Plasma substitution effects of a new hydroxyethyl starch HES 130/0.4 compared with HES 200/0.5 during and after extended acute normovolaemic haemodilution

B. E. Ickx1, F. Bepperling4, C. Melot2, C. Schulman3 and P. J. Van der Linden*,5

1 Department of Anaesthesiology, 2 Department of Intensive Care and 3 Department of Urology, Erasme University Hospital, 808 route de Lennik, B-1070 Brussels, Belgium. 4 Clinical Research, Fresenius Kabi, Bad Homburg, Germany. 5 Department of Cardiac Anaesthesia – BT4, CHU Charleroi, 92 Boulevard Paul Janson, B-6000 Charleroi, Belgium

Corresponding author. E-mail: philippe.vanderlinden@chu-charleroi.be
{dagger}Declaration of interest. Supported by a grant from Fresenius Kabi GmbH, Bad Homburg, Germany. Frank Bepperling is employed by Fresenius Kabi, 61346 Bad Homburg, Germany.

Accepted for publication: April 10, 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. The volume expansion effect of a recently introduced hydroxyethyl starch, HES 130/0.4, was compared with the commonly used HES 200/0.5 after rapid infusion of a single large dose (up to 2 litres) administered during acute normovolaemic haemodilution (ANH).

Methods. This prospective, randomized, double-blind study included 40 patients scheduled for major abdominal surgery with no contraindication to ANH. Patients were randomized to undergo ANH with either HES 130/0.4 (n=20) or HES 200/0.5 (n=20). Blood was collected to reach a target haemoglobin level of about 8.0 g dl–1 and simultaneously replaced by the same volume of colloid (HES 130: 1825 [SD 245] ml; HES 200: 1925 [183] ml). Heart rate, mean arterial pressure, cardiac filling pressure, and cardiac output were measured before induction of anaesthesia (baseline), 10 min after completion of ANH, before surgery, at the end of surgery and on the following morning (postoperative day 1; POD1). ANH blood was systematically retransfused during surgery or before POD1.

Results. Exchange of about 40% of blood volume resulted in similar haemodynamic changes in both groups. Filling pressures increased significantly, while cardiac index remained unchanged (HES 130: from 3.3 [0.4] to 3.2 [0.7] litre min–1 m–2; HES 200: from 3.0 [0.6] to 3.1 [0.7] litre min–1 m–2). Need for crystalloids and colloids was similar between the groups during surgery and on POD1. Total blood loss (HES 130: median 2165 ml, range 660–2970 ml; HES 200: median 2464 ml, range 640–19 380 ml) and amount of allogeneic red blood cells transfused (HES 130: median 0, range 0–4 units; HES 200: median 0, range 0–18 units) were comparable in the two groups.

Conclusions. This study demonstrates a good immediate and medium-term plasma volume substitution effect of HES 130 compared with HES 200. HES 130 could represent a suitable synthetic colloid for plasma volume substitution during extensive ANH.

Br J Anaesth 2003; 91: 196–202

Keywords: blood, colloid substitution; blood, haemodilution; cardiovascular system; complications, acute anaemia; oxygen, transport


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In surgical patients, synthetic colloids are widely used as plasma substitutes because of their ability to increase and maintain circulating blood volume. Hydroxyethyl starch (HES) solutions are increasingly preferred in this setting. However, the pharmacology of HES varies greatly from one solution to another, depending on their specifications.1 2 These specifications, which include in vitro molecular weight, the degree of hydroxyethyl substitution, and the C2/C6 ratio of hydroxyethylation, determine the in vivo molecular weight, which is responsible for the volume expansion and adverse effects of each HES. In particular, interference with blood coagulation has limited the clinical use of some HES specifications.2

Efforts have been made to develop a new HES with an improved pharmacokinetic profile leading to a shorter half-life in patients with normal and impaired renal function,3 4 because of the absence of plasma accumulation even after repetitive dosing. HES 130 (Voluven®, Fresenius Kabi, Bad Homburg, Germany) is a novel HES characterized by an average molecular weight of 130 000 dalton, a molar substitution of 0.4 and a C2/C6 hydroxyethylation ratio greater than 8.

From a theoretical point of view, the improved pharmaco kinetic profile of this new HES bears the risk of a reduced pharmacodynamic effect (e.g. the plasma expansion effect might be shorter when compared with other HES specifications). In healthy volunteers, Waitzinger and colleagues 5 observed that after isovolaemic replacement of 500 ml of blood, HES 130 resulted in a plasma substitution effect equal to the volume infused, which persisted for at least 6 h. This effect appears to be comparable to that obtained with a HES 200/0.5 solution, as observed by Kasper and colleagues.6 However, the clinical relevance of these observations is limited by the fact that only a small part of the blood volume was exchanged in a non-surgical setting.

If used correctly for the appropriate patient population, preoperative acute normovolaemic haemodilution (ANH) can be an effective way to decrease exposure to allogeneic blood transfusion.7 This has been recently demonstrated by Matot and colleagues8 in patients undergoing liver resection. In these conditions, ANH results in a sudden fluid exchange and therefore represents a suitable model to investigate the plasma substitution effect of various colloids. The present study compares the pharmacodynamic effects of HES 130 and HES 200 after rapid infusion of a single large dose (up to 2 litres) administered in the context of ANH, performed as part of the blood sparing strategy in patients undergoing major abdominal surgery. The primary end-point of the study was to compare the immediate plasma substitution effect of two HES products by measurement of right ventricular end-diastolic volume (RVEDV) index and cardiac output (CO). The secondary end-point was to compare the medium-term volume expansive effect by determination of the fluid balance until the end of surgery and for the first 24 h following HES administration. In addition, any significant interference with the haemostatic system was studied in the two groups by assessing blood transfusion requirements, blood losses during and after surgery and conventional coagulation variables.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After approval by the institutional ethics committee, 40 ASA class II or III patients scheduled for major abdominal cancer surgery were enrolled in this prospective, randomized, double-blind study, after giving written informed consent. Criteria for inclusion in the study were a haemoglobin (Hb) concentration above 12 g dl–1 and the absence of contraindications to normovolaemic haemodilution, including the presence of disabling or unstable angina pectoris, heart failure (New York Heart Association >II), valvular disease, ECG rhythms other than regular sinus, uncontrolled hypertension, significant respiratory disease (PaO2 <8 kPa at room air), uncontrolled diabetes mellitus, acute infection and coagulopathy. Preoperative exclusion criteria were age less than 18 yr, chronic renal insufficiency (serum creatinine >1.3 mg dl–1 (115 µmol l–1) for males or >1.2 mg dl–1 (106 µmol l–1) for females), liver dysfunction (total bilirubin >1.5 mg dl–1, or aspartate aminotransferase or alanine aminotransferase more than twice the upper normal range), known allergy to HES, body weight >100 kg, or pregnancy and patients who were post partum. Usual medication, except for platelet inhibitors, which were discontinued at least 1 week before surgery, was administered on the morning of the procedure.

Anaesthetic management
Patients were premedicated with alprazolam 0.5 mg orally 1 h before arrival in the operating theatre. Monitoring included a lead V5 ECG, pulse oximeter and non-invasive arterial pressure monitoring. Oxygen 40% was provided through a face mask. A 16-gauge catheter was inserted in a peripheral vein for fluid and drug infusion. After i.v. administration of midazolam 2 mg, a radial artery catheter and a pulmonary artery catheter (Swan Ganz model 93A-431H-7, 5F, Baxter-Edwards, Irvine, CA) were inserted under local anaesthesia. This pulmonary artery catheter allowed measurement of right ventricular ejection fraction (RVEF) and determination of RVEDV.

General anaesthesia was induced with fentanyl 200 µg, thiopental 3 mg kg–1 and cisatracurium 0.15 mg kg–1. Patients were ventilated with a nitrous oxide/oxygen mixture (FIO2 0.40) after tracheal intubation. Ventilatory frequency was set at 12 bpm and tidal volume was adjusted to obtain an end-tidal carbon dioxide between 4.5 and 5 kPa. Anaesthesia was maintained with isoflurane 0.4–1.0 vol% end-tidal, and additional doses of fentanyl and cisatracurium were given as appropriate. Hypothermia was prevented using a convection air warmer system and by warming infusion fluids.

Acute isovolaemic haemodilution (ANH)
Blood (up to 2 litres) was withdrawn from a peripheral vein in order to reach a target Hb level of about 8 g dl–1 and was simultaneously replaced by the same volume of HES. Patients were randomly assigned to receive either HES 130/0.4 6% (HES 130 group; n=20) or HES 200/0.5 6% (HES 200 group; n=20) (HAES-steril®, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany). The sample size was chosen arbitrarily. The solutions were blinded by the manufacturer and were indistinguishable. Random ization was performed using the method of randomly permuted blocks. A maximum of 2000 ml of starch was allowed. During ANH, no crystalloids or other colloids were infused. Hb concentration was measured using a co-oximeter (Instrumentation Laboratory, Milan, Italy).

Haemodynamic measurements and fluid management
The ECG was used to determine heart rate. Mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary artery occlusion pressure (PAOP) and right atrial pressure (RAP) were measured through pressure transducers (model T321571A, Baxter), with the zero reference set at the mid-chest level. CO was determined at least in triplicate by the thermodilution technique, using cold saline (<10 °C) 10 ml and a closed system (CO-set). Each injection was started at the end of expiration.9 RVEF was determined simultaneously with each CO measurement, using an algorithm based on exponential analysis of the thermodilution curve (computer REF-1, Baxter). The normal value for RVEF is approximately 45% with this technique.10 Immediately after CO determination, arterial and mixed venous blood gases were sampled and analysed with an automated system (Instrumentation Laboratory, Milan, Italy), and oxygen saturation and Hb concentration were measured with a co-oximeter. Cardiac index (CI), stroke volume index (SVI), systemic vascular resistance (SVR), left ventricular stroke work index (LVSWI), and oxygen delivery (DO2) were calculated using standard formulae. RVEDV index was calculated by dividing SVI by RVEF. Body temperature was monitored continuously by the thermistor of the flow-directed thermodilution catheter.

During surgery and in the postoperative period, crystalloids (Ringer’s lactate) were infused according to routine clinical practice (8 ml kg –1 h–1 during surgery; 2 ml kg–1 h–1 after surgery). Additional need for plasma volume expansion was based on haemodynamic variables, taking into account heart rate (>100 beats min–1), MAP (<60 mm Hg), cardiac filling pressures (PAOP < baseline values) and blood loss. In these cases, colloids other than starches were used. No cell saving device was used during surgery. The transfusion trigger was a Hb concentration of 7 g dl–1 during surgery and 8 g dl–1 in the postoperative period. Autologous blood harvested by ANH was first administered in the reverse order of collection, followed by allogeneic blood units if necessary. Intraoperative blood loss was evaluated by measuring the volume of blood collected in the suction reservoir and by calculating the weight change of the surgical sponges and drapes. Postoperative blood loss was evaluated by measuring abdominal tube drainage.

Measurements and data analysis
Haemodynamic measurements were performed within 10 min of insertion of the catheters before induction of anaesthesia (baseline), 10 min after completion of the haemodilution protocol (ANH), at the beginning of surgery (surgery), at the end of surgery when the patient was admitted to the post anaesthesia care unit (PACU), and on the morning following surgery (POD1).

Colloid osmotic pressure was measured by an oncometer (cut-off membrane 30 000 dalton) just before and after ANH. Laboratory tests included Hb concentration, haematocrit, platelet count, prothrombin time, activated partial thromboplastin time and creatinine concentrations. These variables were measured on the day before surgery (preop), on arrival in the PACU, and on PODI.

Statistical analysis
Physical characteristics and intraoperative and postoperative fluid input and output were compared between the two groups using Student’s t-test. Differences for sex were assessed using Fischer’s exact probability test. Haemodynamic data were compared between the two groups using a two-way ANOVA for repeated measurements, followed by pairwise comparisons using Tukey’s honestly significant difference test. P<0.05 was considered significant. Results are presented as mean (SD) unless specified otherwise.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics are presented in Table 1. There were no differences between the two groups in age, sex, weight, body surface area, type of surgery or cardiovascular medication. The volume of colloid used to reach the target Hb level during ANH was 1825 (245) ml in the HES 130 group, and 1925 (183) ml in the HES 200 group. Time to perform haemodilution was similar in the two groups (HES 130 group: 47 (15) min; HES 200 group: 43 (9) min).


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Table 1 Physical characteristics of patients and their therapy
 
Table 2 gives the haemodynamic data obtained in the two groups during the entire study period. Body temperature remained stable and within normal range in both groups (data not shown). ANH was associated with a significant decrease in MAP, SVR and LVSWI in both groups. Heart rate and SVI did not change in either group. Cardiac filling pressures increased significantly, while RVEDV index remained unchanged. In the absence of a significant increase in CI, the marked decrease in Hb concentration resulted in a significant decrease in DO2.


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Table 2 Perioperative and postoperative haemodynamic data. ANH, 10 min after completion of the haemodilution protocol. Surgery, at the beginning of surgery; PACU, at the end of surgery when the patient was admitted to the post anaesthesia care unit; POD1, postoperative day 1. Data are mean (SD); *P<0.05; **P<0.01 vs baseline in that group
 
In the immediate postoperative period, CI increased significantly, while SVR remained significantly lower than baseline. DO2 increased and returned to baseline values. There was no difference in any of the measured haemo dynamic variables between the two groups at any time.

Duration of surgery was comparable in the two groups (253 (97) min and 249 (110) min in the in the HES 130 and HES 200 groups, respectively). Peri- and postoperative fluid input and output are given in Table 3. The volume of crystalloid and additional colloid administered during and after surgery was similar in both groups. Approximately 90% of the ANH blood was retransfused before the end of surgery (Table 3). Peri- and postoperative blood losses were not significantly different between groups.


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Table 3 Volume input and output. Data are mean (SD) or median (range). ANH blood, blood harvested during acute normovolaemic haemodilution; PRBC, packed red blood cells; FFP, fresh frozen plasma
 
Three patients experienced major perioperative haemorrhage, one in the HES 130 group and two in the HES 200 group. One patient in each group had to undergo further surgery for extensive blood loss. All patients received their autologous blood before POD1. Two patients (10%) in the HES 130 group and six (30%) in the HES 200 received allogeneic packed red blood cells during the study period. Two patients in the HES 130 group and one in the HES 200 group received fresh frozen plasma in the immediate postoperative period (Table 3).

Table 4 shows the laboratory data in the two groups. There were no significant differences between the two groups in any of the measured variables. Colloid osmotic pressure remained stable following ANH and was not different between the groups.


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Table 4 Laboratory data. PACU, at the end of surgery when the patient was admitted to the post anaesthesia care unit; POD1, postoperative day 1; discharge, just before discharge from hospital; ANH, 10 min after completion of the haemodilution protocol. Data are mean (SD)
 
Side-effects
No colloid-related side-effects, including allergic reactions or pruritus, were observed in either group. No patient died. One patient in the HES 200 group experienced a myocardial infarction in the immediate postoperative period. Two patients experienced deep vein thrombosis (one in each group). Length of hospital stay was similar in the two groups:15.5 (4.8) days and 14.8 (3.9) days in the HES 130 and HES 200 groups, respectively.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary end-point of this prospective, randomized, double-blind study was to compare the immediate plasma volume substitution effects of HES 130 and HES 200. Plasma volume expansion measurements could have been determined using labelled red cells or indocyanine green pulse spectrophotometry. However, these approaches are relatively complex and difficult to realise in a daily clinical routine. Determination of flow (e.g. CO), volumes (e.g. RVEDV), pressures (RAP, PAOP) and colloid osmotic pressure were used to compare the volume effect of the two HES. The replacement of about 40% of the circulating blood volume associated with ANH resulted in a similar haemodynamic response with both HES. In particular, CI and RVEDV index remained unchanged and comparable with both colloids. Cardiac filling pressures increased comparably with both HES and colloid osmotic pressure remained unaltered with both solutions. All these observations indicate a similar plasma substitution effect with HES 130 and HES 200. Considering the difference observed for CI after haemodilution between the two colloids, the number of patients to be included to obtain a significant difference with a power of 80% would be 444 patients per group. For an equivalence study, the number of patients should be increased to 532 per group to observe a maximum difference of 0.25 litre min–1 m–2 for CI.

Any immediate plasma substitution effect of colloids depends primarily on the number of osmotically active molecules, which is reflected in the resulting colloid osmotic pressure. This number is closely related to the in vitro mean molecular weight and the concentration of the product. For a similar concentration, HES 130 contains a higher number of osmotically active molecules than with HES 200. The number of molecules above the renal threshold of HES 130/0.4 is higher while the amount of large molecules is reduced. This leads to a lower initial renal elimination rate. However, this theoretical advantage is counterbalanced by a more rapid distribution phase than HES 200,3 11 so that the immediate plasma substitution effect appeared similar with the two starches. Only one study has compared the immediate plasma expansion effect of HES 200 and HES 130 in the preoperative phase.12 Our results are in agreement with those of Boldt and colleagues,12 although the volume infused in our study was twice that administered by these authors.

Surprisingly, CI did not increase in response to ANH. This could be attributed to the cardiodepressant properties of the anaesthetic technique used in the present study.13 Vasodilating properties and negative inotropic effects may both be implicated and may explain the apparent discrepancy between the absence of change in RVEDV and a significant increase in cardiac filling pressures.

The second end-point of this study was to compare the medium-term plasma expansion effect of HES 130 and HES 200. In order to investigate potential differences in the pharmacodynamics of the two starches, no additional HES was administered after ANH. As shown in Table 3, fluid replacement until the end of surgery and during the postoperative phase was mainly achieved by infusion of crystalloids, and the need for additional plasma volume expansion was relatively low. This was to be expected in this type of surgery where blood loss occurs mainly during the procedure. Consequently, retransfusion of ANH blood started during surgery. Up to 24 h after HES infusion, comparable haemodynamics were achieved without any difference in the amount of fluids infused between the two groups.

Exchange models (e.g. ANH) are different from repetitive bolus infusion regimens with respect to volume and duration of infusion, which were used in the other clinical trials comparing the two starches. Langeron and colleagues 14 and Huet and colleagues15 compared the clinical efficacy of HES 130/0.4 and HES 200/0.5 in orthopaedic and cardiac surgery, respectively. In these clinical conditions, there was no difference in the amount of colloid needed to restore or maintain haemodynamic stability until POD1.

As the plasma expanding effect and plasma half-life of HES solutions are generally correlated, our results were unexpected, especially after administration of a single large bolus dose during ANH and a long observation period. Indeed, pharmacokinetic studies using the same model demonstrated that the terminal half-lives of HES 130/0.4 and HES 200/0.5 are 12.1 h and 30.6 h, respectively.3 11 However, differences in plasma concentrations might be compensated for, over a limited period, by a greater number of small oncotically active molecules, as a lower in vivo molecular weight is achieved earlier.3 11 This hypothesis is supported by studies from Köhler and colleagues16 and Waitzinger and colleagues,5 who measured blood and plasma volume after blood exchange with HES 130 and HES 200 in healthy volunteers. Blood and plasma volume expanding effects were comparable for about 6 h with the two HES. Our data in patients undergoing extended ANH supported the hypothesis that despite a shorter half-life, the lower in vivo molecular weight of HES 130/0.4 appears to maintain comparable haemodynamics.

A larger difference in half-life of starch specifications could, however, be associated with a significant difference in the duration of the plasma expansion effect. Boldt and colleagues17 compared HES 130/0.4 with HES 450/0.7 in maintaining haemodynamics until the second postoperative day in patients undergoing abdominal surgery. The difference in volume to be administered was significant 5 h after surgery. In this case, the lower in vivo molecular weight of HES 130 could not compensate for the higher plasma HES concentrations achieved with HES 450/0.7. Indeed, HES 450/0.7 has the longest half-life of all available starches.18

Under the conditions of our study, there was no significant difference in perioperative and postoperative blood loss nor in allogeneic blood transfusion requirements between the two HES. This is in contrast to recent studies showing a reduction in total blood loss,15 or a reduced need for allogeneic blood transfusion14 with HES 130 compared with HES 200. However, our study was not specifically designed to address this problem and the number of patients included was too small. High in vitro molecular weight starches with a high degree of substitution such as HES 450/0.7 influence coagulation more profoundly, resulting in higher surgical blood losses than HES 130/0.4.17 A compromise between plasma volume substitution effect and adverse events is important when starches are used for plasma replacement.

Admittedly on a small sample size, the results of the present study demonstrate a good immediate and medium-term plasma volume substitution effect of HES 130 compared with HES 200. HES 130 could represent a suitable synthetic colloid for plasma volume substitution during extensive ANH in the context of major abdominal surgery.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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15 Huet RCG, Siemons AW, Baus D, et al. A novel hydroxyethylstarch (Voluven®) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 2000; 47: 1207–15[Abstract]

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17 Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend®) on measures of coagulation. Br J Anaesth 2002; 89: 722–8[Abstract/Free Full Text]

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