Dong Hee Kim, M.D. INTRODUCTION

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1 Anesth Pain Med 2009; 4: 235~241 임상연구 Seventy-two hour peri-operative volume replacement with 6% HES 130/0.4 vs. 20% albumin in patients undergoing abdominal, cranial, and orthopedic surgery Department of Anesthesiology and Pain Medicine, College of Medicine, Dankook University, Cheonan, Korea Dong Hee Kim, M.D. Background: This study was designed to compare hydroxyethylstarch (HES) to albumin in high-risk surgery patients infused over 72 h peri-operatively; hemodynamic changes, oxygen transport parameters, blood gases, blood coagulation, blood loss, blood use, outcome, and costs were compared. Methods: High-risk surgical patients undergoing high-risk abdominal, cranial, and orthopaedic surgery were treated with 6% HES (130/0.4; n = 41) or 20% albumin (n = 19). The goal of volume therapy was to maintain a normal cardiac index (CI; 3.0 L/min/m 2 ) over 72 h peri-operatively. Results: The hemodynamic and cardiac effects of 6% HES were superior to 20% albumin. HES reduced disturbances in blood coagulation, blood loss, and blood use as compared to albumin. Volume therapy with HES and albumin improved patient outcomes. Use of HES resulted in a significant cost reduction compared to albumin. Conclusions: Volume replacement with 6% HES and 20% albumin in surgery over 72 h peri-operatively improved hemodynamic parameters and oxygen transport to normal values. HES provides a cost-effective alternative to albumin in surgery with improved efficacy and safety. (Anesth Pain Med 2009; 4: ) Key Words: albumin, cardiac index, high risk surgery, hydroxyethylstarch, volume replacement. INTRODUCTION Hydroxyethylstarch (HES) have shown to improve organ function, system functions, ICU-, ventilator- and hospital days, mortality and costs have been documented in goal directed clinical trials performed in surgery, trauma, sepsis and burns, and in cardiogenic or septic shock. 1-4) In these studies, patients were treated with colloids (HES, albumin, gelatine) using normal 논문접수일 :2009 년 4 월 2 일책임저자 : 김동희, 충남천안시안서동산 16-5 단국대학교의과대학마취통증의학교실우편번호 : Tel: , Fax: ybs90@unitel.co.kr 235 dosages versus larger dosages, to study the outcome improving effect of goal directed volume therapy to supranormal values of hemodynamics, oxygen delivery, oxygen consumption and tissue oxygenation (CI, DO2, VO2, ptco2). HES versus crystalloids showed superior hemodynamic and oxygen transport effects with colloids. 5) Albumin is still the preferred colloid solution in USA and also used in Asia, mainly in China, Taiwan, Korea and Japan. Albumin is used in these countries in large scale for volume replacement in patients with hypovolemia and shock in surgery, trauma, sepsis and burns. In Europe HES solutions, gelatine and dextran solutions are used instead of albumin and crystalloids. Clinical trials demonstrate the equivalent blood volume and hemodynamic effects of HAES-steril/Voluven and 5% albumin in surgery and trauma 3) and the superior effects in sepsis. 2) Other clinical trials also document the superior hemodynamic and oxygen transport effects of HAES-steril/Voluven vs. crystalloids in trauma and intensive care. 6) Albumin is a natural colloidal solution manufactured from donor blood, and may carry risks of blood transfusion like side effects such as infections, reactions and albumin is very costly and a major financial burden on hospitals budget. Crystalloid solutions are lower in cost and in side effects, but carry the risks of poor hemodynamic efficacy, hypovolemia, edema formation and organ/system failure. Objectives of the described study were to compare hemodynamic, oxygen transport, outcome effects and laboratory parameters of 20% albumin and 6% HES used as volume replacement therapy during the intra op. and post op. periods in high risk surgery patients over 72 h.

2 236 Anesth Pain Med Vol. 4, No. 3, 2009 MATERIALS AND METHODS After approval of the study protocol by the Ethical Committee at Dankook University Hospital a randomized controlled prospective investigator driven study was performed in high risk surgery patients with hypovolemia and shock: Volume therapy was performed with 20% albumin (A-group) or with 6% HES (H-group) in high risk surgery patients to stabilize hemodynamics and organ functions up to 72 h. 60 high risk surgery patients were randomly allocated using a randomization list to two treatment groups receiving either albumin 20% (A-group) or HES (H-group). Both solutions were administered after surgery during intensive care to cover post op. blood losses and to optimize circulatory blood flow and organ/system functions. Goal directed fluid management with both colloids was performed to normalize mean arterial pressure (MAP), blood/plasma volume (BV), hemodynamics (CI), oxygen delivery (DO2), tissue oxygenation (ptco2), oxygen consumption (VO2) and organ/system functions during the entire 72 h pre, intra and postop. period. Additional crystalloidal fluids were administered to patients of both groups daily to correct interstitial and intracellular fluid losses with the urine and fluid losses by perspiration and other causes in order to maintain adequate hydration. Hemodynamic parameters, blood gas parameters, coagulation parameters, patient outcome and total costs were compared in A-group and H-group patients from preop. until postop. 72 h. Inclusion criteria of the patients were defined as follows: age years, elective surgery requiring anaesthesia grade ASA III-IV, extensive surgery planned for carcinoma, (eg. esophagectomy, gastrectomy, lung resections, large bowel resections), prolonged surgery > 8 h, massive acute blood loss (> 8 units) or blood volume < 1.5 L/m 2, shock: MAP < 60 mmhg, CVP < 15 cm H 2O and UO < 20 ml/h, acute abdominal catastrophies with hemodynamic instability (GI bleeding), late stage vascular disease involving aortic disease, severe nutritional problems, eg. weight loss > 10 kg, plasma albumin < 3 g/dl. Exclusion criteria included: history of cardiac surgery, severe congestive heart failure, acute renal failure, hepatic diseases, pancreatitis, coagulation disorders, known allergy to starch, pregnancy or nursing, participation in another clinical trial. Volume therapy with both fluid regimens (albumin or HES) was administered preop until 72 h to maintain cardiac index at normal values (3.0 L/min, m 2 ). Packed red blood cells (PRBC) were transfused, to maintain hematocrit (Hct) values > 30%, fresh frozen plasma (FFP) was infused to maintain hemostasis (aptt > 70 s, fibrinogen < 1.5 g/dl). In all patients the same anesthetic technique was performed: Induction with propofol, maintenance with oxygen, nitrous oxide and sevofluren. Ventilation was performed pre, intra and postop. until 72 h. PaO 2 was kept between 100 and 150 mmhg and PaCO 2 between 38 and 50 mmhg by modifying fraction of inspired oxygen (FiO 2) or ventilation pattern. Hemodynamic measurements were obtained preop., intraop. and after 12, 24, 36, 48 and 72 h using noninvasive cardiothoracic bioimpedance technique (BioZ-System, Cardiodynamics, USA). Hemodynamic parameters included mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), cardiac output (CO), stroke index (SI), stroke volume (SV), systemic vascular resistance index (SVRI), stroke volume (SVR) and base thoracic impedance (Zo) (Thoracic fluid content). Oxygen delivery (DO 2) was calculated from CI, Hb and SaO 2 according to the formula: DO 2 = CI Hb SaO Further more specific cardiac parameters were assessed with the BioZ-System like acceleration index (ACI), velocity index (VI), thoracic fluid content (TFC), left cardiac work index (LCWI), left cardiac work (LCW), systolic time ratio (STR), pre ejection period (PEP, left ventricular ejection time (LVET). Further oxygen related parameters monitored during 72 h included: fraction of inspired oxygen (FiO 2), arterial blood ph (ph), arterial oxygen tension (PaO 2), arterial carbon dioxide tension (PaCO 2), plasma bicarbonate (HCO 3 ), arterial carbon dioxide tension (PaCO 2), base excess (BE), arterial oxygen saturation (SaO 2), oxygen delivery index (DO 2I), Hct, prothrombin time (PT) partial thromboplastin time (PTT). Vasoactive drugs were administered preop., intraop and postop according to following criteria: dopamine was titrated in doses of 2 10μg/kg/min, if MAP decreased to values < 65 mmhg or if there was no response to fluid challenge with 100 ml colloids or crystalloids. Noradrenaline was titrated in doses of 1 4μg/kg/min, if there was no response to dopamine. Adrenaline was titrated in doses of 1 2μg/kg/min, if there was no response to noradrenaline. Nitroglycerine was finally titrated in doses of 5 15μg/kg/min, if MAP increased to values > 120 mmhg. Therapy was initiated preop. and was continued intra-op. and postop. until 72 h. Monitoring of central hemodynamics was performed with cardiothoracic bioimpedance (Bio Z. System, Cardiodynamics, San Diego CA 92121, 6175 Nancy Ridge Drive, Suite 300, USA). Electrocardiogram (ECG) was assessed with an ECG

3 Dong Hee Kim:72 h perioperative volume replacement 237 monitor (ECG-Monitor model Space Labs, USA). MAP and HR were measured with a blood pressure monitor (Model 90431, Spacelabs, USA). SaO 2 and blood gases (PaO 2, PaCO 2) were monitored with a blood gas analyser (Model Spacelabs, USA) and ABGA (GEM premier plus Instrumentation Laboratory, Italy). Hct and hemoglobin (Hb) were assessed with CBC monitor (XE2100, Sysmex, Japan). PTT and PT finally were measured with coagulation monitor (ACL 9000, Instrumentation Laboratory, Italy). Measurements of all parameters were performed by physicians, who were not involved in the study and not aware of randomization plan. Primary target parameters included CI, DO2, SVR, SV and Zo (preop, intraop and postop up to 72 h), ventilator days, ICU days, hospital days, organ complications, organ/system failure, mortality and cost of treatment. Secondary target variables included peripheral hemodynamic parameters like MAP, HR, further hemodynamic and cardiac parameters, blood gases and laboratory parameters. Statistical analysis of group differences was performed by Student t-test. Table 1. Patients Characteristics, Underlying Disease, and Data from Intensive Care Management A-group (n = 19) H-group (n = 41) Age (yr) ± ± Weight (kg) ± ± Type of surgery Orthopedic 2 Abdominal Thoracic Head 2 14 Volume therapy prior to the study Packed red blood cells 0.28 ± ± 0.46 (units) Fresh frozen plasma 0.00 ± ± 0.56 (units) Crystalloid (ml) 1, ± , ± Survivors 19/19 38/41 Score at baseline ISS (Injury severity score) 5.00 ± ± 5.51* APACHE II (Acute 3.72 ± ± 4.97 physiology and chronic health evaluation) Data are mean ± SD. *P < 0.05 vs corresponding A-group. RESULTS Demographic data of the patients treated with albumin (A-group) or with HES (H-group) are illustrated in Table 1. There were no significant differences between age, weight, type of surgery, volume therapy, blood component therapy prior to the study or catecholamine therapy between both groups. There were no differences of fluid support with packed red cells, fresh plasma or crystalloids prior to the study. In the A-group, Injury Severity Score (ISS) at baseline was significantly lower than in the H-group (P < 0.05). The Apache II score was no significant group difference. Table 2 is listing Apache Score and cumulative intravascular fluid therapy during the study period preop. until 72 h including blood losses, crystalloid infusions, colloid infusions (HES vs. albumin), urine output, packed red cell and FFP transfusions. Apache II score in A-group and H-group improved at postop. 72 h and in H-group from 5.78 pre op to 6.66 at postop. 72 h with no significant group differences. and H-group received larger infusions of colloids (6% HES) than A-group (20% albumin) (P < 0.05). H-group patients had less blood loss than A-group (P < 0.05). A- group patients required 1.23 units red cells (PRBC), H-group patients required less PRBC than A-group (P < 0.05). H-group patients required less FFP than A-group (P < 0.05). Blood pressures, hemodynamic parameters and oxygen delivery were maintained in A-group and in H-group preop. until 72 h at normal values. In the A-group, preop. CI was 2.99 ± 0.48 L/min/m 2 and CI reached 2.46 ± 0.88 L/min/m 2 at postop. 72 h. In the H-group, preop. CI was 3.09 ± 1.75 L/min/m 2 and CI reached 2.75 ± 0.82 L/min/m 2 at postop. 72 h (Fig. 1). In the A-group, preop. oxygen delivery (DO 2) was ± ml/min/m 2 and was maintained at ± ml/min/m 2 at postop. 72 h. In the H-group, preop. DO 2 was ± and was maintained at ± ml/min/m 2 at 72 h postop. 72 h. In H-group patients several hemodynamic parameters showed significantly larger values of CI, CO, LCWI at 24 h, lower values of LVET and SVR at 12 h, and of TFC at 12 h, 24 h and 36 h vs. A-group patients (Fig. 2-6). In the H-group also significantly lower PaCO 2 values were registered at 12 h and lower PT values at 36 h, 48 h or 72 h postop. vs. A-group patients (P < 0.05) (Fig. 7, 8). These differences were in favour of the H-group vs. the A-group. Cost of volume treatment in H-group was significantly lower than A-group (P < 0.05). Organ complication rate, mortality, ICU days, ventilatory days had no signicant difference between two groups (Table 3).

4 238 Anesth Pain Med Vol. 4, No. 3, 2009 Table 2. APACHE II Score and Cumulative Intravascular Fluid Therapy During the Study Period PreOp PO24 PO48 PO72 APACHE II score (Acute physiology and chronic health evaluation) A-group 3.72 ± ± ± ± 3.56 H-group 5.78 ± ± ± ± 5.40 Bleeding (ml) A-group ± ± ± H-group ± * ± * ± * Crystalloids (ml) A-group ± , ± 1, , ± , ± H-group 1, ± , ± 1, , ± , ± Colloids (ml) A-group ± ± ± H-group ± ± * 1, ± * Urine output (ml) A-group 2, ± , ± 1, , ± , ± H-group 2, ± , ± 1, , ± , ± Packed red cells (total units) A-group 0.28 ± ± ± ± 0.24 H-group 0.12 ± ± 0.70* 0.46 ± ± 0.46 Fresh frozen plasma (total units) A-group 0.00 ± ± ± ± 1.29 H-group 0.12 ± ± ± 0.56* 0.39 ± 1.20 Data are mean ± SD. Preop: preoperative, IO: intraoperative, PO12: postoperative 12 h, PO24: postoperative 24 h, PO48: postoperative 48 h, PO72: postoperative 72 h. *P < 0.05 vs corresponding A-group. P < 0.05 vs corresponding preop. data. Fig. 1. Changes in cardiac index (CI). This illustrates the changes of CI at preop, intraop, postop 12, 24, 36, 48, 72 h. Data are mean ± SD. PreOp: preoperative, IO: intraoperative, PO: postoperative. *P < 0.05 vs corresponding H-group. Fig. 2. Changes in cardiac output (CO). This illustrates the changes of CO at preop, intraop, postop 12, 24, 36, 48, 72 h. Data are mean ± SD. PreOp: preoperative, IO: intraoperative, PO: postoperative. *P < 0.05 vs corresponding H-group. DISCUSSION In the critically ill patient, changes of cardiorespiratory physiology play a key role in outcome. Adequate and early goal directed volume therapy with effective colloidal plasma substitutes is essential to optimize tissue perfusion and to prevent development of multiple organ failure (MOF). There is also growing consensus that reduction in microcirculatory flow and of endothelial integrity is an important trigger for MOF. An association exists between intramucosal acidosis in the gut and organ failure. There is evidence that systemic mediators are

5 Dong Hee Kim:72 h perioperative volume replacement 239 Fig. 3. Changes in left cardiac work index (LCWI). This illustrates the changes of LCWI at preop, intraop, postop 12, 24, 36, 48, 72 h. Data Fig. 5. Changes in systemic vascular resistance (SVR). This illustrates the changes of SVR at preop, intraop, postop 12, 24, 36, 48, 72 h. Data Fig. 4. Changes in left ventricular ejection time (LVET). This illustrates the changes of LVET at preop, intraop, postop 12, 24, 36, 48, 72 h. Data Fig. 6. Changes in thoracic fluid content (TFC). This illustrates the changes of TFC at preop, intraop, postop 12, 24, 36, 48, 72 h. Data released from the gut in critical illness and cause inflammatory reactions, sepsis, ARDS and MOF. 7,8) In this context, splanchnic hypoperfusion may be a common denominator in the development of multiple organ dysfunction syndrome. Thus the correction of microcirculatory maldistribution by colloidal volume therapy appears to be of central importance in the critically ill patient. 9) There is recent evidence that HES 200/0.5 and HES 130/0.4 actually reduces inflammation and endothelial activation in elderly patients undergoing major surgery. Rates of anaphylactoid side effects of HES are lower than with other colloids as shown in a large multicenter study performed in 50 hospitals in 20,000 surgery patients in France. Anaphylactic side effects were equivalent in frequency with albumin and significantly (3- or 2-fold) lower than with gelatines or dextrans. 10) In our prospective randomized clinical trial HES was tested in high risk surgery patients vs. albumin 20% over 1 op. and 2 postop. days up to 72 h to assess hemodynamics, oxygen transport, blood coagulation, blood requirements, organ functions, mortality, length of stay and costs. Hemodynamics and oxygen transport parameters were monitored continuously over 3 days using a noninvasive cardiothoracic bio impedance system. High risk surgery, trauma, sepsis or burns may cause hypovolemia due to blood loss and plasma losses resulting in low

6 240 Anesth Pain Med Vol. 4, No. 3, 2009 Table 3. Patient Outcome A-group H-group Organ complication Organ failure 1/19 2/41 Systemic failure 0 0 Mortality 0/19 3/41 ICUdays 3.83 ± ± 7.90 Ventilator days 0.72 ± ± 2.97 Cost (U.S. dollars) ± ± * Data are mean ± SD. *P < 0.05 corresponding albumin 20% group. Fig. 7. Changes in arterial carbon dioxide pressure (PaCO 2). This illustrates the changes of PaCO 2 at preop, intraop, postop 12, 24, 36, 48, 72 h. Data are mean ± SD. PreOp: preoperative, IO: intraoperative, PO: postoperative. Fig. 8. Changes in prothrombin time (PT) and partial thromboplastin time (PTT). This illustrates the changes of PT, PTT at preop, intraop, postop 12, 24, 36, 48, 72 h. Data are mean ± SD. PreOp: preoperative, IO: intraoperative, PO: postoperative. or uneven blood flow, reduced tissue perfusion, tissue oxygenation and deficits of oxygen consumption. Perioperative accumulation of oxygen debt (deficit of oxygen consumption) may cause organ/system complications, which increase length of ICU/ventilator days, mortality and raise cost of treatment. 1-4) Effective colloidal plasma substitutes like albumin, starches, dextrans orgelatines are useful to prevent and treat hypovolemia and shock in patients due to surgery, trauma, sepsis and burns. Pentastarch (6%HES 200/0.5) is the most commonly used hydroxyethylstarch, which has been documented since 1980 in clinical trials documenting improvement of hemodynamic, oxygen transport and oxygen consumption parameters. Tetrastarch (6% HES 130/0.4) is a more recent hydroxyethylstarch available since 2000, with accelerated elimination from plasma and tissues, reduced interference with blood coagulation and increased daily dosage up to 50 ml/kg bw. Plasma volume effects of 6% HES 200/0.5 and 6% HES 130/0.4 are 100% of the infused volume with a duration of 6 8 h. 11) Significant improved hemodynamic and oxygen transport effects of 6% HES 200/0.5 (HAES-steril) and of 6% HES 130/0.4 (Voluven) were found in studies in cardiac, vascular, orthopedic surgery and in high risk surgery, trauma, sepsis and burns. Hemodynamic and oxygen transport effects registered with HES were comparable to 5% albumin in high risk surgery, vascular surgery patients, cardiac surgery, intensive care patients and patients with severe burns. In a study in sepsis patients superior hemodynamic effects were reported with HES versus albumin. 5) Early optimization of cardiorespiratory physiology has a major influence on patient outcome. Goal directed volume therapy prevents deficits of intravascular volume, cardiac output, oxygen delivery, tissue oxygenation, oxygen consumption (oxygen debt) and thus may prevent organ/system failure and death. HES versus crystalloids have shown significantly larger hemodynamic and oxygen transport responses in clinical trials. HES 130/0.4 has a 100% relative volume effect, which is maintained over 4 hours and which is comparable with HES 200/0.5. The clinical effects of HES 130/0.4 versus HES 200/0.5 have been demonstrated in various prospective randomized clinical trials performed in patients undergoing cardiac, orthopaedic, abdominal and urologic surgery. Hemodynamic improvement after 6% HES 130/0.4 in clinical studies was comparable with 6% HES 200/0.5. Blood losses and blood requirements with HES 130/0.4 were reduced versus HES 200/0.5 at the same daily dose or were comparable at larger daily doses of Voluven. 12) HES 130/0.5 caused less decrease of

7 Dong Hee Kim:72 h perioperative volume replacement 241 FVIII and Ristocetin and less prolongation of aptt than HES 200/0.5. Due to less interference with hemostasis the maximum daily dose of HES 130/0.4 may be increased to 50 ml/kg/day versus 33 ml/kg/day for HES 200/ times lower incidencec of anaphylactoid side effects were reported with HES and albumin, versus dextrans or gelatine in a French clinical multicenter trial in surgery patients. 13) In our goal directed hemodynamic study in high risk surgery patients volume therapy with albumin 20% (A-group) was performed during 72 h and did not reveal a benefit as compared to volume therapy performed with HES 130/0.4 (H-group). Objectives of the described study were to compare hemodynamic, oxygen transport, outcome effects and laboratory parameters of 20% albumin and 6% HES as volume replacement therapy during the intra op. and post op. periods in high risk surgery patients over 72 h. 6% HES and 20% albumin used for volume replacement in surgery preop. until 72 h post op. improved hemodynamic parameters, oxygen transport to normal values. Hemodynamic and cardiac effects of 6% HES were equivalent to 20% albumin. HES reduced depression of blood coagulation, blood loss and blood use vs. albumin. Volume therapy with HES and albumin improved patient outcome. Use of HES resulted in significant cost reduction vs. albumin. HES provides a cost effective alternative to albumin with improves efficacy and safety in surgery. REFERENCES 1. Van der Linden PJ, De Hert SG, Deraedt D, Cromheecke S, De Decker K, Paep R, et al: Hydroxyethylstarch 130/0.4 versus modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. Anesth Analg 2005; 101: Boldt J, Heesen M, Müller M, Pabsdorft M, Hempelmann G: The effects of albumin versus hydroxyethylstarch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth Analg 1996; 83: Kim JY, Lee JW, Kweon TD, Kwak YL, Kim JH, Bang SO: The effect of 6% hydroxyethylstarch 130/0.4 on hemostasis and hemodynamic efficacy in off-pump coronary artery bypass surgery: a comparison with 6% hydroxyethylstarch 200/0.5. Korean J Anesthesiol 2007; 53 (Suppl): Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-Butijn WT, Haagenaars JA, van Oeveren W, et al: A novel hydroxyethyl starch (Voluven R ) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 2000; 47: Boldt J, Lehmann A, Rompert R, Haisch G, Isgro F: Volume therapy with new hydroxyethyl starch solution in cardiac surgical patients before cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000; 14: Karanko MS, Klossner JA, Laaksonen VO: Restoration of volume by crystalloid versus colloid after coronary bypass: hemodynamics, lung water, oxygenation, and outcome. Crit Care Med 1987; 15: Fiddian-Green RG: Associations between intramucosal acidosis in the gut and organ failure. Crit Care Med 1993: 21 (Suppl 2): Haglund U: Systemic mediators released from the gut in critical illness. Crit Care Med 1993; 21 (Suppl 2): Landow L, Anderson LW: Splanchnic ischaemia and its role in multiple organ failure. Acta Anaesthesiol Scand 1994; 38: Boldt J, Knothe C, Zickmann B, Andres P, Dapper F, Hempelmann G: Influence of different intravascular volume therapies on platelet function in patient undergoing cardiopulmonary bypass. Anesth Analg 1993; 76: Waitzinger J, Bepperling F, Pabst G, Opitz J; Hydroxyethylstarch (HES) [130/0.4], a new HES specification: pharmacokinetics and safety after multiple infusions of 10% solution in healthy volunteers. Drug RD 2003; 4: Kasper SM, Meinert P, Kampe S, Görg C, Geisen C, Mehlhorn U, et al: Large-dose hydroxyethylstarch 130/0.4 does not increase blood loss and transfusuon requirements in coronary artery bypass surgery compared with hydroxyethylstarch 200/0.5 at recommended doses. Anesthesiology 2003; 99: Laxenaire MC, Charpentier C, Feldman L: Anaphylactoid reactions to colloidal plasma substitutes: incidence, risk factors, mechanisms. A French multicenter prospective study. Ann Fr Anesth Reanim 1994; 13: