Characterized with more rapid restoration of hemodynamic stability, improvement of microcirculation, and attenuation of oxidative stress or inflammatory response as well, hydroxyethyl starch (HES) was commonly used for fluid therapy in patients with sepsis worldwide. However, increasing experimental data suggested that HES, even the newest generation of HES130/0.4 or 0.42 (HES130/0.4*), had toxicity potential to induce interstitial proliferation, macrophage infiltration, and tubular damage, which consequently contributed to impairment of renal function. Furthermore, several trials have currently demonstrated that compared with treatment of crystalloids, administration of HES130/0.4* for volume therapy was associated with an increased 90-day mortality, in addition to an extra need for renal replacement therapy (RRT), in patients with severe sepsis or septic shock. Accordingly, a significant concern on the safety of HES solutions for volume therapy has been seriously raised in patients with sepsis now.
However, heterogeneity was found in these randomized control trials (RCTs) reporting HES-associated excess mortality over control fluids. Inconsistent with Perner's trial for example, the Myburgh et al.'s and a recently published RCT did not demonstrate a significant increase of mortality in septic patients receiving HES130/0.4* compared with control fluids. Importantly, this heterogeneity might impact the pooled estimation of the adverse effect of HES130/0.4* on outcome in these trials. Sources for these diverging results remained unclear, but likely attributable to both study design including different disease's severity of study population, randomization as well as blinding, and protocol for fluid therapy such as highly varied indication, timing, quantity, etc. However, each of these factors has not been successfully linked with this heterogeneity by a sound data in any RCT or meta-analyses up to now. Interestedly, the administrated doses of HES as study fluid were not identical, or even incomparable in these RCTs according to the originally published data. In addition, a variety of fluid balance was followed by different study protocols for volume therapy in these trials. We, therefore, conducted a systematic review and meta-regression to determine whether the administrated dose of HES130/0.4* or delta daily fluid balance (i.e., daily fluid balance in HES group over or below control group) were proportional to the heterogeneity of HES-associated excess mortality over treatment with control fluids for volume therapy in septic patients in these RCTs.
This systematic review was performed according to Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). No Institutional Review Board approval or consents were needed for this systematic review because the data were extracted from the previously published studies.
Eligible studies were included if all criteria were met: (1) RCTs comparing 6% HES, with a molecular weight of 130 kDa and molar substitution ratio of 0.4 or 0.42 in any carrier or of any origin, with any type of fluid (crystalloids or colloids); (2) Patients aged 18 years or older; (3) Patients who were diagnosed with sepsis presented at randomization; (4) Study fluids for volume therapy was defined as fluid required to increase or maintain intravascular volume; and (5) Mortality was reported.
A literature search on three databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials) was last updated on October 10, 2014. We also hand-searched the reference lists of included trials and other systematic reviews for additional studies that met inclusion criteria. No restriction on language or publication status was applied. The search terms for HES solutions included hydroxyethyl starch, hetastarch, HES, or 130/0.4 or 0.42. The search terms for sepsis were sepsis, severe sepsis, and septic shock, while the search terms for RCT included randomized controlled trial, control clinical trial, randomized, randomly, or RCT.
Study selection and data extraction
Two reviewers independently screened the initially identified studies from the search. Full-text articles of potentially eligible studies were independently assessed against the eligibility criteria. When there was more than one paper derived from the same study, we only included the most potential eligible records considering the integrity and availability of data. The main reasons for exclusion of trials were described in Figure 1. The same two reviewers independently extracted the data from each study using European Research Council data collection form for intervention reviews of RCTs that was downloaded from Cochrane Collaboration. The following variables pertaining to patients and setting were collected: Published year, number of participating centers, total number of patients, clinical setting, protocol of fluid therapy (indication, dose, treatment duration, and comparator fluid), and major outcomes. Differences were then compared and referred to the consultants (Dr. Xiao-Xia Peng and Dr. Peng-Lin Ma) for resolution.
Calculation of the dose of hydroxyethyl starch 130/0.4*
Data about the total dose of HES130/0.4* were extracted by two authors (Dr. Ma and Dr. Peng), and expressed as mean and standard deviation (SD). When the original data were expressed as median (M) and range (minimum [Min], maximum [Max]), then mean was estimated as (Max + 2M + Min)/4 and SD was estimated as (Max − Min)/4. If median and inter-quartile range (IQR) rather than median and range were provided, we only assumed that those data had a normal distribution and the mean was similar to the median, and SD was estimated by dividing the IQR by 1.35.
Daily delta fluid balance
Daily delta fluid balance was defined as the mean of daily positive fluid balance in HES group minus that in control group within study period, based on the published data. Thus, a positive daily delta fluid balance indicated a large mean value of positive fluid balance in HES group over control group, while a negative daily delta fluid balance suggested mean value of positive fluid balance was less in HES group than control group.
Risk of bias assessment
To determine the validity of the enrolled studies, the same two reviewers independently assessed the risk of bias as advised by the Cochrane Collaboration, including the domains of randomization sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Trials with all domains assessed as low were judged to have a low risk of bias. If more than one domain was assessed as high or unclear, the trial was classified as having a high risk of bias. The trials with one domain being high or unclear were judged to have an intermediate risk of bias.
We summarized data from the included studies using Review Manager (RevMan, Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The risk ratio (RR) with 95% confidence intervals (CI) of death for 6% HES130/0.4* compared to control fluids were calculated in each trial, and then pooled via a meta-analysis with the random-effects model. Subgroup assignment was performed to determine summary effect estimates of HES130/0.4* in relation to specific comparator fluids. Then, the potential impact of trial quality and risk of bias on outcome was examined through sensitivity analysis. With Mantel–Haenszel test, statistical heterogeneity was assessed using the Chi-squared test (with significance being set at P < 0.1) and I2 statistic to estimate the total variation across studies or between the two subgroups. A meta-regression analysis was performed to examine the association between the overall mortality and the administrated dose of HES solutions or daily delta fluid balance (STATA 12 version).
Publication bias was assessed by plotting the effect size against standard error for each trial (funnel plot), and statistically examined by the Egger's test. Statistical significance was selected to be P < 0.05 for the primary analyses, as well as for meta-regression.
Figure 1 outlines the PRISMA flow diagram illustrating the results of the literature search. The search yielded 327 potential studies, of which 11 trials were eligible for the systematic review. All studies reported mortality and the total dose of HES130/0.4*. But, daily fluid balance within study days was only available in 6 out of 11 RCTs.
Characteristics of the included trials
The characteristics of the 11 enrolled trials were summarized in Table 1. A total number of 4408 patients with sepsis (ranged from 25 to 1935) were recruited in these trials. Six percent HES130/0.4 or 0.42 was used in all trials, with 0.9% normal saline (n = 4), Ringer's lactate (n = 3) or Ringer's acetate (n = 1), both 0.9% normal saline and Ringer's fluids (n = 1), and human albumin (n = 2) as control fluids.
Risk of bias assessment
The quality of included trials was detailed in Table 2. Only 5 out of 11 trials were judged to have a low risk of bias in all domains, while 3 of the left 6 trials (trial from China, Argentina, and Italy, respectively) had a high risk of bias due to nonblind and insufficient allocation concealment. Other 3 trials had an intermediate risk of bias.
Risk ratio for mortality and heterogeneity
Data were obtained from all trials including 4408 patients. The pooled RR showed no significant difference for overall mortality in patients with administration of HES130/0.4* compared with treatment of control fluids (RR: 1.02, 95% CI: 0.90–1.17; P = 0.73; I2 = 34%; Figure 2). Similarly, significant pooled RR of HES130/0.4* for mortality was demonstrated neither in comparing with crystalloids (RR: 1.01, 95% CI: 0.88–1.16; P = 0.90; I2= 42%) nor with albumin (RR: 1.64, 95% CI: 0.72–3.73; P = 0.65; I2= 0) in subgroup analysis.
Based on original data, 6 of 11 recruited trials reported an excess mortality in patients receiving HES130/0.4* in comparison with administration of control fluids (crystalloids in 4 trials and albumin in 2 trials). But, statistical significance was only emerged in Perner's trial. The other 5 trials reported a lower mortality in HES group than in control group (crystalloids in all 5 trials), but all without statistical significance. A moderate heterogeneity across recruited trials was found as assessing overall mortality (I2= 34%, P = 0.13, Figure 2). In subgroup with crystalloids as control fluids, a significant variation was demonstrated with I2= 42% (P < 0.1). However, the test for subgroup difference was not significant (χ2= 1.29, P = 0.26, I2= 22.4%).
Sensitivity and meta-regression analysis
Excluding the 3 trials with high risk of bias, sensitivity analysis revealed that the pooled RR of exposure of HES130/0.4* for mortality was still not significant in comparing with control fluids (RR: 1.06, 95% CI: 0.95–1.17; P = 0.29), although variation across studies (I2) was lowed from 34% to 16% [Figure 3].
The cumulative total doses of HES130/0.4* administrated as study fluid within study days (ranged from 1 to 7 days) were reported in all 11 trials as shown on Table 3. The dosages were ranged from 500 ± 0 in Zhu's trial (within 1-day) to 4017 ± 462 ml in Perner's trial (within 3-day). Daily delta fluid balance (predefined in methods) within the study days was extracted from the published data of 6 trials. We sent an E-mail to each of corresponding author for the other 5 articles to inquire about the fluid balance data, but failed. Daily delta fluid balance was positive from 86 to 667 ml (i.e., more positive daily fluid balance in HES130/0.4* group than in control group, mean value in the study days) in 3 trials, and negative from − 61 to − 3749 ml in other 3 trials (i.e., less positive daily fluid balance in HES130/0.4* group than in control group, mean value in the study days). Meta-regression analysis did not find a significant association between the RR for mortality and total administrated dose of HES130/0.4* (logRR = −0.124,10 + 0.000,06 × total dose of HES, P = 0.298, Figure 4). However, it demonstrated a trend of dose-effect relationship between daily delta fluid balance and RR for mortality in patients receiving HES130/0.4* for volume therapy in these trials (logRR = 0.111,77 + 0.000,39 × delta daily fluid balance, P = 0.079, Figure 5).
The funnel plot constructed with overall mortality and the result of Egger's test without significance (P = 0.31) suggested an absence of potential publication bias [Figure 6].
Different from previous meta-analyses, our results revealed that exposure of HES130/0.4* did not significantly increase the pooled RR for mortality in comparison with treatment of control fluids (crystalloids or albumin) in septic patients. We found a moderate heterogeneity in all recruited trials (I2= 34%, P = 0.73) and a significant variation across trials with crystalloids as control fluids (I2= 42%, P < 0.1). Moreover, meta-regression analysis did not determine that the total administrated dose of HES130/0.4* was the source for this heterogeneity [Figure 4]. Interestedly, daily delta fluid balance was suggested to be likely associated with mortality in patients receiving HES130/0.4* in these trials (P = 0.079, Figure 5).
As well-known, HES solutions have been identified to be renal toxicity potential in previously basic researches and clinical trials, which most likely contributes to morbidity and mortality in critically ill patients. Several previous trials have questioned the safety of HES solutions including HES130/0.4* too. However, only Perner's trial reported a significant long-term (90-day) mortality in septic patients with administration of HES130/0.4* compared with control fluids so far [Table 1]. Their data weighted the highest in both Haase's (31.3%,) and Patel's (47.3%,) meta-analyses, which was closely tied with a border significance in increasing RR of HES130/0.4* administration for all-cause mortality in subgroup of trials with low risk of bias and only for 90-day mortality, respectively. In our meta-analysis, sample size was largely expanded (n = 4408, 11 RCTs) over Haase's (n = 3414, 9 RCTs) and Patel's recruits (n = 3033, 6 RCTs) by adding updated data. However, our results did not convince Haase's and Patel's findings, but suggested that insufficient data proved HES130/0.4* administration being a significant risk factor for overall mortality in septic patients.
Trial's quality was commonly examined to determine the source of heterogeneity, which could counterbalance the effect of intervention in conventional meta-analysis. Successfully lowering the variation across studies (I2) from 34% to 16%, however, sensitivity analysis indicated that trials with high risk of bias unlikely confounded the pooled estimates for mortality in our work [Figure 3], in spite of being a significant impact on Haase's results. In addition, under predefined dose limitation (the highest dosage of 33 ml·kg−1·d−1 was used by most of study protocols), a dose-effect of cumulative HES130/0.4* administration on mortality was not demonstrated by meta-regression analysis [Figure 4]. These results indicated that certain events, rather than domains with high risk of bias in evaluating the quality of trials and the dosage of HES130/0.4* as well, were more probably associated with the divergent outcomes in these RCTs.
Interestedly, it was calculated that delta daily fluid balance (i.e., less or more positive daily fluid balance in HES130/0.4* group than in control group) was largely varied from − 3749 to + 667 ml in 6 of 11 trials during the study days. In addition, meta-regression analysis demonstrated that daily delta fluid balance was positively correlated with the RR for mortality in patients receiving HES130/0.4* for volume therapy in these RCTs (log RR = 0.111,77 + 0.000,39 × ml of delta daily fluid balance, P = 0.079, Figure 5). Furthermore, added on data of a prospective sequential comparison, the effect of delta daily fluid balance was significant (P = 0.03, not shown here). These results were alert at least for that fluid balance, an immediate consequence of fluid therapy, was more likely linked with the excess harmful effect of HES130/0.4* over control fluids on mortality. However, it was unadjusted in these RCTs.
It was well-indicated that inappropriate fluid balance has been associated with worse outcomes in patients with severe sepsis and septic shock, a very complex syndrome with high risk of death. For example, in a multicenter observational cohort including 198 Intensive Care Units (ICUs) from 24 European countries, Vincent et al. suggested that mean fluid balance within the first 72 h of ICU admission was an independent risk factor for death in septic patients, with odds ratio (OR) of 1.1 for each 1-liter increase in cumulative fluid balance. In another study, to determine the association between daily fluid balance and outcomes in critically ill patients receiving RRT, Bellomo et al. found that patients achieving a negative fluid balance had a markedly reduced risk of death at 90-day (OR: 0.31, 95% CI: 0.24–0.43; P < 0.0001). Despite the ongoing debates about whether this association represents causality or merely a marker of severity of illness indicating hemodynamic instability, it becomes widely acknowledged that patients receiving unnecessary fluids are more likely to develop complications related to fluid overload (such as tissue edema, organ dysfunction including acute kidney injury (AKI), or even death), which was tightly associated with excess mortality. In fact, the inappropriate fluid balance was highly suspected in these enrolled trials with positive daily delta fluid balance in HES group. First of all, study protocols for volume therapy had not specifically addressed the issue of preventing patients from unnecessary fluid input in these studies, although all of their protocols were claimed to follow Surviving Sepsis Campaign guidelines delivered suggestions and recommendations. In Perner's trial, for example, the baseline levels of central venous pressure, central venous oxygen saturation, and lactate in both groups suggested that most patients might not have severe intravascular volume depletion, who would be highly susceptible to fluid overload had any additional resuscitation fluids been administered. Next, the volume of accumulative fluids was reported similar or even more pronounced in HES group than the control group in these trials. In general, HES130/0.4* provided larger plasma volume expansion than crystalloids. Characterized with high incidence of, therefore, patients with severe sepsis or septic shock were more likely placed at high risk of receiving unnecessary fluids as more volume of accumulative fluids was given in HES group. Furthermore, there was no significant relationship between the daily administrated dose of HES130/0.4* and daily delta fluid balance (calculated with the data on Table 3, not shown here). It indicated that positive daily delta fluid balance was not mainly caused by the effects of HES130/0.4* on both plasma expansion and possible renal impairment (which could lead a significant decrease of urine output), but more probably resulted from unstandardized study protocol for fluid balance control. Thus, multivariate regression analysis with involved individual data of fluid balance would provide more valid information on the association of HES130/0.4* administration with mortality of septic patients in these RCTs. As a covariate, the comparable fluid balance was essential for comparing the impact of different type of fluid on mortality in septic patients.
The important limitation of this meta-analysis was that the data of either total dose of HES130/0.4* or delta daily fluid balance in HES group in these trials was not mathematical, most of the mean values were calculated from original published data with median (range, or interquartile) or estimated with optimal body weight of 65 kg from data represented with ml/kg. In addition, lack of data in 5 of 11 trials limited our meta-regression to determine the information of fluid balance confounding the harmful effect of HES130/0.4* on mortality.
In conclusion, currently significant concern has been raised on the safety of HES solutions including HES130/0.4 or 0.42 for fluid therapy in septic patients. However, HES130/0.4 or 0.42 associated excess mortality over control fluids were not demonstrated in this meta-analysis. Heterogeneity of RR for mortality was existed, which was significant in trials with crystalloids as control fluids. Meta-regression analysis did not determine a dose-effect relationship of HES130/0.4 or 0.42 with mortality, but suggested daily delta fluid balance being likely associated with mortality in septic patients receiving HES130/0.4 or 0.42 in these enrolled RCTs. Our results indicated that incomparable fluid balance was likely one of the important sources for heterogeneity of RR for mortality in these RCTs comparing HES130/0.4 or 0.42 with control fluids for volume therapy in septic patients.
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Conflicts of interest
There are no conflicts of interest.
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Edited by: Li-Shao Guo