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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.
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 Author Affiliations: Author
affiliations are listed at the end of this
exploratory and requires further study before reaching conclusions about efficacy.
article.
Corresponding Author: Djillali
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942 Annane, MD, PhD, University of
Versailles, 104 Blvd Raymond
JAMA. 2013;310(17):1809-1817. doi:10.1001/jama.2013.280502 Poincaré, 92380 Garches, France
Published online October 9, 2013. (djillali.annane@rpc.aphp.fr).
1809
T
housands of patients in intensive care units (ICUs) sia (additional information appears in the Supplement),
throughout the world are treated with fluid therapy to accounting for more than 5000 potentially eligible patients.
restore effective blood volume and ensure optimal or- To be eligible, research participants had to have received no
gan perfusion.1,2 Fluid therapy includes a broad variety of prod- prior fluids for resuscitation during their ICU stay and now
ucts that are typically categorized as crystalloids and col- require fluid resuscitation for acute hypovolemia as defined
loids. Although the goal is to use intravenous fluids to expand by the combination of (1) hypotension: systolic arterial pres-
the intravascular space, fluid also moves into the extravascu- sure of less than 90 mm Hg, mean arterial pressure of less
lar space. Crystalloids are thought to counteract that move- than 60 mm Hg, orthostatic hypotension (ie, a decrease in
ment via the osmotic pressure exerted by their solutes, whereas systolic arterial pressure of at least 20 mm Hg from the
colloids are designed to exploit oncotic pressure gradients for supine to the semirecumbent position), or a delta pulse
the same effect.2 Thus, theoretically, expansion of blood vol- pressure of 13% or higher; (2) evidence for low filling pres-
ume may be proportional to solute tonicity or oncotic power. sures and low cardiac index as assessed either invasively or
The crystalloid family includes isotonic and hypertonic so- noninvasively; and (3) signs of tissue hypoperfusion or
lutions that are also categorized into nonbuffered (eg, isotonic hypoxia, including at least 2 of the following clinical symp-
saline) and buffered solutions (eg, Ringer lactate, acetate, ma- toms: a Glasgow Coma Scale score of less than 12, mottled
leate). The colloid family includes hypooncotic (eg, gelatins, 4% skin, urinary output of less than 25 mL/h, or capillary refill-
or 5% of albumin) and hyperoncotic (eg, dextrans, hydroxy- ing time of 3 seconds or longer; and arterial lactate levels
ethyl starches, and 20% or 25% of albumin) solutions. Gener- higher than 2 mmol/L, blood urea nitrogen higher than 56
ally, colloid solutions are thought to be more efficient than crys- mg/dL, or a fractional excretion of sodium of less than 1%.
talloids in terms of the amount of fluid that remains in the The reasons for exclusion are listed in Figure 1 and eTable 1
intravascular space,2 and so less fluid is required when using col- in Supplement.
loids vs crystalloids to achieve similar hemodynamic goals.3,4
However, there are other effects of these fluids, including al- Randomization
terations to the immune response to critical illness.1,2 Addition- A computer-generated list with fixed-block permutation
ally, there is concern that hydroxyethyl starches may increase (n = 4) was used to randomize patients on a 1 to 1 ratio.
the risk of death or acute kidney injury.5,6 Most colloid solu- Randomization was stratified by center and by 3 admission
tions are also more expensive than crystalloids. diagnoses: sepsis, 1 0 multiple trauma, or other causes
In recent studies of general ICU patient populations, fluid of hypovolemic shock. Allocation concealment used
replacement with 5% of albumin7 or with 6% of hydroxyethyl sealed envelopes at the bedside to allow randomization of
starch4 showed similar effects on mortality compared with iso- eligible patients without any delay and was done blinded to
tonic saline. Although there was a suggestion that the subset block size.
of patients with severe sepsis might benefit from resuscita-
tion with albumin,8 the current Surviving Sepsis Campaign Study Treatments
guidelines recommended crystalloids as the preferred fluid Eligible patients were randomly allocated to fluid resuscita-
therapy and against the use of hydroxyethyl starches.9 tion with crystalloids (control group) or with colloids (experi-
The Colloids Versus Crystalloids for the Resuscitation of mental group). In the crystalloids group, allowed treatments
the Critically Ill (CRISTAL) trial was designed to test whether included isotonic or hypertonic saline and any buffered solu-
colloids altered mortality compared with crystalloids for fluid tions. In the colloids group, hypooncotic (eg, gelatins, 4% or
resuscitation in critically ill patients. 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
Methods whichever fluids were available at their institution. The amount
Study Design of fluid and duration of treatment was left at the discretion of
CRISTAL was a pragmatic, international, randomized trial per- the investigators with the following restrictions: (1) the daily
formed in 2 parallel groups. The study protocol was approved by total dose of hydroxyethyl starch could not exceed 30 mL/kg
the Committee for the Protection of People of Saint-Germain-en- of body weight and (2) investigators were required to follow
Laye for French sites and at institutional review boards elsewhere. any local regulatory agency recommendations governing use.
Waiver of consent was provided from all ethics committees and Adherence to these recommendations was strictly controlled
deferred informed consent was obtained from participants or le- by local pharmacists and regularly checked during random
gally authorized surrogates. The trial investigator committees are quality audits.
listed in the Supplement. The first patients were recruited for the Patients were managed exclusively with the category of
study in February 2003 and the last patients in August 2012. The fluid to which they were randomized from the time of ran-
end of follow-up occurred in November 2012. domization until discharge from the ICU except for (1) main-
tenance fluids, which were isotonic crystalloids, regardless
Study Participants of treatment group, and (2) in instances in which physicians
Eligible patients were adults admitted to any of 57 partici- wished to administer albumin in response to demonstrated
pating ICUs in France, Belgium, Canada, Algeria, and Tuni- hypoalbuminemia (serum albumin level <20 g/dL).
Figure 1. Patient Enrollment in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill
(CRISTAL) Trial
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
CI, 0.88-1.04]; P = .26) (Figure 2 and Table 2). At 90 days, there dence against any proportionality of treatment effect over time
were 434 deaths (30.7%) in the colloids group vs 493 deaths (P = .54). There was no significant heterogeneity in the effect
(34.2%) in the crystalloids group (RR, 0.92 [95% CI, 0.86- of treatment on mortality in any of the predefined strata at 28
0.99]; P = .03) (eFigure 2A in Supplement). There was no evi- days (P = .70; Figure 3) or at 90 days (P = .84; eFigure 2B in
Crystalloids
sets (Table 3 and Table 4).
Colloids
0.2
There were 156 patients (11.0%; 9.5%-12.8%) in the col-
loids group who required renal replacement therapy vs 181
patients (12.5%; 10.9%-14.4%) in the crystalloids group (RR,
0.1 0.93 [95% CI, 0.83-1.03]; P = .19). In these patients, the num-
ber of days alive and not receiving renal replacement therapy
was not significantly different between the 2 groups within
0
0 5 10 15 20 25 30 the first 7 days (mean [SD], 4.8 [2.9] days in the colloids
Time Since Randomization, d group vs 4.6 [2.9] days in the crystalloids group; P = .99) or
No. at risk
Colloids 1414 1233 1167 1124 1099 1076
within 28 days (mean [SD], 13.9 [11.3] days vs 13.1 [11.4] days,
Crystalloids 1443 1239 1172 1124 1089 1064 respectively; P = .90). There was also no difference in SOFA
scores between the 2 groups over 28 days (eFigure 4 in
Abbreviations: ICU, intensive care unit; RR, relative risk; SOFA, Sequential Organ not receiving mechanical ventilation, vasopressor therapy, and renal
Failure Assessment. replacement therapy and days alive without organ system failure were
a
For mortality end points, the analysis was performed using the compared between randomized groups using the nonparametric Wilcoxon
Mantel-Haenszel test stratified based on admission diagnosis (ie, sepsis, rank sum test.
trauma, or other causes of hypovolemic shock). The number of days alive and
multiple trauma, or hypovolemic shock (without sepsis and ceived significantly more fluid volumes to achieve the same
nonhemorrhagic).19 hemodynamic targets than patients in the colloids group, which
A computer-generated list of randomization using per- was an expected outcome.2,3,9
mutation blocks with allocation concealment minimized the Resuscitation with colloids was associated with more
risk of selection bias. The absence of loss to follow-up rapid weaning from life-support treatments as shown by
for vital status up to 90 days postrandomization and the significantly more days alive without mechanical ventila-
limited proportion of crossover minimized the risk of attri- tion or vasopressor therapy. In this trial, there was no evi-
tion bias. dence for a colloids-related increase in the risk for renal
Waiver for informed consent and treatment availability at replacement therapy. These findings are in contrast to
the bedside minimized delays to study initiation and pre- previous reports showing increased incidence of acute
vented administration of nontrial fluid therapy. In fact, other kidney injury following administration of hydroxyethyl
than maintenance fluids, no other fluids were administered starches.3-6,20
in the ICU prior to to randomization. There are 3 potential explanations for this discrepancy.
Hence, the study population differs from other recent First, the total dose of starches in the current trial never
trials3,4,20 of fluid administration in ICU patients in that it fo- exceeded the dose recommended by regulatory agencies,
cuses only on patients presenting with hypotension and lac- and we excluded patients with severe chronic renal failure.
tic acidosis. This difference in the hemodynamic status of pa- Second, the use of colloids was associated with a significant
tients at randomization may at least partly account for the reduction in cardiovascular and respiratory failures, as
discrepancy in observed effects of colloids on mortality be- suggested by the reduced need for vasopressor therapy
tween the CRISTAL trial and previous trials.3,4,20 and mechanical ventilation that may have contributed
The trial was powered to detect a 5% difference in the to renal protection. Third, the vast majority of patients
risk of death at 28 days with the use of colloids compared in the crystalloids group received a chloride-rich solution
with a baseline risk of death of 20% in the crystalloids (ie, normal saline) that may increase the risk of kidney
group, according to information available from a meta- injuries compared w ith a chloride-restric ted fluid
analysis17 at the time of study design. Note that the stratifi- therapy.22
cation of the test on the diagnosis stratum was ignored
when computing sample size. Study Limitations
There was no significant difference in mortality rates at Our trial has some limitations, including the use of open-
28 days postrandomization. Unexpectedly, there were fewer labeled fluids and a recruitment period of 9 years. We delib-
deaths at 90 days among patients treated with colloids than erately chose to compare 2 therapeutic strategies (ie, fluid
among patients treated with crystalloids. The observed therapy with crystalloids vs colloids) rather than comparing
increase in the magnitude of treatment effect between 28 2 molecules because fluid therapy is a more appropriate
days and 90 days was previously reported in 2 trials investi- reflection of routine practice in most countries. Hence, in
gating fluid therapies.3,20 In these trials, as in our trial, sepa- this pragmatic randomized trial, investigators used fluid
ration of survival curves occurred after 3 weeks, resulting in solutions available at the bedside in their institution. The
a delayed statistically significant RR of dying without clear broad variety of drugs in each class, and the unpredictable
explanation. total amount of fluid to be administered during the entire
Notably, there was no evidence of violation of the pro- ICU stay, rendered unrealistic the preparation of blinded
portional hazards assumption. In the 2 largest trials compar- treatments for the trial. In addition, the robustness of the
ing a colloid with a crystalloid (ie, isotonic saline), evidence primary outcome (ie, mortality) and its recording by a
for an increased risk of death was not shown with either 5% blinded outcome assessor minimized the risk of assessment
of albumin 7 or with 6% of hydroxyethyl starch with a bias. Requirement of renal replacement therapy may have
molecular weight of 130 kD and a molar substitution ratio of been influenced by knowledge of allocation of the study
0.4.4 Two small trials suggested an excess risk of death with drugs by physicians. However, this would have likely
hydroxyethyl starch compared with buffered crystalloids resulted in an increased use of renal replacement therapy in
(ie, Ringer solutions).3,20 Thus, these findings at 90 days are patients treated with colloids. In addition, adjusting treat-
consistent with other studies suggesting lack of harm with ment effects by date of enrollment did not modify the direc-
colloids. However, given the null findings at 28 days and the tion and size of estimates.
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
outcome.
Conclusions
In the crystalloids group, about 86% of patients were re- Among ICU patients with hypovolemia, the use of colloids com-
suscitated with isotonic saline and about 17% with buffered pared with crystalloids did not result in a significant differ-
solutions. In the colloids group, about 70% of patients re- ence in 28-day mortality. Although 90-day mortality was lower
ceived hydroxyethyl starches and about 35% received gela- among patients receiving colloids, this finding should be con-
tins. These features are in keeping with routine practices in the sidered exploratory and requires further study before reach-
participating countries.21 Patients in the crystalloids group re- ing conclusions about efficacy.
ARTICLE INFORMATION Funding/Support: The study was funded by the Consensus Conference: definitions for sepsis and
Published Online: October 9, 2013. French Ministry of Health, Programme Hospitalier de organ failure and guidelines for the use of
doi:10.1001/jama.2013.280502. Recherche Clinique 2001 and 2010 (AOM 01 020). innovative therapies in sepsis. Crit Care Med.
Role of the Sponsor: The study sponsors had no 1992;20(6):864-874.
Author Affiliations: Raymond Poincaré Hospital,
Garches, France (Annane); CH d’Etampes, Etampes, role in the design and conduct of the study; 11. Knaus WA, Zimmerman JE, Wagner DP, Draper
France (Siami); CHU Montpelier, Montpelier, France collection, management, analysis, and EA, Lawrence DE. APACHE—Acute Physiology And
(Jaber); AP-HM Hôpital Nord, Marseille, Farnce interpretation of the data; preparation, review, or Chronic Health Evaluation: a physiologically based
(Martin); EPS Taher Sfar Mahdia, Mahdia, Tunisia approval of the manuscript; and decision to submit classification system. Crit Care Med.
(Elatrous); Antoine Béclère, Clamart, France the manuscript for publication. 1981;9(8):591-597.
(Declère); CHU de Liège, Liège, Belgium (Preiser); Correction: This article was corrected on January 8, 12. McCabe WA, Jackson GG. Gram negative
CHI de Poissy St Germain, Poissy, France (Outin); 2014, to fix 2 misspelled author names. bacteremia, I: etiology and ecology. Arch Intern
CH André Mignot, Versailles, France (Troché); Med. 1962;110:847-855.
Hôpital Central, Nancy, France (Charpentier); Pitié REFERENCES 13. Le Gall JR, Lemeshow S, Saulnier F. A new
Salpêtrière, Paris, France (Trouillet); Hôpital 1. Oliveira RP, Velasco I, Soriano FG, Friedman G. Simplified Acute Physiology Score (SAPS II) based
Brabois, Nancy, France (Kimmoun); CH de Meaux, Clinical review: hypertonic saline resuscitation in on a European/North American multicenter study.
Meaux, France (Forceville); Hôpital Saint Louis, sepsis. Crit Care. 2002;6(5):418-423. JAMA. 1993;270(24):2957-2963.
Paris, France (Darmon); CH de Sherbrooke,
Sherbrooke, Quebec, Canada (Lesur); CH de la 2. American Thoracic Society. Evidence-based 14. Vincent JL, Moreno R, Takala J, et al; Working
Roche sur Yon, Roche sur Yon, France (Reignier); colloid use in the critically ill: American Thoracic Group on Sepsis-Related Problems of the European
CHU Monastir, Monastir, Tunisia (Abroug); CH de Society Consensus Statement. Am J Respir Crit Care Society of Intensive Care Medicine. The SOFA
Chalons en Champagne, Champagne, France Med. 2004;170(11):1247-1259. (Sepsis-related Organ Failure Assessment) score to
(Berger); Hôpital Avicenne, Bobigny, France 3. Brunkhorst FM, Engel C, Bloos F, et al; German describe organ dysfunction/failure. Intensive Care
(Clec’h); CHU de Reims, Reims, France (Cousson); Competence Network Sepsis (SepNet). Intensive Med. 1996;22(7):707-710.
CH de la Réunion, Réunion Island, France (Thibault); insulin therapy and pentastarch resuscitation in 15. Kim Y, Jung KY, Kim CY, Kim YI, Shin Y.
Hôpital Saint Louis, Paris, France (Chevret). severe sepsis. N Engl J Med. 2008;358(2):125-139. Validation of the International Classification of
Author Contributions: Drs Annane and Chevret 4. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Diseases 10th edition-based Injury Severity Score
had full access to all of the data in the study and Investigators; Australian and New Zealand Intensive (ICISS). J Trauma. 2000;48(2):280-285.
take responsibility for the integrity of the data and Care Society Clinical Trials Group. Hydroxyethyl 16. Weinberg PF, Matthay MA, Webster RO, Roskos
the accuracy of the data analysis. starch or saline for fluid resuscitation in intensive KV, Goldstein IM, Murray JF. Biologically active
Study concept and design: Annane, Martin, Preiser, care. N Engl J Med. 2012;367(20):1901-1911. products of complement and acute lung injury in
Troché, Chevret. 5. Perel P, Roberts I, Ker K. Colloids versus patients with the sepsis syndrome. Am Rev Respir
Acquisition of data: Annane, Siami, Jaber, Elatrous, crystalloids for fluid resuscitation in critically ill Dis. 1984;130(5):791-796.
Declère, Preiser, Outin, Troché, Charpentier, patients. Cochrane Database Syst Rev. 17. Alderson P, Schierhout G, Roberts I, Bunn F.
Trouillet, Kimmoun, Forceville, Darmon, Lesur, 2013;2(2):CD000567. Colloids versus crystalloids for fluid resuscitation in
Reignier, Abroug, Berger, Clec’h, Cousson, Thibault. critically ill patients. Cochrane Database Syst Rev.
Analysis and interpretation of data: Annane, Preiser, 6. Zarychanski R, Abou-Setta AM, Turgeon AF,
et al. Association of hydroxyethyl starch 2000;(2):CD000567.
Lesur, Chevret.
Drafting of the manuscript: Annane, Martin, administration with mortality and acute kidney 18. Whitehead J. The Design and Analysis of
Elatrous, Preiser, Lesur, Thibault, Chevret. injury in critically ill patients requiring volume Sequential Clinical Trials. 2nd ed. New York, NY: Ellis
Critical revision of the manuscript for important resuscitation: a systematic review and Horwood; 1992.
intellectual content: Annane, Siami, Jaber, Declère, meta-analysis. JAMA. 2013;309(7):678-688. 19. Weil MH, Shubin H. Proposed reclassification of
Preiser, Outin, Troché, Charpentier, Trouillet, 7. Finfer S, Bellomo R, Boyce N, French J, Myburgh shock states with special reference to distribution
Kimmoun, Forceville, Darmon, Reignier, Abroug, J, Norton R; SAFE Study Investigators. A defects. In: Hinshaw LN, Cox BG, eds. The
Berger, Clec’h, Cousson, Chevret. comparison of albumin and saline for fluid Fundamental Mechanisms of Shock. New York, NY:
Statistical analysis: Chevret. resuscitation in the intensive care unit. N Engl J Plenum Press; 1972:13-23.
Obtained funding: Annane, Preiser, Lesur. Med. 2004;350(22):2247-2256. 20. Perner A, Haase N, Guttormsen AB, et al; 6S
Administrative, technical, or material support: 8. Delaney AP, Dan A, McCaffrey J, Finfer S. The Trial Group; Scandinavian Critical Care Trials Group.
Annane, Siami, Martin, Declère, Preiser, Outin, role of albumin as a resuscitation fluid for patients Hydroxyethyl starch 130/0.42 versus Ringer’s
Troché, Trouillet, Kimmoun, Lesur, Reignier, with sepsis: a systematic review and meta-analysis. acetate in severe sepsis [published correction
Abroug. Crit Care Med. 2011;39(2):386-391. appears in N Engl J Med. 2012;367:481]. N Engl J
Study supervision: Annane, Jaber, Martin, Preiser, Med. 2012;367(2):124-134.
Forceville, Lesur, Reignier, Chevret. 9. Dellinger RP, Levy MM, Rhodes A, et al;
Surviving Sepsis Campaign Guidelines Committee 21. Finfer S, Liu B, Taylor C, et al; SAFE TRIPS
Conflict of Interest Disclosures: The authors have Including the Pediatric Subgroup. Surviving Sepsis Investigators. Resuscitation fluid use in critically ill
completed and submitted the ICMJE Form for Campaign: international guidelines for adults: an international cross-sectional study in 391
Disclosure of Potential Conflicts of Interest. Dr management of severe sepsis and septic shock: intensive care units. Crit Care. 2010;14(5):R185.
Jaber reported serving as a consultant and 2012. Crit Care Med. 2013;41(2):580-637.
receiving payment for lectures from Drager 22. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L,
Ventilation and Maquet Ventilation. Dr Forceville 10. American College of Chest Physicians; Society Bailey M. Association between a chloride-liberal vs
reported being employed, having patent interests, of Critical Care Medicine Consensus Conference chloride-restrictive intravenous fluid administration
and owning stock in Sérénité-Forceville, which is an Committee. American College of Chest strategy and kidney injury in critically ill adults.
early stage start-up company. No other disclosures Physicians/Society of Critical Care Medicine JAMA. 2012;308(15):1566-1572.
were reported.