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TITLE: Hydroxyethyl Starch versus Other Plasma Volume Expanders: A Review of the

Clinical and Cost-Effectiveness, and Guidelines for Use DATE: 23 May 2013 CONTEXT AND POLICY ISSUES Fluid resuscitation is indicated for the management of hypovolemia (decreased blood plasma volume) and hypovolemic shock,1 and its ultimate objective is to restore organ perfusion and tissue oxygenation.2 Hypovolemia can be induced by a wide range of clinical conditions such as dehydration, burns, sepsis, malignancies, trauma, hemorrhage, and surgical anesthesia. Clinical signs of hypovolemia include blood pressure, urine output, mental status, and peripheral perfusion.1 There are two main types of fluids used for fluid resuscitation, colloids and crystalloids. Crystalloid solutions include normal saline and balanced fluids such as Ringer’s lactate.3 Human albumin preparations are natural colloids while dextran, gelatin, and starch products are synthetic colloids, also called synthetic plasma volume expanders.3 Hydroxyethyl starches are a common choice for fluid resuscitation.4 They are preferred over albumin because of their relatively lower price.5 These starches are supplied with different molecular weights ranging from 120 kDa to >450kDa. They are also characterized by the degree of substitution which is the molar substitution by hydroxyethyl groups. The degree of substitution ranges from 0.4 to 0.7. It is believed that the molecular weight and degree of substitution can affect patient outcomes.6 Four hydroxyethyl starches are available in Canada; these are Volvulen, Volulyte, Pentaspan and Hextend. Characteristics of these solutions are presented in Table 1. Table 1. Characteristics of the Hydroxyethyl Starch Solutions Available in Canada

Solution Type of starch

Molecular weight (kda)

Degree of substitution Solvent/ medium Tonicity Maximum

dose Volvulen Tetrastarch 130 0.4 Isotonic electrolyte 6% 50 ml/kg/day Volulyte Tetrasarch 130 0.4 0.9% NaCl 6% 33 ml/kg/day

Pentaspan Pentastarch 200-300 0.4-0.5 0.9% NaCl 10% 28 ml/kg/day Hextend Hexastarch 450-800 0.75 Lactate electrolyte 6% 20 ml/kg/day

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

The use of hydroxyethyl starches for fluid resuscitation is undergoing a comprehensive review.7 Results from recent randomized controlled trials suggest that these starches may be associated with increased risk of bleeding, renal dysfunction and mortality.7 However, results from these RCTs were not consistent; some RCTs such as the CRYSTMAS trial reported that HES did not differ from normal saline in terms of adverse events,8 while the 6S and VISEP trials reported that HES was associated with increased mortality and kidney injury.9,10 On the other hand, CHEST trial evaluated almost 7000 ICU patients who were resuscitated with HES or saline. The trial concluded that HES, compared to saline, was not associated with a significant increase in mortality, but it increased the incidence of renal replacement therapy.11,12 The evaluation of HES was further complicated by the retraction from the peer-reviewed literature of the studies published by Boldt and co-workers.11,13. Given these issues, the appropriate use of HES for fluid resuscitation remains unclear. The objective of the current review is to evaluate the evidence surrounding the use of hydroxyethyl starch in intensive-care units. RESEARCH QUESTIONS 1. What is the clinical effectiveness of hydroxyethyl starch compared with other plasma

volume expanders for use in patients in the intensive care unit? 2. What are the guidelines regarding the use of hydroxyethyl starch as a volume expander

for patients in the intensive care unit? 3. What is the cost-effectiveness of hydroxyethyl starch used as a volume expander for

patients in the intensive care unit? KEY FINDINGS Twelve meta-analyses, two clinical guidelines, and one cost-effectiveness study were included in the review. The available evidence indicates the use of hydroxyethyl starch is associated with increased risk of mortality and renal dysfunction when used for fluid resuscitation in critically ill patients and patients with severe sepsis. The available evidence suggests that the use of hydroxyethyl starch in patients undergoing surgery may be associated with increased risk of bleeding and reoperation due to bleeding. One cost-effectiveness analysis showed that hydroxyethyl starches were less cost-effective, compared with albumin, when used for fluid resuscitation in sepsis patients.

Hydroxyethyl Starch versus Other Plasma Volume Expanders 2

METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2013, Issue 4), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between Jan 1, 2010 and Apr 24, 2013.

Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed for relevance. Full texts of any relevant titles/abstracts were retrieved, and assessed for inclusion. The final article selection was based on the inclusion criteria presented in Table 2. Table 2 : Selection Criteria

Population Patients who need fluid replacement treated in intensive care unit, and patients who could be considered as intensive care (e.g., trauma, post-surgery)

Intervention Hydroxyethyl starch (HES), a colloidal starch

Comparator Crystalloid solutions (e.g., saline, Ringer’s lactate) Albumin

Outcomes Q1: comparative clinical effectiveness (benefits, harms, safety) Q2: evidence-based guidelines Q3: cost-effectiveness, comparative or not

Study Designs Systematic reviews, meta-analyses, health technology assessments and cost-effectiveness studies

Exclusion Criteria Systematic reviews and meta-analyses were excluded if they included primary trials conducted on healthy volunteer and of stable patients with chronic diseases. An additional exclusion criteria for systematic reviews was the inclusion of uncontrolled trials and observational studies. This was justified by the abundance of RCTs evaluating HES in different medical contexts; a scoping literature search detected more than 70 RCTs published between 2008 and 2013. Therefore, the inclusion of systematic reviews with uncontrolled trials or observational studies would have compromised the quality of evidence without additional value in terms of information quantity. Furthermore, reviews were excluded if they did not evaluate HES specifically i.e., reviews on colloids without specifying HES as a separate subgroup.


Systematic reviews or guidelines with a more recent update were be considered duplicates and were excluded; the most recent update will be considered the primary publication, and previous versions were used as secondary source of data. Critical Appraisal of Individual Studies Critical appraisal of the included studies was based on study design. The Appraisal of Guidelines Research and Evaluation (AGREE) instrument14 was used to evaluate the quality of the included guideline. The methodological quality of the included systematic reviews and meta-analyses was evaluated using the “assessment of multiple systematic reviews” (AMSTAR).15 AMSTAR is an 11-item checklist that has been developed to ensure reliability and construct validity of systematic reviews. The methodological quality of the included cost-effectiveness study was assessed using the guidelines for appraisal of economic studies by Drummond et al.16 For the included studies a numeric score was not calculated. Instead, the strengths and limitations of the study were described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 713 potential citations were identified by searching the bibliographic database, with 683 citations being excluded during the title and abstract screening based on their irrelevance to the questions of interest. The full text documents of the remaining 30 articles were retrieved. Three additional articles were identified by grey literature and hand search. Of the 33 articles, 18 did not meet the inclusion criteria and were excluded; leaving 15 articles that reported 12 meta-analyses, two guidelines, and one cost-effectiveness study. A PRISMA diagram demonstrating the study selection process is presented in Appendix 1. Summary of Study Characteristics Fifteen articles that addressed at least one of the review questions were included in this report. The use of HES for resuscitation of critically ill patients was evaluated in seven meta-analyses17-

23 and one guideline.24 Resuscitation with HES in patients with sepsis was assessed in two meta-analyses,25,26 one guideline,27 and one cost-effectiveness study.5 Finally, the use of HES in surgical settings was evaluated in two meta-analyses.6,28 Details on studies characteristics are tabulated in APPENDIX 2. Critically ill patients (Table 3, Table 4) The meta-analyses in this category included RCTs on patients treated in intensive care unit or emergency room; however, the medical condition for which fluid resuscitation was indicated was not systematically reported or considered in the analysis. One systematic review conducted subgroup analysis by diving trials’ population into sepsis and non-sepsis subgroups.23 The size of the analyzed population ranged from 1,61219 to almost 11,000 patients.17 Recent RCTs, with publication dates up to 2012, were included in three meta-analyses.17,18,20


Four meta-analyses evaluated non-specific formulation of HES.17-19,23 In these reviews, data from different HES formulations were pooled together. The molecular weights of the studied HES ranged from 120 kDa to 450 kDa; the degree of substitution ranged from 0.4 to 0.7.17-19,23 Two meta-analyses included RCTs that studies HES 130 kDa, 0.4 degree of substitution (130/0.4),20,21 and one meta-analysis evaluated hyperoncotic HES (10%) without specifying the molecular formulation.22 Comparators were crystalloids only,18 colloids only,19 or a both colloids and crystalloids which were pooled together as single comparator group.17,20-23 The two meta-analyses that evaluated HES 130/0.4 formulation included other HES formulations in the comparators group.20,21 The included meta-analyses focused on two safety outcomes mainly, mortality and renal failure. Five studies reported comparisons in the incidence death events,17-22 three studies reported on acute kidney injury or renal replacement therapy.17,22,23. One guideline was identified on the management of fluid resuscitation for critically ill patients.24 The guideline development was based on a literature review of published systematic reviews and meta-analyses. The recommendations were supported by an overall assessment of benefits, risks and economic burden associated with the use of fluid resuscitation. Sepsis Patients (Table 5, Table 6, and Table 7) Patel et al.25 and Haase et al.26 conducted two meta-analyses of RCTs on patients with sepsis and RCTs that reported sepsis patients in separate subgroups. Patel et al. included six RCTs published between 2006 and 2012; patients in these RCTs (n= 3000) were diagnosed with severe sepsis or septic shock.25 Haase et al. included RCTs on sepsis patients without specifying the severity.26 Nine RCTs were included, of which six were included by Patel et al. The two meta-analysis evaluated HES 130/0.40 and HES 130/0.42 at an isoncotic concentration.25,26 Comparators were both non-HES colloids and crystalloids. Patel et al. reported separate analyses for colloids, crystalloids, and both groups pooled together.25 They also provided subgroup analysis based on the origin of starch: maize or potato.25 Haase et al. reported results of studies using colloids and crystalloids as comparators pooled together.26 Different analyses were reported by the two meta-analyses, and they are considered complementary to each other.25,26 Patel et al. reported risk ratio of mortality at 28 days, 90 days and the overall mortality.25 Haase et al. reported all-cause mortality estimates within 28 days of follow-up and beyond 28 days of follow-up.26 One guideline on the management of sepsis patients was identified.27 In 2013, Dellinger et al. provided an update for the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock” last published in 2008.27 The guideline considered survival of sepsis patients and their length of stay in the ICU as the basis for the recommendations.27 The analysis conducted by Farrugla et al. evaluated the cost-effectiveness of using HES in sepsis as compared with albumin.5 The estimation was based on a non-systematic literature search of RCTs on sepsis patients. The incremental cost-effectiveness ratio was estimated using decision analysis model.


Surgery Patients (Table 8) Martin et al. included 17 RCTs on patients undergoing elective surgeries.6 The included trials were published between 2000 and 2011, and they included 1230 patients. Navickis et al. and Shi et al. included 18 and 52 RCTs respectively; these RCTs were conducted on patients undergoing cardiac surgeries. Martin’s meta-analysis compared the effects of HES 130/0.4 with a mix of crystalloids and colloids that included HES 200.6 Outcomes included acute renal failure, creatinine levels and length of stay. The meta-analyses by Navickis and Shi compared a pool of HES formulations with albumin,4,29 gelatin,29 and crystalloids.29 Outcomes reported in these two studies included mortality, reoperation, and blood loss.4,29 Summary of Critical Appraisal Details on studies appraisal are tabulated in APPENDIX 3. Critically ill patients The seven meta-analyses evaluating the use of HES for resuscitation in critically ill patients shared major strengths and limitations.17-23 They were based on systematic review of literature that was conducted by at least two investigators for each meta-analysis. The quality of the included RCTs was evaluated in all meta-analyses. Limitations of the meta-analyses might affect the external validity of their results. In six meta-analyses the medical condition, for which fluid resuscitation was needed, was not reported or considered in the interpretation of results.17-22 The intervention in four meta-analyses was considered as a pool composed of different HES formulations.17-19,23 These analyses might mask the differences between HES formulations on patients outcomes. Three meta-analyses used the same concept of pooling for the comparator group;20,21,23 the results of crystalloids and colloid fluids were pooled together as one comparator. The guideline published by Reinhart et al. was based on published systematic reviews and meta-analyses.24 The quality of evidence was incorporated in the recommendations. One potential shortcoming is that the guideline validation method was not reported, and it could not be evaluated. Examples of methods for guidelines validated are the peer review process and the collection of feedback from stakeholders, end users, or the target group of patients. Sepsis Patients The meta-analyses by Patel et al. and Haase et al. were based on systematic review of the literature and evidence evaluation.25,26 Furthermore, these two meta-analyses evaluated the effects of the length of follow-up and the HES formulation on patients’ outcomes. They also reported the fluid dose and its total volume; however, this was not factored in the analyses. One potential limitation was detected for Patel’s meta-analysis; for trials that had more than one comparator arm, the analysis considered one arm only without further explanation on how this arm was selected.25


One potential limitation could be detected in Patel’s meta-analysis.25 The analysis included four RCTs that had more than one comparator arm; however, only one arm was selected for the analyses. The selection criteria for the comparator arm from these four trials was not specified.25 The guideline published by Dellinger et al. was based on several systematic reviews and previous meta-analyses.27 The quality of evidence was incorporated in the recommendations. There were no major limitations to report for this guideline. Surgery Patients The three meta-analyses were based on systematic reviews of literature; two of them did not report if the quality of the included RCTs was evaluated.4,6 The medical condition for which fluid resuscitation was indicated was not considered in two meta-analyses.4,29 Martin’s meta-analysis reported inappropriate comparisons in which the intervention and comparator groups were compared in terms of baseline values and in terms of extreme post-intervention values separately.6 The analysis did not report the comparison of change from baseline to extreme values between the intervention and comparator groups. Summary of Findings Details on studies appraisal are tabulated in APPENDIX 4. Reports on Critically ill patients (Table 9 and Table 10) Three types of analysis were identified in the literature on critically ill patients. The first type grouped different HES formulation as one intervention, the second considered HES 130/0.4 as an independent intervention, and the third situation considered hyperoncotic HES formulation as an independent intervention. Various HES formulations Different HES formulations were analyzed together as one group of intervention. This was the case in four included meta-analyses.17-19,23 The comparator group in these meta-analyses was a mix of colloids and crytalloids,17,23 colloids only,19 or crystalloids only.18 Results of mortality showed that HES was associated with a statistically significant increased risk of death when compared with crystalloids only; the relative risk (RR) was 1.1 (95% confidence interval [CI] 1.02 to 1.19).18 This risk became statistically significant when HES was compared with either albumin or gelatin.19 The comparison with both colloids and crystalloids showed that HES was associated with a statistically increased risk of death only when trials published by Boldt’s et al. were removed from the analysis; RR 1.09 (95% CI 1.02 to 1.17).17 Renal replacement therapy was reported in two meta-analyses.17,23 The most recent one was published in 2013 by Zarychanski et al., and it included RCTs from 2012.17 Zarychanski reported that HES was associated with an increased risk of renal replacement therapy; RR 1.32 (95% CI 1.15 to 1.50).17 The second meta-analysis was published in 2010 by Dart et al.; its most recent RCTs were published in 2008.23 Dart reported that HES was not associated with statistically increased risk of renal replacement therapy; however, the subgroup analysis showed that HES increased this risk in sepsis patients; RR 1.59 (95% CI 1.20 to 2.10).23 The non-sepsis subgroup did not show a risk difference.23


Acute renal failure was also reported by Zarychanski and Dart.17,23 Zarychanski showed that HES was associated with a statistically increased risk of acute renal failure when compared with colloids and crystalloids; RR 1.27 (95% CI 1.09 to 1.47). Dart reported that HES was not associated with an increased risk of acute renal failure according to the RIFLE criteria;23 however, it was shown that, when kidney failure was evaluated as per authors’ definition, HES increased the risk of kidney failure; RR 1.50 (95% CI 1.20 to 1.87).23 Subgroup analysis showed that this risk was derived mainly for the sepsis patients subgroup; RR 1.55 (95% CI 1.22 to 1.96).23 The non-sepsis subgroup did not show a significant increase of risk.23 Zarychanski et al. reported that HES, compared to colloids and crystalloids, was associated with an increased rate of patients who needed red blood cell (RBC) transfusion; RR was 1.42 (95% CI 1.15, 1.75).17 They also reported that HES was associated with lower urine output; standardized mean difference (SMD) -0.15 (95% CI -0.19 to -0.1).17 On the other hand, the meta-analysis did not show statistical differences in terms of length of stay in intensive care unit or overall stay, major hemorrhage, or volume of transfused RBC. HES 130/0.4 HES 130/0.4 alone was compared with both colloids and crystalloids which were pooled together.20,21 Both meta-analyses by Gattas21 and Weidermann20 did not show statistically significant increased risk of mortality associated with HES. Worth mentioning that the direction of the relative risk changed from favoring HES in Gattas review21 to favoring comparators in Wiedermann analysis.20 This might be explained be the fact that Wiedermann excluded all trials published by Boldt et al. and included two additional trials; FIRST and CRYSTMAS trials. Both analyses did not include the CHEST trial which was published in November 2012 after the meta-analyses were published. Hyperoncotic HES Hyperoncotic HES (10% concentration) was compared with both colloids and crystalloids which were pooled together.22 In this 2010 meta-analysis, Wiedermann reported that HES was associated with increased risk of mortality and acute kidney injury; the associated relative risks were 1.41 (95% CI 1.01 to 1.96) and 1.92 (95% CI 1.31 to 2.81) respectively.22 The guidelines published by Reinhart et al. on the management of fluid resuscitation in critically ill patients recommended against the use of HES with molecular weight of ≥200 kDa and/or degree of substitution >0.4 in patients with sepsis.24 The guideline also recommended that the use of HES 130/0.4 should be restricted to a clinical research context for severe sepsis patients and other ICU patients with increased risk of acute kidney injury or bleeding.24 These were strong recommendations based on moderate quality evidence. Reports on Sepsis Patients (Table 11, Table 12, Table 13) Meta-analyses by Patel et al.25 and Haase et al.26 both evaluated safety outcomes associated with the use of HES 130/0.40-0.42 compared with other resuscitation fluids used in patients with sepsis.25,26 Both meta-analyses showed that the use of HES was associated with an increased risk of mortality at a follow-up longer than 28 day or at 90-day follow-up; RR were 1.11 (95% CI 1.01 to 1.22)26 and 1.13 (95% CI 1.02 to 1.25)25 respectively. This risk was not statistically significant at follow-ups below 28 days.25,26


HES 130/0.40-0.42 was also associated with an increased risk of renal replacement therapy;25,26 evaluation at anytime was associated with RR of 1.36 (95% CI 1.08 to 1.72),26 and evaluation at 90 days gave a RR of 1.41 (1.08 to 1.84).25 The guidelines published by Dellinger et al. on the management of sepsis patients reported a strong recommendation against the use of HES for fluid resuscitation in patients with severe sepsis or septic shock.27 Cost-effectiveness analysis published by Farrugia et al. showed that the use of HES for fluid resuscitation in sepsis patients was associated with unfavorable incremental cost-effectiveness ratio when compared with albumin.5 Reports on Surgery Patients (Table 14) Two systematic reviews reported that the use of HES was not associated with increased risk of adverse effects when used in surgery settings.6,29 Shi’s meta-analysis included 12 RCTs published by Boldt et al.;29 these trials had a high risk of data falsification.11,13 The meta-analysis by Navickis et al. reported that the use of HES for cardiopulmonary bypass patients was associated with increased risk of bleeding; SMD was 0.33 (95% CI 0.18 to 0.48), and reoperation due to bleeding; RR 2.24 (95% CI 1.14 to 4.40).4 This meta-analysis did not show statistically significant differences between HES and albumin in terms of fluid balance, heart rate, length of stay in the ICU or mortality.4 Limitations The included trials evaluated trials conducted on patients requiring fluid resuscitation; however, the medical conditions that cause patients to need resuscitation were not systematically considered in the analyses. The study of patients with sepsis and patients undergoing major surgeries provided clearer information about the safety of HES solutions in these two patients groups. However, conditions such as burns and trauma were not evaluated separately; therefore, the generalizability of findings to these conditions remains unclear. Furthermore, most of the included trials did not consider factors associated with fluid administration that could affect patients’ outcomes. These factors include the dose of fluid, the daily and total volume administered, and the strategy of fluid administration. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING This report aimed to evaluate effectiveness of hydroxyethyl starches used for fluid resuscitation. The clinical guidelines and cost-effectiveness of these fluids were also reviewed. A total of twelve meta-analyses, two guidelines and one cost-effectiveness study were retrieved. With respect to the effectiveness of hydroxyethyl starches, the included reports focused mainly on safety outcomes without a full assessment of efficacy. Therefore, conclusions should be made on the safety of starches rather than effectiveness. The use of hydroxyethyl starches was shown to be associated with increased risk of mortality and need for renal replacement therapy when used for fluid resuscitation of patients with severe sepsis and critically ill patients. This risk was accrued after four weeks of fluid administration. This risk could not be established in patients undergoing major surgeries, however the available evidence suggests that the use of hydroxyethyl starch in patients undergoing surgery may be associated with increased risk of


bleeding and reoperation due to bleeding. The included guidelines recommended against the use hydroxyethyl starches in patients with sepsis and other patients treated in intensive care settings who present an increased risk of renal failure. The cost-effectiveness analysis showed that hydroxyethyl starches were not cost-effective, compared with albumin, when used for fluid resuscitation in sepsis patients. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca


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28. Van der LP, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg. 2013 Jan;116(1):35-48.

29. Shi XY, Zou Z, He XY, Xu HT, Yuan HB, Liu H. Hydroxyethyl starch for cardiovascular surgery: a systematic review of randomized controlled trials. Eur J Clin Pharmacol. 2011 Aug;67(8):767-82.

30. Cramer JA, Bradley-Kennedy C, Scalera A. Treatment persistence and compliance with medications for chronic obstructive pulmonary disease. Can Respir J [Internet]. 2007 Jan [cited 2013 Mar 26];14(1):25-9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690446/pdf/crj14025.pdf

31. Bland JM, Altman DG. The use of transformation when comparing two means. BMJ [Internet]. 1996 May 4 [cited 2013 May 23];312(7039):1153. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2350653



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690446/pdf/crj14025.pdf


APPENDIX 1: SELECTION OF INCLUDED STUDIES

683 citations excluded

30 potentially relevant articles retrieved for scrutiny (full text, if

available)

3 potentially relevant reports retrieved from other sources (grey

literature, hand search)

33 potentially relevant reports

18 reports excluded: Population not of interest (1) Intervention not of interest (8) Outcomes not of interest (1) Study design not of interest (3) Duplicates (5)

15 reports included in review

713 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of the Included Systematic Reviews and Guideline 1. Critically Ill Patients Table 3. Characteristics of the Included Systematic Reviews on Critically Ill Patients (Seven Meta-analyses) Objectives/Scope Type of primary

studies Population/

Medical context Intervention Comparator Outcomes Notes

1/7. Zarychanski et al. 201317 – Meta-analysis on Critically ill Patients To evaluate the association of HES use with mortality and acute kidney injury when used for resuscitation of critically-ill patients

RCTs only • A total of 38 trials,

were included in the review; of which, 10 trials were included in the meta-analysis of Perel et al.18

• Trials were published between 1982 and 2012

• A total of 10,880 patients contributed to mortality analysis

The review included trials on critically ill adults in emergency or ICU settings. The medical condition for which patients were treatment in the ICU was not considered in the analysis

• HES o 450: 3 trials o 300-500: 1 trial o 200-300: 20

trials o 130/0.4: 11

trials o 130/0.42: 1 trial o 120/0.7: 1 trials o Unknown: 1

trial

Colloids: • Albumin: 12 trials • Gelatin: 8 trials • Plasma: 1 trial

Crystalloids: • Ringer’s solution:

7 trials • 0.9% saline: 8

trials • 4% saline: 1 trial • Hartman solution:

1 trial

• Mortality • AKI • RIFLE criteria • Urine output • ICU LoS • Overall LoS • RBC transfusion o patients o volume

The duration of follow-up or the time of outcome assessment were not considered in the analysis

Trials conducted by Boldt et al. were used as sensitivity analysis criteria

2/7. Perel et al. 201318 – Meta-analysis on Critically ill Patients To evaluate the effects on mortality of using colloids as compred to crystalloids when used for resuscitation in critically ill patients


were included in the review; of which, 25 trials evaluated HES vs. crystalloids


• HES trials included total of 9174 patients.

The review included trials on critically ill patients who require volume replacement. The medical condition for which patients were treatment in the ICU was not considered in the analysis

Colloids: • Dextran 70 • HES o 450: 2 trials o 200: 2 trials o 139/0.4: 1 trial o 130/0.4: 6 trials o 130/0.42: 1 trial o Pentastarch: 3

trials o Hetastarch: 1 trial o Haes steril: 1 trial o Unknown: 9 trials • Modified gelatine • Albumin • PPF

Crystalloids: • Isotonic • Hypertonic

• Mortality The duration of follow-up or the time of outcome assessment were not considered in the analysis

The review excluded trials on patients undergoing elective surgical patients The review excluded studies with cross-over design Trials conducted by Boldt et al. were used as sensitivity analysis criteria


Table 3. Characteristics of the Included Systematic Reviews on Critically Ill Patients (Seven Meta-analyses) Objectives/Scope Type of primary

studies Population/


AKI= acute kidney failure; HES= hydroxyethyl starch; ICU= intensive care unit; LoS= length of stay; PPF= plasma protein fraction; RBC= red blood cells 3/7. Bunn et al. 201219 – Meta-analysis on Critically ill patients To compare the effects of different colloid solution on patients’ outcome


were included in the review; of which, 53 trials compared HES with other colloids


• A total of patients contributed to mortality analysis

The review included trials on patients requiring volume replacement or maintenance of colloid osmotic pressure. The medical condition requiring volume expansion was not considered in the analysis

Colloids: • Albumin or

plasma protein fraction

• Gelatin • Dextran • HES

Colloids: • Albumin or

plasma protein fraction

• Gelatin • Dextran • HES


The review excluded trials that used colloids during plasma exchange or for priming extracorporeal circuits. The protocol reported that trials conducted by Boldt et al. will be evaluated in sensitivity analysis. However, this analysis was not included in the report.

4/7. Gattas et al. 201221 – Meta-analysis on Critically ill Patients To update the effects of HES 130/0.4 on mortality of critically ill patients


were included in the review;


• A total of 1582 patients contributed to mortality analysis

The review included trials on patients who are critically ill or undergoing major surgery, and who are requiring fluid resuscitation. Resuscitation was needed for sepsis, cardiovascular surgery, or hypovolemia

HES 130/0.4 The type of solvent was not reported The strategy used for fluid administration was not reported

Colloids: • Albumin: 8 trials • Gelatin: 10 • HES (other

formulations): 14 Crystalloids: • Ringers’ solution:

7 trials • Normal saline: 1

trial


Retracted publications by Boldt. et al. were included as sensitivity analysis

HES= hydroxyethyl starch



studies Population/


5/7. Wiedermann et al. 201220 – Meta-analysis on Critically ill Patients

To provide an update to Gattas et al.21


were included in the meta-analysis;


• A total of 1131 patients contributed to mortality analysis

The review included trials on patients who are critically ill or undergoing major surgery, and who are requiring fluid resuscitation.


Colloids Crystalloids


The review excluded all trials/ publications by Boldt et al. The review included FIRST and CRYSMAS trials; these two trials were not included in the meta-analysis by Gatta et al.30

6/7. Dart et al. 201023 – Meta-analysis on Critically ill Patients

To evaluate the effects of HES on kidney functions compared to other resuscitation fluids in different patient populations

RCTs and quasi-RCTs • A total of 34 trials,

were included in the review;


• A total of 2607 patients contributed to kidney failure analysis

The review included trials on patients who received fluids for the treatment of effective intravascular volume depletion

HES – any formulation

Colloids Crystalloids

• Need for renal replacement therapy

• RIFLE criteria • Creatinine

clearance • Glomerular

filtration rate • Serum creatinine Outcomes had to be assessed at least 24 hours after treatment

The review excluded cross-over trials and trials conducted on healthy volunteers Medical conditions requiring fluid resuscitation were classified as sepsis and non-sepsis indications; this was used as subgroup analysis



studies Population/


HES= hydroxyethyl starch 7/7. Wiedermann et al. 201022 – Meta-analysis on Critically ill Patients To evaluate the effect hyperoncotic colloids on the incidence of acute kidney injury

RCTs • A total of 11 trials,

were included in the review; 4 trials compared hyperoncotic HES with other fluids


• A total of 696 patients were included in the HES trials

The patient population was not clearly defined in the report. The included trials used fluid resuscitation for surgery (abdominal or cardiac), sepsis and hypovolemia

Hyperoncotic colloids: • 20% or 10%

Albumin • 10% HES The volume and strategy of fluid administration were not considered

Crystalloids Hypo-oncotic colloids (4% or 5% albumin) Trials that used iso-oncotic (6%) HES were excluded

• Acute kidney injury

• Mortality

Cross-over studies were not included in the review



Table 4. Characteristics of the Included Guidelines on the Management of Critically Ill Patients Objectives Methodology

Intended users/ Target population

Intervention and Practice

Considered

Major Outcomes Considered

Evidence collection, Selection and

Synthesis

Evidence Quality and Strength

Recommendation Formulation and

Evaluation

Guideline Validation

Reinhart et al. 201224 – Guidelines for the Management of Fluid Resuscitation in Critically ill Patients Intended users were not clearly defined. However, this can be deducted from the reported that this can any medical staff who is in charge or contribute in the management of fluid resuscitation of critically ill patients

Fluid resuscitation for critically ill patients

Benefits (efficacy) Risk and burden Cost

Systematic literature search for published systematic reviews, meta-analyses and health technology assessment.

Four classes of evidence were used: A: RCT or upgraded observational data B: Downgraded RCT or upgraded observational data C: Well-done observational studies or down-graded RCT D: Down-graded observational or RCT data

The recommendations were developed through a voting process to achieve consensus. Two grades for the strength of recommendations were used: Grade 1: Strong Grade 2: weak The grades were attributed for individual outcomes of interest and not for individual studies

Not reported


2. Sepsis Patients Table 5. Characteristics of the Included Systematic Reviews on Sepsis Patients Objectives/Scope Type of primary

studies Population/


1/2. Patel et al. 201325 – Meta-analysis To evaluate the safety of 6% hydroxyethyl starch when used in the treatment of severe sepsis patients

RCTs only • A total of 6 trials • Trials were

published between 2006 and 2012

• Trials were included if they reported mortality outcome at 90 days, 28 days, or another follow-up time point

Patients diagnosed with severe sepsis treated in critical/intensive care unit setting. Fluid therapy was administered for volume expansion after randomization. Trials were included if they included severe sepsis exclusively or if they presented data for sepsis patients in subgroup analysis.

HES 130/0.40 – 5 trials HES 130/0.42 – 1 trial Subgroup analysis was based on: • Starch origin: o Potato or o Waxy maize • C2/C6 hydroxylation ratio: o 6:1 o 9:1

Colloids (non-HES) • Albumin – 2 trials Crystalloids • 0.9% saline – 3

trials • Ringer’s acetate –

1 trial

• 90-day mortality • Overall mortality

at final follow-up • 28-day mortality • RRT at any time • AKI • Allogeneic

transfusion support

• Adverse events

• For trials that had more than one comparator arms, only one arm was pooled in the analysis. Full explanation for selecting the comparator arm was not provided

2/2. Haase et al. 201326 – Meta-analysis To evaluate the effects of HES 130/0.38-0.45 patients’ adverse outcomes


6 of which were included by Patel et al.25


Patients diagnosed with sepsis. A total of 3456 patients were included Trials were included if they included sepsis patients exclusively or if they presented data for sepsis patients in subgroup analysis

HES 130/0.38-0.45 • HES 130/0.40 – 6

trials • HES 130/0.42 – 1

trial The intervention period ranged from 24 hours to >90 days

Colloids (non-HES) • Albumin – 2 trials Crystalloids • 0.9% saline – 4

trials • Ringer’s acetate –

3 trials

• Overall mortality • RRT at the end of

follow-up • RRT at any time • AKI • RBC transfusion

(number of patients and total volume)

• Blood loss (number of patients and total volume)

• Number of patients having serious adverse events

AKI= acute kidney injury; RRT = renal replacement therapy


Table 6. Characteristics of the Included Guidelines on Sepsis Patients Objectives Methodology

Intended users/ Target population

Intervention and Practice

Considered

Major Outcomes Considered

Evidence collection, Selection and

Synthesis

Evidence Quality and Strength

Recommendations Formulate and

Evaluation

Guideline Validation

Dellinger et al. 201327 – Guidelines on Sepsis Management Nurses and advanced practice nurses, emergency medical paramedics, health care providers, hospitals, physician and physician assistants/ Adult and pediatric patients with severe sepsis or septic shock

To update the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock” last published in 2008.

Survival of patients and length of stay in ICU

Systematic literature searches and reviews. Several systematic reviews of the literature were performed to cover different areas of sepsis management. Developers reviewed published meta-analyses and systematic reviews as well.

Four classes of evidence were used: A: RCT B: Downgraded RCT or upgraded observational studies C: Well-done observational studies D: Case series or expert opinion

The recommendations were developed using the Delphi and nominal group technique to achieve consensus. Two grades for the strength of recommendations were used: Grade 1: Strong Grade 2: weak

Peer review process

ICU= intensive care unit;

Table 7. Characteristics of the Included Cost-Effectiveness Analysis on Sepsis Patients Objectives Intervention and Comparator Source of data and Assumptions Method of anlaysis

Farrugia et al. 20135 – Cost-effectiveness analysis To evaluate the evidence and cost-effectiveness of colloids used in sepsis

HES versus Albumin Non-systematic literature search • The analysis assumed the willingness to pay $10,000

incremental life-year gain from fluid therapy. • Post-discharge mortality rate of 23%

Decision analysis model

ICU= intensive care unit;


3. Surgery Patients Table 8. Characteristics of the Included Systematic Reviews on Surgery Patients Objectives/Scope Type of primary

studies Population/


1/3. Martin et al. 20136 – Meta-anlaysis To evaluate renal safety of the third generation HES preparation in surgery



• The length of trials was not reported

Patients undergoing elective surgery. • A total of 1230

patients The included surgeries were: • Cardiovascular –

11 trials • Abdominal and

liver – 5 trials • Spine surgery – 1

trial


Colloids: • Gelatin solution –

5 trials • Human albumin

– 3 trials • HES 200 – 4

trials Crystalloids: • Ringer solution –

4 trials • Isotonic saline –

2 trials One trial used “standard of care” as comparator

• Creatinine clearance; estimated and calculated (average of 2 days after the surgery)

• Acute renal failure

The review excluded trials on kidney transplant surgery, sepsis or trauma patients. The review excluded all trials published by Boldt et al. Two studies had 2 different comparators; the review pooled data from the different comparator arms and compared it to HES 130/0.40

2/3. Navickis et al. 20124 – Meta-analysis To evaluate the effects of HES on bleeding after CPB surgery




Adults undergoing cardiopulmonary bypass surgery. • A total of 970

patients Indication for colloid use: • Volume expansion

– 9 trials • Pump priming – 5

trials • Both volume

expansion and pump priming – 4 trials

HES: • HES 450/0.7 • HES 200/0.5 • HES 130/0.7 • HES 130/0.4 The solvent was saline in all trials except one that evaluated one arm with HES 450/0.7 in balanced electrolyte The strategy used for fluid administration was not reported

Albumin • Cumulative blood loss during the first 24 hours after CPB.

• Reoperation for bleeding and blood product transfusion during the first 24 postoperative hours

• hemodynamics • fluid balance • ventilator time • intensive care

unit stay • mortality

The review excluded trials if patients were crossed-over between the investigated interventions. Trials conducted by Boldt et al. were excluded due to the disclosed scientific misconduct. The review excluded trials if they did not report blood loss data


Table 8. Characteristics of the Included Systematic Reviews on Surgery Patients Objectives/Scope Type of primary

studies Population/


CPB= cardiopulmonary bypass; FFP= fresh-frozen plasma; HES= hydroxyethyl starch; RBC= red blood cells; 3/3. Shi et al. 201129 – Meta-analysis To evaluate the safety of HES preparations when used in cardiovascular surgery




Patients undergoing cardiovascular surgery. • A total of 3,234

patients Indication for colloid use: • Volume expansion

– 26 trials • Pump priming –

15 trials • Both volume

expansion and pump priming – 11 trials

HES: • HES 450 • HES 400 • HES 264 • HES 200 • HES 130 • HES 120 Neither molecular substitution nor the type of solvent were reported The strategy used for fluid administration was not reported

Colloids: • Albumin • Gelatin Crystalloids: • Not described Blood-based products: • Fresh-frozen

plasma

• Blood loss. • Blood transfusion

(volume and number of patients)

• Reoperation • Mortality • Renal function • Complications

The review did not specify the exclusion of cross-over trials. The review included 12 trials conducted by Boldt et al. The review excluded trials if they did not report blood loss data

CPB= cardiopulmonary bypass; FFP= fresh-frozen plasma; HES= hydroxyethyl starch; RBC= red blood cells;


APPENDIX 3: Critical Appraisal of the Included Systematic Reviews and Guideline 1. Critically Ill Patients

Strengths Limitations Perel et al. 201318 – Meta-analysis on Critically-ill Patientsa

Zarychanski et al. 201317 – Meta-analysis on Critically ill Patientsa

Bunn et al. 201219 – Meta-analysis on Critically ill patientsa

• literature search and data extraction were conducted by two investigators • Review outcomes and data to be extracted were predefined a priori • The quality of the included studies was evaluated • Trials conducted by Boldt et al. were used as sensitivity analysis criteria

• The review did not evaluate the impact of patients’ medical condition on patients’ outcome. Patients were treated in the ICU for different medical conditions, but they were considered equal in the analysis. • The review pooled different formulations of HES, and did not evaluate the effect of these formulations on patients’ outcomes • The review did not consider the impact of the solvent used with HES nor the strategy used for fluid administration. These factors might affect patients’ outcomes. • The follow-up period for patients’ outcome assessment were not evaluated.

Gattas et al. 201221 – Meta-analysis on Critically ill Patientsa

Wiedermann et al. 201220 – Meta-analysis on Critically ill Patientsa

• literature search and data extraction were conducted by two investigators • The quality of the included studies was evaluated. • Retracted publications by Boldt. et al. were included as sensitivity analysis

• The review did not evaluate the impact of patients’ medical condition on patients’ outcome. Patients were resuscitated for different medical conditions, but they were considered equal in the analysis. • The review pooled different formulations of HES with other colloids or crystalloids, and did not evaluate the effect of these comparators on patients’ outcomes • The review did not consider the impact of the solvent used with HES nor the strategy used for fluid administration. These factors might affect patients’ outcomes. • The follow-up period for patients’ outcome assessment were not evaluated.

Dart et al. 201023 – Meta-analysis on Critically ill Patients • literature search and data extraction were conducted by two investigators • Review outcomes and data to be extracted were predefined a priori • The quality of the included studies was evaluated. • The medical indication for fluid resuscitation was used as subgroups analysis. However, these were only classified to main groups of sepsis and non-sepsis indications.

• The volume and strategy of fluid administration were not taken into consideration in the analysis or results interpretation • The review pooled all HES formulations. The different comparators were pooled as well; these included colloids and crystalloids fluids. This pragmatic analysis might mask existing differences between the compared fluids in terms of patients’ outcomes.

Wiedermann et al. 201022 – Meta-analysis on Critically ill Patients • literature search and data extraction were conducted by all investigators • Review outcomes and data to be extracted were predefined a priori • The quality of the included studies was evaluated.

• The patient population was clearly defined in the review. • The review did not considered information on patients’ medical condition, fluid administration management, and the different HES formulations. These factors might affect patients outcomes


Strengths Limitations a Studies were grouped together because of the similarity of their strengths and limitations Reinhart et al. 201224 – Guidelines for the Management of Fluid Resuscitation in Critically ill Patients • The development was based on literature review of published systematic reviews and meta-analyses • The guideline was developed by individuals experienced in intensive and critical care, anesthesiology, and epidemiology • The quality of evidence was evaluated and used to support the strength of recommendations • The source of evidence was cited.

• Methods used for guideline validation were not reported


2. Sepsis Patients

Strengths Limitations

Patel et al. 201325 – Meta-analysis on Patients with Severe Spesis • literature search and data extraction were conducted by two investigators • Review outcomes and data to be extracted were predefined a priori • The quality of the included studies was evaluated. • The length of follow-up period was considered in the analysis • The review evaluated starch characteristics such as the origin and C2/C6 hydroxylation ratio; these factors were believed to affect patients outcomes • The dose and total volume of fluid administration were reported. However, this information was not taken into consideration in the analysis or results interpretation

• For trials that had more than one comparator arms, only one arm was pooled in the analysis. Full explanation for selecting the comparator arm was not provided.

Haase et al. 201326 – Meta-analysis on Patients with Sepsis • literature search and data extraction were conducted by two investigators • Review outcomes and data to be extracted were predefined a priori • The quality of the included studies was evaluated. • The length of follow-up period was considered in the analysis • The dose and total volume of fluid administration were reported. However, this information was not taken into consideration in the analysis or results interpretation

• No major limitations

Dellinger et al. 201327 – Guidelines on Sepsis Management • The development was based on several systematic reviews of the literature and previous meta-analysis • The guideline was developed by individuals experienced in intensive and critical care, emergency medicine, microbiology and infectious diseases, and sepsis management • The quality of evidence was evaluated and used to support the strength of recommendations • The source of evidence was cited, but it was not listed in full. Therefore, the inclusion of results from the most recent RCTs could not be verified.

• No major limitations

Farrugia et al. 20135 – Cost-effectiveness analysis • The analysis used decision analysis model • The analysis was not based on a

systematic review of the literature • Costs and burden attributed renal replacement therapy was not reported. • The time horizon of costs and benefits were not reported • Statistical testing for cost-effectiveness the estimates was not reported


3. Surgery Patients


Navickis et al. 20124 – MA on Cardiac Surgery Patients • literature search and data extraction were conducted by two investigators • Review outcomes and data to be extracted were predefined a priori • The review investigators contacted trials authors for additional data

• The quality of the included trials was not evaluated or considered in the interpretation of results • The review included trials that used colloids for different reasons/ indications; however, the systematic review did not evaluate the effect of each indication on the measured outcomes. • The review did not report the length of the included trials and the follow-up periods. • The review pooled the results of two arms from one trial. One arm evaluated HES 450/0.7 in balanced electrolyte; the other arm used HES 450/0.7 in saline. Pooling decision was justified by the equivalence of the mean chest tube draining. However, the mean chest tube drain was not justified or defended as an appropriate surrogate for the clinical outcomes. • The volume and strategy of fluid administration were not taken into consideration in the analysis or results interpretation • The review reported the means and standard deviations of several outcomes. These measures showed signs of severe skewness.31 The use of skewed data in the meta-analysis without adjustment is a methodological flaw.

Shi et al. 201129 – MA on Cardiac Surgery Patients • literature search and data extraction were

conducted by two investigators • Review outcomes and data to be extracted

were predefined a priori • The quality of the included studies was

evaluated. This evaluation was used a sensitivity analysis during the result interpretation.

• The review included trials that used colloids for different reasons/ indications; however, the systematic review did not evaluate the effect of each indication on the measured outcomes.

• The review did not report the length of the included trials and the follow-up periods.

• The volume and strategy of fluid administration were not taken into consideration in the analysis or results interpretation

• The molecular substitution and the carrier solvents were not reported in the review. These factors might affect the fluid behavior and patients’ outcomes.

• The review included 12 trials that present high risk of data falsification.

• The review reported the means and standard deviations of several outcomes. These measures showed signs of severe skewness.31 The use of skewed data in the meta-analysis without adjustment is a methodological flaw.



Martin et al. 20136 – Meta-analysis on Surgery Patients • literature search and data extraction were conducted by all authors • Review outcomes and data to be extracted were predefined a priori • The review excluded all trials published by Boldt et al. to avoid the potential of biased data.

• The quality of the included trials was not evaluated or considered in the interpretation of results • The review did not report the length of the included trials and the follow-up periods. • The volume and strategy of fluid administration were not taken into consideration in the analysis or results interpretation • The review compared HES 130/0.4 with other colloids including a hydroxyethyl starch and crystalloids. One trial had “standard of care” as comparator. The pooling of all these comparators might bias the results toward the null difference because of the inclusion a hydroxyethyl starch (HES 200). This starch has the potential to mimic the behavior of HES 130/0.4 due to the similar. Furthermore, the generalizability of these comparators was compromised by the ambiguous standard of care that was used as comparator in one trial. • The comparisons between HES 130/0.4 and the comparators in terms of serum creatinine, calculated creatinine, and urea were made for the value registered at baseline and for the most extreme values. The analysis did not compare the change between baseline and extreme values. This analysis makes the differences between groups at baseline, and can be considered as cross-sectional comparison rather than prospective randomized cohort comparison.


APPENDIX 4: Main Study Findings and Authors’ Conclusions 1. Critically Ill Patients Table 9. Summary of Findings from Studies on Critically Ill Patients (Seven Meta-analyses)

Main Study Findings Conclusions 1/7. Zarychanski et al. 201317 – Meta-analysis on Critically ill Patients • A total of 38 trials, were included in the review; of which, 10 trials were included in the

meta-analysis of Perel et al.18 • A total of 10,880 patients contributed to mortality analysis trials evaluated HES vs.

crystalloids. • Different HES formulations ranged in molecular weight from 450 to 120 kD; these

formulations were pooled together. No subgroup analysis was performed. • HES was compared to different colloids and crystalloids; these comparators were

pooled with no subgroup analysis • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • Fluids were used for resuscitation of patients with sepsis, burns, hypovolemia, or

trauma. These groups were analyzed collectively.

The authors concluded that the use of HES for resuscitating critically ill patients did not improve patients’ survival. When Boldt et al.’s trials were excluded, HES was associated with increased risk of mortality and acute kidney injury. Reviewer’s comments: • The medical condition, for which patients were resuscitated, was not considered in the outcome analysis. • The analysis did not consider the length of trials and follow-up periods. The strategy and volume of fluid administration was not considered in the analysis. These factors might affect patients’ outcomes.

Outcome/ subgroup

No. of trials

No. of patients

HES vs. Comparators MDa or RR (95% CI)

Mortality – all studies 35 10880 RR: 1.07 (1.00, 1.14) • Boldt’s studies removed 28 10290 RR: 1.09 (1.02, 1.17) • Boldt’s studies alone 7 590 RR: 0.91 (0.74, 1.12) Renal replacement therapy 10 9258 RR: 1.32 (1.15, 1.50) RIFLE criteria • Risk 4 8111 RR: 0.89 (0.77, 1.03) • Injury 4 8111 RR: 0.93 (0.81, 1.06) • Failure, acute 5 8725 RR: 1.27 (1.09, 1.47) • Failure, chronic 1 196 RR: 0.69 (0.23, 2.09) • Loss 3 1038 RR: 0.87 (0.34, 2.22) • End-stage 3 1038 OR: 1.00 (0.06, 15.9) Urine output, mL 11 6909 SMDb: -0.15 (-0.19, -0.1) ICU LoS, days 5 7016 MD: 0.35 (-0.20, 0.90) Overall LoS, days 6 7337 MD: 0.32 (-0.45, 0.09) Major hemorrhage 1 800 RR: 1.52 (0.94, 2.47) RBC transfusion, patients RR: 1.42 (1.15, 1.75) RBC transfusion, volume MD: 46.3 (-610.8, 703.4) a the difference was based on (HES – comparator); positive MD favors comparator b positive SMD favors HES CI= confidence interval; HES= hydroxyethyl starch; MD= mean difference; SMD= standardized mean difference

2/7. Perel et al. 201318 – Meta-analysis on Critically Ill Patients • A total of 56 trials, were included in the review; of which, 25 trials evaluated HES vs.

crystalloids. HES trials included total of 9174 patients • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • Fluids were used for resuscitation of patients with trauma, burns or surgery. These

groups were analyzed collectively.

The authors concluded that the use of HES might increase mortality. Reviewer’s comments: Same as per comments on the review by Zarychanski et al.17

Mortality No. of trials

No. of patients

HES vs. Crystalloids RR (95% CI)

All studies included 25 9174 1.10 (1.02, 1.19) Boldt et al.’s studies excluded 21 8976 Not changed


Table 9. Summary of Findings from Studies on Critically Ill Patients (Seven Meta-analyses) Main Study Findings Conclusions


3/7. Bunn et al. 201219 – Meta-analysis on Critically ill patients • A total of 86 trials were included; 53 trials compared HES with other colloids • • Different HES formulations ranged in molecular weight from 450 to 120 kD; these

formulations were pooled together. No subgroup analysis was performed. • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • Fluids were used for volume expansion; the medical conditions requiring volume

expansion was not considered in the analysis

The authors concluded that there was no evidence that one colloid is more effective of safe than any other. Reviewer’s comments: • The medical condition, for which patients were resuscitated, was not considered in the outcome analysis. • The analysis did not consider the length of trials and follow-up periods. • The strategy and volume of fluid administration was not considered in the analysis. These factors might affect patients’ outcomes.

Outcome Comparisons – Relative Risk (95% CI)

Albumin or plasma protien vs. HES Gelatin vs. HES

Mortality 31 trials/ n=1719 1.06 (0.86, 1.31)

22 trials/ n= 1612 1.02 (0.84, 1.26)


4/7. Gattas et al. 201221 – Meta-analysis on Critically ill Patients • A total of 36 trials, were included in the review; 16 of which contributed to the mortality

analysis • Trials were published between 2000 and 2010 • A total of 1582 patients contributed to mortality analysis • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • Fluids resuscitation was indicated for different medical conditions; these conditions

were not considered in the analysis

The authors concluded that the included trials were of poor quality and reported too few events to reliably evaluate the benefits/ risk of HES 130/0.4 Reviewer’s comments: Same as per comments on Bunn et al.19 Outcome/

Subgroup No. of trials

No. of patients

HES vs. Comparators RR (95% CI)

Mortality – all studies 25 1582 RR: 0.92 (0.63, 1.34) • Retracted Boldt’s

studies removed 16 1063 RR: 0.95 (0.64, 1.42)

• Retracted Boldt’s studies alone

11 519 RR: 0.73 (0.24, 2.16)

CI= confidence interval; HES= hydroxyethyl starch 5/7. Wiedermann et al. 201220 – Meta-analysis on Critically ill Patients • A total of 13 trials, were included in the review; trials were published between 2000 and

2012. o The review included the FIRST and CRYSMAS trials; these two trials were not

included in the meta-analysis by Gatta et al.30 o The review excluded all publications by Boldt et al.

• A total of 1131 patients contributed to mortality analysis • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • Fluids resuscitation was indicated for different medical conditions; these conditions

were not considered in the analysis

Authors concluded that the available evidence suggested a trend toward higher mortality among HES 130/0.4 recipients Reviewer’s comments: Same as per comments on Bunn et al.19

Outcome/ subgroup

No. of trials

No. of patients

HES vs. Comparators RR (95% CI)

Mortality 13 1131 RR: 1.25 (0.98, 1.58) CI= confidence interval; HES= hydroxyethyl starch


Table 9. Summary of Findings from Studies on Critically Ill Patients (Seven Meta-analyses) Main Study Findings Conclusions

6/7. Dart et al. 201023 – Meta-analysis on Critically ill Patients • A total of 34 trials; these were published between 1982 and 2008 • A total of 2607 patients contributed to kidney failure analysis • The length of follow-up was not considered. • The strategy of fluid administration was not considered in the analysis. The total

volume and rate of fluid administration were not evaluated. • The review evaluated the effect of the medical conditions requiring fluid resuscitation;

these were classified as sepsis/ non-sepsis and were used in subgroup analysis

Authors concluded that the potential for increased risk of acute kidney failure should be considered when using HES fluids for resuscitation, particularly in septic patients.

Outcome/ Subgroup

No. of trials

No. of patients

HES vs. Comparators MD or RR (95% CI)

Renal replacement therapy 12 1236 RR: 1.38 (0.89, 2.16) • Non-sepsis 8 487 RR: 0.44 (0.14, 1.38) • Sepsis 3 702 RR: 1.59 (1.20, 2.10) • Deceased organ donor 1 47 RR: 6.67 (0.92, 48.45) RIFLE criteria

1. Risk or worse 4 325 RR: 1.21 (0.81, 1.80) • Non-sepsis 2 185 RR: 0.88 (0.27, 2.85) • Sepsis 2 140 RR: 1.28 (0.81, 2.02)

2. Injury or worse 4 325 RR: 1.34 (0.83, 2.15) • Non-sepsis 2 185 RR: 0.81 (0.12, 5.40) • Sepsis 2 140 RR: 1.39 (0.84, 2.30)

3. Failure 4 325 RR: 1.33 (0.75, 2.36) • Non-sepsis 2 185 RR: 0.49 (0.07, 3.73) • Sepsis 2 140 RR: 1.45 (0.80, 2.64) Kidney failure 8 1199 RR: 1.50 (1.20, 1.87) • Non-sepsis 5 367 RR: 1.13 (0.57, 2.25) • Sepsis 4 832 RR: 1.55 (1.22, 1.96) Creatinine clearance 3 199 MD: 2.33 (-6.01, 10.67) Creatinine – 1 day postoperative (by fluid) 15 1084 MD: -2.29 (-6.64, 2.07)

• HES vs. albumin 8 646 MD: -2.82 (-8.38, 2.74) • HES vs. gelatine 6 418 MD: -3.28 (-10.88, 4.31) • HES vs. crystalloids 1 20 MD: 19.0 (-3.86, 41.86) Creatinine – 1 day postoperative (by patient) 15 1084 MD: -2.29 (-6.64, 2.07)

• Non-sepsis 14 914 MD: -2.06 (-6.58, 2.47) • Sepsis 2 170 MD: -5.73 (-21.95, 10.49) 7/7. Wiedermann et al. 201022 – Meta-analysis on Critically ill Patients

• A total of 11 trials, were included in the review; 4 trials compared hyperoncotic HES with other fluids

• Trials were published between 1981 and 2008 • A total of 696 patients were included in the HES trials

Authors concluded that the available evidence suggested that hyperoncotic HES might increase the incidence of acute kidney injury and death.

Outcome/ Subgroup

No. of trials

No. of patients

Hyperoncotic HES vs. Comparators OR (95% CI)

Acute kidney injury 4 696 OR: 1.92 (1.31, 2.81) Mortality 4 696 OR: 1.41 (1.01, 1.96) HES= hydroxyethyl starch; OR= odd ratio


Table 10. Summary of Findings from Guidelines on the Management of Critically Ill Patients Main Study Findings Conclusions

Reinhart et al. 201224 – Guidelines for the Management of Fluid Resuscitation in Critically ill Patients Relevant Recommendations: • The use of HES with molecular weight of ≥200 kDa and/or degree of substitution

>0.4 is not recommended in patients with sepsis (grade 1B): Strong recommendation based on downgraded RCT or upgraded observational studies

• The use of HES is not recommended in ICU patients with increased risk of acute

kidney injury (grade 1C): Strong recommendation based well-done observational studies or down-graded RCT

• The guideline recommended that the use of HES 130/0.4 should to be restricted

to clinical research context for severe sepsis patients and other ICU patients with increased risk of acute kidney injury or bleeding (grade 1C): Strong recommendation based well-done observational studies or down-graded RCT

• The use of HES or gelatin in organ donors is not recommended outside the context of clinical trials (grade 1C): Strong recommendation based well-done observational studies or down-graded RCT

Authors concluded that colloids were not recommended to be used in patients with head injury, and they suggested not use hyperoncotic solutions for fluid resuscitation.


2. Sepsis Patients Table 11. Summary of Findings from Studies on Patients with Sepsis (Two Meta-analyses)

Main Study Findings Conclusions 1/2. Patel et al. 201325 – Meta-analysis on Severe Sepsis Patients • A total of 6 trials and 3033 sepsis patients were reviewed. Of which, 1937 patients

were reported in one trial; these patients were a mix of severe sepsis and septic shock patients

• The length of follow-up was <6 days in two trials, 28 days in one trial, and 90 days in three trials

• The median hydroxyethyl starch dose exposure was 37.4 ml/kg (range 30-43 ml/kg) or 14 ml/kg/day (range 8-37 ml/kg/day)

• Fluid administration ranged from 1 to 5 days; the median was 3.5 days.

The authors concluded that the overall and 90-day mortality were significantly higher in severe sepsis patients receiving 6% tetrastarch 130 kDa solutions as part of the initial fluid resuscitation.

Outcome/ subgroups

HES 130/0.4 vs. Comparators – Relative Risk (95% CI)

Colloids Crystalloids Colloids &

crystalloids combined

90-day mortality

No trials

3 trials/ n= 2913 1.13 (1.02, 1.25)

Same as previous Maize-derived HES (C2/C6 ratio 9:1)

2 trials/ n= 2115 1.09 (0.94, 1.26)

Potato-derived HES (C2/C6 ratio 6:1)

1 trial/ n= 798 1.17 (1.01, 1.36)

28-day mortality 1 trial/ n= 56 1.73 (0.55, 5.47)

Not reported separately

3 trialsa/ n= 1049a

1.10 (0.94, 1.30)a

Overall mortality 2 trials/ n= 76 1.53 (0.66, 3.53)

4 trials/ n= 2937 1.12 (1.01, 1.24)

6 trials/ n= 3013 1.13 (1.02, 1.25)

Maize-derived HES (C2/C6 ratio 9:1)

2 trials/ n= 76 1.53 (0.66, 3.53)

3 trials/ n= 2139 Not reported

5 trials/ n= 2215 1.09 (0.94, 1.25)

Potato-derived HES (C2/C6 ratio 6:1) No trials 1 trial/ n= 798

1.17 (1.01, 1.36) Same as previous

Renal replacement No trials 2 trialsa/ n= 994a

1.41 (1.08, 1.84)a Same as previous

Allogeneic transfusion No trials 2 trials/ n= 972

1.21 (1.08, 1.36) Same as previous a CHEST trial was not included in the analysis because it reported results for all patients enrolled in to the sepsis and non-sepsis groups. 2/2. Haase et al. 201326 – Meta-analysis on Patients with Sepsis • A total of 9 trials were included; 6 trials were already included by Patel et al.25 • A total of 3456 sepsis patients were included in these trials. • The length of intervention ranged was <6 days in 6 trials, up to 90 days in two trials,

and for one trial this information was not reported • The total HES dose ranged from 2104 ml to 6383 ml • The review pooled the results of all comparators; these included albumin, Ringer’s

solution, and isotonic saline

The authors concluded that HES 130/0.38-0.45, compared with crystalloid or albumin, increased the use of RRT and transfusion with red blood cells.

Outcome/ Subgroups

No. of trials

No. of patients

HES vs. Comparators MD or RR (95% CI)

All-cause mortality 8 3414 RR: 1.04 (0.89, 1.22) <28-day follow-up 4 258 RR: 0.63 (0.35, 1.15) >28-day follow-up 4 3156 RR: 1.11 (1.01, 1.22) RRT at any time 5 NR RR: 1.36 (1.08, 1.72) Acute kidney injury 4 997 RR: 1.18 (0.99, 1.40) RBC transfusion (patients) 3 973 RR: 1.29 (1.13, 1.48) RBC transfusion (volume) MD: 65 ml (-20, 149) Bleeding (patients) 2 993 RR: 1.34 (0.81, 2.21) Bleeding (volume) MD: 26 ml (-89, 140) HES= hydroxyethyl starch; MD= mean difference; RBC= red blood cells; RR= relative risk; RRT= renal replacement therapy Table 12. Summary of Findings from Guidelines on Patients with Sepsis


Main Study Findings Conclusions Dellinger et al. 201327 – Guidelines on Sepsis Management

Relevant Recommendations: Fluid Therapy of Severe Sepsis • Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and

septic shock (grade 1B): Strong recommendation based on downgraded RCT or upgraded observational studies

• The guideline recommended against the use of hydroxyethyl starches for fluid

resuscitation of severe sepsis and septic shock (grade 1B): Strong recommendation based on the results of the VISEP, CRYSTMAS, 6S, and CHEST trials. The results of CRYSTAL trial were not considered.

• Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids (grade 2C): Weak recommendation based on well-done observational studies

The authors concluded that there were strong agreement among a large cohort of international experts regarding many strong recommendations for the best care of patients with severe sepsis

Table 13. Summary of Findings from Cost-effectiveness Analysis on Patients with Sepsis

Main Study Findings Conclusions

Farrugia et al. 20135 – Cost-effectiveness analysis • The analysis considered 15 RCTs that reported renal replacement therapy, and it

considered four studies for mortality Authors concluded that the use of albumin in septic patients, when colloid fluid therapy is indicated, shows superior cost-effectiveness to HES when all medical costs incurred from therapy associated adverse events are considered.

Outcome HES Albumin Life-years gained -0.69 0.84 Incremental life-year -1.53 Total medical costs $48,488 $20,403 Incremental costs $28,085 ICER Dominant ICER= incremental cost-effectiveness ratio


3. Surgery Patients Table 14. Summary of Findings from Studies on Patients Undergoing Surgery (Three Meta-analyses)

Main Study Findings Conclusions

1/3. Navickis et al. 20124 – MA on Cardiac Surgery Patients

• A total of 18 trials were included. • A median of 48 patients were included per trial; the total number was 970 patients • The length of follow-up was not provided • Indication for colloid use:

o Volume expansion – 9 trials; o Pump priming – 5 trials; o Both volume expansion and pump priming – 4 trials

• The review pooled the results of two arms from one trial. One arm evaluated HES 450/0.7 in balanced electrolyte; the other arm used HES 450/0.7 in saline. Pooling decision was justified by the equivalence of the mean chest tube draining.

• The strategy of fluid administration was not reported. The total volume and rate of fluid administration were not reported

The authors of the systematic review concluded that HES was found to increase postoperative bleeding, reoperation due to bleeding, and blood product transfusion when used for patients undergoing cardiopulmonary bypass. The authors recommended that HES should be avoided or used with cautious. Reviewer’s comments: The main objective of the systematic review was to evaluate bleeding after CPB surgery. The reported results showed inconsistent signs of efficacy and safety issues. The results were either favoring albumin over HES or showing no statistical difference between the two interventions. Results should be interpreted in light of the fact that the systematic review excluded trials that did not report blood loss data; therefore the efficacy results can’t be considered as comprehensive of all trials conducted in this type of population. The rates of bleeding events or blood product administration was not reported or compared. This kind of analysis gives more insights at the patient’s level.

Outcome Comparisons HES 450/0.7 vs.

Albumin HES 200/0.5 vs.

Albumin HESa vs. Albumin

Efficacy Outcomes Fluid bal. (mL): MD (95% CI)b

2 trials 212 (-361, 785)

4 trials -105 (-621, 411)

6 trials 37 (-347, 420)

Heart rate (bt/min): MD (95% CI)b

No data was presented

5 trials -2.3 (-5.5, 0.8)

6 trials -3.2 (6.0, -0.5)

Cardiac index: MD (95% CI)c

3 trials -0.06 (-0.38, 0.25)

5 trials -0.14 (-0.26, -0.03)

8 trials -0.17 (-0.24, -0.11)

MAP (mmHg): MD (95% CI)c


4 trials -2.9 (-6.3, 0.4)

4 trials -2.9 (-6.3, 0.4)

CVP (mmHg): MD (95% CI)c


5 trials -0.97 (-1.82, -0.12)

5 trials -0.97 (-1.82, -0.12)

Safety Outcomes Bleeding (vol): SMD (95% CI)b

9 trials 0.36 (0.17, 0.55)

6 trials 0.285 (0.04, 0.53)

15 trials 0.333 (0.18, 0.48)

Reoperations (n): RR (95% CI)

4 trials/ 281 patients 2.13 (0.84, 5.38)

3 trials/ 117 patients 2.38 (0.89, 6.38)

7 trials/ 398 patients 2.24 (1.14, 4.40)

RBC transf. (vol.): SMD (95% CI)b

8 trials 0.340 (0.14, 0.54)

5 trials 0.181 (-0.09, 0.45)

13 trials 0.284 (0.12, 0.45)

FFP transf. (vol.): SMD (95% CI)b

4 trials 0.256 (-0.006, 0.52)

3 trials 0.446 (0.006, 0.89)

7 trials 0.306 (0.08, 0.53)

Platelets (vol.): SMD (95% CI)b

2 trials 0.325 (0.02, 0.63)

2 trials 0.224 (-0.29, 0.74)

4 trials 0.298 (0.03, 0.56)

Ventilator time (h): MD (95% CI)b

3 trials 0.79 (-0.21, 1.8)

2 trials 0.86 (-2.74, 4.46)

5 trials 0.80 (0.17, 1.76)

ICU stay (d): MD (95% CI)b

5 trials -0.04 (-0.17, 0.09)

2 trials 0.51 (0.05, 0.96)

7 trials 0.00 (-0.12, 0.12)

Mortality (n): RR (95% CI)

2 trials 0.71 (0.16, 3.12)


3 trials 0.99 (0.27, 3.57)

a both HES 450/0.7 and HES 200/0.5 were pooled against albumin b the difference was based on (HES – albumin); positive SMD favors albumin c the difference was based on (HES – albumin); negative SMD favors albumin bal.= balance; bt/min= beats/minute; CI= confidence interval; CVP= central venous pressure; d= days; h= hours; HES= hydroxyethyl starch; MAP= mean arterial pressure; SMD= standardized mean difference; vol.= volume


Table 14. Summary of Findings from Studies on Patients Undergoing Surgery (Three Meta-analyses) Main Study Findings Conclusions

2/3. Shi et al. 201129 – MA on Cardiac Surgery Patients • A total of 52 trials were included. Nine trials were included in the MA of Navickis et al.

20124 • The total number was 3,234 patients • The length of follow-up was not provided • Indication for colloid use:

o Volume expansion – 26 trials; o Pump priming – 15 trials; o Both volume expansion and pump priming – 11 trials

• The review review included 12 trials conducted by Boldt et al.; these trials have high risk of falsification

• The strategy of fluid administration was not reported. The total volume and rate of fluid administration was not reported

Blood loss; Results presented in terms of SMDa (95% CI) and RRb (95% CI)

The authors concluded that the administration of HES preparations did not cause more renal damage, complications, reoperation or mortality than control solutions. Perioperative administration of HES preparations was comparatively safe in cardiovascular surgery. Reviewer’s Comments: The reported results do not permit the conclusion of absolute safety HES preparations, for the following reasons: • The inclusion of Boldt et al.

trials • The results of blood loss

were not consistent across the comparators and the different HES preparations.

• It was not clear from the review how blood loss assessment was done in the included trials. Information on when these bleedings occurred and their cause were not reported or discussed.

• The review did not report on how or when the renal function was assessed. Different measured are available for this assessment, and some of these measures are time-dependent.

• The collective evaluation (pooling) of all HES preparations against all comparators is a practical flaw. This is because of the different behaviour of the various HES preparations as well as the used comparators. Furthermore, this flaw was added to the fact that the volume and strategy used to administer the fluids were not reported or discussed. Therefore, the exact interventions evaluated in these trials can’t be generalised.

HES preparation Comparator Albumin Gelatin Crystalloid

HES 450 SMD (95% CI) RR (95% CI)

7 trialsc 0.47 (0.26, 0.68) 1.77 (1.15, 2.73)

1 trialc 2.07 (1.16, 2.98) 1.50 (0.29, 7.73)

5 trials 0.22 (-0.10, 0.55) Not assessable

HES 400 SMD (95% CI) RR (95% CI)

1 trial 0.87 (0.11, 1.62) Not reported

No data was presented for this comparison

1 trial 0.29 (-0.52, 1.09) Not reported

HES 264 SMD (95% CI) RR (95% CI)

3 trials 0.18 (-0.11, 0.47) Not reported


HES 250 SMD (95% CI) RR (95% CI)


2 trials 0.21 (-0.01, 0.44) Not reported

HES 200 SMD (95% CI) RR (95% CI)

7 trialsc -0.01 (-0.29, 0.28) 1.23 (0.68, 2.23)

7 trialsc 0.26 (0.02, 0.49) 1.4 (0.65, 3.00)

7 trialsc -0.20 (-0.46, 0.06) 0.58 (0.23, 1.49)

HES 130 SMD (95% CI) RR (95% CI)

7 trialsc -0.61 (-0.82, -0.40) 0.77 (0.62, 0.94)

10 trialsc -2% (-16, 12) 1.03 (0.86, 1.24)

3 trials -0.19 (-0.45, 0.08) 0.67 (0.13, 3.44)

HES 120 SMD (95% CI) RR (95% CI)




Reoperation: Relative risk (95% CI)

HES preparation Comparator Albumin Gelatin Crystalloid

HES 450 2.04 (0.52, 8.07) Not assessable 0.36 (0.01, 9.19) HES 200 Not assessable 2.25 (0.48, 10.53) 0.32 (0.03, 3.18) HES 130 0.33 (0.01, 7.89) 1.16 (0.32, 4.16) Not assessable Renal Function;

HES (all preparations) vs. All Comparators 17 trials; RR (95 CI) : 0.77 (0.35, 1.70) Mortality:

HES (all preparations) vs. All Comparators 27 trials; of which 15 trials reported no death events RR (95% CI): 0.59 (0.32, 1.09) a difference was based on (HES – Control); positive SMD favors control solution b Relative risk c Trials from Boldt et al. were included in this analysis HES= hydroxyethyl starch; RR= relative risk; SMD= standardized mean difference;


Table 14. Summary of Findings from Studies on Patients Undergoing Surgery (Three Meta-analyses) Main Study Findings Conclusions

3/3. Martin et al. 20136 – Meta-analysis on Surgery Patients • A total of 17 trials were included. • The total number of patients was 1230 • The length of follow-up was not provided • The included surgeries were:

o Cardiovascular – 11 trials/ one trial was included in Navickis et al.4, and eight trials were included in Shi et al.29

o Abdominal and liver – 5 trials o Spine surgery – 1 trial

• The review pooled the results of all comparators; these included gelatin, albumin, HES 200, Ringer’s solution, isotonic saline and “standard of care”.

• The strategy of fluid administration was not reported. The total volume and rate of fluid administration was not reported.

• The review calculated an average effect size calculated from weighted averages (+d) based on the variance of unbiased effect sizes for each trial. This method was described by Hedges and Olkin. However, this effect size was calculated for the baseline values and for the extreme values, but it is was not calculated for the difference between groups in change form baseline until the registration of the extreme values.

The authors concluded that there was no verifiable association between the administration of HES 130/0.40 and changes of serum creatinine, calculated creatinine clearance, or the incidence of acute renal failure Reviewer’s comments: The results of the meta-analysis are limited by the following: • The analysis did not

compare the changes from baseline between HES 130/0.4 and comparators.

• The analysis pooled all kinds of comparators including one HES preparation. The analysis did not take into consideration the class effect of starch fluids

• The analysis did not consider the length of trials and follow-up periods. Renal failure is a delayed adverse event which could be missed in the included trials

• The strategy and volume of fluid administration was not considered in the analysis. These factors could affect patients’ outcomes.

Outcome/ Time of assessment

No. of trials

No. of patients

HES 130/0.4 vs. Comparators +da or RD (95% CI)

Serum creatinine • Baseline 13 NR +d: -0.021 (-0.261, 0.219) • Extreme 14 NR +d: +0.068 (-0.227, 0.362) Calculated creatinine • Baseline NR 344 +d: +0.302 (-0.098, 0.703) • Extreme +d: +0.783 (-0.229, 1.795) Urea • Baseline NR 390 +d: -0.068 (-0.371, 0.236) • Extreme +d: -0.148 (-1.077, 0.782) ICU length of stay NR 723 +d: +0.113 (-0.172, 0.398) Hospital length of stay NR 940 +d: +0.212 (-0.035, 0.46) Acute renal failure 8 NR RD: 0.000298 (-0.18, 0.019) Renal replacement therapy NR 531 RD: -0.003 (-0.028, 0.022) a the effect size was based on the difference HES 130/0.4 – comparators; negative sings favors HES 130/0.4 RD= risk difference
