Hydroxyethyl starch (HES) is a synthetic colloid used for fluid resuscitation since the 1960s. Its use is controversial. On one hand, well-designed, adequately powered clinical studies1,2 and a meta-analysis3 showed that fluid resuscitation with HES does not improve clinical outcomes. Moreover, HES impairs renal function and coagulation in patients with an increased risk of renal dysfunction and bleeding; this evidence is based on large clinical trials,2,4,5 systematic reviews and retrospective analyses,6–10 and a pharmacovigilance report.11 On the other hand, recent surveys showed that >70%–80% of respondents from anesthesia and intensive care departments in Germany and Switzerland believed that HES improves outcomes12,13 and HES is also widely used in other countries.14–17
A “third-generation” HES 130/0.4 is considered to be an improved and safer HES solution because of its altered pharmacokinetic properties with lower molecular weight (130 kd) and lower degree of substitution (0.4), which lead to less plasma accumulation and more rapid renal excretion.18 The U.S. Food and Drug Administration approved HES 130/0.4 in 2007 on the basis of accumulated clinical data.19 We have previously argued that these studies are not suitable to prove the safety of this compound because they have severe methodological limitations and are restricted to the surgical setting.20 In contrast, studies that have revealed harmful effects of HES were adequately powered randomized controlled trials (RCTs) that used longer study periods, used higher doses of study fluid, and were performed in the critical care setting.2,4,5
Our goal was to systematically assess the methodological quality of RCTs of fluid resuscitation with HES 130/0.4 in order to judge whether these studies are able to prove the safety of this compound. Harmful effects associated with HES are dose related and concern increased renal failure,2,4,5 impaired coagulation,9,11 itching, tissue storage,21,22 and increased mortality.2 Studies intending to address safety concerns should ideally use control fluids devoid of nephrotoxic effects such as crystalloids or albumin, use study periods longer than 5 days with long-term follow-ups to identify effects presumably associated with tissue storage,2 and use meaningful clinical variables with adequate statistical power.
As a secondary outcome, we intended to determine crystalloid-to-colloid volume ratios in the surgical setting. The underlying rationale for HES use is the belief, from pathophysiological inference, that intravascular volume repletion with crystalloid solutions requires 3 times as much fluid volume or even more than if colloids are used.23 This is being questioned3 because in the critical care setting, actual volume ratios were below 2 and thereby much less than expected.2,24 In the surgical setting, crystalloid-to-colloid volume ratios have not been systematically assessed.
All RCTs in adults—which used HES 130/0.4 as a therapy for the prevention or treatment of acute hypovolemia in the surgical, emergency, or critical care setting—were eligible, provided the control group received any other form of fluid therapy. Accordingly, 6% or 10% HES 130/0.4 was considered an intervention fluid, and any other colloid or noncolloid fluids were considered control fluids.
We excluded trials on hemodilution for idiopathic sensorineural hearing loss, ovarian hyperstimulation syndrome, acute stroke or brain injury, central retinal vein occlusion, diabetic ketoacidosis, hypertensive disorders of pregnancy, and extracorporeal liver support. We excluded cross-over trials, which are not suitable because of the long-lasting effects of HES and also excluded trials in which the study fluid was given to normovolemic volunteers. Because of the limited number of RCTs with older and newer starches in children and neonates and our lack of expertise in these fields, we excluded these trials. We included studies in English, German, French, Spanish, Chinese, and Russian, but excluded publications in Japanese (n = 2) for language reasons.
We searched Medline (via OVID and ISI-Web of Science), EMBASE, and the Cochrane library and in addition hand-searched reviews and our own extensive literature archive. For Medline searches we used a modification of previously published search strategies6,10 The Cochrane Central Register of Controlled Trials (CENTRAL) was searched, using the term hydroxyethyl starch. EMBASE was also searched using the terms HES 130/0.4 or Voluven. Because HES 130/0.4 was introduced in 1999, results were limited to years 1997 to 2010. The last search date was March 15, 2010 (see Appendix for the detailed search strategy and keywords). Study flow is depicted in Figure 1.
One reviewer examined the titles and abstracts of all articles returned by the search strategy to identify potentially eligible articles and compile a short list for full-text review. Full-text articles were screened by 2 reviewers, and differences were resolved by discussion. When relevant data were missing, corresponding authors were contacted by e-mail.
Data were extracted into a standardized form by 2 authors; disagreements were resolved by discussion. When there was more than 1 publication of a study, only the publication with the most complete data was included. Extracted data included clinical condition, sample size, type of control fluid, fluid volumes, fluid management, reported outcomes (see below), and study periods. Risk of bias was assessed by Jadad score,25 which includes information on reporting and conduct of randomization (0 to 2 points) and blinding (0 to 2 points) and reporting of participant withdrawal (0 to 1 point). Total scores indicate methodologic quality, with 5 denoting the highest possible quality. We further assessed sponsorship, industrial authorship (authors receiving a salary from manufacturers of the tested product), trial registration, and multicenter studies. Duration of study period was defined as the time point at which either the primary or the exploratory end points were measured.
Reported outcomes were defined as primary if they were based on an a priori sample size calculation or as exploratory when they were not.
We analyzed study data for information on safety outcomes, namely, coagulopathy, renal impairment, pruritus, tissue storage, or mortality.6,10,22,26,27
As variables of renal function, serum creatinine concentration or creatinine clearance are now being recognized by consensus as being too unspecific to assess short-term changes in the level of kidney function.28 Instead, the need for renal replacement therapy or RIFLE or AKIN (Acute Kidney Injury Network) criteria of acute kidney injury (AKI)29,30 should be used. RIFLE criteria (Risk-Injury-Failure-Loss-End Stage Renal Disease) are more specific to detect changes in renal function and provide a standardized classification system, which is now also used by the Cochrane Collaboration.6 As variables of coagulation impairment, observed or calculated blood or drainage loss are popular, but they are not standardized and may be prone to observer bias. Cochrane meta-analyses assess patient exposure to allogeneic transfusion.31,32 HES-associated pruritus is due to deposition of starch molecules in cutaneous nerves.33 It has been reported to occur dose-dependently in 12% to 42% of patients after HES administration.22 However, reliable sample size estimates for assessment of pruritus may suffer from lack of epidemiological data.34 Tissue storage may be assessed by histology35 or may be estimated indirectly as the difference between total administered amount of HES and the sum of HES remaining in plasma and excreted via the urine.36 This so-called “detection deficit” may amount to 20%–50% of the administered amount of HES with a medium degree of substitution (e.g., HES 200/0.5).36
Sample Size Calculation
HES-associated renal failure has been identified in populations with a high risk for kidney injury.2,4,5 Providing evidence of its safety in patients with less risk would require more patients. For instance, assuming a 10% baseline incidence of AKI in cardiac surgical patients,7 demonstration of a 5% difference in the occurrence of AKI would require an RCT with approximately 1000 patients (power of 80% and a 2-tailed α error of 0.05). Other sample size estimates that give an idea of the order of magnitude for different risks and populations are provided in Table 1.
Crystalloid-Colloid Volume Ratios in the Surgical Setting
We calculated the ratios of total fluid volumes administered in the crystalloid and the colloid groups of RCTs performed in the surgical setting in trials in which fluid regimen was directed to achieve a hemodynamic goal.
Data were analyzed using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL). The primary analysis of the data was descriptive, determining the proportion of studies meeting each of the criteria. Summarized fluid volumes were calculated as median values from all reported mean or median fluid volumes or from median/mean values for cumulative dose and body weight, if available. Sample size calculations were done using the statistics software R (R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2010. Available at: http://www.r-project.org).
Overview of Included Studies
A total of 558 records were identified in the first round. After screening of abstracts and removing duplicate or ineligible citations, we shortlisted 141 records for full-text retrieval and 56 RCTs remained for final analysis (Fig. 1).
Forty-five RCTs were from the elective surgical setting (cardiac surgery, n = 21; abdominal aortic surgery, n = 2; abdominal surgery, n = 12; liver transplantation, n = 2; gynecological, orthopedic, or general surgery, n = 8), and 1 was in patients receiving emergency abdominal surgery. Other studies concerned severe sepsis (n = 2), burn (n = 1), or fluid preload or acute normovolemic hemodilution before surgery or spinal or epidural block for cesarean delivery or transurethral prostatectomy (n = 7). The mean Jadad score (±SD) was 2.42 ± 1.03 in all elective surgical studies (n = 45) and 2.26 ± 0.75 in all studies of cardiac and abdominal aortic surgery (n = 23). Study characteristics and risk of bias of all 56 studies is given in Supplementary Tables 1 and 2 (see Supplementary Digital Content 1, https://links.lww.com/AA/A217).
Sample Size, Study Period, HES 130/0.4 Volumes, and Types of Control Fluids
In surgical studies (n = 45), the median number of patients in HES 130/0.4 groups was 25 (range 10 to 90), median study period was 12 hours (range 0.5 to 144), and median volume of HES 130/0.4 was 2465 (range 328 to 6229) mL (Table 2). Fifty-six RCTs had 75 control groups, because some studies used up to 3 different control fluids (Table 3 with a list of control fluids). In elective surgical studies, 40 control groups (64.5%) used 11 different kinds of synthetic colloids, mainly other starches (n = 19) or gelatins (n = 19).
Thirty-seven studies provided a primary end point with a power analysis (Table 2). Ten primary end points related to coagulation (chest tube drainage, n = 2; calculated net red blood cell loss, n = 1; thrombelastography, n = 7), and 6 primary end points related to renal function (creatinine clearance, n = 4; serum creatinine concentration, n = 1; urinary alpha1 microglobulin:creatinine ratio, n = 1). The remaining 21 primary end points did not concern safety outcomes, but related instead to comparison of required colloid volumes (volume equivalence, n = 6), interleukin-6 secretion (n = 4), cardiac output (n = 3), serum chloride concentration or base excess (n = 2), arterial blood pressure (n = 2), natriuretic peptide (n = 1), extravascular lung water (n = 1), postoperative nausea and vomiting (n = 1), and oxygen tension in deltoid muscle (n = 1). Table 4 gives an overview of primary end points and study findings.
Several studies that were not powered for such outcomes reported blood or drainage loss, transfusion of allogeneic blood products, creatinine concentrations or creatinine clearance, and survival at different time points. However, because these studies were small and heterogeneous with different control fluids and in different clinical conditions, we did not summarize these random findings. Patients with severe sepsis had a 28-day mortality of 18%, which did not differ between HES and non-HES groups;37 after emergency abdominal surgery, 30-day mortality was 1 out of 14 vs. 2 out of 15 (6% HES 130/0.4 vs. 7.5% NaCl), corresponding to an overall mortality rate of 10%.38 Two surgical studies reported itching after 15 or 30 days but found no difference between groups.39,40
Crystalloid to Colloid Ratios
The ratio of total fluid volumes required in the crystalloid or in the colloid volume groups could be derived from 5 studies with 6 fluid comparisons, which used a goal-directed fluid regimen (Table 5). All studies investigated perioperative fluid therapy in cardiac or abdominal surgery with study periods of 24 or 48 hours. In these studies, the mean crystalloid-to-colloid-volume ratio was 1.8 (SD = 0.14).
Fifty-six RCTs were identified in which third-generation 6% HES 130/0.4 was used for fluid resuscitation, mainly in elective surgery (80%). We analyzed the study design with particular regard to sample size, duration of study period, total volumes, and control fluids, because in the past, only studies that had the statistical power, used longer observation periods, higher cumulative fluid doses, and suitable controls were able to reveal harmful effects of HES.
Coagulation, renal function, pruritus or tissue storage, and mortality are the main issues in the HES safety debate.6,9,10,21,22
Studies were without exception rather small, with a median sample size of 25 patients in the intervention group and 29 patients in the control group. As we have shown by some exemplary sample size calculations in Table 1, such small sample sizes are clearly inadequate. They are also in stark contrast to the considerably greater power of trials that identified adverse effects of HES.2,5,7
Study periods were very short; the median study length in elective surgical studies was 12 hours. Clearly, this period is too short to monitor the development of effects on organ function. Studies that examined end points of renal function or coagulation mostly used nonspecific and nonsensitive variables such as creatinine clearance or serum creatinine concentration.28 It is not surprising that these outcomes did not differ between groups, except in 1 study in which the control group received a significantly higher colloid load and had a lower creatinine clearance.41 Other studies used surrogate variables such as thrombelastography or examined whether there was a difference in total volume need or immediate hemodynamic response. No study used sensitive and specific consensus criteria (RIFLE criteria and AKIN classification),29,30 as has been suggested by the authors of a recent meta-analysis on renal impairment associated with HES fluid therapy.6
In two-thirds of the studies, control fluids were synthetic colloids, i.e., other HES solutions or gelatins, which carry a similar risk profile.9,26,42 Gelatin was withdrawn from the market in 1978 in the United States because of impaired coagulation in patients.43 RCTs with gelatin are rare; therefore their use in studies of HES safety4,5 may have masked their potential for adverse renal effects. It should also be considered that similar volumes of 3% or 4% solutions (gelatins) lead to less overall colloid load than do 6% solutions (HES). There are the first reports of gelatin-associated dose-dependent renal failure in severe sepsis8,44 and acute renal failure in a patient after aortobifemoral grafting.45 In a rodent model of early sepsis, both gelatin and HES 130/0.4, but not crystalloids, were associated with tubular vesicle formation, overall increased histopathological injury score, and an increase in NGAL (neutrophil gelatinase-associated lipocalin, an early marker of kidney injury). Moreover, creatinine and urea levels increased only in the gelatin group.46
Most studies were in elective surgical patients with relatively low risk. Overall, this group of mostly low-risk patients receiving fluid therapy for elective surgery or acute normovolemic hemodilution or volume load before elective surgery contained 207 patients with HES 130/0.4 and 229 patients with crystalloids or 4% or 5% albumin (Supplementary Table 3, see Supplementary Digital Content 1, https://links.lww.com/AA/A217). These numbers are too small for a meaningful meta-analysis of mortality data, considering that in the SAFE study with 7000 intensive care unit patients, no difference in mortality rate was found between albumin and normal saline.24 Only 380 of patients in our analysisi (175 vs. 205) received cardiac or major vascular surgery, and this sample size is also too small to assess renal effects by AKI criteria (Table 1). Moreover these studies did not collect the data that would allow assessment of AKI by the RIFLE criteria.29
Only 3 studies with a total of 50 patients receiving HES related to emergency surgery or severe sepsis.37,38,47 The sepsis studies compared the effects of HES 130/0.4 or albumin 20% on extravascular lung water or hemodynamic measurements over 3 to 5 days.37,47 The study in the emergency setting had a major flaw because all 29 patients additionally received a median volume of 1000 mL gelatin in comparison with 750 mL HES in the interventional group.38 The poor database of critically ill patients is a concern because HES 130/0.4 is used widely and for longer periods of time with higher doses in these patients. Well-designed studies on the safety of HES 130/0.4 in critically ill patients are conspicuously missing. The Food and Drug Administration granted United States market approval to HES 130/0.4 in 2008 under provision of a postmarketing commitment to perform safety studies in sepsis patients.19
Lastly, the median cumulative dose of HES administered in all 56 studies was approximately 35 mL/kg. This is a very low dose, considering that side effects increase with cumulative dose2,7,22,42,48 and that HES 130/0.4 may be given in doses up to 50 mL/kg per day for an unlimited period of time. Median cumulative doses of 70.4 mL/kg 10% HES 200/0.5 and 31 mL/kg 6% HES 200/0.6 were associated with increased renal failure in septic patients,2,5 and cardiac surgical patients with AKI received 16.9 mL/kg 10% HES 200/0.45.7 Studies in which lower HES doses were used did not find evidence of renal impairment.49,50 It is not known which doses are safe. Historically, dose limits for HES were set in accordance with dose limits for dextran, because observers found that both colloids affected coagulation to a similar degree.51
It is interesting that we found a median crystalloid-to-colloid volume ratio of 1.8 in cardiac or abdominal surgical studies with goal-directed fluid management. This is the first time that this ratio was systematically investigated in surgical patients. The ratio of fluids required in crystalloid groups in comparison with colloid groups in critically ill patients is also in a similar range, having been determined as 1.3 in intensive care unit patients24 and 1.6 in sepsis patients2 on the first treatment day. Verheij et al.52 found that goal-directed fluid loading was achieved with a crystalloid ratio of 1 (in comparison with 4% gelatin), 1.1 (5% albumin), or 1.3 (6% HES) in 67 mechanically ventilated patients after cardiac or major vascular surgery without affecting pulmonary permeability or edema. Van der Heijden et al. used a similar fluid-loading protocol and reported an overall crystalloid-to-colloid volume ratio of 1.2 without a difference in pulmonary edema or injury score in 48 septic and nonseptic patients.53 Study periods in the last 2 studies were 90 minutes.
These ratios do not fit with the current teaching that at least 3 times more volume is required for adequate resuscitation in acute hypovolemia when crystalloids are used.23 The belief that resuscitation will be achieved with much less volume is a common rationale for colloid preference but, as data from critically ill and surgical patients show, this may need to be reconsidered. It has been shown that colloids in general and HES in particular do not improve mortality,2,3,24 but HES supporters still argue that administration of HES may be associated with additional benefits.54
Although cost was not an outcome in our review, the question of cost effectiveness also arises. Although HES 130/0.4 is several times less expensive than albumin, it is also several times more expensive than are crystalloids.
None of the 56 RCTs on fluid resuscitation with HES 130/0.4 was designed well enough to provide reliable outcome data on relevant issues of HES safety, in particular coagulation, renal function, pruritus and tissue storage, and mortality. Studies were underpowered with short observation periods, used an unspecific or clinically irrelevant end point, and used mostly synthetic colloids as comparators and cumulative HES 130/0.4 doses well below 1 daily recommended maximum. Notably, almost all studies were performed in patients undergoing elective surgery. The current evidence base does not support the contention that the safety risk of HES 130/0.4 is less than that of older starches. Fortunately, well-designed studies with large numbers of patients and crystalloid control fluids are now underway in critically ill patients (CHEST, clinicaltrials.gov NCT00935168; 6S, clinicaltrials.gov NCT00962156) or planned in cardiac surgical patients (clinicaltrials.gov NCT00801190). An industry-funded trial with planned 240 consecutive patients with sepsis, severe sepsis, and septic shock has been in progress since December 2007 (BaSES trial, NCT00273728), but may not be large enough to detect clinically relevant differences in important outcomes such as death and AKI.
The strengths of this systematic review include the focus on newer starches, the comprehensive search for articles, clear selection criteria, duplicate conduct of the article selection and abstraction, the clarity of the findings, and conclusions about the general methodological design as well as specific study requirements, i.e., choice or lack of end points, sample size, control fluids, observation periods, and cumulative dose, which renders the RCTs unable to detect differences in clinically important outcomes or unhelpful at measuring meaningful end points (e.g., RIFLE criteria or renal replacement therapy rather than creatinine). The study also has some limitations. We excluded 2 Japanese language trials for language reasons; however, their results would have needed to be extremely powerful to change the outcome of our analysis. RCTs in patients with stroke or brain injury were excluded (n = 4), because these administered HES for hypervolemic hemodilution, an important topic that we felt to be outside the scope of this review.
Fifty-six RCTs were identified on fluid resuscitation with HES 130/0.4. Without exception, they were designed too poorly to allow conclusions about the safety of this compound. Studies are needed that have sufficient power and sensitive clinical end points, have longer observation periods, use higher cumulative doses, and avoid synthetic colloid controls.
Volume repletion with only crystalloids required <2 times the volume used in the colloid groups. This casts doubt on the common belief that intravascular volume repletion with crystalloids in comparison with colloids requires at least 3 to 4 times larger fluid volumes.
In summary, use of HES is not associated with a considerable reduction in fluid load. Use of older HES solutions may be associated with serious side effects, and clinicians should be aware that there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies.
Name: Christiane S. Hartog, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Christiane S. Hartog approved the final manuscript.
Name: Matthias Kohl, PhD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Matthias Kohl approved the final manuscript.
Name: Konrad Reinhart, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Konrad Reinhart approved the final manuscript.
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