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Caring for the Critically Ill Patient |

Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation:  A Systematic Review and Meta-analysis FREE

Ryan Zarychanski, MD, MSc; Ahmed M. Abou-Setta, MD, PhD; Alexis F. Turgeon, MD, MSc; Brett L. Houston, BSc; Lauralyn McIntyre, MD, MSc; John C. Marshall, MD; Dean A. Fergusson, PhD, MHA
[+] Author Affiliations

Author Affiliations: Department of Internal Medicine, Sections of Critical Care and Hematology and Medical Oncology (Dr Zarychanski), George & Fay Yee Center for Healthcare Innovation (Drs Zarychanski and Abou-Setta), University of Manitoba, and Winnipeg Regional Health Authority (Drs Zarychanski and Abou-Setta), and Cancercare Manitoba (Dr Zarychanski), Winnipeg, Canada; Division of Critical Care Medicine, Department of Anesthesiology, Centre de recherche du CHU de Québec, Enfant-Jésus Hospital, Axe Traumatologie-Urgence-Soins Intensifs, Université Laval, Québec City, Québec (Dr Turgeon); Faculty of Medicine, University of Manitoba, Winnipeg (Ms Houston); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Department of Medicine, University of Ottawa, Ottawa, Ontario (Drs McIntyre and Fergusson); Department of Surgery, University of Toronto, and the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario (Dr Marshall).


Caring for the Critically Ill Patient Section Editor: Derek C. Angus, MD, MPH, Contributing Editor, JAMA (angusdc@upmc.edu).

More Author Information
JAMA. 2013;309(7):678-688. doi:10.1001/jama.2013.430.
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Published online

Importance Hydroxyethyl starch is commonly used for volume resuscitation yet has been associated with serious adverse events, including acute kidney injury and death. Clinical trials of hydroxyethyl starch are conflicting. Moreover, multiple trials from one investigator have been retracted because of scientific misconduct.

Objectives To evaluate the association of hydroxyethyl starch use with mortality and acute kidney injury.

Data Sources Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, HealthStar, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to October 2012), reference lists of relevant articles, and gray literature.

Study Selection Two reviewers independently identified randomized controlled trials comparing hydroxyethyl starch with other resuscitation fluids in critically ill patients receiving acute volume resuscitation.

Data Extraction Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the risk of bias tool; the strength of evidence was adjudicated using the GRADE methodology.

Results We included 38 eligible trials comparing hydroxyethyl starch to crystalloids, albumin, or gelatin. The majority of trials were categorized as having an unclear risk or high risk of bias. For the 10 880 patients in studies contributing mortality data, the risk ratio (RR) for death among patients randomized to receive hydroxyethyl starch was 1.07 (95% CI, 1.00 to 1.14; I2, 0%; absolute risk [AR], 1.20%; 95% CI, −0.26% to 2.66%). This summary effect measure included results from 7 trials performed by an investigator whose subsequent research had been retracted because of scientific misconduct. When we excluded these 7 trials that involved 590 patients, hydroxyethyl starch was found to be associated with increased mortality among 10 290 patients (RR, 1.09; 95% CI, 1.02 to 1.17; I2, 0%; AR, 1.51%; 95% CI, 0.02% to 3.00%), increased renal failure among 8725 patients (RR, 1.27; 95% CI, 1.09 to 1.47; I2, 26%; AR, 5.45%; 95% CI, 0.44% to 10.47%), and increased use of renal replacement therapy among 9258 patients (RR, 1.32; 95% CI, 1.15 to 1.50; I2, 0%; AR, 3.12%; 95% CI, 0.47% to 5.78%).

Conclusion and Relevance In critically ill patients requiring acute volume resuscitation, use of hydroxyethyl starch compared with other resuscitation solutions was not associated with a decrease in mortality. Moreover, after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct, hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury. Clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns.

Figures in this Article

Fluids are a core element in the resuscitation of critically ill patients and the relative superiority and safety of different resuscitation solutions has been the focus of considerable debate. Crystalloid solutions are inexpensive and readily available, while colloid solutions may minimize resuscitation volumes, and may sustain intravascular volume for longer durations.1 Conflicting results from clinical trials and systematic reviews have not resolved this debate, leaving clinicians to select resuscitation fluids based on suboptimal evidence.

Hydroxyethyl starch is a synthetic colloid derived from partially hydrolyzed and variably hydroxyethylated plant starch, and is commonly administered to patients requiring fluid resuscitation.2 Clinical trials and systematic reviews have suggested a greater incidence of renal damage and mortality in patients receiving hydroxyethyl starch,36 but these findings have been inconsistent.7,8 The differing results may be due to a combination of factors including differing patient populations, types and volumes of hydroxyethyl starch and the safety profile of the comparator fluids.9 A further explanatory factor may be the influence of research misconduct or author bias.10,11

In 2011, 86% (88 of 102) of the research published by Joachim Boldt, MD, since 1999 was retracted after a government investigation reported research misconduct reflecting failure to acquire ethical approval for research and fabrication of study data.10,11 The effect of these retractions has been far-reaching. All major systematic reviews and clinical guidelines are now being revised to account for the retracted data and permit sensitivity analyses on the remaining publications by Boldt et al.

We performed a quantitative systematic review of randomized controlled trials comparing hydroxyethyl starch with other intravenous fluids for acute fluid resuscitation in critically ill patients. Our primary outcomes of interest were mortality and the incidence of acute kidney injury. Additionally, we investigated the influence of the studies conducted by Boldt and his colleagues on these outcomes.

Using an a priori published protocol,12 we conducted our systematic review using methodological approaches outlined in the Cochrane Handbook for Systematic Reviewers13 and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria.14 A technical panel of experts from multiple fields (eg, hematology, internal medicine, critical care medicine, research methodology) formulated the review questions, reviewed the search strategies and review methods, and provided input throughout the review process.

Populations, Interventions, Comparators, Outcome Measures, Settings, and Study Designs

We included only randomized, controlled trials of critically ill adult patients treated in an emergency or intensive care setting (eTable 1). The primary research question was “In critically ill patients requiring acute volume resuscitation, what is the comparative efficacy and potential harm of hydroxyethyl starch solutions compared with other resuscitation fluids?”

The main outcome measures were mortality and renal injury according to the RIFLE criteria15 stratifying kidney damage into: Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage kidney disease. Secondary outcomes were the incidence of renal recovery (10% of baseline function or independence of renal replacement therapy), incidence of major bleeding, transfusion of red blood cells, and reported allergic reactions. We also evaluated intensive care unit and overall length of stay, as well as the duration of mechanical ventilation. Inclusion and exclusion criteria are presented in eTable 2.

Search Strategy for Identification of Studies

We searched MEDLINE, EMBASE, CENTRAL (Cochrane Library), Global Health, and HealthStar from inception to October 2012 for relevant citations of published trials using individualized search strategies prepared for each database. The MEDLINE strategy is presented in eTable 3. We searched the World Health Organization's International Clinical Trials Registry Platform and hand-searched relevant conference proceedings for the preceding 5 years to identify planned, ongoing, or recently completed but unpublished trials of starch-based solutions (eTable 4). We performed forward searches in Scopus and Web of Science to identify additional citations that might have been missed through traditional searching methods. Finally, the reference lists of narrative and systematic reviews and included trials were hand-searched for relevant citations. We performed reference management in EndNote (version X5, Thomson Reuters).

Study Selection

We used a 2-stage process for study screening and selection using standardized and piloted screening forms. Two reviewers independently screened the titles and abstracts of search results to determine whether a citation met the inclusion criteria. The full text of citations classified as include or unclear were reviewed independently with reference to the predetermined inclusion and exclusion criteria. Discrepancies between the 2 reviewers were resolved through consensus by discussion with a third reviewer, as required.

Data Abstraction and Management

Two reviewers independently extracted data, using standardized and piloted data extraction forms, from included trial reports. Discrepancies between the 2 reviewers were resolved through consensus in discussion with a third reviewer, as required. Extracted data included demographics of the enrolled patient population, interventions, study outcomes, and funding sources. Data management was performed using Microsoft Excel 2010 (Excel version 14, Microsoft Corp).

Assessment of Methodological Quality and Potential Risk of Bias

We assessed internal validity using the Cochrane Collaboration's Risk of Bias tool.16 This tool consists of 6 domains and assesses 5 specific biases. We also assessed the source(s) of funding for each study and its potential influence on the outcome measures. We used information pertaining to methodological quality and risk of bias to guide sensitivity analyses and to explore sources of heterogeneity. To investigate the effect of trials conducted by Boldt, we performed a sensitivity analysis by author teams (Boldt et al vs other author teams).

Measures of Treatment Effect

We analyzed data from the included studies using Review Manager (RevMan, version 5.2, the Nordic Cochrane Center, the Cochrane Collaboration), Comprehensive Meta-Analysis (Biostat Inc, version 2.0), and Microsoft Excel (Excel version 14, Microsoft Corp). A formal meta-analysis was conducted if the data were statistically and clinically homogeneous. We expressed pooled continuous effect measures as the mean difference or standardized mean difference with 95% CIs. Pooled dichotomous data were expressed as risk ratio (RR), or Peto odds ratio (OR) in the event of rare outcomes17 and absolute risk (AR). We used the random-effects model for all analyses, with the exception of the Peto OR (fixed effect model).

Statistical heterogeneity of the data was explored and quantified, using the I2 test, with 95% uncertainty intervals.18 If significant statistical heterogeneity was detected (I2 >50%), a sensitivity analysis was conducted. Publication bias was assessed using funnel plot techniques, the Begg rank test, and the Egger regression test, as appropriate given the known limitations of these methods.19 All tests of statistical inference reflect a 2-sided α of .05.

Subgroup, Sensitivity, and Meta-Regression Analyses

Subgroup, sensitivity, and meta-regression analyses were performed to determine summary effect estimates of hydroxyethyl starch in specific patient populations, effects relative to specific comparator fluids, and the effect of other potentially confounding factors.12 Analyses were dependent on the number of studies included and the availability of appropriate outcomes and covariates. In additional analyses, trials conducted by Boldt et al were excluded.

Grading the Evidence

We graded the strength of evidence for our primary outcomes (external validity) using the GRADE methodology.20 Two reviewers evaluated the strength of the body of evidence. GRADE methodology assesses the evidence according to the following domains: study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations (eg, evidence of publication bias). This approach classifies the strength of evidence as high, moderate, low, or very low.

Of the 3779 citations identified from electronic and hand-searches, we included 38 unique trials (plus 4 companion publications) with 12 to 7000 patients (median, 42; interquartile range [IQR], 28 to 122) (Table 1, Table 2, Table 3, and Figure 1). Trials were published between 1982 and 2012 (median, 2004; IQR, 1996 to 2010), and all but one21 were published in peer-reviewed journals. Most trials were single-center randomized trials of patients with sepsis, trauma, or both in an acute care setting in European centers and published in an English language journal. Four2224 trials were from North America, and five2528 were published in non-English languages (eTable 5).

Table Graphic Jump LocationTable 1. Characteristics of Individual Trials, Patient Populations, and Interventions, 1988-1998
Table Graphic Jump LocationTable 2. Characteristics of Individual Trials, Patient Populations, and Interventions, 2000-2009
Table Graphic Jump LocationTable 3. Characteristics of Individual Trials, Patient Populations, and Interventions, 2010-2012
Place holder to copy figure label and caption
Figure 1. Study Flow Diagrama
Graphic Jump Location

aThis flow diagram follows the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA)14 with modifications.
bCompanion articles represent reports of previously published analyses involving the same study population.

The mean age of study patients ranged from 28 to 79 years; 61% of patients were men and 95% of the trials were adjudicated to be of unclear risk or high risk of bias; 3 trials29,30,54 were considered to have a low risk of bias ( eTable 6).

Primary Outcomes

Mortality. For 10 880 patients involved in the 35 studies contributing mortality data, the pooled RR for death among patients randomized to receive hydroxyethyl starch was 1.07 (95% CI, 1.00 to 1.14; I2, 0%; AR, 1.20%; 95% CI, −0.26% to 2.66%) (Figure 2). We did not detect publication bias, but given that the majority of trials were considered to be of unclear or high risk of bias, we graded the overall strength of evidence as low.

Place holder to copy figure label and caption
Figure 2. Mortality and Hydroxyethyl Starch
Graphic Jump Location

The varying sizes of the boxes represent the weight in the analysis. HES indicates hydroxyethyl starch. Risk ratios (RRs) are derived by a random-effects model using Mantel-Haenszel tests.

In 7 trial reports by Boldt et al7,2934 that had not been retracted (investigations into research misconduct and ethics violations were limited to trials published since 1999; the 7 trials included herein were published before 1999), we observed no association between hydroxyethyl starch and all-cause mortality among the studies' 590 patients (RR, 0.91; 95% CI, 0.74 to 1.12; I2, 0%; AR, −5.26%; 95% CI, −12.08% to 1.56%). In contradistinction to the findings of Boldt et al, pooled results from 10 290 patients involved in 28 trials3,4,44,2124,26,28,3543,4554 conducted by other investigators demonstrated that hydroxyethyl starch was significantly associated with increased death (RR, 1.09; 95% CI, 1.02 to 1.17; I2, 0%; AR, 1.51%; 95% CI, 0.02% to 3.00%). The heterogeneity between the 2 groups of trials was substantially high55 (I2, 59.4%). After removing the 7 trials from the analyses of mortality, none of the other mortality subgroups, sensitivity analyses, or meta-regression analyses had marked statistical heterogeneity between the trials (eTable 7). Given the measured statistical heterogeneity, coupled with the history of retractions of other trials conducted by Boldt et al, we excluded these 7 trials from further analyses. Without these trials, we graded the overall strength of evidence as moderate.

Acute Kidney Injury

Ten trials3,4,22,26,35,37,44,5254 reported on the incidence of renal replacement therapy use in 9258 patients (Figure 3). Pooled results demonstrate a significant relationship between hydroxyethyl starch administration and risk of receiving renal replacement therapy (RR, 1.32; 95% CI, 1.15 to 1.50; I2, 0%; AR, 3.12%; 95% CI, 0.47% to 5.78%) compared with other fluids (Figure 3). Two trials52,53 involving 996 patients reported all the RIFLE criteria for acute kidney injury, whereas another 5 trials3,4,35,44,54 reported on individual RIFLE components in 7886 patients (Table 4). The incidence of acute renal failure reported in a total of 5 trials3,44,52,54 involving 8725 patients was significantly higher in receiving hydroxyethyl starch (RR, 1.27; 95% CI, 1.09 to 1.47; I2, 26%; AR, 5.45%; 95% CI, 0.44% to 10.47%). We did not detect evidence of publication bias for this outcome and graded the strength of evidence as moderate.

Place holder to copy figure label and caption
Figure 3. Renal Replacement Therapy and Hydroxyethyl Starch
Graphic Jump Location

The varying sizes of the boxes represent the weight in the analysis. HES indicates hydroxyethyl starch. Risk ratios (RRs) are derived by a random-effects model using Mantel-Haenszel tests.

Secondary Outcome Measures

Among 6909 patients involved in 10 trials,4,24,25,3537,42,47,54,56 hydroxyethyl starch administration was associated with a reduction in urine output (standardized mean difference, −0.15; 95% CI, −0.19 to −0.10; I2, 0%) (Table 4). Included trials did not report changes in the glomerular filtration rates, incidence of renal recovery, or the incidence of anuria among patients. No differences in intensive care unit length of stay21,40,46,52,54 (n = 7016, 5 trials) or overall hospital length of stay21,23,26,35,52,54 (n = 7337, 6 trials) were reported. There was no reported difference in the average duration of ventilation days32,3554 (n = 6984, 3 trials). The reports on the incidence of hemorrhage and use of blood transfusions were conflicting with most trials providing no extractable data (Table 4). None of the included trials reported the average volume of blood loss among patients; however, 1 trial53 involving 800 patients reported no significant difference in the incidence of severe hemorrhage. Pooled results from 5 trials23,36,44,53,57 involving 1482 patients showed a significantly higher incidence of red blood cell transfusions in patients randomized to receive hydroxyethyl starch (RR, 1.42; 95% CI, 1.15 to 1.75; I2, 0%); however, the transfusion volume was not reported to be different between groups in 3 trials4,23,56 involving 162 patients (Table 4). Most trials did not systematically screen for, or report the incidence of allergic reactions to resuscitation fluids. When reported, allergies rarely (<1%) occurred50,51,53 among 984 patients involved in 3 trials (Table 4).

Subgroup, Sensitivity and Meta-Regression Analyses

Subgroup analyses by trial region (North America vs other regions), sponsorship (industry vs other sources), publication type (peer-reviewed publication vs conference abstract), intervention (6% vs 10% hydroxyethyl starch doses), comparator (albumin, crystalloids, gelatin), patient population (sepsis vs trauma vs other populations), or the date of trial publication (before vs after Surviving Sepsis Campaign guidelines) demonstrated no major differences; however, most subgroups were subject to type II errors due to small sample sizes ( eTable 7). Using meta-regression we did not find a correlation between patient mortality and the duration of the study intervention or study follow-up (eFigures 1 and 2).

In this systematic review, we observed the overall RR for mortality associated with hydroxethyl starch to be 1.07 (95% CI, 1.00-1.13). With the exclusion of trials conducted by Boldt et al,7,2934 hydroxyethyl starch administration was significantly associated with increased mortality and severe kidney injury (acute renal failure and renal replacement therapy).

Hydroxyethyl starch solutions are effective volume expanders but are not localized to the circulatory system and are known to deposit in the skin, liver, muscle, spleen, endothelial cells, and kidneys of patients who receive these products.58,59 The toxic effects on renal function have been well documented in experimental and clinical studies, but some researchers have argued that adverse effects depend on the volume and molecular weight of the hydroxyethyl starch preparations and patient population.5 Proponents of starch solutions have argued increased safety with each newly marketed product, but evidence from randomized trials do not support these claims.29,30,54

Risk of bias is a major concern when adjudicating clinical trials of therapeutic interventions. The possibility of inaccurate or fraudulent data further complicates assessment and may be challenging to detect. In our systematic review, we demonstrated that inclusion of such studies can influence how the global medical community interprets a given body of literature and how exclusion of questionable studies can shift the balance of evidence toward benefit or harm. This state of affairs is not unique to trials evaluating hydroxyethyl starch; published retractions have prompted the reexamination of the superiority of multimodal pain management60; the association between autism and the measles, mumps, and rubella vaccine61; and, most recently, the efficacy of serotonin 5-HT3 receptor antagonists for the treatment postoperative nausea and vomiting.62

The strengths of this review include the completeness of the search including searching multiple citation databases and trial registries, hand searching of the gray literature, and forward searching. In addition, the use of unpublished data and non-English publications increases the validity of the results. We also used an a priori published protocol and followed established methodological guidelines in the conduct and reporting of this review.

Our systematic review has limitations. We pooled trials from distinct patient populations (all of which were considered to be seriously ill requiring acute volume resuscitation), hydroxyethyl starch formulations of differing molecular weights, and competitors (eg, albumin, crystalloids, gelatin). This is, however, consistent with the clinical use of fluid resuscitation in that patients are often resuscitated with a mixture of different fluids. The subgroup analyses of mortality were susceptible to type II errors due to the relative small sample sizes, but showed a consistent trend with the main analysis. Finally, the internal validity of the trials was often unclear due to underreporting of the safeguards against the commonly identified biases, which ultimately downgraded the strength of evidence.

Although larger trials generally contribute more weight to summary effect measures in meta-analyses, the distribution of events between groups remains an important consideration. The 5 trials that enrolled 200 or more patients accounted for 64% of the weighting in the meta-analysis of mortality. The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) alone accounts for 35% of the weighting, but its exclusion neither influences the direction nor the significance of our study findings.40

The clinical use of colloidal starch solutions, including hydroxyethyl starch, has increased despite their higher cost relative to crystalloid solutions, lack of evidence of their clinical superiority,8 and pervasive safety concerns.5,63 Over the years, hydroxyethyl starch products have appeared in several resuscitation guidelines, including those of the US Hospital Consortium64 and have often been advocated as the cornerstone of resuscitation therapy. However, recommendations are being revisited in light of major retractions,64 recent trials,5254 and evidence from systematic reviews.5,6 Moreover, based on available clinical data, there is no a priori reason to conclude that newer hydroxyethyl starch products with lower molecular weights are safer.52,53 Ongoing randomized trials65,66 will provide further clarity regarding the efficacy and safety of hydroxyethyl starch in critically ill patients.

In conclusion, among critically ill patients requiring acute volume resuscitation, use of hydroxyethyl starch, compared with other resuscitation solutions was not associated with reduced mortality. Moreover, after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct, hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury. Clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns.

Corresponding Author: Ryan Zarychanski, MD, MSc, University of Manitoba, Department of Internal Medicine, Sections of Critical Care and of Hematology and Medical Oncology, University of Manitoba, ON2056-675 McDermot Ave, Winnipeg, Manitoba R3E 0V9, Canada (ryan.zarychanski@cancercare.mb.ca).

Author Contributions: Drs Zaryhanski and Abou-Setta 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: Zarychanski, Abou-Setta, Turgeon, McIntyre, Fergusson.

Acquisition of data: Zarychanski, Abou-Setta, Houston.

Analysis and interpretation of data: Zarychanski, Abou-Setta, Turgeon, McIntyre, Marshall, Fergusson.

Drafting of the manuscript: Zarychanski, Abou-Setta, Turgeon, McIntyre, Fergusson.

Critical revision of the manuscript for important intellectual content: Zarychanski, Abou-Setta, Turgeon, Houston, McIntyre, Marshall, Fergusson.

Statistical analysis: Zarychanski, Abou-Setta.

Administrative, technical, or material support: Zarychanski, Abou-Setta.

Study supervision: Zarychanski, Abou-Setta.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Zarychanski and McIntyre reported that they receive salary support from the Canadian Institutes of Health Research (CIHR). Dr Turgeon reported that he receives salary support from the Fonds de la Recherche du Québec - Santé du (FRQ-S). Dr McIntyre reported that she has received unrestricted grant support from Bristol-Myers Squibb and Abbott Laboratories.

Additional Contributions: We thank Jaro Wex, MD, PhD (German, Russian, Ukrainian language translations; PharmArchitecture Ltd), Michele Shemilt, BSc, MSc candidate (French language translations; Université Laval, Québec City, Québec, Canada), Dongfeng Sun, MD (Chinese language translations; CancerCare Manitoba, Winnipeg, Canada) for their assistance in this review. No specific compensation was provided to these individuals.

This article was corrected for errors on March 29, 2013.

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Zhu GC, Quan ZY, Shao YS, Zhao JG, Zhang YT. The study of hypertonic saline and hydroxyethyl starch treating severe sepsis [in Chinese].  Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23(3):150-153
PubMed
Boldt J, Heesen M, Müller M, Pabsdorf M, Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients.  Anesth Analg. 1996;83(2):254-261
PubMed
Boldt J, Heesen M, Padberg W, Martin K, Hempelmann G. The influence of volume therapy and pentoxifylline infusion on circulating adhesion molecules in trauma patients.  Anaesthesia. 1996;51(6):529-535
PubMed   |  Link to Article
Boldt J, Heesen M, Welters I, Padberg W, Martin K, Hempelmann G. Does the type of volume therapy influence endothelial-related coagulation in the critically ill?  Br J Anaesth. 1995;75(6):740-746
PubMed   |  Link to Article
Boldt J, Mueller M, Menges T, Papsdorf M, Hempelmann G. Influence of different volume therapy regimens on regulators of the circulation in the critically ill.  Br J Anaesth. 1996;77(4):480-487
PubMed   |  Link to Article
Boldt J, Müller M, Heesen M, Heyn O, Hempelmann G. Influence of different volume therapies on platelet function in the critically ill.  Intensive Care Med. 1996;22(10):1075-1081
PubMed   |  Link to Article
Boldt J, Muller M, Heesen M, Neumann K, Hempelmann GG. Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients.  Crit Care Med. 1996;24(3):385-391
PubMed   |  Link to Article
Du XJ, Hu WM, Xia Q,  et al.  Hydroxyethyl starch resuscitation reduces the risk of intra-abdominal hypertension in severe acute pancreatitis.  Pancreas. 2011;40(8):1220-1225
PubMed   |  Link to Article
Dubin A, Pozo MO, Casabella CA,  et al.  Comparison of 6% hydroxyethyl starch 130/0.4 and saline solution for resuscitation of the microcirculation during the early goal-directed therapy of septic patients.  J Crit Care. 2010;25(4):659.e1-e8
PubMed   |  Link to Article
Vlachou E, Gosling P, Moiemen NS. Hydroxyethylstarch supplementation in burn resuscitation--a prospective randomised controlled trial.  Burns. 2010;36(7):984-991
PubMed   |  Link to Article
Gondos T, Marjanek Z, Ulakcsai Z,  et al.  Short-term effectiveness of different volume replacement therapies in postoperative hypovolaemic patients.  Eur J Anaesthesiol. 2010;27(9):794-800
PubMed   |  Link to Article
Heradstveit BE, Guttormsen AB, Langørgen J,  et al.  Capillary leakage in post-cardiac arrest survivors during therapeutic hypothermia - a prospective, randomised study.  Scand J Trauma Resusc Emerg Med. 2010;18:29Link to Article
PubMed   |  Link to Article
Inal MT, Memiş D, Karamanlioglu B, Sut N. Effects of polygeline and hydroxyethyl starch solutions on liver functions assessed with LIMON in hypovolemic patients.  J Crit Care. 2010;25(2):361.e1-361.e5
PubMed   |  Link to Article
Dolecek M, Svoboda P, Kantorová I,  et al.  Therapeutic influence of 20 % albumin versus 6% hydroxyethylstarch on extravascular lung water in septic patients: a randomized controlled trial.  Hepatogastroenterology. 2009;56(96):1622-1628
PubMed
van der Heijden M, Verheij J, van Nieuw Amerongen GP, Groeneveld AB. Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia.  Crit Care Med. 2009;37(4):1275-1281
PubMed   |  Link to Article
Li F, Sun H, Han XD. The effect of different fluids on early fluid resuscitation in septic shock.  Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2008;20(8):472-475
PubMed
Brunkhorst FM, Engel C, Bloos F,  et al; German Competence Network Sepsis (SepNet).  Intensive insulin therapy and pentastarch resuscitation in severe sepsis.  N Engl J Med. 2008;358(2):125-139
PubMed   |  Link to Article
Veneman TF, Oude Nijhuis J, Woittiez AJ. Human albumin and starch administration in critically ill patients: a prospective randomized clinical trial.  Wien Klin Wochenschr. 2004;116(9-10):305-309
PubMed   |  Link to Article
Molnár Z, Mikor A, Leiner T, Szakmány T. Fluid resuscitation with colloids of different molecular weight in septic shock.  Intensive Care Med. 2004;30(7):1356-1360
PubMed   |  Link to Article
Asfar P, Kerkeni N, Labadie F, Gouëllo JP, Brenet O, Alquier P. Assessment of hemodynamic and gastric mucosal acidosis with modified fluid versus 6% hydroxyethyl starch: a prospective, randomized study.  Intensive Care Med. 2000;26(9):1282-1287
PubMed   |  Link to Article
Younes RN, Yin KC, Amino CJ, Itinoshe M, Rocha e Silva M, Birolini D. Use of pentastarch solution in the treatment of patients with hemorrhagic hypovolemia: randomized phase II study in the emergency room.  World J Surg. 1998;22(1):2-5
PubMed   |  Link to Article
Beards SC, Watt T, Edwards JD, Nightingale P, Farragher EB. Comparison of the hemodynamic and oxygen transport responses to modified fluid gelatin and hetastarch in critically ill patients: a prospective, randomized trial.  Crit Care Med. 1994;22(4):600-605
PubMed   |  Link to Article
Rackow EC, Mecher C, Astiz ME, Griffel M, Falk JL, Weil MH. Effects of pentastarch and albumin infusion on cardiorespiratory function and coagulation in patients with severe sepsis and systemic hypoperfusion.  Crit Care Med. 1989;17(5):394-398
PubMed   |  Link to Article
Carli P, Goldstein P, Lejay M, Facon A, Orliaguet G, Petit P. Remplissage vasculaire prehospitalier en taumatologie: hesteril 6% versus plasmion.  Jeur. 2000;13(1-2):101-105
Guidet B, Martinet O, Boulain T,  et al.  Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study.  Crit Care. 2012;16(3):R94
PubMed   |  Link to Article
Perner A, Haase N, Guttormsen AB,  et al; 6S Trial Group; Scandinavian Critical Care Trials Group.  Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.  N Engl J Med. 2012;367(2):124-134
PubMed   |  Link to Article
Myburgh JA, Finfer S, Bellomo R,  et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group.  Hydroxyethyl starch or saline for fluid resuscitation in intensive care.  N Engl J Med. 2012;367(20):1901-1911
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Falk JL, Rackow EC, Astiz ME, Weil MH. Effects of hetastarch and albumin on coagulation in patients with septic shock.  J Clin Pharmacol. 1988;28(5):412-415
PubMed   |  Link to Article
Randell T, Orko R, Höckerstedt K. Peroperative fluid management of the brain-dead multiorgan donor.  Acta Anaesthesiol Scand. 1990;34(7):592-595
PubMed   |  Link to Article
Kamann S, Flaig MJ, Korting HC. Hydroxyethyl starch-induced itch: relevance of light microscopic analysis of semi-thin sections and electron microscopy.  J Dtsch Dermatol Ges. 2007;5(3):204-208
PubMed   |  Link to Article
Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related.  Br J Anaesth. 1999;82(4):510-515
PubMed   |  Link to Article
Rama-Maceiras P, Ingelmo II, Fàbregas JN, Hernández-Palazón J. Fraudulent pain research: a hurt so deep nothing can alleviate it.  Rev Esp Anestesiol Reanim. 2009;56(6):372-379
PubMed
 Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.  Lancet. 2010;375(9713):445
PubMed   |  Link to Article
Carlisle JB. The analysis of 168 randomised controlled trials to test data integrity.  Anaesthesia. 2012;67(5):521-537
PubMed   |  Link to Article
Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients.  Lancet. 1996;348(9042):1620-1622
PubMed   |  Link to Article
Vermeulen LC Jr, Ratko TA, Erstad BL, Brecher ME, Matuszewski KA. A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions.  Arch Intern Med. 1995;155(4):373-379
PubMed   |  Link to Article
Siegemund M. BaSES Trial: Basel Starch Evaluation in Sepsis. ClinicalTrials.gov 2012; http://clinicaltrials.gov/ct2/show/study/NCT00273728. Accessed October 31, 2012
Sadaka F. The Effect of Three Different Fluids(Albumin 5%, Normal Saline, Hydroxyethyl Starch 130 kD) on Microcirculation in Severe Sepsis/Septic Shock Patients. ClinicalTrials.gov 2012; http://clinicaltrials.gov/ct2/show/NCT01319630. Accessed October 31, 2012

Figures

Place holder to copy figure label and caption
Figure 1. Study Flow Diagrama
Graphic Jump Location

aThis flow diagram follows the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA)14 with modifications.
bCompanion articles represent reports of previously published analyses involving the same study population.

Place holder to copy figure label and caption
Figure 2. Mortality and Hydroxyethyl Starch
Graphic Jump Location

The varying sizes of the boxes represent the weight in the analysis. HES indicates hydroxyethyl starch. Risk ratios (RRs) are derived by a random-effects model using Mantel-Haenszel tests.

Place holder to copy figure label and caption
Figure 3. Renal Replacement Therapy and Hydroxyethyl Starch
Graphic Jump Location

The varying sizes of the boxes represent the weight in the analysis. HES indicates hydroxyethyl starch. Risk ratios (RRs) are derived by a random-effects model using Mantel-Haenszel tests.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Individual Trials, Patient Populations, and Interventions, 1988-1998
Table Graphic Jump LocationTable 2. Characteristics of Individual Trials, Patient Populations, and Interventions, 2000-2009
Table Graphic Jump LocationTable 3. Characteristics of Individual Trials, Patient Populations, and Interventions, 2010-2012

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Nagy KK, Davis J, Duda J, Fildes J, Roberts R, Barrett J. A comparison of pentastarch and lactated Ringer's solution in the resuscitation of patients with hemorrhagic shock.  Circ Shock. 1993;40(4):289-294
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Haupt MT, Rackow EC. Colloid osmotic pressure and fluid resuscitation with hetastarch, albumin, and saline solutions.  Crit Care Med. 1982;10(3):159-162
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Chen J, Han CM, Xia SC, Tang ZJ, Su SJ. Evaluation of effectiveness and safety of a new hydroxyethyl starch used in resuscitation of burn shock.  Zhonghua Shao Shang Za Zhi. 2006;22(5):333-336
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Berard JP, Curt I, Piech JJ, Ruiz F. Hydroxyethylamidons versus gelatines: impact sur le cout du rempissage dans un service de reanimation.  Ann Fr Anesth Reanim. 1995;14:R335
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Lv J, Zhao HY, Liu F, An YZ. The influence of lactate Ringer solution versus hydroxyethyl starch on coagulation and fibrinolytic system in patients with septic shock [in Chinese].  Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012;24(1):38-41
PubMed
Zhu GC, Quan ZY, Shao YS, Zhao JG, Zhang YT. The study of hypertonic saline and hydroxyethyl starch treating severe sepsis [in Chinese].  Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23(3):150-153
PubMed
Boldt J, Heesen M, Müller M, Pabsdorf M, Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients.  Anesth Analg. 1996;83(2):254-261
PubMed
Boldt J, Heesen M, Padberg W, Martin K, Hempelmann G. The influence of volume therapy and pentoxifylline infusion on circulating adhesion molecules in trauma patients.  Anaesthesia. 1996;51(6):529-535
PubMed   |  Link to Article
Boldt J, Heesen M, Welters I, Padberg W, Martin K, Hempelmann G. Does the type of volume therapy influence endothelial-related coagulation in the critically ill?  Br J Anaesth. 1995;75(6):740-746
PubMed   |  Link to Article
Boldt J, Mueller M, Menges T, Papsdorf M, Hempelmann G. Influence of different volume therapy regimens on regulators of the circulation in the critically ill.  Br J Anaesth. 1996;77(4):480-487
PubMed   |  Link to Article
Boldt J, Müller M, Heesen M, Heyn O, Hempelmann G. Influence of different volume therapies on platelet function in the critically ill.  Intensive Care Med. 1996;22(10):1075-1081
PubMed   |  Link to Article
Boldt J, Muller M, Heesen M, Neumann K, Hempelmann GG. Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients.  Crit Care Med. 1996;24(3):385-391
PubMed   |  Link to Article
Du XJ, Hu WM, Xia Q,  et al.  Hydroxyethyl starch resuscitation reduces the risk of intra-abdominal hypertension in severe acute pancreatitis.  Pancreas. 2011;40(8):1220-1225
PubMed   |  Link to Article
Dubin A, Pozo MO, Casabella CA,  et al.  Comparison of 6% hydroxyethyl starch 130/0.4 and saline solution for resuscitation of the microcirculation during the early goal-directed therapy of septic patients.  J Crit Care. 2010;25(4):659.e1-e8
PubMed   |  Link to Article
Vlachou E, Gosling P, Moiemen NS. Hydroxyethylstarch supplementation in burn resuscitation--a prospective randomised controlled trial.  Burns. 2010;36(7):984-991
PubMed   |  Link to Article
Gondos T, Marjanek Z, Ulakcsai Z,  et al.  Short-term effectiveness of different volume replacement therapies in postoperative hypovolaemic patients.  Eur J Anaesthesiol. 2010;27(9):794-800
PubMed   |  Link to Article
Heradstveit BE, Guttormsen AB, Langørgen J,  et al.  Capillary leakage in post-cardiac arrest survivors during therapeutic hypothermia - a prospective, randomised study.  Scand J Trauma Resusc Emerg Med. 2010;18:29Link to Article
PubMed   |  Link to Article
Inal MT, Memiş D, Karamanlioglu B, Sut N. Effects of polygeline and hydroxyethyl starch solutions on liver functions assessed with LIMON in hypovolemic patients.  J Crit Care. 2010;25(2):361.e1-361.e5
PubMed   |  Link to Article
Dolecek M, Svoboda P, Kantorová I,  et al.  Therapeutic influence of 20 % albumin versus 6% hydroxyethylstarch on extravascular lung water in septic patients: a randomized controlled trial.  Hepatogastroenterology. 2009;56(96):1622-1628
PubMed
van der Heijden M, Verheij J, van Nieuw Amerongen GP, Groeneveld AB. Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia.  Crit Care Med. 2009;37(4):1275-1281
PubMed   |  Link to Article
Li F, Sun H, Han XD. The effect of different fluids on early fluid resuscitation in septic shock.  Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2008;20(8):472-475
PubMed
Brunkhorst FM, Engel C, Bloos F,  et al; German Competence Network Sepsis (SepNet).  Intensive insulin therapy and pentastarch resuscitation in severe sepsis.  N Engl J Med. 2008;358(2):125-139
PubMed   |  Link to Article
Veneman TF, Oude Nijhuis J, Woittiez AJ. Human albumin and starch administration in critically ill patients: a prospective randomized clinical trial.  Wien Klin Wochenschr. 2004;116(9-10):305-309
PubMed   |  Link to Article
Molnár Z, Mikor A, Leiner T, Szakmány T. Fluid resuscitation with colloids of different molecular weight in septic shock.  Intensive Care Med. 2004;30(7):1356-1360
PubMed   |  Link to Article
Asfar P, Kerkeni N, Labadie F, Gouëllo JP, Brenet O, Alquier P. Assessment of hemodynamic and gastric mucosal acidosis with modified fluid versus 6% hydroxyethyl starch: a prospective, randomized study.  Intensive Care Med. 2000;26(9):1282-1287
PubMed   |  Link to Article
Younes RN, Yin KC, Amino CJ, Itinoshe M, Rocha e Silva M, Birolini D. Use of pentastarch solution in the treatment of patients with hemorrhagic hypovolemia: randomized phase II study in the emergency room.  World J Surg. 1998;22(1):2-5
PubMed   |  Link to Article
Beards SC, Watt T, Edwards JD, Nightingale P, Farragher EB. Comparison of the hemodynamic and oxygen transport responses to modified fluid gelatin and hetastarch in critically ill patients: a prospective, randomized trial.  Crit Care Med. 1994;22(4):600-605
PubMed   |  Link to Article
Rackow EC, Mecher C, Astiz ME, Griffel M, Falk JL, Weil MH. Effects of pentastarch and albumin infusion on cardiorespiratory function and coagulation in patients with severe sepsis and systemic hypoperfusion.  Crit Care Med. 1989;17(5):394-398
PubMed   |  Link to Article
Carli P, Goldstein P, Lejay M, Facon A, Orliaguet G, Petit P. Remplissage vasculaire prehospitalier en taumatologie: hesteril 6% versus plasmion.  Jeur. 2000;13(1-2):101-105
Guidet B, Martinet O, Boulain T,  et al.  Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study.  Crit Care. 2012;16(3):R94
PubMed   |  Link to Article
Perner A, Haase N, Guttormsen AB,  et al; 6S Trial Group; Scandinavian Critical Care Trials Group.  Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.  N Engl J Med. 2012;367(2):124-134
PubMed   |  Link to Article
Myburgh JA, Finfer S, Bellomo R,  et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group.  Hydroxyethyl starch or saline for fluid resuscitation in intensive care.  N Engl J Med. 2012;367(20):1901-1911
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Falk JL, Rackow EC, Astiz ME, Weil MH. Effects of hetastarch and albumin on coagulation in patients with septic shock.  J Clin Pharmacol. 1988;28(5):412-415
PubMed   |  Link to Article
Randell T, Orko R, Höckerstedt K. Peroperative fluid management of the brain-dead multiorgan donor.  Acta Anaesthesiol Scand. 1990;34(7):592-595
PubMed   |  Link to Article
Kamann S, Flaig MJ, Korting HC. Hydroxyethyl starch-induced itch: relevance of light microscopic analysis of semi-thin sections and electron microscopy.  J Dtsch Dermatol Ges. 2007;5(3):204-208
PubMed   |  Link to Article
Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related.  Br J Anaesth. 1999;82(4):510-515
PubMed   |  Link to Article
Rama-Maceiras P, Ingelmo II, Fàbregas JN, Hernández-Palazón J. Fraudulent pain research: a hurt so deep nothing can alleviate it.  Rev Esp Anestesiol Reanim. 2009;56(6):372-379
PubMed
 Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.  Lancet. 2010;375(9713):445
PubMed   |  Link to Article
Carlisle JB. The analysis of 168 randomised controlled trials to test data integrity.  Anaesthesia. 2012;67(5):521-537
PubMed   |  Link to Article
Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients.  Lancet. 1996;348(9042):1620-1622
PubMed   |  Link to Article
Vermeulen LC Jr, Ratko TA, Erstad BL, Brecher ME, Matuszewski KA. A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions.  Arch Intern Med. 1995;155(4):373-379
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Siegemund M. BaSES Trial: Basel Starch Evaluation in Sepsis. ClinicalTrials.gov 2012; http://clinicaltrials.gov/ct2/show/study/NCT00273728. Accessed October 31, 2012
Sadaka F. The Effect of Three Different Fluids(Albumin 5%, Normal Saline, Hydroxyethyl Starch 130 kD) on Microcirculation in Severe Sepsis/Septic Shock Patients. ClinicalTrials.gov 2012; http://clinicaltrials.gov/ct2/show/NCT01319630. Accessed October 31, 2012

Letters

June 5, 2013
John P. A. Ioannidis, MD, DSc
JAMA. 2013;309(21):2209. doi:10.1001/jama.2013.5817.
June 5, 2013
Ryan Zarychanski, MD, MSc; Alexis F. Turgeon, MD, MSc; Ahmed M. Abou-Setta, MD, PhD
JAMA. 2013;309(21):2209. doi:10.1001/jama.2013.5820.
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Supplemental Content

Zarychanski R, Abou-Setta AM, Turgeon AF, et al . Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;308(7):doi:10.1001/jama.2013.430.

eTable 1. Research question using PICO structure

eTable 2. Review eligibility criteria

eTable 3. Ovid Medline search strategy

eTable 4. Conferences searches for unpublished trials

eTable 5. Study demographics

eTable 6. Summary risks of bias

eTable 7. Mortality and hydroxyethyl starch: subgroup and sensitivity analysis*

eFigure 1. Regression of time (duration of the study protocol) on log risk ratio for mortality (n = 15)

eFigure 2. Regression of time (duration of follow-up) on log risk ratio for mortality (n = 10)

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