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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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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.

http://www.thecochranelibrary.com

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .120NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

[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 Groups 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 RCTs 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 Ringers 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 Groups Specialised Registeron November 19, 2012 through contact with the Trials SearchCo-ordinator using search terms relevant to this review.The Cochrane Renal Groups 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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http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/RENAL/frame.htmlhttp://onlinelibrary.wiley.com/o/cochrane/clabout/articles/RENAL/frame.htmlhttp://onlinelibrary.wiley.com/o/cochrane/clabout/articles/RENAL/frame.html

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 Chi test on N-1 degrees offreedom, with an alpha of 0.05 used for statistical significance andwith the I test (Higgins 2003). I 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 usedRingers lactate or acetate (Brunkhorst 2008; Du 2011; Perner2012); one study used Hartmanns 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), Ringers 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 ringers 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; I = 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: Chi = 2.74, df = 2 (P = 0.25), I = 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; I = 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; I = 0%) when comparedto another type of fluid therapy. The results of the test for sub-group differences were: Chi = 1.59, df = 1 (P = 0.21), I = 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; I = 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; I =0%) when compared to other fluid therapies. The results of thetest for subgroup differences were: Chi = 1.52, df = 1 (P = 0.22),I = 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; I = 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; I = 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; I = 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; I = 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; I = 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; I = 0%). The results of the test for subgroup differenceswere: Chi = 12.88, df = 1 (P = 0.0003), I = 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; I =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; I = 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; I = 0%). The results of the test for subgroup differenceswere: Chi = 17.64, df = 1 (P < 0.0001), I = 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; I =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; I = 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; I = 0%). The results of the tests for subgroupdifferences were: Chi = 1.31, df = 1 (P = 0.25), I = 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; I = 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; I = 41%). Theresults of the test for subgroup differences were: Chi = 1.25, df =1 (P = 0.26), I = 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; I = 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; I = 25%) whencompared to other fluid therapies. The results of the test for sub-group differences: Chi = 1.48, df = 1 (P = 0.22), I = 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; I = 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

19Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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

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% 130/0.4s 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 1990s, 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 RCTs 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

20Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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

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 Groups 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 reviews 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).

21Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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

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. ArabJournal of Gastroenterology 2010;11(1):249. [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):16306. [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]. AppliedCardiopulmonary Pathophysiology 2012;16:1912.

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):510. [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. [Hydroxythylamidonsversus glatines: Impact sur le cot du remplissage dans unservice de ranimation]. Annales Francaises d Anesthesie et deReanimation 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 EnglandJournal of Medicine 2008;358(2):12539. [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):58491. [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):16202. [MEDLINE: 8961992]

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

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

22Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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

impairment. Journal of Clinical Anesthesia 2001;13(2):10311. [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):6749. [MEDLINE:6184023]

Dolecek 2009 {unpublished data only}

Dolecek M, Svoboda P, Kantorov I, Scheer P, Sas I,Bbrov 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):16228. [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):12205. [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):6589.[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):11122. [MEDLINE: 22513516]

Fernandez 2005 {published and unpublished data}

Fernndez J, Monteagudo J, Bargallo X, Jimnez W,Bosch J, Arroyo V, et al.A randomized unblinded pilotstudy comparing albumin versus hydroxyethyl starch inspontaneous bacterial peritonitis. Hepatology 2005;42(3):62734. [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. CanadianJournal of Anaesthesia 2000;47(12):120715. [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 Anaesthesiology2008;25(12):98694. [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, Langrgen 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). BritishJournal of Anaesthesia 2011;107(5):693702. [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):19. [MEDLINE: 14725484]

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

Kasper SM, Meinert P, Kampe S, Grg 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):427. [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):112430. [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):2397402. [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 & CardiovascularSurgery 1989;97(5):78597. [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 CareMedicine 2010;36:S378. [EMBASE: 70291386 ]

23Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review)

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

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. BritishJournal of Surgery 2007;94(4):42733. [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):81926. [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):92430. [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):190111. [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):14539.[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 Ringers acetate in severe sepsis. New EnglandJournal of Medicine 2012;367(2):12434. [MEDLINE:22738085]

Protsenko 2009 {published data only}

Protsenko DN, Leiderman IN, Grigorev EV, Kokarev EA,Levit AL, Gelfand BR. Evaluation of the effectivenessand safety of synthetic colloid solutions in the treatmentof severe abdominal sepsis: a randomized comparativestudy. Anesteziologiia i Reanimatologiia 2009, (5):913.[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):11518. [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):9116. [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 ofSurgery 1983;118(7):8049. [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):S312. [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 & Analgesia2005;101(3):62934. [MEDLINE: 16115963]

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

Vlachou E, Gosling P, Moiemen NS. Hydr