Crystalloids Versus Colloids: Exploring Differences

in Fluid Requirements by Systematic Review and

Meta-Regression
Diego Orbegozo Cortés, MD, Teresa Gamarano Barros, MD, Hassane Njimi, MSc, PhD,
and Jean-Louis Vincent, MD, PhD

BACKGROUND: Positive fluid balance has been associated with worse outcomes, and knowledge
of differences in the amounts of different types of fluid needed to achieve the same end points
may have important clinical implications. Large molecules persist longer in the blood vessels
than smaller molecules, such that less IV colloid may be needed to achieve similar hemody-
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namic end points compared with crystalloid. Recent clinical data have, however, challenged this
physiological concept, with investigators reporting lower-than-expected crystalloid/colloid ratios
in various populations.
METHODS: We performed a systematic search in MEDLINE, EMBASE, and CENTRAL up to December
18, 2013, to retrieve all studies comparing (any) crystalloid with (any) colloid in all types of patients.
The crystalloid/colloid ratio was calculated for each study. Descriptive analysis was performed for
all studies, and a meta-analysis was performed in those studies reporting full data (in terms of
means and standard deviations) of infused fluid volumes. Studies were grouped according to study
and population characteristics. A meta-regression analysis was then performed to evaluate some
of the possible reasons for differences in crystalloid/colloid ratios across studies.
RESULTS: From 976 studies, 48 were retained for the final analysis; 24 of the studies had
sufficient data for meta-analysis. The crystalloid/colloid ratio across all the studies included
in the meta-analysis was 1.5 (95% confidence interval, 1.36–1.65) with marked heterogeneity
among studies (I2 = 94%). From the meta-regression analysis, decade of publication across all
publications (P = 0.001) and concentration (tonicity) in the subgroup of albumin studies (P =
0.001) were associated with the administered crystalloid/colloid ratio. The reduction in hetero-
geneity among studies for all publications in the meta-regression was minimal, with the maximal
decrease obtained when decade of publication was considered (R2 = 12%).
CONCLUSIONS: Greater fluid volumes are required to meet the same targets with crystalloids than
with colloids, with an estimated ratio of 1.5 (1.36–1.65), but there is marked heterogeneity among
studies. The crystalloid/colloid ratio seems to have decreased over the years, and differences
in ratios are correlated with the concentration of albumin solutions; however, the main reasons
behind the high heterogeneity among studies remain unclear.  (Anesth Analg 2015;120:389–402)

B
ecause of their large molecular weight (MW) and dif-
ficulty crossing the endothelium, colloid solutions
are expected to remain in the intravascular space
longer than crystalloids. One would therefore anticipate
that less colloid would need to be administered than crys-
talloid to achieve the same end points. Data from animal
studies and healthy volunteers strongly support such a
concept.1,2 In a recent animal study, Bansch et al.1 infused
Ringer’s acetate solution or 5% albumin in a ratio of 4.5
to 1.0 for resuscitation of rats undergoing hemorrhage or
with sepsis: the plasma volume-expanding effect was the
same for the 2 solutions after 2 and 4 hours of follow-up.
Even when fluids are administered rapidly to avoid redis-
tribution of crystalloids into the interstitium, there are
From the Department of Intensive Care, Erasme Hospital, Université Libre
de Bruxelles, Brussels, Belgium.
Accepted for publication October 12, 2014.
Funding: No external funding.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Jean-Louis Vincent, MD, PhD, Department of In-
tensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Len-
nik 808, 1070 Brussels. Address e-mail to jlvincen@ulb.ac.be.
Copyright © 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000564
important differences. In healthy volunteers, McIlroy and
Kharasch2 created moderate hypovolemia by withdraw-
ing 900 mL of blood and thereafter infused 1 L of Ringer’s
solution or 6% hetastarch over 5 to 7 minutes: the hetas-
tarch solution was associated with an intravascular vol-
ume expansion effect twice as large as that of crystalloid
solution at the end of the bolus.
This long-held theory has, however, been challenged by
some experts, especially in view of recent trials, in which
there was no large difference between the amounts of col-
loid and crystalloid solutions administered.3–9 There are
several possible reasons for the differences in crystalloid/
colloid ratios reported in the various studies. First, the study
populations are different; for example, capillary leakage
with fluid losses into the interstitium, as in sepsis, may limit
the vascular effects of colloids and reduce the normal crys-
talloid/colloid ratio. Second, fluid administration is now
started earlier so that by the time patients are enrolled in a
study, they may have already received a significant amount
of fluid, complicating the calculation of a crystalloid/colloid
ratio. Third, the studied fluids may be different; albumin,
starches, gelatins, and dextrans have different pharmaco-
kinetic properties, different effects on the glycocalyx and
microcirculation, and different effects on plasma expansion.
Fourth, the ratio may vary according to the time at which

February 2015 • Volume 120 • Number 2 www.anesthesia-analgesia.org 389

Crystalloids Versus Colloids: Different Fluid Requirements
it is measured; for example, many study protocols allow
for additional crystalloid to be administered once maximal
doses of colloid have been used so that a calculation at this
time point will reflect a crystalloid to mixed crystalloid +
colloid ratio rather than a pure crystalloid/colloid ratio.
Similarly, the ratio may vary according to the end point cho-
sen to assess the effect of fluid administration.
Several studies have already shown that a positive fluid
balance can worsen outcomes in hospitalized patients,
especially when congestive heart failure or renal dysfunc-
tion is present,10,11 so information regarding differences in
the amounts of different types of fluids needed to achieve
the same end points is important when considering which
fluid(s) to administer in clinical practice. We, therefore,
performed a systematic literature review to evaluate the
reported crystalloid/colloid ratios in clinical studies com-
paring these types of fluids. We also performed a meta-
regression to attempt to unravel some of the possible
reasons for the observed differences.
METHODS
We systematically searched MEDLINE, EMBASE, and
CENTRAL until December 18, 2013, for all studies compar-
ing any crystalloid versus any colloid for fluid replacement.
A highly sensitive search was built using indexed terms in
each database, filtered to human studies in adult popula-
tions, as described in the Appendix. We did not limit our
searches by date or language. We also examined the reference
lists of included studies and previously published reviews to
insure no studies had been missed. Articles were excluded if
they included burn patients; involved preoperative volume
loading or normovolemic hemodilution, fluid administra-
tion during paracentesis, or fluids given by formula (with an
already set ratio); evaluated healthy volunteers; or evaluated
only priming for cardiac surgery. Papers that had later been
retracted also were excluded. When 2 articles presented the
same set of data, we used the most detailed report.
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Two authors read the titles and abstracts of reports iden-
tified by the search to produce a list of possibly relevant arti-
cles and checked the list to determine which articles fit the
inclusion criteria. After reading the full text of preselected
articles, any disagreements were resolved after consulta-
tion with a third author. Data were extracted to prespecified
tables considering year and decade of publication, number
of subjects, characteristics of the administered solutions,
and study design. Articles were classified as randomized
controlled trials (RCTs) or not.
Studies were grouped into 5 categories according to
the studied population: severe sepsis/septic shock; other
cause of shock; cardiovascular surgery; other surgery; and
mixed populations. Because some studies had resuscitation
protocols for periods of instability along with concomitant
maintenance administration of other fluids, we classified
studies into those that evaluated acute resuscitation with
strict protocols and those that did not. An additional classi-
fication was made, separating studies according to whether
they reported the infused volumes less than or more than
12 hours after randomization. Studies also were grouped
into those that incorporated a measure of preload (central
venous pressure [CVP], pulmonary artery occlusion pres-
sure, left atrial pressure) or not in their protocols. A final
classification was made to evaluate the possible role of
observer bias, classifying studies as double-blinded or not.
For studies that included albumin, a separate categoriza-
tion was made considering the concentration of the solu-
tions and, similarly, studies of HES solutions were classified
according to the MW of the HES, with low MW considered
as MW ≤130 kDa and high MW as >130 kDa. The quality of
the studies was evaluated using the Jadad score.
We used a pragmatic approach, recording the total
amount of infused fluid used in each cohort (colloids +
crystalloids versus crystalloids) for analysis because the
majority of articles did not make a distinction between these
groups and because in clinical practice colloids generally
Figure 1. Flowchart of selection process for
included articles.
anesthesia & analgesia
  

Table 1.  Studies with Cohorts Comparing Crystalloid and Albumin Solutions

Study, Volume crystalloid Volume colloid
publication Jadad Double Concentration cohort, mean ± SD cohort, mean ± SD
date RCT score blinded of albumin (%) Population Indication Characteristics Subjects Comparison or [median] or [median] Ratio
Lowe et al., Yes 3 No 5 Surgery Mixed Resuscitation and maintenance 141 RL 5370 ± 3380 5870 ± 3050 0.91
197727 pre- and intraoperatively
Shah et al., Yes 3 No 5 Other shock Resuscitation Fluid resuscitation guided by 17 RL 14,600 ± 400 7100 2.06
197728 LVSWI and PAOP
Virgilio et al., Yes 2 No 5 Cardiac surgery Mixed Intraoperative volume guided to 29 RL 5800 ± 2240 3400 ± 1940 1.82
197918 PAOP, CI, BE, and diuresis
Moss et al., Yes 2 No 4 Other shock Resuscitation Initial resuscitation guided by 36 RL [8800] [8600] 1.02
198129 HR, diuresis, and SBP
Shires et al., Yes 1 No 5 Cardiac surgery Mixed Liquids administered 18 RL 8400 ± 600 4800 ± 900 1.75
198319 intraoperatively guided by
CO, PAOP, and urinary output.
Data after 24 h

February 2015 • Volume 120 • Number 2

Rackow et al., Yes 1 No 5 Other shock Resuscitation Resuscitation with boluses 17 NS 3906 ± 2676 1083 ± 636 3.61
198331 until PAOP of 15 mm Hg
Metildi et al., Yes 2 No 5 Heterogeneous Mixed Maintenance of volume status 46 RL 12,500 ± 11,300 9400 ± 3000 1.33
198412 guided by PAOP over 48 h
Metildi et al.,a Yes 2 No 5 Sepsis Mixed Maintenance of volume status 24 RL 17,900 ± 13,600 10,400 ± 3100 1.72
198412 guided by PAOP over 48 h
Weisel et al., Yes 1 No Plasma Cardiac surgery Mixed Resuscitation and maintenance 27 RL 14,500 ± 11,600 6500 ± 6900 2.23
198420 guided by LAP in 3 d
Gallagher et al., Yes 2 No 5 Cardiac surgery Mixed Liquid administered to maintain 10 RL 3110 ± 736 3313 ± 897 0.94
198521 adequate PAOP in around 17
h after surgery
Hankeln et al.,b No – – 20 Other shock Resuscitation Crossover design. 221 25 RL 789 ± 812 175 ± 216 4.51
198813 measurements in 25
patients under resuscitation
guided by PAOP
Hankeln et al., No – – 5 Other shock Resuscitation Crossover design. 221 25 RL 789 ± 812 325 ± 448 2.43
198813 measurements in 25
patients under resuscitation
guided by PAOP
Prien et al., Yes 0 No 20 Surgery Mixed Liquids infused to maintain CVP 12 RL 4608 ± 1531 972 ± 438 4.74
199033
McNulty et al., Yes 2 No 5 Cardiac surgery Mixed Maintenance after 28 PL 1093 ± 465 930 ± 373 1.18
199322 extracorporeal circulation
Pockaj et al., Yes 3 No 5 Other shock Mixed Infusion over days with episodes 107 NS 9500 ± 6600 7700 ± 5100 1.23
199434 of instability to maintain SBP,
diuresis, and HR
Tølløfsrud et al., Yes 2 No 4 Cardiac surgery Mixed Boluses during surgery to correct 20 RA 1483 ± 754 685 ± 330 2.16
199514 MAP, PAOP, and diuresis
Ernest et al., Yes 1 No 5 Sepsis Resuscitation Boluses to achieve adequate 18 NS 18.6 ± 9.2 10.5 ± 5.3 1.77
199915 PAOP <60 min. Data as
mL/kg
Ernest et al., Yes 1 No 5 Cardiac surgery Resuscitation Boluses to achieve adequate 40 NS 16 ± 6 8±3 2.00

www.anesthesia-analgesia.org
200124 PAOP under 60 min. Data
as mL/kg

391
(Continued)
Crystalloids Versus Colloids: Different Fluid Requirements

are administered along with some crystalloid. When this

RCT = randomized controlled trial; SD = standard deviation; RL = Ringer’s lactate; LVSWI = left ventricular stroke work index; PAOP = pulmonary artery occlusion pressure; CI = cardiac index; BE = base excess; HR =
heart rate; SBP = systolic blood pressure; CO = cardiac output; NS = normal saline 0.9%; LAP = left atrial pressure; CVP = central venous pressure; PL = plasmalyte; MAP = mean arterial blood pressure; RA = Ringer’s
Ratio
1.30

1.09

0.89

1.22

1.10
value was not given directly, we calculated it by adding the
mean values for each fluid, but it was then not possible to
calculate the standard deviations. The ratio was then cal-
cohort, mean ± SD

culated as the ratio of total infused fluid in the 2 cohorts.

8500 ± 4900
Volume colloid

1467 ± 308

1492 ± 380
or [median]

We recorded the earliest values for volume of infused fluids

[1650]
NA

reported in each study, because over longer periods, colloid

infusion often is restricted and combined with crystalloids,
which tends to underestimate the real effect of the colloids.

Statistical Analysis
cohort, mean ± SD
Volume crystalloid

All studies were considered for descriptive purposes and

7600 ± 4900
or [median]

1642 ± 387
1783 ± 41

initial exploration of data. Meta-analysis for RCTs that

[1800]
NA

reported complete data for fluid volumes in terms of means

and standard deviations was performed. The crystalloid/
colloid ratio was used as the summary measure, taking into
consideration the variability in the units used to report the
Subjects Comparison

infused volume (mL, mL/kg, mL/kg/h). The pooled-ratio

NS

NS

OC

NS

NS

and its 95% confidence interval were calculated using the

DerSimonian and Laird random effects model, considering
the large heterogeneity in study design. Heterogeneity was
evaluated with the Q Cochrane statistic and the I2 index,
6933

34

232

12

12

which provides an approximation of the proportion of total

variability in point estimates that can be attributed to het-
erogeneity. To offset the fact that the statistical power of the
Administered liquids over 36 h

heterogeneity test may be low, we tested the homogeneity

considered by intensivist
Cardiac surgery Resuscitation Protocol guided by CVP and
resuscitation periods as

for different indications

Resuscitation Boluses in 90 min guided

Resuscitation Boluses in 90 min guided

Fluid administered during

hypothesis at the 10% level.

Characteristics

We conducted a meta-regression analysis to examine the

PAOP over 90 min

association of treatment effect with some of the reported study

characteristics and hence to investigate which study character-
istics could explain the heterogeneity found in the main meta-
by CVP

by CVP

analysis. Each considered predictor variable (type of solution,

decade and year of publication, type of population, time of
assessment less than or more than 12 hours after resuscita-
tion, presence or not of a clear resuscitation protocol, doubled-
Indication

blinded or not, use of a preload target for fluid administration)

was tested independently in the model. The between-study
Mixed

Mixed

acetate; NA = not available; OC = other crystalloid or a mixture of different crystalloids.

variability was estimated by the R2, which can be regarded as

the amount of (residual) heterogeneity in the reduced model
Heterogeneous

that can be explained by the presence of the predictor in the

Population

Other shock

Other shock

full model. All reported P values are 2-sided, and a P value of

<0.05 was considered statistically significant, unless otherwise
Sepsis

indicated. Statistical analyses were performed using R statisti-

All infused volumes are in milliliters unless otherwise specified.

cal software (version 3.0.1, R Foundation, Vienna, Austria).

Jadad Double Concentration

RESULTS
(%)
4

20

A total of 976 publications were identified, and 48

met our inclusion criteria (Fig.  1),3–9,12–52 present-
Subgroup of septic patients from whole cohort.

ing data on 71 different comparisons between col-

RCT score blinded

loid and crystalloid cohorts. The earliest trial was from

Yes

No

No

No
–

1977,27 and the most recent from November 2013.52

Of the 48 articles, 43 were RCTs.3–5,7–9,12,14–31,33–40,42–47,49–52
­Meta-analysis was performed only in the 36 cohorts (24
Table 1.  (Continued)

2
–

Subgroup of septic patients.

­articles4,7,12,14–22,24,27,31,33,34,36,39,42,45,46,50,51) that presented full

Yes

Yes

Yes

Yes

mean and standard deviation data in both groups.

No

Hyperoncotic albumin.

The end points used to guide fluid administration dif-

fered among the studies and included heart rate, mean arte-
Verheij et al.,
Finfer, 20049

rial blood pressure, systolic arterial pressure, serum lactate

publication

Schortgen,

Trof et al.,c

Trof et al.,
200625

200841

201042

201042

levels, base excess, CVP, left atrial pressure, pulmonary

Study,

artery occlusion pressure, cardiac index, stroke volume,

date

left ventricular stroke work index, central venous oxygen

b
a

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Table 2.  Studies with Cohorts Comparing Crystalloid and Starch Solutions

Mol. weight/ Volume crystalloid Volume colloid
Jadad Double mol. subst./ cohort, mean ± SD cohort, mean ± SD
Author RCT score blinded concentration Source Population Indication Characteristics Subjects Comparison or [median] or [median] Ratio
Rackow et al., Yes 1 No 450/0.7/6 Corn Other shock Resuscitation Resuscitation with boluses 17 NS 3906 ± 2676 1639 ± 1239 2.38
198331 until PAOP of 15 mm Hg
Macintyre Yes 0 No 450/0.7/6 Corn Surgery Mixed Volume infused during 20 OC 2720 3070 0.89
et al., surgery
198530
Gallagher Yes 2 No NA/NA/6 NA Cardiac Mixed Liquid administered to 10 RL 3110 ± 736 3708 ± 873 0.84
et al., surgery maintain adequate
198521 PAOP in around 17 h
after surgery
Hankeln No – – 450/0.7/6 Corn Other shock Resuscitation Crossover design. 221 25 RL 789 ± 812 459 ± 972 1.72
et al.,a measurements in
198813 25 patients under

February 2015 • Volume 120 • Number 2

resuscitation guided by
PAOP
Hankeln et al., No – – 200/0.5/10 Corn Other shock Resuscitation Crossover design. 221 25 RL 789 ± 812 465 ± 1015 1.70
198813 measurements in
25 patients under
resuscitation guided by
PAOP
Hankeln et al., No – – NA/NA/10 Corn Other shock Resuscitation Crossover design. 44 15 RL 800 ± 704 480 ± 610 1.67
198932 measurements in
15 patients under
resuscitation guided by
PAOP
Prien et al., Yes 0 No 200/0.5/10 Corn Surgery Mixed Liquids infused to maintain 12 RL 4608 ± 1531 2320 ± 671 1.99
199033 CVP
Marik et al., Yes 2 No 450/0.7/6 NA Cardiac Mixed Fluids administered to 30 RL 4577 ± 1112 3775 1.21
199723 surgery maintain PAOP during
surgery
Younes et al., Yes 2 No 260/0.5/10 NA Other shock Resuscitation Boluses for resuscitation 23 NS 1420 ± 298 356 ± 64 3.99
199836 until MAP was restored
Bothner Yes 2 No 200/0.5/6 Corn Surgery Mixed Liquids administered 481 RL 1349 ± 447 1328 1.02
et al.,b during surgery
199837
Bothner et al., Yes 2 No 200/0.5/6 Corn Surgery Mixed Liquids administered 488 RL 1349 ± 447 1386 0.97
199837 during surgery
Yorozu et al., Yes 1 No 70/0.5/NA Corn Surgery Mixed Maintenance during 67 RL 1298 ± 503 973 ± 339 1.33
200239 surgery
Moretti et al., Yes 3 No 550/0.7/6 Corn Surgery Mixed Protocol with boluses 60 RL 5946 ± 1909 4351 1.37
200338 guided by HR, SAP, CVP,
and diuresis surgery
Moretti et al.,c Yes 3 No 670/0.7/6 Corn Surgery Mixed Protocol with boluses 60 RL 5946 ± 1909 4690 1.27
200338 guided by HR, SAP, CVP,
and diuresis surgery

www.anesthesia-analgesia.org
Verheij et al., Yes 3 No 200/0.5/6 Corn Cardiac Resuscitation Protocol guided by CVP 33 NS [1800] [1400] 1.29
200625 surgery and PAOP in 90 min
(Continued)

393
 Table 2.  (Continued)
Mol. weight/ Volume crystalloid Volume colloid
Jadad Double mol. subst./ cohort, mean ± SD cohort, mean ± SD

394   
Author RCT score blinded concentration Source Population Indication Characteristics Subjects Comparison or [median] or [median] Ratio
Ando et al., Yes 1 No 70/0.5/NA Corn Surgery Mixed Protocol guided by CVP 21 RA [4152] [3953] 1.05
200849 during surgery until 24 h
Brunkhorst, Yes 3 No 200/0.5/10 Corn Sepsis Mixed Protocol guided by CVP, 537 RL NA NA 1.58
20083 MAP, and ScvO2. Ratio
given at 24 h
Mittermayr Yes 3 No 130/0.4/6 Corn Surgery Mixed Maintenance and to treat 40 RL [3650] [1954] 1.87
et al., hypovolemia. Result
200840 over the first 90 min.
Trof et al.,d Yes 2 No 200/0.5/6 Corn Sepsis Resuscitation Boluses in 90 min guided 12 NS 1783 ± 41 1358 ± 344 1.31
201042 by CVP
Trof et al., Yes 2 No 200/0.5/6 Corn Other shock Resuscitation Boluses in 90 min guided 12 NS 1642 ± 387 1617 ± 172 1.02
201042 by CVP

www.anesthesia-analgesia.org
Dubin et al., Yes 3 No 130/0.4/6 Corn Sepsis Resuscitation Resuscitation with protocol 20 NS 8368 ± 2405 4682 ± 1371 1.79
201016 guided to MAP, Scvo2,
and CVP over 24 h
Magder et al., Yes 5 Yes 250/0.4/10 Corn Cardiac Resuscitation Boluses until stabilization 237 NS 1397 ± 1041 887 ± 546 1.57
20107 surgery guided by MAP, CI,
Crystalloids Versus Colloids: Different Fluid Requirements

diuresis, and CVP

Bayer et al., No – – 130/0.4/6 Corn Sepsis Mixed Standard treatment 258 OC [43] [19] 2.26
20116 of hypovolemia in
emergency department,
critical care, and
operating room over the
first 24 h in mL/kg
Zhu et al., Yes 1 No 130/0.4/NA NA Sepsis Resuscitation Protocol to restore 90 RL 3497 ± 326 2506 ± 276 1.40
201150 diuresis. Data at 6 h
Lee et al., Yes 2 No 130/0.4/6 Corn Cardiac Mixed Maintenance of volume 106 OC 8342 ± 1794 8152 1.02
20115 surgery status guided by CI,
Svo2, and urinary output
over 24 h
Lv et al., Yes 2 No 130/0.4/6 NA Sepsis Mixed Fluid administration 42 RL 3460 ± 730 2770 ± 590 1.25
201217 protocol during the first
24 h
Guidet, 20124 Yes 5 Yes 130/0.4/6 Corn Sepsis Resuscitation Liquids administered 174 NS 1709 ± 1164 1379 ± 886 1.24
until hemodynamic
stability guided by MAP,
CVP, Scvo2, and urinary
output in around 12 h
6S, 20128 Yes 5 Yes 130/0.4/6 Potato Sepsis Mixed Whenever volume 798 RA [3000] [3000] 1.00
expansion was needed
judged by intensivist
criteria
Myburgh, Yes 5 Yes 130/0.4/6 Corn Heterogeneous Mixed Fluid administered during 6742 NS 2590 1970 1.31
201243 resuscitation periods
as considered by
intensivist

anesthesia & analgesia

(Continued)
  

Table 2.  (Continued)
Mol. weight/ Volume crystalloid Volume colloid
Jadad Double mol. subst./ cohort, mean ± SD cohort, mean ± SD
Author RCT score blinded concentration Source Population Indication Characteristics Subjects Comparison or [median] or [median] Ratio
Bayer et al., No – – 130/0.4/6 Corn Sepsis Mixed Standard treatment of 679 OC [4.4] [2.75] 1.60

February 2015 • Volume 120 • Number 2

201248 hypovolemia over the
first 24 h in mL/kg/h
Topçu et al., Yes 2 No 130/0.4/6 Corn Surgery Mixed Fluids administered to 50 RL 3850 ± 1730 2850 ± 460 1.35
201245 normovolemia
Alavi et al., Yes 2 No 130/0.4/6 Corn Cardiac Mixed Fluids administration 61 RL 6100 ± 400 3500 ± 210 1.74
201246 surgery guided by CVP during
24 h
BaSES,e Yes 5 Yes 130/0.4/6 Corn Sepsis Mixed Intervention over 5 d for 241 RL [9895] [9129] 1.08
201347 maintaining adequate
volume status
Feldheiser Yes 5 Yes 130/0.4/6 Corn Surgery Resuscitation Protocol guided by SV 48 OC [5000] [3300] 1.52
et al.,
201344
Lindroos Yes 3 No 130/0.4/6 Corn Surgery Resuscitation Protocol guided by SV 28 RA 450 ± 156 343 ± 94 1.31
et al.,
201351
All infused volumes are in milliliters unless otherwise specified.
RCT = randomized controlled trial; mol. subst. = molar substitution; SD = standard deviation; PAOP = pulmonary artery occlusion pressure; NS = normal saline 0.9%; OC = other crystalloid or a mixture of different
crystalloids; RL = Ringer’s lactate; CVP = central venous pressure; MAP = mean arterial blood pressure; HR = heart rate; SAP = systolic arterial pressure; RA = Ringer’s acetate; Svo2 = mixed venous oxygen saturation;
Scvo2 = central venous oxygen saturation; NA = not available; CI = cardiac index; SV = stroke volume.
a
High-molecular-weight cohort.
b
Cohort of Hemohes compared with HAES-steril.
c
Diluted in not balanced crystalloid compared with a balanced crystalloid.
d
Subgroup of septic patients.
e
Data retrieved from published meta-analysis, definitive data not published yet.

www.anesthesia-analgesia.org
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 Table 3.  Studies with Cohorts Comparing Crystalloids with Gelatins, Dextran, or a Mixture of Colloids
Volume crystalloid Volume colloid
Jadad Double cohort, mean ± SD cohort, mean ±

396   
Author RCT score blinded Solution Population Indication Characteristics Subjects Comparison or [median] SD or [median] Ratio
Tølløfsrud et al., Yes 2 No D Cardiac Mixed Boluses during surgery to 20 RA 1483 ± 754 700 ± 275 2.12
199514 surgery correct MAP, PAOP, and
diuresis
Tølløfsrud et al., Yes 2 No G Cardiac Mixed Boluses during surgery to 20 RA 1483 ± 754 530 ± 535 2.80
199514 surgery correct MAP, PAOP, and
diuresis
Evans et al., Yes 1 No G Other shock Resuscitation Fluids given until stable vital 25 RL [2200] [1000] 2.20
199635 signs
Verheij et al., Yes 3 No G Cardiac Resuscitation Protocol guided by CVP and 32 NS [1800] [1800] 1.00
200625 surgery PAOP in 90 min
Mittermayr Yes 3 No G Surgery Mixed Maintenance and to treat 42 RL [3650] [2268] 1.61
et al., 200840 hypovolemia. Result over

www.anesthesia-analgesia.org
the first 90 min.
Soares et al., Yes 3 No G Cardiac Mixed Intraoperative volume 40 NS 50 ± 10 35 1.43
200926 surgery guided to CVP in mL/kg
Trof et al.,a Yes 2 No G Sepsis Resuscitation Boluses in 90 min guided 12 NS 1783 ± 41 1317 ± 240 1.35
201042 by CVP
Crystalloids Versus Colloids: Different Fluid Requirements

Trof et al., Yes 2 No G Other shock Resuscitation Boluses in 90 min guided 12 NS 1642 ± 387 1483 ± 422 1.11
201042 by CVP
Bayer et al., No – – G Sepsis Mixed Standard treatment 227 OC [43] [22] 1.95
20116 of hypovolemia in
emergency department,
critical care, and
operating room over the
first 24 h in mL/kg
Bayer et al., No – – G Sepsis Mixed Standard treatment of 728 OC [4.4] [3.95] 1.11
201248 hypovolemia over the first
24 h in mL/kg/h
Topçu et al., Yes 2 No G Surgery Mixed Fluids administered until 50 RL 3850 ± 1730 2530 ± 500 1.52
201245 normovolemia
Alavi et al., Yes 2 No G Cardiac Mixed Fluids administration guided 60 RL 6100 ± 400 5300 ± 380 1.15
201246 surgery by CVP during 24 h
postoperatively
Annane, 201352 Yes 0 No M Other shock Mixed Fluid administration 2857 OC [3000] [2000] 1.50
as determined by
intensivist criteria, except
maintenance solutions.
All infused volumes are in milliliters unless otherwise specified.
RCT = randomized controlled trial; SD = standard deviation; D = dextran; MAP = mean arterial blood pressure; PAOP = pulmonary artery occlusion pressure; RA = Ringer’s acetate; G = gelatin; RL = Ringer’s lactate; CVP
= central venous pressure; NS = normal saline 0.9%; OC = other crystalloid or a mixture of different crystalloids; M = mixture of different colloids.
a
Subgroup of septic patients.

anesthesia & analgesia

 

Figure 2. Ratio of all cohorts according to publication date and infused solution.*Subgroup of septic patients from whole cohort; ‡hypertonic
albumin; †high-molecular-weight cohort; £cohort of Hemohes compared with HAES-steril; &diluted in nonbalanced crystalloid compared with a
balanced crystalloid; ^subgroup of septic patients; §data retrieved from published meta-analysis, definitive data not published yet.

saturation (ScvO2), urine output, and even physician judg-
ment. The characteristics of the studies and the estimated
crystalloid/colloid ratios for the different types of colloids
are shown in Tables 1 to 3. A timeline showing the reported
ratios according to year of study publication is shown in
Figure 2. The older studies generally reported greater crys-
talloid/colloid ratios and more frequently used albumin
than the more recent studies. The crystalloid/colloid ratio
varied between 0.8941 and 4.7433 in 23 cohorts on albumin,
0.8421 and 3.9936 in 35 cohorts on starches, 1.0025 and 2.8014
in 11 cohorts on gelatins, 2.1214 in the 1 cohort on dextran,
and 1.50 in 1 cohort with a mixture of colloids.52 When con-
sidering the different study populations, the ratios varied
between 1.008 and 2.266 for severe sepsis/septic shock, 0.8941
and 4.5113 for other types of shock, 0.8421 and 2.8014 for car-
diac surgery, 0.8930 and 4.7433 for other surgery, and 1.309
and 1.5052 for heterogeneous.
Meta-Analysis of RCTs
The pooled crystalloid/colloid ratio in the RCTs included
in the meta-analysis was 1.50 (1.36–1.64) (Fig.  3), with
considerable heterogeneity seen among studies (Q = 605,
P < 0.001 and I2 = 94%). Meta-regression was performed for
all the categories detailed earlier, and the estimated ratios
are shown in Table 4. There were statistically significant dif-
ferences in the crystalloid/colloid ratio according to decade
of publication when considering all the studies and accord-
ing to concentration for the albumin studies. There were
no significant differences according to type of solution,
indication for fluid, studied population, use of a preload
target to guide fluid administration, double blinding, or
time of assessment. None of the explored variables substan-
tively decreased the heterogeneity from the general model
(Table 4). The estimated decrease in the ratio over time was
1% (95% confidence interval, 0%–3%) per year, but this find-
ing was not statistically significant (P = 0.16) (Fig. 4).
DISCUSSION
Our review supports the physiologic concept of reduced
fluid requirements when using colloid compared with crys-
talloid solutions. Experimental data in humans have dem-
onstrated that colloids have a more prolonged effect in the
intravascular compartment compared to crystalloids.2,53
Svensén and Hahn53 demonstrated that the intravascular
expansion from Ringer’s acetate solution decreased rapidly
by >65% at 30 minutes after the end of the fluid infusion,
whereas the effect of 6% dextran 70 remained stable for >2
hours. In our review, the ratio of the total amount of crys-
talloid compared with colloid received to achieve hemo-
dynamic targets was substantially >1 in most studies, and
the global ratio calculated from the RCT data was 1.5. This
finding must be interpreted from a clinical practice point
of view, in which patients who receive colloids usually also
receive crystalloids to complete fluid resuscitation. Indeed,
in studies in which authors evaluated the infused volumes
<12 hours after randomization, when fluid administration

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Crystalloids Versus Colloids: Different Fluid Requirements
Figure 3. Forest plot of calculated mean ratios from each randomized controlled trial (RCT) included in the meta-analysis.
was still largely restricted to the study fluid, crystalloid/
colloid ratios were greater than those that evaluated the
volumes later when crystalloids had generally been added
to the colloid regimes (1.59 vs 1.35). The observation that
larger quantities of crystalloid than colloid were needed
was true for all patient groups, including those with sepsis,
suggesting that the permeability alterations associated with
sepsis are not associated with complete leak of large mol-
ecules outside the vessels.
Some recent studies have reported no major differences
in the amounts of colloids and crystalloids required3,8;
therefore, doubts have been raised regarding the concept
that larger volumes of crystalloids than colloids are needed
to achieve the same end points. By the time patients were
randomized to one type of fluid versus another in these
studies, however, they had already received a significant
amount of fluid: In the VISEP (i.e., Volume Substitution
and Insulin Therapy in Severe Sepsis) study,3 for example,
patients had already received a median of 2000 mL of crys-
talloid plus 725 mL of colloids in the crystalloid group and
2000 mL of crystalloid plus 979 mL of colloid in the HES
group; the CVP was 12 mm Hg, ScvO2 75%, and lactate 2.2
mEqL at baseline, suggesting a degree of fluid resuscitation
had already been achieved. In the 6S study,8 CVP 10 (7–13)
mm Hg, ScvO2 75%, and lactate 2.0 mEqL were reported at
398   
www.anesthesia-analgesia.org
baseline. Our data show that the crystalloid/colloid ratio
has tended to decrease over the years (Fig.  2), possibly
because fluid administration is being started earlier than in
the past, such that patients already had received more fluid
at the time of inclusion in the more recent studies compared
with older trials.
Experimental data in humans have suggested differ-
ent intravascular volume expansion effects with different
colloid solutions.54 In general in our review, crystalloid/
colloid ratios were greater for albumin than for syn-
thetic colloids, and especially gelatins. This finding may
not be too surprising for gelatins, with an MW of only
30 to 35,000, that is, about one-half the MW of albumin.
Moreover, although there may be some degree of albu-
min extravasation from the intravascular compartment,55
interventional studies have shown an increase in albu-
min levels when albumin is administered to critically ill
patients, including those with more severe permeability
alterations,56 suggesting that albumin may remain more
in the intravascular space than other solutions and thus
reduce the total amount of fluid needed. Nevertheless,
the meta-regression suggests that the type of fluid per se
(starch versus albumin versus gelatin) does not influence
the crystalloid/colloid ratio, although the concentration
of albumin did have an effect.
anesthesia & analgesia
 

Table 4.  Estimation of the Global Effect of the Crystalloid/Colloid Ratio and Correlations with Different
Categories from Meta-Regression of RCT Data
Calculated ratio Residual heterogeneity Comparisons
Ratio (95% confidence I2 (95% confidence
n interval), P Q (df), P interval) R2 P
Type of solution 36 384 (33), <0.001 93 (91–98) 6% 0.688
 Albumin 16 1.55 (1.33–1.79), <0.001 Ref
 Starches 15 1.50 (1.31–1.71), 0.013 0.751
 Gelatin 5 1.36 (1.07–1.74), <0.001 0.387
Decade 36 501 (32), <0.001 94 (93–98) 12% 0.001
 2010–2013 16 1.33 (1.17–1.50), <0.001 Ref
 2000–2009 2 1.62 (1.13–2.31), <0.001 0.306
 1990–1999 8 2.17 (1.76–2.68), 0.008 <0.001
  Before 1989 10 1.41 (1.17–1.71), <0.001 0.598
Population 36 571 (31), <0.001 95 (94–98) 0% 0.884
 Sepsis 9 1.41 (1.15–1.72), 0.001 Ref
  Other shock 7 1.66 (1.29–2.13), <0.001 0.319
  Cardiac surgery 12 1.51 (1.25–1.81), <0.001 0.623
  Other surgery 7 1.54 (1.22–1.95), <0.001 0.558
 Heterogeneous 1 1.33 (0.68–2.62), <0.409 0.878
Indication 36 605 (34), <0.001 94 (94–98) 0% 0.611
 Resuscitation 16 1.55 (1.33–1.81), <0.001
 Mixed 20 1.47 (1.27–1.69), <0.001
Double blinded 36 605 (34), <0.001 95 (94–98) 0% 0.714
 No 34 1.50 (1.36–1.66), <0.001
 Yes 2 1.40 (0.96–2.03), 0.079
Time assessment 36 605 (34), <0.001 94 (94–98) 0% 0.150
  <12 h 24 1.59 (1.40–1.81), <0.001
  >12 h 12 1.35 (1.13–1.61), <0.001
Preload target 36 605, (34), <0.001 95 (94–98) 0% 0.504
 No 10 1.43 (1.19–1.72), <0.001
 Yes 26 1.54 (1.36–1.75), <0.001
HES molecular weighta 14 234, (12), <0.001 95 (94–99) 0% 0.086
 Low 8 1.41 (1.19–1.68), <0.001
 High 6 1.80 (1.45–2.24), <0.001
Albumin concentrationa 15 69, (13), <0.001 81 (64–95) 31% 0.001
 Low 14 1.44 (1.22–1.71), <0.001
 High 1 4.74 (2.34–9.58), <0.001
Q Cochrane and I2 represent heterogeneity for the global estimation and the residual heterogeneity after meta-regression in each category; R2 represents the
reduction in the between study heterogeneity attributable to the studied variable; P values for comparisons across each category are presented in bold letters;
and other P values represent comparisons within the reference subgroup.
Ref = reference category for comparisons.
a
Analysis performed only in the subgroup specified and not considering the whole population.

studies,21,27,30,37 but also in the CRYstalloids or COlloids

Figure 4. Calculated crystalloid/colloid ratios over time. Dotted
lines represent 95% confidence interval (CI).
Inverse ratios, in which the amount of colloid used was
larger than that of crystalloids, were seen largely in older
(CRYCO) study published in 2008.41 Nevertheless, although
the CRYCO study included a large number of patients, it was
a cohort, noninterventional study so that the groups were
not randomized, which limits the interpretation of the ratio
in this study.
This review has several limitations, including the hetero-
geneity of the study types and patient populations (includ-
ing preoperative and postoperative patients), numbers of
patients enrolled, objectives, designs, different protocols,
and end points for fluid administration, fluid challenge,
and shock (fluid resuscitation), which made it difficult to
compare the studies. This is confirmed by the fact that in
the meta-regression none of the investigated covariates
reduced the heterogeneity between studies to any extent
so that explanatory factors could not be identified, and are
likely related to differences in study design that cannot be
quantified from the available published data. Moreover,
the concomitant administration of crystalloids in the col-
loid cohorts leads to an underestimation of the real volume
expansion power of colloids but reflects the situation in clin-
ical practice where crystalloids generally are administered

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Crystalloids Versus Colloids: Different Fluid Requirements
with colloids. Finally, most of the studies did not present
data for total infused volumes in each cohort as means and
standard deviations, or the data were not complete so we
were unable to include many studies, including some of the
larger ones, in the meta-regression analysis. Thus, extrapo-
lation of our results to other groups of critically ill patients
is limited.
In conclusion, however, our literature review confirms,
in a clinical context, the basic physiological concept that less
colloid than crystalloid needs to be administered to achieve
the same hemodynamic end points. Reported crystalloid/
colloid ratios are quite variable, largely related to the het-
erogeneity of study populations and the amounts of crystal-
loid administered concomitantly with colloid. E
DISCLOSURES
Name: Diego Orbegozo Cortés, MD.
Contribution: This author helped design the study, perform the
literature search and synthesis, and prepare the manuscript.
Attestation: Diego Orbegozo Cortés attests to having approved
the final manuscript and to the integrity of the original data and
the analysis reported in this manuscript.
Name: Teresa Gamarano Barros, MD.
Contribution: This author helped design the study, perform the
literature search and synthesis, and prepare the manuscript.
Attestation: Teresa Gamarano Barros attests to having approved
the final manuscript, attests to the integrity of the original data and
the analysis reported in this manuscript, and is the archival author.
Name: Hassane Njimi, MSc, PhD.
Contribution: This author performed all statistical analyses
and helped interpret the data.
Attestation: Hassane Njimi attests to having approved the final
manuscript.
Name: Jean-Louis Vincent, MD, PhD.
Contribution: This author helped design the study and criti-
cally review the manuscript.
Attestation: Jean-Louis Vincent attests to having approved the
final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
Appendix
SEARCH SYNTAX
Date: December 18, 2013:
PUBMED
(“Colloids”[Mesh] OR “Starch”[Mesh] OR “Gelatin”[Mesh]
OR “Albumins”[Mesh] OR “Dextrans”[Mesh]) AND (“crys-
talloid solutions”[Supplementary Concept] OR “Isotonic
Solutions”[Mesh]) AND (“humans”[MeSH Terms] AND
“adult”[MeSH Terms])
336 articles
EMBASE
‘colloid’/exp OR ‘starch’/exp OR ‘hetastarch’/exp OR
‘gelatin’/exp OR ‘dextran’/exp OR ‘albumin’/exp AND
(‘crystalloid’/exp OR ‘isotonic solution’/exp) AND ([adult]/
lim OR [aged]/lim) AND [humans]/lim AND [embase]/lim
435 articles
CENTRAL
Crystalloid AND Colloid as Key-terms filtered by Trials
205 articles
400   
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