Article

Chevret S, for the CI. Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock: The CRISTAL Randomized Trial

Raymond Poincaré Hospital, Garches, France.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 10/2013; DOI: 10.1001/jama.2013.280502
Source: PubMed

ABSTRACT

Importance
Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear.Objective
To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock.Design, Setting, and Participants
A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012.Interventions
Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay.Main Outcomes and Measures
The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy.Results
Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, −0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, −0.04 to 2.10] days; P = .03).Conclusions and Relevance
Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.Trial Registration
clinicaltrials.gov Identifier: NCT00318942

Full-text

Available from: Fekri Abroug
Effects of Fluid Resuscitation With Colloids vs Crystalloids
on Mortality in Critically Ill Patients Presenting
With Hypovolemic Shock
The CRISTAL Randomized Trial
Djillali Annane, MD, PhD; Shidasp Siami, MD; Samir Jaber, MD, PhD; Claude Martin, MD, PhD; Souheil Elatrous, MD; Adrien Descorps Declère, MD;
Jean Charles Preiser, MD; Hervé Outin, MD; Gilles Troché, MD; Claire Charpentier, MD; Jean Louis Trouillet, MD; Antoine Kimmoun, MD;
Xavier Forceville, MD, PhD; Michael Darmon, MD; Olivier Lesur, MD, PhD; Jean Régnier, MD; Fékri Abroug, MD; Philippe Berger, MD;
Christophe Clech, MD; Joël Cousson, MD; Laure Thibault, MD; Sylvie Chevret, MD, PhD; for the CRISTAL Investigators
IMPORTANCE
Evidence supporting the choice of intravenous colloid vs crystalloid solutions
for management of hypovolemic shock remains unclear.
OBJECTIVE To test whether use of colloids compared with crystalloids for fluid resuscitation
alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock.
DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial stratified by case
mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids
Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but
outcome assessment was blinded to treatment assignment. Recruitment began in February
2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France,
Belgium, North Africa, and Canada; follow-up ended in November 2012.
INTERVENTIONS Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20%
of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lac tate solution)
for all fluid interventions other than fluid maintenance throughout the ICU stay.
MAIN OUTCOMES AND MEASURES The primary outcome was death within 28 days. Secondary
outcomes included 90-day mortality; and days alive and not receiving renal replacement
therapy, mechanical ventilation, or vasopressor therapy.
RESULTS Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths
(27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90
days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids
group (RR, 0.92 [95% CI, 0.86 to 0 .99]; P = .03). Renal replacement therapy was used in 156
(11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03];
P = .19). There were more days alive without mechanical ventilation in the colloids group vs the
crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI,
0. 0 9 to 0 .48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10
[95% CI, 0.14 to 2. 06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5. 0
vs 4.7 days; mean difference, 0 .30 [95% CI, −0 .03 to 0.50] days; P = . 04) and by 28 days
(mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, −0.04 to 2.10] days; P = .03).
CONCLUSIONS AND RELEVANCE Among ICU patients with hypovolemia, the use of colloids vs
crystalloids did not result in a signif icant difference in 28-day mortality. Although 90-day
mortality was lower among patients receiving colloids, this finding should be considered
exploratory and requires further study before reaching conclusions about efficacy.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942
JAMA. doi:10.1001/jama.2013.280502
Published online October 9, 2013.
Editorial
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Djillali
Annane, MD, PhD, University of
Versailles, 104 Blvd Raymond
Poincaré, 92380 Garches, France
(djillali.annane@rpc.aphp.fr).
Research
Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT
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T
housands of patients in intensive care units (ICUs)
throughout the world are treated with fluid therapy to
restore effective blood volume and ensure optimal or-
gan perfusion.
1,2
Fluid therapy includes a broad variety of prod-
ucts that are typically categorized as crystalloids and col-
loids. Although the goal is to use intravenous fluids to expand
the intravascular space, fluid also moves into the extravascu-
lar space. Crystalloids are thought to counteract that move-
ment via the osmotic pressure exerted by their solutes, whereas
colloids are designed to exploit oncotic pressure gradients for
the same effect.
2
Thus, theoretically, expansion of blood vol-
ume may be proportional to solute tonicity or oncotic power.
The crystalloid family includes isotonic and hypertonic so-
lutions that are also categorized into nonbuffered (eg, isotonic
saline) and buffered solutions (eg, Ringer lactate, acetate, ma-
leate). The colloid family includes hypooncotic (eg, gelatins, 4%
or 5% of albumin) and hyperoncotic (eg, dextrans, hydroxy-
ethyl starches, and 20% or 25% of albumin) solutions. Gener-
ally, colloid solutions are thought to be more efficient than crys-
talloids in terms of the amount of fluid that remains in the
intravascular space,
2
and so less fluid is required when using col-
loids vs crystalloids to achieve similar hemodynamic goals.
3,4
However, there are other effects of these fluids, including al-
terations to the immune response to critical illness.
1,2
Addition-
ally, there is concern that hydroxyethyl starches may increase
the risk of death or acute kidney injury.
5,6
Most colloid solu-
tions are also more expensive than crystalloids.
In recent studies of general ICU patient populations, fluid
replacement with 5% of albumin
7
or with 6% of hydroxyethyl
starch
4
showed similar effects on mortality compared with iso-
tonic saline. Although there was a suggestion that the subset
of patients with severe sepsis might benefit from resuscita-
tion with albumin,
8
the current Surviving Sepsis Campaign
guidelines recommended crystalloids as the preferred fluid
therapy and against the use of hydroxyethyl starches.
9
The Colloids Versus Crystalloids for the Resuscitation of
the Critically Ill (CRISTAL) trial was designed to test whether
colloids altered mortality compared with crystalloids for fluid
resuscitation in critically ill patients.
Methods
Study Design
CRISTAL was a pragmatic, international, randomized trial per-
formed in 2 parallel groups. The study protocol was approved by
the Committee for the Protection of People of Saint-Germain-en-
LayeforFrench sites and at institutionalreview boardselsewhere.
Waiver of consent was provided from all ethics committees and
deferred informed consent was obtained from participants or le-
gally authorized surrogates. The trial investigatorcommittees are
listed in the Supplement. The first patients were recruited for the
study in February 2003 and the last patients in August 2012. The
end of follow-up occurred in November 2012.
Study Participants
Eligible patients were adults admitted to any of 57 par-
ticipating ICUs in France, Belgium, Canada, Algeria, and
Tunisia (additional information appears in the Supplement),
accounting for more than 5000 potentially eligible patients.
To be eligible, research participants had to have received no
prior fluids for resuscitation during their ICU stay and now
require fluid resuscitation for acute hypovolemia as defined
by the combination of (1) hypotension: systolic arterial pres-
sure of less than 90 mm Hg, mean arterial pressure of less
than 60 mm Hg, orthostatic hypotension (ie, a decrease in
systolic arterial pressure of at least 20 mm Hg from the
supine to the semirecumbent position), or a delta pulse
pressure of 13% or higher; (2) evidence for low filling pres-
sures and low cardiac index as assessed either invasively or
noninvasively; and (3) signs of tissue hypoperfusion or
hypoxia, including at least 2 of the following clinical symp-
toms: a Glasgow Coma Scale score of less than 12, mottled
skin, urinary output of less than 25 mL/h, or capillary refill-
ing time of 3 seconds or longer; and arterial lactate levels
higher than 2 mmol/L, blood urea nitrogen higher than 56
mg/dL, or a fractional excretion of sodium of less than 1%.
The reasons for exclusion are listed in Figure 1 and eTable 1
in Supplement.
Randomization
A computer-generated list with fixed-block permutation (n = 4)
was used to randomize patients ona1to1ratio.Randomiza-
tion was stratified by center and by 3 admission diagnoses:
sepsis,
10
multiple trauma, or other causes of hypovolemic
shock. Allocation concealment used sealed envelopes at the
bedside to allow randomization of eligible patients without any
delay and was done blinded to block size.
Study Treatments
Eligible patients were randomly allocated to fluid resuscita-
tion with crystalloids (control group) or with colloids (experi-
mental group). In the crystalloids group, allowed treatments
included isotonic or hypertonic saline and any buffered solu-
tions. In the colloids group, hypooncotic (eg, gelatins, 4% or
5% of albumin) and hyperoncotic (eg, dextrans, hydroxy-
ethyl starches, and 20% or 25% of albumin) solutions were per-
mitted.
Within each treatment group, investigators could use
whichever fluids were available at their institution. The amount
of fluid and duration of treatment was left at the discretion of
the investigators with the following restrictions: (1) the daily
total dose of hydroxyethyl starch could not exceed 30 mL/kg
of body weight and (2) investigators were required to follow
any local regulatory agency recommendations governing use.
Adherence to these recommendations was strictly controlled
by local pharmacists and regularly checked during random
quality audits.
Patients were managed exclusively with the category of
fluid to which they were randomized from the time
of randomization until discharge from the ICU except for (1)
maintenance fluids, which were isotonic crystalloids,
regardless of treatment group, and (2) in instances in which
physicians wished to administer albumin in response
to demonstrated hypoalbuminemia (serum albumin level
<20 g/dL).
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Blinding
The blinding of the clinicians to the fluid interventions was con-
sidered by the study advisors to be inappropriate or infea-
sible because study treatments had to be available immedi-
ately for resuscitation to ensure avoidance of nonstudy fluids
in emergent situations. Also, because the intervention would
be continued until ICU discharge, and could thus be highly vari-
able, there was no practical way to stock sites with adequate
supplies of masked fluid solutions. However, the mortality end
points were collected and assessed by study members blinded
to treatment assignment. Similarly, the principal investiga-
tor, study sponsor, and the members of the data and safety
monitoring board remained blinded to the study interven-
tions until all patients were followed up and the final analysis
was executed.
Data Collection at Baseline and Follow-up
We systematically recorded demographic and anthropomet-
ric data, time of hospital and ICU admission, patient location
prior to ICU admission, disability scale score
11
and comorbid-
ity (as measured by McCabe class
12
), vital signs, Simplified
Acute Physiology Score II,
13
Sequential Organ Failure Assess-
ment (SOFA) score,
14
Injury Severity Score
15
for trauma pa-
tients, any intervention, standard laboratory tests, and a chest
x-ray score.
16
Patients were followed up for 90 days.
Study Outcomes
The primary outcome was mortality at 28 days. Secondary out-
comes included death rates at 90 days and at ICU and hospi-
tal discharge; number of days alive and not receiving renal re-
placement therapy, mechanical ventilation, or vasopressor
therapy; days without organ system failure (ie, SOFA score <6);
and days not in the ICU or hospital.
Assessment of Data Quality
As per the French regulation, all individual data were inde-
pendently checked for accuracy by the Delegation à la Recher-
che Clinique d’Ile de France. Quality audits included control
of the validity of informed consent, compliance to good clini-
cal practices and to the protocol, validity of data recorded in
the electronic case report form compared with the original
medical charts of patients, and accuracy of reporting of seri-
ous adverse events.
Statistical Analysis
We anticipated a mortality rate of 20% at 28 days among pa-
tients with acute hypovolemia and treated with crystalloids.
17
Using 2-sided χ
2
tests, assuming a .05 type I error and a statis-
tical power level of 90%, we calculated that 1505 patients per
group (ie, a total of 3010 patients) were needed to detect an
absolute difference of 5% in 28-day mortality with colloids.
Interim Analyses and Stopping Rules
For safety reasons, a triangular test was planned to sequen-
tially check the difference in 28-day mortality between the 2
randomized groups.
18
The triangular test is a sequential analy-
sis that enables repeated statistical analyses to be performed
throughout a trial recruitment period while maintaining a pre-
specified power and type I error. Thus, the trial could be
stopped as soon as the information accumulated was consid-
Figure 1. Patient Enrollment in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill
(CRISTAL) Trial
6498 Critically ill patients assessed
for eligibility
3641 Excluded
2305 Received fluid therapy in the intensive care unit
602 Had anesthesia-related hypotension
265 Had advanced chronic liver disease
188 Had chronic renal failure
93 Had an acute anaphylactic reaction
19 Had inherited coagulation disorders
18 Had do-not-resuscitate order
15 Pregnant
15 Burned >20% of body surface area
11 Had an allergy to any study drug
11 Refused consent
8 Dehydrated
2 Brain death or organ donor
89 Other reasons
2857 Randomized
1414 Included in primary analysis 1443 Included in primary analysis
0 Lost to follow-up or discontinued
intervention
0 Lost to follow-up or discontinued
intervention
1414 Randomized to receive colloids
1414 Received intervention as
randomized
1443 Randomized to receive crystalloids
1443 Received intervention as
randomized
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ered sufficient to reach a conclusion. Accordingly, the accu-
mulated data were inspected at every 100 deaths in a blinded
manner by the data and safety monitoring board.
The boundaries of the sequential plan were drawn to dem-
onstrate an absolute difference of 5% in the 28-day mortality
rate between the 2 treatment groups, assuming a 20% mortal-
ity rate in the crystalloids group with an α and β level of .05
and .10, respectively. At each inspection, 2 statistics were com-
puted, namely, Z and V (eFigure 1 in Supplement). Briefly, Z
represents the difference in the main outcome measures be-
tween the 2 randomized groups and V is related to the num-
ber of patients that have been included. When a boundary is
crossed, enrollment in the study may be stopped, but the con-
clusion depends on which boundary has been crossed.
Final Analysis
The final analysis was performed according to the intention-
to-treat principle after the enrollment period ended for the
study. Categorical variables are expressed as number and per-
centage and medians and interquartile range (IQR) are given
for continuous variables unless otherwise specified. Survival
curves have been constructed according to the Kaplan-Meier
method. For mortality end points, the analysis was per-
formed using the Mantel-Haenszel test stratified by admis-
sion diagnosis (ie, sepsis, trauma, or other causes of hypovo-
lemic shock) and using a Breslow-Day test for the homogeneity
of the odds ratios.
Relative risks (RRs) with 95% confidence intervals (de-
rived by combining strata-specific estimates) were used as the
summary measures of treatment effect. For secondary end
points, categorical variables were similarly compared. Num-
ber of days alive and not receiving mechanical ventilation, va-
sopressor therapy, and renal replacement therapy and with-
out organ system failure were computed within both 7 days
and 28 days from ICU admission, and the numbers of days alive
and not in the ICU or hospital were computed for the 28 days
following ICU admission and compared between random-
ized groups using the nonparametric Wilcoxon rank sum test.
Comparisons across randomized groups were then ad-
justed for prognostic factors (baseline SOFA, McCabe, and
Knaus scores) and admission diagnosis using logistic or gen-
eralized linear regression models whenever appropriate,
whereas center effect was tested using mixed-effects mod-
els. There were some missing data for these prognostic fac-
tors (range from 0 to 3.1% across variables) so that only a simple
imputation method could be used (recoding those values by
the sample mode).
To further examine potential interactions of treatment ef-
fect on the hazard ratio of death with the diagnosis stratum
or the center, separately, forest plots and the Gail and Simon
test were used. In addition, exploratory subset analyses of treat-
ment effect on the overall survival within the first 28 or 90 days
according to the administered fluid received on the random-
ization day were performed; only patients who were admin-
istered 1 type of fluid were examined.
Statistical analyses were performed using SAS version 9.3
(SAS Institute Inc). All statistical tests were 2-sided. A P value
of .05 was considered statistically significant.
Results
Patients
The lower boundary of the triangular test was crossed at the
sixth interim analysis (performed on July 2012) after the ob-
servation of 706 deaths in 2612 consecutive patients enrolled
up to March 16, 2012 (date of inclusion of the 706th nonsurvi-
vor) (eFigure 1 in Supplement). Because there was no statis-
tical difference in 28-day mortality between the 2 groups, re-
cruitment into the trial was stopped in August 2012 before the
fixed sample size of 3010 patients was reached. Between March
and August 2012, we recruited an additional 245 patients.
A total of 2857 patients (1414 in the colloids group and 1443
in the crystalloids group) were enrolled in the study (Figure 1).
Baseline characteristics were comparable between the 2 groups
(Table 1 and eTable 2 in Supplement). Severe sepsis was the
main diagnosis at admission in both groups. Prior to ICU ad-
mission, crystalloids were given to 526 patients in the col-
loids group for a median volume of 1000 mL (IQR, 500-1000
mL) and to 402 patients in the crystalloids group for a median
volume of 650 mL (IQR, 500-1000 mL). Colloids were given to
585 patients in the colloids group for a median volume of 1000
mL (IQR, 500-2000 mL) and to 685 patients in the crystal-
loids group for a median volume of 1000 mL (IQR, 500-2000
mL). The median time from ICU admission to randomization
was 0 days (IQR, 0-1 days) in both groups.
Fluid Therapy and Treatment Effects
The median cumulated volume of fluid (except for mainte-
nance therapy) administered for the first 7 days in the ICU was
2000 mL (IQR, 1000-3502 mL) in the colloids group vs 3000
mL (IQR, 500-5200 mL) in the crystalloids group (P < .001). The
median duration of treatment was 2 days (IQR, 1-3 days) in both
the colloids and crystalloids groups (P = .93). The total dose
and duration of each type of fluids given for both groups ap-
pear in eTable 3 in Supplement. A total of 237 patients in the
crystalloids group also received albumin supplementation
(eTable 3 in Supplement). In the colloids group, protocol vio-
lations included administration of normal saline in 252 pa-
tients (17.8%), Ringer lactate solution in 88 (6.2%), and hyper-
tonic saline in 19 (1.3%). In the crystalloids group, gelatins were
wrongly administered in 24 patients (1.7%) and hydroxyethyl
starches in 69 (4.8%).
During the first 24 hours following randomization, mean
blood pressure, urinary output, weight, and chest x-ray scores
were not significantly different between the 2 groups (eTable
4 in Supplement). There were 377 patients (26.7%) in the col-
loids group who received blood products at least once during
the first 7 days vs 358 (24.8%) in the crystalloids group (P = .25).
There was no evidence of any difference between groups for
the total amount of blood products transfused (mean [SD], 223.5
[495] mL in the colloids group vs 217.4 [517] mL in the crystal-
loids group; P = .75).
Outcomes
At 28 days, there were 359 deaths (25.4%) in the colloids group
vs 390 deaths (27.0%) in the crystalloids group (RR, 0.96 [95%
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CI, 0.88-1.04]; P = .26) (Figure 2 and Table 2). At 90 days, there
were 434 deaths (30.7%) in the colloids group vs 493 deaths
(34.2%) in the crystalloids group (RR, 0.92 [95% CI, 0.86-
0.99]; P = .03) (eFigure 2A in Supplement). There was no evi-
dence against any proportionality of treatment effect over time
(P = .54). There was no significant heterogeneity in the effect
of treatment on mortality in any of the predefined strata at 28
days (P = .70; Figure 3)orat90days(P = .84; eFigure 2B in
Table 1. Baseline Characteristics
Colloids Group
(n = 1414)
Crystalloids Group
(n = 1443)
Age, median (IQR), y 63 (50-76) 63 (50-75)
Male sex, No. (%) 880 (62.2) 902 (62.5)
Weight, median (IQR), kg 70 (60-81) 70 (61-81)
Height, median (IQR), cm 170 (161-175) 169 (162-175)
Source of admission to ICU, No. (%)
Community 674 (48.2) 745 (52.0)
Hospital ward 617 (44.1) 575 (40.1)
Other ICU 57 (4.1) 65 (4.5)
Long-term care facility 50 (3.6) 48 (3.3)
Type of ICU admission, No. (%) (n = 1399) (n = 1432)
Medical 991 (70.8) 1040 (72.6)
Emergency surgery 276 (19.7) 267 (18.6)
Scheduled surgery 109 (7.8) 89 (6.2)
Trauma 23 (1.6) 36 (2.5)
McCabe class, No. (%)
No underlying disease or no fatal disease 903 (63.9) 913 (63.3)
Underlying ultimately fatal disease (>5 y) 429 (30.3) 469 (32.5)
Underlying rapidly fatal disease (<1 y) 82 (5.8) 61 (4.2)
Knaus disability scale, No. (%)
Prior good health, no functional limitations 342 (24.5) 375 (26.3)
Mild to moderate limitation of activity because of chronic
medical problem
439 (31.5) 446 (31.3)
Chronic disease producing serious but not incapacitating
restriction of activity
323 (23.2) 325 (22.8)
Severe restriction of activity due to disease, includes
persons bedridden or institutionalized due to illness
289 (20.8) 278 (19.5)
Physiology score, median (IQR)
SAPS II
a
48 (35-64) 50 (36-65)
SOFA
b
8 (5-11) 8 (5-11)
Injury Severity
c
(n = 79)
21 (14-27)
(n = 88)
22 (14-34)
Glasgow Coma Scale score, median (IQR) (n = 1326)
11 (3-15)
(n = 1353)
11 (3-15)
Systolic blood pressure, median (IQR), mm Hg (n = 1337)
92 (80-112)
(n = 1372)
94 (80-113)
Heart rate, median (IQR), beats/min (n = 1335)
105 (86-123)
(n = 1366)
105 (88-21)
Urinary output, median (IQR), mL/h (n = 1245)
40 (20-70)
(n = 1259)
40 (20-60)
Lactate levels, median (IQR), mmol/L (n = 1151)
2.3 (1.3-3.8)
(n = 1176)
2.4 (1.4-4.5)
Fluid administration prior ICU admission (within the past
12 h)
Crystalloids, No. (%) 526 (37.2) 402 (27.9)
Dose, median (IQR), mL 1000 (500-1000) 650 (500-1000)
Colloids, No. (%) 585 (41.4) 685 (47.5)
Dose, median (IQR), mL 1000 (500-2000) 1000 (500-2000)
Mechanical ventilation, No. (%) 1007 (71.2) 1061 (73.5)
Renal replacement therapy, No. (%) 67 (4.7) 73 (5.1)
Predefined strata, No. (%)
Sepsis 774 (54.7) 779 (54.0)
Trauma 85 (6.0) 92 (6.4)
Hypovolemic shock (without sepsis or trauma) 555 (39.3) 572 (39.6)
Abbreviations: ICU, intensive care
unit; IQR, interquartile range; SAPS II,
Simplified Acute Physiology Score II;
SOFA, Sequential Organ Failure
Assessment.
a
Score range from 0 to 163 with
higher scores indicating more
severe organ dysfunction.
b
Score range from 0 to 24 with
higher scores indicating more
severe organ dysfunction.
c
Score range from 0 to 75 with
higher scores indicating more
severe injuries.
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Supplement). There was significant heterogeneity in mortal-
ity rates across centers (P < .001; eFigure 3A in Supplement),
but no evidence of any interaction with treatment effect (eFig-
ure 3B in Supplement). In addition, estimated treatment ef-
fects were not markedly modified when considering fluid sub-
sets (Table 3 and Table 4).
There were 156 patients (11.0%; 9.5%-12.8%) in the col-
loids group who required renal replacement therapy vs 181 pa-
tients (12.5%; 10.9%-14.4%) in the crystalloids group (RR, 0.93
[95% CI, 0.83-1.03]; P = .19). In these patients,the number of days
alive and not receiving renal replacement therapy was not sig-
nificantly different between the 2 groups within the first 7 days
(mean [SD], 4.8 [2.9] days in the colloids group vs 4.6 [2.9] days
in the crystalloids group; P = .99) or within 28 days (mean [SD],
13.9 [11.3] days vs 13.1 [11.4] days, respectively; P = .90). There
was also no difference in SOFA scores between the 2 groups
Figure 2. Cumulative Incidence of Death Within First 28 Days After
Randomization
0
0
1414
1443
5
1233
1239
10
1167
1172
15
1124
1124
20
1099
1089
25
1076
1064
30
Cumulative Incidence of Death
Time Since Randomization, d
0.3
0.2
0.1
Colloids
No. at risk
Crystalloids
Colloids
Crystalloids
Table 2. Study Outcomes by Treatment Group
No. (%) of Patients
RR (95% CI) P Value
a
Colloids
(n = 1414)
Crystalloids
(n = 1443)
Death
Within 28 d 359 (25.4) 390 (27.0) 0.96 (0.88 to 1.04) .26
Within 90 d 434 (30.7) 493 (34.2) 0.92 (0.86 to 0.99) .03
In ICU 355 (25.1) 405 (28.1) 0.92 (0.85 to 1.00) .06
In hospital 426 (30.1) 471 (32.6) 0.94 (0.87 to 1.02) .07
No. of days alive and without the following treatment or condition Mean (SD) Mean Difference (95% CI)
Mechanical ventilation within the first 7 d 2.1 (2.4) 1.8 (2.3) 0.30 (0.09 to 0.48) .01
Mechanical ventilation within the first 28 d 14.6 (11.4) 13.5 (11.5) 1.10 (0.14 to 2.06) .01
Renal replacement therapy within the first 7 d 4.8 (2.9) 4.6 (2.9) 0.2 (−0.4 to 0.8) .99
Renal replacement therapy within the first 28 d 13.9 (11.3) 13.1 (11.4) 0.8 (−1.6 to 3.3) .90
Organ failure (SOFA score <6) within the first 7 d 6.2 (1.8) 6.1 (1.8) 0.06 (−0.10 to 0.20) .31
Organ failure (SOFA score <6) within the first 28 d 21.4 (10.3) 20.9 (10.6) 0.6 (−0.4 to 1.5) .16
Vasopressor therapy within the first 7 d 5.0 (3.0) 4.7 (3.1) 0.30 (−0.03 to 0.50) .04
Vasopressor therapy within the first 28 d 16.2 (11.5) 15.2 (11.7) 1.04 (−0.04 to 2.10) .03
ICU stay within the first 28 d 8.3 (9.0) 8.1 (9.2) 0.2 (−0.5 to 0.9) .69
Hospital stay within the first 28 d 11.9 (11.1) 11.6 (11.4) 0.3 (−0.5 to 1.1) .37
Abbreviations: ICU, intensive care unit; RR, relative risk; SOFA, Sequential Organ
Failure Assessment.
a
For mortality end points, the analysis was performed using the
Mantel-Haenszel test stratified based on admission diagnosis (ie, sepsis,
trauma, or other causes of hypovolemic shock). The number of days alive and
not receiving mechanical ventilation, vasopressor therapy, and renal
replacement therapy and days alive without organ system failure were
compared between randomized groups using the nonparametric Wilcoxon
rank sum test.
Figure 3. Assessment of Treatment×Diagnosis Interaction and Death Within First 28 Days
0.5 3.01.0
Favors
Colloids
Favors
Crystalloids
HR (95% CI)
Reason for ICU
Admission
HR
(95% CI)
Other causes of
hypovolemic shock
0.87 (0.69-1.10)
Colloids Group
(n
=
1414)
No. of
Patients
555
No. of
Deaths
131
Crystalloids Group
(n
=
1443)
No. of
Patients
572
No. of
Deaths
152
Sepsis 0.95 (0.78-1.10)774 215 779 226
85
1414
13
359
92
1443
12
390
Trauma 1.19 (0.54-2.60)
All patients 0.93 (0.80-1.10)
HR indicates hazard ratio; ICU,
intensive care unit. P =.70for
interaction of homogeneity of HR
across the 3 strata, which was
calculated using the Gail and Simon
statistic test.
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over 28 days (eFigure 4 in Supplement) or in the number of days
alive without organ failure within 7 days (mean [SD], 6.2 [1.8]
days in the colloids group vs 6.1 [1.8] days in the crystalloids
group; P = .31) or within 28 days (21.4 [10.3] days vs 20.9 [10.6],
respectively; P = .16).
There was no evidence for a difference between groups for
the number of ICU- and hospital-free days (Table 2). There were
significantly more days alive without mechanical ventilation
within 7 days in patients in the colloids group vs patients in
the crystalloids group (mean [SD], 2.1 [2.4] days vs 1.8 [2.3] days;
P = .01) and within 28 days (mean [SD], 14.6 [11.4] days vs 13.5
[11.5] days, respectively; P = .01). There also were more days
without vasopressor therapy within 7 days in patients in the
colloids group vs patients in the crystalloids group (mean [SD],
5.0 [3.0] days vs 4.7 [3.1] days; P = .04) and within 28 days (mean
[SD], 16.2 [11.5] days vs 15.2 [11.7] days, respectively; P = .03).
Discussion
In a heterogeneous population of patients admitted to ICUs,
there was no evidence for a difference in 28-day mortality be-
tween patients resuscitated with crystalloids and those resus-
citated with colloids. However, there were fewer deaths at 90
days in the patients treated with colloids than in the patients
treated with crystalloids.
A large sample size, participation of ICUs from 3 conti-
nents (Europe, Canada, and North Africa), and from both
university and community hospitals strengthen the general-
izability of the CRISTAL trial. We chose to stratify random-
ization according to admission diagnosis because both the
risk of death and the clinical management and responses to
fluid therapy may differ in patients with sepsis, multiple
Table 4. Mortality Outcomes in Patients With Sepsis
Colloids Group, No. Crystalloids Group, No.
HR (95% CI)Patients Deaths Patients Deaths
28-d Mortality
Entire population 774 215 779 226 0.95 (0.78-1.14)
HES vs isotonic saline 375 105 557 157 0.97 (0.76-1.25)
Gelatins vs isotonic saline 152 40 557 157 0.90 (0.63-1.27)
HES vs Ringer solution 375 105 37 12 0.84 (0.46-1.53)
Gelatins vs Ringer solution 152 40 37 12 0.77 (0.40-1.47)
Albumin vs isotonic saline 59 19 557 157 1.16 (0.72-1.87)
90-d Mortality
Entire population 774 252 779 286 0.87 (0.73-1.03)
HES vs isotonic saline 375 120 557 197 0.89 (0.71-1.11)
Gelatins vs isotonic saline 152 47 557 197 0.84 (0.61-1.16)
HES vs Ringer solution 375 120 37 16 0.71 (0.42-1.20)
Gelatins vs Ringer solution 152 47 37 16 0.67 (0.38-1.18)
Albumin vs isotonic saline 59 22 557 197 1.07 (0.69-1.67)
Abbreviations: HES, hydroxyethyl
starches; HR, hazard ratio.
Table 3. Mortality Outcomes in Patients Who Received Only 1 Type of Fluid
Colloids Group, No. Crystalloids Group, No.
HR (95% CI)Patients Deaths Patients Deaths
28-d Mortality
Entire population 1414 359 1443 390 0.92 (0.80-1.07)
HES vs isotonic saline 645 149 1035 275 0.83 (0.68-1.01)
Gelatins vs isotonic saline 281 69 1035 275 0.90 (0.69-1.17)
HES vs Ringer solution 645 149 72 22 0.71 (0.45-1.11)
Gelatins vs Ringer solution 281 69 72 22 0.78 (0.48-1.26)
Albumin vs isotonic saline 80 24 1035 275 1.10 (0.72-1.68)
90-d Mortality
Entire population 1414 434 1443 493 0.88 (0.77-0.99)
HES vs isotonic saline 645 181 1035 346 0.79 (0.66-0.95)
Gelatins vs isotonic saline 281 84 1035 346 0.87 (0.68-1.10)
HES vs Ringer solution 645 181 72 26 0.72 (0.48-1.09)
Gelatins vs Ringer solution 281 84 72 26 0.80 (0.51-1.24)
Albumin vs isotonic saline 80 28 1035 346 1.02 (0.69-1.50)
Abbreviations: HES, hydroxyethyl
starches; HR, hazard ratio.
Colloids vs Crystalloids and Mortality Original Investigation Research
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Page 7
trauma, or hypovolemic shock (without sepsis and
nonhemorrhagic).
19
A computer-generated list of randomization using
permutation blocks with allocation concealment minimized
the risk of selection bias. The absence of loss to follow-up
for vital status up to 90 days postrandomization and the
limited proportion of crossover minimized the risk of attri-
tion bias.
Waiver for informed consent and treatment availability at
the bedside minimized delays to study initiation and pre-
vented administration of nontrial fluid therapy. In fact, other
than maintenance fluids, no other fluids were administered
in the ICU prior to to randomization.
Hence, the study population differs from other recent
trials
3,4,20
of fluid administration in ICU patients in that it
focuses only on patients presenting with hypotension and
lactic acidosis. This difference in the hemodynamic status of
patients at randomization may at least partly account for the
discrepancy in observed effects of colloids on mortality
between the CRISTAL trial and previous trials.
3,4,20
The trial was powered to detect a 5% difference in the
risk of death at 28 days with the use of colloids compared
with a baseline risk of death of 20% in the crystalloids group,
according to information available from a meta-analysis
17
at
the time of study design. Note that the stratification of the
test on the diagnosis stratum was ignored when computing
sample size.
There was no significant difference in mortality rates at
28 days postrandomization. Unexpectedly, there were fewer
deaths at 90 days among patients treated with colloids than
among patients treated with crystalloids. The observed
increase in the magnitude of treatment effect between 28
days and 90 days was previously reported in 2 trials investi-
gating fluid therapies.
3,20
In these trials, as in our trial, sepa-
ration of survival curves occurred after 3 weeks, resulting in a
delayed statistically significant RR of dying without clear
explanation.
Notably, there was no evidence of violation of the pro-
portional hazards assumption. In the 2 largest trials compar-
ing a colloid with a crystalloid (ie, isotonic saline), evidence
for an increased risk of death was not shown with either 5%
of albumin
7
or with 6% of hydroxyethyl starch with a
molecular weight of 130 kD and a molar substitution ratio of
0.4.
4
Two small trials suggested an excess risk of death with
hydroxyethyl starch compared with buffered crystalloids (ie,
Ringer solutions).
3,20
Thus, these findings at 90 days are con-
sistent with other studies suggesting lack of harm with col-
loids. However, given the null findings at 28 days and the
fact that the confidence limit approaches 1, the finding of
improved mortality with colloids should be considered
exploratory until replicated in a study focusing on this out-
come.
In the crystalloids group, about 86% of patients were re-
suscitated with isotonic saline and about 17% with buffered
solutions. In the colloids group, about 70% of patients re-
ceived hydroxyethyl starches and about 35% received gela-
tins. These features are in keeping with routine practices in the
participating countries.
21
Patients in the crystalloids group re-
ceived significantly more fluid volumes to achieve the same
hemodynamic targets than patients in the colloids group, which
was an expected outcome.
2,3,9
Resuscitation with colloids was associated with more
rapid weaning from life-support treatments as shown by
significantly more days alive without mechanical ventila-
tion or vasopressor therapy. In this trial, there was no evi-
dence for a colloids-related increase in the risk for renal
replacement therapy. These findings are in contrast to
previous reports showing increased incidence of acute
kidney injury following administration of hydroxyethyl
starches.
3-6,20
There are 3 potential explanations for this discrepancy.
First, the total dose of starches in the current trial
never exceeded the dose recommended by regulatory agen-
cies, and we excluded patients with severe chronic renal
failure. Second, the use of colloids was associated with a
significant reduction in cardiovascular and respiratory fail-
ures, as suggested by the reduced need for vasopressor
therapy and mechanical ventilation that may have contrib-
uted to renal protection. Third, the vast majority of patients
in the crystalloids group received a chloride-rich solution
(ie, normal saline) that may increase the risk of kidney
injuries compared with a chloride-restricted fluid
therapy.
22
Study Limitations
Our trial has some limitations, including the use of open-
labeled fluids and a recruitment period of 9 years. We delib-
erately chose to compare 2 therapeutic strategies (ie, fluid
therapy with crystalloids vs colloids) rather than comparing
2 molecules because fluid therapy is a more appropriate
reflection of routine practice in most countries. Hence, in
this pragmatic randomized trial, investigators used fluid
solutions available at the bedside in their institution. The
broad variety of drugs in each class, and the unpredictable
total amount of fluid to be administered during the entire
ICU stay, rendered unrealistic the preparation of blinded
treatments for the trial. In addition, the robustness of the
primary outcome (ie, mortality) and its recording by a
blinded outcome assessor minimized the risk of assessment
bias. Requirement of renal replacement therapy may have
been influenced by knowledge of allocation of the study
drugs by physicians. However, this would have likely
resulted in an increased use of renal replacement therapy in
patients treated with colloids. In addition, adjusting treat-
ment effects by date of enrollment did not modify the direc-
tion and size of estimates.
Conclusions
Among ICU patients with hypovolemia, the use of colloids com-
pared with crystalloids did not result in a significant differ-
ence in 28-day mortality. Although 90-day mortality was lower
among patients receiving colloids, this finding should be con-
sidered exploratory and requires further study before reach-
ing conclusions about efficacy.
Research Original Investigation Colloids vs Crystalloids and Mortality
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Page 8
ARTICLE INFORMATION
Published Online: October 9, 2013.
doi:10.1001/jama.2013.280502.
Author Aff iliations: Raymond Poincaré Hospital,
Garches, France (Annane); CH d’Etampes, Etampes,
France (Siami); CHU Montpelier, Montpelier, France
(Jaber); AP-HM Hôpital Nord, Marseille, Farnce
(Martin); EPS Taher Sfar Mahdia, Mahdia, Tunisia
(Elatrous); Antoine Béclère, Clamart, France
(Declère); CHU de Liège, Liège, Belgium (Preiser);
CHI de Poissy St Germain, Poissy, France (Outin);
CH André Mignot, Versailles, France (Troché);
Hôpital Central, Nancy, France (Charpentier); Pitié
Salpêtrière, Paris, France (Trouillet); Hôpital
Brabois, Nancy, France (Kimmoun); CH de Meaux,
Meaux, France (Forceville); Hôpital Saint Louis,
Paris, France (Darmon); CH de Sherbrooke,
Sherbrooke, Quebec, Canada (Lesur); CH de la
Roche sur Yon, Roche sur Yon, France (Régnier);
CHU Monastir, Monastir, Tunisia (Abroug); CH de
Chalons en Champagne, Champagne, France
(Berger); Hôpital Avicenne, Bobigny, France (Clech);
CHU de Reims, Reims, France (Cousson); CH de la
Réunion, Réunion Island, France (Thibault); Hôpital
Saint Louis, Paris, France (Chevret).
Author Contributions: Drs Annane and Chevret
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Annane, Martin, Preiser,
Troché, Chevret.
Acquisition of data: Annane, Siami, Jaber, Elatrous,
Declère, Preiser, Outin, Troché, Charpentier,
Trouillet, Kimmoun, Forceville, Darmon, Lesur,
Régnier, Abroug, Berger, Clech, Cousson, Thibault.
Analysis and interpretation of data: Annane, Preiser,
Lesur, Chevret.
Drafting of the manuscript: Annane, Martin,
Elatrous, Preiser, Lesur, Thibault, Chevret.
Critical revision of the manuscript for important
intellectual content: Annane, Siami, Jaber, Declère,
Preiser, Outin, Troché, Charpentier, Trouillet,
Kimmoun, Forceville, Darmon, Régnier, Abroug,
Berger, Clech, Cousson, Chevret.
Statistical analysis: Chevret.
Obtained funding: Annane, Preiser, Lesur.
Administrative, technical, or material support:
Annane, Siami, Martin, Declère, Preiser, Outin,
Troché, Trouillet, Kimmoun, Lesur, Régnier, Abroug.
Study supervision: Annane, Jaber, Martin, Preiser,
Forceville, Lesur, Régnier, Chevret.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Jaber reported serving as a consultant and
receiving payment for lectures from Drager
Ventilation and Maquet Ventilation. Dr Forceville
reported being employed, having patent interests,
and owning stock in Sérénité-Forceville, which is an
early stage start-up company. No other disclosures
were reported.
Funding/Support: The study was funded by the
French Ministry of Health, Programme Hospitalier
de Recherche Clinique 2001 and 2010 (AOM
01 020).
Role of the Sponsor: The study sponsors had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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  • Source
    • "There were also fewer days of mechanical ventilation and cardiovascular support with colloids (mainly starches) when compared with crystalloids. In fact, patients treated with colloids in that study had better 90-day survival [14]. As expected, the median volume administered in the first 7 days was significantly higher in the crystalloid group. "
    Preview · Article · Mar 2016 · Intensive Care Medicine
  • Source
    • "This is especially the case of the VISEP study, where very high amounts (quite above the recommended dose) of hyperoncotic pentastarch were used [8]. The only large study which investigated the effects of therapy with crystalloids versus colloids in the initial rescue and optimization phases was the recently published CRISTAL trial [12]. In this study patients were included very early in the disease process, when arterial hypotension , hypovolemia, and tissue perfusion abnormalities were still present. "
    Preview · Article · Mar 2016 · Intensive Care Medicine
  • Source
    • "Risk of bias is very important when interpreting trials of HES. When adding mortality data from the subgroup of patients with sepsis in the CRISTAL trial (even though not strictly randomizing patients to HES vs crystalloid [18]) to the cumulative evidence of HES vs crystalloid/ albumin in sepsis [3], there was heterogeneity in the results for mortality based on risk of bias; the high risk of bias trials showed the opposite of the low risk of bias trials (for details, see Fig. 1). It is well established that risk of bias results in overestimation of the intervention effect on objective outcome measures in RCTs [19], and this appears also to be the case for the effect of HES vs crystalloid/albumin on mortality. "
    Preview · Article · Mar 2016 · Intensive Care Medicine
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