Of special interest is renal function where the risk of renal impairment is increased: after kidney or hepatic transplantation or abdominal aortic surgery. In a trial of 80 patients undergoing renal transplantation, 40 were randomly allocated to receive a tetrastarch and 40 were given 4% succinylated gelatin,57 with volumes of colloid and red cells administered and operative duration that did not differ between the groups. After transplantation, serum creatinine, serum β2 microglobulin, urinary β2 microglobulin, and α1 microgloblulin concentration decreased similarly in the 2 groups, but BUN decreased more rapidly and urinary microalbumin reached a statistically lower concentration in the tetrastarch group than that in the gelatin group. In a trial of 40 patients undergoing hepatic transplantation, 20 patients were randomly allocated to receive either a tetrastarch or a human serum albumin.40 There were no significant differences for serum creatinine or creatinine clearance between the 2 groups. A study of 65 patients (random allocation: 32 given a tetrastarch, 33 given gelatin) with preoperative renal impairment who underwent abdominal aortic surgery found no differences between the 2 groups for postoperative serum creatinine, creatinine clearance, or urine output.51 Another study randomly allocated 21 patients to be given a tetrastarch, 21 patients to be given a pentastarch, and 20 patients to be given gelatin during aortic aneurysm surgery.41 Urinary α1 microglobulin, immunoglobulin G:creatinine ratio, BUN, and creatinine were lower in the tetrastarch group than that in the gelatin group.
Thirty-five trials with 2616 patients compared urine output after random allocation to receive a tetrastarch (1264 patients) or a comparator (1352). No study reported a statistical difference between groups. Although some trials had a relatively small sample size, none of the reported values were of sufficient magnitude to suggest that larger studies would detect a difference that might be clinically meaningful.
In summary, 24 trials evaluated the need for RRT or creatinine clearance or concentration in 1134 patients given a tetrastarch and 1177 given a comparator. There was no evidence that tetrastarch administration induced renal impairment as judged by these variables, including in subpopulations of patients at high risk for postoperative degradation of renal function.
We found that trials randomly allocating patients to receive tetrastarch just before or during surgery, or both, do not appear to indicate that tetrastarch is associated with the adverse clinical outcomes of increased blood loss, increased use of allogeneic red cells, increased incidence of renal impairment or failure, or mortality. The data failed to provide any suggestion of such adverse consequences of tetrastarch administration in the surgical environment. We assessed only trials that randomly allocated patients to receive the tetrastarch or the comparator to minimize bias, but we did evaluate both blinded and unblinded trials. Although an unblinded trial is vulnerable to greater bias compared with a blinded trial, we did not detect any difference in the results of these 2 types of studies.
It is worth noting that the duration of follow-up in the trials that we evaluated was relatively short. It is understandable that the follow-up period was limited, as most of the trials were performed before any suspicion was raised of possible long-term adverse effects. Furthermore, many of the trials examined were for regulatory purposes, and their design was driven by regulatory considerations. The relatively limited duration of reporting, in part, may account for the difference between our results of no adverse safety effects and the opposite finding of other reports, such as the recently completed so-called 6S study.13 In that trial, follow-up was for 90 days, but no differences in survival were noted until 60 days after HES administration. In addition to the issue of reporting duration and study design (a randomized clinical trial versus review of previously published studies), other important differences, such as the long-term use of large volumes of HES, likely contributed to the differing results. Patient population is perhaps the most important difference between the studies that we analyzed and the 6S trial. It is likely that the preponderance of patients we included had relatively normal, intact endovascular function and glycocalyces; the opposite is likely to have been the case in the septic shock patients studied in the 6S trial (only 45 of the 798 patients were not in septic shock at the time of enrollment, and there was no suggestion of an adverse outcome in that small subpopulation). The endovascular glycocalyx acts as a selective barrier for exchange of fluid and molecules between plasma as tissue spaces,59–61 and its degradation results in immediate tissue edema.61 Septic shock and hypoxia degrade endovascular integrity and the glycocalyx,16,62 resulting in the extravasation of large molecules and fluid from intravascular to extravascular spaces. Such substantial extravasation of HES, together with an increased need for volume augmentation, would have resulted in the loss of its intravascular colloidal function, creating a need for additional fluid therapy, and unknown consequences for abnormal amounts of extravascular HES, either or both of which could have contributed to the observed increased late mortality in the 6S trial.
A recent meta-analysis assessed 25 trials of either perioperative or acutely ill patients, attempting to discern the influence of retracted publications, apparently as a prelude to the CHEST.18 Six of the trials were in intensive care units, and 3 of those trials were in severe sepsis encompassing 101 patients of the total 1608 reviewed. We assessed considerably more trials strictly in the surgical setting, with more than 3 times as many patients. Thus, the 2 reviews differ in scope and intent.
It should be further noted that none of the trials we examined, except the 2 trials with an HBOC,34,35 had a substantial number of patients, thus limiting the power of any one individual study. However, examination of the 38 surgical trials that reported blood loss in 1602 patients treated with tetrastarch and compared with 1678 patients given a comparator and 1134 patients given a tetrastarch and compared with 1177 patients given a comparator in 24 trials in whom renal function (RRT or creatinine) was examined did not provide a hint of increased blood loss, decreased renal function, or mortality. In fact, in those trials in which the comparator fluid was either other starches or human serum albumin, the blood loss with the tetrastarches was 0.88 and 0.75 of those comparators, respectively, with 95% CIs that did not cross 1.0. In addition, the 18 trials of 2022 patients reporting data for numbers of patients transfused with allogeneic red cells (not including the 2 trials that reported “no difference” without presenting data) suggest the possibility of a lesser transfusion rate with a tetrastarch than the comparators.
Of further consideration is the reliability of the primary clinical end point we assessed for coagulation function: that of blood loss. The estimation of intraoperative blood loss is subject to interperson variability,63 and those values frequently differ from those estimated from changes in hematocrit.64 While the absolute values reported in the clinical trials we assessed might have inaccuracies, the relative values comparing tetrastarches to other fluids administered should be more reliable, as within a trial the blood losses were estimated in the same manner by the same personnel.
Only 1 study in blunt trauma patients reported a higher exposure to blood product in patients treated with HES 130/0.4 compared with those treated with NaCl 0.9%.46 In blunt trauma patients where there is more diffuse microvascular damage, adverse effects on coagulation may lead to greater blood loss and higher exposure to blood products. However, the authors (and we) could not form a conclusion regarding the influence of HES 130/0.4 on coagulopathy and bleeding in the blunt trauma patients as that particular group had a higher injury severity and the worst coagulation screen on admission, perhaps reflecting a higher incidence or severity of trauma-induced coagulopathy.19
We had decided, before analyzing the reports, not to perform a formal meta-analysis because we judged from our knowledge that the trials were too heterogeneous in design and populations studied. We did not examine the use other HES products (pentastarches and hetastarches) for use in surgery or the use of tetrastarches during other circumstances (e.g., sepsis), and thus our conclusions apply only to tetrastarches when used in the surgical setting.
In summary, we conclude that data in the peer-reviewed literature do not suggest an adverse safety signal when tetrastarches are used intraoperatively or in the immediate postoperative period or both. We did not address the continued postoperative use, as is being performed in the CHEST trial; thus, the data set we have presented here will stand separately from whatever those findings will be. The limitations (such as duration of follow-up) of the underlying data we examined suggest that it may be worthwhile to gather additional data in the postoperative period. On the basis of our inability to detect a hint of an adverse signal, at this time it would seem an inappropriate use of resources to conduct a full-scale randomized controlled trial. Rather, as hypothesis generating, it could be useful to examine existing databases or generate data in registries.
The authors thank Dr Frank Bepperling and Dr Martin Holler of Fresenius-Kabi for their careful respect of the rules established by the authors that provided the authors complete freedom and prohibited their input or influence on the process and the manuscript, for which the authors are solely responsible.
The authors are grateful to Dr Edward Burdett for having conducted the literature search and to Dr Christoph Messer and DBM Agentur Für Marketing Und Kommunikation GmbH for having organized the retrieved references and produced extracts of data contained therein.
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