Van der Linden, Philippe J. MD, PhD*; De Hert, Stefan G. MD, PhD†; Deraedt, Dirk MD‡; Cromheecke, Stefanie MD†; De Decker, Koen MD‡; Paep, Rudi De MD‡; Rodrigus, Inez MD, PhD§; Daper, Anne MD*; Trenchant, Anne MD*
Plasma volume expansion is of substantial importance during major surgery. To achieve this goal, colloids may be preferred to crystalloids, as they more effectively increase blood volume and, by inference, cardiac output (1). A number of studies have compared the different available colloids. In almost all these studies, the outcome was either not an endpoint or was not reported (2,3). It is therefore not surprising that reasons for choosing specific products remain unclear (4)
Gelatins (GEL) have the advantage of their unlimited daily dose recommendation and minimal effect on hemostasis (5). However, they are associated with a more frequent incidence of allergic reaction (6). Urea-linked GEL are associated with more than twice the incidence as the modified fluid form (7). Hydroxyethyl starches (HES) have the advantage of a higher plasma-expanding effect and an infrequent incidence of allergic reactions, but they have more pronounced effects on hemostasis (8).
A recent prospective study has compared 3.5% urea-linked GEL and 6% HES 200/0.5 in patients undergoing cardiac surgery (9). Total blood loss was higher in the HES group, resulting in increased use of allogeneic blood. As the HES-related effects on hemostasis appear to be related to their specifications (10), a new HES with a lower in vivo molecular weight (HES 130/0.4) has been introduced. This new synthetic colloid appears to have fewer effects on hemostasis (11–13) while maintaining the same effectiveness as medium molecular weight HES (13–15). In patients undergoing cardiac (16) or major abdominal surgery, Haisch et al. (17) reported similar coagulation alterations between 6% HES 130/0.4 and 4% modified fluid GEL. HES 130/0.4 might therefore be equivalent to modified fluid GEL with regard to blood loss and transfusion requirements in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). The present study tested this hypothesis using calculated net red blood cell (RBC) loss (18) as the primary outcome variable.
This prospective, randomized, single-blind study was approved by the Institutional Ethical Committee and written informed consent was obtained from all subjects. One-hundred-thirty-two patients with a preoperative left ventricular ejection fraction more than 35% undergoing elective primary cardiac surgery were studied. Exclusion criteria included a history of allergic reactions to HES or GEL and the presence of significant liver (serum alanine aminotransferase and serum aspartate aminotransferase >2.5 times normal) or renal (serum creatinine > 1.3 mg/dL) dysfunction. All preoperative cardiac medication was continued until the morning of surgery, except for angiotensin-converting enzyme inhibitors, angiotensin II antagonists, and acetyl salicylic acid that were discontinued 1 and 7 days before surgery, respectively.
Patients received routine monitoring including 5-lead electrocardiography, radial and pulmonary artery catheters, pulse oximetry, capnography, and blood and urine temperature monitoring. Anesthetic regimen (remifentanil, midazolam, sevoflurane, pancuronium bromide), surgical technique, and cardioprotective strategies were standardized in all patients. After porcine heparin administration (300 U/kg), surgery was performed under moderate hypothermia (coronary surgery, 32°C; valve + coronary surgery, 28°C) using a nonpulsatile CPB (pump flow 2.4 L/min.m2), and a coated membrane oxygenator (Optima™; Cobe Cardiovascular Inc, Arvada, CO). All patients received aprotinin given as a bolus dose of 2.106 kallikrein-inhibiting units (KIU) followed by a continuous infusion of 500,000 KIU/h and an additional bolus of 2.106 KIU in the pump prime. Kaolin activated clotting time (ACT) was maintained at more than 450 s throughout the bypass with additional boluses of heparin (50–100 U/kg). After discontinuation of CPB, heparin activity was neutralized with protamine sulfate at a ratio of 1 mg protamine per 100 U heparin. Protamine administration was further guided by ACT measurements aiming at a value of 140 s.
Patients were randomly allocated (computer generated) to receive either 6% HES 130/0.4 (Voluven, Fresenius Kabi, Bad Hombourg, Germany) (HES group: n = 64) or 3% modified fluid GEL (Geloplasma, Fresenius Kabi) (GEL group: n = 68) for intraoperative (including priming of the CPB machine) and postoperative volume management with a maximum dosage of 50 mL/kg/day.
Volume replacement was guided by the use of the routine perioperative care aiming to maintain pulmonary artery occluded pressure between 8 and 15 mm Hg, cardiac index > 2.5 L/min.m2, and urine production more than 0.5 mL · kg−1 · h−1. If additional fluid was required, isotonic crystalloid (Plasmalyte A; Baxter, Lessines, Belgium) was used. Inotropic (dobutamine) and vasoactive (phenylephrine or noradrenaline) drugs were administered according to the routine clinical protocol described previously (19). The study period comprised intraoperative and postoperative investigations up to 20 h after surgery. Transfusion policy, based on the hemoglobin level (intensive care unit [ICU], 7 g/dL; ward, 8 g/dL) was standardized. In the presence of abnormal clinical bleeding, transfusion of platelet and fresh-frozen plasma was guided by an algorithm based on the platelet count, prothrombin time (PT), and partial thromboplastin times (20). Strict adherence to transfusion algorithms was obtained (21).
Hemodynamic measurements included heart rate, mean arterial blood pressure, right atrial pressure, pulmonary artery pressure, and pulmonary artery occluded pressure. Cardiac output was measured using the thermodilution technique. Three consecutive measurements were performed at each time and averaged. Derived data were calculated using standard equations. Measurements were performed after induction of anesthesia, before any colloid administration (T1), at the end of surgery (T2), at arrival in the ICU (T3), and 4 (T4), 12 (T5), and 20 h (T6) later.
Laboratory measurements including hemoglobin concentration, hematocrit, PT, activated partial thromboplastin time, platelet count, creatinine, and liver enzymes were performed the day before surgery (T-1), at T6 and on postoperative day 5.
Fluid administration, urine production, and blood loss were carefully measured in the perioperative period and up to 20 h postoperatively. Blood losses were also calculated by using the equations developed by Mercuriali and Inghilleri (18), considering sex, preoperative body weight, and hematocrit (preoperatively and on postoperative day 5) and volume of allogeneic blood transfusion. Calculated blood loss was expressed in mL of RBC (at the hematocrit of 100%).
Assuming the two fluid regimens were similar with regard to the calculated blood loss, a difference <195 mL (hematocrit 100%, similar to one RBC unit with a hematocrit of 60%–65%) was considered as clinically equivalent. Based on an estimated net RBC loss of 529 ± 277 mL on postoperative day 5 (internal data base), a total number of at least 120 patients appeared appropriate to have a power of 0.9 and α = 0.05.
Demographic data and data on fluid management were compared between groups using Fisher exact and unpaired Student’s t-test where appropriate. Hemodynamic and laboratory data were compared using a two-way analysis of variance for repeated measurements followed by a post hoc Tukey test. A P value < 0.05 was considered statistically significant.
Patients’ characteristics were comparable in both groups (Table 1). Total study drug administered was 48.9 ± 17.2 mL/kg in the HES group and 48.9 ± 14.6 mL/kg in the GEL group (Table 2). There was no difference in the number of patients receiving rescue crystalloid or in the amount of crystalloid administered. Intraoperative and postoperative urine production was similar in both groups. Measured intraoperative and postoperative blood losses were similar in both groups. Calculated net RBC loss was equivalent. Neither the number of patients transfused with allogeneic blood nor the volume of packed RBC administered was different between groups. Fresh-frozen plasma and platelets administration also did not differ between groups.
There was no significant difference in any of the measured laboratory data between the two groups throughout the study period (Table 3).
All hemodynamic variables measured up to 20 h postoperatively were similar in both groups (Table 4). Use of inotropic support or a vasoconstrictive drug was also similar in both groups. Duration of mechanical ventilation and ICU length of stay did not differ between groups (Table 5). Three patients (1 in the HES group and 2 in the GEL group) required re-operation for hemorrhage. One patient in the GEL group died postoperatively from myocardial infarction.
Costs related to colloid administration throughout the study period were $92.0 ± $23.5 in the HES group (500 mL solution: $11.6) and $40.5 ± $11.1 in the GEL group (500 mL solution: $5.15) (P < 0.01), which represented respectively 32% and 24% of the total costs related to fluid and blood product transfusion management (Table 6).
In the conditions of the present study, HES 130/0.4 up to 50 mL/kg and modified fluid GEL were associated with equivalent perioperative blood losses. This result contrasts with previous observations reporting larger blood losses with HES 200/0.5 than with GEL (9). Depending on their physico-chemical characteristics, HES may interfere with normal hemostasis resulting in an increased perioperative blood loss. Indeed, HES solutions have been shown to directly compromise platelet contribution to hemostasis by reducing the availability of the functional receptor for fibrinogen on the platelet surface (22). In addition to these direct effects, abnormalities such as a decrease in von Willebrand factor (8,23) may contribute to the decreased platelet responsiveness observed after HES administration. These different effects appear closely related to intrinsic properties of the different solutions, such as the in vitro molecular weight and the degree of hydroxyethyl substitution (13,24). HES 130/0.4 exhibits a lower in vitro molecular weight and a lower degree of hydroxyethyl substitution than HES 200/0.5. Therefore it could have less impact on hemostasis, in particular on the factor VIII-von Willebrand factor complex (13), and on platelet aggregability (24). Some studies in orthopedic and cardiac surgery reported that the use of HES 130/0.4 was indeed associated with less blood losses and transfusion requirements than HES 200/0.5 (11,12).
Measured as well as calculated net RBC loss, based on the hematocrit measured preoperatively and on postoperative day 5, were not different between the two groups. In major surgical procedures, calculated instead of measured blood losses have been proposed to better define the risk of allogeneic transfusion (18). Calculated blood loss was used as the primary outcome variable instead of allogeneic exposure rate because the introduction of a multidisciplinary blood conservation strategy has resulted in a marked reduction in blood transfusion (21). In the presence of a current blood transfusion rate of 20% (rate derived from the local departmental database), demonstration of allogeneic blood exposure equivalency for both volume replacement strategies with a power of 0.8 and α = 0.05, would require a sample size of more than 1100 patients.
A large-dose aprotinin scheme was used in all patients. Interfering at different levels of the hemostatic cascade, aprotinin has been demonstrated to significantly reduce blood loss and transfusion requirements in cardiac surgery (25). Although the use of aprotinin may have blunted the negative effects of some colloids on blood losses, the same aprotinin regimen was applied in both groups.
The amount of colloids required to achieve routine hemodynamic endpoints was not different between the two groups. According to the available pharmacodynamic data, modified fluid GEL is expected to have a lower and shorter plasma-expanding effect than HES 130/0.4. Studies comparing the plasma-expanding effect of GEL and starches reported conflicting results. Haisch et al. (16) reported that a similar volume of 4% modified fluid GEL and 6% HES 130/0.4 was required to keep central venous pressure between 10 and 14 mm Hg. In contrast, Boldt et al. (26) reported that more gelatin than HES 130/0.4 was required to keep central venous pressure between 12 and 14 mm Hg. These different results may be attributed to different fluid management protocols and because Boldt et al. (26) measured fluid administration up to the second postoperative day.
The use of a routine hemodynamic protocol for fluid management represented a rather imprecise evaluation of the patients’ circulating blood volume. In addition, colloid administration was limited to 50 mL/kg per day, as this was the maximal recommended daily dose for HES 130/0.4 in Belgium. Therefore, the current study does not allow formation of conclusions on the relative plasma-expanding efficacy of the two studied colloids.
Routine coagulation tests did not differ between groups. Although very sensitive, these tests are poorly specific of hemostatic disorders (27,28). No adverse reactions were observed in both groups, but study sample size was not sufficient to address this question.
The costs related to colloid administration were higher in the HES than in the GEL group. However, when compared with the expenses related to the total perioperative fluid therapy, this difference becomes negligible.
For technical reasons, it was not possible to reliably blind the two colloids in our institutions. The absence of a double-blind comparison may represent a limitation of the present study. However, the primary outcome variable was the calculated blood loss, which was determined without knowing the group assignment of the patients.
Calculation of blood loss was performed with postoperative hematocrit measured on day 5. As most interventions that affect blood loss occur within the first 24 hours, calculation based on hematocrit measured on the first postoperative day might have resulted in somewhat different conclusions. However, doing so, calculated net RBC loss was 596 ± 242 mL in the HES group and 565 ± 237 mL in the GEL group (P = not significant).
In conclusion, in the conditions of the present study, HES 130/0.4 up to 50 mL/kg was associated with similar blood loss compared to GEL in patients undergoing cardiac surgery with CPB. As these results contrast with those obtained with HES 200/0.5 (9), this may indicate that HES 130/0.4 should be preferred to HES 200/0.5 for plasma volume expansion in cardiac surgery patients.
1. Mc Ilroy DR, Kharasch ED. Acute intravascular volume expansion with rapidly administered crystalloid or colloid in the setting of moderate hypovolemia. Anesth Analg 2003;96:1572–7.
2. Boldt J. New light on intravascular volume replacement regimens: what did we learn from the past three years? Anesth Analg 2003;97:1595–604.
3. Bunn F, Alderson P, Hawkins V. Colloid solutions for fluid resuscitation. The Cochrane Database of Systematic Reviews 2003;1:CD001319.
4. Miletin MS, Stewart TE, Norton PG. Influences on physicians’ choice of intravenous colloids. Intensive Care Med 2003;28:917–24.
5. Van der Linden P, Schmartz D. Pharmacology of gelatins. In: Baron JF, ed. Plasma volume expansion. Paris: Arnette, 1992:67–74.
6. Laxenaire MC, Charpentier C, Feldman L. Anaphylactoid reactions to colloid plasma substitutes: incidence, risk factors, mechanisms: a French multicenter prospective study. Ann Fr Anesth Réanim 1994;13:301–10.
7. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitute. Lancet 1977;1:467–9.
8. Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med 1999;25:258–68.
9. Van der Linden P, De Hert S, Daper A, et al. 3.5 % urea-linked gelatin is as effective as 6% HES 200/0.5 for volume management in cardiac surgery patients. Can J Anaesth 2004;51:236–41.
10. Treib J, Haass A, Pindur G, et al. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorheologic conditions, and coagulation. Transfusion 1996;36:450–5.
11. Langeron O, Doelberg M, Engl-Than A, et al. Voluven (R), a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg 2001;92:855–62.
12. Gallandat Huet RCG, Siemons AW, Baus D, et al. A novel hydroxyethyl starch (Voluven) for effective perioperative volume substitution in cardiac surgery. Can J Anaesth 2000;47:1207–15.
13. Jungheinrich C, Sauermann W, Bepperling F, Vogt NH. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery. Drugs R&D 2004;5:1–9.
14. Ickx B, Bepperling F, Melot C, et al. 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. Br J Anaesth 2003;91:1–7.
15. Boldt J, Lehmann A, Römpert R, et al. Volume therapy with a new hydroxyethyl starch solution in cardiac surgical patients before cardiopulmonary bypass. J Cardiothorac Anesth 2000;14:264–8.
16. Haisch G, Boldt J, Krebs C, et al. Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients. J Cardiothorac Vasc Anesth 2001;15:318–21.
17. Haisch G, Boldt J, Krebs C, et al. The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. Anesth Analg 2001;92:565–71.
18. Mercuriali F, Inghilleri G. Proposal of an algorithm to help the choice of the best transfusion strategy. Curr Med Res Opin 1996;13:465–78.
19. De Hert S, Van der Linden P, Cromheecke S, et al. Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 2004;101:9–20.
20. Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271–9.
21. Van der Linden P, De Hert S, Daper A, et al. A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery. Can J Anaesth 2001;48:894–901.
22. Stögermüller B, Stark J, Willschke H, et al. The effect of hydroxyethyl starch 200 kD on platelet function. Anesth Analg 2000;91:823–7.
23. Strauss RG, Pennell BJ, Stump DC. A randomized blinded trial comparing the hemostatic effects of pentastarch versus hetastarch. Transfusion 2002;42:27–36.
24. Franz A, Bräunlich P, Gamsjäger T, et al. The effects of hydroxyethyl starches of varying molecular weights on platelet function. Anesth Analg 2001;92:1402–7.
25. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940–7.
26. Boldt J, Brenner T, Lehmann A, et al. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of new starch preparation with gelatin. Intensive Care Med 2003;29:763–9.
27. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995;81:360–5.
28. Ciavarella D, Reed RL, Counts RB, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol 1987;67:365–8.