Fluid resuscitation for hypovolaemia is a mainstay of the medical management of critically ill patients, whether as a result of trauma, burns, major surgery or sepsis. Although some studies (Bickell 1994) have suggested that the timing of volume replacement deserves careful consideration, when it comes to selecting the resuscitation fluid, clinicians are faced with a range of options. At one level the choice is between a colloid or crystalloid solution. Colloids are widely used, having been recommended in a number of resuscitation guidelines and intensive care management algorithms (Armstrong 1994; Vermeulen 1995).
The US Hospital Consortium Guidelines recommend that colloids are used in haemorrhagic shock prior to the availability of blood products, and in non-haemorrhagic shock following an initial crystalloid infusion. However, a 1995 survey of US academic health centres found that the use of colloids far exceeded even the Hospital Consortium recommendations (Yim 1995). Surveys of burn care in the US (Fakhry 1995) and in Australia (Victorian DUAC 1991) found that the use of colloids for resuscitation varied without a set pattern.
The choice of fluid has considerable cost implications. Volume replacement with colloids is considerably more expensive than with crystalloids. Clinical studies have shown that colloids and crystalloids have different effects on a range of important physiological parameters. Because of these differences, all-cause mortality is arguably the most clinically relevant outcome measure in randomised trials comparing the two fluid types.
Why it is important to do this review
Although there have been previous meta-analyses of mortality in randomised trials comparing colloids and crystalloids (Bisonni 1991; Velanovich 1989), neither of these satisfy the criteria that have been proposed for scientific overviews (Oxman 1994), and they predate most of the trials that have been conducted using synthetic colloids, and hypertonic crystalloid solutions. The purpose of this systematic review is to identify and synthesise all available unconfounded evidence of the effect on mortality in critically ill patients of colloids compared to crystalloids for volume replacement.
To assess the effects on mortality of using colloids compared to crystalloids, during fluid resuscitation in critically ill patients.
Criteria for considering studies for this review
Types of studies
Controlled trials in which participants were randomised to treatment groups (colloid or control) on the basis of random allocation. As the comparison between fluid type was in terms of effects on mortality, we excluded randomised cross-over trials.
Types of participants
Critically ill patients (excluding neonates and pregnant women) who required volume replacement. We included patients who were critically ill as a result of trauma, burns, undergoing surgery, or had other critical conditions such as complications of sepsis.
We excluded preoperative elective surgical patients.
Types of interventions
We considered the following colloids: dextran 70, hydroxyethyl starches, modified gelatins, albumin or plasma protein fraction.
There is overlap between albumin given for volume replacement and albumin given as a nutritional supplement, and many patients with a critical illness have low serum albumin. Where the trial was of total parenteral nutrition with or without albumin, we excluded it. We included trials where the albumin was given as part of volume replacement guided by colloid osmotic pressure or albumin levels.
The control group received crystalloid (isotonic or hypertonic) for fluid replacement. We included trials in which both groups received blood.
We excluded trials of fluids used for other purposes. For example, we excluded trials of pre-loading in preparation for elective surgery, and trials in patients undergoing fluid loading before cardiopulmonary bypass.
Types of outcome measures
The principal outcome measure was mortality from all causes, assessed at the end of the follow-up period scheduled for each trial.
Search methods for identification of studies
We did not restrict the search for trials by date, language or publication status.
We searched the following electronic databases:
- Cochrane Injuries Group Specialised Register (17 October 2012);
- the Cochrane Central Register of Controlled Trials (The Cochrane Library) (Issue 10, 2012);
- MEDLINE (OvidSP) 1946 to October, Week 1, 2012;
- EMBASE (OvidSP) 1980 to 2012, Week 41;
- ISI Web of Science: Science Citation Index Expanded (1970 to October 2012);
- ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to October 2012);
- PubMed (October 2012);
- National Research Register (2006, Issue 4).
All search strategies are listed in full in Appendix 1.
Searching other resources
We searched the reference lists of all relevant papers and published review articles. We also contacted known trialists to identify any further studies that we may have missed. We searched the online trials registers www.clinical trials.gov and www.controlled-trials.com for published and unpublished studies.
Data collection and analysis
The Injuries Group Trials Search Coordinator ran the electronic database searches, collated the results and removed duplicates before passing the list of citations to the lead review author (PP) for screening.
Selection of studies
Two review authors independently examined the list of citations for eligibility. We obtained full-text copies of all relevant records and independently assessed whether each met the pre-defined inclusion criteria. We resolved disagreement by discussion.
Assessment of risk of bias in included studies
We scored allocation concealment as described by Higgins 2011, assigning 'high risk of bias' to poorest quality and 'low risk of bias' to best quality (the presence of solutions in identical containers was only taken to mean adequate concealment if the fluid containers were used sequentially).
- Low risk of bias = trials deemed to have taken adequate measures to conceal allocation (i.e. central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained elements convincing of concealment).
- Unclear = trials in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into one of the other categories.
- High risk of bias = trials in which concealment was inadequate (such as alternation or reference to case record numbers or to dates of birth).
We collected but did not score information on blinding and loss to follow-up.
As a result of comments on the previous version of this review, we have stratified trials by type of fluid rather than type of original injury.
We calculated risk ratios (RRs) and 95% confidence intervals (CI) for each study using a fixed-effect model. We then inspected each comparison visually for evidence of heterogeneity and performed a Chi
We then excluded trials with allocation concealment judged as inadequate and repeated the calculations.
The editorial group is aware that a clinical trial by Professor Joachim Boldt has been found to have been fabricated (Boldt 2009). As the editors who revealed this fabrication point out (Reinhart 2011; Shafer 2011), this casts some doubt on the veracity of other studies by the same author. All Cochrane Injuries Group reviews that include studies by this author have therefore been edited to show the results with this author's trials included and excluded. Readers can now judge the potential impact of trials by this author on the conclusions of the review.
Description of studies
We identified 78 trials meeting the inclusion criteria for study design, participants and interventions (Figure 1). We were able to obtain mortality data for 70 of these. We have reported details of the included trials in the 'Characteristics of included studies' table.
|Figure 1. Study flow diagram: the numbers reflect the most recent update only (17th October 2012)|
Reasons for exclusion of trials were: the use of a cross-over design, testing a resuscitation algorithm, giving the control group oral fluids, the intervention being directed to the maintenance of serum albumin levels, for haemodilution, for fluid loading and for the reduction of intracranial pressure (see 'Characteristics of excluded studies' table).
Of the 70 trials with data on deaths, the quality of allocation concealment was adequate in 17 trials and unclear in most of the others.
There were 56 trials comparing colloid with crystalloid (add-on colloid), 11 trials comparing colloid in hypertonic crystalloid with isotonic crystalloid, and three trials comparing colloid with hypertonic crystalloid.
Risk of bias in included studies
In general, the design of studies was not well reported. This is reflected in the number of unclear scores given for allocation concealment. We also collected information on blinding and loss to follow-up. Blinding was not well reported and loss to follow-up was generally small. The characteristics for each trial are listed in the 'Characteristics of included studies' table.
Effects of interventions
Colloids compared to crystalloids
Albumin or plasma protein fraction
Twenty-four trials reported data on mortality, including a total of 9920 patients. The pooled RR was 1.01 (95% CI 0.93 to 1.10). When trials by Boldt were removed, the results were unchanged (RR 1.01; 95% CI 0.93 to 1.10). When we excluded the trial with poor-quality allocation concealment (Lucas 1978), pooled RR was 1.00 (95% CI 0.92 to 1.09).
Twenty-five trials compared hydroxyethyl starch with crystalloids, including a total of 9147 randomised patients. The pooled RR for mortality was 1.10 (95% CI 1.02 to 1.19). When trials by Boldt were removed, the results were unchanged.
Eleven trials compared modified gelatin with crystalloid, including a total of 506 randomised patients. The pooled RR for mortality was 0.91 (95% CI 0.49 to 1.72). When trials by Boldt were removed, the results were unchanged.
Nine trials compared dextran with a crystalloid, including a total of 834 randomised patients. The pooled RR for mortality was 1.24 (95% CI 0.94 to 1.65).
Colloids in hypertonic crystalloid compared to isotonic crystalloid
One trial compared albumin and hypertonic saline with isotonic crystalloid. The RR of mortality was 0.50 (95% CI 0.06 to 4.33). One trial compared 6% hydroxyethyl starch 130/0.4 and hypertonic saline with Ringer's lactate. The RR of mortality was 0.25 (95% CI 0.03 to 2.15).
Nine trials compared dextran in hypertonic crystalloid with isotonic crystalloid, including 1879 randomised patients. The pooled RR of mortality was 0.91 (95% CI 0.79 to 1.06).
Colloids in isotonic crystalloid compared to hypertonic crystalloid
Three trials compared colloids in isotonic crystalloid with hypertonic crystalloid. In two of these, where the colloid was either gelatin or starch, there were no deaths in either group. In the remaining trial, with 38 patients, there was a RR of death of 7.00 (95% CI 0.39 to 126.93) for use of colloid, based on three deaths in the treatment group and none in the control group.
This systematic review synthesises the evidence from RCTs comparing colloid and crystalloid fluid resuscitation across a wide variety of clinical conditions. The review has been updated and extensively revised to take into account the comments made since it was first published in 1997. In particular, several commentators pointed out that it is inappropriate to combine effect estimates from studies of different colloids. For example, it was argued that large molecular weight colloids such as hydroxyethyl starch may be better retained in the vascular compartment than albumin and gelatins, and would therefore be more likely to show a favourable effect on mortality (Gosling 1998). In response to these concerns, the review has been stratified by type of colloid. However, the pooled RRs fail to show a mortality benefit for resuscitation with any type of colloid.
There is a trend towards a favourable effect on mortality for colloids in hypertonic crystalloid, compared to isotonic crystalloids. Nevertheless, the results are compatible with the play of chance.
Common to all meta-analyses, this systematic review may have included studies whose interventions and patient characteristics are sufficiently incomparable that the calculation of a summary effect measure may be questioned. The resuscitation regimen differed between trials. Some trials randomised participants to an initial quantity of colloid or crystalloid, and then proceeded with some form of standard resuscitation for all participants. Other trials resuscitated with the allocated fluid to pre-determined end points, either resuscitation end points, or in the case of trauma, until corrective surgery. In addition, the type of colloid or crystalloid, the concentration, and the protocol to determine the quantity of fluid varied. Despite these differences, all participants were in need of volume replacement, and we believe that this variation in the intervention would have an impact on the size of the effect, rather than on its direction.
As regards the effects of albumin versus crystalloid, most of the information (as indicated by the weighting in the meta-analysis) was provided by the SAFE (Saline versus Albumin Fluid Evaluation) trial (SAFE 2004) a large, well conducted, and low risk of bias trial. The pooled RR for death with albumin in this updated meta-analysis is 1.01 (95% CI 0.93 to 1.10).
As for hydroxyethyl starch, the updated meta-analysis provides a more precise estimate of its effect on mortality since it includes many thousands of patients and the number of deaths is large. Furthermore, the two studies that contribute 80% of the weight in the meta-analysis (Myburgh 2012; Perner 2012) were of high methodological quality with a low risk of bias. The pooled relative risk of death with hydroxyethyl starch is 1.10 (95% CI 1.02 to 1.19) suggesting that a mortality reduction is highly unlikely and that there may be an increase in the risk of death.
The results of this updated meta-analysis have important policy implications. There is still no evidence that colloids are superior to crystalloids as a treatment for intravascular volume resuscitation in critically ill patients, and some of them may even increase mortality. In addition, colloids are considerably more expensive than crystalloids. The economic opportunity cost of ongoing colloid use is likely to be considerable, and for this reason the ongoing use of colloids is unjustified.
Implications for practice
There is no evidence from randomised controlled trials that resuscitation using colloids compared with crystalloids reduces the risk of death in patients with trauma, burns or following surgery. The use of hydroxyethyl starch might even increase mortality. Since colloid use is not associated with improved survival and colloids are considerably more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified.
Implications for research
Further clinical trials of colloid use need to justify carefully the potential for patient benefit.
We acknowledge the contribution of Phil Alderson, Frances Bunn, Paul Chinnock, Gillian Schierhout and Mia Pearson who were authors of earlier versions of this review.
We would like to acknowledge the Intensive Care National Audit and Research Network in London (UK), for assistance with identification of trials for this review.
We thank Dr. Frank M. Brunkhorst for providing the Supplementary Appendix to the paper Brunkhorst 2008.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Search strategy
Cochrane Injuries Group Specialised Register
colloid* or hydrocolloid* or crystalloid*
Cochrane Central Register of Controlled Trials (The Cochrane Library)
#1 MeSH descriptor Plasma Volume explode all trees
#2 MeSH descriptor Fluid Therapy explode all trees
#3 MeSH descriptor Resuscitation explode all trees
#4 (fluid* OR volume OR plasma OR rehydrat* OR blood OR oral) next (replac* OR therapy OR substitut* OR restor* OR resuscitat* OR rehydrat*):ti,ab,kw
#5 (#1 OR #2 OR #3 or #4)
#6 MeSH descriptor Colloids explode all trees
#7 MeSH descriptor Hetastarch explode all trees
#8 MeSH descriptor Rehydration Solutions explode all trees
#9 MeSH descriptor Isotonic Solutions explode all trees
#10 MeSH descriptor Serum explode all trees
#11 MeSH descriptor Plasma explode all trees
#12 MeSH descriptor Plasma Substitutes explode all trees
#13 MeSH descriptor Albumins explode all trees
#14 MeSH descriptor Serum Albumin explode all trees
#15 (colloid* OR hydrocolloid* or crystalloid* OR albumin* OR albumen* OR plasma OR starch* OR dextran* OR gelofus* OR hemaccel* OR haemaccel* OR serum OR hetastarch OR isotonic OR ringer* OR gelatin* OR gentran* OR pentastarch* OR pentaspan* OR hartman OR sodium OR potassium OR saline):ti
#16 (Isotonic next saline next solution*) OR (Blood next substitut*) OR (blood next expan*) OR (plasma next volume next expan*) OR (volume next expan*)
#17 (#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16)
#18 (#5 AND #17)
1. exp Plasma Volume/
2. exp Fluid Therapy/
3. exp Resuscitation/
4. ((fluid* or volume or plasma or rehydrat* or blood or oral) adj1 (replac* or therapy or substitut* or restor* or resuscitat* or rehydrat*)).ab,ti.
5. 1 or 2 or 3 or 4
6. exp Colloids/
7. exp Hetastarch/
8. exp Rehydration Solutions/
9. exp Isotonic Solutions/
10. exp Serum/
11. exp Plasma/
12. exp Plasma Substitutes/
13. exp Albumins/
14. exp Serum Albumin/
15. (colloid* or hydrocolloid* or crystalloid* or albumin* or albumen* or plasma or starch* or dextran* or gelofus* or hemaccel* or haemaccel* or serum or hetastarch or isotonic or ringer* or gelatin* or gentran* or pentastarch* or pentaspan* or hartman or sodium or potassium or saline).ti.
16. ((Isotonic adj1 saline adj1 solution*) or (Blood adj1 substitut*) or (blood adj1 expan*) or (plasma adj1 volume adj1 expan*) or (volume adj1 expan*)).ab,ti.
18. 5 and 17
20. randomized controlled trial.pt.
21. controlled clinical trial.pt.
23. clinical trials as topic.sh.
26. 19 or 20 or 21 or 22 or 23 or 24 or 25
27. (animals not (humans and animals)).sh.
28. 26 not 27
29. 18 and 28
1. exp plasma volume/
2. exp fluid therapy/
3. exp fluid resuscitation/
4. ((fluid* or volume or plasma or rehydrat* or blood or oral) adj1 (replac* or therapy or substitut* or restor* or resuscitat* or rehydrat*)).ab,ti.
5. 1 or 2 or 3 or 4
6. exp colloid/
7. exp hetastarch/
8. exp "solution and solubility"/
9. exp isotonic solution/
10. exp serum/
11. exp serum albumin/
12. exp crystalloid/
13. exp hetastarch/
14. exp plasma/
15. exp plasma substitute/
16. exp albumin/
17. exp serum albumin/
19. (th or ad or iv).fs.
20. 18 and 19
21. (colloid* or hydrocolloid* or crystalloid* or albumin* or albumen* or plasma or starch* or dextran* or gelofus* or hemaccel* or haemaccel* or serum or hetastarch or isotonic or ringer* or gelatin* or gentran* or pentastarch* or pentaspan* or hartman or sodium or potassium or saline).ti.
22. ((Isotonic adj1 saline adj1 solution*) or (Blood adj1 substitut*) or (blood adj1 expan*) or (plasma adj1 volume adj1 expan*) or (volume adj1 expan*)).ab,ti.
23. 20 or 21 or 22
24. exp Randomized Controlled Trial/
25. exp controlled clinical trial/
28. *Clinical Trial/
31. 24 or 25 or 26 or 27 or 28 or 29 or 30
32. exp animal/ not (exp human/ and exp animal/)
33. 31 not 32
34. 5 and 23 and 33
ISI Web of Science: Science Citation Index Expanded, ISI Web of Science: Conference Proceedings Citation Index-Science
#1 colloid* OR hydrocolloid* or crystalloid*)
#2 (Isotonic NEAR/1 saline NEAR/1 solution*) OR (Blood NEAR/1 substitut*) OR (blood NEAR/1 expan*) OR (plasma NEAR/1 volume NEAR/1 expan*) OR (volume NEAR/1 expan*))
#3 #1 OR #2
#4 (fluid* OR volume OR plasma OR rehydrat* OR blood OR oral) NEAR/2 (replac* OR therapy OR substitut* OR restor* OR resuscitat* OR rehydrat*))
#5 (random*) NEAR/3 (study or trial)
#6 (singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*) NEAR/3 (study or trial)
(((((((colloid* OR hydrocolloid* OR crystalloid* OR albumin* OR albumen* OR plasma OR starch* OR dextran* OR gelofus* OR hemaccel* OR haemaccel* OR serum OR hetastarch OR isotonic OR ringer* OR gelatin* OR gentran* OR pentastarch* OR pentaspan* OR hartman OR sodium OR potassium OR saline) AND title)) OR (colloids[MeSH Terms]))) AND ((((fluid* OR volume OR plasma OR rehydrat* OR blood OR oral) AND (replac* OR therapy OR substitut* OR restor* OR resuscitat* OR rehydrat*))) OR (((plasma volume[MeSH Terms]) OR fluid therapy) OR resuscitation)))) AND ((randomised OR randomized OR randomly OR random order OR random sequence OR random allocation OR randomly allocated OR at random OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh]) NOT ((models, animal[mh] OR Animals[mh] OR Animal Experimentation[mh] OR Disease Models, Animal[mh] OR Animals, Laboratory[mh]) NOT (Humans[mh])))
Last assessed as up-to-date: 17 October 2012.
Protocol first published: Issue 4, 1997
Review first published: Issue 4, 1997
Contributions of authors
July 2007: PP and IR examined trials for inclusion or exclusion, reaching agreement by discussion. PP and IR extracted data from the new studies. PP, IR and KK amended the text of the review.
April 2009: IR and MP examined trials for inclusion or exclusion, reaching agreement by discussion. IR and MP extracted data from the new study. MP amended the text of the review. PP edited the final version.
February 2011: The Cochrane Injuries Group amended the text (Emma Sydenham, Managing Editor). Both authors agreed with the changes to the manuscript.
November 2012: PP and IR examined trials for inclusion or exclusion, reaching agreement by discussion. PP and KK extracted data from the new studies. PP amended the text of the review. All the authors agreed with the changes in the manuscript.
Declarations of interest
Sources of support
- Institute of Child Health, University of London, UK.
- UK Cochrane Centre, NHS R&D Programme, UK.
- NHS R&D Programme: Mother and Child Health, UK.
- Cochrane Review Incentive Scheme, Department of Health, UK.
The editorial group is aware that a clinical trial by Professor Joachim Boldt has been found to have been fabricated (Boldt 2009). As the editors who revealed this fabrication point out (Reinhart 2011; Shafer 2011), this casts some doubt on the veracity of other studies by the same author. All Cochrane Injuries Group reviews that include studies by this author have therefore been edited to show the results with this author's trials included and excluded. Readers can now judge the potential impact of trials by this author (Boldt 1986; Boldt 1993; Boldt 2001; Lang 2001; Lang 2003) on the conclusions of the review.
Emma Sydenham, Managing Editor, performed the sensitivity analysis.
Medical Subject Headings (MeSH)
Albumins [therapeutic use]; Blood Proteins [therapeutic use]; Colloids [*therapeutic use]; Critical Illness [mortality; *therapy]; Dextrans [therapeutic use]; Fluid Therapy [methods]; Gelatin [therapeutic use]; Hydroxyethyl Starch Derivatives [adverse effects; therapeutic use]; Isotonic Solutions [*therapeutic use]; Plasma Substitutes [adverse effects; therapeutic use]; Randomized Controlled Trials as Topic; Rehydration Solutions [therapeutic use]; Resuscitation [*methods]
MeSH check words
* Indicates the major publication for the study