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Anesth Analg 2003;96:1453-1459 © 2003 International Anesthesia Research Society
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Abstract |
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In this prospective, controlled, randomized, single-center study, we investigated the safety of repetitive large-dose infusion of a novel hydroxyethyl starch solution (6% HES 130/0.4) in cranio-cerebral trauma patients. Patients were randomized to receive either HES 130/0.4 (n = 16) at repetitive doses of up to 70 mL · kg-1 · d-1 (which is the largest HES dose reported in the literature) or the control HES 200/0.5 (n = 15) up to its approved dose limit of 33 mL · kg-1 · d-1 followed by human albumin up to a total dose (HES 200/0.5 + albumin) of 70 mL · kg-1 · d-1. We found no differences between groups in mortality, renal function, bleeding complications, and use of blood products. There were also no major differences in coagulation variables. However, at some time points, factor VIII, von Willebrand factor, and ristocetin cofactor were higher in the HES 130/0.4 group despite the large HES doses administered. We conclude that HES 130/0.4 can safely be used in critically ill head trauma patients over several days at doses of up to 70 mL · kg-1 · d-1.
IMPLICATIONS: There are concerns that infusion of certain hydroxyethyl starch (HES) types for plasma volume expansion may influence coagulation and renal function. We investigated the safety of the novel HES 130/0.4 in patients with severe cranio-cerebral trauma. The repetitive HES doses administered in this study are the largest reported in the literature.
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Introduction |
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Adequate volume management is of major importance in critically ill patients. Especially in severe head injury, it is pivotal, challenging, and, to a certain extent, controversial. Different volume regimens have been advocated. The widely accepted aggressive fluid resuscitation strategy we favor in this study aims to achieve a high cerebral perfusion pressure (CPP). Large repetitive intravascular infusion volumes are required to increase systemic blood pressure and CPP while counteracting increased intracranial pressure (ICP) typical of severe cranio-cerebral trauma (1,2). A variety of infusion solutions, including blood products (fresh frozen plasma and packed red blood cells), human albumin, crystalloids (Ringer’s lactate or normal saline), and synthetic colloids (gelatin, dextran, and hydroxyethyl starch [HES]) may be suitable for this purpose. Each product has its specific limitations.
Frequently used artificial colloids for plasma volume expansion in trauma and surgery are HES solutions. Because native starches are rapidly hydrolyzed by 
-amylase, commercially available HES preparations are polymers of natural amylopectin, chemically modified by hydroxyethylation at the glucose subunit carbon atoms (C2, C3, or C6). Most important physicochemical characteristics are molar substitution (MS; mol hydroxyethyl residues per mol glucose subunits), the pattern of hydroxyethylation (C2:C6 ratio), and the mean molecular weight (Mw). MS and hydroxyethylation ratio are the principle determinants of the in vivo characteristics of the solutions. The higher the MS and C2:C6 ratio, the slower the starch is metabolized. Mw is less important for metabolism than MS. The described physicochemical characteristics of HES solutions are related to different safety profiles of various HES types with respect to coagulation (3–9) and renal function (10–12). In particular, after the repeated administration of certain HES solutions with high MS and, to a lesser extent, a higher mean Mw, large molecules may accumulate in plasma because of decelerated enzymatic degradation. Macromolecules are known to decrease plasma concentrations of coagulation factor VIII, von Willebrand factor (vWF), and ristocetin cofactor, although the pathogenetic mechanism responsible for the adverse effect on factor VIII/vWF-complex is not fully understood. Accelerated elimination after complexing with larger HES molecules is one possible explanation. Several reports and case histories relate administration of older, less metabolizable HES products to deterioration of renal function or to morphological changes in transplanted kidneys. Although the mechanisms are unclear, certain conditions, such as long-term HES administration without sufficient hydration, preexisting nephropathies, or an increase in viscosity of the primary urine, may contribute to renal failure (13).
Therefore, the physicochemical characteristics of the novel HES 130/0.4 solution have been adjusted (Mw 130,000 d, MS 0.4, and C2:C6 ratio of about 9:1) resulting in a faster metabolism without plasma accumulation of macromolecules after repetitive dosing, whereas volume effect is preserved compared with HES 200/0.5. This finally leads to a reduced postoperative influence on coagulation and increased renal elimination (3–9,12,14), which may be particularly important in patients requiring large-dose long-term colloid treatment.
The aim of this study was to investigate the safety of HES 130/0.4 with regard to coagulation and renal function at large repetitive doses. Relevant coagulation end-points include factor VIII, vWF, and ristocetin cofactor, which are influenced by certain HES types but not by crystalloids or albumin (15,16).
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Methods |
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This prospective, controlled, randomized, single-center study was performed between April 1999 and May 2000. The study was conducted in accordance with the principles of Good Clinical Practice and the revised Declaration of Helsinki. Signed, written informed consent was provided by a close relative of the patient. Procedures were approved by both the institutional and the regional ethics committees.
Patients with severe cranio-cerebral trauma were evaluated after admission to the level I trauma intensive care unit of the University Hospital Zurich, Switzerland. Only patients aged 18–65 yr who presented with a pathologic cerebral computed tomography scan, Glasgow Coma Motor Score <5, acute trauma within the previous 24 h, and stabilized hemostasis were included. Patients with bilaterally fixed and dilated pupils, a history of coagulation disorders, chronic renal insufficiency, severe liver insufficiency, or cardiac insufficiency were excluded. All patients were intubated and mechanically ventilated. Patients were randomized for two treatment groups by using opaque sealed envelopes. Importantly, the investigator and the patient were blinded with regard to the study group allocation until the patient had been included and the baseline measurements performed.
In the study group, HES 130/0.4 (Voluven® 6%, Fresenius Kabi, Bad Homburg, Germany) was infused at repetitive large doses of up to 70 mL · kg-1 · d-1 for up to 28 days. The control group received a standard treatment of HES 200/0.5 (6%, Fresenius Kabi) up to its approved dose limit of 33 mL · kg-1 · d-1, followed by human serum albumin (5%, Baxter, Unterschleissheim, Germany) up to a total dose (HES 200/0.5 + albumin) of 70 mL · kg-1 · d-1 for up to 28 days (Fig. 1).
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All patients were treated according to a standardized protocol targeting at the following minimum hemodynamic and cerebral perfusion variables: mean arterial blood pressure (MAP)
80 mm Hg and CPP (CPP = MAP - ICP) 70 mm Hg. Infusion triggers for study and control colloids were defined as follows: MAP <80 mm Hg or persisting CPP <70 mm Hg despite adequate ICP treatment (e.g., add-on analgesia, sedation and neuromuscular blockade, ventilator adjustment, cerebrospinal fluid drainage, mannitol infusion, and body temperature control) and exclusion of intracranial rebleeding with computed tomography scan. Colloid infusions were combined with continuous administration of norepinephrine as required to counteract peripheral vasodilation provided that intravascular volume status was adequate. Limitations for colloidal volume treatment were pulmonary artery occlusion pressure 16 mm Hg, central venous pressure 20 mm Hg, or signs of cardiac failure. Triggers for fresh frozen plasma transfusion were prothrombin time 14.2 s in the absence of bleeding or 10.7 s in the presence of bleeding. Triggers for platelet transfusion were platelet counts 
50/nL (no bleeding) or 80/nL (bleeding). Standard clinical chemistry, creatinine clearance using 24-h urinary collection, hematology, and coagulation end-points were monitored. Special coagulation tests included factor VIII activity (Behring, Marburg, Germany), vWF antigen (Asserachrom vWF, Diagnostica Stago, Asnières-sur-Seine, France), ristocetin cofactor activity (APACT-4, Labor GmbH, Ahrensburg, Germany), thromboelastography® (Haemoscope, Skokie, IL), and platelet function analysis (PFA-100, Dade Behring, Liederbach, Germany). The originally planned sample size of 40 (2 x 20) patients was not based on statistical considerations because of the exploratory character of this study. Of 128 patients screened, 95 patients did not meet the enrollment criteria, and two patients could not be enrolled for logistic reasons. After 31 subjects had been enrolled and randomized (HES 130/0.4, n = 16; HES 200/0.5 + albumin, n = 15), the institutional ethics committee raised questions regarding the occurrence of intracranial bleeding complications in both groups and requested an interim analysis. The study was not continued after the interim analysis because of safety concerns related to the results from the control group. The reasons are discussed below.
All analyses were based on the intention-to-treat population consisting of all 31 patients randomized, except where otherwise stated. Randomization (block size, 6) and all analyses were performed by DATAMAP GmbH (Freiburg, Germany) and by means of the SAS software, version 6.12 (SAS Institute, Cary, NC). Data were compared between groups by the Wilcoxon test, analysis of covariance, and 
2 test. Data are presented as mean ± SD.
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Results |
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The two groups (HES 130/0.4, n = 16; HES 200/0.5 + albumin, n = 15) did not differ regarding demographics and all 6 baseline scores (Table 1). Also, concomitant medication use including norepinephrine (14 of 16 versus 15 of 15), hospital days (20.1 ± 15.4 versus 22.6 ± 11.8), overall incidences and types of adverse events (see below), and mortality (4 of 16 versus 3 of 15; not considered related to investigational or control colloids) were comparable between groups.
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Mean cumulative doses of HES were comparable between groups: 19 ± 16 L of HES 130/0.4 (range, 6–66 L) versus 22 ± 11 L of HES 200/0.5 (6–47 L) (Fig. 2). In terms of number of patients receiving repetitive doses of HES 130/0.4, all 16 subjects received >30 mL · kg-1 · d-1 over several days, 10 patients (63%) received repetitively >60 mL · kg-1 · d-1, and 3 patients were infused with >70 mL · kg-1 · d-1. In the control group, 14 of 15 patients (93%) received repetitively a daily dose >30 mL · kg-1 of HES 200/0.5 (Table 2). Control patients were additionally infused with 7 ± 4 L of albumin (1–15 L). Daily use of total colloids (HES 130/0.4 versus HES 200/0.5 + albumin) for those days when colloid was required as defined by the infusion triggers (colloid treatment days) was also comparable between groups (Table 3). In contrast to the comparable mean cumulative HES doses, the mean daily HES dose was significantly larger in the HES 130/0.4 group than in the control group (Table 3), as expected from the dose regimen planned in the protocol. Blood loss and the need for blood products did not differ between groups (Table 3).
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Coagulation results were generally comparable between groups. In particular, there were no major differences between groups in thromboelastography, platelet function analysis, partial thromboplastin time, prothrombin time, fibrinogen, and platelet count. However, at some time points between treatment Days 2 and 6, factor VIII, vWF, and ristocetin cofactor showed significantly larger increases from baseline in the HES 130/0.4 group than in the control group (Table 4). Intracranial bleeding complications (5 of 16 versus 5 of 15 patients) were related to the underlying cerebral trauma and were not accompanied by coagulation disorders. Renal failure was observed in two patients with multiorgan failure (both in the control group but not related to the control colloids). In the remaining 29 patients, creatinine clearance using urinary collection (Table 5) and mean serum creatinine remained within normal ranges in both groups during the entire study. In the HES 130/0.4 group, ventilation days (mean, 9.6 ± 7.8 versus 15.6 ± 6.2; P < 0.01), colloid treatment days (6.6 ± 5.8 versus 11.8 ± 5.1; P < 0.01), and intensive care unit days (12.7 ± 11.3 versus 19.5 ± 9.1; P = 0.05) were reduced. Additionally, the number of patients with ICP peaks exceeding 30 and 35 mm Hg was significantly smaller in the HES 130/0.4 group than in the control group, and mean cumulative hours of increased ICP showed group differences on all of the four tested levels (Fig. 3). Neurological assessment 3 and 6 mo after hospital discharge revealed no statistically significant difference in Glasgow Outcome Scale (3 mo, 2.9 ± -1.4 versus 3.0 ± 1.1; 6 mo, 3.5 ± 1.8 versus 3.5 ± 1.5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This prospective study was designed to investigate the safety of a novel HES preparation (6% HES 130/0.4) in large-dose therapy for patients with severe head injury. Primary safety end-points were coagulation and renal function. The repetitive HES dose administered in the present study is the largest one reported in the literature. Up to 70 mL · kg-1 · d-1 of HES 130/0.4 (e.g., 5.6 L daily for a patient of 80 kg) was infused over several days in cranio-cerebral trauma without compromising renal function and coagulation and without causing bleeding complications.
Our treatment protocol regarding resuscitation and maintenance of blood pressure is in accordance with the Guidelines for the Management of Severe Head Injury, which were published by the Brain Trauma Foundation and the American Association of Neurological Surgeons in 1996 (2). The guidelines advocate a target CPP >70 mm Hg (MAP >90 mm Hg at a given ICP threshold of 20 mm Hg for intracranial hypertension). The rationale of this concept is strong evidence that supporting blood pressure in patients with severe head injury (pre- and inhospital phase) improves outcome (17).
Coagulation factor VIII, vWF, and ristocetin cofactor frequently exceed normal, pretrauma values as a component of the acute phase reaction after surgery and trauma. This physiologic reaction is suppressed by certain HES products but not by crystalloids or albumin (15,16). Although a posttrauma increase of the above mentioned coagulation factors is also detectable in the control group, at some time points up to Day 6, it was significantly larger in the HES 130/0.4 group, indicating less suppression by HES 130/0.4. This is in accordance with several previous studies (3–9) demonstrating a reduced influence of HES 130/0.4 on coagulation after surgery as well as in vitro. Our results are particularly interesting because the daily dose of HES 130/0.4 was larger than that of HES 200/0.5 (as planned in the protocol).
As in previous studies with HES 130/0.4 (3–7,12,14), we observed no renal complications despite the large doses administered. Reports about potential adverse effects of HES on renal function (10,11) were obtained with HES 200/0.62, a distinct HES type, which is more slowly metabolized and eliminated than HES 130/0.4.
Surprisingly, the HES 130/0.4 group showed significantly reduced ventilation days and colloid treatment days, less patients with ICP peaks exceeding 30 mm Hg and 35 mm Hg, and on all 4 tested thresholds, a significantly smaller mean of cumulative time the ICP ranged above these specific levels. The reason for these findings is not clear. The two treatment groups differed in the HES type infused. Furthermore, albumin as an add-on colloid was used in the control group only. Assuming a regionally disrupted blood-brain barrier and blood-cerebrospinal fluid barrier, respectively, there is evidence that albumin but not HES extravasates into the cerebrospinal fluid (18,19). This may result in increased intracranial volume and therefore increased ICP. As the probability of a good outcome is inversely proportional to the maximum ICP and the cumulative time the ICP of a patient ranges above a certain critical threshold (20), it could explain the reduced colloid treatment days and ventilation days in the HES 130/0.4 group. Even though the mentioned variables (ICP peaks and cumulative time at increased ICP levels) may negatively affect the neurological outcome, Glasgow Outcome Scale evaluated three and six months after hospital discharge did not reveal any statistical difference between the two treatment groups.
The increased incidence of ICP peaks in the control group was the reason for prematurely terminating the study after the interim analysis requested by the institutional ethics committee had been performed. Because an unchanged study design would have potentially exposed further patients to more frequent ICP peaks and prolonged time intervals at increased ICP levels in the HES 200/0.5 + albumin group, we decided to stop the study after the interim analysis and to proceed with the final analysis.
Some study limitations should be mentioned. The number of allocated patients is small because the planned sample size of 2 x 20 patients could not be reached because of the premature study termination. However, as the originally planned patient number was not based on statistical considerations for one single variable (pilot study character), and no major contribution of nine more patients concerning primary safety end-points and group differences was expected, the aims of the study were not endangered regarding biometrical issues. The use of albumin as an add-on colloid in the control group may be controversial because the Cochrane Group’s meta-analyses on the value and potential detrimental effect of albumin in the critically ill have been published (21,22). Nevertheless, there is still a debate about albumin use (23–25), and it is, in fact, still infused as a second-line colloid in many institutions including our hospital. In any case, we believe that the control group chosen was at least a valid comparator concerning evaluation of coagulation and renal function.
We conclude that HES 130/0.4 can safely be used in critically ill cerebral trauma patients over several days at repetitive doses of up to 70 mL · kg-1 · d-1.
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Acknowledgments |
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Supported, in part, by a grant from Fresenius Kabi, Bad Homburg, Germany.
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References |
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