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Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review) Mutter TC, Ruth CA, Dart AB This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 7 http://www.thecochranelibrary.com Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Page 1: Hydroxyethyl starch (HES) versus other fluid therapies ... · Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function Hydroxyethyl starches (HES) are fluid

Hydroxyethyl starch (HES) versus other fluid therapies:

effects on kidney function (Review)

Mutter TC, Ruth CA, Dart AB

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 7

http://www.thecochranelibrary.com

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Page 2: Hydroxyethyl starch (HES) versus other fluid therapies ... · Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function Hydroxyethyl starches (HES) are fluid

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

19DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 HES versus other fluid, Outcome 1 Renal replacement therapy. . . . . . . . . . 86Analysis 1.2. Comparison 1 HES versus other fluid, Outcome 2 Renal replacement therapy by MW. . . . . . . 88Analysis 1.3. Comparison 1 HES versus other fluid, Outcome 3 Renal replacement therapy by volume. . . . . . 89Analysis 1.4. Comparison 1 HES versus other fluid, Outcome 4 Kidney failure (author defined). . . . . . . . 91Analysis 1.5. Comparison 1 HES versus other fluid, Outcome 5 RIFLE (Risk or worse). . . . . . . . . . . 92Analysis 1.6. Comparison 1 HES versus other fluid, Outcome 6 RIFLE (Injury or worse). . . . . . . . . . . 94Analysis 1.7. Comparison 1 HES versus other fluid, Outcome 7 RIFLE (Failure). . . . . . . . . . . . . . 95Analysis 1.8. Comparison 1 HES versus other fluid, Outcome 8 RIFLE (Risk or worse) by MW. . . . . . . . 97Analysis 1.9. Comparison 1 HES versus other fluid, Outcome 9 RIFLE (Risk or worse) by volume. . . . . . . 98Analysis 2.1. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 1 RIFLE (Risk or worse). . . 100Analysis 2.2. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 2 RIFLE (Injury or worse). . 101Analysis 2.3. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 3 RIFLE (Failure). . . . . 102Analysis 3.1. Comparison 3 HES versus other fluid - no subgroups, Outcome 1 Renal replacement therapy. . . . 103Analysis 3.2. Comparison 3 HES versus other fluid - no subgroups, Outcome 2 Kidney failure (author defined). . . 104Analysis 3.3. Comparison 3 HES versus other fluid - no subgroups, Outcome 3 RIFLE (Risk or worse). . . . . . 105Analysis 3.4. Comparison 3 HES versus other fluid - no subgroups, Outcome 4 RIFLE (Injury or worse). . . . . 106Analysis 3.5. Comparison 3 HES versus other fluid - no subgroups, Outcome 5 RIFLE (Failure). . . . . . . . 107Analysis 4.1. Comparison 4 Sensitivity analyses, Outcome 1 RIFLE (Risk or worse) - Creatinine only. . . . . . 108Analysis 4.2. Comparison 4 Sensitivity analyses, Outcome 2 RIFLE (Injury or worse) -Creatinine only. . . . . . 109Analysis 4.3. Comparison 4 Sensitivity analyses, Outcome 3 RIFLE (Failure) - Creatinine only. . . . . . . . . 110

110APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .120NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Hydroxyethyl starch (HES) versus other fluid therapies:effects on kidney function

Thomas C Mutter1, Chelsea A Ruth2, Allison B Dart2

1Department of Anesthesia, University of Manitoba, Winnipeg, Canada. 2Department of Pediatrics and Child Health, University ofManitoba, Winnipeg, Canada

Contact address: Allison B Dart, Department of Pediatrics and Child Health, University of Manitoba, 820 Sherbrook St, Winnipeg,Manitoba, R3A 1R9, Canada. [email protected]. [email protected].

Editorial group: Cochrane Renal Group.Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 7, 2013.Review content assessed as up-to-date: 21 May 2013.

Citation: Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. CochraneDatabase of Systematic Reviews 2013, Issue 7. Art. No.: CD007594. DOI: 10.1002/14651858.CD007594.pub3.

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation to replace intravascular volume, yet they havebeen increasingly associated with adverse effects on kidney function. This is an update of a Cochrane review first published in 2010.

Objectives

To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations.

Search methods

We searched the Cochrane Renal Group’s specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, inThe Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. The most recent search was completed onNovember 19, 2012.

Selection criteria

Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention ortreatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidneyfailure and acute kidney injury (AKI) as defined by the RIFLE criteria.

Data collection and analysis

Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardisedforms. All outcomes were analysed using relative risk (RR) and 95% confidence intervals (95% CI). Authors were contacted whenpublished data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random-effects model.

Main results

This review included 42 studies (11,399 patients) including 19 studies from the original review (2010), as well as 23 new studies.Fifteen studies were excluded from the original review (nine retracted from publication due to concerns about integrity of data and sixlacking individual patient creatinine data for the calculation of RIFLE criteria). Overall, there was a significant increase in the need for

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RRT in the HES treated individuals compared to individuals treated with other fluid therapies (RR 1.31, 95% CI 1.16 to 1.49; 19studies, 9857 patients) and the number with author-defined kidney failure (RR 1.59, 95% CI 1.26 to 2.00; 15 studies, 1361 patients).The RR of AKI based on RIFLE-F (failure) criteria also showed an increased risk of AKI in individuals treated with HES products(RR 1.14, 95% CI 1.01 to 1.30; 15 studies, 8402 participants). The risk of meeting urine output and creatinine based RIFLE-R (risk)criteria for AKI was in contrast in favour of HES therapies (RR 0.95, 95% CI 0.91 to 0.99; 20 studies, 8769 patients). However, whenRIFLE-R urine output based outcomes were excluded as per study protocol, the direction of AKI risk again favoured the other fluidtype, with a non-significant RR of AKI in HES treated patients (RR 1.05, 95% CI 0.97 to 1.14; 8445 patients). A more robust effectwas seen for the RIFLE-I (injury) outcome, with a RR of AKI of 1.22 (95% CI 1.08 to 1.37; 8338 patients). No differences betweensubgroups for the RRT and RIFLE-F based outcomes were seen between sepsis versus non-sepsis patients, high molecular weight (MW)and degree of substitution (DS) versus low MW and DS (≥ 200 kDa and > 0.4 DS versus 130 kDa and 0.4 DS) HES solutions, orhigh versus low dose treatments (i.e. ≥ 2 L versus < 2 L). There were differences identified between sepsis versus non-sepsis subgroupsfor the RIFLE-R and RIFLE-I based outcomes only, which may reflect the differing renal response to fluid resuscitation in pre-renalversus sepsis-associated AKI. Overall, methodological quality of the studies was good.

Authors’ conclusions

The current evidence suggests that all HES products increase the risk in AKI and RRT in all patient populations and a safe volume ofany HES solution has yet to be determined. In most clinical situations it is likely that these risks outweigh any benefits, and alternatevolume replacement therapies should be used in place of HES products.

P L A I N L A N G U A G E S U M M A R Y

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Hydroxyethyl starches (HES) are fluid products that are commonly used in clinical practice, however they have been associated withnegative effects on kidney function. This review examined the effects of HES on kidney function compared to other fluid therapiesin critically ill patients. Forty-two randomised clinical trials (11,399 patients) comparing HES to another fluid therapy qualified forthis review. Overall, the use of HES products was associated with a 59% increased risk of kidney failure, and a 32% increased risk ofdialysis. No significant differences in effect were seen depending on the patient population studied, the type of HES solution, or thedose used. Due to the potential risks associated with HES products, alternative fluid therapies should be used.

B A C K G R O U N D

In all clinical scenarios, the main treatment for intravascular vol-ume depletion is fluid resuscitation with either crystalloid or col-loid. Hydroxyethyl starches (HES) are a group of synthetic col-loids that have been commonly used for fluid resuscitation. A re-cent meta-analysis restricted to critically ill patients, demonstratedincreased risk of renal replacement therapy (RRT) and mortalityin HES treated patients (Zarychanski 2013). However, this reviewexcluded patients that were not deemed critically ill, such as elec-tive surgery patients, and this study did not include data strati-fied by sepsis versus non-sepsis for the largest study in the liter-ature (Myburgh 2012). In addition, authors were not contactedfor unpublished results to broaden the scope of the review. Thus,the external validity of the findings to non-septic patients and lesscritically patients has remained unclear.

Description of the condition

Acute kidney injury (AKI) is a common and serious complica-tion affecting critically ill patients, with mortality rates greaterthan 50% in some studies (Sear 2005; Waikar 2007). It occurs in0.5% to 30% of patients in perioperative and critical care settings,depending on the population studied and the definition utilised(Sear 2005; Waikar 2007).To facilitate valid comparisons of AKI incidence a standardisedclassification system has been developed by consensus and giventhe acronym RIFLE (Bellomo 2004; Figure 1). This graded sys-tem distinguishes between three worsening levels of acute kidneydysfunction (Risk, Injury and Failure) as well as duration of re-quirement of RRT (Loss of kidney function and End-stage kidneydisease). The kidney dysfunction classes are defined by objectivemeasures of glomerular filtration rate (GFR) and urine output.

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They have been validated to predict outcome, with incrementalincreases in mortality associated with worsening acute RIFLE class(RR = 2.4 Risk; RR = 4.15 Injury; RR = 6.37 Failure) (Ricci 2008).

Figure 1. * RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney

function and End-stage kidney disease) classification scheme. The classification system includes separate

criteria for creatinine and urine output. A patient can fulfil the criteria through changes in serum creatinine or

changes in urine output, or both. The criteria that leads to the worst possible classification should be used.

Only GFR based criteria for Risk, Injury and Failure are utilised in this review (Bellomo 2004; with permission)

Similar to previous reviews (Ricci 2008), this review has focusedon the creatinine-based criteria in defining AKI. Compared tothe criteria based on both urine output and creatinine, the creati-nine only-based criteria are superior at predicting mortality (Cruz2007), are not confounded by diuretic use, and are more accessiblewhen retrospectively applying the criteria to existing data (Ricci2008).Renal hypoperfusion, secondary to intravascular volume deple-tion, is commonly implicated as a cause of AKI in critically illpatients (Sear 2005; Waikar 2007). Regardless of the underlying

cause of volume depletion, the mainstay of therapy is the admin-istration of intravenous (IV) crystalloid and/or colloid to restoreintravascular volume, improve renal perfusion and prevent AKI(Bagshaw 2007; Grocott 2005).

Description of the intervention

HES are synthetic colloids used for intravascular volume expan-sion. Products differ by their mean molecular weight (MW), de-gree of hydroxyethylation (or degree of substitution), and C2:

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C6 hydroxyethylation ratio (Grocott 2005; Jungheinrich 2005).These features affect the pharmacokinetics of HES products(Ferber 1985; Jungheinrich 2005). The higher the MW and molarsubstitution, the longer it takes for alpha-amylase to breakdownthe HES molecules. Breakdown of the HES molecules producessmall cleavage products that are subsequently filtered by the kid-ney (Ferber 1985). Therefore, the higher the molecular weight,degree of substitution and C2:C6 ratio, the faster the HES prod-uct accumulates after multiple doses and the longer they persistsin the circulation. These differences were thought to affect sideeffect profiles including effects on kidney function (Jungheinrich2005). However, recent evidence from a meta-analysis of clinicalstudies suggests that despite faster breakdown of newer productswith lower MW and degree of substitution, toxicity may be para-doxically exacerbated by increased tissue uptake, particularly inthe luminal epithelial cells of the renal proximal tubules (Bellmann2012). Despite these and other safety concerns (Barron 2004; Bork2005; Wiedermann 2004), HES products have been popular in awide variety of critical care settings (McIntyre 2007; Miletin 2002;Schortgen 2004) .

How the intervention might work

Potential benefits of HES

Colloids aremore efficient intravascular volume expanders thancrystalloids because more of the infused volume remains in the in-travascular space (American Thoracic Society 2004, Hartog 2011).Compared to other colloids, older generation HES products hada volume efficacy and duration of action that was surpassed onlyby hyperoncotic albumin and some dextran products (AmericanThoracic Society 2004). In recent studies using lower molecu-lar weight products with lower molar substitution, the advantagein intravascular volume expansion compared to crystalloids hasbeen marginal (Perner 2012, Myburgh 2012). Nevertheless, in ex-perimental models, colloids demonstrate more rapid resuscitationand improved tissue perfusion compared to crystalloids (AmericanThoracic Society 2004, Hartog 2011). Furthermore, complemen-tary laboratory and clinical research has demonstrated large vol-ume crystalloid resuscitation has multiple negative effects (Cotton2006) that could impact kidney function indirectly.

Mechanism of HES-related kidney injury

In one hypothesised mechanism, hyperoncotic kidney failure,GFR is decreased secondary to a reduction in filtration fraction(Moran 1987). However, more likely HES products cause kidneyinjury directly as the kidney is a major target organ for HES tis-sue update. HES molecules have been shown to be taken up bythe luminal epithelial cells in the proximal tubules via pinocytosis(Bellmann 2012). Furthermore, increased tissue uptake has beenpostulated to explain the toxicity of the newest HES products withlower MW and degree of substitution (Bellmann 2012). Tissue

uptake does appear to be dose and time dependent (Sirtl 1999)and HES accumulates in cytoplasmic vacuoles that can persist forlong periods of time even after relatively low doses for volumereplacement (Metze 1997).Pathologic evidence in support of these mechanisms is limited.One necropsy study has however demonstrated high concentra-tions of HES in the kidney suggesting tissue accumulation as apathologic mechanism (Lukasewitz 1998). Osmotic nephrosis-like lesions have also been associated with delayed graft functionin kidneys from organ donors treated with HES (Cittanova 1996),however such lesions have also been seen in the absence of graftdysfunction (Legendre 1993).

Why it is important to do this review

Given the clinical popularity of HES and the prognostic signif-icance of AKI, a systematic review evaluating the risk of AKI inHES treated individuals is highly relevant. There have been a num-ber of large RCT’s published on this topic since the last Cochranereview on this subject (Dart 2010) in higher risk patient popula-tions (sepsis), that have rigorously evaluated newer HES productsthat were anticipated to have better side effect profiles. A recentmeta-analysis has synthesized some of this new data and has showna significant increased risk of RRT and mortality in critically illHES treated individuals (Zarychanski 2013). This current reviewadds data from an additional large RCT (BaSES 2012), as wellas previously unpublished subgroup data from the largest studyin the literature (Myburgh 2012) and includes studies of individ-uals undergoing elective surgery. This is important data, becauseprevious reviews have suggested sepsis populations were at highestrisk of AKI, and non-sepsis (mainly surgical patients) were rela-tively protected from renal toxicity (Dart 2010). In addition, inthis review study authors were contacted to obtain additional un-published RIFLE based outcomes. This review thus provides ad-ditional data, and a more complete evaluation of the adverse renaleffects of HES products in at risk populations.

O B J E C T I V E S

This review aimed to:

1. Examine the risk of AKI with HES compared to other fluidtherapies when used in the prevention and treatment of relativeintravascular volume depletion.

2. Determine if kidney outcomes differ amongst patientstreated with HES from different patient populations (sepsis andburns, trauma, cardiac and vascular surgery patients on and offcardiac bypass, non-cardiac surgery patients and organ donors;both paediatric and adult).

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3. Determine if kidney outcomes differ by HES molecularweight (MW), degree of substitution (DS), C2:C6 ratio orsolvent.

4. Determine if kidney outcomes differ by administered doseof HES.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi-RCTs (RCTsin which allocation to treatment was obtained by alternation, useof alternate medical records, date of birth or other predictablemethods) looking at HES as a therapy for the prevention or treat-ment of effective intravascular volume depletion were included,provided that the control group received another eligible form offluid therapy.Crossover studies were excluded due to the lack of a feasible andsufficient wash-out period in fluid management. There were nolanguage restrictions.

Types of participants

Inclusion criteria

Human subjects of all ages who received HES as a fluid therapyfor the treatment of effective intravascular volume depletion wereincluded.

Exclusion criteria

Healthy volunteers who received HES irrespective of volume sta-tus and euvolemic patients who received HES to decrease the vis-cosity of plasma in the treatment of stroke, retinal vein occlu-sion, angina, peripheral arterial disease, hearing loss, tinnitus orcomplications of pregnancy including gestational hypertension,intrauterine growth retardation or ovarian hyperstimulation syn-drome were excluded. Studies of patients with kidney failure re-quiring RRT at the onset of the study were also excluded.

Types of interventions

• Any HES solution (all MWs and molar substitutions)versus any other intravenous fluid therapy including:

◦ crystalloid (i.e. normal saline or Ringer’s lactate)◦ albumin or plasma protein fraction

◦ blood or fresh frozen plasma (FFP)◦ dextran◦ gelatin◦ HES of another MW, molar substitution, C2:C6 ratio

or suspended in a different solvent• Comparisons to synthetic blood products were excluded• Other exclusions:

◦ volume replacement in preoperative autologous blooddonation (remote from surgery)

◦ plasmapheresis and plasma exchange◦ thrombosis prophylaxis.

Types of outcome measures

RRT was the primary outcome studied as it is a marker of se-vere AKI. As there are varying degrees of kidney dysfunction, andmany different definitions utilised to define kidney failure, theRIFLE criteria were utilised to standardise definitions across in-cluded studies. In order to apply the criteria, authors were con-tacted to obtain serial creatinine measurements for each study pa-tient. Where possible, meeting Risk, Injury and Failure were anal-ysed as separate outcome measures, however where data from au-thors could not be obtained, “author defined” kidney failure wasanalysed as the outcome.

Primary outcomes

1. Need for RRT2. Meeting RIFLE GFR criteria for renal risk, injury or failure

(Figure 1)3. Author defined kidney failure

Outcomes had to be assessed at least 24 hours after treatment withHES to be included.

Search methods for identification of studies

Electronic searches

We re-searched the Cochrane Renal Group’s Specialised Registeron November 19, 2012 through contact with the Trials’ SearchCo-ordinator using search terms relevant to this review.The Cochrane Renal Group’s Specialised Register contains studiesidentified from:

1. Quarterly searches of the Cochrane Central Register ofControlled Trials CENTRAL

2. Weekly searches of MEDLINE OVID SP3. Handsearching of renal-related journals and the

proceedings of major renal conferences4. Searching of the current year of EMBASE OVID SP5. Weekly current awareness alerts for selected renal journals

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6. Searches of the International Clinical Trials Register(ICTRP) Search Portal and ClinicalTrials.gov.Studies contained in the Specialised register are identified throughsearch strategies for CENTRAL, MEDLINE, EMBASE based onthe scope of the Cochrane Renal Group. Details of these strategiesas well as a list of handsearched journals, conference proceedingsand current awareness alerts are available in the ’Specialised Reg-ister’ section of information about the Cochrane Renal Group.See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Relevant review articles were identified and their reference listssearched for any clinical studies not previously identified. In ad-dition, the reference lists of included studies were reviewed.

Data collection and analysis

Selection of studies

The references identified by the search strategy were divided suchthat each was screened independently by two of the three authors(AD, TM, CR). The titles, abstracts, and when necessary, the fulltext of the references were first screened to determine if they metthe initial short list inclusion criteria:

• Human study• RCT or quasi-RCT• HES compared to another qualifying fluid therapy• Appropriate participant and intervention population (as

defined above).

Studies which did not meet these criteria were excluded. Conflictswere resolved by consensus of all three authors.Short listed articles were again independently examined by two au-thors, using the most complete publication available for the iden-tification of relevant outcomes. Authors were contacted if data aspublished was incomplete. If articles mentioned serum creatinine(SCr), and were published after 1990 then the authors were alsocontacted for available individual patient creatinine values so thatRIFLE criteria could be applied. If complete RIFLE outcomeswere published in the paper, then authors were not contacted.Foreign language papers were reviewed by volunteers with med-ical backgrounds and proficiency in the language of publication.Translators were found for all languages required. When a studycould not be located through the university library or through theTrials Search Co-ordinator, the study was evaluated using the mostcomplete information available.

Data extraction and management

Data extraction was carried out independently by the same au-thors using standard data extraction forms. Studies reported innon-English language journals had their data extracted onto En-glish data extraction forms by volunteer colleagues. When morethan one publication of a study existed, only the publication withthe most complete data was included. Where relevant outcomeswere published only in earlier versions, these data were used. Anydiscrepancies between published versions were to be highlighted.In order to ensure there was no duplication of data, authors ex-amined closely author lists, time periods of enrolment, treatmentprotocol details, patient demographic data and any other infor-mation that may have revealed duplications. Any further informa-tion required from the original author was requested by written orelectronic correspondence and any relevant information obtainedin this manner was included in the review. Disagreements wereresolved in consultation with ST.

Assessment of risk of bias in included studies

The following items were independently assessed by two authorsusing the risk of bias assessment tool (Higgins 2011) (see Appendix2).

• Was there adequate sequence generation (selection bias)?• Was allocation adequately concealed (selection bias)?• Was knowledge of the allocated interventions adequately

prevented during the study (detection bias)?◦ Participants and personnel◦ Outcome assessors

• Were incomplete outcome data adequately addressed(attrition bias)?

• Are reports of the study free of suggestion of selectiveoutcome reporting (reporting bias)?

• Was the study apparently free of other problems that couldput it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (RRT, RIFLE criteria, or author-de-fined kidney failure results) were expressed as risk ratio (RR) with95% confidence intervals (CI).

Unit of analysis issues

Cross-over studies and cluster-RCTs were not included in thisreview.Studies comparing more than one HES product with another fluid(studies with multiple intervention groups) were included in thereview. In multi-arm studies with more than one non-HES (i.e.control) intervention, all non-HES groups were combined intoa single group as recommended (Higgins 2011). Conversely, inmulti-arm studies with more than one relevant HES group, HES

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groups were analysed separately and the control group dividedappropriately between the HES groups for high versus low MWand high versus low volume meta-analyses. In the latter case, theadvantage of investigating sources of heterogeneity due to differ-ent MW or dose of HES were deemed to outweigh the disadvan-tage of incompletely resolving the unit of analysis issue by havingcorrelated comparisons in the random effects meta-analyses usedin this study. The statistical effect of such correlations is usuallytrivial and this can be confirmed by a sensitivity analysis with afixed effect model (Higgins 2011).

Dealing with missing data

Missing individual data

As the outcomes of interest in this review are adverse effects, anintention-to-treat analysis was not employed. Mortality data wascollected but not reported because it was not consistently measuredcompositely with kidney outcomes. This made the mortality datadifficult to interpret as it was unclear in some cases if individualshad experienced kidney dysfunction before death.

Missing summary data

Authors were contacted with a request to provide relevant outcomedata which was reported as having been obtained but was notpublished.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees offreedom, with an alpha of 0.05 used for statistical significance andwith the I² test (Higgins 2003). I² values of 25%, 50% and 75%correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

Publication bias was assessed with funnel plots where appropriate.

Data synthesis

Significant clinical heterogeneity was anticipated in this review dueto the different patient populations, comparison fluids, and fluidregimens studied. Realizing outcomes between studies would notbe identical but could follow some distribution, data was pooledusing the random-effects model. The fixed-effects model was alsoused to assess the robustness of the model chosen, and its suscep-tibility to outliers and correlated data from multi-arm studies.

Subgroup analysis and investigation of heterogeneity

The following patient type subgroup analyses were planned foreach identified outcome, where numbers permitted:

• Trauma versus sepsis/burns versus non-cardiac bypasssurgery versus cardiac bypass surgery versus organ donors

• Paediatric versus adult• Type of control fluid (i.e. albumin, crystalloid, gelatin,

other HES product)• HES MW, degree of substitution (DS), C2:C6 ratio and

solvent• Dose and/or duration of therapy• Patients with and without pre-existing kidney dysfunction.

As there were insufficient study numbers only the following sub-group analyses were performed:

• Sepsis versus non-sepsis patients• High versus low MW HES (≥ 200 kDa versus 130 kDa).

For the included studies in this review this was equivalent to acomparison between degree of substitution > 0.4 versus 0.4.

• High (≥ 2 L) versus low (< 2 L) cumulative HES dose.

Subgroups were explored for possible sources of heterogeneity, aswell as to estimate the adverse effects unique to individual patientgroups. Heterogeneity of outcomes could be related to these factorsin addition to age, body mass, pre-existing kidney pathology aswell as the effect of the disease process itself on kidney function.

Sensitivity analysis

A fixed effect model was analysed, which is a measure of the ’typicalintervention effect’. A priori proposed subgroup analyses exploredclinical heterogeneity. Sensitivity analyses also included removingstudies of poor methodologic quality as well as studies done in pre-vious eras, to determine if differences exist compared with modernstudies.

R E S U L T S

Description of studies

Results of the search

The updated search resulted in an additional 23 studies. Of theprevious ongoing studies two have been published as full publica-tions (Myburgh 2012; Magder 2010), one has since been retracted(Boldt 2007b) and one has been published in abstract form andis included in a review paper (BaSES 2012). For details of themost recent search please see Figure 2. This review now includes42 RCTs (total 11,399 patients). 15 studies were excluded from

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the original review (9 retracted from publication due to concernsabout integrity of data and 6 lacking individual creatinine dataand thus no longer meeting criteria for inclusion).

Figure 2. Study flow diagram.

Included studies

Of the 42 studies, 3 were published in the 1980s, 4 in the 1990s,16 in the 2000s and 19 since 2010.

Participants

One paediatric study (Akech 2010) qualified for this review; andthe remaining 41 studies involved adults in a variety of perioper-ative and critical care settings. The majority of adult participantswere middle aged to elderly with younger patients represented inthe trauma studies. Male participants were more numerous thanfemales in the majority of studies. The median number of studyparticipants was 60 and only 7 studies had more than 150 partici-pants. The Myburgh study (Myburgh 2012) accounted for 61.4%

of all study participants. Most studies excluded patients with pre-existing severe kidney disease using a variety of definitions.

Interventions

The most common HES preparations investigated were 6% solu-tions of 130/0.4, 200/0.5, 200/0.6 or 450/0.7. Only four stud-ies (Brunkhorst 2008; London 1989; Magder 2010; McIntyre2008) studied hyperoncotic 10% HES (Characteristics of includedstudies) and only one study utilized HES mixed with hyperoncoticsaline (Shmyrev 2011).

Primary outcomes

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Requirement of RRT

Nineteen studies including a total of 9857 patients comparing anHES product to another fluid type reported the primary outcomeof RRT (BaSES 2012; Berard 1995; Brunkhorst 2008; Cittanova1996; Du 2011; Godet 2008; Guidet 2012; James 2011; Kumle1999; Lee 2011; London 1989; Magder 2010; Mahmood 2007;McIntyre 2008; Mukhtar 2009; Myburgh 2012; Perner 2012;Schortgen 2001; Vlachou 2010).Two additional studies comparing two HES products reported theoutcome RRT (Kasper 2003; Ertmer 2012).

Patient populations subgroup

Eight studies included 3899 patients with sepsis or burns (BaSES2012; Brunkhorst 2008; Guidet 2012; McIntyre 2008; Myburgh2012; Perner 2012; Schortgen 2001; Vlachou 2010); eleven in-cluded 5911 non-sepsis patients (Berard 1995; Godet 2008; James2011; Kasper 2003; Kumle 1999; Lee 2011; London 1989;Magder 2010; Mahmood 2007; Mukhtar 2009; Myburgh 2012).Four studies were of cardiac surgical patients (Kasper 2003; Lee2011; London 1989; Magder 2010); two of vascular surgery pa-tients (Godet 2008; Mahmood 2007); four of non-cardiac surgicalpatients (Berard 1995; Godet 2008; Kumle 1999; Mukhtar 2009);one of trauma patients (James 2011); one of pancreatitis patients(Du 2011); and one of intensive care patients (Myburgh 2012).One study was of deceased kidney transplant donors (Cittanova1996) and kidney function in the kidney recipients.

Comparison fluids

The comparison fluid studied was a gelatin in six studies (Berard1995; Cittanova 1996; Godet 2008; Kumle 1999; Mahmood2007; Schortgen 2001). In two studies the comparison fluid was5% albumin (London 1989; Mukhtar 2009), three studies usedRinger’s lactate or acetate (Brunkhorst 2008; Du 2011; Perner2012); one study used Hartmann’s solution (Vlachou 2010), sixstudies used normal saline (BaSES 2012; Guidet 2012; James2011; Magder 2010; McIntyre 2008; Myburgh 2012); and onestudy used a balanced plasma solution (Lee 2011).

Intervention fluids

Doses and durations of therapy ranged from 887 mL over 24 hours(Magder 2010) to 70 mL/kg with a median duration of 14 days(Brunkhorst 2008). The HES solutions studied were 10% 264/0.5 (London 1989) 10% 200/0.5 (Magder 2010;, McIntyre 2008and Brunkhorst 2008 (200/0.5). Other fluids used were 6% 200/0.6 in Cittanova 1996, Schortgen 2001 and Vlachou 2010, 6%200/0.5 and 70/0.5 in Kumle 1999, 6% 200/0.62 and 6% 130/0.4 in Mahmood 2007 and 6% 130/0.4 in the remaining studies.

Two studies evaluated pair-wise comparisons of HES productsand were not included in a meta-analysis (Kasper 2003; Ertmer2012). Kasper 2003 studied 6% 130/0.4 versus 6% 200/0.5 incardiac surgery. In this study 2/59 patients treated with 6% 130/0.4 and 3/58 patients treated with 6% 200/0.5 required RRT.Ertmer 2012 studied 10% HES 130/0.4 versus 10% HES 200/0.5 in the perioperative management of 76 cardiac patients onbypass. RRT was not required in either group.

Author-defined kidney failure

Seventeen studies reported kidney failure (defined by author) asan outcome measure (Abdel-Khalek 2010; Akech 2010; Altman1998; Brunkhorst 2008; Dehne 2001; Diehl 1982; Du 2011;Fernandez 2005; Godet 2008; Heradstveit 2010; Jungheinrich2004; Lee 2011; Neff 2003; Schortgen 2001; Shatney 1983;Shmyrev 2011; Yang 2011). Five of these studies (Brunkhorst2008; Du 2011; Godet 2008; Lee 2011; Schortgen 2001) also re-ported requirement of RRT. For nine of these studies (Akech 2010;Fernandez 2005, Godet 2008; Heradstveit 2010; Jungheinrich2004; Lee 2011; Schortgen 2001; Shmyrev 2011; Yang 2011) datawere also available for RIFLE criteria analysis. Two studies in-cluded only pair wise comparisons of HES products and thereforewere not included in the meta-analysis (Jungheinrich 2004; Neff2003).

Patient population subgroup

Four studies included 741 patients with sepsis (Akech 2010;Brunkhorst 2008; Fernandez 2005; Schortgen 2001). The remain-ing studies were of non-sepsis patients (n=620).

Comparison fluids

Comparison fluids included albumin in six of the studies (Abdel-Khalek 2010; Altman 1998; Diehl 1982; Fernandez 2005; Neff2003; Yang 2011), Ringer’s lactate in four studies (Brunkhorst2008, Dehne 2001, Du 2011, and Yang 2011), gelatin in twostudies (Godet 2008; Schortgen 2001), plasma protein fraction(PPF) in one study (Shatney 1983), dextran in one study (Akech2010), normal saline (Shmyrev 2011) in one study, 7.2% NSin two studies (Heradstveit 2010 and Shmyrev 2011), a plasmasolution in Lee 2011 and another type of HES in Dehne 2001,Jungheinrich 2004 and Neff 2003.

Intervention fluids

The doses and durations of therapy ranged from 4 mL/kg(Shmyrev 2011) to 70 mL/kg with a median duration of 14 days(Brunkhorst 2008). The intervention fluid was 10% 200/0.5 in

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Brunkhorst 2008, 6.5% 200/0.62 in Altman 1998, 6% 450/0.7in Diehl 1982 and Shatney 1983, 6% 200/0.5 in Abdel-Khalek2010, Fernandez 2005, Jungheinrich 2004, Heradstveit 2010, andShmyrev 2011, 6% 200/0.6 in Schortgen 2001, and 6% 130/04in Akech 2010, Du 2011, Godet 2008, Jungheinrich 2004, Lee2011 and Yang 2011. Dehne 2001 evaluated 6% 200/0.5, 6%200/0.62 and 6% 450/0.7.Neff 2003 included 31 neurosurgical patients and treated onegroup with HES 130/0.4 and the other with HES 200/0.5 plus5% albumin. Two patients in the HES 200/0.5 plus 5% albumingroup developed kidney failure (no definition reported by authors)and none in the HES 130/0.4 group. This was the only study thatincluded two HES fluids for this outcome, so it was not includedin a meta-analysis.

AKI defined by RIFLE criteria

Twenty three studies in this review, comparing an HES prod-uct to another fluid type or two HES products, either publishedthe RIFLE criteria risk outcome or forwarded the authors in-dividual level creatinine data to calculate this outcome (Akech2010; Akkucuk 2012; Choi 2010; Dolecek 2009; Dubin 2010;Fernandez 2005; Gallandat 2000; Godet 2008; Guidet 2012;Heradstveit 2010; James 2011; Jungheinrich 2004; Lee 2011;Magder 2010; Myburgh 2012; Perner 2012; Protsenko 2009;Sander 2003; Schortgen 2001; Shmyrev 2011 Van der Linden2005; Yang 2011; Yassen 2011).Nine of the studies included patients with sepsis and burns (Akech2010; Dolecek 2009; Dubin 2010; Fernandez 2005; Guidet 2012;Myburgh 2012; Perner 2012; Protsenko 2009; Schortgen 2001).The other studies evaluated surgical or trauma patients (Akkucuk2012; Choi 2010; Gallandat 2000; Godet 2008; James 2011;Jungheinrich 2004; Lee 2011; Magder 2010; Myburgh 2012;Sander 2003; Shmyrev 2011; Van der Linden 2005; Yang 2011;Yassen 2011) or post cardiac arrest survivors (Heradstveit 2010).Five studies compared an HES product with albumin (Dolecek2009; Choi 2010; Fernandez 2005; Yang 2011; Yassen 2011), fourwith a gelatin (Protsenko 2009; Schortgen 2001, Godet 2008;Van der Linden 2005), one with a dextran (Akech 2010), onewith plasma solution (Lee 2011), six with normal saline (Dubin2010; Guidet 2012; James 2011; Magder 2010; Myburgh 2012;Shmyrev 2011) and one with hypertonic saline (Heradstveit 2010)and two with ringer’s lactate or acetate (Akkucuk 2012; Perner2012). Three additional studies evaluated a lower versus a higherMW HES product (Gallandat 2000; Jungheinrich 2004; Sander

2003). Protsenko 2009 also included 2 different HES groups aswell as a crystalloid group.Doses ranged from 4 mL/kg (Shmyrev 2011) to 49 mL/kg (Vander Linden 2005) while duration of therapy ranged from one to sixdays. The HES studied was 6% 200/0.6 in Schortgen 2001 , 6%200/0.5 in Abdel-Khalek 2010, Fernandez 2005 and Heradstveit2010, 10% 250/0.45 in Magder 2010, 6% 130/0.4-0.42 in Akech2010, Akkucuk 2012, Choi 2010, Dolecek 2009, Dubin 2010,Godet 2008, Guidet 2012, James 2011, Lee 2011, Myburgh 2012,Perner 2012, Van der Linden 2005, Yang 2011 and Yassen 2011and 7.2%NaCl in 6% HES in Shmyrev 2011. The three studiescomparing HES products used 6% solutions of 200/0.5 and 130/0.4.

Excluded studies

Due to the comprehensive nature of the search strategy employed,specific details of the excluded studies are not reported. The ma-jority of studies not short listed did not include the identifiedstudy populations. Of those studies which met short list criteriathe majority were excluded from the final review due to a lack ofimportant reported kidney outcomes. Attempts to contact authorsdid increase the number of included studies.15 studies were excluded from the original review. 7 were retractedfrom publication due to concerns about integrity of data Boldt2000a; Boldt 2000b; Boldt 2003; Boldt 2006; Boldt 2007a; Boldt2007b; Boldt 2008) and another 2 were excluded due to concernsabout the credibility of the author and reliability of data (Boldt1993; Boldt 1998); and 6 contained only mean creatinine dataand thus no longer met criteria for inclusion (Allison 1999; Beyer1997; Langeron 2001; Petrikov 2008; Sade 1985; Vogt 1999).Two studies (Dehne 1997; Kulla 2008) were noted as significantexclusions. Kulla 2008 met all inclusion criteria but the two HESsolutions used in the study were not sufficiently different in com-position for comparison. Dehne 1997 studied postoperative pa-tients in the intensive care unit. The intervention group receiveda 12 mL/kg/d fixed dose of 10% HES 200/0.5 as a continuousinfusion for five days. The study was excluded because the controlgroup did not receive a comparison fluid. Four of 10 patients inthe HES group developed author-defined kidney failure (“acuterenal failure”) compared to 5/15 control patients.

Risk of bias in included studies

Details are available for each study in Characteristics of includedstudies; Figure 3 and Figure 4.

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Figure 3. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.

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Figure 4. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study

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Allocation

A large number of studies did not clearly state their methods forallocation concealment. For this reason, the majority were ratedas unclear.

Blinding

Only a minority of studies were blinded. This was deemed not tobe a significant issue for objective outcome data. In this review, SCrbased outcomes were considered objective as the lab technicianrunning the test was unlikely to be influenced by the study armof the patient. This includes the AKI outcome by RIFLE criteriaas well as those studies where author-defined kidney failure wasbased on creatinine measurements.There is a possibility of bias for the outcome of RRT. In the ma-jority of cases there is concomitant kidney failure evidenced byelevated SCr or electrolyte disturbance. However, RRT for otherindications, such as fluid overload and the timing of initiation ofRRT may be subjective in the absence of concrete pre-defined cri-teria. A general weakness in the majority of studies that evaluatedRRT was the absence of blinding and the absence of clear, objec-tive criteria for RRT initiation. If an outcome was not included inthe study, then a rating of ’unclear’ was assigned.

Incomplete outcome data

This was not an issue in most studies. Most studies had shortfollow-up periods, therefore losses to follow-up were minimal. Twostudies (Altman 1998; Gallandat 2000) had a significant amountof missing data.

Selective reporting

There was minimal evidence of selective reporting in the includedstudies.

Other potential sources of bias

Funnel plots for primary outcomes generally followed expecteddistributions (Figure 5; Figure 6; Figure 7; Figure 8; Figure 9).Small studies favouring HES were sparse for author-defined kidneyfailure and small studies favouring comparator fluids were sparsefor RIFLE-Failure. However, these plots had the fewest studieswith outcomes overall, and little heterogeneity in point estimateswas seen in large studies. Thus, significant publication bias orunrecognised heterogeneity are not suspected for any of the mainanalyses.

Figure 5. Funnel plot of comparison: 1 HES versus other fluid, outcome: 1.1 Renal replacement therapy.

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Figure 6. Funnel plot of comparison: 1 HES versus other fluid, outcome: 1.4 Kidney failure (author defined).

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Figure 7. Funnel plot of comparison: 1 HES versus other fluid, outcome: 1.5 RIFLE (Risk or worse).

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Figure 8. Funnel plot of comparison: 1 HES versus other fluid, outcome: 1.6 RIFLE (Injury or worse).

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Figure 9. Funnel plot of comparison: 1 HES versus other fluid, outcome: 1.7 RIFLE (Failure).

In three studies (Brunkhorst 2008; Godet 2008; Schortgen 2001),differences in baseline kidney function between groups could havebeen a source of bias. In two others (Neff 2003; Shatney 1983),there was no clear definition reported for the outcome of author-defined kidney failure. In Mahmood 2007 it was unclear if patientswho died were included in the author defined RRT counts.

Effects of interventions

HES products versus other fluids

Renal replacement therapy

Nineteen studies (9857 patients) comparing an HES product toanother fluid type reported RRT.Cittanova 1996 (47 patients) randomised deceased organ donorsto HES or gelatin and recorded the need for RRT in the kidneyrecipients, some of whom received kidneys from the same donor.Attempts to reach the primary author to address this unit of analy-sis issue were unsuccessful but a sample of intraclass correlation co-efficients (ICCs), ranging from -0.06 to 0.107 was calculated fromthe literature (Belli 1988; Hetzel 2002; Pfaff 1998; Suri 1999).Due to the uniqueness of this study population and the unit of

analysis issue, this study was analysed as its own subgroup. As theICCs were small, the original study data as published was enteredinto the meta-analysis.For all studies reporting RRT, there was a significant increase in theneed for RRT in the HES-treated individuals compared to thosetreated with other fluid therapies (Analysis 1.1 (19 studies, 9857patients): RR 1.31, 95% CI 1.16 to 1.49; I² = 0%). For surgicaland trauma patients (non-sepsis) the RR was 1.25 (95% CI 0.96to 1.61; Analysis 1.1.1) and the RR for septic patients was 1.32(95% CI 1.15 to 1.53; Analysis 1.1.2). The RR for the one studyof kidney transplant recipients was 6.67 (95% CI 0.92 to 48.45;Analysis 1.1.3). The results of the test for subgroup differenceswere: Chi² = 2.74, df = 2 (P = 0.25), I² = 27.1%.

Molecular weight/degree of substitution

There was a significant increase in the need for RRT in patientstreated with either high MW HES products (Analysis 1.2.1 (9studies, 1183 patients): RR 1.56, 95% CI 1.15 to 2.11; I² = 2%)or low MW HES products (Analysis 1.2.2 (10 studies, 8353 pa-tients): RR 1.26, 95% CI 1.09 to 1.45; I² = 0%) when comparedto another type of fluid therapy. The results of the test for sub-group differences were: Chi² = 1.59, df = 1 (P = 0.21), I² = 37.0%.

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Volume of HES product

There was a significant increase in the need for RRT in thosetreated with either high volume (≥2 L) HES product (Analysis1.3.1 (10 studies, 2220 patients): RR of 1.43 (95% CI 1.20 to1.71; I² = 0%) or low volume (< 2 L) HES product (Analysis 1.3.2(7 studies, 7296 patients): RR 1.22, 95% CI 1.02 to 1.46; I² =0%) when compared to other fluid therapies. The results of thetest for subgroup differences were: Chi² = 1.52, df = 1 (P = 0.22),I² = 34.1%.

Author-defined kidney failure

Overall there was a significant increase in author-defined kidneyfailure in the HES-treated patients (Analysis 1.4 (15 studies, 1361patients): RR 1.59, 95% CI 1.26 to 2.00; I² = 0%). There wasa significant increase in author-defined kidney failure in septicpatients treated with HES products (Analysis 1.4.2 (4 studies,741 patients): RR 1.58, 95% CI 1.24 to 2.02; I² = 0%), but nosignificant difference in non-septic patients (Analysis 1.4.1 (11studies, 620 patients): RR 1.61, 95% CI 0.79 to 3.28; I² = 0%).

Acute kidney injury (by RIFLE criteria)

Twenty studies (8769 patients) compared an HES product withanother fluid type with enough data to evaluate the outcome AKIby RIFLE criteria.

• Risk or worse: Overall, there was a significant decrease inRIFLE-R (risk or worse) in those treated with HES products(Analysis 3.3 (20 studies, 8769 patients): RR 0.95, 95% CI 0.91to 0.99; I² = 0%). There was a significant decrease in RIFLE-Rin non-septic individuals treated with HES products (Analysis1.5.1 (12 studies, 5611 patients): RR 0.90, 95% CI 0.85 to0.94; I² = 0%) but no significant difference for septic individuals(Analysis 1.5.2 (9 studies, 3158 patients): RR 1.04, 95% CI 0.98to 1.12; I² = 0%). The results of the test for subgroup differenceswere: Chi² = 12.88, df = 1 (P = 0.0003), I² = 92.2%.

• Injury or worse: Overall, there was no significant differencein risk of RIFLE -I (injury or worse) in those treated with HESproducts versus other fluid therapies (Analysis 3.4 (18 studies,8583 patients): RR 1.01, 95% CI 0.88 to 1.17; I² =14%). Therewas a significant decrease in RIFLE-I in non-septic individualstreated with HES products versus other fluid therapies (Analysis1.6.1 (11 studies, 5478 patients): RR 0.85, 95% CI 0.78 to0.92; I² = 0%), but no significant difference in septic individuals(Analysis 1.6.2 (8 studies, 3105 patients): RR 1.10, 95% CI 1.00to 1.20; I² = 0%). The results of the test for subgroup differenceswere: Chi² = 17.64, df = 1 (P < 0.0001), I² = 94.3%.

• Failure: Overall, there was a significant increase in RIFLE-F (failure) in those treated with HES products (Analysis 3.5 (15studies, 8402 patients): RR 1.14, 95% CI 1.01 to 1.30; I² =0%). Subgroup analyses showed no significant difference in riskof RIFLE -F for non-septic individuals (Analysis 1.7.1 (8 studies,

5301 patients): RR 1.04, 95% CI 0.86 to 1.27; I² = 0%) howeveran increased risk for RIFLE-F was seen for septic individuals(Analysis 1.7 (8 studies, 3101 patients): RR 1.21, 95% CI 1.03to 1.43; I² = 0%). The results of the tests for subgroupdifferences were: Chi² = 1.31, df = 1 (P = 0.25), I² = 23.8%.

Molecular weight/degree of substitution

There was no significant difference in risk of RIFLE-R in thosetreated with high MW products (Analysis 1.8.1 (6 studies, 435 pa-tients): RR 1.26, 95% CI 0.89 to 1.79; I² = 0%) or low MW HESproducts versus other fluid therapies (Analysis 1.8.2 (15 studies,7993 patients): RR 1.00, 95% CI 0.84 to 1.20; I² = 41%). Theresults of the test for subgroup differences were: Chi² = 1.25, df =1 (P = 0.26), I² = 20.1%.

Volume of HES product

There was no significant difference in risk of RIFLE-R in thosetreated with either high volume (≥2 L) HES (Analysis 1.9.1 (10studies, 854 patients): RR 0.90, 95% CI 0.65 to 1.26; I² = 19%)or low volume (< 2 L) HES product (Analysis 1.9.2 (9 studies,7526 patients): RR 1.13, 95% CI 0.99 to 1.29; I² = 25%) whencompared to other fluid therapies. The results of the test for sub-group differences: Chi² = 1.48, df = 1 (P = 0.22), I² = 32.5%.

High versus low molecular weight/degree of

substitution HES products

Acute kidney injury (by RIFLE criteria)

• Risk or worse: there was no significant difference inRIFLE-R between those treated with high versus low MW HESproducts (Analysis 2.1 (3 studies, 139 patients): RR 1.15, 95%CI 0.18 to 7.8; I² = 4%).

• Injury or worse: there was no significant difference inRIFLE-I between those treated with high versus low MW HESproducts (Analysis 2.2 (4 studies, 188 patients): RR 3.21, 95 %CI 0.14 to 75.68).

• Failure: due to lack of outcomes we were unable to analyseRIFLE-F (Analysis 2.3).

Sensitivity analyses

Multiple sensitivity tests of the data were carried out for primaryoutcomes. If an outcome measure or either of its 95% CI crosseda RR of 1 during a sensitivity analysis, it was considered a signifi-cant change in the results. Also, if subgroup differences became orstopped being significant at the P < 0.05 level then the sensitivityanalysis was considered to have changed the results significantly.

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Analysis of each primary outcome using either a fixed effects modelor a Peto odds ratio (OR) model did not result in any significantchanges in the results.No significant changes in results occurred when studies with base-line differences in kidney function (Godet 2008; Schortgen 2001)were removed from the RRT and author defined kidney failureanalyses. Additionally, no significant changes in results occurredwhen the excluded study Dehne 1997 was added to the author-defined kidney failure results.Finally, an important sensitivity analysis was conducted to removethe urine output based RIFLE outcomes for Myburgh 2012, asonly creatinine based RIFLE outcomes were utilized in the otherstudies. This resulted in a RR of RIFLE-R of 1.05 for HES treatedindividuals compared with other fluid therapies (95% CI 0.97 to1.14) (Analysis 4.1; 20 studies, 8445 patients), a RR of RIFLE-I of 1.22 (95% CI 1.08 to 1.37) (Analysis 4.2; 18 studies, 838patients) and a RR of RIFLE-F of 1.35 (95% CI 1.15 to 1.57)(Analysis 4.3; 15 studies, 8216 patients). This analysis was notpossible for the subgroups as all the data were not available.

D I S C U S S I O N

Summary of main results

This is the most complete systematic review of RCTs publishedof the effects of HES on kidney function. Its completeness stemsfrom its inclusion of all available studies of volume resuscitationwith HES and unpublished RIFLE and subgroup data obtainedfrom included study authors.

HES versus other fluid therapies

This updated review demonstrates an overall 31% increased riskof RRT, 59% increased risk of author-defined kidney failure, and14% increased risk of AKI by RIFLE-Failure criteria in HEStreated individuals versus those treated with an alternate fluid. Theresults of the RIFLE-Risk and -Injury outcomes were more var-ied. When both urine output and creatinine based RIFLE criteriawere included for the studies that reported them, the RIFLE-Riskoutcome showed a small but statistically significant result in theopposite direction, with a 5% reduced risk of AKI in the HEStreated individuals, whereas the RIFLE-Injury outcome showedno differences between groups.In total, 20 studies of over 8000 patients either published RIFLEcriteria or provided individual level creatinines to the authors ofthis review for the determination of RIFLE based outcomes. Theavailability of an adequately powered sample for this validatedoutcome measure greatly strengthens the results of this review. Itwas, however, surprising that the results for the RIFLE-Risk andRIFLE-Injury outcomes were in contrast to the results obtained

for RIFLE-Failure and RRT outcomes. The RIFLE-Risk outcomehas been attributed to pre-renal AKI in some studies (Cerda 2011,Kellum 2008), therefore one potential explanation for these dis-parate findings is that HES products may, at least in the shortterm ameliorate renal perfusion, and thus decrease pre-renal AKI.However, this review has demonstrated that although individualsreceiving a comparator fluid are more likely to develop RIFLE-Risk than patients receiving HES, patients receiving HES are sub-sequently more susceptible to developing more severe RIFLE out-comes and a need for RRT, potentially as HES by-products accu-mulate over time. This finding is consistent with recent evidencethat the mechanism of renal toxicity is secondary to HES particleaccumulation in renal tissue (Bellmann 2012).Further clarification of the differences in RIFLE outcomes was pro-vided by the sensitivity analysis, in which urine output based RI-FLE outcomes were excluded. When urine output based outcomeswere excluded from the RIFLE-Risk outcome as per our studyprotocol, the results were again in favour of non-HES fluid thera-pies, however the results were not statistically significant. For theRIFLE-Injury outcome, a significant difference between groupswas not seen in the initial analysis, however when urine outputbased criteria were excluded, a robust difference was seen betweengroups, with a 22% increased risk of RIFLE -Injury in the HESgroup. The removal of urine-output criteria from the RIFLE- Fail-ure outcome also strengthened the association, and increased therisk of AKI to 35% in HES treated individuals. These findings arein keeping with the hypothesis that HES products increase the riskof established AKI, despite a relatively superior maintenance ofurine output, perhaps again reflecting improved renal perfusion.Furthermore, recent literature also emphasizes the superiority ofSCr based RIFLE criteria over urine output based RIFLE criteriaat predicting important clinical outcomes. Wlodzimirow et al.,in a cohort of critically ill adults (Wlodzimirow 2012) showed asignificant difference in AKI risk when evaluating the combinedurine output and creatinine based outcome (RIFLE-Cr+UO) ver-sus RIFLE-Cr alone (P < 0.001). However, 83% of patients notidentified with RIFLE-Cr recovered within one or more days andthose patients with AKI by RIFLE-Cr alone had increased mortal-ity over those with AKI diagnosed by RIFLE-Cr+UO (38% basedon RIFLE-Cr versus 24% based on RIFLES Cr+UO (P = 0.02)).This study supports the lack of harm in excluding urine outputbased outcomes, as the most at risk patients are still identifiedwithout the addition of urine output to the RIFLE-Cr outcome.The present version of this review excluded secondary outcomesbased on group mean serum creatinine (SCr) that were includedin the initial version. This was due to the moderate to substantialamount of heterogeneity that existed for these outcome measuresand the lack of meaningful results. SCr is influenced by manyclinical factors including age, body mass and hydration status.Changes in SCr, as measured by RIFLE criteria, are more accuratemeasures of kidney function than static measurements. One-timeSCr measurements in acute situations cannot be reliably utilized

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to estimate kidney function, and therefore should not be utilisedalone to evaluate kidney function in this context. This change inprotocol resulted in the elimination of six studies from the originalreview, which are now included only as pertinent exclusions.A common criticism of kidney outcome studies in HES treatedpatients is lack of sufficient follow-up, suggested by the fact thatit took 16 days before 50% of patients receiving HES developedkidney failure in Schortgen 2001. However, inspection of the pub-lished Kaplan-Meier curve reveals subgroup differences in thisstudy after only three days of treatment. Further, in analysing stud-ies according to RIFLE criteria in this review, many outcomes oc-curred early in the course of treatment.

Sepsis versus non-sepsis patient populations

Subgroup analyses by patient population showed statistically sig-nificant differences in RIFLE-Risk and RIFLE-Injury outcomesbetween sepsis and non-sepsis patients. Non-sepsis patients treatedwith HES had fewer adverse outcomes than those treated with acomparator fluid, whereas sepsis patients treated with HES showedworse outcomes than those receiving a comparator fluid. These re-sults appear to be of little clinical significance given the absence ofsubgroup differences for the more important RIFLE-Failure andRRT outcomes, where HES use was associated with worse out-comes in both patient population subgroups. The differences seenfor RIFLE-Risk and Injury outcomes may more likely reflect thediffering initial renal response to fluid resuscitation in pre-renalversus sepsis associated AKI.

High versus low molecular weight (MW) HES and

High versus low degree of substitution (DS)

It was previously hypothesized that new HES products that werelower molecular weight and degree of substitution had better sideeffect profiles. Few clinical studies have directly compared 2 dif-ferent HES solutions to evaluate this hypothesis. RIFLE crite-ria (Gallandat 2000; Jungheinrich 2004; Protsenko 2009; Sander2003) and RRT data (Ertmer 2012, Kasper 2003 Kumle 1999;Mahmood 2007; Neff 2003) were available for only a few studieswith pair-wise comparisons of different HES products. All studieswere in the perioperative period except Protsenko 2009, with fewadverse outcomes reported. In all but one study (Kumle 1999), 6%130/0.4 was compared to 6% 200/0.5 or 6 % 200/0.62. Whenstudies were analysed by comparing high versus low MW and DSHES, no significant differences were found between groups for anyoutcome measure. However, there were few outcomes reportedand the studies were underpowered.Subgroup differences for high versus low molecular weight anddegree of substitution and volume of HES products versus otherfluids for the RRT and RIFLE based outcomes did not show anyevidence of differences between groups. Thus, there is insufficientevidence to support that 6% 130/0.4’s favourable pharmacokinet-ics (Jungheinrich 2005) compared to older HES products result

in improved kidney outcomes compared to higher MW and DSHES products. Newer evidence in fact has shown that the newerproducts actually exhibit increased tissue uptake as a potentialmechanism of toxicity (Bellmann 2012).

Dose of HES product

Subgroup analyses by volume of HES product (≥ 2 L versus < 2L) failed to show statistically significant differences between sub-groups, suggesting a safe dose of HES has not been identified.

Overall completeness and applicability ofevidence

Despite concerns regarding adverse kidney outcomes with HESproducts since the mid 1990’s, hundreds of RCTs identified bythis review did not evaluate kidney outcomes. This data, had itbeen collected, could have contributed significantly to answeringthis important clinical question many years ago.The review includes data across a wide range of critically ill individ-uals. Due to the potential differences in patient populations andcomparison fluids, where sufficient data was available, subgroupanalyses were undertaken to avoid missing true effect differenceswhere they existed. However, in this case no significant subgroupdifferences were identified.The results of the review should only be applied to a patient groupor intervention to the extent that it was represented in the review.The majority of the studies were of adult individuals with normalor moderately reduced kidney function, although exclusion cri-teria varied across studies. Organ donors and paediatric patientswere under-represented, although RCT’s are not justified in thesepatients due to the significant potential for harm from HES prod-ucts.

Quality of the evidence

A total of 42 studies were included in this review with a total of11,399 patients. This review is significantly strengthened since theoriginal review which included less that 3000 individuals.This updated review has been strengthened by the addition of23 new studies, and specifically the addition of 4 large previ-ously ongoing studies in sepsis (BaSES 2012 (BASES), Guidet2012 (CRYSTMAS) Perner 2012 (6S)) and critically ill patients(Myburgh 2012 (CHEST)). These four studies now contribute76.2% of the effect size for the main outcome of interest (require-ment of RRT). These studies include a robust number of patientsin high risk populations for AKI, thus tremendously increasingthe power of the available data to assess renal outcomes. Impor-tantly, they were also the first studies to be double-blinded (i.e. thestudy fluids were packaged in order to be indistinguishable), a veryimportant study characteristic that eliminated the potential risk

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of bias driving the somewhat subjective decision to initiate RRTin some cases. Also the validated, standardized RIFLE criteria forAKI were included in all of these new studies, allowing a morevalid meta-analysis of outcomes.The only RCT that evaluated kidney transplant donors treatedwith HES was Cittanova 1996. It showed that an exposure of 2100mL of 6% 200/0.6 resulted in an increased risk of delayed graftfunction in the recipients, even after addressing a unit of analy-sis issue. This study remains the only RCT for this participantsubgroup and conflicting results have been reported in non-ran-domised studies (Blasco 2008; Deman 1999; Giral 2007; Legendre1993).

Potential biases in the review process

The search strategy utilised was broad and included all potentialarticles that evaluated HES products in patients with intravascularvolume depletion. The initial search strategy itself did not includekidney parameters such that all studies could be evaluated man-ually for potential kidney outcomes. All foreign language articleswere reviewed and systematically evaluated. CENTRAL and theRenal Group’s specialised register were included in the search toevaluate all additional studies that were picked up by handsearch-ing. One potential limitation encountered was the inconsistentdefinition of kidney failure in each paper, but these findings weresupported by more standardised outcomes such as RRT and theRIFLE criteria.

Agreements and disagreements with otherstudies or reviews

Since our Cochrane review was first published (Dart 2010), threeother systematic reviews have been published on the renal effectsof HES products. The first review by Hartog et al (Hartog 2011)discussed the renal adverse effects of HES in a narrative review.The authors concluded that the renal risk is increased by cumu-lative dose, but that no safe upper limit is known. They criticizedthe current literature on modern solutions because of small sam-ple sizes, low cumulative doses, short observation periods and in-adequate control fluids and suggest these solutions should not beused in at risk patients. This was the first quantitative review ofthe adverse kidney effects of HES to update its results since manystudies by Dr J Boldt were retracted by their publisher due to con-cerns about the integrity of data. In 2013 there were two reviewspublished. The first, by Hasse et al. (Haase 2013), included onlystudies evaluating HES 130/0.38-0.45 versus crystalloid or albu-min in patients with sepsis. The RR of RRT for the five includedstudies was 1.36 (95% CI 1.08 to 1.72), a similar result to ourreview, despite the fact that the CHEST trial sepsis subgroup datawas not available (Myburgh 2012). This review did also includethe BaSES trial data. They also evaluated mortality, which was not

different between groups in their main analysis, however in a posthoc subgroup analysis they did show a RR of death of 1.11 (95%CI 1.01 to 1.22) in HES treated patients in those studies with atleast 28 days of follow-up. The last review was published the sameweek, and included only critically ill patients (Zarychanski 2013).This review again showed similar findings with a RR of RRT of1.32 (95% CI 1.15 to 1.50) and RR of mortality of 1.09 (95%CI1.02 to 1.17) for HES treated patients. It also included publishedRIFLE criteria outcome data, however did not contact authors foradditional data, and did not have access to the sepsis subgroupdata from the CHEST trial or the BaSES trial.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

In this review, HES was associated with an increased risk of AKIand RRT in included study patients, with a relative risk of SCrbased RIFLE-Injury, RIFLE-Failure, RRT and author defined kid-ney failure ranging from 1.22 to 1.59. There were no significantdifferences between septic and non-septic patients, nor when re-sults were stratified by molecular weight, degree of substitutionand dose of HES. In all populations where HES is considered foruse in volume resuscitation, these renal risks, along with otherrisks (Barron 2004; Bork 2005; Wiedermann 2004; Zarychanski2013), should be weighed against any evidence of benefit fromHES, and the risks and benefits of any volume replacement alter-natives. In most clinical situations where HES products have beenused, it is likely that these risks outweigh any benefits and othervolume replacement therapies should be used instead of HES.

Implications for research

Authors of published studies in this area are encouraged to con-tribute to this review’s objectives by publishing their data in RI-FLE format or submitting it to the authors of this review to beadded directly to our analyses. Researchers contemplating RCTsinvolving HES for fluid resuscitation should measure individualSCr values daily for analysis by RIFLE criteria. However, due to thesignificant body of literature which has now shown an increasedrisk of AKI and RRT in HES treated individuals, further studiesin this area are not warranted.

A C K N O W L E D G E M E N T S

We wish to thank the following people.

• Shayne Taback, who contributed to the initial version ofthis review (Dart 2010).

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• Michael Tennenhouse, MLS from the Neil John McleanLibrary at the University of Manitoba and Ruth Mitchell, TrialsSearch Coordinator, Cochrane Renal Group for their advice indesigning our search strategy.

• Dr Alexey Litinov, Dr Fabiana Postolow, Dr Tooru Mizuno,Dr Stefan Harms, Dr Regina Kostetsky, Dr Ahmet Leylek, DrIlan Buffo and Dr Arkady Major for their assistance withtranslation.

• Dr Mary Cheang, Biostatistical consulting unit, Universityof Manitoba, for her assistance with the calculation of intraclasscorrelation coefficients.

• The referees for their comments and feedback during thepreparation of this review.

R E F E R E N C E S

References to studies included in this review

Abdel-Khalek 2010 {published data only (unpublished sought but not

used)}

Abdel-Khalek EE, Arif SE. Randomized trial comparinghuman albumin and hydroxyethyl starch 6% as plasmaexpanders for treatment of patients with liver cirrhosis andtense ascites following large volume paracentesis. Arab

Journal of Gastroenterology 2010;11(1):24–9. [EMBASE:2010423152]

Akech 2010 {published and unpublished data}

Akech SO, Jemutai J, Timbwa M, Kivaya E, Boga M, FeganG, et al.Phase II trial on the use of Dextran 70 or starch forsupportive therapy in Kenyan children with severe malaria.Critical Care Medicine 2010;38(8):1630–6. [MEDLINE:20526196]

Akkucuk 2012 {published and unpublished data}

Akkucuk FG, Kanbak M, Ayhan B, Celebioglu B,Ulubay ZO, Aypar U. The effect of hydroxyethyl starch(130/0.4) as the priming solution on renal function inchildren undergoing cardiac surgery [abstract]. Applied

Cardiopulmonary Pathophysiology 2012;16:191–2.

Altman 1998 {published data only (unpublished sought but not used)}

Altman C, Bernard B, Roulot D, Vitte RL, Ink O.Randomized comparative multicenter study of hydroxyethylstarch versus albumin as a plasma expander in cirrhoticpatients with tense ascites treated with paracentesis.European Journal of Gastroenterology & Hepatology 1998;10

(1):5–10. [MEDLINE: 9512946]

BaSES 2012 {unpublished data only}∗ Haase N, Perner A, Hennings LI, Siegemund M, LauridsenB, Wetterslev M, et al.Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis:

systematic review with meta-analysis and trial sequentialanalysis. 2013 BMJ;346:f839. [MEDLINE: 23418281]Siegemund M. Basel study for evaluation of starch (130;0.4)infusion in septic patients: BaSES (130;0.4) Trial. http://clinicaltrials.gov/ct2/show/NCT00273728 (accessed 5 July2013).

Berard 1995 {published data only}∗ Berard JP, Curt I, Piech JJ, Ruiz F. [Hydroxyéthylamidonsversus gélatines: Impact sur le coût du remplissage dans unservice de réanimation]. Annales Francaises d Anesthesie et de

Reanimation 1995;14:R335.

Brunkhorst 2008 {published and unpublished data}

Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A,Ragaller M, Weiler N, et al.Intensive insulin therapy andpentastarch resuscitation in severe sepsis. New England

Journal of Medicine 2008;358(2):125–39. [MEDLINE:18184958]

Choi 2010 {published and unpublished data}

Choi YS, Shim JK, Hong SW, Kim JC, Kwak YL.Comparing the effects of 5% albumin and 6% hydroxyethylstarch 130/0.4 on coagulation and inflammatory responsewhen used as priming solutions for cardiopulmonary bypass.Minerva Anestesiologica 2010;76(8):584–91. [MEDLINE:20661198]

Cittanova 1996 {published data only (unpublished sought but not

used)}

Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B,Coriat P. Effect of hydroxyethylstarch in brain-dead kidneydonors on renal function in kidney-transplant recipients.Lancet 1996;348(9042):1620–2. [MEDLINE: 8961992]

Dehne 2001 {published data only (unpublished sought but not used)}

Dehne MG, Mühling J, Sablotzki A, Dehne K, Sucke N,Hempelmann G. Hydroxyethyl starch (HES) does notdirectly affect renal function in patients with no prior renal

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impairment. Journal of Clinical Anesthesia 2001;13(2):103–11. [MEDLINE: 11331169]

Diehl 1982 {published data only}

Diehl JT, Lester JL 3rd, Cosgrove DM. Clinical comparisonof hetastarch and albumin in postoperative cardiac patients.Annals of Thoracic Surgery 1982;34(6):674–9. [MEDLINE:6184023]

Dolecek 2009 {unpublished data only}

Dolecek M, Svoboda P, Kantorová I, Scheer P, Sas I,Bíbrová J, et al.Therapeutic influence of 20 % albuminversus 6% hydroxyethylstarch on extravascular lung waterin septic patients: a randomized controlled trial. Hepato-

Gastroenterology 2009;56(96):1622–8. [MEDLINE:20214205]

Du 2011 {published data only}

Du XJ, Hu WM, Xia Q, Huang ZW, Chen GY, Jin XD,et al.Hydroxyethyl starch resuscitation reduces the risk ofintra-abdominal hypertension in severe acute pancreatitis.Pancreas 2011;40(8):1220–5. [MEDLINE: 21775917]

Dubin 2010 {published and unpublished data}

Dubin A, Pozo M O, Casabella C A, Murias G, PalizasF, Moseinco M C, et al.Comparison of 6% hydroxyethylstarch 130/0.4 and saline solution for resuscitation of themicrocirculation during the early goal-directed therapy ofseptic patients. Journal of Critical Care 2010;25(4):658–9.[MEDLINE: 20813485]

Ertmer 2012 {published data only (unpublished sought but not used)}

Ertmer C, Wulf H, Van Aken H, Friederich P, Mahl C,Bepperling F, et al.Efficacy and safety of 10% HES 130/0.4versus 10% HES 200/0.5 for plasma volume expansionin cardiac surgery patients. Minerva Medica 2012;103(2):111–22. [MEDLINE: 22513516]

Fernandez 2005 {published and unpublished data}

Fernández J, Monteagudo J, Bargallo X, Jiménez W,Bosch J, Arroyo V, et al.A randomized unblinded pilotstudy comparing albumin versus hydroxyethyl starch inspontaneous bacterial peritonitis. Hepatology 2005;42(3):627–34. [MEDLINE: 16108036]

Gallandat 2000 {published and unpublished data}

Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-Butijn WT, Haagenaars JA, van Oeveren W, et al.A novelhydroxyethyl starch (Voluven) for effective perioperativeplasma volume substitution in cardiac surgery. Canadian

Journal of Anaesthesia 2000;47(12):1207–15. [MEDLINE:11132743]

Godet 2008 {published and unpublished data}

Godet G, Lehot JJ, Janvier G, Steib A, De Castro V, CoriatP. Safety of HES 130/0.4 (Voluven(R)) in patients withpreoperative renal dysfunction undergoing abdominal aorticsurgery: a prospective, randomized, controlled, parallel-group multicentre trial. European Journal of Anaesthesiology

2008;25(12):986–94. [MEDLINE: 18492315]

Guidet 2012 {published data only}

Guidet B, Martinet O, Boulain T, Philippart F, PousselJF, Maizel J, et al.Assessment of hemodynamic efficacyand safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9%

NaCl fluid replacement in patients with severe sepsis:The CRYSTMAS study. Critical Care 2012;16(3):R94.[EMBASE: 2012329428]

Heradstveit 2010 {published and unpublished data}

Heradstveit BE, Guttormsen AB, Langørgen J,Hammersborg SM, Wentzel-Larsen T, Fanebust R, etal.Capillary leakage in post-cardiac arrest survivors duringtherapeutic hypothermia - a prospective, randomised study.Scandinavian Journal of Trauma Resuscitation and Emergency

Medicine 2010;18:29. [MEDLINE: 20500876]

James 2011 {published data only}

James MF, Michell WL, Joubert IA, Nicol AJ, NavsariaPH, Gillespie RS. Resuscitation with hydroxyethyl starchimproves renal function and lactate clearance in penetratingtrauma in a randomized controlled study: the FIRSTtrial (Fluids in Resuscitation of Severe Trauma). British

Journal of Anaesthesia 2011;107(5):693–702. [MEDLINE:21857015]

Jungheinrich 2004 {unpublished data only}

Jungheinrich C, Sauermann W, Bepperling F, Vogt NH.Volume efficacy and reduced influence on measures ofcoagulation using hydroxyethyl starch 130/0.4 (6%) with anoptimised in vivo molecular weight in orthopaedic surgery:a randomised, double-blind study. Drugs in R&D 2004;5(1):1–9. [MEDLINE: 14725484]

Kasper 2003 {published data only (unpublished sought but not used)}

Kasper SM, Meinert P, Kampe S, Görg C, Geisen C,Mehlhorn U, et al.Large-dose hydroxyethyl starch 130/0.4does not increase blood loss and transfusion requirements incoronary artery bypass surgery compared with hydroxyethylstarch 200/0.5 at recommended doses. Anesthesiology 2003;99(1):42–7. [MEDLINE: 12826840]

Kumle 1999 {published data only (unpublished sought but not used)}

Kumle B, Boldt J, Piper S, Schmidt C, Suttner S, Salopek S.The influence of different intravascular volume replacementregimens on renal function in the elderly. Anesthesia &

Analgesia 1999;89(5):1124–30. [MEDLINE: 10553822]

Lee 2011 {published data only}

Lee JS, Ahn SW, Song JW, Shim JK, Yoo KJ, Kwak YL.Effect of Hydroxyethyl Starch 130/0.4 on Blood Loss andCoagulation in Patients With Recent Exposure to DualAntiplatelet Therapy Undergoing Off-Pump CoronaryArtery Bypass Graft Surgery. Circulation Journal 2011;75

(10):2397–402. [MEDLINE: 21817820]

London 1989 {published data only (unpublished sought but not used)}

London MJ, Ho JS, Triedman JK, Verrier ED, Levin J,Merrick SH, et al.A randomized clinical trial of 10%pentastarch (low molecular weight hydroxyethyl starch)versus 5% albumin for plasma volume expansion aftercardiac operations. Journal of Thoracic & Cardiovascular

Surgery 1989;97(5):785–97. [MEDLINE: 2468978]

Magder 2010 {published and unpublished data}

Magder S, Potter B, Fergusson D, Doucette S, De VerennesB. Importance of cardiac output measurements in the fluidafter cardiac surgery study (FACS) [abstract]. Intensive Care

Medicine 2010;36:S378. [EMBASE: 70291386 ]

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Mahmood 2007 {published data only}

Mahmood A, Gosling P, Vohra RK. Randomized clinicaltrial comparing the effects on renal function of hydroxyethylstarch or gelatine during aortic aneurysm surgery. British

Journal of Surgery 2007;94(4):427–33. [MEDLINE:17380548]

McIntyre 2008 {published data only (unpublished sought but not

used)}

McIntyre LA, Fergusson D, Cook DJ, Rankin N, DhingraV, Granton J, et al.Fluid resuscitation in the managementof early septic shock (FINESS): a randomized controlledfeasibility trial. Canadian Journal of Anaesthesia 2008;55

(12):819–26. [MEDLINE: 19050085]

Mukhtar 2009 {published data only (unpublished sought but not

used)}

Mukhtar A, Aboulfetouh F, Obayah G, Salah M, Emam M,Khater Y, et al.The safety of modern hydroxyethyl starchin living donor liver transplantation: a comparison withhuman albumin. Anesthesia & Analgesia 2009;109(3):924–30. [MEDLINE: 19690268]

Myburgh 2012 {published and unpublished data}

Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, GattasD, et al.Hydroxyethyl starch or saline for fluid resuscitationin intensive care. New England Journal of Medicine 2012;367(20):1901–11. [MEDLINE: 23075127]

Neff 2003 {published data only (unpublished sought but not used)}

Neff TA, Doelberg M, Jungheinrich C, Sauerland A,Spahn DR, Stocker R. Repetitive large-dose infusion of thenovel hydroxyethyl starch 130/0.4 in patients with severehead injury. Anesthesia & Analgesia 2003;96(5):1453–9.[MEDLINE: 12707149]

Perner 2012 {published data only}

Perner A, Haase N, Guttormsen AB, Tenhunen J,Klemenzson G, Aneman A, et al.Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. New England

Journal of Medicine 2012;367(2):124–34. [MEDLINE:22738085]

Protsenko 2009 {published data only}

Protsenko DN, Leiderman IN, Grigor’ev EV, Kokarev EA,Levit AL, Gel’fand BR. Evaluation of the effectivenessand safety of synthetic colloid solutions in the treatmentof severe abdominal sepsis: a randomized comparativestudy. Anesteziologiia i Reanimatologiia 2009, (5):9–13.[MEDLINE: 19938709]

Sander 2003 {unpublished data only}

Sander O, Reinhart K, Meier-Hellmann A. Equivalence ofhydroxyethyl starch HES 130/0. 4 and HES 200/0. 5 forperioperative volume replacement in major gynaecologicalsurgery. Acta Anaesthesiologica Scandinavica 2003;47(9):1151–8. [MEDLINE: 12969111]

Schortgen 2001 {published and unpublished data}

Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, HemeryF, Lemaire F, et al.Effects of hydroxyethylstarch and gelatinon renal function in severe sepsis: a multicentre randomisedstudy. Lancet 2001;357(9260):911–6. [MEDLINE:11289347]

Shatney 1983 {published data only}

Shatney CH, Deepika K, Militello PR, Majerus TC,Dawson RB. Efficacy of hetastarch in the resuscitation ofpatients with multisystem trauma and shock. Archives of

Surgery 1983;118(7):804–9. [MEDLINE: 6190466]

Shmyrev 2011 {published and unpublished data}

Shmyrev V, Lomivorotov V, Ponomarev D. A word ofcaution for using hypertonic hydroxyethyl starch solution invalvular heart surgery [abstract]. Journal of Cardiothoracic &

Vascular Anesthesia 2011;25(3 Suppl 1):S31–2. [EMBASE:70428812]

Van der Linden 2005 {published and unpublished data}

Van der Linden PJ, De Hert SG, Deraedt D, CromheeckeS, De Decker K, De Paep R, et al.Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volume expansionin cardiac surgery patients: the effects on perioperativebleeding and transfusion needs. Anesthesia & Analgesia

2005;101(3):629–34. [MEDLINE: 16115963]

Vlachou 2010 {published data only (unpublished sought but not used)}

Vlachou E, Gosling P, Moiemen NS. Hydroxyethylstarchsupplementation in burn resuscitation--a prospectiverandomised controlled trial. Burns 2010;36(7):984–91.[MEDLINE: 20558004]

Yang 2011 {published and unpublished data}

Yang J, Wang WT, Yan LN, Xu MQ, Yang JY. Alternativesto albumin administration in hepatocellular carcinomapatients undergoing hepatectomy: An open, randomizedclinical trial of efficacy and safety. Chinese Medical Journal

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Yassen 2011 {published and unpublished data}

Yassen AM, Elshoubari MM, Salah T, Sultan AM, FlsadanyMM, Wahab MA. Does co-Ad ministration of HES 130/0.4 to albumin 4% affect the transfusion requirements andcoagulation profile in living-donor liver transplantation?[abstract]. Liver Transplantation 2011;Conference:S133.[EMBASE: 70787513]

References to studies excluded from this review

Aksun 2009 {published data only (unpublished sought but not used)}

Aksun M, Damar E, Goktogan T, Yilmaz E, Aran G,Sencan A, et al.Haemodynamic, metabolic and haemostaticeffects of 6% HES 130/0.4 usage as a priming solution inaddition to Ringer’s solution in CABG operations. Journal

of Cardiothoracic & Vascular Anesthesia 2009;23(3 Suppl 1):S36–7. [EMBASE: 70261994]

Allison 1999 {published data only (unpublished sought but not used)}

Allison KP, Gosling P, Jones S, Pallister I, Porter KM.Randomized trial of hydroxyethyl starch versus gelatinefor trauma resuscitation. Journal of Trauma 1999;47(6):1114–21. [MEDLINE: 10608543]

Ando 2008 {published data only}

Ando Y, Terao Y, Fukusaki M, Yamashita K, TakadaM, Tanabe T, et al.Influence of low-molecular-weighthydroxyethyl starch on microvascular permeability inpatients undergoing abdominal surgery: comparison

24Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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with crystalloid. Journal of Anesthesia 2008;22(4):391–6.[MEDLINE: 19011778]

Beyer 1997 {published data only (unpublished sought but not used)}

Beyer R, Harmening U, Rittmeyer O, Zielmann S, MielckF, Kazmaier S, et al.Use of modified fluid gelatin andhydroxyethyl starch for colloidal volume replacement inmajor orthopaedic surgery. British Journal of Anaesthesia

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Boldt 1993 {published data only (unpublished sought but not used)}

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Boldt J, Scholhorn T, Mayer J, Piper S, Suttner S. The valueof an albumin-based intravascular volume replacementstrategy in elderly patients undergoing major abdominalsurgery. Anesthesia & Analgesia 2006;103(1):191–9.[MEDLINE: 16790652]

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Dehne MG, Mühling J, Sablotzki A, Papke G, KuntzschU, Hempelmann G. Effect of hydroxyethyl starch onrenal function in intensive-care patients [Einfluss vonHydroxyethylstarke–Losung auf die Nierenfunktionbei operativen Intensivpatienten]. Anästhesiologie,

Intensivmedizin, Notfallmedizin, Schmerztherapie 1997;32

(6):348–54. [MEDLINE: 9333329]

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Hanart C, Khalife M, De Villé A, Otte F, De Hert S,Van der Linden P. Perioperative volume replacement inchildren undergoing cardiac surgery: albumin versushydroxyethyl starch 130/0.4. Critical Care Medicine 2009;37(2):696–701. [MEDLINE: 19114887]

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Kulla M, Weidhase R, Lampl L. Hydroxyethyl starch 6%130/0.42 in acetate-buffered Ringer’s solution as a partof a balanced-volume resuscitation in abdominal surgery[Hydroxyethylstarke 6% 130/0,42 in Ringerazetat alskomponente eines balancierten volumenersatzes in derabdominalchirurgie]. Anasthesiologie und Intensivmedizin

2008;49(1):7–18. [EMBASE: 2008062037]

Kvalheim 2010 {published data only (unpublished sought but not

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Kvalheim VL, Farstad M, Steien E, Mongstad A, BorgeBA, Kvitting PM, et al.Infusion of hypertonic saline/starch

25Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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during cardiopulmonary bypass reduces fluid overloadand may impact cardiac function. Acta Anaesthesiologica

Scandinavica 2010;54(4):485–93. [MEDLINE: 19878097]

Langeron 2001 {published and unpublished data}

Langeron O, Doelberg M, Ang ET, Bonnet F, Capdevila X,Coriat P. Voluven, a lower substituted novel hydroxyethylstarch (HES 130/0.4), causes fewer effects on coagulationin major orthopedic surgery than HES 200/0.5. Anesthesia

& Analgesia 2001;92(4):855–62. [MEDLINE: 11273914]

Liet 2003 {published data only}

Liet JM, Bellouin AS, Boscher C, Lejus C, Roze JC.Plasma volume expansion by medium molecular weighthydroxyethyl starch in neonates: a pilot study. Pediatric

Critical Care Medicine 2003;4(3):305–7. [MEDLINE:12831411]

NCT00576849 {published data only}

NCT00576849. Phase 4 study of a total balanced volumereplacement regimen in elderly cardiac surgery patients.www.clinicaltrials.gov/ct2/show/NCT00576849 (accessed5 July 2013). [CLINICALTRIALS.GOV: NCT00576849]

Ooi 2009 {published data only (unpublished sought but not used)}

Ooi JS, Ramzisham AR, Zamrin MD. Is 6% hydroxyethylstarch 130/0.4 safe in coronary artery bypass graft surgery?. Asian Cardiovascular & Thoracic Annals 2009;17(4):368–72. [MEDLINE: 19713332]

Petrikov 2008 {published data only}

Petrikov SS, Solodov AA, Titova IuV, Davydov BV, KrylovVV. Tactics of infusion therapy in the acute period ofintracranial hemorrhages. Anesteziologiia i Reanimatologiia

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Sade 1985 {published data only}

Sade RM, Stroud MR, Crawford FA Jr, Kratz JM, DearingJP, Bartles DM. A prospective randomized study ofhydroxyethyl starch, albumin, and lactated Ringer’s solutionas priming fluid for cardiopulmonary bypass. Journal of

Thoracic & Cardiovascular Surgery 1985;89(5):713–22.[MEDLINE: 2581099]

Schewior 2008 {published data only (unpublished sought but not

used)}

Schewior L, Frei U, Neuhaus P, Junge G. Treatment andimpact of hepatorenal syndrome for patients on waiting listfor liver transplantation [abstract]. Liver Transplantation

2008;14(7 (Suppl 1)):S219.

Shahbazi 2011 {published data only}

Shahbazi S, Zeighami D, Allahyary E, Alipour A, EsmaeeliM J, Ghaneie M. Effect of colloid versus crystalloidadministration of cardiopulmonary bypass prime solutionon tissue and organ perfusion. Iranian Cardiovascular

Research Journal 2011;5(1):24–31.

Tiryakioglu 2008 {published data only (unpublished sought but not

used)}

Tiryakio lu O, Yildiz G, Vural H, Goncu T, Ozyazicioglu

A, Yavuz . Hydroxyethyl starch versus Ringer solution incardiopulmonary bypass prime solutions (a randomized

controlled trial). Journal of Cardiothoracic Surgery 2008;3:45. [MEDLINE: 18620591]

Vernetta 2012 {published data only}

Vernetta D, Alvarez A, Churruca I, Hernando D, PuigvertF. The effects of hydroxyethyl 130/0.4 (Voluven) onrenal function in laparoscopic nephrectomy [abstract].British Journal of Anaesthesia 2012;108:ii13–4. [EMBASE:70718972]

Vogt 1999 {published data only (unpublished sought but not used)}

Vogt N, Bothner U, Brinkmann A, de Petriconi R, GeorgieffM. Peri-operative tolerance to large-dose 6% HES 200/0.5in major urological procedures compared with 5% humanalbumin. Anaesthesia 1999;54(2):121–7. [MEDLINE:10215706]

Wu 2010 {published data only (unpublished sought but not used)}

Wu Y, Wu AS, Wang J, Tian M, Jia XY, Rui Y, etal.Effects of the novel 6% hydroxyethyl starch 130/0.4on renal function of recipients in living-related kidneytransplantation. Chinese Medical Journal 2010;123(21):3079–83. [MEDLINE: 21162959]

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References to other published versions of this review

Dart 2009

Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethylstarch (HES) versus other fluid therapies: effects on kidneyfunction. Cochrane Database of Systematic Reviews 2009,Issue 1. [DOI: 10.1002/14651858.CD007594]

Dart 2010

Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethylstarch (HES) versus other fluid therapies: effects on kidneyfunction. Cochrane Database of Systematic Reviews 2010,Issue 1. [DOI: 10.1002/14651858.CD007594.pub2]

∗ Indicates the major publication for the study

28Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Abdel-Khalek 2010

Methods • Design: RCT• Time frame: April 2008 to February 2009

Participants • Country: Egypt• Setting: multi-centre• Adult patients undergoing paracentesis with volume replacement• Number (treatment/control): 67/68• Age (mean ± SD) years: treatment group (46 ± 2.96); control group (47 ± 3.54)• Sex (males): treatment group (54%); control group (52%)• Exclusions: kidney disease (creatinine > 2 mg/dL)

Interventions Treatment group• Poly 0-2-HES Hemohes 6% 0.45 to 0.55, 8 g/L of ascites removed, half after the

procedure and the remainder over 6 to8 hours◦ No volume reported

Control group• Albumin 20%, 8 g/L of ascites removed, half after the procedure and the

remainder over 6 to8 hours◦ No volume reported

Outcomes • Kidney failure (Cr > 50% increase from baseline and over 1.5 mg/dL)

Notes • Published data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’random numbers generated by SAS’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective outcome measure

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Abdel-Khalek 2010 (Continued)

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data; death only losses

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Akech 2010

Methods • Design: RCT• Time frame: June 2006 to December 2008

Participants • Country: Kenya• Setting: single centre• Paediatric patients with severe malaria• Number (treatment/control): 40/39• Age: groups combined 40 months (IQR 28-53)• Sex: NS• Exclusions: established kidney failure

Interventions Treatment group• HES 130/0.4 Voluven, up to 2 doses of 20 mL/kg

◦ 50 (42 to 58) mL/kgControl group

• Dextran 6%, up to 2 doses of 20 mL/kg◦ 49 (41 to 57) mL/kg

Outcomes • Author defined kidney failure ’evidence of renal impairment’• RIFLE

Notes • Published and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’an independent person not involved in therecruitment’

Allocation concealment (selection bias) Low risk ’opaque envelopes’

30Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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Akech 2010 (Continued)

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk ’no evidence of renal impairment’

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Akkucuk 2012

Methods • Design: RCT• Time frame: NS

Participants • Country: Turkey• Setting: single centre• Children 2-16 years undergoing cardiac surgery - pump• Number (treatment/control): 12/12• Age (mean ± SD) years: treatment group (5.1 ± 3.7); control group (3.9 ± 1.7)• Sex (M/F): treatment group (7/5); control group (6/6)• Exclusions: Kidney disease (Cr > 1.5 mg/dL)

Interventions Treatment group• HES 130/0.4%• Volume (mean ± SD): 1,538.5 ± 999.2 mL over 2 to 4 days

Control group• Ringers Lactate• Volume (mean ± SD): 387.9 ± 186.7 mL over 2 to 4 days

Outcomes • RIFLE

Notes • Published study of abstract found in review

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Akkucuk 2012 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Divided into two randomised groups

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

Altman 1998

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: France• Setting: Multicentre• Adult patients with cirrhotic ascites requiring paracentesis, repeated daily until

ascites drained• Number (treatment/control): 27/33• Age (mean ± SD) years: treatment group (56.3 ± 11.2); control group (55.9 ± 11.

2)• Sex (M/F): treatment group (21/6); control group (23/10)• Exclusions: kidney disease (Cr > 1.4 mg/dL)

32Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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Altman 1998 (Continued)

Interventions Treatment group• Elohes 6.5%• Volume (mean ± SD): 1538.5 ± 999.2 mL over 2 to 4 days

Control group• 20% albumin• Volume (mean ± SD): 387.9 ± 186.7 mL over 2 to 4 days

Outcomes • Kidney failure (50% increase from baseline or > 1.4 mg/dL)

Notes • Published data only - unsuccessful attempt to contact author

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’randomly allocated (random number table)’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective criteria

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

High risk Excluded patients after randomisation

Selective reporting (reporting bias) Low risk Subgroup analysis but compared as subset ofwhole

Other bias Low risk The study appears to be free of other sources ofbias

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BaSES 2012

Methods • Design: RCT• Time frame: 2006-2011

Participants • Country: Switzerland• Setting: single centre• Adult ICU patients with sepsis• Number : 241

Interventions Treatment group• 6% HES Voluven• Volume median: 3775 mL (IQR 2019 to 6347)

Control group• Isotonic saline

Outcomes • RRT

Notes • Published data only available in systematic review published by the authors Haase2013

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Unable to assess as not published

Allocation concealment (selection bias) Unclear risk Unable to assess as not published

Blinding (performance bias and detectionbias)RRT

Unclear risk Unable to assess as not published

Blinding (performance bias and detectionbias)Creatinine based

Unclear risk Unable to assess as not published

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Unable to assess as not published

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Unable to assess as not published

Incomplete outcome data (attrition bias)All outcomes

Unclear risk Unable to assess as not published

Selective reporting (reporting bias) Unclear risk Unable to assess as not published

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BaSES 2012 (Continued)

Other bias Unclear risk Unable to assess as not published

Berard 1995

Methods • Design: RCT• Time Frame: May 1992 to March 1993

Participants • Country: France• Setting: NS• Adult patients with GI bleeding• Number (treatment/control): unclear• Age (mean ± SD) years: treatment group (58.5 ± 16/6); control group (62.1±15.8)• Sex (males): treatment group (65.75%); control group (64%)

Interventions Treatment group• HES: hydroxyethylamidons

Control group• gelatin

Volumes: NS

Outcomes • RRT only

Notes • French abstract

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’tires au sort’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Insufficient information to permit judge-ment

Blinding (performance bias and detectionbias)Creatinine based

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Insufficient information to permit judge-ment

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Insufficient information to permit judge-ment

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Berard 1995 (Continued)

Incomplete outcome data (attrition bias)All outcomes

Unclear risk Insufficient information to permit judge-ment

Selective reporting (reporting bias) Unclear risk Insufficient information to permit judge-ment

Other bias Unclear risk Insufficient information to permit judge-ment

Brunkhorst 2008

Methods • Design: parallel RCT• Time frame: April 2003 to June 2005

Participants • Country: Germany• Setting: multicentre (18 academic tertiary hospitals)• Adult sepsis patients with intravascular volume depletion• Number (treatment/control): 262/275• Age (mean ± SD) years: treatment group (64.4 ± 13.3); control group (64.9 ± 14.

1)• Sex (males): treatment group (60.3%); control group (59.6%)• Exclusions: kidney disease (dialysis dependent or Cr > 320 µmol/L)

Interventions Treatment group• 10% Hemohes 200/0.5 for 21 days, death or ICU discharge• Volume: Median 70.4 mL/kg (IQR 33.4 to144.2)

Control group• Ringer’s lactate for 21 days, death or ICU discharge• Volume: 1.32 x HES group

Outcomes • RRT (published)• Kidney failure (2x baseline Cr or need for RRT (published)• 2x baseline Cr (unpublished subgroup data)• Death (published)

Notes • Could receive up to 1000 mL HES prior to entry, 18/275 in Ringer’s lactategroup received H

• Published data only - no further data provided by author

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Stratified by hospital and using randompermuted blocks with variable size (supple-mentary online appendix)

Allocation concealment (selection bias) Unclear risk NS

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Brunkhorst 2008 (Continued)

Blinding (performance bias and detectionbias)RRT

High risk No criteria and no blinding

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk Subjective need for RRT part of author de-fined kidney failure

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk All patients accounted for and reported,study stopped early after safety analysis

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study was stopped after the first stageof a two-stage adaptive study design for glu-cose arm only

Choi 2010

Methods • Design: RCT• Time frame: January to November 2008

Participants • Country: South Korea• Setting: single centre• Adult cardiac surgery patient on bypass• Number (treatment/control): 18/18• Age (mean ± SD) years: treatment group (54 ± 12); control group (55 ± 14)• Sex (M/F): treatment group (5/13); control group (6/12)• Exclusions: kidney disease (Cr > 1.4 mg/dL pre op)

Interventions Treatment group• 6% 130/0.4 HES for pump prime• Volume: 500 mL for pump prime plus mean 921 ± 361 mL 8 hours

postoperatively and 15 ± 45 mL 16 hours postoperativelyControl group

• 5% Albumin 500 mL for pump prime• Volume: 500 mL albumin plus HES mean 799 ± 241 mL 8 hours postoperatively

and 14 ± 42 mL 16 hours postoperatively

Outcomes • RIFLE (unpublished data)

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Choi 2010 (Continued)

Notes • Both groups received HES postoperatively

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computerized randomisation table’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Cittanova 1996

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: France• Setting: single centre• Deceased organ donors• Number (treatment/control): 21/21• Age (mean ± SD) years: Treatment group (45.6 ± 10.8); control group (45.7 ± 11.

1)• Sex (M/F): treatment group (12/8); control group (12/9)• Exclusions: none

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Cittanova 1996 (Continued)

Interventions Treatment group• 6% HES 130/0.4 Voluven (Fresenius Kabi, Germany)

Control group• Gelofusine ® (B/Braun, Germany) 4% succinylated gelatin

Volumes not clearly reported

Outcomes • RRT• Author defined kidney failure

Notes • Published data only - attempted to contact author, unsuccessful

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk NS

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Low risk Outcome assessors blinded to fluid type

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome criteria

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Insufficient information to permit judgement

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not included

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Unit of analysis issue: analysis of recipients with-outadjustment for multiple kidneys from samedonor

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Dehne 2001

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Germany• Setting: single centre• ASA I/II middle ear surgery patients with expected surgery duration > 3 hours• Number (group 1/group 2/group 3/control): 15/15/15/15• Age (mean ± SD) years: group 1 (50.4 ± 13.5); group 2 (53.2 ± 0.6); group 3 (50.

2 ± 10.6); control group (51.9 ± 7.9)• Sex (M/F): NS• Exclusions: kidney disease (’absence of renal dysfunction’)

Interventions Treatment group 1• 6% HES 200/0.5• Volume: 15 mL/kg over 1 day (actual not reported)

Treatment group 2• 6% HES 200/0.62• Volume: 15 mL/kg over 1 day (actual not reported)

Treatment group 3• 6% HES 450/0.7• Volume: 15 mL/kg over 1 day (actual not reported)

Control group• Ringer’s lactate• Volume: 60 mL/kg over 1 day (actual not reported)

Outcomes • Kidney failure (’evidence of renal dysfunction’)• death (all graph values)

Notes • Published data only - author contacted, no further data available• Only 6% 200/0.5 versus Ringer’s lactate presented in Analysis 1.4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’prospectively randomised’

Allocation concealment (selection bias) Low risk ’via sealed envelope assignment’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

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Dehne 2001 (Continued)

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk No specified threshold, markers used of uncertainsignificance, no blinding

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources ofbias

Diehl 1982

Methods • Design: Quasi-RCT• Time frame: NS

Participants • Country: USA• Setting: single centre• Adult cardiac surgery patients on cardiac bypass requiring fluids for intravascular

volume depletion; kidney disease included• Number (treatment/control): 27/33• Age (mean ± SD) years: treatment group (58.0 ± 8.0); control group (56.6 ± 8.1)• Sex (M/F): treatment group (29/4); control group (20/7)• Exclusions: NS

Interventions Treatment group• 6% HES 450 70-90% substitution• Volume (mean ± SD): 1210 ± 273 mL over 1 day

Control group• 5% albumin• Volume (mean ± SD): 1241 ± 481 mL over 1 day

Outcomes • Kidney failure (Cr > 1.5 mg/dL)• Death

Notes • Published data only - author not contacted, study too remote

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

High risk ’preoperatively randomly divided...according tohospital identification number’

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Diehl 1982 (Continued)

Allocation concealment (selection bias) High risk ’preoperatively randomly divided...according tohospital identification number’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective outcome measure (Cr > 1.5 mg/dL andCr > 2.0 mg/dL)

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes reported

Other bias Low risk The study appears to be free of other sources ofbias

Dolecek 2009

Methods • Design: RCT• Time frame: May 2005 to 2008

Participants • Country: Czech Republic• Setting:single centre trauma hospital• Adult patients with severe sepsis requiring artificial ventilation• Number (treatment/control): 26/30• Age (median, range) years: treatment group (47, 19-81); control group (43, 23-

67)• Sex (M/F): treatment group (22/4); control group (26/4)• Exclusions: ’acute renal failure’

Interventions Treatment group• 6% HES 130/0.4• Volume 250ml every 6 hours for 72 hours (3000 mL)

Control group• 20% albumin• Volume 100ml every 12 hours for 72 hours (600 mL)

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Dolecek 2009 (Continued)

Outcomes • RIFLE only

Notes • Unpublished data only

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computer generated randomisation list’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Du 2011

Methods • Design: RCT• Time frame: 2008 to 2009

Participants • Country: China• Setting: single centre• Severe acute pancreatitis• Number (treatment/control): 21/21• Age (mean ± SD) years

◦ Treatment group: donor (38 ± 12); recipient (44 ± 1)

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Du 2011 (Continued)

◦ Control group: donor (40 ± 17); recipient (44 ± 11)• Sex (M/F)

◦ Treatment group: donor (11/4); recipient (20/7)◦ Control group: donor (8/4); recipient (9/11)

• Exclusions: renal insufficiency

Interventions Treatment group• Elohes 6% 200/0.6 (max 33 mg/kg)• Donor volume (mean ± SD): HES 2100 ± 660 mL over 1 day

Control group• Ringer’s lactate• Donor volumes (mean ± SD): gelatin 2875 ± 1384 mL over 1 day

Outcomes • RRT

Notes • Published data only - attempted to contact author, unsuccessful

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computer derived random number sequence’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

High risk ’not blinded’

Blinding (performance bias and detectionbias)Creatinine based

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

High risk Patients who died at less than 72 hours wereexcluded

Selective reporting (reporting bias) High risk Patients who died at less than 72 hours wereexcluded

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Du 2011 (Continued)

Other bias Low risk The study appears to be free of other sourcesof bias

Dubin 2010

Methods • Design: pilot RCT• Time frame: NS

Participants • Country: Argentina• Setting: multicentre• Adult sepsis/burns with intravascular volume depletion• Number (treatment/control): 12/13• Age (mean ± SD) years: treatment group (62 ± 21); control group (65 ± 12)• Sex (males): treatment group (67%); control group (55%)• Exclusions: NS

Interventions Treatment group• Voluven 130/0.4 6% for volume expansion for 24 hours according to protocol

then for 5 days ongoing hydration• Volume (median, 90% CI): 2610 ± 885 mL then 2071 ± 486 mL

Control group• Normal saline for volume expansion for 24 hours according to protocol then for 5

days ongoing hydration• Volume (median, 90% CI): 6254 ± 2603 mL then 2114 ± 726 mL

Outcomes • RIFLE criteria (unpublished)• Death

Notes • Unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’simple randomisation’

Allocation concealment (selection bias) Low risk ’sealed envelopes’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

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Dubin 2010 (Continued)

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

High risk 4 excluded after randomisation due to loss of follow-up, and one excluded as not meeting criteria

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Small study with difference in group creatinines atbaseline

Ertmer 2012

Methods • Design: RCT (post-hoc analysis)• Time frame: November 2004 to July 2005

Participants • Country: Germany• Setting: multicentre• Adult cardiac surgery patients on cardiac bypass requiring fluids for intravascular

volume depletion; kidney disease included• Number (treatment/control): 37/39• Age (mean ± SD) years: treatment group (61 ± 11); control group 62 ± 11)• Sex (M/F): treatment group (31/6); control group (33/6)• Exclusions: pre-operative creatinine > 2mg/dL or oliguria (urine excretion <500

mL/d)

Interventions Treatment group• 10% HES 130/0.4 for perioperative replacement• Volume:1577 mL

Control group• 10% HES 200/0.5 for perioperative replacement• Volume: 1540 mL

Outcomes • RRT

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Permutated blocks of six

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Ertmer 2012 (Continued)

Allocation concealment (selection bias) Low risk By patient number offsite

Blinding (performance bias and detectionbias)RRT

Low risk Identical bottles

Blinding (performance bias and detectionbias)Creatinine based

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk One study centre excluded from results

Fernandez 2005

Methods • Design: parallel RCT• Time frame: January 2002 to February 2003

Participants • Country: Spain• Setting: single centre• Adult patients with cirrhosis and spontaneous bacterial peritonitis and

intravascular volume depletion• Number (treatment/control): 10/10• Age (mean ± SD) years: treatment group (60 ± 10); control group (62 ± 9)• Sex (M/F): treatment group (5/5); control group (6/4)• Exclusions: ’renal parenchymal disease’

Interventions Treatment group• 6% Hesteril (HES) 200/0.5 for 3 days• Volume

◦ Baseline: 25 mL/kg◦ Day 3: 16.6 mL/kg (either fluid)

Control group• 20% albumin for 3 days• Volume

◦ Baseline: 7.5 mL/kg

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Fernandez 2005 (Continued)

◦ Day 3: 5 mL/kg

Outcomes • Author defined kidney failure (Cr > 1.5 mg/dL or BUN > 25 mg/dL) (published)• RIFLE (unpublished)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’random numbers generated by SAS’

Allocation concealment (selection bias) Low risk ’sealed envelopes’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome criteria

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective outcome criteria, Cr > 1.5 mg/dL or BUN > 25 mg/dL

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome criteria

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Gallandat 2000

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Netherlands• Setting: multicentre• Adult cardiac surgery patients on cardiac bypass for pump priming and

intravascular volume depletion

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Gallandat 2000 (Continued)

• Number (group 1/group 2): 30/29• Age (mean ± SD) years: group 1 (63.5 ± 9.0); group 2 (61.0 ± 10.3)• Sex (M/F): group 1 (25/5); group 2 (25/5)• Exclusions: kidney disease (’renal disorders’)

Interventions Treatment group 1• Low MW HES: Voluven 6% 130/0.4 from intraoperatively until 16 hours

postoperatively• Volume (mean ± SD): 2550 ± 561 mL

Treatment group 2• High MW HES: Pentaspan 6% 200/0.5 from intraoperatively until 16 hours

postoperatively• Volume (mean ± SD): 2466 ± 516 mL

Outcomes • RIFLE (unpublished)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’randomised’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Ojective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

High risk Only two patients from Voluven group with noCr values at postoperative day 1 (unpublisheddata), multiple missing values sufficient to effectchange in outcomes from postoperative day 2(unpublished data)

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Gallandat 2000 (Continued)

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources ofbias

Godet 2008

Methods • Design: parallel RCT• Time frame: April 2002 to June 2004

Participants • Country: France• Setting: multicentre• Adult vascular surgery patients, not on cardiac bypass with intravascular volume

depletion; kidney disease (Cr > 250 µmol/L or CrCl < 80 mL/min)• Number (treatment/control): 32/33• Age (mean (range)) years: treatment group (72.9 (57 to 89)); control group (73

(55 to 86))• Sex (M/F): treatment group (28/4); control group (28/5)• Exclusions: NS

Interventions Treatment group• Voluven 6% 130/0.4• Volume (mean ± SD): 2350 ± 1355 mL over 6 days

Control group• 3% Plasmion (gelatin) up to 50 mL/kg• Volume (mean ± SD): 2136 ± 1174 mL over 6 days

Outcomes • RRT• Death• Kidney failure (Cr > normal or increase by 44.2 µmol/L from baseline) all

published• RIFLE (unpublished)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’the randomisation list was generated byDATAMAP using balanced blocks’

Allocation concealment (selection bias) Low risk ’envelopes identified by the randomisationnumber’

Blinding (performance bias and detectionbias)RRT

High risk Open study, no objective criteria

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Godet 2008 (Continued)

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Differences in kidney function betweengroups at baseline

Guidet 2012

Methods • Design: RCT• Time frame: 2012

Participants • Country: France/Germany• Setting: multicentre• Sepsis patients with intravascular volume depletion;• Number (treatment/control): 100/96• Age (mean ± SD) years: treatment group (65.8 ± 15.4); control group (65.9 ± 14.

7)• Sex (M/F): treatment group (28/4); control group (28/5)• Exclusions: creatinine >3.39 mg/dL or anuria > 8 hours

Interventions Treatment group• 6% HES 130/0.4 for 4 days• Volume 50 mL/kg first day, 25 mL/kg for days 2 to 4 (2615 ± 1499 mL)

Control group• Normal saline• Volume no maximum (2788 ± 1799 mL)

Outcomes • RRT• Death• RIFLE• All published outcomes

Notes

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Guidet 2012 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk NS

Allocation concealment (selection bias) Low risk ’double blind’

Blinding (performance bias and detectionbias)RRT

Low risk ’double blind’

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Unclear risk Insufficient information to permit judgement

Selective reporting (reporting bias) Unclear risk Insufficient information to permit judgement

Other bias High risk Fresenius-Kabi involved in study design, analysis andpreparation of report

Heradstveit 2010

Methods • Design: RCT• Time frame: September 2005-March 2007

Participants • Country: Norway• Setting: single centre• Adult patients with witnessed out of hospital cardiac arrest in ICU• Number (treatment/control): 10/9• Age (median (range)) years: treatment group (60 (48 to 74)); control group (60

(22 to 75))• Sex (M/F): treatment group (8/2); control group (8/1)• Exclusions: NS

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Heradstveit 2010 (Continued)

Interventions Treatment group• HyperHAES 6% 200/0.5• Volume median (range): 4750 mL (3150 to 9075)• 500 mL HyperHAES then Ringer’s lactate/normal saline

Control group• 7.2% NaCl• Volume median (range): 8010 mL (5515 to 12,908)

Outcomes • Author defined kidney failure• RIFLE (unpublished)

Notes • Published and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’stratified randomisation’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk Not blinded and no definition for ’renalfailure’

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Deferred consent, 5 excluded after ran-domisation which met exclusion criteria(low risk). Differences at baseline (3 in HESgroup had balloon pumps at baseline)

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James 2011

Methods • Design: RCT• Time frame: NS

Participants • Country: South Africa• Setting: single Centre• Severe trauma requiring greater than 3L volume, subgroup by penetrating versus

blunt trauma• Number (treatment/control) penetrating: 36/31, blunt: 20/22• Age (median (range)) years

◦ penetrating treatment: 27.6 (18 to 49)◦ penetrating control: 32.6 (21 to 56)◦ blunt treatment: 33.0 (18 to 50)◦ blunt control: 35.7 (20 to 58)

• Sex (M/F)◦ penetrating treatment: 33/3◦ penetrating control: 27/4◦ blunt treatment: 15/5◦ blunt control: 15/7

• Exclusions: excluded pre-existing kidney failure with oliguria or anuria

Interventions Treatment group• HES 130/0.4• Volume mean (SD)

◦ penetrating treatment: 5093 ± 2733 mL◦ blunt treatment: 6113 ± 1919 mL

Control group• 0.9% NS• Volume mean (SD)

◦ penetrating control: 7473 ± 4321 mL◦ blunt control: 6295 ± 2197 mL

Outcomes • Need for dialysis• RIFLE

Notes • Published data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’random numbers grouped in blocks of 8’

Allocation concealment (selection bias) Low risk ’pre packed numbered boxes containing study fluid la-belled’

Blinding (performance bias and detectionbias)RRT

Low risk ’identical bags’

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James 2011 (Continued)

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

High risk Not true intention to treat,excluded some patients fromanalysis

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

Jungheinrich 2004

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Germany• Setting: multicentre• Adult orthopaedic surgery patients with expected blood loss > 2000 mL• Number: 26/26• Age (mean ± SD) years: group 1 (63 ± 12); group 2 (61 ± 8)• Gender (M/F): group 1 (16/10); group 2 (16/10)• Exclusions: ’renal dysfunction’

Interventions Treatment group 1• Low MW HES: 6% Voluven 130/0.56% from induction to 5 hours

postoperatively• Volume (mean ± SD): 1602 ± 569 mL at end of surgery; 2035 ± 446mL

postoperative day 1Treatment group 2

• High MW HES: HAES-steril 6% 200/0.5 from induction to 5 hourspostoperatively

• Volume (mean ± SD): 1635 ± 567 mL at end surgery; 2000 ± 424 mLpostoperative day 1

Outcomes • RIFLE injury/failure• Author defined kidney failure (double baseline Cr)

Notes

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Jungheinrich 2004 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’performed using a method of randomly per-muted blocks of six’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure, ’solutions wereblinded by the manufacturer and indistinguish-able from each other’

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Funded by Fresenius Kabi, Bad Homburg, Ger-many.

Kasper 2003

Methods • Design: parallel RCT• Time frame: August 2000 to April 2001

Participants • Country: Germany• Setting: single centre• Adult cardiac surgery patients on cardiac bypass with intravascular volume

depletion• Number (group 1/group 2): 59/58• Age (mean ± SD) years: group 1 (63 ± 8); group 2 (64 ± 7)• Sex (M/F): group 1 (47/12); group 2 (46/12)• Exclusions: kidney disease (Cr > 1.5 mg/dL)

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Kasper 2003 (Continued)

Interventions Treatment group 1• Low MW HES: Voluven 6% 130/0.4 intraoperatively until 24 hours

postoperatively• Volume (mean (range)): 3500 mL (2000 to 4500)

Treatment group 2• High MW HES: Haes-steril 6% 200/0.5 intraoperatively until 24 hours

postoperatively• Volume (mean (range)): 2500 mL (1850 to 3250)

Outcomes • Cr (mg/dL) at 24 hours (ICU) and postoperative day 7• RRT• Death

Notes • Published data only - author contacted, no further data available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computer generated code that was pre-pared at a remote site’

Allocation concealment (selection bias) Low risk ’sealed in sequentially numbered opaqueenvelopes’

Blinding (performance bias and detectionbias)RRT

Low risk ’HES solutions supplied in identical look-ing sequentially numbered plastic bags’ ’pa-tients were kept blinded throughout thestudy’

Blinding (performance bias and detectionbias)Creatinine based

Low risk ’HES solutions supplied in identical look-ing sequentially numbered plastic bags’ ’pa-tients were kept blinded throughout thestudy’

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk Pre-specified outcomes were reported

Selective reporting (reporting bias) Low risk Dropped 1 (Voluven) and 2 (Haes-steril)from analysis, re-explored for bleeding and

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Kasper 2003 (Continued)

found to have non-generalized bleeding,therefore unlikely to be related to primaryoutcome

Other bias Low risk The study appears to be free of othersources of bias

Kumle 1999

Methods • Design: parallel RCT, stratified by age (< 65 and 65 to 85)• Time frame: NS

Participants • Country: Germany• Setting: single centre• Adult surgical (non-cardiac) patients, intravascular volume depletion• Number (group 1/group 2/control): 20/20/20• Age (mean ± SD < 65; mean ± SD > 65) years

◦ Group 1: 52.6 ± 8.8; 73.9 ± 5.7◦ Group 2: 53 ± 9; 72 ± 6◦ Control: 52.9 ± 4.4; 71 ± 3.1

• Sex (M/F < 65; > 65)◦ Group 1: 6/4; 4/6◦ Group 2: 6/4; 6/4◦ Control: 3/7; 5/5

• Exclusions: kidney disease (Cr > 180 µmol/L)

Interventions Treatment group 1• High MW HES: Hemohes 6% 200/0.5• Volume (mean ± SD < 65; > 65): 1690 ± 560 mL; 1600 ± 570 mL over 3 days

Treatment group 2• Low MW HES: Rheohes 6% 70/0.5• Volume (mean ± SD < 65; > 65): 2150 ± 470 mL; 1964 ± 520 mL over 3 days

Control group• 35 kD Gelafundin (gelatin)• Volume over 3 days (mean ± SD < 65; > 65): 2100 ± 460 mL; 2180 ± 510 mL

Outcomes • RRT• Death

Notes • Published data only - author contacted, no further data available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’the random number table used to ran-domise patients was generated using FILE-MAKER PRO 4.0’

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Kumle 1999 (Continued)

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

High risk No blinding, no criteria

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of othersources of bias

Lee 2011

Methods • Design: RCT• Time frame: NS

Participants • Country: Korea• Setting: single centre• Adult surgical (cardiac) patients, intravascular volume depletion• Number: 53/53• Age (mean ± SD) years: treatment group (63 ± 8); control group (65 ± 9)• Sex (M/F): treatment group (43/10); control group (44/9)• Exclusions: kidney disease

Interventions Treatment group• HES: HES 130/0.4• Volume (mean ± SD): 1458 ± 465 mL + crystalloid

Control group• Crystalloid• Volume (mean ± SD): 8342 ± 1794 mL

Outcomes • RRT (published)• RIFLE (unpublished)• Author defined kidney failure (published)

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Lee 2011 (Continued)

Notes • Published data only - author contacted, no further data available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’randomly allocated’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Open label trial, ’endpoints assessed blindly’

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk ’endpoints assessed blindly’

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

London 1989

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: USA• Setting: single centre• Adult cardiac surgery patients, on cardiac bypass, postoperative intravascular

volume depletion; Cr > 2.0 mg/dL• Number: 50/44• Age (mean ± SD) years: treatment group (63 ± 7); control group (64 ± 7)• Sex (M/F): 89/1

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London 1989 (Continued)

Interventions Treatment group• 10% Pentastarch 264/0.45 for 24 hours postoperatively• Volume (mean ± SD): 1706 ± 393 mL

Control group• 5% albumin for 24 hours postoperatively• Volume (mean ± SD): 1794 ± 341 mL

Outcomes • RRT

Notes • Published data only - author contacted, no further data available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’randomised’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Insufficient information to permit judgement

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data (deaths/causes ac-counted for)

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources ofbias

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Magder 2010

Methods • Design: RCT• Time frame: NS

Participants • Country: Canada• Setting: single centre• Adult patients on bypass cardiac surgery• Number (treatment/control): 119/118• Age (mean ± SD) years: treatment group (65.5 ± 10.6); control group (65.9 ± 10.

6)• Sex (males): treatment group (74.8%); control group (69.5%)• Exclusions: NS

Interventions Treatment group• 250 MW 10% Pentastarch• Volume as boluses (mean ± SD): 887 ± 546 mL

Control group• Normal saline• Volume as boluses (mean ± SD): 1397 ± 1041 mL

Outcomes • RRT• RIFLE

Notes • Published data and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computerized random generator by central pharmacy’

Allocation concealment (selection bias) Low risk ’unmarked bags in numbered boxes’

Blinding (performance bias and detectionbias)RRT

Low risk ’unmarked bags’

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

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Magder 2010 (Continued)

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Only patients admitted prior to 14:30 to ICU were ran-domised, all patients received 750ml HES in pump prime

Mahmood 2007

Methods • Design: parallel RCT• Time frame: April 2001 to January 2003

Participants • Country: UK• Setting: single centre• Adult vascular surgery patients off cardiac bypass for intravascular volume

depletion• Number (group 1/group 2/control): 21/21/20• Age (mean ± SD) years: group 1 (72 ± 7); group 2 (72 ± 7); control group (73 ± 8)• Sex (M/F): group 1 (16/5); group 2 (19/2); control group (15/2)• Exclusions: kidney disease (Cr > 177 µmol/L)

Interventions Treatment group 1• Elohes (HES) 6% 200/0.62• Volume (mean ± SD): 3443 ± 1769 mL

Treatment group 2• Voluven (HES) 6% 130/0.4• Volume (mean ± SD): 3911 ± 1783 mL

Control group• 4% Gelofusin (gelatin)• Volume (mean ± SD): 4490 ± 1499 mL

Outcomes • RRT• Death

Notes • Published data only - author not contacted

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Randomisation by blocks using randomnumber table

Allocation concealment (selection bias) Low risk ’sealed envelopes’

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Mahmood 2007 (Continued)

Blinding (performance bias and detectionbias)RRT

High risk No criteria, no blinding

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data; death only losses

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk “The study was funded by Fresenius Kabi,including the salary of the research fellow(A. Mahmood). Dr P. Gosling and Mr R.Vohra are full-time employees of UniversityHospital Birmingham NHS Trust with noconflicts of interest. The sponsor had norole in study assimilation, design, analysisor in the writing of the manuscript at anystage. The data and final manuscript werethe authors’ responsibility.”

McIntyre 2008

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Canada, New Zealand• Setting: International multicentre• Adult patients in early septic shock; patients with renal insufficiency (Cr > 300

µmol/L)• Number (treatment/control): 21/19• Age (mean ± SD) years: treatment group (63.1 ± 13.1); control group: (63.6 ± 16.

3)• Sex (M/F): treatment group (13/8); control group (11/8)• Exclusions: ’chronic renal failure requiring dialysis’

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McIntyre 2008 (Continued)

Interventions Treatment group• Pentastarch 10% 200/0.5 HES• Volume (mean ± SD): 1.9 ± 2.1 L (maximum 3 L or 28 mL/kg)

Control group• Normal saline for first 12 hours after randomisation• Volume (mean ± SD): 5.2 ± 1.91 L (maximum 3 L or 28 mL/kg)

Outcomes • 7 day organ failure (RRT)• Death

Notes • Published data only - author contacted, no further data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’central computerized permuted 4-block ran-domisation scheme’

Allocation concealment (selection bias) Low risk ’only the designated pharmacist at each institu-tion was aware of the treatment allocation for in-dividual patients’

Blinding (performance bias and detectionbias)RRT

Low risk ’only the designated pharmacist at each institu-tion was aware of the treatment allocation for in-dividual patients’, ’study fluids blinded’

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Unclear risk Insufficient information to permit judgement

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources ofbias

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Mukhtar 2009

Methods • Design: RCT• Time frame: NS

Participants • Country: Egypt• Setting: NS• Adult patients recipients of living donor liver transplant• Number (treatment/control): 20/20• Age (mean ± SD) years: treatment group (55 ± 5.8); control group (51 ± 6)• Sex (M/F): treatment group (19/1); control group (16/4)• Exclusions: ’primary renal dysfunction’

Interventions Treatment group• Voluven 6% HES 130/0.4• Volume (mean ± SD): 3080 ± 417 mL intraoperative, 6229 ± 1140 mL

postoperativeControl group

• Albumin 5%• Volume (mean ± SD): 3500 ± 1000 mL intraoperative, 4636 ± 1140 mL

postoperative

Outcomes • RRT

Notes • Published data only - author contacted, no further data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’randomly allocated’

Allocation concealment (selection bias) Low risk ’sealed envelope’

Blinding (performance bias and detectionbias)RRT

High risk Not blinded and criteria not listed

Blinding (performance bias and detectionbias)Creatinine based

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

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Mukhtar 2009 (Continued)

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Unclear risk All 3 patients with severe renal impairment randomisedto HES group

Myburgh 2012

Methods • Design: RCT• Time frame: December 2009 to January 2012

Participants • Country: Australia and New Zealand• Setting: multi centre• Adult patients admitted to ICU• Number (treatment/control): 3500/3500• Age (mean ± SD) years: treatment group (63.1 ± 17.0); control group (62.9 ± 16.

9)• Sex (males): treatment group (60.5%); control group (60.3%)• Exclusions: please see article for complete list. Excluded patients who had already

received RRT

Interventions Treatment group• Voluven 6% HES 130/0.4 up to a daily maximum of 50 mL/kg• Volume (daily mean ± SD): 526 ± 425 mL

Control group• 0.9% saline• Volume (daily mean ± SD): 616 ± 488 mL

Outcomes • RRT• RIFLE

Notes • Unpublished data provided by author included RRT and RIFLE outcomes forpatients with sepsis. Non-sepsis outcomes were calculated by subtraction from totalspublished

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’web based randomisation system’

Allocation concealment (selection bias) Low risk ’encrypted web based randomisation sys-tem’

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Myburgh 2012 (Continued)

Blinding (performance bias and detectionbias)RRT

Low risk Indistinguishable bags

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk 0.1% lost to follow-up, similar in bothgroups

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk Fresenius Kabi unrestricted grant

Neff 2003

Methods • Design: parallel RCT• Time frame: April 1999 to May 2000

Participants • Country: Switzerland• Setting: single centre• Adult head injury patients• Number (group 1/group 2): 16/15• Age (mean ± SD) years: group 1 (36 ± 13); group 2 (39 ± 12)• Sex (M/F): group 1 (14/2); group 2 (13/2)• Exclusions: chronic renal insufficiency

Interventions Treatment group 1• Voluven (HES) 6% 130/0.4 for up to 28 days• Volume (mean ± SD): 19,000 ± 16,000 mL

Treatment group 2• HES 6% 200/0.5 + 5% albumin for up to 28 days• Volume (mean ± SD): 22,000 ± 11,000 mL

Outcomes • Kidney failure (’renal failure in multiorgan failure’)• Death• Cr (statement)

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Neff 2003 (Continued)

Notes • Exclusions for kidney disease unknown• Published data only - author contacted, no further data available

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’randomised in block size 6 performed byDATA-MAP Gmb H’

Allocation concealment (selection bias) Low risk ’opaque sealed envelopes’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk No definition of kidney failure given, notblinded

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Unclear risk CrCl has significant losses to follow-up notaccounted for in day 8 figures, numberslower in earlier data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk No definition for kidney failure given; sup-ported, in part, by a grant from FreseniusKabi, Bad Homburg, Germany

Perner 2012

Methods • Design: RCT• Time frame: December 2009 to November 2011

Participants • Countries: Denmark, Norway, Finland, Iceland• Setting: multicentre• adult patients in ICU with severe sepsis• Number (treatment/control): 398/400• Age (median (IQR)) years: treatment group (66 (56 to 75)); control group (67

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Perner 2012 (Continued)

(56 to 76))• Sex (male): treatment group (60%); control group (61%)• Exclusions: need for RRT, see complete list in article

Interventions Treatment group• Voluven 6% HES 130/0.42 to maximum 33 mL/kg/d• Volume (median (IQR)): 3000 mL (1507 to 5100)

Control group• Ringer’s acetate• Volume (median (IQR)): 3000 mL (2000 to 5750)

Outcomes • RRT• RIFLE

Notes • Published data only , no further data required

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computer generated allocation sequence’

Allocation concealment (selection bias) Low risk ’treatment assignments were concealed’ atall levels of trial including analysis

Blinding (performance bias and detectionbias)RRT

Low risk ’treatment assignments were concealed’ atall levels of trial including analysis

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk ’treatment assignments were concealed’ atall levels of trial including analysis

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

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Perner 2012 (Continued)

Other bias Low risk The study appears to be free of othersources of bias

Protsenko 2009

Methods • Design: RCT, triple arm• Time frame: NS

Participants • Country: Russia• Setting: multicentre• Abdominal sepsis• Number: group 1(15); group 2 (11); control group (10)• Age: 32 to 72 years• Sex: NS• Exclusions: ’severe chronic renal failure’

Interventions Treatment group 1• Hemohes® 6% (B/Braun, Germany) 200/0.5• Volume: 11.3 mL/kg

Treatment group 2• Venofundin® 6% (B/Braun, Germany) 130/0.4• Volume: 12.9 mL/kg

Treatment group 3• Gelofusine® (B/Braun, Germany) Gelatin 4% succinylated gelatin• Volume: 12.7 mL/kg

Duration: NS (likely single infusion)

Outcomes • RIFLE

Notes • Published and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk NS

Allocation concealment (selection bias) Unclear risk Envelopes

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

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Protsenko 2009 (Continued)

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sourcesof bias

Sander 2003

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Germany• Setting: single centre• Adult major gynaecological surgery patients• Number (group 1/group 2): 27/29• Age (mean ± SD) years: group 1 (45 ± 15); group 2 (47 ± 14)• Sex: All female• Exclusions: kidney disease (Cr > 120 µmol/L)

Interventions Treatment group 1• 6% HES 200/0.5• Volume (mean ± SD): 1389 ± 610 mL

Treatment group 2• 6% HES 130/0.4• Volumes (mean ± SD): 1224 ± 544 mL

Outcomes • RIFLE

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’block randomisation computerized using aRANCODE’

Allocation concealment (selection bias) Unclear risk NS

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Sander 2003 (Continued)

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk Missing data insufficient to affect outcomes

Selective reporting (reporting bias) Low risk Missing data insufficient to affect outcomes

Other bias High risk The study was supported by grants of B.Braun Melsungen AG, D-34212 Melsungen, andSerum-Werk Bernburg AG, D-06406 Bernburg,Germany

Schortgen 2001

Methods • Design: parallel RCT• Time frame: April 1998 to September 1999

Participants • Country: France• Setting: multicentre (3)• Adult sepsis patients with intravascular volume depletion• Number (treatment/control): 65/64• Age (median (range)) years: treatment group (60 (47 to 74)); control group (56

(44 to 71))• Sex (M/F): treatment group (43/22); control group (46/18)• Exclusions: kidney disease (previous dialysis or Cr > 320 µmol/L)

Interventions Treatment group• Elohes (HES) 6% 200/0.6 for up to 4 days• Volume (median (IQR)): 31 mL/kg (19 to 51)

Control group• 3% gelatin (35 kDa) for up to 28 days• Volume (median (IQR)): 43 mL/kg (19 to 60)

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Schortgen 2001 (Continued)

Outcomes • RRT• Kidney failure (2x increase in serum Cr from baseline or need for RRT, composite

outcome)• Death (all published)• Subgroup of 2x increased Cr (unpublished), RIFLE (unpublished)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’centralized randomisation, blocks pre-pared for each treatment centre by statisti-cians not involved in executing treatmentassignments’

Allocation concealment (selection bias) Low risk ’sealed opaque envelopes serially numberedand used in sequence’

Blinding (performance bias and detectionbias)RRT

High risk Not blinded, no objective criteria

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Cr based or need for RRT

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data (death onlylosses)

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Difference in Cr at baseline betweengroups. The study was supported by grantCRC 97151 from the Assistance Publique-Hôpitaux de Paris

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Shatney 1983

Methods • Design: Quasi-RCT• Time frame: NS

Participants • Country: USA• Setting: single centre• Adult trauma patients• Number (group 1/group 2): 16/16• Age (mean (range)) years: group 1 (30.4 (16 to 55)); group 2 (30.6 (18 to 66)• Sex (M/F): group 1 (12/4); group 2 (13/3)• Exclusions: NS

Interventions Treatment group 1• 6% Hetastarch for 5 days• Volume (mean): 3900 mL (extrapolated from graph)

Treatment group 2• Plasma protein fraction for 5 days• Volume (mean): 3900 mL (extrapolated from graph)

Outcomes • Kidney failure (’renal failure’)

Notes • Published data only - author not contacted, study too old

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

High risk ’alternation’

Allocation concealment (selection bias) High risk ’alternation’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk No evidence of blinding

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

Low risk No missing outcome data

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Shatney 1983 (Continued)

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk Lack of definition for kidney failure

Shmyrev 2011

Methods • Design: RCT• Time frame: NS

Participants • Country: Russia• Setting: NS• Adult cardiac surgery patients on bypass• Number (treatment/control): 8/7• Age (mean ± SD) years: treatment group (48 ± 13.8); control group (46.2 ± 11.1)• Sex (M/F): treatment group (2/6); control group (2/5)• Exclusions: pre-existing kidney disease

Interventions Treatment group• 7.2% NaCl in hyperHAES 6% 200/0.5• Volume (mean): 4 mL/kg

Control group• Normal saline• Volume (mean): 4 mL/kg

Outcomes • Author defined kidney failure• RIFLE (from unpublished data)

Notes • Published and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Blind randomisation protocol

Allocation concealment (selection bias) Low risk Sealed envelopes

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome criteria

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Shmyrev 2011 (Continued)

Blinding (performance bias and detectionbias)Author defined kidney failure

Low risk Aiken criteria

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome criteria

Incomplete outcome data (attrition bias)All outcomes

Low risk All outcome data reported; no losses to follow-up

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

Van der Linden 2005

Methods • Design: parallel RCT• Time frame: NS

Participants • Country: Belgium• Setting: single centre• Adult cardiac surgery patients on cardiac bypass for pump priming and

intravascular volume depletion• Number (treatment/control): 65/68• Age (mean ± SD) years: treatment group (67 ± 11); control group (66 ± 8)• Sex (M/F): treatment group (50/15); control group (48/20)• Exclusions: kidney disease (Cr > 1.3 mg/dL)

Interventions Treatment group• 6% HES 130/0.4 intraoperatively until 20 hours postoperative• Volume (mean ± SD): 48.9 ± 17.2 mL/kg

Control group• 3% gelatin intraoperatively until 20 hours postoperative• Volume (mean ± SD): 48.9 ± 14.6 mL/kg

Outcomes • Death (published)• RIFLE (unpublished)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’randomly allocated (computer generated)’

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Van der Linden 2005 (Continued)

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk All outcome data reported; death only losses

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources ofbias

Vlachou 2010

Methods • Design: RCT• Time frame: 2004 to 2006

Participants • Country: Birmingham• Setting: single centre• Adult patients with burns (15% to 80% BSA)• Number (treatment/control): 12/14• Age (mean ± SD) years: treatment group (40.8 ± 20.1); control group (42.4 ± 23.

5)• Sex (M/F)• treatment group (7/5); control group (10/4)• Exclusions: Cr > 130 µmol/L on admission

Interventions Treatment group• 6% HES 200/0.6 Elo-Haes• Volume: 1585 mL colloid at 24 hours

Control group• Hartmann’s solution• Volume: 8450 mL at 24 hours

Outcomes • RRT

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Vlachou 2010 (Continued)

Notes • Published data only (unpublished sought)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Block randomisation

Allocation concealment (selection bias) Low risk Sealed envelope system

Blinding (performance bias and detectionbias)RRT

Unclear risk Criteria (NS); blinding (NS)

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Unclear risk Outcome not reported

Incomplete outcome data (attrition bias)All outcomes

High risk 3 patients not analysed, not intention to treat

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias High risk High number of eligible patients not enrolled

Yang 2011

Methods • Design: RCT• Time frame: NS

Participants • Country: China• Setting: NS• Adult surgical (non cardiac, hepatocellular carcinoma)• Number (treatment/control 1/control 2): 26/30/25• Age (mean ± SD) years: treatment group (49.7 ± 1.8); control group 1 (47.8 ± 11.

9); control group 2 (51.2 ± 12.9)• Sex: (M/F): treatment group (21/5); control group 1 (25/5); control group 2 (22/

3)• Exclusions: kidney failure requiring dialysis

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Yang 2011 (Continued)

Interventions Treatment group• Voluven 6% 130/0.4 for 5 days• Volume (mean ± SD): 3484 ± 1072.5 mL

Control group 1• 20% albumin for 5 days• Volumes (mean ± SD): 3163 ± 999.5 mL

Control group 2• Ringer’s lactate for 5 days• Volumes (mean ± SD): 3372 ± 965 mL

Outcomes • Author defined kidney failure• RIFLE

Notes • Published and unpublished data

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk ’computerized random number generator’

Allocation concealment (selection bias) Unclear risk NS

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

High risk Not blinded and not defined

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

High risk 4 patients in HES and 5 in RL required albumin and wereexcluded

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

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Yassen 2011

Methods • Design: RCT• Time frame: NS

Participants • Country: NS• Setting: NS• Adult patients recipients of living donor liver transplant• Number (treatment 1/treatment 2/control): 15/15/15• Age: NS• Sex: NS• Exclusions: NS

Interventions Treatment group 1• Voluven 6% HES 130/0.4 low dose 30 mL/kg/d

Treatment group 2• Voluven 6% HES 130/0.4 high dose 50 mL/kg/d

Control group• Albumin 4%

Outcomes • RIFLE

Notes • Published and unpublished data, abstract only

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk ’randomly stratified’

Allocation concealment (selection bias) Unclear risk ’blind’

Blinding (performance bias and detectionbias)RRT

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)Creatinine based

Low risk Objective outcome measure

Blinding (performance bias and detectionbias)Author defined kidney failure

Unclear risk Outcome not reported

Blinding (performance bias and detectionbias)RIFLE

Low risk Objective outcome measure

Incomplete outcome data (attrition bias)All outcomes

Low risk All outcome data reported

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Yassen 2011 (Continued)

Selective reporting (reporting bias) Low risk Pre-specified outcomes were reported

Other bias Low risk The study appears to be free of other sources of bias

BUN - blood urea nitrogen; Cr - creatinine; CrCl - creatinine clearance; IQR - interquartile range; NS - not stated; RRT - renalreplacement therapy

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Aksun 2009 No individual creatinines available

Allison 1999 No individual creatinines available

Ando 2008 No individual creatinines available

Beyer 1997 No individual creatinines available

Boldt 1993 Excluded due to concern regarding reliability of data

Boldt 1998 Excluded due to concern regarding reliability of data

Boldt 2000a Retracted

Boldt 2000b Retracted

Boldt 2003 Retracted

Boldt 2006 Retracted

Boldt 2007a Retracted

Boldt 2007b Retracted

Boldt 2008 Retracted

Boldt 2009 Retracted

Boldt 2010 Retracted

Chen 2006 No individual creatinines available

Dehne 1997 The intervention group received a 12 mL/kg/d fixed dose of 10% HES 200/0.5 as a continuous infusion for 5days. The study was excluded because the control group did not receive a comparison fluid

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(Continued)

Hanart 2009 No individual creatinines available

Kalayanarooj 2008 10% Haes-steril versus Dextran in Dengue Fever patients, mean creatinines reported only, unable to contactauthor for individual data

Kulla 2008 Double intervention, 6% 130/0.42 in acetate + balanced electrolyte crystalloid versus 6% 130/0.42 in NS +less balanced electrolyte crystalloid

Kvalheim 2010 No individual creatinines available

Langeron 2001 No individual creatinines available

Liet 2003 Volume not used in management of hypovolemia

NCT00576849 Questionable data quality

Ooi 2009 No individual creatinines available

Petrikov 2008 No individual creatinines available

Sade 1985 No individual creatinines available

Schewior 2008 No individual creatinines available

Shahbazi 2011 No individual creatinines available

Tiryakioglu 2008 Voluven versus Ringer’s lactate in cardiac surgery patients on bypass, mean creatinines reported only, unable tocontact author for individual patient data for RIFLE analysis

Vernetta 2012 Inappropriate study group - patients undergoing nephrectomy

Vogt 1999 No individual creatinines available

Wu 2010 No individual creatinines available

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D A T A A N D A N A L Y S E S

Comparison 1. HES versus other fluid

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Renal replacement therapy 19 9857 Risk Ratio (M-H, Random, 95% CI) 1.31 [1.16, 1.49]1.1 Non-sepsis 11 5911 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.96, 1.61]1.2 Sepsis 8 3899 Risk Ratio (M-H, Random, 95% CI) 1.32 [1.15, 1.53]1.3 Deceased organ donor 1 47 Risk Ratio (M-H, Random, 95% CI) 6.67 [0.92, 48.45]

2 Renal replacement therapy byMW

17 9536 Risk Ratio (M-H, Random, 95% CI) 1.32 [1.16, 1.50]

2.1 High MW 9 1183 Risk Ratio (M-H, Random, 95% CI) 1.56 [1.15, 2.11]2.2 Low MW 10 8353 Risk Ratio (M-H, Random, 95% CI) 1.26 [1.09, 1.45]

3 Renal replacement therapy byvolume

17 9516 Risk Ratio (M-H, Random, 95% CI) 1.32 [1.16, 1.50]

3.1 High Volume 10 2220 Risk Ratio (M-H, Random, 95% CI) 1.43 [1.20, 1.71]3.2 Low Volume 7 7296 Risk Ratio (M-H, Random, 95% CI) 1.22 [1.02, 1.46]

4 Kidney failure (author defined) 15 1361 Risk Ratio (M-H, Random, 95% CI) 1.59 [1.26, 2.00]4.1 Non-sepsis 11 620 Risk Ratio (M-H, Random, 95% CI) 1.61 [0.79, 3.28]4.2 Sepsis 4 741 Risk Ratio (M-H, Random, 95% CI) 1.58 [1.24, 2.02]

5 RIFLE (Risk or worse) 20 8769 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.89, 1.06]5.1 Non-sepsis 12 5611 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.85, 0.94]5.2 Sepsis 9 3158 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.98, 1.11]

6 RIFLE (Injury or worse) 18 8583 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.87, 1.18]6.1 Non-sepsis 11 5478 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.78, 0.92]6.2 Sepsis 8 3105 Risk Ratio (M-H, Random, 95% CI) 1.10 [1.00, 1.20]

7 RIFLE (Failure) 15 8402 Risk Ratio (M-H, Random, 95% CI) 1.14 [1.01, 1.29]7.1 Non-sepsis 8 5301 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.86, 1.27]7.2 Sepsis 8 3101 Risk Ratio (M-H, Random, 95% CI) 1.21 [1.03, 1.43]

8 RIFLE (Risk or worse) by MW 20 8428 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.93, 1.23]8.1 high MW 6 435 Risk Ratio (M-H, Random, 95% CI) 1.26 [0.89, 1.79]8.2 low MW 15 7993 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.84, 1.20]

9 RIFLE (Risk or worse) byvolume

19 8380 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.92, 1.23]

9.1 high volume 10 854 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.65, 1.26]9.2 low volume 9 7526 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.99, 1.29]

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Comparison 2. High MW/DS HES versus low MW/DS HES

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 RIFLE (Risk or worse) 3 139 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.18, 7.48]2 RIFLE (Injury or worse) 4 188 Risk Ratio (M-H, Random, 95% CI) 3.21 [0.14, 75.68]3 RIFLE (Failure) 4 188 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

Comparison 3. HES versus other fluid - no subgroups

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Renal replacement therapy 19 9857 Risk Ratio (M-H, Random, 95% CI) 1.32 [1.17, 1.50]2 Kidney failure (author defined) 15 1361 Risk Ratio (M-H, Random, 95% CI) 1.59 [1.26, 2.00]3 RIFLE (Risk or worse) 20 8769 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.91, 0.99]4 RIFLE (Injury or worse) 18 8583 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.88, 1.17]5 RIFLE (Failure) 15 8402 Risk Ratio (M-H, Random, 95% CI) 1.14 [1.01, 1.30]

Comparison 4. Sensitivity analyses

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 RIFLE (Risk or worse) -Creatinine only

20 8445 Risk Ratio (M-H, Random, 95% CI) 1.05 [0.97, 1.14]

2 RIFLE (Injury or worse)-Creatinine only

18 8338 Risk Ratio (M-H, Random, 95% CI) 1.22 [1.08, 1.37]

3 RIFLE (Failure) - Creatinineonly

15 8216 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.15, 1.57]

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Analysis 1.1. Comparison 1 HES versus other fluid, Outcome 1 Renal replacement therapy.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 1 Renal replacement therapy

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Non-sepsis

Kumle 1999 0/40 0/20 0.0 [ 0.0, 0.0 ]

Mahmood 2007 2/42 3/20 0.32 [ 0.06, 1.75 ]

Godet 2008 0/32 1/33 0.34 [ 0.01, 8.13 ]

James 2011 2/56 3/53 0.63 [ 0.11, 3.63 ]

Magder 2010 1/119 1/118 0.99 [ 0.06, 15.67 ]

Mukhtar 2009 1/20 1/20 1.00 [ 0.07, 14.90 ]

London 1989 1/50 1/50 1.00 [ 0.06, 15.55 ]

Berard 1995 5/146 4/153 1.31 [ 0.36, 4.78 ]

Myburgh 2012 111/2373 86/2418 1.32 [ 1.00, 1.73 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Du 2011 1/21 0/21 3.00 [ 0.13, 69.70 ]

Subtotal (95% CI) 2952 2959 1.25 [ 0.96, 1.61 ]

Total events: 125 (HES), 100 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 4.50, df = 9 (P = 0.88); I2 =0.0%

Test for overall effect: Z = 1.68 (P = 0.093)

2 Sepsis

Vlachou 2010 0/12 0/14 0.0 [ 0.0, 0.0 ]

Myburgh 2012 124/979 110/957 1.10 [ 0.87, 1.40 ]

Schortgen 2001 13/65 11/64 1.16 [ 0.56, 2.40 ]

BaSES 2012 28/117 23/124 1.29 [ 0.79, 2.11 ]

Perner 2012 87/398 65/400 1.35 [ 1.01, 1.80 ]

Brunkhorst 2008 81/261 51/272 1.66 [ 1.22, 2.25 ]

Guidet 2012 21/100 11/96 1.83 [ 0.93, 3.59 ]

McIntyre 2008 3/19 1/21 3.32 [ 0.38, 29.23 ]

Subtotal (95% CI) 1951 1948 1.32 [ 1.15, 1.53 ]

Total events: 357 (HES), 272 (Other fluid)

0.01 0.1 1 10 100

Favours HES Favours other fluid

(Continued . . . )

86Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Heterogeneity: Tau2 = 0.0; Chi2 = 6.00, df = 6 (P = 0.42); I2 =0.0%

Test for overall effect: Z = 3.81 (P = 0.00014)

3 Deceased organ donor

Cittanova 1996 9/27 1/20 6.67 [ 0.92, 48.45 ]

Subtotal (95% CI) 27 20 6.67 [ 0.92, 48.45 ]

Total events: 9 (HES), 1 (Other fluid)

Heterogeneity: not applicable

Test for overall effect: Z = 1.87 (P = 0.061)

Total (95% CI) 4930 4927 1.31 [ 1.16, 1.49 ]

Total events: 491 (HES), 373 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 13.24, df = 17 (P = 0.72); I2 =0.0%

Test for overall effect: Z = 4.26 (P = 0.000021)

Test for subgroup differences: Chi2 = 2.74, df = 2 (P = 0.25), I2 =27%

0.01 0.1 1 10 100

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Analysis 1.2. Comparison 1 HES versus other fluid, Outcome 2 Renal replacement therapy by MW.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 2 Renal replacement therapy by MW

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 High MW

Brunkhorst 2008 81/261 51/272 1.66 [ 1.22, 2.25 ]

Cittanova 1996 9/27 1/20 6.67 [ 0.92, 48.45 ]

Kumle 1999 0/20 0/20 0.0 [ 0.0, 0.0 ]

London 1989 1/50 1/50 1.00 [ 0.06, 15.55 ]

Magder 2010 1/119 1/118 0.99 [ 0.06, 15.67 ]

Mahmood 2007 1/21 2/10 0.24 [ 0.02, 2.33 ]

McIntyre 2008 3/19 1/21 3.32 [ 0.38, 29.23 ]

Schortgen 2001 13/65 11/64 1.16 [ 0.56, 2.40 ]

Vlachou 2010 0/12 0/14 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 594 589 1.56 [ 1.15, 2.11 ]

Total events: 109 (HES), 68 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 6.13, df = 6 (P = 0.41); I2 =2%

Test for overall effect: Z = 2.90 (P = 0.0038)

2 Low MW

BaSES 2012 28/117 23/124 1.29 [ 0.79, 2.11 ]

Godet 2008 0/32 1/33 0.34 [ 0.01, 8.13 ]

Guidet 2012 21/100 11/96 1.83 [ 0.93, 3.59 ]

James 2011 2/56 3/53 0.63 [ 0.11, 3.63 ]

Kumle 1999 0/20 0/20 0.0 [ 0.0, 0.0 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Mahmood 2007 1/21 1/10 0.48 [ 0.03, 6.86 ]

Mukhtar 2009 1/20 1/20 1.00 [ 0.07, 14.90 ]

Myburgh 2012 235/3352 196/3375 1.21 [ 1.00, 1.45 ]

Perner 2012 87/398 65/400 1.35 [ 1.01, 1.80 ]

Subtotal (95% CI) 4169 4184 1.26 [ 1.09, 1.45 ]

Total events: 376 (HES), 301 (Other fluid)

0.01 0.1 1 10 100

Favours HES Favours other fluid

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88Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Heterogeneity: Tau2 = 0.0; Chi2 = 3.68, df = 8 (P = 0.88); I2 =0.0%

Test for overall effect: Z = 3.16 (P = 0.0016)

Total (95% CI) 4763 4773 1.32 [ 1.16, 1.50 ]

Total events: 485 (HES), 369 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 11.79, df = 15 (P = 0.69); I2 =0.0%

Test for overall effect: Z = 4.32 (P = 0.000016)

Test for subgroup differences: Chi2 = 1.59, df = 1 (P = 0.21), I2 =37%

0.01 0.1 1 10 100

Favours HES Favours other fluid

Analysis 1.3. Comparison 1 HES versus other fluid, Outcome 3 Renal replacement therapy by volume.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 3 Renal replacement therapy by volume

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 High Volume

BaSES 2012 28/117 23/124 1.29 [ 0.79, 2.11 ]

Brunkhorst 2008 81/261 51/272 1.66 [ 1.22, 2.25 ]

Cittanova 1996 9/27 1/20 6.67 [ 0.92, 48.45 ]

Godet 2008 0/32 1/33 0.34 [ 0.01, 8.13 ]

Guidet 2012 21/100 11/96 1.83 [ 0.93, 3.59 ]

James 2011 2/56 3/53 0.63 [ 0.11, 3.63 ]

Mahmood 2007 2/42 3/20 0.32 [ 0.06, 1.75 ]

Mukhtar 2009 1/20 1/20 1.00 [ 0.07, 14.90 ]

Perner 2012 87/398 65/400 1.35 [ 1.01, 1.80 ]

0.01 0.1 1 10 100

Favours HES Favours other fluid

(Continued . . . )

89Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Schortgen 2001 13/65 11/64 1.16 [ 0.56, 2.40 ]

Subtotal (95% CI) 1118 1102 1.43 [ 1.20, 1.71 ]

Total events: 244 (HES), 170 (Other fluid)

Heterogeneity: Tau2 = 0.00; Chi2 = 9.04, df = 9 (P = 0.43); I2 =0%

Test for overall effect: Z = 3.93 (P = 0.000087)

2 Low Volume

Kumle 1999 0/40 0/20 0.0 [ 0.0, 0.0 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

London 1989 1/50 1/50 1.00 [ 0.06, 15.55 ]

Magder 2010 1/119 1/118 0.99 [ 0.06, 15.67 ]

McIntyre 2008 3/19 1/21 3.32 [ 0.38, 29.23 ]

Myburgh 2012 235/3352 196/3375 1.21 [ 1.00, 1.45 ]

Vlachou 2010 0/12 0/14 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 3645 3651 1.22 [ 1.02, 1.46 ]

Total events: 241 (HES), 199 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.17, df = 4 (P = 0.88); I2 =0.0%

Test for overall effect: Z = 2.12 (P = 0.034)

Total (95% CI) 4763 4753 1.32 [ 1.16, 1.50 ]

Total events: 485 (HES), 369 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 11.74, df = 14 (P = 0.63); I2 =0.0%

Test for overall effect: Z = 4.31 (P = 0.000016)

Test for subgroup differences: Chi2 = 1.52, df = 1 (P = 0.22), I2 =34%

0.01 0.1 1 10 100

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Analysis 1.4. Comparison 1 HES versus other fluid, Outcome 4 Kidney failure (author defined).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 4 Kidney failure (author defined)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Non-sepsis

Abdel-Khalek 2010 1/67 1/68 1.01 [ 0.06, 15.90 ]

Altman 1998 0/27 0/33 0.0 [ 0.0, 0.0 ]

Dehne 2001 0/15 0/15 0.0 [ 0.0, 0.0 ]

Diehl 1982 2/27 0/33 6.07 [ 0.30, 121.33 ]

Du 2011 0/21 0/21 0.0 [ 0.0, 0.0 ]

Godet 2008 8/32 7/33 1.18 [ 0.48, 2.87 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Shatney 1983 0/16 0/16 0.0 [ 0.0, 0.0 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 302 318 1.61 [ 0.79, 3.28 ]

Total events: 17 (HES), 9 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.27, df = 5 (P = 0.81); I2 =0.0%

Test for overall effect: Z = 1.30 (P = 0.19)

2 Sepsis

Akech 2010 0/20 0/39 0.0 [ 0.0, 0.0 ]

Brunkhorst 2008 91/261 62/272 1.53 [ 1.16, 2.01 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Schortgen 2001 27/65 15/64 1.77 [ 1.04, 3.01 ]

Subtotal (95% CI) 356 385 1.58 [ 1.24, 2.02 ]

Total events: 119 (HES), 77 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.40, df = 2 (P = 0.82); I2 =0.0%

Test for overall effect: Z = 3.72 (P = 0.00020)

Total (95% CI) 658 703 1.59 [ 1.26, 2.00 ]

Total events: 136 (HES), 86 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.61, df = 8 (P = 0.96); I2 =0.0%

Test for overall effect: Z = 3.94 (P = 0.000082)

Test for subgroup differences: Chi2 = 0.00, df = 1 (P = 0.97), I2 =0.0%

0.005 0.1 1 10 200

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Analysis 1.5. Comparison 1 HES versus other fluid, Outcome 5 RIFLE (Risk or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 5 RIFLE (Risk or worse)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Non-sepsis

Akkucuk 2012 1/12 2/12 0.50 [ 0.05, 4.81 ]

Choi 2010 1/18 3/18 0.33 [ 0.04, 2.91 ]

Godet 2008 8/32 6/33 1.38 [ 0.54, 3.52 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 14/56 23/53 0.58 [ 0.33, 1.00 ]

Lee 2011 3/53 3/53 1.00 [ 0.21, 4.73 ]

Magder 2010 22/119 24/117 0.90 [ 0.54, 1.51 ]

Myburgh 2012 1209/2342 1369/2387 0.90 [ 0.85, 0.95 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Van der Linden 2005 2/60 5/60 0.40 [ 0.08, 1.98 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Yang 2011 0/26 1/25 0.32 [ 0.01, 7.53 ]

Yassen 2011 2/30 2/15 0.50 [ 0.08, 3.21 ]

Subtotal (95% CI) 2792 2819 0.90 [ 0.85, 0.94 ]

Total events: 1267 (HES), 1439 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 8.44, df = 11 (P = 0.67); I2 =0.0%

Test for overall effect: Z = 4.14 (P = 0.000034)

2 Sepsis

Akech 2010 1/34 5/33 0.19 [ 0.02, 1.57 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 2/9 1/11 2.44 [ 0.26, 22.80 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

0.005 0.1 1 10 200

Favours HES Favours other fluid

(Continued . . . )

92Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Guidet 2012 22/100 23/96 0.92 [ 0.55, 1.53 ]

Myburgh 2012 579/967 543/948 1.05 [ 0.97, 1.13 ]

Perner 2012 206/362 203/366 1.03 [ 0.90, 1.17 ]

Protsenko 2009 2/15 0/5 1.88 [ 0.10, 33.66 ]

Protsenko 2009 0/11 0/5 0.0 [ 0.0, 0.0 ]

Schortgen 2001 26/61 20/59 1.26 [ 0.79, 1.99 ]

Subtotal (95% CI) 1595 1563 1.04 [ 0.98, 1.11 ]

Total events: 839 (HES), 795 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 4.58, df = 7 (P = 0.71); I2 =0.0%

Test for overall effect: Z = 1.26 (P = 0.21)

Total (95% CI) 4387 4382 0.97 [ 0.89, 1.06 ]

Total events: 2106 (HES), 2234 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 25.95, df = 19 (P = 0.13); I2 =27%

Test for overall effect: Z = 0.67 (P = 0.50)

Test for subgroup differences: Chi2 = 12.88, df = 1 (P = 0.00), I2 =92%

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 1.6. Comparison 1 HES versus other fluid, Outcome 6 RIFLE (Injury or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 6 RIFLE (Injury or worse)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Non-sepsis

Akkucuk 2012 0/12 1/12 0.33 [ 0.01, 7.45 ]

Choi 2010 1/18 1/18 1.00 [ 0.07, 14.79 ]

Godet 2008 3/32 2/33 1.55 [ 0.28, 8.65 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 6/56 11/53 0.52 [ 0.21, 1.30 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Magder 2010 8/119 7/117 1.12 [ 0.42, 3.00 ]

Myburgh 2012 727/2306 880/2361 0.85 [ 0.78, 0.92 ]

Shmyrev 2011 1/8 0/7 2.67 [ 0.13, 56.63 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/55 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 2700 2778 0.85 [ 0.78, 0.92 ]

Total events: 749 (HES), 904 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 5.57, df = 9 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 4.14 (P = 0.000035)

2 Sepsis

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 1/9 0/11 3.60 [ 0.16, 79.01 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Guidet 2012 9/100 12/96 0.72 [ 0.32, 1.63 ]

Myburgh 2012 403/959 373/939 1.06 [ 0.95, 1.18 ]

Perner 2012 154/362 130/366 1.20 [ 1.00, 1.44 ]

Schortgen 2001 24/61 17/59 1.37 [ 0.82, 2.27 ]

Subtotal (95% CI) 1561 1544 1.10 [ 1.00, 1.20 ]

Total events: 592 (HES), 533 (Other fluid)

0.001 0.01 0.1 1 10 100 1000

Favours HES Favours other fluid

(Continued . . . )

94Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Heterogeneity: Tau2 = 0.0; Chi2 = 4.60, df = 6 (P = 0.60); I2 =0.0%

Test for overall effect: Z = 1.97 (P = 0.049)

Total (95% CI) 4261 4322 1.01 [ 0.87, 1.18 ]

Total events: 1341 (HES), 1437 (Other fluid)

Heterogeneity: Tau2 = 0.02; Chi2 = 27.84, df = 16 (P = 0.03); I2 =43%

Test for overall effect: Z = 0.16 (P = 0.87)

Test for subgroup differences: Chi2 = 17.64, df = 1 (P = 0.00), I2 =94%

0.001 0.01 0.1 1 10 100 1000

Favours HES Favours other fluid

Analysis 1.7. Comparison 1 HES versus other fluid, Outcome 7 RIFLE (Failure).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 7 RIFLE (Failure)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Non-sepsis

Choi 2010 0/18 0/18 0.0 [ 0.0, 0.0 ]

Godet 2008 1/32 1/33 1.03 [ 0.07, 15.79 ]

Heradstveit 2010 0/10 0/9 0.0 [ 0.0, 0.0 ]

Lee 2011 0/53 0/53 0.0 [ 0.0, 0.0 ]

Magder 2010 1/119 4/117 0.25 [ 0.03, 2.17 ]

Myburgh 2012 182/2286 174/2326 1.06 [ 0.87, 1.30 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/25 0.0 [ 0.0, 0.0 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

0.005 0.1 1 10 200

Favours HES Favours other fluid

(Continued . . . )

95Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 2630 2671 1.04 [ 0.86, 1.27 ]

Total events: 184 (HES), 181 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.89, df = 3 (P = 0.41); I2 =0.0%

Test for overall effect: Z = 0.42 (P = 0.67)

2 Sepsis

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 0/9 0/11 0.0 [ 0.0, 0.0 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Guidet 2012 5/100 7/96 0.69 [ 0.23, 2.09 ]

Myburgh 2012 154/957 127/937 1.19 [ 0.96, 1.47 ]

Perner 2012 84/362 67/366 1.27 [ 0.95, 1.69 ]

Schortgen 2001 19/61 13/59 1.41 [ 0.77, 2.60 ]

Subtotal (95% CI) 1559 1542 1.21 [ 1.03, 1.43 ]

Total events: 263 (HES), 215 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.38, df = 5 (P = 0.79); I2 =0.0%

Test for overall effect: Z = 2.31 (P = 0.021)

Total (95% CI) 4189 4213 1.14 [ 1.01, 1.29 ]

Total events: 447 (HES), 396 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 6.61, df = 9 (P = 0.68); I2 =0.0%

Test for overall effect: Z = 2.05 (P = 0.041)

Test for subgroup differences: Chi2 = 1.31, df = 1 (P = 0.25), I2 =24%

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 1.8. Comparison 1 HES versus other fluid, Outcome 8 RIFLE (Risk or worse) by MW.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 8 RIFLE (Risk or worse) by MW

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 high MW

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

Magder 2010 19/119 18/118 1.05 [ 0.58, 1.89 ]

Protsenko 2009 2/15 0/9 3.13 [ 0.17, 58.63 ]

Schortgen 2001 26/61 20/59 1.26 [ 0.79, 1.99 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Subtotal (95% CI) 223 212 1.26 [ 0.89, 1.79 ]

Total events: 53 (HES), 39 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.32, df = 5 (P = 0.80); I2 =0.0%

Test for overall effect: Z = 1.29 (P = 0.20)

2 low MW

Akech 2010 1/34 5/33 0.19 [ 0.02, 1.57 ]

Akkucuk 2012 1/12 2/12 0.50 [ 0.05, 4.81 ]

Choi 2010 1/18 3/18 0.33 [ 0.04, 2.91 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 2/9 1/11 2.44 [ 0.26, 22.80 ]

Godet 2008 8/32 6/33 1.38 [ 0.54, 3.52 ]

Guidet 2012 22/100 23/96 0.92 [ 0.55, 1.53 ]

James 2011 14/56 23/53 0.58 [ 0.33, 1.00 ]

Lee 2011 3/53 3/53 1.00 [ 0.21, 4.73 ]

Myburgh 2012 928/3149 760/3171 1.23 [ 1.13, 1.33 ]

Perner 2012 206/362 203/366 1.03 [ 0.90, 1.17 ]

Protsenko 2009 0/11 0/9 0.0 [ 0.0, 0.0 ]

Van der Linden 2005 2/60 5/60 0.40 [ 0.08, 1.98 ]

Yang 2011 0/26 1/55 0.69 [ 0.03, 16.42 ]

Yassen 2011 2/30 2/15 0.50 [ 0.08, 3.21 ]

0.005 0.1 1 10 200

Favours HES Favours other fluid

(Continued . . . )

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 3978 4015 1.00 [ 0.84, 1.20 ]

Total events: 1190 (HES), 1037 (Other fluid)

Heterogeneity: Tau2 = 0.02; Chi2 = 20.18, df = 12 (P = 0.06); I2 =41%

Test for overall effect: Z = 0.05 (P = 0.96)

Total (95% CI) 4201 4227 1.07 [ 0.93, 1.23 ]

Total events: 1243 (HES), 1076 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 22.78, df = 18 (P = 0.20); I2 =21%

Test for overall effect: Z = 0.98 (P = 0.33)

Test for subgroup differences: Chi2 = 1.25, df = 1 (P = 0.26), I2 =20%

0.005 0.1 1 10 200

Favours HES Favours other fluid

Analysis 1.9. Comparison 1 HES versus other fluid, Outcome 9 RIFLE (Risk or worse) by volume.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 1 HES versus other fluid

Outcome: 9 RIFLE (Risk or worse) by volume

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 high volume

Akech 2010 1/34 5/33 0.19 [ 0.02, 1.57 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 2/9 1/11 2.44 [ 0.26, 22.80 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 8/32 6/33 1.38 [ 0.54, 3.52 ]

Guidet 2012 22/100 23/96 0.92 [ 0.55, 1.53 ]

James 2011 14/56 23/53 0.58 [ 0.33, 1.00 ]

Schortgen 2001 26/61 20/59 1.26 [ 0.79, 1.99 ]

0.005 0.1 1 10 200

Favours HES Favours other fluid

(Continued . . . )

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(. . . Continued)Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Van der Linden 2005 2/60 5/60 0.40 [ 0.08, 1.98 ]

Yang 2011 0/26 1/55 0.69 [ 0.03, 16.42 ]

Subtotal (95% CI) 414 440 0.90 [ 0.65, 1.26 ]

Total events: 76 (HES), 84 (Other fluid)

Heterogeneity: Tau2 = 0.05; Chi2 = 9.83, df = 8 (P = 0.28); I2 =19%

Test for overall effect: Z = 0.60 (P = 0.55)

2 low volume

Choi 2010 1/18 3/18 0.33 [ 0.04, 2.91 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

Lee 2011 3/53 3/53 1.00 [ 0.21, 4.73 ]

Magder 2010 19/119 18/118 1.05 [ 0.58, 1.89 ]

Myburgh 2012 928/3149 760/3171 1.23 [ 1.13, 1.33 ]

Perner 2012 206/362 203/366 1.03 [ 0.90, 1.17 ]

Protsenko 2009 0/11 0/9 0.0 [ 0.0, 0.0 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Yassen 2011 2/30 2/15 0.50 [ 0.08, 3.21 ]

Subtotal (95% CI) 3760 3766 1.13 [ 0.99, 1.29 ]

Total events: 1164 (HES), 990 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 9.33, df = 7 (P = 0.23); I2 =25%

Test for overall effect: Z = 1.83 (P = 0.067)

Total (95% CI) 4174 4206 1.06 [ 0.92, 1.23 ]

Total events: 1240 (HES), 1074 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 21.81, df = 16 (P = 0.15); I2 =27%

Test for overall effect: Z = 0.84 (P = 0.40)

Test for subgroup differences: Chi2 = 1.48, df = 1 (P = 0.22), I2 =33%

0.005 0.1 1 10 200

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Analysis 2.1. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 1 RIFLE (Risk or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 2 High MW/DS HES versus low MW/DS HES

Outcome: 1 RIFLE (Risk or worse)

Study or subgroup High MW HES Low MW HES Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Gallandat 2000 0/29 0/28 0.0 [ 0.0, 0.0 ]

Protsenko 2009 2/15 0/11 3.75 [ 0.20, 71.12 ]

Sander 2003 1/27 2/29 0.54 [ 0.05, 5.59 ]

Total (95% CI) 71 68 1.15 [ 0.18, 7.48 ]

Total events: 3 (High MW HES), 2 (Low MW HES)

Heterogeneity: Tau2 = 0.07; Chi2 = 1.04, df = 1 (P = 0.31); I2 =4%

Test for overall effect: Z = 0.15 (P = 0.88)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours high MW HES Favours low MW HES

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Analysis 2.2. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 2 RIFLE (Injury or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 2 High MW/DS HES versus low MW/DS HES

Outcome: 2 RIFLE (Injury or worse)

Study or subgroup High MW HES Low MW HES Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Gallandat 2000 0/29 0/28 0.0 [ 0.0, 0.0 ]

Jungheinrich 2004 0/25 0/24 0.0 [ 0.0, 0.0 ]

Protsenko 2009 0/15 0/11 0.0 [ 0.0, 0.0 ]

Sander 2003 1/27 0/29 3.21 [ 0.14, 75.68 ]

Total (95% CI) 96 92 3.21 [ 0.14, 75.68 ]

Total events: 1 (High MW HES), 0 (Low MW HES)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 0.72 (P = 0.47)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours high MW HES Favours low MW HES

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Analysis 2.3. Comparison 2 High MW/DS HES versus low MW/DS HES, Outcome 3 RIFLE (Failure).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 2 High MW/DS HES versus low MW/DS HES

Outcome: 3 RIFLE (Failure)

Study or subgroup High MW HES Low MW HES Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Gallandat 2000 0/29 0/28 0.0 [ 0.0, 0.0 ]

Jungheinrich 2004 0/25 0/24 0.0 [ 0.0, 0.0 ]

Protsenko 2009 0/15 0/11 0.0 [ 0.0, 0.0 ]

Sander 2003 0/27 0/29 0.0 [ 0.0, 0.0 ]

Total (95% CI) 96 92 0.0 [ 0.0, 0.0 ]

Total events: 0 (High MW HES), 0 (Low MW HES)

Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours high MW HES Favours low MW HES

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Analysis 3.1. Comparison 3 HES versus other fluid - no subgroups, Outcome 1 Renal replacement therapy.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 3 HES versus other fluid - no subgroups

Outcome: 1 Renal replacement therapy

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

BaSES 2012 28/117 23/124 1.29 [ 0.79, 2.11 ]

Berard 1995 5/146 4/153 1.31 [ 0.36, 4.78 ]

Brunkhorst 2008 81/261 51/272 1.66 [ 1.22, 2.25 ]

Cittanova 1996 9/27 1/20 6.67 [ 0.92, 48.45 ]

Du 2011 1/21 0/21 3.00 [ 0.13, 69.70 ]

Godet 2008 0/32 1/33 0.34 [ 0.01, 8.13 ]

Guidet 2012 21/100 11/96 1.83 [ 0.93, 3.59 ]

James 2011 2/56 3/53 0.63 [ 0.11, 3.63 ]

Kumle 1999 0/40 0/20 0.0 [ 0.0, 0.0 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

London 1989 1/50 1/50 1.00 [ 0.06, 15.55 ]

Magder 2010 1/119 1/118 0.99 [ 0.06, 15.67 ]

Mahmood 2007 2/42 3/20 0.32 [ 0.06, 1.75 ]

McIntyre 2008 3/19 1/21 3.32 [ 0.38, 29.23 ]

Mukhtar 2009 1/20 1/20 1.00 [ 0.07, 14.90 ]

Myburgh 2012 235/3352 196/3375 1.21 [ 1.00, 1.45 ]

Perner 2012 87/398 65/400 1.35 [ 1.01, 1.80 ]

Schortgen 2001 13/65 11/64 1.16 [ 0.56, 2.40 ]

Vlachou 2010 0/12 0/14 0.0 [ 0.0, 0.0 ]

Total (95% CI) 4930 4927 1.32 [ 1.17, 1.50 ]

Total events: 491 (HES), 373 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 12.00, df = 16 (P = 0.74); I2 =0.0%

Test for overall effect: Z = 4.36 (P = 0.000013)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

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Analysis 3.2. Comparison 3 HES versus other fluid - no subgroups, Outcome 2 Kidney failure (author

defined).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 3 HES versus other fluid - no subgroups

Outcome: 2 Kidney failure (author defined)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Abdel-Khalek 2010 1/67 1/68 1.01 [ 0.06, 15.90 ]

Akech 2010 0/20 0/39 0.0 [ 0.0, 0.0 ]

Altman 1998 0/27 0/33 0.0 [ 0.0, 0.0 ]

Brunkhorst 2008 91/261 62/272 1.53 [ 1.16, 2.01 ]

Dehne 2001 0/15 0/15 0.0 [ 0.0, 0.0 ]

Diehl 1982 2/27 0/33 6.07 [ 0.30, 121.33 ]

Du 2011 0/21 0/21 0.0 [ 0.0, 0.0 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 8/32 7/33 1.18 [ 0.48, 2.87 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Schortgen 2001 27/65 15/64 1.77 [ 1.04, 3.01 ]

Shatney 1983 0/16 0/16 0.0 [ 0.0, 0.0 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Total (95% CI) 658 703 1.59 [ 1.26, 2.00 ]

Total events: 136 (HES), 86 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 2.61, df = 8 (P = 0.96); I2 =0.0%

Test for overall effect: Z = 3.94 (P = 0.000082)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 3.3. Comparison 3 HES versus other fluid - no subgroups, Outcome 3 RIFLE (Risk or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 3 HES versus other fluid - no subgroups

Outcome: 3 RIFLE (Risk or worse)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 1/34 5/33 0.19 [ 0.02, 1.57 ]

Akkucuk 2012 1/12 2/12 0.50 [ 0.05, 4.81 ]

Choi 2010 1/18 3/18 0.33 [ 0.04, 2.91 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 2/9 1/11 2.44 [ 0.26, 22.80 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 8/32 6/33 1.38 [ 0.54, 3.52 ]

Guidet 2012 22/100 23/96 0.92 [ 0.55, 1.53 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 14/56 23/53 0.58 [ 0.33, 1.00 ]

Lee 2011 3/53 3/53 1.00 [ 0.21, 4.73 ]

Magder 2010 22/119 24/117 0.90 [ 0.54, 1.51 ]

Myburgh 2012 1788/3309 1912/3335 0.94 [ 0.90, 0.98 ]

Perner 2012 206/362 203/366 1.03 [ 0.90, 1.17 ]

Protsenko 2009 2/15 0/5 1.88 [ 0.10, 33.66 ]

Protsenko 2009 0/11 0/5 0.0 [ 0.0, 0.0 ]

Schortgen 2001 26/61 20/59 1.26 [ 0.79, 1.99 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Van der Linden 2005 2/60 5/60 0.40 [ 0.08, 1.98 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Yang 2011 0/26 1/25 0.32 [ 0.01, 7.53 ]

Yassen 2011 2/30 2/15 0.50 [ 0.08, 3.21 ]

Total (95% CI) 4387 4382 0.95 [ 0.91, 0.99 ]

Total events: 2106 (HES), 2234 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 15.77, df = 18 (P = 0.61); I2 =0.0%

Test for overall effect: Z = 2.54 (P = 0.011)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

105Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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Analysis 3.4. Comparison 3 HES versus other fluid - no subgroups, Outcome 4 RIFLE (Injury or worse).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 3 HES versus other fluid - no subgroups

Outcome: 4 RIFLE (Injury or worse)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Akkucuk 2012 0/12 1/12 0.33 [ 0.01, 7.45 ]

Choi 2010 1/18 1/18 1.00 [ 0.07, 14.79 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 1/9 0/11 3.60 [ 0.16, 79.01 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 3/32 2/33 1.55 [ 0.28, 8.65 ]

Guidet 2012 9/100 12/96 0.72 [ 0.32, 1.63 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 6/56 11/53 0.52 [ 0.21, 1.30 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Magder 2010 8/119 7/117 1.12 [ 0.42, 3.00 ]

Myburgh 2012 1130/3265 1253/3300 0.91 [ 0.85, 0.97 ]

Perner 2012 154/362 130/366 1.20 [ 1.00, 1.44 ]

Schortgen 2001 24/61 17/59 1.37 [ 0.82, 2.27 ]

Shmyrev 2011 1/8 0/7 2.67 [ 0.13, 56.63 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/55 0.0 [ 0.0, 0.0 ]

Total (95% CI) 4261 4322 1.01 [ 0.88, 1.17 ]

Total events: 1341 (HES), 1437 (Other fluid)

Heterogeneity: Tau2 = 0.01; Chi2 = 17.42, df = 15 (P = 0.29); I2 =14%

Test for overall effect: Z = 0.17 (P = 0.86)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 3.5. Comparison 3 HES versus other fluid - no subgroups, Outcome 5 RIFLE (Failure).

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 3 HES versus other fluid - no subgroups

Outcome: 5 RIFLE (Failure)

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Choi 2010 0/18 0/18 0.0 [ 0.0, 0.0 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 0/9 0/11 0.0 [ 0.0, 0.0 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 1/32 1/33 1.03 [ 0.07, 15.79 ]

Guidet 2012 5/100 7/96 0.69 [ 0.23, 2.09 ]

Heradstveit 2010 0/10 0/9 0.0 [ 0.0, 0.0 ]

Lee 2011 0/53 0/53 0.0 [ 0.0, 0.0 ]

Magder 2010 1/119 4/117 0.25 [ 0.03, 2.17 ]

Myburgh 2012 336/3243 301/3263 1.12 [ 0.97, 1.30 ]

Perner 2012 84/362 67/366 1.27 [ 0.95, 1.69 ]

Schortgen 2001 19/61 13/59 1.41 [ 0.77, 2.60 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/25 0.0 [ 0.0, 0.0 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Total (95% CI) 4189 4213 1.14 [ 1.01, 1.30 ]

Total events: 447 (HES), 396 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 6.04, df = 8 (P = 0.64); I2 =0.0%

Test for overall effect: Z = 2.08 (P = 0.037)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 4.1. Comparison 4 Sensitivity analyses, Outcome 1 RIFLE (Risk or worse) - Creatinine only.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 4 Sensitivity analyses

Outcome: 1 RIFLE (Risk or worse) - Creatinine only

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 1/34 5/33 0.19 [ 0.02, 1.57 ]

Akkucuk 2012 1/12 2/12 0.50 [ 0.05, 4.81 ]

Choi 2010 1/18 3/18 0.33 [ 0.04, 2.91 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 2/9 1/11 2.44 [ 0.26, 22.80 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 8/32 6/33 1.38 [ 0.54, 3.52 ]

Guidet 2012 22/100 23/96 0.92 [ 0.55, 1.53 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 14/56 23/53 0.58 [ 0.33, 1.00 ]

Lee 2011 3/53 3/53 1.00 [ 0.21, 4.73 ]

Magder 2010 22/119 24/117 0.90 [ 0.54, 1.51 ]

Myburgh 2012 462/3149 415/3171 1.12 [ 0.99, 1.27 ]

Perner 2012 206/362 203/366 1.03 [ 0.90, 1.17 ]

Protsenko 2009 0/11 0/5 0.0 [ 0.0, 0.0 ]

Protsenko 2009 2/15 0/5 1.88 [ 0.10, 33.66 ]

Schortgen 2001 26/61 20/59 1.26 [ 0.79, 1.99 ]

Shmyrev 2011 3/8 1/7 2.63 [ 0.35, 19.85 ]

Van der Linden 2005 2/60 5/60 0.40 [ 0.08, 1.98 ]

Yang 2011 0/26 1/25 0.32 [ 0.01, 7.53 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Yassen 2011 2/30 2/15 0.50 [ 0.08, 3.21 ]

Total (95% CI) 4227 4218 1.05 [ 0.97, 1.14 ]

Total events: 780 (HES), 737 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 16.79, df = 18 (P = 0.54); I2 =0.0%

Test for overall effect: Z = 1.19 (P = 0.23)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 4.2. Comparison 4 Sensitivity analyses, Outcome 2 RIFLE (Injury or worse) -Creatinine only.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 4 Sensitivity analyses

Outcome: 2 RIFLE (Injury or worse) -Creatinine only

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Akkucuk 2012 0/12 1/12 0.33 [ 0.01, 7.45 ]

Choi 2010 1/18 1/18 1.00 [ 0.07, 14.79 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 1/9 0/11 3.60 [ 0.16, 79.01 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 3/32 2/33 1.55 [ 0.28, 8.65 ]

Guidet 2012 9/100 12/96 0.72 [ 0.32, 1.63 ]

Heradstveit 2010 2/10 0/9 4.55 [ 0.25, 83.70 ]

James 2011 6/56 11/53 0.52 [ 0.21, 1.30 ]

Lee 2011 1/53 0/53 3.00 [ 0.12, 72.02 ]

Magder 2010 8/119 7/117 1.12 [ 0.42, 3.00 ]

Myburgh 2012 245/3149 191/3171 1.29 [ 1.08, 1.55 ]

Perner 2012 154/362 130/366 1.20 [ 1.00, 1.44 ]

Schortgen 2001 24/61 17/59 1.37 [ 0.82, 2.27 ]

Shmyrev 2011 1/8 0/7 2.67 [ 0.13, 56.63 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/55 0.0 [ 0.0, 0.0 ]

Total (95% CI) 4145 4193 1.22 [ 1.08, 1.37 ]

Total events: 456 (HES), 375 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 10.54, df = 15 (P = 0.78); I2 =0.0%

Test for overall effect: Z = 3.19 (P = 0.0014)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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Analysis 4.3. Comparison 4 Sensitivity analyses, Outcome 3 RIFLE (Failure) - Creatinine only.

Review: Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Comparison: 4 Sensitivity analyses

Outcome: 3 RIFLE (Failure) - Creatinine only

Study or subgroup HES Other fluid Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Akech 2010 0/34 1/33 0.32 [ 0.01, 7.68 ]

Choi 2010 0/18 0/18 0.0 [ 0.0, 0.0 ]

Dolecek 2009 0/26 0/30 0.0 [ 0.0, 0.0 ]

Dubin 2010 0/9 0/11 0.0 [ 0.0, 0.0 ]

Fernandez 2005 1/10 0/10 3.00 [ 0.14, 65.90 ]

Godet 2008 1/32 1/33 1.03 [ 0.07, 15.79 ]

Guidet 2012 5/100 7/96 0.69 [ 0.23, 2.09 ]

Heradstveit 2010 0/10 0/9 0.0 [ 0.0, 0.0 ]

Lee 2011 0/53 0/53 0.0 [ 0.0, 0.0 ]

Magder 2010 1/119 4/117 0.25 [ 0.03, 2.17 ]

Myburgh 2012 221/3149 154/3171 1.45 [ 1.18, 1.76 ]

Perner 2012 84/362 67/366 1.27 [ 0.95, 1.69 ]

Schortgen 2001 19/61 13/59 1.41 [ 0.77, 2.60 ]

Van der Linden 2005 0/60 2/60 0.20 [ 0.01, 4.08 ]

Yang 2011 0/26 0/25 0.0 [ 0.0, 0.0 ]

Yang 2011 0/26 0/30 0.0 [ 0.0, 0.0 ]

Total (95% CI) 4095 4121 1.35 [ 1.15, 1.57 ]

Total events: 332 (HES), 249 (Other fluid)

Heterogeneity: Tau2 = 0.0; Chi2 = 7.05, df = 8 (P = 0.53); I2 =0.0%

Test for overall effect: Z = 3.74 (P = 0.00018)

Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours HES Favours other fluid

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A P P E N D I C E S

Appendix 1. Electronic search strategies

Database Electronic search terms

CENTRAL 1. hetastarch:ti,ab,kw2. (hydroxyethyl next starch*):ti,ab,kw3. hydroxyethylstarch*:ti,ab,kw4. (hydroxy next ethyl next starch*):ti,ab,kw5. hydroxyathyl*:ti,ab,kw6. hydroxyethylstarke:ti,ab,kw7. (hydroxyethyl next starke):ti,ab,kw8. hydroksyetyloskrobia:ti,ab,kw9. hydroxyethylamidon*:ti,ab,kw

10. hydroxyethylamylopectin:ti,ab,kw11. (amylopectin and hydroxyethyl):ti,ab,kw12. hespan:ti,ab,kw13. haes-steril:ti,ab,kw14. haessteril:ti,ab,kw15. hesteril:ti,ab,kw16. (hes next steril):ti,ab,kw17. hespander:ti,ab,kw18. hexten:ti,ab,kw19. hemohes:ti,ab,kw20. haes:ti,ab,kw21. hestar:ti,ab,kw22. hyperhaes:ti,ab,kw23. heafusine:ti,ab,kw24. pentastarch:ti,ab,kw25. pentafraction:ti,ab,kw26. pentaspan:ti,ab,kw27. plasmasteril:ti,ab,kw28. plasmafusin:ti,ab,kw29. expafusin:ti,ab,kw30. “elo hes”:ti,ab,kw31. elohes:ti,ab,kw32. elohast:ti,ab,kw33. elohaest:ti,ab,kw34. expahes:ti,ab,kw35. polyhydroxyamylopectin:ti,ab,kw36. “asl 607”:ti,ab,kw37. asl607:ti,ab,kw38. ketastarch:ti,ab,kw39. isoh*es:ti,ab,kw40. onkohaes:ti,ab,kw41. onkohes:ti,ab,kw42. volex:ti,ab,kw43. voluven:ti,ab,kw

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(Continued)

44. lomol:ti,ab,kw45. “iles esteril”:ti,ab,kw46. varihes:ti,ab,kw47. rheohes:ti,ab,kw48. tetrahes:ti,ab,kw49. tetrastarch:ti,ab,kw50. salinhes:ti,ab,kw51. isohas:ti,ab,kw52. venofundin:ti,ab,kw53. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR#37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48OR #49 OR #50 OR #51 OR #52)54. (HES and not (hypereosinophil* or embryo* or HES-1 or HES1 or HES-6 or HES6 or (hospitalnext episode next stat*) or (health next examination next survey*))):ti,ab,kw55. (#53 OR #54)

MEDLINE 1. Hetastarch/2. hetastarch*.tw.3. hydroxyethyl starch*.tw.4. hydroxyethylstarch*.tw.5. hydroxy ethyl starch*.tw.6. hydroxyathyl*.tw.7. hydroxyethylstarke.tw.8. hydroxyethyl starke.tw.9. hydroksyetyloskrobia.tw.

10. hydroxyethylamidon*.tw.11. hydroxyethylamylopectin.tw.12. hes steril.tw.13. haes-steril.tw.14. haessteril.tw.15. hespander.tw.16. hextend.tw.17. hespan.tw.18. hemohes.tw.19. haes.tw.20. hestar.tw.21. hesteril.tw.22. hyperhaes.tw.23. pentastarch.tw.24. pentafraction.tw.25. pentaspan.tw.26. plasmasteril.tw.27. (amylopectin and hydroxyethyl).tw.28. heafusine.tw.29. plasmafusin.tw.30. expafusin.tw.31. elo hes.tw.

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(Continued)

32. elohes.tw.33. elohast.tw.34. elohaest.tw.35. expahes.tw.36. polyhydroxyamylopectin.tw.37. asl 607.tw.38. asl607.tw.39. ketastarch.tw.40. isoh?es.tw.41. isohas.tw.42. onkohaes.tw.43. onkoh#s.tw.44. volex.tw.45. voluven.tw.46. venofundin.tw.47. lomol.tw.48. il?es esteril.tw.49. varihes.tw.50. rheohes.tw.51. tetrahes.tw.52. tetrastarch.tw.53. salinhes.tw.54. or/1-5355. (HES not (hypereosinophil* or embryo* or HES-1 or HES1 or HES-6 or HES6 or hospital episodestat* or health examination survey*)).tw.56. or/54-55

EMBASE 1. Hetastarch/2. hetastarch*.tw.3. hydroxyethyl starch*.tw.4. hydroxyethylstarch*.tw.5. hydroxy ethyl starch*.tw.6. hydroxyathyl*.tw.7. hydroxyethylstarke.tw.8. hydroxyethyl starke.tw.9. hydroksyetyloskrobia.tw.

10. hydroxyethylamidon*.tw.11. hydroxyethylamylopectin.tw.12. haes-steril.tw.13. hes steril.tw.14. haessteril.tw.15. hespander.tw.16. hextend.tw.17. hespan.tw.18. hemohes.tw.19. haes.tw.20. hestar.tw.21. hesteril.tw.22. hyperhaes.tw.

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(Continued)

23. pentastarch.tw.24. pentafraction.tw.25. pentaspan.tw.26. plasmasteril.tw.27. (amylopectin and hydroxyethyl).tw.28. heafusine.tw.29. plasmafusin.tw.30. expafusin.tw.31. elo hes.tw.32. elohes.tw.33. elohast.tw.34. elohaest.tw.35. expahes.tw.36. polyhydroxyamylopectin.tw.37. asl 607.tw.38. asl607.tw.39. ketastarch.tw.40. isoh?es.tw.41. isohas.tw.42. onkohaes.tw.43. onkoh#s.tw.44. volex.tw.45. voluven.tw.46. venofundin.tw.47. lomol.tw.48. il?es esteril.tw.49. varihes.tw.50. rheohes.tw.51. tetrahes.tw.52. tetrastarch.tw.53. salinhes.tw.54. or/1-5355. (HES not (hypereosinophil* or embryo* or HES-1 or HES1 or HES-6 or HES6 or hospital episodestat* or health examination survey*)).tw.56. or/54-55

MetaRegister keywords 1. hetastarch*2. hydroxyethyl starch*3. hydroxyethylstarch*4. hydroxy ethyl starch*5. hydroxyathyl*6. hydroxyethylstarke7. hydroxyethyl starke8. hydroksyetyloskrobia9. hydroxyethylamidon*

10. hydroxyethylamylopectin11. hes steril12. haes-steril13. haessteril

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(Continued)

14. hespander15. hextend16. hespan17. hemohes18. haes19. hestar20. hesteril21. hyperhaes22. pentastarch23. pentafraction24. pentaspan25. plasmasteril26. (amylopectin and hydroxyethyl)27. heafusine28. plasmafusin29. expafusin30. elo hes31. elohes32. elohast33. elohaest34. expahes35. polyhydroxyamylopectin36. asl 60737. asl60738. ketastarch39. isohes40. isohas41. onkohaes42. onkohas43. volex44. voluven45. venofundin46. lomol47. ilaes esteril48. varihes49. rheohes50. tetrahes51. tetrastarch52. salinhes

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Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inade-quate generation of a randomised sequence

Low risk of bias: Random number table; computer random num-ber generator; coin tossing; shuffling cards or envelopes; throwingdice; drawing of lots; minimization (minimization may be imple-mented without a random element, and this is considered to beequivalent to being random)

High risk of bias: Sequence generated by odd or even date of birth;date (or day) of admission; sequence generated by hospital orclinic record number; allocation by judgement of the clinician; bypreference of the participant; based on the results of a laboratorytest or a series of tests; by availability of the intervention

Unclear: Insufficient information about the sequence generationprocess to permit judgement

Allocation concealment

Selection bias (biased allocation to interventions) due to inade-quate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would notallow investigator/participant to know or influence interventiongroup before eligible participant entered in the study (e.g. centralallocation, including telephone, web-based, and pharmacy-con-trolled, randomisation; sequentially numbered drug containers ofidentical appearance; sequentially numbered, opaque, sealed en-velopes)

High risk of bias: Using an open random allocation schedule (e.g. alist of random numbers); assignment envelopes were used withoutappropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation;date of birth; case record number; any other explicitly unconcealedprocedure

Unclear: Randomisation stated but no information on methodused is available

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventionsby participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the re-view authors judge that the outcome is not likely to be influencedby lack of blinding; blinding of participants and key study per-sonnel ensured, and unlikely that the blinding could have beenbroken

High risk of bias: No blinding or incomplete blinding, and theoutcome is likely to be influenced by lack of blinding; blindingof key study participants and personnel attempted, but likely thatthe blinding could have been broken, and the outcome is likelyto be influenced by lack of blinding

Unclear: Insufficient information to permit judgement

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(Continued)

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions byoutcome assessors

Low risk of bias: No blinding of outcome assessment, but the reviewauthors judge that the outcome measurement is not likely to beinfluenced by lack of blinding; blinding of outcome assessmentensured, and unlikely that the blinding could have been broken

High risk of bias: No blinding of outcome assessment, and theoutcome measurement is likely to be influenced by lack of blind-ing; blinding of outcome assessment, but likely that the blindingcould have been broken, and the outcome measurement is likelyto be influenced by lack of blinding

Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incompleteoutcome data

Low risk of bias: No missing outcome data; reasons for missingoutcome data unlikely to be related to true outcome (for survivaldata, censoring unlikely to be introducing bias); missing outcomedata balanced in numbers across intervention groups, with similarreasons for missing data across groups; for dichotomous outcomedata, the proportion of missing outcomes compared with observedevent risk not enough to have a clinically relevant impact on theintervention effect estimate; for continuous outcome data, plau-sible effect size (difference in means or standardized difference inmeans) among missing outcomes not enough to have a clinicallyrelevant impact on observed effect size; missing data have beenimputed using appropriate methods

High risk of bias: Reason for missing outcome data likely to berelated to true outcome, with either imbalance in numbers or rea-sons for missing data across intervention groups; for dichotomousoutcome data, the proportion of missing outcomes compared withobserved event risk enough to induce clinically relevant bias inintervention effect estimate; for continuous outcome data, plau-sible effect size (difference in means or standardized difference inmeans) among missing outcomes enough to induce clinically rel-evant bias in observed effect size; ‘as-treated’ analysis done withsubstantial departure of the intervention received from that as-signed at randomisation; potentially inappropriate application ofsimple imputation

Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reportingLow risk of bias: The study protocol is available and all of thestudy’s pre-specified (primary and secondary) outcomes that are ofinterest in the review have been reported in the pre-specified way;the study protocol is not available but it is clear that the publishedreports include all expected outcomes, including those that werepre-specified (convincing text of this nature may be uncommon)

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High risk of bias: Not all of the study’s pre-specified primary out-comes have been reported; one or more primary outcomes is re-ported using measurements, analysis methods or subsets of thedata (e.g. subscales) that were not pre-specified; one or more re-ported primary outcomes were not pre-specified (unless clear jus-tification for their reporting is provided, such as an unexpectedadverse effect); one or more outcomes of interest in the review arereported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcomethat would be expected to have been reported for such a study

Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the tableLow risk of bias: The study appears to be free of other sources ofbias.

High risk of bias: Had a potential source of bias related to the spe-cific study design used; stopped early due to some data-dependentprocess (including a formal-stopping rule); had extreme baselineimbalance; has been claimed to have been fraudulent; had someother problem

Unclear: Insufficient information to assess whether an importantrisk of bias exists; insufficient rationale or evidence that an iden-tified problem will introduce bias

W H A T ’ S N E W

Last assessed as up-to-date: 21 May 2013.

Date Event Description

21 May 2013 New citation required and conclusions have changed Updated review

19 November 2012 New search has been performed Re-ran search and revised review

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H I S T O R Y

Protocol first published: Issue 1, 2009

Review first published: Issue 1, 2010

Date Event Description

14 April 2011 Amended Letter added to address Boldt’s retracted studies

C O N T R I B U T I O N S O F A U T H O R S

1. Draft the protocol: AD, TM, CR

2. Study selection: AD, TM, CR

3. Extract data from studies: AD, TM, CR

4. Enter data into RevMan: AD, TM, CR

5. Carry out the analysis: AD, TM, CR

6. Interpret the analysis: AD, TM, CR

7. Draft the final review: AD, TM, CR

8. Disagreement resolution: All authors

9. Update the review: AD, TM, CR

D E C L A R A T I O N S O F I N T E R E S T

None declared.

S O U R C E S O F S U P P O R T

Internal sources

• Department of Anesthesia, Faculty of Medicine, University of Manitoba, Canada.Funds for statistical consultation were provided through a department grant.

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External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Normovolaemic and hypervolaemic haemodilution studies were removed because they were not treatments of intravascular volumedepletion. Due to insufficient data, the patient population subgroup analysis was modified after studies were selected but before anyanalysis was undertaken.

N O T E S

April 7, 2011

Comment regarding studies by Dr Joachim Boldt

There have recently been major concerns discovered about the work of Dr Joachim Boldt, the first author of nine studies included inthis systematic review. Four of his studies were included in the outcome analysis, need for renal replacement therapy (Boldt 2003;Boldt 2007a; Boldt 2006; Boldt 2008). One study was included in the outcome “author defined” renal failure analysis (Boldt 1998)and seven studies were included in one of the creatinine based outcome analyses (Boldt 1993; Boldt 1998; Boldt 2000a; Boldt 2000b;Boldt 2003; Boldt 2007a; Boldt 2008).

Landesärztekammer Rheinland-Pfalz (“LÄK-RLP”), the State Medical Association of Rheinland-Pfalz, Germany, is the InstitutionalReview Board (IRB) responsible for clinical research performed at Klinikum Ludwigshafen. Dr. Boldt’s most recent work was performedat this centre. A review was conducted by the LÄK-RLP of 102 published articles by Dr. Boldt and colleagues, submitted since 1999.It was determined that 88 of these studies did not have IRB approval, as had been stated in the papers. Although it has not beendetermined at this point that the studies are fraudulent, they were deemed unethical, due to lack of IRB approval. An editors-in-chiefjoint statement was published online March 12, 2011 (Editors-in-Chief Statement 2011), which stated that all 88 articles would beretracted from their respective journals, including four studies included in this systematic review (Boldt 2003; Boldt 2006; Boldt 2007a;Boldt 2008)

In addition, it was confirmed that two of the studies in this systematic review did have appropriate IRB approval (Boldt 2000a; Boldt2007a). The three additional studies were not included in their review (Boldt 1993; Boldt 1998; Boldt 2000a), therefore, it is unknownat this point whether these studies have IRB approval or not. An investigating committee has been commissioned by KlinikumLudwigshafen to verify the authenticity of the results in Dr Boldt’s papers.

Due to the severe concerns regarding the validity of the results in these studies, we have run a sensitivity analysis removing Dr. Boldt’sretracted papers from our primary outcome analyses. There were no retracted papers in the renal failure categories - RIFLE or authordefined. The removal of the four retracted studies from the renal replacement therapy outcome did not change our results significantly.The RR changed from 1.38 (95% CI 0.89 to 2.16) for need for RRT to RR 1.43 (95% CI 0.89 to 2.28).

Our systematic review is due for an updated literature search in May, 2011 and for publication in January 2012. There will certainlybe more information about the validity of Dr Boldt’s publications prior to the publication of our updated review. We will thoroughlyreview all available information, such that our analyses and conclusions reflect only reliable data.

Sincerely

Dr Allison Dart, Dr Thomas Mutter, Dr Chelsea Ruth and Dr Shayne Taback

University of Manitoba; Winnipeg, Manitoba; Canada

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I N D E X T E R M S

Medical Subject Headings (MeSH)

Acute Kidney Injury [∗chemically induced]; Blood Volume; Hetastarch [∗adverse effects]; Plasma Substitutes [∗adverse effects]; Ran-domized Controlled Trials as Topic

MeSH check words

Humans

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