Fluid resuscitation is a fundamental intervention in acute medicine. There is wide variation in the selection and use of resuscitation fluids, which is primarily influenced by the personal preferences of clinicians, local availability of fluids, and marketing.1,2 Although hydroxyethyl starch (HES) is the most frequently prescribed colloid for resuscitation on a global basis,1 there is a paucity of high-quality evidence to justify such widespread use.3 – 7
On October 28, 2010,a Anesthesia & Analgesia retracted an article by Boldt et al.8 reporting a randomized controlled trial evaluating 6% HES 130/0.4 as a priming fluid for cardiopulmonary bypass circuits. Subsequently, 18 journals retracted a further 87 reports from the same first author. Eleven of the retracted articles reported the use of 6% HES 130/0.4 for fluid resuscitation, predominantly in patients undergoing anesthesia and in perioperative settings.b , c These reports constitute a substantive body of published literature describing the safety and efficacy of 6% HES 130/0.4, some of which have been cited in manufacturers' product information sheets, submissions to regulatory authorities, and subsequent study protocols.9
Accordingly, there is an imperative to reevaluate the available evidence regarding the safety and efficacy data for 6% HES 130/0.4. Consequently, we conducted a systematic review of published high-quality evidence and determined whether the exclusion of the retracted trials had altered the balance of evidence.
The aim of this review was to determine whether there was a difference in patient-centered outcomes, primarily mortality and acute renal injury, in acutely ill adult patients receiving 6% HES 130/0.4 for fluid resuscitation compared with other resuscitation fluids.
Eligibility Criteria and Validity Appraisal
Potentially eligible studies included the following requirements: (1) prospective, randomized controlled trials, (2) patients older than 18 years, (3) a hospital or prehospital clinical setting, (4) patients who were acutely ill or undergoing major surgery, (5) study fluids were administered for resuscitation (defined as fluid required to increase or maintain intravascular volume), (6) at least 1 intervention group received 6% HES 130/0.4 in any carrier solution, (7) at least 1 intervention group received another colloid or any type of crystalloid solution for resuscitation, and (8) the study reported at least 1 of the following 5 outcomes: (i) mortality, (ii) need for renal replacement therapy (RRT), (iii) urine output, (iv) transfusion of red blood cells (RBCs), and (v) estimated or measured blood loss.
Studies were excluded if any of the following criteria were present: (1) studies enrolling only healthy volunteers or blood donors, (2) administration of fluid solely for the purposes of a planned anesthetic procedure including spinal or epidural anesthesia, acute normovolemic hemodilution, hypervolemic hemodilution, or priming of a cardiopulmonary bypass circuit without subsequent intra- or postoperative use, and (3) administration of fluid solely for intravascular volume therapy (hemodilution) after ischemic stroke or subarachnoid hemorrhage.
In addition to the above outcome measures, we collected data on transfusion of other blood products (plasma, platelets, cryoprecipitate), peak serum creatinine, and adverse events. We attempted to collect individual patient data that would be suitable for computing a RIFLE score (Risk, Injury, Failure, Loss, End-stage kidney disease categories for acute kidney injury),10 or the score itself if reported directly. We did not extract outcomes pertaining to coagulation function in vitro, injury biomarkers, or inflammatory mediators.
Studies with a high risk of bias (as defined below) were included unless 2 reviewers (DG, AD) both agreed that there was a stated methodological flaw of sufficient magnitude to completely invalidate all of the outcomes of interest. Internal validity was evaluated using a tool based on “yes/no” responses to the following 5 domains: randomization, allocation concealment, blinding, intention-to-treat analysis, and minimal loss to follow-up.11 Low risk of bias was defined as scoring “yes” to all 5 domains. Intermediate risk of bias was defined as scoring “yes” to 4 of 5 domains. High risk of bias was defined as scoring “yes” to 3 or fewer of 5 domains. For randomization, use of the term “randomization” in any form without a clear description of sequence generation was deemed pseudorandomization and judged “no” to randomization. Allocation concealment was considered to have been “yes” if any method for doing so was described. Blinding was assessed in 3 areas (patient, clinicians, outcome assessors) with all 3 elements required to be stated as blinded in order for the trial to be considered blinded overall. Blinding of the fluid alone without any further description was considered to be “no” to blinding. Intention-to-treat analysis was interpreted strictly, with any patients removed from analysis after randomization considered to be “no” for that trial. Loss to follow-up of <10% for the primary outcome was considered acceptable.
Four electronic databases were searched on December 24, 2010: Ovid MEDLINE (1950 to November week 3, 2010), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the metaRegister of Controlled Trials (controlled-trials.com). In addition, the reference lists from other published systematic reviews were hand-searched for any additional studies that met inclusion criteria. No language restriction was placed on the search. Contact was made with experts in the field for any unpublished trials. The search terms used in MEDLINE, EMBASE, and CENTRAL are contained in the Appendix.
Study Selection and Data Extraction
Two reviewers (DG, AD) screened the results of the search independently. Full-text manuscripts of potentially eligible articles were obtained and assessed independently against inclusion and exclusion criteria. The same 2 authors independently extracted the data and appraised the internal validity of each study. Differences were then compared and resolved by agreement or referral to a third reviewer (JM). The variables pertaining to patients and setting were total number of patients, number of participating centers, clinical setting, and diagnostic group. We collected details regarding volume of 6% HES 130/0.4 as an indication of dose on a milliliter/kilogram/day basis.
For the clinical setting, we transformed the data into 3 categories: perioperative (defined as fluid used intraoperatively and postoperatively), operative (fluid used intraoperatively only), and intensive care unit (ICU) (patients admitted to an ICU at the time of enrollment for a reason that was not associated with routine postoperative care).
For volume of fluid administered, we transformed the data into 3 categories according to the mean daily cumulative volume of exposure to 6% HES 130/0.4 throughout the study period: <1 L, 1 to 3 L, or >3 L. These groupings were chosen to approximate low (<15 mL/kg), medium (15–40 mL/kg), and higher (>40 mL/kg) dose exposure to 6% HES 130/0.4 for a typical 70-kg individual, in accordance with current dosing limits approved by regulatory authorities such as the Food and Drug Administration and Therapeutic Goods Administration of Australia.
All-cause mortality was collected preferentially if reported. When mortality was reported at more than one time point, we used the longest complete follow-up time after exposure to study fluids. Studies that were retracted at the time of submission for publication were included in the database if they met the review inclusion criteria, but excluded from the primary analyses.
Prespecified subgroup analyses were control group fluid (6% HES 130/0.4 versus crystalloid; non-HES colloids and other HES solutions), and setting (ICU versus other). We conducted a sensitivity analysis in which we included all the retracted studies.
The relative risk of death for 6% HES 130/0.4 compared with control group fluid was calculated for each study and then pooled via a meta-analysis with random effects using the metan routine in Stata version 11 (StataCorp LP, College Station, TX). I 2 was calculated as a measure of consistency. Trials with no deaths were excluded from the pooled estimate of relative risk. Studies with 0 deaths in 1 intervention group were added to the pooled estimate by adding 0.5 to each cell of the 2-by-2 table.12
For studies with >1 control group, a single control comparison was selected with preference given to a crystalloid control group, then another class of colloid, and finally another HES comparator. If there was >1 crystalloid control group, these were pooled to make a single comparison between 6% HES 130/0.4 and crystalloid. The remaining control groups were not included in the pooled mortality analysis.
The study flow diagram is shown in Figure 1. The initial search yielded 3504 results. After title and abstract screening, full text manuscripts for 170 potentially eligible studies were obtained. Two further studies were excluded because of inability to obtain language translation.13,14 One trial was excluded because of high risk of bias in relation to randomization.15 One trial was excluded because there was no response from the contacted author.16 After application of the inclusion and exclusion criteria, 36 studies were included in the review, of which 11 had been retracted and so were not included in the primary analysis.17 – 27
The characteristics of the included studies are summarized in Table 1. The total number of participants in the 25 studies was 1608, an average of 64 participants per study; 6 (24%) of the trials were multicentered. The overall mortality rate was 8.7% (104 of 1184). In 11 of 25 reports (n = 696), 6% HES 130/0.4 was compared with other formulations of HES as the control group. Five of 25 studies (n = 372) compared 6% HES 130/0.4 with at least 1 crystalloid control group.
Six trials (n = 362) enrolled patients in an ICU setting, of which 3 trials enrolled patients with severe sepsis (n = 101),28 – 30 and 1 enrolled patients with severe traumatic brain injury (n = 31).31 The remaining 2 ICU trials enrolled patients with hypovolemia (n = 230).32,33
Four of 25 trials exposed participants to a mean cumulative daily dose of >3 L of 6% HES 130/0.4 (approximately 40 mL/kg for a 70-kg person). Only 1 of these studies was in critically ill patients (patients with traumatic brain injury) (n = 31) and this trial was stopped early because of safety concerns in the control group (HES 200/0.5).31 In 9 of the remaining trials, the cumulative mean exposure of the study group to 6% HES 130/0.4 was <1 L or not stated.
Study quality and the risk of bias are summarized in Table 2. No studies were judged to have a low risk of bias (scoring “yes” to all 5 domains of validity), and 17 (68%) were adjudicated to have a high risk of bias (scoring “yes” to ≤3 domains). There were 8 studies (32%) that were of good quality in all domains other than blinding.
Eleven of 36 reports (n = 541) were retracted at the time of this writing. This represents 31% of the published reports and 25% of enrolled participants in 6% HES 130/0.4 trials meeting our criteria as fluid resuscitation trials.
Sixteen (64%) remaining, unretracted studies reported mortality. The pooled estimate of the relative risk of death in patients assigned to receive 6% HES 130/0.4 in these studies was 0.95 (95% confidence interval 0.64–1.42), with no significant heterogeneity (I 2 = 0%, P = 0.73) (Fig. 2). The relative risk of death in patients assigned to receive 6% HES 130/0.4 when the retracted articles were included was 0.92 (95% confidence interval 0.63–1.34, I 2 = 0%, P = 0.95). Subgroup analyses pertaining to type of control fluid and setting (ICU versus other) were not amenable to meta-analysis because of the multitude of comparator fluids and the small number of studies conducted in ICUs.
The data reporting acute kidney injury and need for RRT are described in Table 3. Five of 9 studies reporting need for RRT have been retracted. There were no data that made the calculation of a RIFLE category possible, and RIFLE criteria were not reported in any studies. There were no studies reporting need for RRT in which 6% HES 130/0.4 was compared with a crystalloid control. Four studies reported 7 RRT events among 238 patients in which 6% HES 130/0.4 was compared with gelatin or colloid. Urine output was reported in 12 studies, of which 5 compared 6% HES 130/0.4 with crystalloid. Tabulation of data relating to acute kidney injury or urine output was not amenable to meta-analysis.
Transfusion of RBCs was reported in 20 (80%) of 25 studies. Bleeding was reported in 18 (72%) of 25 studies. There was a high degree of variability in the summary measures and reporting standards. Similarly, data for other outcomes such as transfusion of non-RBC blood products, peak serum creatinine, and adverse events were sparse. Tabulation of data relating to bleeding was not amenable to meta-analysis.
The principal finding of this systematic review was that there was no difference in the relative risk of death in acutely ill patients resuscitated with 6% HES 130/0.4 compared with other resuscitation fluids. However, the confidence intervals for the effect on mortality were wide, making it possible that resuscitation with 6% HES 130/0.4 may confer significant benefit or may cause substantial harm. This difference was not altered by the inclusion of retracted studies. Almost all studies had a high risk of bias and small sample sizes: fewer than 2200 participants have been enrolled in randomized controlled trials that compared 6% HES 130/0.4 with other resuscitation fluids. Few studies reported patient-centered outcomes such as mortality, need for RRT, and bleeding.
The strength of this review is that it is focused on 6% HES 130/0.4 and patient-centered outcomes reported in high-quality randomized controlled trials. Trial adjudication and meta-analysis were conducted in accordance with methodological guidelines.34 This review was conducted promptly after the simultaneous retraction of a number of articles that comprised a substantial proportion of data on the safety and efficacy of 6% HES 130/0.4. This is a unique event in intensive care medicine.35 We determined that removing the retracted data did not alter the conclusion that there was no empirical evidence that the pooled estimate for mortality (or any other patient-centered outcome) shifted the point estimate in the direction of benefit or harm without these data. We also determined that the overall quality and quantity of published data were low.
Previous systematic reviews of this topic, pertaining to critically ill patients and/or fluid resuscitation, have concluded that colloids do not exert benefit or reduce harm when compared with other fluids.3,4,7 Other reviews have focused on safety concerns such as renal toxicity5,6,36 or bleeding,37,38 but have not differentiated between different formulations of HES, or concluded that safety data for 6% HES 130/0.4 are lacking. Other reviews in specific subpopulations are not generalizable to acutely ill adults in the hospital setting.39 – 41 A limitation of this systematic review is that we concentrated on outcomes relevant to acutely ill patients receiving fluid for resuscitation in the ICU; 6% HES 130/0.4 is used in other settings, particularly anesthetic and perioperative settings. This review did not compare the effects of older preparations of HES unless the trial included a 6% HES 130/0.4 group, but the potential adverse renal effects of these preparations are now recognized.5,6,42,43 As with all systematic reviews, the results of pooled analysis are only as robust as the results of included studies. The retractions of studies highlight the ethical and scientific imperative to determine the safety and efficacy of 6% HES 130/0.4 in critically ill patients in high-quality randomized controlled trials.
The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) is an investigator-initiated, 7000-patient, multicentered, randomized controlled trial comparing the effect of 6% HES 130/0.4 with normal saline on day-90 mortality in patients receiving the fluid for resuscitation in 33 medical and surgical ICUs in Australia and New Zealand (ClinicalTrials.gov Identifier: NCT00935168). The study protocol9 was developed closely on the lines of the Saline versus Albumin Fluid Evaluation study44 that was conducted by the same group of investigators. Recruitment commenced in December 2009 and the first interim analysis was performed on March 8, 2011 after the first 2000 patients had completed 90-day follow-up. Recruitment is currently scheduled to be completed by November 2011 and the results are anticipated to be available in 2012.
In response to the retraction of articles reporting the safety or efficacy of HES 130/0.4, the CHEST Management Committee instituted a number of measures to inform study investigators, the Data Safety and Monitoring Committee, and IRBs about the potential impact of the retractions on the conduct of the trial.45 Central to this was the conduct of this systematic review comparing the effects of 6% HES 130/0.4 with other resuscitation fluids on the primary and secondary outcomes of CHEST, with a sensitivity analysis including the retracted articles, 4 of which were cited in the background section of the CHEST protocol.
When completed, we expect that CHEST may provide robust and reliable evidence to inform clinicians of the safety and efficacy of 6% HES 130/0.4 compared with saline in critically ill patients. The results of this trial and other high-quality trials of fluid resuscitation are urgently required to address the safety and efficacy of a fundamental intervention in intensive care medicine.
Name: David J. Gattas, MB BS, MMed, FCICM.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: David J. Gattas has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: Dr. Gattas is a member of the management committee and a site investigator for the Crystalloid versus Hydroxyethyl Starch Trial (CHEST). This trial is partially funded and receives study fluid and logistical support from Fresenius Kabi through the University of Sydney to the George Institute for Global Health. Dr. Gattas is also an honorary fellow of the Critical Care and Trauma division of this institute.
Name: Arina Dan, MB BS, FCICM.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Arina Dan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: Dr. Dan is partly employed as a research fellow of the Critical Care and Trauma division of the George Institute for Global Health. This institution is conducting CHEST. This trial is partially funded and receives study fluid and logistical support from Fresenius Kabi through the University of Sydney to the George Institute for Global Health.
Name: John Myburgh, MBBCh, PhD, FCICM.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: John Myburgh has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: Professor Myburgh has received travel and speaker expenses from Fresenius Kabi. He is Chief Investigator for the Crystalloid versus Hydroxyethyl Starch Trial (CHEST) that has received unrestricted grant funding from Fresenius through the University of Sydney to the George Institute.
Name: Laurent Billot, MSc, DEA, AStat.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Laurent Billot has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: Mr. Billot is employed by the George Institute for Global Health. This institution is conducting CHEST. This trial is partially funded and receives study fluid and logistical support from Fresenius Kabi through the University of Sydney to the George Institute for Global Health.
Name: Serigne Lo, PhD, AStat.
Contribution: This author helped analyze the data.
Attestation: Serigne Lo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: Dr. Lo is employed by the George Institute for Global Health. This institution is conducting CHEST. This trial is partially funded and receives study fluid and logistical support from Fresenius Kabi through the University of Sydney to the George Institute for Global Health.
Name: Simon Finfer.
Contribution: This author helped write the manuscript.
Attestation: Simon Finfer approved the final manuscript.
Conflicts of Interest: Professor Finfer has received travel and speaker expenses from Fresenius Kabi. He is a Principal and Site Investigator for the Crystalloid versus Hydroxyethyl Starch Trial (CHEST) that has received unrestricted grant funding from Fresenius through the University of Sydney to the George Institute. Professor Finfer has received travel and speaker expenses from CSL. CSL has supported meetings of the ANZICS Clinical Trials Group, which endorses CHEST.
Name: CHEST Management Committee members: John Myburgh (Chair), Julie Harland (Senior Project Manager), Rinaldo Bellomo, Alan Cass, Simon Finfer, David Gattas, Parisa Glass, Jeff Lipman, Bette Liu, Colin McArthur, Shay McGuinness, Dorrilyn Rajbandhari, Colman Taylor, and Steve Webb.
Contributions: The authors reviewed the final manuscript.
Attestations: The authors approved the final manuscript.
Conflicts of Interest: The authors have no conflicts of interest to report.
This manuscript was handled by: Michael Murray, MD, PhD.
The authors thank Lei Min, MD, who provided assistance with language translation.
a Shafer SL. Notice of Retraction. Available at: http://www.aaeditor.org/NoticeofRetraction.pdf. Accessed February 20, 2011.
b Rasmussen LS, et al. Editors-in-Chief Statement Regarding IRB Approval of Clinical Trials by Joachim Boldt. Available at: http://www.aaeditor.org/EICJointStatement.pdf. Accessed February 20, 2011.
c Shafer SL. 25 February 2011 Notice. Available at: http://www.anesthesia-analgesia.org/site/misc/25.February.2011.Notice.pdf. Accessed March 1, 2011.
APPENDIX Electronic Search Strategy
The intersection of: fluid resuscitation, hydroxyethyl starch, and randomized controlled trials.
- exp Fluid Therapy
- ((fluid$ or volume$ or plasma$ or rehydrat$) adj3 (replace$ or therap$ or substitut$ or restor$ or resuscitat$ or rehydrat$)).ab,ti.
- or/1 to 2
- exp Starch
- exp Blood Substitutes
- exp Colloids
- hydroxyethyl starch.tw.
- hydroxy ethyl starch.tw.
- or/4 to 13
- 3 and 14
- limit 15 to “therapy (sensitivity)” [from the MEDLINE limit “Clinical Queries,” based on Haynes et al.65]
- #14. #3 AND #12 AND #13
- #13. random:ti OR ‘clinical trial':de,rn,ab,ti OR ‘health care quality'/exp
- #12. #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
- #11. tetrastarch
- #10. voluven*
- #9. pentastarch
- #8. ‘hydroxy ethyl starch'
- #7. hydroxyethylstarch
- #6. ‘hydroxyethyl starch'
- #5. hetastarch*
- #4. ‘starch'/exp OR starch
- #3. #1 OR #2
- #2. (fluid* OR volum* OR plasma* OR rehydrat*) NEAR/3 (therap* OR substitut* OR restor* OR resusc* OR replac*)
- #1. ‘fluid therapy'/exp OR ‘fluid therapy'
- #1. starch* or *starch or voluven* in Clinical Trials
- #2. MeSH descriptor Fluid Therapy explode all trees
- #3. ((fluid* or volume* or plasma* or rehydrat*) NEAR/3 (replace* or therap* or substitut* or restor* or resuscitat* or rehydrat*)):ab,ti in Clinical Trials
- #4. (#2 OR #3)
- #5. (#1 AND #4)
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2. Miletin MS, Stewart TE, Norton PG. Influences on physicians' choices of intravenous colloids. Intensive Care Med 2002;28:917–24
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37. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P. The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesth Analg 2008;107:382–90
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