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Anesth Analg 2009; 108:30-36
© 2009 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31818c1282
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CARDIOVASCULAR ANESTHESIOLOGY

Rapidly Degradable Hydroxyethyl Starch Solutions Impair Blood Coagulation After Cardiac Surgery: A Prospective Randomized Trial

Alexey A. Schramko, MD, Raili T. Suojaranta-Ylinen, MD, PhD, Anne H. Kuitunen, MD, PhD, Sinikka I. Kukkonen, MD, PhD, and Tomi T. Niemi, MD, PhD

From the Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital, Meilahti Hospital, Helsinki, Finland.

Address correspondence and reprint requests to Alexey Schramko, MD, Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital, Meilahti Hospital, PO Box 340, Helsinki, FI-00029 HUS, Finland. Address e-mail to alexey.schramko{at}hus.fi.

Abstract

BACKGROUND: There is continuing concern about the effect of hydroxyethyl starch (HES) solutions on blood coagulation. Rapidly degradable HES solutions with more favorable effects on clot strength have therefore been developed. Because the risk of bleeding is increased after cardiopulmonary bypass, we examined whether these types of HES solutions could be administered after cardiac surgery without an alteration of coagulation.

METHODS: Two new rapidly degradable HES solutions were compared with human albumin in 45 patients scheduled for elective primary cardiac surgery. After admission to the cardiac surgical intensive care unit, the patients were allocated in random order to receive either 15 mL/kg of HES solution with low molecular weight and low molar substitution (either 6% HES200/0.5 or 6% HES130/0.4) or 4% human albumin solution as a short-time (70–240 min) infusion.

RESULTS: Clot formation time was prolonged and maximum clot firmness was decreased in thromboelastometry tracings after infusion of both HES solutions. This impairment in thromboelastometry tracings partly recovered (using InTEM® and ExTEM® coagulation activators) at 2 h after the completion of the study infusion. Platelet contribution to maximum clot firmness remained unaffected in all of the study groups. HES did not induce fibrinolysis. No changes in thromboelastometry tracings were observed after human albumin infusion. Chest tube drainage was comparable in the study groups.

CONCLUSIONS: We conclude that a short-time infusion of rapidly degradable HES solutions after cardiac surgery produces impairment in fibrin formation and clot strength in thromboelastometry tracings. In this clinical setting, human albumin does not impair hemostasis.

Colloids are often used during cardiac surgery because of their ability to maintain intravascular volume and regional tissue perfusion more efficiently than crystalloids.1–4 All hydroxyethyl starch (HES) solutions modify blood coagulation as measured by thromboelastometry. They decrease clot strength and prolong clot formation.5 The degree of impairment of the hemostatic system depends on the molecular weight and substitution degree of HES solutions. Previously, rapidly degradable HES solutions (molecular weight under 200 kDa, molar substitution ratio under 0.5) had no clinically significant effect on coagulation when administered as a relatively slow infusion.6 In contrast, high molecular weight HES solutions with a high molar substitution ratio increased blood loss when administrated during cardiac surgery.1,7

The effect of human albumin (HA) solution on blood coagulation is negligible.5,8 HA is therefore sometimes infused for correction of hypovolemia in patients with coagulation disorders,7 but generally HA does not offer any benefits in critical care.9

Cardiopulmonary bypass (CPB) causes activation of the hemostatic system, and postoperatively the risk of bleeding is increased.10,11 In a previous study11 we have shown that the administration of HES200/0.5 in the immediate postoperative phase after cardiac surgery impaired clot strength and was associated with increased chest tube drainage. In the present study we compared a newer rapidly degradable HES solution (130/0.4) with HES200/0.5 and HA after cardiac surgery. We assessed coagulation with a whole blood coagulation assay and hypothesized that HES130/0.4 would impair coagulation less than HES200/0.5.

METHODS

Forty-five patients scheduled for elective primary cardiac surgery were included in the study. The Ethics Committee for Surgery of the Hospital District of Helsinki and Uusimaa and the National Agency of Medicines in Finland accepted the study protocol. All of the patients gave their written informed consent to participate in the study. Patients with any preoperative coagulation disorder, renal or hepatic failure (plasma creatinine >120 µmol/L, alanine amino transferase >90 U/L, or aspartate amino transferase >70 U/L), and patients who had received warfarin, heparin, low molecular weight heparin, clopidogrel, or acetylsalicylic acid within 5 days before surgery were excluded from the study.

Patients were premedicated with lorazepam 0.3 mg/kg, and their regular oral cardiovascular medications were given. Patients received fentanyl 5 µg/kg or sufentanil 2 µg/kg and propofol 1–1.5 mg/kg or etomidate 0.2 mg/kg for induction of anesthesia. Pancuronium or rocuronium was used as muscle relaxant. Anesthesia was maintained with continuous infusions of propofol 0.5 mg · kg–1 · h–1 and fentanyl 5–7.5 µg · kg–1 · h–1 or sufentanil 1.5–2 µg · kg–1 · h–1 until the end of surgery. Isoflurane or sevoflurane (1–1.3 minimum alveolar anesthetic concentration) supplementation was used to achieve a Bispectral Index level below 50.

CPB was instituted using a nonpulsatile pump and a membrane oxygenator. The bypass circuit was primed with 2000 mL of Ringer’s acetate solution and 100 mL of 15% mannitol. During cardiac arrest the patients were kept at mild hypothermia (nasopharyngeal temperature between 30 and 33°C). For CPB, the patients were anticoagulated with heparin 300 IU/kg, and 5000 IU of heparin was added to the priming solution. Activated clotting time (ACT using kaolin activator) was measured every 30 min and kept above 480 s during CPB with additional doses of 5000 IU of heparin if required. During CPB, hematocrit was kept above 20%. After CPB heparin was neutralized with 1 mg of protamine for each 100 IU of the initial dose of heparin. Additional doses of 25 mg of protamine were given to achieve the prebypass ACT level. Shed mediastinal blood was not retransfused. After termination of CPB, blood from the CPB circuit was collected into nonanticoagulated blood bags and retransfused. Ringer’s acetate solution was given during surgery. Tranexamic acid, {epsilon}-aminocaproic acid, aprotinin, and colloid solutions were not given during surgery. During CPB, all the patients were rewarmed (nasopharyngeal temperature up to 36°). In the intensive care unit (ICU), the patients were warmed with a blanket external warming system (Bair Hugger®, model 505, Arizant Healthcare, UK) until their core temperature measured from a pulmonary artery catheter reached 36.0°C. Immediately after admission to the ICU, the patients were allocated in random order (closed envelopes were prepared before beginning of the study) to receive one of the following infusions:

  1. 6% HES solution, 15 mL/kg (HAESSteril®; 60 mg/mL, average molecular weight 200 kDa, molar substitution ratio 0.5; Fresenius Kabi, Bad Homburg, Germany) (HES200/0.5 group, n = 15)
  2. 6% HES solution, 15 mL/kg (Voluven®; 60 mg/mL, average molecular weight 130 kDa, molar substitution ratio 0.4; Fresenius Kabi, Bad Homburg, Germany) (HES130/0.4 group, n = 15)
  3. 4% albumin solution, 15 mL/kg (4% Albumin SPR®; Finnish Red Cross Blood Transfusion Service, Helsinki, Finland) (HA group, n = 15).

The infusion rate was adjusted to keep the pulmonary artery wedge pressure between 10 and 14 mm Hg and the cardiac index over 2.0 L · min–1 · m–2. Epinephrine was infused (0.02–0.2 µg · kg–1 · min–1) when the cardiac index remained <2.0 L · kg–1 · min–1 despite an adequate pulmonary artery wedge pressure. Norepinephrine infusion (0.01–0.1 · µg · kg–1 · min–1) was started whenever the mean systemic arterial blood pressure was below 70 mm Hg despite adequate filling pressures and cardiac index. After the study solution infusion, Ringer’s acetate was administered to maintain adequate left ventricular filling pressure (pulmonary capillary wedge pressure 10–14 mm Hg).

In the ICU hemoglobin concentration was maintained above 8.0 g/dL with infusions of packed red blood cells if necessary. If the postoperative blood loss exceeded 200 mL/h, ACT (ACTII®, Medtronic, Minneapolis, MN), prothrombin time (Nycotest PT®, Oslo, Norway) and platelet count were determined. If the platelet count was below 100 x 109/L, 1 U of platelet concentrate was given for every 10 kg of body weight. If the ACT was prolonged more than 10 s compared with the prebypass level, 25 mg of protamine was administered. If the prothrombin time was more than 30 s, 10 mL/kg of fresh frozen plasma was transfused. If bleeding continued, 1 g of tranexamic acid was given.

Blood samples for thromboelastometry were collected via a nonheparinized radial artery catheter into polypropylene tubes (BD Vacutainer®, BD Diagnostics, Plymouth, UK) containing 3.2% buffered citrate before the administration of the study colloid (Pre), immediately after completion of the study infusion (Post), and 2 h after completion of the study infusion (2 h). Hemoglobin concentration, hematocrit value, platelet count, and ACT were measured Pre, Post, 2 h, and on the first postoperative morning (1 POM). Before sampling for coagulation and other measurements 5 mL of blood was discarded. Modified thromboelastometry coagulation analysis (ROTEM®; Pentapharm GmBh, Munich, Germany) using 4 activators (intrinsic ROTEM [InTEM®]; extrinsic ROTEM [ExTEM®]; fibrinogen ROTEM [FibTEM®]; and aprotinin ROTEM [ApTEM®]) was performed by an investigator blinded to the study colloid. Tests, definitions, and normal values of variables of thromboelastometry (ROTEM) are presented on the Pentapharm GmBh web-site (www.pentapharm.de) (Table 1). With the FibTEM activator, platelet function has been inhibited by adding cytochalasin D, which prevents the formation of a platelet cytoskeleton in the blood sample. The FibTEM tracing measures the quality of fibrin polymerization. ApTEM identifies hyperfibrinolysis by addition of aprotinin to the ExTEM coagulation activator.


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  		Table 1. Tests and Normal Values of Parameters of Thromboelastometry (ROTEM)

 

Coagulation was initiated with all four coagulation activators using a semiautomated electronic pipette system according to the manufacturer’s instructions. Coagulation was allowed to proceed 60 min. The measured ROTEM variables were: coagulation time, clot formation time, {alpha}-angle (degree), and maximum clot firmness (MCF, mm). Furthermore, shear elastic modulus (G = 5000 x MCF [100 – MCF]–1) was calculated. G is a parametric measure of clot strength expressed in metric units calculated from MCF.12 The effect of platelets on clot strength was assessed by the difference between ExTEM- and FibTEM-induced MCF: Platelet MCF = ExTEM MCF – FibTEM MCF.11

Hemoglobin concentration, hematocrit value, and platelet count in whole blood were determined using the Cell-Dyn 610 hematology analyzer (Sequila-Turner Corp., Mountain View, CA). ACT was measured with the ACT II® device (Medtronics, Minneapolis, MN).

The cumulative chest tube drainage, urine output, and the cumulative amount of transfused blood products and Ringer’s acetate solution were recorded on arrival in the ICU, when the study infusion was discontinued, 2 h later, and on the first POM.

The number of patients needed was based on an expected difference in MCF of the thromboelastometry tracing. Based on our previous study,11 15 patients per group were considered necessary to detect statistical significance with {alpha}- and β -errors of 0.05 and 0.2, respectively. Since the data were not normally distributed (Kolmogorov-Smirnov test) nonparametric tests were applied. The differences between and within the groups were analyzed with the Kruskall-Wallis and Friedman tests, respectively. After the Kruskall-Wallis test the Mann-Whitney test was performed to analyze differences between two groups. The Wilcoxon test was used for paired comparisons. The data are presented as median and percentile or range. Frequencies were tested with the {chi}2-test. P values <0.05 were considered to be statistically significant. The statistical analyses were performed with SPSS for Windows (version 15.0).

RESULTS

Patients in all three groups were comparable regarding demographic and preoperative data (Table 2). The patients’ routine laboratory tests were within the normal range preoperatively. Two patients in the HES200/0.5- and 2 in the HA-group received transfusions of packed red blood cells during CPB (P = 0.52 among all groups). Neither platelet concentrate nor fresh frozen plasma was transfused intraoperatively.


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  		Table 2. Demographic and Operative Data

 

The median (range) infusion times were 100 (70–240) min in the HES130/0.4, 105 (40–167) min in the HES200/0.5 and 95 (35–180) min in the HA group (P = 0.728 among all groups). The doses of Ringer’s acetate solution administered intraoperatively (P = 0.83), colloids and Ringer’s acetate solution administered postoperatively were comparable in all 3 groups (P = 0.35), but urine output was higher in the HES130/0.4-group in comparison with the HA-group postoperatively (P = 0.006, Table 3). The observations concerning the hemodynamic changes of our patient population are presented elsewhere.13


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  		Table 3. Postoperative Fluid Balance and Blood Transfusions

 

We did not observe low-output syndrome during the first postoperative day in the study patients. The number of patients who received low-dose norepinephrine (HES130/0.4 8/15 patients, HES200/0.5 8/15 patients, HA 6/15, P = 0.103 among all groups) or epinephrine (HES130/0.4 4/15 patients, HES200/0.5 6/15 patients, HA 5/15, P = 0.741 among all groups) during the study period was not different among the groups. The highest doses of norepinepherine and epinepherine were 0.13 µg · kg–1 · min–1 and 0.08 µg · kg–1 · min–1, respectively.

The baseline thromboelastometry parameters were comparable in the study groups. An equal decrease in {alpha}-angle and prolongation in clot formation time was observed immediately after the completion of the HES200/0.5 and HES130/0.4 infusions and 2 h thereafter. In the HA group these parameters remained unchanged (Table 4).


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  		Table 4. Initial Fibrin Formation and Build-Up (ROTEM) Before (Pre), Immediately (Post), and at 2 h after Completion (2 h) of Infusion

 

MCF and shear elastic modulus were decreased significantly in both HES groups instantly after the completion of the infusion (Figs. 1 and 2). With FibTEM and ApTEM coagulation activators MCF was still impaired at 2 h after completion of the infusion. HA had no effect on MCF or shear elastic modulus. Platelet MCF (ExTEM MCF–FibTEM MCF)11 remained unchanged during the study period in all groups (P > 0.05, data not shown). The clot lysis parameters (lysis 30 min and lysis 60 min) were in the normal range and there were no differences among the 3 groups. The difference between ExTEM and ApTEM lysis parameters were also not significant (P > 0.05, data not shown).


Figure 17
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  		Figure 1. Median maximum clot firmness changes (ROTEM) before (Pre), immediately (Post) and at 2 h after completion (2 h) of infusion (mm) Kruskall-Wallis test for difference among all groups, Mann-Whitney test for difference between two groups, *P < 0.05 between both HES and HA groups, #P < 0.05 between HES130/0.4 and HA groups. HES = hydroxyethyl starch solution; HA = albumin solution 4% MCF = maximum clot firmness.

 


Figure 27
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  		Figure 2. Shear elastic modulus changes before (Pre), immediately (Post), and at 2 h after completion (2 h) of infusion Kruskall-Wallis test for difference among all groups, Mann-Whitney test for difference between two groups, *P < 0.05 between both HES and HA groups, #P < 0.05 between HES130/0.4 and HA groups. HES200 = hydroxyethyl starch solution; HA = albumin solution 4% G = shear elastic modulus.

 
In the ICU hemoglobin concentration and hematocrit were similar among the groups (Table 5). After the study infusions, these parameters decreased significantly (P < 0.05) and were higher in the HA group than in both HES groups (P = 0.007). On the first POM hemoglobin concentration was lower in the HA group than in the HES groups (P = 0.046). Platelet count decreased immediately after the infusion in both HES groups, but recovered to baseline level by the first POM.


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  		Table 5. Data on Postoperative Hemoglobin, Hematocrit, and Platelets

 

Chest tube drainage during the first 18 h after surgery was comparable in all 3 groups. There were no differences in the amount of administered packed red blood cell concentrates, fresh frozen plasma or platelet concentrates postoperatively (Table 3).

DISCUSSION

In the present study we demonstrated a similar impairment in whole blood coagulation after a short-term infusion of either HES200/0.5 or HES130/0.4 during the postoperative phase after cardiac surgery. We observed that clot formation and firmness, assessed by thromboelastometry, were significantly inferior immediately after the infusion in both HES groups when compared with the HA group. Delayed kinetics of fibrin was still seen at 2 h after the completion of both HES solutions. Thus, our results contradict earlier reports of HES 130/0.4 having no negative effects on hemostasis in cardiac surgical patients.2,14

After CPB, patients are predisposed to bleeding complications because CPB induces platelet dysfunction, reduces the amount of coagulation factors, and promotes fibrinolysis.15,16 It is therefore important to avoid IV fluids that might compromise hemostasis.

Several mechanisms by which HES solutions influence hemostasis have been suggested.17,18 Large HES molecules interfere with fibrinogen, coagulation factor VIII, and von Willebrand factor more than expected as a result of hemodilution only.19,20 HES also promotes platelet dysfunction.1 In studies assessing whole blood viscoelastic properties, HES has been consistently demonstrated to disturb fibrin formation and to decrease clot firmness.5,11,21 Under such conditions, the resulting thrombus might be less stable and more susceptible to lysis.

We performed thromboelastometry using four different coagulation activators to clarify the mechanisms of HES-induced impairment of hemostasis. Our study shows that HES solutions alter extrinsic and intrinsic pathway coagulation globally, including alterations in initial fibrin formation, fibrin polymerization, and in the strength of the whole blood clot.5,10,18,19,22 Our result of decreased fibrin MCF (FibTEM activator) indicates an impairment in fibrin-fibrinogen interaction resulting in an unstable fibrin clot. Since platelet contribution to clot strength was not altered by HES200/0.5 or HES130/0.4, the observed coagulation disorder is mainly mediated by impaired kinetics of fibrin up to 2 h after the infusion.23

In our patient population there was no excessive fibrinolytic activity after elective open heart surgery and before the HES infusions, since we did not observe any improvement in clot strength by inhibition of fibrinolysis in the ApTEM thrombelastometry analysis. HES200/0.5 or HES130/0.4 solutions did not induce profound fibrinolysis either, which agrees with a recent study.24 However, some in vitro25,26 and in vivo27 investigations have demonstrated that the blood clot is vulnerable after HES-hemodilution in the setting of hyperfibrinolysis. Our results further support the idea28 that routine perioperative administration of antifibrinolytics in cardiac surgical patients is not indicated, although antifibrinolytics may be indicated after long-lasting CPB or deep hypothermia.29

We observed slightly different hemoglobin and hematocrit concentrations between the HA and both HES groups immediately after completion of the infusions. This might be related to the different volume effects of the test solutions and might have affected our thromboelastometry results.8 However, this difference in hematocrit was not clinically significant (hematocrit 24% in HES 200/0.5, 25% in HES 130/0.4, and 27% in the HA group).

In the present study we showed that HES 130/0.4 and HES 200/0.5 have similar untoward effects on coagulation. This finding contradicts earlier clinical reports. In patients undergoing hip replacement, HES 130/0.4 had a more favorable coagulation profile than HES 200/0.5.30 Gallandat et al. also observed a larger total perioperative blood loss in HES200/0.5- than in HES130/0.4- treated patients during cardiac surgery.2 A reason for this discrepancy may be our single, relatively low-dose, and more rapid infusion of HES, which corresponds to the dosage of experimental in vitro hemodilution investigations. Also, we only administered HES during the period when there was still the CPB-promoted coagulation defect.

Increased postoperative blood loss has been reported when high molecular-weight HES (400/0.7) has been given to patients undergoing cardiac surgery.7,31 In a meta-analysis of published studies, the average 24-h postoperative blood loss after cardiac surgery was 96 mL more after HES solutions compared to albumin.7 Both HES 200/0.5 and HES 400/0.7 solutions were included, and they were infused as either priming fluids or intra- and postoperative infusions.

The findings of our study are limited by the relatively small patient population having different types of cardiac surgeries. Furthermore, our study was not powered to demonstrate a difference in the cumulative chest tube drainage. However, the surgical trauma (median sternotomy, cannulation, and the use of CPB) was similar in all of the patients.

We conclude that, after elective cardiac surgery, a short-term infusion of either HES 130/0.4 or HES 200/0.5 causes a comparable coagulation derangement. Albumin does not impair whole blood coagulation.

ACKNOWLEDGMENTS

The authors gratefully acknowledge Peter Raivio, MD, PhD for critical review of the manuscript.

Footnotes

Accepted for publication June 26, 2008.

Supported by a Government Grant for Health Care Research; Research Foundation of Orion Corporation, Helsinki, Finland.

The work was partly presented at the Annual Meeting of the European Association of Cardiothoracic Anesthesiologists, 2007, Krakow, Poland.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2009 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press