Comparison of HES 130/0.42 and HES 200/0.5 for hemodynamic stabilisation in major urological surgery

Purpose: Different hydroxyethyl starches (HES) may lead to different volume effects. We compared a new HES130/0.42 with an established HES200/0.5 with respect to perioperative volume requirements, hemodynamic effects, safety and tolerability. Methods: After approval of the local ethics committee we investigated in a prospective, randomized double-blinded clinical trial 100 adult patients scheduled for elective major urological surgery. The study fluids were administered according to patients ́ individual need from induction of anesthesia until 12:00 midnight on the day of surgery. Infusion trigger were mean arterial pressure, central venous pressure, heart rate, or other clinical reasons. The required volume of study medication served as primary endpoint. Secondary endpoints were safety and tolerability. Equivalence was tested using the confidence interval inclusion method. A p < 0.05 indicates a high probability of equivalence. Hemodynamic and laboratory data were compared with the t-test, Mann-Whitney U-test or χ2-test as appropriate. In this case a probability value of less than 0.05 was considered as statistically significant. Results: Groups did not differ at baseline. Intraoperatively and during ICU stay equivalent amounts of HES were administered [mean ± SD] (HES 130/0.42: 1150 ± 574mL vs. HES 200/0.5: 1070 ± 572mL, p = 0.0002 (OP); HES 130/0.42: 1390 ± 955 mL vs. HES 200/0.5: 1245 ± 715 mL, p = 0.0196 (ICU)). Statistical equivalence over the whole observation period could not be achieved (HES 130/0.42: 2540 ± 1232 mL, HES 200/0.5: 2290 ± 1040mL, p = 0.1379). There was no difference in total fluid requirements, hemodynamics, routine chemistry, and blood coagulation parameters. Intraoperatively red blood cells were administered more frequently in group HES 200/0.5 (HES 130/0.42: 4/50 patients; HES200/0.5: 11/50 patients; p = 0.0499). Over the entire observation period no serious adverse events occurred. Conclusions: HES 130/0.42 can be used as safely and efficiently for perioperative plasma volume expansion to maintain hemodynamic stability during major urological surgery as a standard HES 200/0.5 formulation. 12 H. Heinze, K. Hage, F. Hackmann, R. Schäfer, R. Zulkowski, K.-F. Klotz ethyl groups to glucose residues (3). Side-effects like hemostatic interaction, renal dysfunction and the risk of accumulation were found to be associated with increasing values of these pharmacokinetic characteristics (2). To reduce these side-effects, efforts have been made to develop new HES solutions with a smaller molecular weight and a lower degree of substitution. Indeed fewer side effects – especially on coagulation parameters – have been reported with the use of HES 130 when compared to HES with higher molecular weight and degree of molar substitution (4-6). The novel potato starch-based HES solution (Venofundin®, B.Braun Melsungen AG, Germany) is characterized by an average molecular weight of 130 ± 15 kD, a degree of substitution of 0.42, and a C2/C6 ratio of 6:1. The molecular weight distribution is the narrowest of all available HES types, i.e., the proportion of very large and very small molecules was significantly reduced. In addition, the lower C2/C6 hydroxyethylation ratio may lead to further reduced side-effects. It is known that lower molecular weight starch preparations may be less effective in restoring plasma volume, as they have shorter half-life times (7), therefore more volume may be needed compared to HES with a higher molecular weight (8). In addition, the low C2/C6 ratio may increase the metabolic degradation and subsequent renal excretion. Venofundin® was compared with a HES 200/0.5 solution in a clinical trial in women undergoing major gynecological surgery (9). It demonstrated therapeutic equivalence in maintaining hemodynamic stability. The mean volume administered was 1224 ± 544 mL (9). As much larger doses are frequently infused during surgery and intensive care therapy volume requirements may increase to achieve hemodynamic stability. But side-effects may increase and tolerability decrease with increasing volume. It was the aim of this clinical trial to compare the new HES 130/0.42 formulation (Venofundin®, B.Braun Melsungen AG, Germany) with an established HES 200/0.5 (Infukoll® HES, Serumwerk Bernburg, Germany) with respect to perioperative volume requirements, hemodynamic effects, safety and tolerability in patients scheduled for major urological surgery with an expected fluid requirement of more than 3 L during the perioperative period. The primary goal was to show equivalence of perioperative need of both HES to achieve hemodynamic stability. As secondary objectives safety and tolerability were investigated by comparing clinical and laboratory parameters. Methods This prospective, randomized, double-blinded, parallel-group, single-centre clinical phase III trial was carried out at the clinic for urology, University of Luebeck. It was approved by the local ethics committee. After written informed consent 100 patients scheduled for major urological surgery with an expected fluid requirement of more than 3 L were included into the study. They were randomly assigned to receive either HES 200/0.5 or HES 130/0.42 coded as treatment A or treatment B, respectively. Block randomization each 8 was computerized using Rancode® by an employee of B.Braun Melsungen AG, Germany. The main conductor of the trial (K.-F. K.) received blinded envelops containing the code “A” or “B” to be opened only after inclusion of each patient into the study. Decoding envelops were deposited by K.-F. K. to be opened in case of emergencies. After completion of the study no envelope had been opened. Exclusion criteria were emergency surgery, increased anesthetic risk (ASA>III), myocardial insufficiency (NYHA>III), myocardial infarction in the last 3 months, renal insufficiency with serum creatinine > 150 μmol L–1, known liver insufficiency or liver transplantation, blood coagulation disorders, preoperative HES infusion (within 48 hours prior to randomization), known HES allergy, and general contraindication to volume replacement therapy. General anesthesia was induced intravenously with propofol, sufentanil, and rocuronium in doses adapted for the patient’s need. Maintenance of anesthesia was achieved by use of propofol and intermittent boli of sufentanil as appropriate. Ventilation was adjusted to achieve normocapnia (etCO2 35 – 40 mmHg). A heat blanket was used to prevent hypothermia. After induction of anesthesia patients received a 4-F thermistortipped arterial catheter (4-Fr Pulsiocath, Pulsion Medical Systems, Munich, Germany) inserted to the femoral artery and an 8-F central venous catheter inserted into the internal jugular vein. After compensation of preoperative fasting with 1 L of Ringer solution, crystalloids were infused at a constant rate of 5 – 10 mL kg–1 h–1. The hydroxyethyl starch study solution could be administered from induction of anesthesia until 12:00 midnight of the operation day according to individual requirements of the patients. One unit (500 mL) of the study medication was infused if one or more of the following infusion triggers was observed for more than 5 minutes. HES 130/0.42 for hemodynamic stabilisation 13 – Mean arterial pressure (MAP) < 80 % of the individual value measured on the day before surgery – Stroke volume (SV) < 60 mL – Central venous pressure < 5 mmHg – Other clinical reasons, e.g. reduced cardiac output (CO) (< 4 L min–1), increased stroke volume variability (> 20%), and reduced diuresis (< 0.5 mL kg–1). Blood loss was estimated by measuring blood volume in suction containers from the surgical field and in drainages postoperatively. Vasoconstrictors were given if MAP was below 60 mmHg despite adequate volume replacement. Triggers for transfusion of packed red blood cells were hemoglobin < 90 g L–1 and for platelets a platelet count < 60000 μL–1. Study medications contained either a test substance of HES 130/0.42 with an average mean molecular weight of 130 kD, a molar substitution of 0.42 and a C2/C6 ratio of 6:1 or the reference solution of HES 200/0.5 with an average mean molecular weight of 200 kD, a molar substitution of 0.5 and a C2/C6 ratio of 6:1. Test and reference preparations were equally 6 % concentrated HES dissolved in 0.9 % sodium chloride. Solutions were isooncotic, isotonic and indistinguishably blinded. Randomization was concealed until end of the study. For efficacy measurements the primary variable was defined as the volume of the study medication infused from induction of anesthesia until 12 pm to maintain hemodynamic stability. Secondary variables comprised: Suitability of the substance for postoperative volume replacement, hemodynamics including arterial blood pressure, intrathoracic blood volume (ITBV), extravascular lung water (EVLW), cardiac output (CO), stroke volume variability (SVV), central venous pressure (CVP), and heart rate (HR); hematology and coagulation including hemoglobin, hematocrit, platelet count, prothrombin time, partial thromboplastin time, thrombin time, fibrinogen; clinical chemistry including total protein, albumin, creatinine, sodium, potassium, calcium, glucose; overall requirements of fluid replacement and transfusion, separated by study medication, crystalloids, blood and blood derivates; volume of perioperative blood and fluid loss via drainage and urinary output; and finally acid-base-balance parameters like pH, pCO2, pO2, base excess (BE), and bicarbonate. In addition, adverse events were recorded. Arterial blood pressure and heart rate was recorded on the day before surgery, intraoperatively after induction of anesthesia every 10 minutes and postoperatively during intensive care treatment every 30 minutes. Hemodynamic parameters like ITBV, EVLW, SVV, CO, and CVP were recorded intraoperatively every 20 minutes and postoperatively every 60 minutes till 12:00 midnight of the operative day. Blood samples for evaluation of laboratory parameters were taken before induction of anesthesia, after surgery and every four hours postoperatively. Study ended at 12:00 midnight on the day of surgery. For measurements the arterial thermodilution catheter was connected to the monitor for pulse contour analysis and transpulmonary thermodilution (PICCO, Pulsion Medical Systems, Munich, Germany). Three consecutive measurements of CO by transpulmonary thermodilution were performed by injecting 10 – 15 mL iced saline 0.9 % randomly across the respiratory circle into the distal port of the central venous catheter. CO, ITBV, EVLW, SVV were recorded.