-

1.86), p=0.003.

CRYSTMAS  RCT HES (n=100) Amount of Time to achieve

trial[5]  ICU vs. NS (n=96) study drug (ml) initial HDS

patients required to (hours):

D
with severe achieve initial 11.810.1 vs.

sepsis
TE
hemodynamic

stability:
14.311.1, p=NS.

Length of stay in
EP
1,379876 vs. ICU (days):
C

1,7091,164 15.411.1 days

AC

ml, p=0.0185. vs. 20.222.2,

p=NS.

Length of stay in
ST

the hospital
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(days): 37.726.5

vs. 42.731.6,

p=NS.

Mortality rate at

day 28: was

 31/100 (31.0%)

vs. 24/95

(25.3%), p=0.37.

VISEP  RCT HES 200/0.5 Death at 28 Deaths at 90

trial[23]  Patients (n=262) vs. days: 70 days: 107 (41.0%)

with severe Ringer's (26.7%) vs. 66 vs. 93 (33.9%),

sepsis lactate (24.1%), p=0.09.

(n=275) p=0.48. Acute renal

D
Morbidity failure: 91

TE
(mean SOFA (34.9%) vs. 62

score): 8 (95% (22.8%), p=0.002.

EP
CI 7.5-8.5) vs. RRT: 81 (31%) vs.

7.5 (7.1-8.0), 51 (18.8%),

C

p=0.16. p=0.001.
AC

Red cell

transfusion: 199
ST

(76%) vs. 189

(68.7%), p=0.06.
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Number of red

cell units: median

6 (IQR 4-12) vs. 4

(2-8), p<0.001.
6S  RCT HES Death or Death at 28 days:

trial[24]  ICU 130/0.42 dependence 154 (39%) vs. 144

patients (n=398) vs on dialysis 90 (36%), RR 1.08

with severe Ringer’s days after (95% CI 0.90-

sepsis acetate randomization: 1.28), p=0.43.

(n=400) 202 (51%) vs. Severe bleeding:

173 (43%), RR 38 (10%) vs. 25

1.17 (95% CI (6%), RR 1.52

1.01-1.36), (95% CI 0.94-

D
p=0.03. 2.48), p=0.09.

TE
Death at 90 Severe

days: 201 reactions:

allergic

1
EP
(51%) vs. 172 (0.25%) vs 0

(43%), RR 1.17 (0%), p=0.32.

C

(95% CI 1.01- SOFA score at

AC

1.36), p=0.03. day 5: median 6

vs 6, p=0.64.
ST

RRT: 87 (22%) vs.

65 (16%), RR 1.35
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(95% CI 1.01-

1.80), p=0.04.

CHEST  RCT HES Death at 90 RIFLE-renal

trial[25]  Mixed ICU (130/0.42; days: 597 dysfunction at 90

 patients n=3,500) vs. (18.0%) vs. 566 days: 1,788

NS (n=3,500) (17.0%), RR (54.0%) vs. 1,912

1.06 (95% CI (57.3%), RR 0.94

0.96-1.18), (95% CI 0.90-

p=0.26. 0.98), p=0.007.

RRT: 235 (7.0%)

vs. 196 (5.8%),

RR 1.21 (95% CI

1.00-1.45),

D
p=0.04.

TE New

cardiovascular
EP
organ failure:

663 (36.5%) vs.

C

722 (39.9%), RR
AC

0.91 (95% CI

0.84-0.99),
ST

p=0.03.

New hepatic
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failure: 55 (1.9%)

vs. 36 (1.2%), RR

1.56 (95% CI

1.03-2.36),
 p=0.03.

*Values indicate number of patients, except otherwise mentioned.

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, and End-stage kidney disease classification;

AKI=acute kidney injury; SOFA=Sepsis-related Organ Failure Assessment

D
TE
EP
C
AC
ST
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Table 2. When to use and when to avoid Ringer’s Lactate

Indications Contraindications

 Surgical patients  Severe metabolic alkalosis

 Patients with trauma  Lactic acidosis with impaired lactate

 Septic patients clearance

 Patients with diabetic  Severe hyperkalemia

ketoacidosis  Co-administration with citrated blood

 Patients with burns products

 Patients with acute  Patients at risk of developing brain edema

D
pancreatitis (traumatic brain disease, neurosurgical

TE
patients or conditions associated with
EP
increased secretion of antidiuretic

hormone)
C

 Co administration of NaHCO3
AC
ST
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Table 3. Studies with sample >50 patients that have compared balanced solutions
with normal saline (arranged by study population)*.

Study Design and study Solutions Primary Secondary

population outcome(s) outcome(s)

SPLIT  Cluster NS AKI at 90 days: RRT: 38

trial[70] randomized, (n=1,110) 94 (9.2%) vs. (3.4%) vs. 38

double- vs 102 (9.6%), RR (3.3%), RR

crossover trial Plasmalyte 1.04 (95% CI 0.96 (95% CI

-148 0.80-1.36), 0.62-1.50),

 ICU patients

D
(n=1,152) p=0.77. p=0.91.

TE In-hospital

mortality: 95
EP
(8.6%), 87

(7.6%), RR
C

0.88 (95% CI
AC

0.67-1.17),

p=0.40.
ST

Yunos N.  Prospective, Chloride- Serum RRT: 49 (6.3%,

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et al[62] open-label, restrictive creatinine 95% CI 4.6%-

sequential (n=760) vs concentration: 8.1%) vs. 78

period (duration chloride- 22.6 (95% CI (10%, 95% CI

of each period 6 liberal 17.5-27.7) vs. 8.1%-12%),

months) study intravenou 14.8 (95% CI p=0.005.

  ICU patients s fluid 9.8-19.9) No

strategy μmol/L, differences in

(n=773) p=0.03). hospital

mortality,
RIFLE-defined
hospital or
AKI: 65 (8.4%,
ICU length of
95% CI 6.4%-
stay, or need
10%) vs. 105
for RRT after
(14%, 95% CI
hospital
11%-16%),

D
discharge.
p<0.001.

Hadimiogl  TE
RCT (duration 7 NS (n=30) Compared Compared
EP
u N. et days) vs. RL with baseline, with baseline,

al[71] (n=30) vs. NS decreased RL increased

 Adults
C

Plasmalyte pH (7.440.50 lactate levels

undergoing
AC

-148 vs. 7.360.05) (0.480.29 vs

living-related
(n=30) and base 1.950.48).
kidney
ST

excess
transplantation No significant
(0.43.1 vs. –
changes with
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4.32.1), and
Plasmalyte-
increased
148.
serum chloride

(1042 vs
 1253 mM/L).

Kim S. et  RCT NS (n=30) NS group Graft failure

al[72] vs developed requiring

 Patients
Plasmalyte significantly dialysis: 1 vs.
undergoing
(n=30) lower values 3 episodes
kidney
of pH, base- (p=0.30)
transplantation
excess, and during the

D
effective first 7

TE
strong

differences
ion postoperative

days.
EP
compared

with
C

Plasmalyte
AC

group during

surgery.
ST

Khajavi M.  RCT NS (n=26) Mean serum Thrombotic

et al[73] vs. RL K+ levels: events: 0% vs.

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 Patients
(n=26) 4.88±0.7 vs. 7.7%, p=0.49.
undergoing
during 4.03±0.8
kidney
surgery meq/L,
transplantation
p<0.001.
 Mean changes

in serum K+:

+0.5±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,

D
p<0.001.

Modi M.  RCT NS (n=37) pH:TE decrease K+: from

EP
et al[74] vs. RL from 7.43 to 3.94±0.45 to
 Patients
(n=37) 7.33 vs. no 4.31±0.59 vs.
undergoing live-
C

during change (p not 3.76±0.75 to

related renal
AC

surgery shown). 3.99±0.71,

transplantation
p<0.05
HCO3: from
ST

between
20.87±3.89 to
groups.
19.47±3.02 vs.
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from Urine output:

21.88±4.63 to similar

21.62±3.56, between

p<0.05 groups.
 between

groups.

O’Malley  RCT NS (n=26) Postoperative Episodes of

C. et al[75] vs RL (day 3) serum biopsy-proven

 Patients
(n=25) creatinine rejection: 4
undergoing
during concentration: vs. 2 patients.
kidney
surgery 2.3±1.8 vs.
transplantation Peak
2.1±1.7 mg/dL,
intraoperative
p=0.70.

D
serum K+:

TE 5.1±0.6

5.1±1.1
vs.
EP
mEq/L.

Serum K+ >6.0
C

mEq/L: 19%
AC

vs. 0%

(p=0.05).
ST

Shaw A. et  Observational NS Major Use of dialysis

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al[76] study (n=30,994) morbidity: in the 3:1

vs 33.7% vs. 23%, matched

 Patients
balanced p<0.001. cohort: 1.0%
undergoing
crystalloid (95% CI 0.05-
major open In-hospital
solution 1.8) vs. 4.8%
abdominal mortality:
 surgery (Plasma- 5.6% vs. 2.9%, (95% CI 4.1-

Lyte A or p<0.001. 5.7), p<0.001.

Plasma-
Fewer Transfusion:
Lyte 148;
complications 11.5% (95% CI
n=926) on
with balanced 10.3-12.7) vs
the day of
solution in the 1.8% (95% CI
surgery
3:1 1.2-2.9),

propensity- p<0.001.

matched

D
Tests to
sample (odds

TE
ratio 0.79, 95%
evaluate

acidosis:
EP
CI 0.66-0.97).
arterial blood

gases 22.3%
C

(95% CI 21.3-
AC

24.5) vs.

13.7% (95% CI
ST

11.7-16.1)

and lactic acid

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levels 8.0%

(95% CI 7.0-

9.1) vs. 3.3%

(95% CI 2.4-
 4.7], p<0.001

Waters J.  RCT NS (n=33) NS patients No difference

et al[77] vs. RL developed in the

 Patients
(n=33) hyperchloremi postoperative
undergoing
c acidosis and complications
aortic
received more and death.
reconstructive
bicarbonate
surgery
therapy

compared

D
with RL group

TE
(3062mL vs.
EP
416 mL).

NS group
C

received
AC

significantly

more blood
ST

products

(p=0.02).
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Zunini G.  Retrospective NS (n=63) Metabolic Hyponatremia

et al[78] study vs RL acidosis: 66% : 40% vs. 26%

(n=59) vs. 26% in the first 2

 Children aged
(p=0.015) in hours and
<5 years who
 had a the first 2 and 52% vs. 50%

craniofacial 80% vs. 37% in the next 2

surgery (p=0.027) in hours (both

the next 2 p=NS).

hours.
Hypokalemia:

Severe 13% vs 5%

acidosis: 39% (p=0.30) in

vs 8% the first 2

(p=0.003). hours and

D
19.5% vs 3%

TE (p=0.03) in
EP
the next 2

hours.
C

Hasman H.  RCT NS (n=30) In all groups No significant

AC

et al[79] vs. pH values changes in

 Patients with
Plasmalyte were in the potassium,
dehydration in
ST

148 (n=30) physiological sodium, or

the emergency
vs. RL range (7.35- chloride
department
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(n=30) (all 7.45) levels.

at 20 throughout

ml/kg/h for the 2-hour

2 hours) period.
 NS group:

significant

tendency to

lower pH

values (from

7.40 to 7.36).

Van Jyl D.  RCT RL (n=28) Time to Unadjusted

et al[80] vs. NS venous pH time to lower

 Patients with
(n=29) normalization blood glucose

D
diabetic
(pH=7.32): to 14 mmol/l:
ketoacidosis
TE
hazard ratio 410 min (IQR
EP
1.863 (95% CI 240-540) vs.

0.937-3.705), 300 min (IQR

C

p = 0.076. 235-420),
AC

p=0.044.
Median time

to reach a pH Time to
ST

of 7.32: 540 resolution of

min (95% CI diabetic

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184-896) vs. ketoacidosis:

683 min (95% No difference

CI 378-988), (adjusted

p=0.251). p=0.758).
**Values indicate number of patients, except otherwise mentioned.

NS=normal saline; RL=Ringer’s Lactated; 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 kidney disease classification;

AKI=acute kidney injury

Table 4. Conditions associated with increased antidiuretic hormone levels, which

D
predispose to the development of hyponatremia

 Hypovolemia TE
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 Congestive heart failure

 Cirrhosis with ascites

C

 Central nervous system diseases

AC

 Post-obstructive condition

 Cancer
ST

 Pulmonary diseases, especially associated with hypoxemia and hypercapnia

 Administration of drugs such as selective serotonin reabsorption inhibitors,

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carbamazepine, thiazides.
Table 5. Basic principles of potassium chloride (KCl) administration

 In patients with normal potassium balance administration of 60-80 mEq

K+/day in the infusates (2-3 L/day) to cover the daily potassium needs is

indicated.

 In patients with a negative potassium balance:

o KCl should be added only to saline (and not to dextrose) solutions

o No more than 60 mEq K+/L can be given; preferably K+ should be

administrated in a large vein.

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o Potassium-rich infusates should be slowly given to avoid hyperkalemia

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o KCl should be added preferably to hypotonic saline solutions to avoid

circulatory overload [since KCl contains osmotically active ions, e.g. 1

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L 0.45% saline solution + 54 (4 amp) mEq KCl is nearly isotonic to
C

plasma]
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o Frequent determination of serum potassium levels are necessary

during treatment
ST
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Table 6. Basic principles of NaHCO3 solution administration

 NaHCO3 should not be given with Ringer’s Lactate solutions

 NaHCO3 should not be administrated in patients with lactic acidosis or

diabetic ketoacidosis, unless pH is <7.10

 NaHCO3 should not be given in a isotonic saline solution to avoid circulatory

overload, but with hypotonic solutions (e.g. 1 L 0.45% saline solution + 45

mEq NaHCO3 + 30 mEq KCl is nearly isotonic to plasma)

D
TE
EP
C
AC
ST
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References
1. McDermid RC, Raghunathan K, Romanovsky A, et al. Controversies in fluid

therapy: Type, dose and toxicity. World J Crit Care Med 2014;3:24-33.

2. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med 2013;369:2462-

3.

3. Lobo DN, Stanga Z, Aloysius MM, et al. Effect of volume loading with 1 liter

intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6%

hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a

randomized, three-way crossover study in healthy volunteers. Crit Care Med

D
2010;38:464-70.

4. TE
Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for
EP
fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56.

5. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy

C

and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in

AC

patients with severe sepsis: the CRYSTMAS study. Crit Care 2012;16:R94.

6. Moeller C, Fleischmann C, Thomas-Rueddel D, et al. How safe is gelatin? A

ST

systematic review and meta-analysis of gelatin-containing plasma expanders vs

crystalloids and albumin. J Crit Care 2016;35:75-83.

JU

7. Orbegozo Cortes D, Gamarano Barros T, Njimi H, et al. Crystalloids versus

colloids: exploring differences in fluid requirements by systematic review and meta-

regression. Anesth Analg 2015;120:389-402.

8. Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and

recovery of kidney function in critically ill patients with acute kidney injury. Kidney

Int 2009;76:422-7.

9. Vaara ST, Korhonen AM, Kaukonen KM, et al. Fluid overload is associated

with an increased risk for 90-day mortality in critically ill patients with renal

replacement therapy: data from the prospective FINNAKI study. Crit Care

2012;16:R197.

10. Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs

crystalloids on mortality in critically ill patients presenting with hypovolemic shock:

D
the CRISTAL randomized trial. JAMA 2013;310:1809-17.

11.
TE
Perner A, Haase N, Wetterslev J. Mortality in patients with hypovolemic

shock treated with colloids or crystalloids. JAMA 2014;311:1067.

EP
12. Brun-Buisson C, Sun J, Natanson C. Mortality in patients with hypovolemic

shock treated with colloids or crystalloids. JAMA 2014;311:1068-9.

C

13. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with

AC

severe sepsis or septic shock. N Engl J Med 2014;370:1412-21.

14. van Haren F, Zacharowski K. What's new in volume therapy in the intensive
ST

care unit? Best Pract Res Clin Anaesthesiol 2014;28:275-83.

15. Alderson P, Bunn F, Li Wan Po A, et al. Human albumin solution for

JU

resuscitation and volume expansion in critically ill patients. Cochrane Database Syst

Rev 2011:CD001208.

16. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a

systematic review and network meta-analysis. Ann Intern Med 2014;161:347-55.

17. Greco T, Biondi-Zoccai G, Saleh O, et al. The attractiveness of network meta-

analysis: a comprehensive systematic and narrative review. Heart Lung Vessel

2015;7:133-42.

18. Jiang L, Jiang S, Zhang M, et al. Albumin versus other fluids for fluid

resuscitation in patients with sepsis: a meta-analysis. PLoS One 2014;9:e114666.

19. Patel A, Laffan MA, Waheed U, et al. Randomised trials of human albumin for

adults with sepsis: systematic review and meta-analysis with trial sequential analysis

of all-cause mortality. BMJ 2014;349:g4561.

20. FDA prescribing information.

D
https://www.google.gr/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ve

TE
d=0ahUKEwje97vXldLPAhWB2RoKHdh1BSMQFggaMAA&url=http%3A%2F%2Fwww.fda.gov

%2Fdownloads%2FBiolog...ionatedPlasmaProducts%2Fucm056844.pdf&usg=AFQjCNH_6ihb
EP
P5RfaC_gqirVyuCA9rzdcg&sig2=qi7mTxb1yEpIdJo3I_AFgw&bvm=bv.135475266,d.d2s.

Accessed at 10/10/16.
C

21. Johnston A, Uren E, Johnstone D, et al. Low pH, caprylate incubation as a

AC

second viral inactivation step in the manufacture of albumin. Parametric and

validation studies. Biologicals 2003;31:213-21.

ST

22. Miekka SI, Forng RY, Rohwer RG, et al. Inactivation of viral and prion

pathogens by gamma-irradiation under conditions that maintain the integrity of

JU

human albumin. Vox Sang 2003;84:36-44.

23. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and

pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-39.

24. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42

versus Ringer's acetate in severe sepsis. N Engl J Med 2012;367:124-34.

25. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid

resuscitation in intensive care. N Engl J Med 2012;367:1901-11.

26. Schick MA, Isbary TJ, Schlegel N, et al. The impact of crystalloid and colloid

infusion on the kidney in rodent sepsis. Intensive Care Med 2010;36:541-8.

27. Huter L, Simon TP, Weinmann L, et al. Hydroxyethylstarch impairs renal

function and induces interstitial proliferation, macrophage infiltration and tubular

damage in an isolated renal perfusion model. Crit Care 2009;13:R23.

28. Raiman M, Mitchell CG, Biccard BM, et al. Comparison of hydroxyethyl starch

colloids with crystalloids for surgical patients: A systematic review and meta-analysis.

D
Eur J Anaesthesiol 2016;33:42-8.

29.
TE
Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl

starch administration with mortality and acute kidney injury in critically ill patients
EP
requiring volume resuscitation: a systematic review and meta-analysis. JAMA

2013;309:678-88.
C

30. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding
AC

after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac

Cardiovasc Surg 2012;144:223-30.

ST

31. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in

cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann

JU

Thorac Surg 2001;72:527-33; discussion 34.

32. He B, Xu B, Xu X, et al. Hydroxyethyl starch versus other fluids for non-septic

patients in the intensive care unit: a meta-analysis of randomized controlled trials.

Crit Care 2015;19:92.

33. Sirtl C, Laubenthal H, Zumtobel V, et al. Tissue deposits of hydroxyethyl

starch (HES): dose-dependent and time-related. Br J Anaesth 1999;82:510-5.

34. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and

substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical

studies. Clin Pharmacokinet 2012;51:225-36.

35. Metze D, Reimann S, Szepfalusi Z, et al. Persistent pruritus after hydroxyethyl

starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J

Dermatol 1997;136:553-9.

36. Bork K. Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol

D
2005;152:3-12.

37.
TE
Kimme P, Jannsen B, Ledin T, et al. High incidence of pruritus after large

doses of hydroxyethyl starch (HES) infusions. Acta Anaesthesiol Scand 2001;45:686-

EP
9.

38. Stander S, Richter L, Osada N, et al. Hydroxyethyl starch-induced pruritus:

C

clinical characteristics and influence of dose, molecular weight and substitution. Acta
AC

Derm Venereol 2014;94:282-7.

39. Patel A, Waheed U, Brett SJ. Randomised trials of 6% tetrastarch

ST

(hydroxyethyl starch 130/0.4 or 0.42) for severe sepsis reporting mortality:

systematic review and meta-analysis. Intensive Care Med 2013;39:811-22.

JU

40. U.S. Food and Drug administration.

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Accessed

at 11/10/2016.

41. Hartog CS, Natanson C, Sun J, et al. Concerns over use of hydroxyethyl starch

solutions. BMJ 2014;349:g5981.

42. Albrecht FW, Glas M, Rensing H, et al. A change of colloid from hydroxyethyl

starch to gelatin does not reduce rate of renal failure or mortality in surgical critical

care patients: Results of a retrospective cohort study. J Crit Care 2016;36:160-65.

43. Wu CY, Chan KC, Cheng YJ, et al. Effects of different types of fluid

resuscitation for hemorrhagic shock on splanchnic organ microcirculation and renal

reactive oxygen species formation. Crit Care 2015;19:434.

44. Demir A, Aydinli B, Toprak HI, et al. Impact of 6% Starch 130/0.4 and 4%

Gelatin Infusion on Kidney Function in Living-Donor Liver Transplantation. Transplant

Proc 2015;47:1883-9.

D
45. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a

46.
TE
systematic review and network meta-analysis. Ann Intern Med 2014;161:347-55.

Bunn F, Trivedi D. Colloid solutions for fluid resuscitation. Cochrane Database

EP
Syst Rev 2012:CD001319.

47. Zhong JZ, Wei D, Pan HF, et al. Colloid solutions for fluid resuscitation in
C

patients with sepsis: systematic review of randomized controlled trials. J Emerg Med
AC

2013;45:485-95.

48. Rasmussen KC. Effect of perioperative colloid and crystalloid fluid therapy on
ST

coagulation competence, haemorrhage and outcome. Dan Med J 2016;63.

49. Wang JW, Li JP, Song YL, et al. Hypertonic saline in the traumatic hypovolemic
JU

shock: meta-analysis. J Surg Res 2014;191:448-54.

50. Shrum B, Church B, McArthur E, et al. Hypertonic salt solution for peri-

operative fluid management. Cochrane Database Syst Rev 2016:CD005576.

51. Berger-Pelleiter E, Emond M, Lauzier F, et al. Hypertonic saline in severe

traumatic brain injury: a systematic review and meta-analysis of randomized

controlled trials. CJEM 2016;18:112-20.

52. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in

critically ill patients. Cochrane Database Syst Rev 2013;2:Cd000567.

53. Liamis G, Filippatos TD, Elisaf MS. Correction of hypovolemia with crystalloid

fluids: Individualizing infusion therapy. Postgrad Med 2015;127:405-12.

54. Muller L, Lefrant J. Metabolic Effects of Plasma Expanders. Transfusion Alter

Transfusion Med 2010;11:10-21.

D
55. Orbegozo Cortes D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a

56.
TE
structured review of the literature. Br J Anaesth 2014;112:968-81.

Raghunathan K, Nailer P, Konoske R. What is the ideal crystalloid? Curr Opin

EP
Crit Care 2015;21:309-14.

57. McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after

C

noncardiac surgery is independently associated with increased morbidity and

AC

mortality: a propensity-matched cohort study. Anesth Analg 2013;117:412-21.

58. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous

ST

fluid restriction on postoperative complications: comparison of two perioperative

fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg

JU

2003;238:641-8.

59. Lobo DN, Awad S. Should chloride-rich crystalloids remain the mainstay of

fluid resuscitation to prevent 'pre-renal' acute kidney injury?: con. Kidney Int

2014;86:1096-105.
60. Moritz ML, Ayus JC. Maintenance Intravenous Fluids in Acutely Ill Patients. N

Engl J Med 2015;373:1350-60.

61. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice

of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit

Care Med 2014;42:1585-91.

62. Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal

vs chloride-restrictive intravenous fluid administration strategy and kidney injury in

critically ill adults. Jama 2012;308:1566-72.

63. Yunos NM, Kim IB, Bellomo R, et al. The biochemical effects of restricting

D
chloride-rich fluids in intensive care. Crit Care Med 2011;39:2419-24.

64.
TE
Chua HR, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148 vs 0.9% saline for

fluid resuscitation in diabetic ketoacidosis. J Crit Care 2012;27:138-45.

EP
65. Filippatos TD, Liamis G, Christopoulou F, et al. Ten common pitfalls in the

evaluation of patients with hyponatremia. Eur J Intern Med 2016;29:22-5.

C

66. Filippatos TD, Liamis G, Elisaf MS. Ten pitfalls in the proper management of
AC

patients with hyponatremia. Postgrad Med 2016;128:516-22.

67. Liamis G, Filippatos TD, Liontos A, et al. Hyponatremia in patients with liver
ST

diseases: not just a cirrhosis-induced hemodynamic compromise. Hepatol Int

2016;10:762-72.
JU

68. Liamis G, Filippatos TD, Elisaf MS. Thiazide-associated hyponatremia in the

elderly: what the clinician needs to know. J Geriatr Cardiol 2016;13:175-82.

69. Lira A, Pinsky MR. Choices in fluid type and volume during resuscitation:

impact on patient outcomes. Ann Intensive Care 2014;4:38.

70. Young P, Bailey M, Beasley R, et al. Effect of a Buffered Crystalloid Solution vs

Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT

Randomized Clinical Trial. JAMA 2015;314:1701-10.

71. Hadimioglu N, Saadawy I, Saglam T, et al. The effect of different crystalloid

solutions on acid-base balance and early kidney function after kidney

transplantation. Anesth Analg 2008;107:264-9.

72. Kim SY, Huh KH, Lee JR, et al. Comparison of the effects of normal saline

versus Plasmalyte on acid-base balance during living donor kidney transplantation

using the Stewart and base excess methods. Transplant Proc 2013;45:2191-6.

D
73. Khajavi MR, Etezadi F, Moharari RS, et al. Effects of normal saline vs. lactated

74.
TE
ringer's during renal transplantation. Ren Fail 2008;30:535-9.

Modi MP, Vora KS, Parikh GP, et al. A comparative study of impact of infusion
EP
of Ringer's Lactate solution versus normal saline on acid-base balance and serum

electrolytes during live related renal transplantation. Saudi J Kidney Dis Transpl
C

2012;23:135-7.
AC

75. O'Malley CM, Frumento RJ, Hardy MA, et al. A randomized, double-blind

comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation.
ST

Anesth Analg 2005;100:1518-24.

76. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality,
JU

and resource utilization after open abdominal surgery: 0.9% saline compared to

Plasma-Lyte. Ann Surg 2012;255:821-9.

77. Waters JH, Gottlieb A, Schoenwald P, et al. Normal saline versus lactated

Ringer's solution for intraoperative fluid management in patients undergoing

abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001;93:817-22.

78. Zunini GS, Rando KA, Cox RG. Fluid replacement in craniofacial pediatric

surgery: normal saline or ringer's lactate? J Craniofac Surg 2011;22:1370-4.

79. Hasman H, Cinar O, Uzun A, et al. A randomized clinical trial comparing the

effect of rapidly infused crystalloids on acid-base status in dehydrated patients in the

emergency department. Int J Med Sci 2012;9:59-64.

80. Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis--

Ringer's lactate versus normal saline: a randomized controlled trial. QJM

2012;105:337-43.

81. Scheingraber S, Rehm M, Sehmisch C, et al. Rapid saline infusion produces

D
hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology

1999;90:1265-70.

82.
TE
Takil A, Eti Z, Irmak P, et al. Early postoperative respiratory acidosis after
EP
large intravascular volume infusion of lactated ringer's solution during major spine

surgery. Anesth Analg 2002;95:294-8.

C

83. Cho YS, Lim H, Kim SH. Comparison of lactated Ringer's solution and 0.9%
AC

saline in the treatment of rhabdomyolysis induced by doxylamine intoxication.

Emerg Med J 2007;24:276-80.

ST

84. Mahajan V, Sajan SS, Sharma A, et al. Ringers lactate vs Normal saline for

children with acute diarrhea and severe dehydration- a double blind randomized
JU

controlled trial. Indian Pediatr 2012;49:963-8.

85. Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in hospitalized

children: a systematic review and meta-analysis. J Pediatr 2014;165:163-69 e2.

86. Corona G, Giuliani C, Parenti G, et al. The Economic Burden of Hyponatremia:

Systematic Review and Meta-Analysis. Am J Med 2016;129:823-35 e4.

87. McNab S, Ware RS, Neville KA, et al. Isotonic versus hypotonic solutions for

maintenance intravenous fluid administration in children. Cochrane Database Syst

Rev 2014;12:Cd009457.

88. Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in hospitalized

children: a systematic review and meta-analysis. J Pediatr 2014;165:163-69.e2.

89. Padua AP, Macaraya JR, Dans LF, et al. Isotonic versus hypotonic saline

solution for maintenance intravenous fluid therapy in children: a systematic review.

Pediatr Nephrol 2015;30:1163-72.

90. Cotton BA, Guy JS, Morris JA, Jr., et al. The cellular, metabolic, and systemic

D
consequences of aggressive fluid resuscitation strategies. Shock 2006;26:115-21.

91.
TE
Kozek-Langenecker SA. Fluids and coagulation. Curr Opin Crit Care

2015;21:285-91.
EP
92. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a

worse outcome in patients with acute renal failure. Crit Care 2008;12:R74.
C

93. Acheampong A, Vincent JL. A positive fluid balance is an independent

AC

prognostic factor in patients with sepsis. Crit Care 2015;19:251.

94. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African
ST

children with severe infection. N Engl J Med 2011;364:2483-95.

95. Maitland K, George EC, Evans JA, et al. Exploring mechanisms of excess
JU

mortality with early fluid resuscitation: insights from the FEAST trial. BMC Med

2013;11:68.