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*Département d’Anesthésie-Réanimation, Centre Hospitalo-universitaire (CHU) Pitié-Salpêtrière, Paris, France; Fresenius Kabi, Fluid Therapy Division, Bad Homburg, Germany; Département d’Anesthésie-Réanimation, Centre Hospitalo-universitaire (CHU) Beaujon, Clichy, France; §Département d’Anesthésie-Réanimation, Centre Hospitalo-universitaire (CHU) Tenon, Paris, France; ||Département d’Anesthésie-Réanimation, Centre Hospitalo-universitaire (CHU) Lapeyronie, Montpellier, France
Address correspondence and reprint requests to O. Langeron, MD, Département d’Anesthésie-Réanimation, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cédex 13, France. Address e-mail to olivier.langeron{at}psl.ap-hop-paris.fr
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Abstract |
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Implications: Hydroxyethyl starches are common plasma volume expanders, but may interfere with coagulation at large doses. We tested a novel hydroxyethyl starch specification (Voluven®; Fresenius Kabi, Bad Homburg, Germany) which was developed to reduce hemostatic interactions while preserving its efficacy in restoring plasma volume in comparison to HAES-steril® (pentastarch; Fresenius Kabi) in major orthopedic surgery.
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Introduction |
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-amylase, and therefore account for the pharmacological differences between various HES specifications (3). The average molecular weight plays only a minor role in determining the pharmacological profile of HES solutions (4,5). HES may interfere with coagulation and accumulate in plasma and tissues (3). The most pronounced side effects were found with large and highly substituted (i.e., ratio of hydroxyethyl groups to glucose residues) HES molecules (3,6–10), like hetastarch which has an average molecular weight of 450.000 dalton and a high degree of substitution of 0.7. Voluven® (Fresenius Kabi, Bad Homburg, Germany) is a novel HES type. Voluven® has an average molecular weight of 130.000 dalton and a degree of substitution of 0.4 (HES 130/0.4). Its molecular weight distribution is the most narrow of all available HES types, i.e., the proportion of very large and very small molecules was significantly reduced. In the present study, Voluven® was compared with HAES-steril® (pentastarch, average molecular weight 200.000 dalton, degree of substitution 0.5; Fresenius Kabi) which is commonly used in Europe (8,11).
Voluven® does not accumulate in plasma after multiple dosing over 10 days, which is in contrast to all other HES types (12). Accordingly, renal excretion of Voluven® is increased (13). These pharmacological properties result in a 75% reduction in tissue storage as compared with HAES-steril® (14). In vitro and in vivo coagulation seem to be less compromised by Voluven® than by other HES specifications (15–17). Voluven® may not be associated with the typical undesired effects of higher substituted and higher molecular weight HES types, e.g., plasma accumulation, impairment of coagulation, and tissue storage. Regarding theoretical efficacy, Voluven® has a volume effect of approximately 100% (of the infused volume) and a 4- to 6-h duration (18), which is comparable with the current European standard HES, i.e., HAES-steril® (1).
The present prospective, randomized, double-blinded, multicenter study was performed in a large clinical setting during major orthopedic surgery to confirm the plasma-expanding properties of Voluven® reported in preliminary studies (12–16,18–21). The hypothesis was that perioperative administration of Voluven® in large-blood–loss surgery is comparable to the standard HAES-steril® (pentastarch) properties in restoring plasma volume. Plasma-expanding properties of Voluven® and standard HAES-steril® were assessed by comparing the colloid volumes infused in either group. Moreover, coagulation variables, estimated blood loss, and blood transfusion requirements were also compared between the two groups, as these are clearly the most relevant secondary endpoints in a fluid replacement study.
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Methods |
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Adult male and female patients scheduled for elective major orthopedic surgery with an expected blood loss of more than 2.0 L were included. Exclusion criteria were ASA physical status classification > III; hematocrit < 30% or hemoglobin < 10 g/dL; cardiac insufficiency (New York Heart Association > II); myocardial infarction during the last 6 mo; unstable angina pectoris; renal dysfunction (serum creatinine > 1.2 mg/dL or > 106 µmol/L for women, > 1.3 mg/dL or > 115 µmol/L for men); severe hepatic disorders (bilirubin > 1.5 times upper limit of normal, or aspartate aminotransferase or alanine aminotransferase > 2 times upper limit of normal); diabetes insipidus; severe infectious diseases; history of coagulation disorders; known allergy to starch; body weight > 100 kg; pregnancy or lactation.
There were no restrictions with regard to concomitant medication. Patients were premedicated with 5 mg of midazolam orally. All patients underwent general anesthesia, which was induced with propofol (2–3 mg/kg) and sufentanil (1 µg/kg). Muscular relaxation for tracheal intubation was achieved with vecuronium 0.1 mg/kg. Anesthesia was maintained with isoflurane, sufentanil (0.5 µg · kg-1 · h-1) and 60% N2O in oxygen. Ventilation was adjusted to keep end tidal CO2 at 35–40 mm Hg. Hypothermia was prevented during the surgery and the recovery period by using a heating blanket and perfusion warming. No acute normovolemic hemodilution was done. Crystalloid solutions were infused at a constant rate of approximately 10 mL · kg-1 · h-1. Triggers for the administration of blood components were a hematocrit < 25% for red blood cells transfusion and a platelet count < 80 G/L for platelets transfusion.
Plasma volume replacement for treatment of perioperative hypovolemia was performed either with 6% Voluven® or with the control solution 6% HAES-steril®. The solutions were blinded by the manufacturer. The treatment period started after the induction of anesthesia and ended 5 h after the end of surgery. During this period, the triggers for infusion of the study HES solutions were a systolic blood pressure of <90 mm Hg and/or a decrease of >20% from baseline, a heart rate of >100 bpm and/or an increase of >30% from baseline, and/or a urine output of <0.4 mL · kg-1 · h-1. The infusion was continued until these hemodynamic goals were met. The maximum dose of Voluven® or HAES-steril® was 33 mL/kg body weight (e.g., 2.5 L for a patient of 75 kg), which is the maximum dose that is approved for HAES-steril® (pentastarch) in Europe. If larger doses were required, any other routinely used colloid than HES had to be administered. The IV fluid input and the complete fluid output were documented.
Other data recorded were adverse events, preexisting diseases, concomitant medication administered, systolic and diastolic blood pressure, heart rate, and body temperature. Laboratory tests included: red blood cells, hemoglobin, hematocrit, leukocytes, platelets, Quick, thrombin time, partial thromboplastin time (PTT), factor VIII concentration (chronometry with factor VIII deficient plasma, Behring, Germany), factor VIII-associated antigen/von Willebrand factor (ELISA test; Diagnostica Stago, Asnières, France), factor VIII ristocetin cofactor (agglutination test, Behring, Germany), blood gases, serum electrolytes, creatinine, lactate, bilirubin, glucose, lactate dehydrogenase, -amylase, 
-glutamyl transferase, and liver transaminases. Measurements were performed 1 day before surgery, after the induction of anesthesia, every hour after incision, at the end of surgery, 5 h after the end of surgery, and 1 day after surgery. Not all of the variables were determined at each time point.
The primary efficacy variable was the total volume of colloids (as described above) required during the treatment period, i.e., from the induction of anesthesia until 5 h after the end of surgery. The hypothesis was that the volume need in both groups would be equivalent within a range of ±500 mL (corresponding to one HES bottle), indicating equal efficacy of both HES specifications (calculation of two-sided 95% confidence intervals on an intent-to-treat basis, analysis of variance [ANOVA] with effects for treatment and center [ = 0.05 and ß = 0.01]). All analyses were performed by using SAS®, version 6.09 (SAS Institute, Cary, NC), on a DECstation 5000/200. The expected standard deviation as deduced from previous observations in orthopedic patients was ±600 mL (11). With 100 patients included, the power of this confirmatory study was calculated at 99%. Blood transfusion and blood loss data were not normally distributed. For blood transfusion, the majority of values was zero. Therefore, standard nonparametric tests (problem of ties) or standard log transformation were not appropriate. For those endpoints, a Van-der-Waerden two-sample test was calculated after processing of the ties by either random procedure or mean ranks procedure. In addition, we performed a classification according to the distribution of the amount of red blood cells transfused according to 5 "classes" (0 mL, 1 to 500 mL, 501 to 1000 mL, 1001 to 2000 mL, and more than 2000 mL) for homologous, autologous, or total blood transfusion. Then, a Mantel-Haenszel test of the classified data was calculated to compare the distribution of red blood cells transfused between groups. A P value <0.05 was considered statistically significant.
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Results |
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The total blood loss (i.e., sum of cell saver, drainage, and estimated other blood loss) was not significantly different between groups (medians, 1800 mL in Voluven® group versus 2350 mL in control group) by using a modified Van-der-Waerden two-sample test. The total amount of autologous and homologous red blood cells transfused was not significantly different between groups by using a modified Van-der-Waerden two-sample test and a Mantel-Haenszel test of the classified data (Fig. 1 and Table 3, respectively). Patients in the Voluven® group required significantly less homologous red blood cells than those in the control group (Fig. 1 and Table 3). Only one patient (control group) received platelets.
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-amylase in both treatment groups. However, the mean increase in Voluven® patients (from 74 U/L at baseline to 158 U/L 1 day after surgery) was significantly smaller (P = 0.04) than that in HAES-steril® patients (from 74 U/L to 255 U/L). With regard to all other laboratory variables, both groups were comparable. There were no major differences between treatment groups regarding adverse events. No patient died. Study drug relationship as judged by the investigators was probable for only one adverse event (postoperative hemorrhage, control group).
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Discussion |
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Elective major orthopedic surgery was chosen because it offers a frequent and standardized surgical setting allowing the study design to be based largely on clinical routine. The study solutions were infused after a simple algorithm aimed at preventing hypovolemia. When a maximum HES dose of 33 mL/kg body weight was reached, any other common colloid could be used for further volume replacement. Importantly, the strictly double-blinded design of the study precluded any bias regarding the decision for colloid infusion. Also, the results were not influenced by different crystalloid use as crystalloid volumes infused were very similar in both groups. The primary efficacy variable was the total amount of colloids required perioperatively, namely from the induction of anesthesia until five hours after the end of surgery. With regard to efficacy, equivalence of Voluven® and HAES-steril® (pentastarch) was clearly demonstrated. This confirms previous observations in healthy volunteers after bleeding and using an isovolemic model (18), in autologous blood donation (19), and in cardiac surgery (16,21). However, those previous results had to be confirmed in a larger clinical setting as in the present study.
Patients treated with Voluven® had somewhat smaller blood loss (not significant) and received significantly less homologous red blood cells than the control group. In addition, the number of patients with the largest blood transfusion requirement (i.e., >2000 mL) was smaller in the Voluven® group compared with the control group for homologous and total blood transfusion (Table 3). The decreased homologous blood transfusion need in this subclass of the Voluven® group contributed to making the difference between groups significant for the overall homologous blood transfusion. Furthermore, as it is mandatory, autologous transfusion is always performed before homologous transfusion; then differences in blood transfusion requirements will mainly become apparent for homologous blood. This may explain why homologous, but not autologous, blood transfusion was reduced in the Voluven® group compared with the control group. In a previous study (16) comparing Voluven® versus HAES-steril® in cardiac surgery, mean blood loss appeared also to be somewhat less in the Voluven® group (1301 mL vs 1821 mL, not significant) compared with the control group as in our study. In our study, the volumes of fresh-frozen plasma transfused were rather small, with no significant differences between groups (Fig. 1). Therefore, it is unlikely that the favorable red blood cell transfusion and coagulation results obtained with Voluven® were influenced by transfusion of fresh-frozen plasma. Furthermore, the types and duration of surgery were comparable between groups, indicating that the severity of the intervention did not differ between groups (Table 1). Thus, there is no indication that there was more surgical bleeding in the control group than in the Voluven® group.
The blood transfusion results discussed above are consistent with the finding that factor VIII concentration and PTT were significantly less compromised by Voluven® than by HAES-steril® in the early postoperative phase. These two coagulation variables are relevant for the evaluation of any new HES type, as it is known that higher substituted and higher molecular weight HES types lead to a prolonged PTT and a lower postoperative increase in factor VIII (6,8,22). Postoperative increases in factor VIII, von Willebrand factor, and ristocetin cofactor are part of the physiologic acute phase reaction to surgical stress (23–25). Large and highly substituted HES molecules (hetastarch, HES 450.000/0.7) attenuate this physiologic response as compared with human albumin (24) or crystalloids (25), although the mechanism is not known (3,10). Similarly, in our study the control HES specification significantly attenuated the factor VIII response as compared with Voluven®. Very similar results were obtained in previous clinical studies with Voluven® (15,16). The reduced influence of Voluven® on coagulation was also shown in an in vitro study (17).
The increase observed in serum -amylase was significantly less in Voluven® patients than in control patients. Serum -amylase is transiently increased by all available HES solutions. This is because of the formation of a HES-amylase complex resulting in a decreased renal elimination of -amylase. This effect is directly correlated with plasma HES concentration (5). Problems might result from interference with the diagnosis of pancreatitis. Therefore, the reduced influence of Voluven® on serum -amylase is potentially beneficial. Furthermore, this observation confirms the improved pharmacokinetic profile of Voluven®.
All the above-mentioned data relating to improved safety are consistent with the fact that Voluven® is more rapidly eliminated from the body than conventional HES types (12–14). This is not in conflict with its evident equivalence in efficacy. The reason is that in older HES types, very high molecular weight molecules account for a large proportion of the total mass. These large molecules are thought to be responsible for the undesired storage and coagulation phenomena (3,10). However, the oncotic (water-binding) effect of colloids primarily depends on the number of molecules rather than on their size. The number of molecules in Voluven® is relatively large because of its lower average molecular weight and its narrow molecular weight distribution, which both result in a very small proportion of large molecules. This surplus oncotic effect of Voluven® counterbalances its more rapid elimination.
We conclude that in large-blood–loss surgery, Voluven® may have a favorable coagulation profile and may lead to less homologous blood consumption compared with HAES-steril® (pentastarch), while the efficacy of both solutions in restoring plasma volume is equivalent. Nevertheless, further studies are required to show whether Voluven® can safely be used at larger dosages than currently recommended.
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