https://orcid.org/0009-0008-2307-9408
Figures
Abstract
Background
The outcome of patients undergoing major surgery treated with HES for hemodynamic optimization is unclear. This post-hoc analysis of a randomized clinical pilot trial investigated the impact of low-molecular balanced HES solutions on the coagulation system, blood loss and transfusion requirements.
Methods
The Trial was registered: EudraCT 2008-004175-22 and ethical approval was provided by the ethics committee of Berlin. Patients were randomized into three groups receiving either a 10% HES 130/0.42 solution, a 6% HES 130/0.42 solution or a crystalloid following a goal-directed hemodynamic algorithm. Endpoints were parameters of standard and viscoelastic coagulation laboratory, blood loss and transfusion requirements at baseline, at the end of surgery (EOS) and the first postoperative day (POD 1).
Results
Fifty-two patients were included in the analysis (HES 10% (n = 15), HES 6% (n = 17) and crystalloid (n = 20)). Fibrinogen decreased in all groups at EOS (HES 10% 338 [298;378] to 192 [163;234] mg dl-1, p<0.01, HES 6% 385 [302;442] to 174 [163;224] mg dl-1, p<0.01, crystalloids 408 [325;458] to 313 [248;370] mg dl-1, p = 0.01). MCF FIBTEM was decreased for both HES groups at EOS (HES 10%: 20.5 [16.0;24.8] to 6.5 [5.0;10.8] mm, p = <0.01; HES 6% 27.0 [18.8;35.2] to 7.0 [5.0;19.0] mm, p = <0.01). These changes did not persist on POD 1 for HES 10% (rise to 16.0 [13.0;24.0] mm, p = 0.88). Blood loss was not different in the groups nor transfusion requirements.
Citation: Eckers A, Hunsicker O, Spies C, Balzer F, Rubarth K, von Heymann C (2024) In vivo effects of balanced, low molecular 6% and 10% hydroxyethyl starch compared with crystalloid volume replacement on the coagulation system in major pancreatic surgery—a sub-analysis of a prospective double-blinded, randomized controlled trial. PLoS ONE 19(7): e0303165. https://doi.org/10.1371/journal.pone.0303165
Editor: Samuele Ceruti, Sant Anna Hospital: Clinica Sant’Anna, SWITZERLAND
Received: September 18, 2023; Accepted: April 19, 2024; Published: July 11, 2024
Copyright: © 2024 Eckers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The Tetraspan study was sponsored by B. Braun, Melsungen, Germany (sponsor-initiated trial, SIT). The implementation of the EDM technology in the department was supported by Deltex Medical by an unrestricted grant unrelated to this study. The funders had no role into or control over data collection, the analysis and interpretation of data.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Alexander Eckers, Oliver Hunsicker and Kerstin Rubarth have declared that no competing interests exist. Claudia Spies has received research funding from B.Braun during the study DOI: 10.1097/MD.0000000000010579. Outside the submitted manuscript she has received research funding and honoraria from German Research Society (DFG), German Aerospace Center (DLR), Einstein Foundation Berlin, German Federal Joint Commitee (G-BA), Inner University grants, Project Management Agency (DLR), Stifterverband, European Society of Anaesthesiology and Intensive Care, German Federal Ministry of Economic Affairs and Climate Action, Georg Thieme Verlag, Dr. F. Köhler Chemie GmbH, Sintetica GmbH, Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., Stifterverband für die deutsche Wissenschaft e.V./Metronic, Philips Electronics Nederland BV, BMBF/RKI, G-BA Innovationsfonds outside the submitted work. In addition, Dr. Spies has following patents licensed: 10 2014 215 211.9; 10 2018 114 364.8; 10 2018 110 275.5; 50 2015 010 534.8; 50 2015 010 347.7; 10 2014 215 212.7. Felix Balzer has received research grants from Einstein Foundation, German Federal Ministry of Education and Research, German Federal Ministry of Health, Berlin Institute of Health, Hans Böckler Stiftung, Berlin university Alliance, as well as honoraria from Medtronic, GE outside this work. Christian von Heymann has received honoraria from Artcline GmbH, CSL Behring, Daiichi Sankyo, HICC GbR, Mitsubishi Pharma, Novo Nordisk, Sobi Pharma and Shionogi Pharma that were not related to the topic of this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
During major surgery, adequate fluid and volume therapy is a cornerstone to maintain hemostasis, blood volume and reduce perioperative complications [1–4]. Hydroxyethyl starch (HES) was used for years to maintain intravascular volume because of a longer volume expansion effect as compared to crystalloids [5]. Compared to older HES preparations, modern low molecular weight solutions show less side effects on the coagulation system, such as dilutional coagulopathy [6], induced von Willebrand disorder [7] or dysfunction in fibrin polymerisation [8, 9]. Most of this evidence generates from in vitro studies, which may not fully reflect the effect of the biological environment on hemostasis in the clinical setting [10, 11].
Of note the U.S. Food and Drug Administration and the European Medicines Agency (EMA) recommend to avoid HES solutions in critical ill patients since 2013 due to an increased risk for acute kidney injury and mortality [12, 13]. After strengthening this statement in 2018, the EMA now has completely lifted the approval after an ongoing clinical overuse [14, 15]. However, recent data suggest that these results must not be generalized to patients undergoing major surgery [16–18].
This subanalysis of a previously published, prospective, randomized, double-blinded study on HES and renal function in patients undergoing major abdominal surgery [19] focuses on the effect of HES solutions on the coagulation system in pancreatic surgery, for which reliable data from randomized controlled clinical trials are scarce.
We hypothesized that balanced low molecular HES solutions, irrespective of their concentration (iso oncotic 6% versus hyper oncotic 10%), and used within a goal directed hemodynamic optimization algorithm [4, 19] to improve surgical outcomes, will impair the coagulation system more severely as compared to crystalloids in the clinical setting of pancreatic surgery. Furthermore, it is hypothesized that this effect will be greater in a 10% HES than in a 6% HES solution.
Methods
Ethics and study registration
Ethical approval for this study (No. ZS EK 11026/09) was provided by the ethics committee of Berlin (Ethik-Kommission des Landes Berlin), Germany (Chairman Dr. C. von Dewitz) on 25th February 2009. The Trial was registered: EudraCT 2008-004175-22; ClinicalTrials.gov: NCT01117649, principal investigator: Christian von Heymann, 25.02.2009.
Setting and intervention
The presented study is a predefined subanalysis of a randomized, double blind controlled pilot trial comparing a hyperoncotic balanced 10% HES 130/0.42 solution (Tetraspan 10%®, B. Braun, Melsungen, Germany), an isooncotic balanced 6% HES 130/0.42 solution (Tetraspan 6%®, B. Braun) or a balanced crystalloid (Sterofundin ISO®, B. Braun) within a goal-directed hemodynamic algorithm to improve surgical outcomes in patients undergoing pancreatic surgery. This subanalysis investigates the impact of low molecular HES solutions on the coagulation system that was not reported in the previous publication of the main study. Study design, interventions and patient enrollment have been described earlier [19].
Between June 2010 and July 2012 the study was conducted in three German hospitals. Patients between 18 and 80 years, scheduled for elective surgery of the pancreatic head were enrolled. Compromised hemostasis as seen as a reduced prothrombin time ratio<60%, impaired liver function of Child Pugh C severity or a known bleeding disorder were part of the exclusion criteria. Written informed consent was obtained from all patients before surgery who were independently randomized into three groups in a 1:1:1 ratio to either receive a hyperoncotic balanced 10% HES 130/0.42 solution, an isooncotic balanced 6% HES 130/0.42 solution or a balanced crystalloid.
The perioperative care followed the standard operating procedures of each study site. For the hemodynamic management an esophageal Doppler monitored (EDM, CardioQ-ODMTM, Deltex Medical, Chichester, UK), goal-directed hemodynamic algorithm guided the application of the study solutions as described earlier [4, 19]. Transfusion of packed red blood cells were triggered by a hematocrit < 25% or in case of severe bleeding according to physician’s judgement.
Reaching the maximum dose for HES 10% of 30 ml kg-1 body weight (BW), the following, still blinded study medication was balanced crystalloid solution until a maximum of 50 ml kg-1 BW was reached. Thereafter, the protocol switched to open labeled balanced crystalloid solution. In analogy, we used open labeled balanced crystalloid solution after reaching a maximum dose of 50 ml kg-1 BW of either HES 6% or balanced crystalloid solution.
Trial endpoints
The endpoints of this subanalysis that described the effects of the study solutions on the coagulation system were the activated partial thromboplastin time (aPTT, reference range: 26-36s), prothrombin time ratio (PTR, reference range: 70–130%), fibrinogen (reference range: 2.0–4.0g dl-1), platelet count (reference range: 150-400nl-1), von Willebrand factor antigen (vWF-Ag, reference range: 50–170%), ristocetin cofactor (vWF-RiCo, reference range: 50–150%) and factor VIII activity (reference range: 70–200%). Additionally, we measured rotational thromboelastometry (ROTEM®delta, Tem innovations GmbH, Munich, Germany) focusing on coagulation time (CT, reference range: 38-79s) and maximum clot firmness (MCF, reference range: EXTEM® 50-72mm; FIBTEM® 9-25mm) in EXTEM® and FIBTEM® as point-of-care testing. Furthermore, the volume of blood loss was measured by surgical suction device and the number of transfused packed red blood cells were calculated.
Blood samples were drawn into either tri-sodium-citrate-buffered or EDTA-buffered tubes (Vacutainer®, Becton Dickinson, Heidelberg, Germany) at three time points (1.) prior to the first application of the study medication (baseline, BL); (2.) at the end of surgery (EOS) and (3.) in the morning of the first postoperative day (POD 1) except for fibrinogen. All coagulation measurements were performed by the local laboratory immediately after blood sampling.
Statistical analysis
After an interim analysis of the first 60 patients included in the pilot phase of the index study, a new sample size calculation was done without unblinding based on the pool standard deviation of HES solution administered. This sample size calculation resulted in a need for 753 patients in each group. In consequence, we followed the recommendation of an independent data monitoring committee (IDMC) and terminated the study after including 63 patients.
Data was analyzed descriptively; metric variables are presented as medians with 25%/75% quartiles. Categorical variables are characterized by absolute and relative frequencies. In order to model the two-way factorial design we applied linear mixed model analysis, with time and type of solution as fixed factors as well as with the patient identifier as a random factor with subsequent Tukey-type multiple comparison tests (R-packages “lme4” and “lsmeans”), which adjust for multiple testing within an endpoint. However, due to the exploratory nature of this study, we did not control for multiplicity over all endpoints simultaneously Hence, p-values are interpreted as hypothesis generating, not in a confirmatory manner. We considered a p-value < 0.05 as statistically significant. Blood loss was analyzed with pairwise Wilcoxon rank sum tests due to its skewed distribution. Transfusion requirements were only reported descriptively since few patients required transfusion.
Results
Until study termination, 217 patients were screened. 63 of them fulfilled inclusion criteria and gave their written informed consent to participate. After excluding 11 patients due to not having received study medication (n = 2), change of intraoperative procedure (n = 7), loss of reports (n = 1) or wrong application of the study medication (n = 1) (a total of 52 patients remained for statistical analysis (HES 10% (n = 15), HES 6% (n = 17) and crystalloid (n = 20) (Fig 1).
Neither basic patient characteristics nor indication for surgery showed any significant differences between the study groups. Basic intraoperative data including volumes of study drugs and fluid requirements were not different between the groups (Table 1).
Regarding the outcomes Table 2 shows standard parameters of the coagulation system as PTR, aPTT, fibrinogen and platelet count in the intergroup analysis. We measured a decrease of the PTR for both HES groups at EOS compared to crystalloid, while the results of both HES groups were not different at EOS. An increase in the aPTT and a decrease of fibrinogen was measured only for HES 6% vs. crystalloid at EOS. On POD 1 there were no more differences for PTR and aPTT between the groups. The platelet count was not different in the intergroup comparison.
In the subgroup analysis over time (Table 3), we noted decreases for PTR and fibrinogen between baseline and EOS as well as for BL to POD 1 for all study drugs. Furthermore we measured an increase in aPTT except for the crystalloid group in the comparison between BL and EOS. PTR and aPTT were significantly altered in the EOS to POD 1 comparison in the crystalloid group only. PTR decreased below the reference range on POD 1 for the crystalloid group, and at EOS and POD 1 for both HES groups, while aPTT remained within the reference range for all groups and time points.
Platelet count showed in the BL to EOS comparison a decrease for both HES groups, while in the BL to POD 1 comparison the decrease was significant for the HES 6% and the crystalloid group. At any time point it remained within the reference range for all solutions.
Fig 2 shows the results of the ROTEM® measurements as CT and MCF for the EXTEM® and MCF for the FIBTEM® assays between the study groups and over time:
The CT EXTEM® was significantly prolonged for the HES 10% group compared to the other groups at EOS and in the baseline to EOS comparison over time. This effect did not last on POD 1 in the HES 10% group. Crystalloid and HES 6% volume replacement exerted no changes on the CT EXTEM® over time.
CT = clotting time, MCF = maximum clot firmness, HES = hydroxyethyl starch, a: p<0.05 vs. baseline, b: p<0.05 vs. end of surgery, c: p< 0.05 vs. crystalloid, d: p< 0.05 vs. HES 6%.
The prolongation in CT EXTEM® for HES 10% exceeded the reference range at EOS, while all other values remained in the reference range at all time points.
In the intergroup comparison of the MCF EXTEM® there was only a decrease at EOS for the HES 10% group compared to crystalloids. The MCF EXTEM® showed significant decreases in both HES groups in the baseline to EOS comparison and a significant increase for the HES 6% group in the EOS to POD 1 comparison. On POD 1 the MCF EXTEM® was no more different in the baseline to POD 1 comparison in all groups. No significant changes were noted for the crystalloid group.
For the MCF FIBTEM® significant decreases were measured for both HES groups for the comparison of baseline to the EOS time point, which was not significant compared to crystalloid at the end of surgery. On POD 1 the MCF FIBTEM® increased for all solutions. This increase was significant for HES 10% for the EOS to POD 1 comparison, but not for crystalloid or HES 6%. In the HES 6% group the MCF FIBTEM® remained significantly smaller on POD 1 compared to baseline, while the MCF returned close to baseline values in the crystalloid and HES 10% group.
For the MCF EXTEM® all values remained in the reference range on all time points, while the MCF FIBTEM® decreased in both HES groups under the reference range at EOS.
Tables 4 and 5 describe the results of the von Willebrand parameters: in the intergroup analysis (Table 4) significantly decreased activities of vWF-RiCo were measured for both HES groups at the EOS time point compared to crystalloids as well as a significantly decrease of vWF-Ag and factor VIII activities for HES 6% versus crystalloids. On POD 1 all parameters were no more different between the groups.
In the analysis over time (Table 5) the crystalloid group and both HES groups showed a significant increase in the activity of vWF-AG and vWF-RiCo in the baseline versus POD 1 and EOS versus POD 1 analysis. FVIII activity showed a different pattern with a significant decrease from baseline to EOS and a significant increase in the EOS to POD 1 comparison for both HES groups while factor VIII activity showed a significant increase from BL to POD 1 in the crystalloid group.
Intraoperative blood loss was not significantly different between the groups (Table 6).
Intraoperative only 4 patients received packed red blood cells (PBRC) in the crystalloid group, while in both HES groups 6 patients received PRBC. Of these patients only 1 patient in the crystalloid group and 2 patients in each HES group received PRBC postoperative. For the transfusion of fresh frozen plasma (FFP) there were 6 patients in the crystalloid group and 4 patients in each HES group who received FFP during surgery. Postoperative only 1 patient received FFP in the HES 10% and in the crystalloid group and 2 patients in the HES 6% group.
Discussion
The main findings of the presented study are that (1) significant impairments in certain parameters of the coagulation laboratory after major abdominal surgery were found in patients receiving balanced 6% and 10% HES solutions used in a hemodynamic optimization protocol and dosed until the maximum daily dose was reached as compared to crystalloids; (2) that these changes either normalized or remained stable on POD 1 with the exception of the MCF in the HES 6% group which remained significantly reduced compared to baseline and EOS; and (3) that, intraoperative blood loss was not significantly different between the study groups.
In recent years the effect of different volume replacement solutions on the plasmatic coagulation system focused on in vitro studies using point of care devices (thromboelastometry or thromboelastography) or in vitro studies [20, 21]. The drawbacks of these studies are the missing or reduced effects of the biological environment (missing endothelial response to trauma, activation of the plasmatic coagulation system, increase in coagulation factor activities and platelet numbers after surgery) [22] and the lack of clinical consequences of hemodilution, e.g. blood loss and transfusion requirements, so that the discussion of our results mainly refers to clinical studies.
A meta-analysis of in vivo studies investigated the effect of HES based volume replacement on clinical outcomes [23]: for non-cardiac surgery there was a more pronounced reduction in maximum amplitude as measured by thromboelastography using HES solutions, which corresponds well with our findings for the EOS time point. However, a significantly higher blood loss and transfusion requirement after receiving HES-based solutions (including low molecular weight HES) versus crystalloid in non-cardiac surgery was reported. The difference to our results may be explained by using a hemodynamic optimization protocol for the study solutions and packed red blood cells and fresh frozen plasma to prevent an uncritical volume and blood product replacement.
An earlier prospective, randomized, double-blinded study investigated the effects of acute hypervolemic fluid infusion (AFHI) with 30ml/kg HES 6% (130 kD) and Ringer’s Lactate during gastrectomy [24]. Similar to our findings the authors described significant changes over time for both groups and for the PT after AFHI, but without difference in the intergroup comparison after 4 hours. Thromboelastography showed a significantly reduced clot firmness and prolonged reaction time for HES after AFHI, but did not compare differences between the groups. Different to our study, this study did not measure differences in vWF-Ag levels and a decreased factor VIII activity. Despite these changes, the intraoperative blood loss was–similar to our study—not different between the study groups.
However, due to the short observation period this study did not monitor the further course of the coagulation parameters, e.g. increase in coagulation parameters on the first postoperative day and the postoperative blood loss.
Another prospective, randomized clinical study of 66 orthopedic patients undergoing greater spine surgery investigated the effects of volume replacement with HES 6% (130 kD) versus Ringer’s Lactate solution [25].
Similar to our findings the authors showed a significant prolongation for the aPTT in the intergroup comparison at 3 hours after start of surgery. This difference persisted for 6 hours after start of surgery, which is confirmed by our results at the EOS time point, and supports a transient effect of HES solutions on coagulation parameters.
The results of their thromboelastometric analysis are, in part, in line with our results showing no difference between HES 6% and crystalloid on the CT EXTEM®. The decrease in MCF FIBTEM® and factor VIII activity in both HES groups at the end of surgery was confirmed by Mittermayr for the time point 3 hours after start of surgery.
However, our results describe a significant decrease in Ristocetin-cofactor activity, MCF FIBTEM® and factor VIII activity, that remained either unchanged (or not measured) in the work of Mittermayr [25]. This may be explained by a smaller infusion volume of HES as compared to our study. The calculated blood losses between the groups were not different in this study, however the HES group received more red cell transfusion than the crystalloid group. This finding is not supported by our results, which may be explained by the avoidance of unnecessary volume replacement by the use of a hemodynamic optimization protocol in our study. Despite a recent published meta-analysis also showed a higher need in intraoperative blood transfusions when using HES solutions for volume replacement [26].
The clinical data on the impact of 10% HES on the coagulation system is still rare. Shin et al. compared in a blinded randomized clinical trial for patients undergoing hip arthroplasty three different HES solutions (Pentastarch 10% 260/0.45; Tetrastarch 6% 130/0.4 either in 0,9% saline or balanced electrolyte solution) [27]. They showed a reduced platelet count directly after as well as on the second day after surgery. All groups showed a reduced PTR, but only the 10% pentastarch and the saline based 6% HES solution showed a prolonged aPTT after surgery. Also MCF FIBTEM® and MCF EXTEM® were reduced at the end of surgery in all groups. For these parameters the changes were significantly more pronounced in the HES 10% group. In contrast, our results do not confirm a difference between balanced HES 6% and HES 10% solution at the EOS time point. Moreover, our results suggest a transient impact of starch solutions on coagulation parameters and clot strength at the end of surgery, as the coagulopathic effect of the investigated HES solutions remained stable on the first postoperative day and was not associated with significantly different blood losses or transfusions requirements.
With regard to the effect of HES on the von Willebrand-system and factor VIII, the triple-blinded randomized clinical trial by Arellano et al. showed a decrease in vWF-Ag and factor VIII-activity after infusion of up to 45ml/kg of 10% HES (264/0.45) against 5% albumin solution over time [28]. Our data confirm a decrease of vWF-Ag, vWF-RiCo and factor VIII-activity at the end of surgery, that was no more different on the first postoperative day, which suggest either a transient impact of the HES solutions on these parameters or a postoperative acute phase reaction with release of FVIII and von Willebrand factor from the endothelium [29]. Unfortunately no postoperative coagulation data are reported by Arellano et al. so that the time course of the coagulopathic effect of HES cannot be assessed.
Limitations
The major limitation of this analysis is the small number of participants due to the early stop of enrollment for futility. Out of this reason the results should be regarded as exploratory and hypothesis-generating only, but may serve as a basis for larger trials in the future. Furthermore, our data from surgery of the pancreatic head may not be generalizable to other major abdominal surgeries with less trauma and blood loss, but may well work as a model for major surgeries with higher blood loss and transfusion requirements.
Moreover, the volume replacement following the hemodynamic optimization algorithm was only performed during surgery and not continued in the ICU. However, the attending intensivists of the postoperative ICU were aware of the study enrollment and the aim of the study but not of study group allocation. The measurements of coagulation parameters were not continued after POD 1 and did not comprise parameters of the endothelial activation, so that a prolonged impact of the study solutions on the coagulation system and the endothelium could not be assessed.
The strengths of our study are that we used a double-blind prospective setting to avoid confounding, used two different HES concentrations and a crystalloid control group and applied a goal-directed optimization algorithm to prevent uncritical infusion of HES solutions in clinical practice in a fairly homogenous group of patients and a standardized surgical procedure. Moreover, we used a variety of coagulation parameters that included parameters of the standard coagulation laboratory, of the von Willebrand-system and thromboelastometric analyses to provide a broad assessment of the impact of different HES solutions on the coagulation system.
Conclusion
Our data suggest that volume replacement with low molecular 6% and 10% HES for major pancreatic surgery stronger deteriorates the standard and point of care parameters of the coagulation system compared to crystalloid solutions. This effect was statistically significant at the end of surgery, but no more on the first postoperative day. This may be interpreted as a transient effect of low-molecular 6% and 10% HES preparations on the coagulation system that did not result in increased blood loss or transfusion requirements.
Supporting information
S1 Checklist. Reporting checklist for randomised trial.
https://doi.org/10.1371/journal.pone.0303165.s001
(DOCX)
Acknowledgments
The authors would like to thank M. Helfer, MD, T. Henze, MD, S. Herz, MD, U. Wittkowski, MD, J. Werner, MD, for their help with the study and K. Goerlinger, MD, for the critical discussion and interpretation of the results.
References
- 1. Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, et al; Australian and New Zealand College of Anaesthetics Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med. 2018 Jun 14;378(24):2263–2274.
- 2. Lassen K, Soop M, Nygren J, Cox PB, Hendry PO, Spies C, et al; Enhanced Recovery After Surgery (ERAS) Group. Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations. Arch Surg, 2009 Oct;144(10):961–9. pmid:19841366
- 3. Rahbari NN, Zimmermann JB, Schmidt T, Koch M, Weigand MA, Weitz J. Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery. Br J Surg. 2009 Apr;96(4):331–41. pmid:19283742.
- 4. Feldheiser A, Pavlova V, Bonomo T, Jones A, Fotopoulou C, Sehouli J, et al; Balanced crystalloid compared with balanced colloid solution using a goal‐directed haemodynamic algorithm. Br J Anaesth. 2013 Feb;110(2):231–40. pmid:23112214
- 5. Joosten A, Delaporte A, Ickx B, Touihri K, Stany I, Barvais L, et al. Crystalloid versus Colloid for Intraoperative Goal-directed Fluid Therapy Using a Closed-loop System: A Randomized, Double-blinded, Controlled Trial in Major Abdominal Surgery. Anesthesiology. 2018 Jan;128(1):55–66. pmid:29068831
- 6. Gandhi SD, Weiskopf RB, Jungheinrich C, Koorn R, Miller D, Shangraw RE, et al. Volume replacement therapy during major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology. 2007 Jun;106(6):1120–7. pmid:17525586
- 7. de Jonge E, Levi M, Büller HR, Berends F, Kesecioglu J. Decreased circulating levels of von Willebrand factor after intravenous administration of a rapidly degradable hydroxyethyl starch (HES 200/0.5/6) in healthy human subjects. Intensive Care Med. 2001 Nov;27(11):1825–9. pmid:11810130
- 8. Nielsen VG. Colloids decrease clot propagation and strength: role of factor XIII-fibrin polymer and thrombin-fibrinogen interactions. Acta Anaesthesiol Scand. 2005 Sep;49(8):1163–71. pmid:16095459
- 9. Fries D, Innerhofer P, Klingler A, Berresheim U, Mittermayr M, Calatzis A, et al. The effect of the combined administration of colloids and lactated Ringer’s solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG). Anesth Analg. 2002 May;94(5):1280–7, table of contents. pmid:11973205
- 10. Scharbert G, Kozek-Langenecker S. Limitations of in vitro experiments on hydroxyethyl starch solutions. Anesth Analg. 2007 Sep;105(3):885; author reply 885–6. pmid:17717268
- 11. Kozek-Langenecker S.A. and Scharbert G. Effects of hydroxyethyl starches on hemostasis. Transfusion Alternatives in Transfusion Medicine 2007, 9: 173–181.
- 12. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901–11. pmid:23075127
- 13. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, et al; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124–34. pmid:22738085
- 14. Bundesinstitut für Arzneimittel und Medizinprodukte. Risikoinformation 2018. Available from https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2018/rhb-hes.pdf?__blob=publicationFile
- 15. Bundesinstitut für Arzneimittel und Medizinprodukte. Risikoinformation 2022. Available from https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2022/rhb-hes.pdf?__blob=publicationFile
- 16. Kabon B, Sessler DI, Kurz A; Crystalloid–Colloid Study Team. Effect of Intraoperative Goal-directed Balanced Crystalloid versus Colloid Administration on Major Postoperative Morbidity: A Randomized Trial. Anesthesiology. 2019 May;130(5):728–744. pmid:30882476
- 17. Gillies MA, Habicher M, Jhanji S, Sander M, Mythen M, Hamilton M, et al. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth. 2014 Jan;112(1):25–34. pmid:24046292
- 18. Futier E, Garot M, Godet T, Biais M, Verzilli D, Ouattara A, et al. Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial. JAMA. 2020 Jan 21;323(3):225–236. pmid:31961418
- 19. Werner J, Hunsicker O, Schneider A, Stein H, von Heymann C, Freitag A, et al. Balanced 10% hydroxyethyl starch compared with balanced 6% hydroxyethyl starch and balanced crystalloid using a goal-directed hemodynamic algorithm in pancreatic surgery: A randomized clinical trial. Medicine (Baltimore). 2018 Apr;97(17):e0579. pmid:29703051
- 20. Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review. Intensive Care Med. 2011 Nov;37(11):1725–37. pmid:21989733
- 21. Casutt M, Kristoffy A, Schuepfer G, Spahn DR, Konrad C. Effects on coagulation of balanced (130/0.42) and non-balanced (130/0.4) hydroxyethyl starch or gelatin compared with balanced Ringer’s solution: an in vitro study using two different viscoelastic coagulation tests ROTEMTM and SONOCLOTTM. Br J Anaesth. 2010 Sep;105(3):273–81. Epub 2010 Jul 21. pmid:20659913.
- 22. Tuma M, Canestrini S, Alwahab Z, Marshall J. Trauma and Endothelial Glycocalyx: The Microcirculation Helmet? Shock. 2016 Oct;46(4):352–7. pmid:27082315
- 23. Rasmussen KC, Secher NH, Pedersen T. Effect of perioperative crystalloid or colloid fluid therapy on hemorrhage, coagulation competence, and outcome: A systematic review and stratified meta-analysis. Medicine (Baltimore). 2016 Aug;95(31):e4498. pmid:27495098
- 24. Jin SL, Yu BW. Effects of acute hypervolemic fluid infusion of hydroxyethyl starch and gelatin on hemostasis and possible mechanisms. Clin Appl Thromb Hemost. 2010 Feb;16(1):91–8. pmid:19825916
- 25. Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, et al. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. Anesth Analg. 2007 Oct;105(4):905–17, table of contents. pmid:17898365
- 26. Pensier J, Deffontis L, Rollé A, Aarab Y, Capdevila M, Monet C, et al. Hydroxyethyl Starch for Fluid Management in Patients Undergoing Major Abdominal Surgery: A Systematic Review With Meta-analysis and Trial Sequential Analysis. Anesth Analg. 2022 Apr 1;134(4):686–695. pmid:34854822
- 27. Shin HJ, Na HS, Jeon YT, Lee GW, Do SH. Changes in blood coagulation after colloid administration in patients undergoing total hip arthroplasty: comparison between pentastarch and tetrastarches, a randomized trial. Korean J Anesthesiol. 2015 Aug;68(4):364–72. pmid:26257849
- 28. Arellano R, Gan BS, Salpeter MJ, Yeo E, McCluskey S, Pinto R, et al. A triple-blinded randomized trial comparing the hemostatic effects of large-dose 10% hydroxyethyl starch 264/0.45 versus 5% albumin during major reconstructive surgery. Anesth Analg. 2005 Jun;100(6):1846–1853. pmid:15920225
- 29. Kahlon A, Grabell J, Tuttle A, Engen D, Hopman W, Lillicrap D, et al. Quantification of perioperative changes in von Willebrand factor and factor VIII during elective orthopaedic surgery in normal individuals. Haemophilia. 2013 Sep;19(5):758–64. pmid:23711418