British Journal of Anaesthesia 91 (2): 196±202 (2003) DOI: /bja/aeg159

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1 British Journal of Anaesthesia 91 (2): 196±202 (2003) DOI: /bja/aeg159 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 ² B. E. Ickx 1, F. Bepperling 4, C. Melot 2, C. Schulman 3 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. philippe.vanderlinden@chu-charleroi.be 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 or HES 200/0.5. 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 lling 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 signi cantly, 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± 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 Accepted for publication: April 10, 2003 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 speci cations. 12 These speci cations, which include in vitro molecular weight, the degree of hydroxyethyl substitution, and the C2/ ² Declaration of interest. Supported by a grant from Fresenius Kabi GmbH, Bad Homburg, Germany. Frank Bepperling is employed by Fresenius Kabi, Bad Homburg, Germany. Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003

2 HES 130/0.4 and HES 200/0.5 during and after extended acute normovolaemic haemodilution 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 speci cations. 2 Efforts have been made to develop a new HES with an improved pharmacokinetic pro le leading to a shorter halflife in patients with normal and impaired renal function, 34 because of the absence of plasma accumulation even after repetitive dosing. HES 130 (Voluvenâ, Fresenius Kabi, Bad Homburg, Germany) is a novel HES characterized by an average molecular weight of dalton, a molar substitution of 0.4 and a C2/C6 hydroxyethylation ratio greater than 8. From a theoretical point of view, the improved pharmacokinetic pro le 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 speci cations). 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 colleagues 8 in patients undergoing liver resection. In these conditions, ANH results in a sudden uid 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 uid balance until the end of surgery and for the rst 24 h following HES administration. In addition, any signi cant 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 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, signi cant respiratory disease (Pa O2 <8 kpa at room air), uncontrolled diabetes mellitus, acute infection and coagulopathy. Preoperative exclusion criteria were age less than 18 yr, chronic renal insuf ciency (serum creatinine >1.3 mg dl ±1 (115 mmol l ±1 ) for males or >1.2 mg dl ±1 (106 mmol 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 V 5 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 uid 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 mg, thiopental 3 mg kg ±1 and cisatracurium 0.15 mg kg ±1. Patients were ventilated with a nitrous oxide/oxygen mixture (FI O2 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 iso urane 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 uids. 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/ 197

3 Ickx et al % (HES 130 group; n=20) or HES 200/0.5 6% (HES 200 group; n=20) (HAES-sterilâ, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany). The sample size was chosen arbitrarily. The solutions were blinded by the manufacturer and were indistinguishable. Randomization 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 uid 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 (DO 2 ) were calculated using standard formulae. RVEDV index was calculated by dividing SVI by RVEF. Body temperature was monitored continuously by the thermistor of the ow-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 lling 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 rst 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 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 uid 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 signi cant difference test. P<0.05 was considered signi cant. Results are presented as mean (SD) unless speci ed otherwise. Results 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). 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 signi cant decrease in MAP, SVR and LVSWI in both groups. Heart rate and SVI did not change in either group. Cardiac lling pressures increased signi cantly, while RVEDV index remained unchanged. In the absence of a signi cant increase in CI, the marked decrease in Hb concentration resulted in a signi cant decrease in DO 2. In the immediate postoperative period, CI increased signi cantly, while SVR remained signi cantly lower than baseline. DO 2 increased and returned to baseline values. There was no difference in any of the measured haemodynamic variables between the two groups at any time. 198

4 HES 130/0.4 and HES 200/0.5 during and after extended acute normovolaemic haemodilution Table 1 Physical characteristics of patients and their therapy HES 130 group HES 200 group Mean age (yr) (range) 62 (47±72) 62 (44±69) Sex (male/female) 20/0 19/1 Weight (kg) 77.2 (11.1) 78.8 (6.7) Body surface area (m 2 ) 1.90 (0.15) 1.93 (0.13) Cardiovascular medication (no. patients) b-blockers 7 4 Angiotensin-converting enzyme 2 1 inhibitors Calcium blockers 2 2 Type of surgery (no. patients) Radical prostatectomy Cystectomy 2 2 Duodenopancreatectomy 1 0 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 uid 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 signi cantly different between groups. 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 signi cant 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. 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 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 dif cult to realise in a daily clinical routine. Determination of ow (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 lling 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 signi cant 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 re ected 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, 311 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 signi cant increase in cardiac lling 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, uid replacement until the end of surgery and during the postoperative phase was mainly achieved by infusion of 199

5 Ickx et al. 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 HES 130 group HES 200 group Heart rate (beats min ±1 ) Baseline 74 (13) 72 (14) ANH 68 (10) 68 (13) Surgery 67 (9) 65 (12) PACU 91 (14)** 84 (17) POD1 83 (15) 80 (18) Mean arterial pressure (mm Hg) Baseline 103 (13) 108 (17) ANH 69 (13)** 72 (13)** Surgery 75 (13)** 75 (12)** PACU 93 (17) 90 (12)** POD1 94 (14) 86 (15)** Mean pulmonary artery pressure (mm Hg) Baseline 16.2 (3.7) 16.0 (3.1) ANH 19.8 (4.3) 19.4 (5.1) Surgery 21.9 (5.4)* 19.9 (3.8) PACU 18.6 (7.6) 18.8 (6.5) POD (4.6) 16.4 (4.3) Pulmonary artery occlusion pressure (mm Hg) Baseline 11.3 (2.9) 10.5 (3.6) ANH 15.2 (4.8) 14.2 (5.2) Surgery 17.5 (4.9)** 16.1 (4.2)** PACU 11.7 (5.1) 12.5 (5.8) POD1 9.6 (3.3) 10.7 (4.5) Right atrial pressure (mm Hg) Baseline 6.7 (2.8) 6.5 (3.6) ANH 10.6 (3.5)* 10.1 (4.4) Surgery 11.8 (3.6)** 10.9 (3.6)** PACU 7.8 (4.3) 8.0 (4.7) POD1 6.7 (2.9) 6.4 (2.5) Cardiac index (litre min ±1 m ±2 ) Baseline 3.31 (0.43) 3.00 (0.62) ANH 3.24 (0.70) 3.11 (0.70) Surgery 3.35 (0.79) 2.98 (0.67) PACU 4.67 (1.18)** 4.34 (0.78)** POD (0.88) 3.75 (0.73) Stroke index (ml m ±2 ) Baseline 45.1 (5.8) 42.6 (7.4) ANH 47.5 (8.9) 46.0 (8.0) Surgery 50.8 (13.4) 46.0 (7.8) PACU 52.8 (15.4) 53.3 (13.2) POD (13.4) 48.6 (12.4) Right-ventricular end-diastolic volume index (ml m ±2 ) Baseline ANH Surgery PACU POD1 103 (22) 114 (27) 125 (43) 112 (35) 107 (29) 99 (15) 109 (25) 119 (33) 107 (24) 115 (39) Systemic vascular resistance (d s cm ±5 ) Baseline 1268 (312) 1428 (237) ANH 789 (202)** 846 (1860** Surgery 849 (338)** 930 (240)** PACU 830 (308)** 800 (138)** POD1 979 (346)* 910 (261)** Left ventricular stroke work index (g m m ±2 ) Baseline 56.0 (7.1) 57.0 (15.5) ANH 34.9 (9.8)** 35.9 (8.6)** Surgery 39.0 (10.4)** 36.8 (10.2)** PACU 57.1 (16.1) 57.4 (20.0) POD (14.3) 49.9 (15.4) Haemoglobin concentration measured by co-oximeter (g dl ±1 ) Baseline 13.4 (0.9) 14.0 (1.0) ANH 8.2 (1.0)** 8.3 (0.8)** Surgery 8.2 (1.0)** 8.2 (0.9)** PACU 9.8 (0.9)** 10.1 (1.6)** POD1 9.9 (1.3)** 10.3 (1.0)** Arterial oxygen saturation (%) Baseline 96.4 (1.9) 96.3 (1.8) ANH 96.8 (2.2) 97.2 (0.9) Surgery 96.9 (1.8) 97.0 (1.0) PACU 96.1 (1.9) 96.4 (1.6) POD (1.6) 96.8 (0.9) Oxygen delivery (ml min ±1 m ±2 ) Baseline 609 (94) 581 (145) ANH 375 (89)** 368 (85)** Surgery 390 (104)** 347 (89)** PACU 622 (153) 597 (114) POD1 556 (173) 531 (105) 200

6 HES 130/0.4 and HES 200/0.5 during and after extended acute normovolaemic haemodilution 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 HES 130 group HES 200 group Preoperative Investigated colloid (ml) 1825 (245) 1925 (183) Perioperative Crystalloids (ml) 3340 (1800) 3753 (2799) Colloids (ml) 390 (492) 630 (484) ANH blood (ml) 1635 (417) 1673 (494) No. allogeneic PRBC (units) 0 (0±1) 0 (0±16) No. patients transfused 1 2 Blood loss (ml) 2000 (600±2800) 2200 (500±18000) Urine (ml) 516 (431) 578 (528) Postoperative day 1 Crystalloids (ml) 2137 (540) 2317 (1103) Colloids (ml) 145 (242) 212 (297) No. allogeneic PRBC (units) 0 (0±3) 0 (0±5) No. patients transfused 2 6 No. FFP (units) 0 (0±4) 0 (0±7) No. patients transfused 2 1 Blood loss (ml) 140 (10±630) 215 (20±1380) Urine (ml) 1935 (863) 1779 (483) Total hospital stay Number of allogeneic PRBC 0 (0±4) 0 (0±18) (units) No. patients transfused 5 7 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 uids 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 colleagues 15 compared the clinical ef cacy 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 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. 311 This hypothesis is supported by studies from KoÈhler and colleagues 16 and Waitzinger and colleagues, 5 who measured blood and 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) HES 130 group HES 200 group Haemoglobin (g dl ±1 ) Preoperative 14.9 (1.0) 15.2 (1.1) PACU 9.8 (1.1) 10.2 (1.4) POD1 9.9 (1.2) 10.1 (1.3) Discharge 9.8 (1.7) 10.3 (1.3) Haematocrit (%) Preoperative 44.2 (3.1) 45.7 (3.2) PACU 29.5 (4.0) 29.9 (4.2) POD (3.8) 29.5 (4.1) Discharge 29.3 (5.2) 30.4 (4.3) Creatinine (mg dl ±1 ) Preoperative 1.05 (0.13) 1.15 (0.12) PACU 0.95 (0.19) 1.02 (0.12) Prothrombin time (%) Preoperative 105 (24) 111 (15) PACU 71 (12) 71 (11) POD1 82 (16) 83 (15) Activated partial thromboplastin time (s) Preoperative 27.7 (2.7) 28.5 (2.9) PACU 32.2 (7.2) 32.8 (6.3) POD (3.4) 36.2 (6.5) Platelet count (1000 mm ±3 ) Preoperative 248 (53) 218 (49) PACU 175 (39) 155 (40) POD1 156 (41) 138 (36) Colloid osmotic pressure (mm Hg) Preoperative 22.1 (2.4) 21.2 (2.3) ANH 22.1 (1.5) 21.6 (1.9) 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 speci cations could, however, be associated with a signi cant difference in the duration of the plasma expansion effect. Boldt and colleagues 17 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 signi cant 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 signi cant 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 transfusion 14 with HES 130 compared with HES 200. However, our study was not speci cally designed to address this problem and the number of patients included 201

7 Ickx et al. was too small. High in vitro molecular weight starches with a high degree of substitution such as HES 450/0.7 in uence coagulation more profoundly, resulting in higher surgical blood losses than HES 130/ 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 mediumterm 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 1 Mishler IV JM. Synthetic plasma volume expanders ± their pharmacology, safety and clinical ef cacy. Clin Haematol 1984; 13: 75±92 2 Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med 1999; 25: 258±68 3 Waitzinger J, Bepperling F, Pabst G, Opitz J, MuÈller M, Baron JF. Pharmacokinetics and tolerability of a new hydroxyethyl starch (HES) speci cation (HES 130/0.4) after single-dose infusion of 6% or 10% solutions in healthy volunteers. Clin Drug Invest 1998; 16: 151±60 4 Jungheinrich C, Scharpf R, Wargenau M, Bepperling F, Baron JF. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 6% in mild-to-severe renal impairment. Anesth Analg 2002; 95: 544±51 5 Waitzinger J, Bepperling F, Pabst G, Opitz J, Fackelmeyer A, Boldt J. Effect of a new hydroxyethyl starch (HES) speci cation [HES (130/0.4)] on blood and plasma volumes after bleeding in 12 healthy male volunteers. Clin Drug Invest 1999; 17: 119±25 6 Kasper SM, Stromich A, Kampe S, Radbruch L. Evaluation of a new hydroxyethyl starch solution (HES 130/0.4) in patients undergoing preoperative autologous blood donation. J Clin Anesth 2001; 13: 486±90 7 Weiskopf RB. Hemodilution and candles. Anesthesiology 2002; 97: 773±5 8 Matot I, Scheinin O, Jurim O, Eid A. Effectiveness of acute normovolemic hemodilution to minimize allogeneic blood transfusion in major liver resections. Anesthesiology 2002; 97: 794±800 9 Daper A, Parquier J-N, Preiser J-C, Contempre B, Vincent J-L. Timing of cardiac output measurements during mechanical ventilation. Acute Care 1989; 12: 113±16 10 Viitanen A, Salmenpera M, Heinonen J. Right ventricular response to hypercarbia after cardiac surgery. Anesthesiology 1991; 73: 393± Weidler B, von Bormann B, Sommermeyer K, Lohmann E, Peil J, Hempelmann G. Pharmakokinetische Merkmale als Kriterien fuèr den klinischen Einsatz von HydroxyethylstaÈrke. Drug Res 1991; 41: 494±8 12 Boldt J, Lehmann A, RoÈmpert R, Haisch G, Isgro F. Volume therapy with a new hydroxyethyl starch solution in cardiac surgical patients before cardiopulmonary bypass. J Cardiothorac Anesth 2000; 14: 264±8 13 Ickx B, Rigolet M, Van der Linden P. Cardiovascular and metabolic response to acute normovolemic anemia: effects of anesthesia. Anesthesiology 2000; 93: 1011±16 14 Langeron O, Doelberg M, Eng-Than A, Bonnet F, Capdevila X, Coriat P. Voluven â, a lower substituted novel hydroxyethylstarch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg 2001; 92: 855±62 15 Huet RCG, Siemons AW, Baus D, et al. A novel hydroxyethylstarch (Voluven â ) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 2000; 47: 1207±15 16 KoÈhler H, Zschiedrich H, Linfante A, Appel F, Pitz H, Clasen R. Die Elimination von HydroxyethylstaÈrche 200/0.5, Dextran 40 und Oxypolygelatine. Klin Wochenschr 1982; 60: 293± Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A. Effects of a new modi ed, balanced hydroxyethyl starch preparation (Hextend â ) on measures of coagulation. Br J Anaesth 2002; 89: 722±8 18 Yacobi A, Stoll RG, Sum CY, Lai CM, Gupta SD, Hulse JD. Pharmacokinetics of hydroxyethyl starch in normal subjects. J Clin Pharmacol 1982; 22: 206±12 202