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© 1999 International Anesthesia Research Society
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Abstract |
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Hextend® (BioTime, Inc., Berkeley, CA) is a new plasma volume expander containing 6% hetastarch, balanced electrolytes, a lactate buffer, and physiological levels of glucose. In preclinical studies, its use in shock models was associated with an improvement in outcome compared with alternatives, such as albumin or 6% hetastarch in saline. In a prospective, randomized, two-center study (n = 120), we compared the efficacy and safety of Hextend® versus 6% hetastarch in saline (HES) for the treatment of hypovolemia during major surgery. Patients at one center had a blood sample drawn at the beginning and the end of surgery for thromboelastographic (TEG) analysis. Hextend® was as effective as HES for the treatment of hypovolemia. Patients received an average of 1596 mL of Hextend®: 42% received >20 mL/kg up to a total of 5000 mL. No patient received albumin. Hextend®-treated patients required less intraoperative calcium (4 vs 220 mg; P < 0.05). In a subset analysis of patients receiving red blood cell transfusions (n = 56; 47%), Hextend®-treated patients had a lower mean estimated blood loss (956 mL less; P = 0.02) and were less likely to receive calcium supplementation (P = 0.04). Patients receiving HES demonstrated significant prolongation of time to onset of clot formation (based on TEG) not seen in the Hextend® patients (P < 0.05). No Hextend® patient experienced a related serious adverse event, and there was no difference in the total number of adverse events between the two groups. The results of this study demonstrate that Hextend®, with its novel buffered, balanced electrolyte formulation, is as effective as 6% hetastarch in saline for the treatment of hypovolemia and may be a safe alternative even when used in volumes up to 5 L.
Implications: Hextend® (BioTime, Inc., Berkeley, CA) is a new plasma volume expander containing 6% hetastarch, balanced electrolytes, a lactate buffer, and a physiological level of glucose. It is as effective as 6% hetastarch in saline for the treatment of hypovolemia but has a more favorable side effects profile in volumes of up to 5 L compared with 6% hetastarch in saline.
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Introduction |
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The etiology of postoperative morbidity is multifactorial; however, occult hypovolemia is thought to be the most significant avoidable cause of organ dysfunction and death (1,2). The administration of colloid as a plasma volume expander during the intraoperative period is associated with improved outcome and reduction in hospital stay (3–5). The two commonly used colloids in North America, 6% hetastarch in saline and 5% albumin have specific limitations. The administrations of large volumes of 6% hetastarch in saline can cause coagulation abnormalities (6,7) and can lead to electrolyte imbalances, such as metabolic hyperchloremic acidosis, due to the high chloride content. These concerns have prompted cautious use of 6% hetastarch >20 mL · kg-1 · d-1. Albumin 5% is derived from plasma; hence, its availability depends on donor supply (8) and is associated with higher costs and potential risk of viral contamination compared with 6% hetastarch in saline. Recently, albumin has been linked to increased mortality due to capillary leak syndrome and coagulopathy (9,10).
Hextend® (BioTime, Inc., Berkeley, CA), a new preparation of hydroxyethyl starch, is composed of 6% hetastarch (mean molecular weight 550 kD) in a solution of electrolytes (Na+, K+, Ca2+, Mg2+, Cl-), physiological levels of glucose (90 mg/dL), and a lactate buffer that is more likely to provide a more favorable acid-base balance. Preclinical use of Hextend® in shock models was associated with an improvement in outcome compared with alternatives such as albumin or lactated Ringer's solution (11). Recent in vitro studies of the effects of Hextend® in human plasma have shown that, at dilutions of up to 75% Hextend® and 25% human plasma, there were no adverse effects on hemostatic variables except those expected by hemodilution (12). Immediately before the main study, six patients received Hextend® in an open-labeled study. Volumes of up to 3000 mL (1385 ± 1116, mean ± SD) were infused with no adverse effects related to the study drug (13).
In a prospective, randomized, double-blinded trial, we tested the hypothesis that the intraoperative administration of Hextend® to patients undergoing major elective surgery is as safe and effective as 6% hetastarch in saline when used for the treatment of hypovolemia.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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After institutional review board approval and written, informed patient consent, ASA physical status I–III adult patients presenting for major elective general, gynecological, orthopedic, or urological surgery with anticipated blood loss >500 mL were enrolled at Duke University Medical Center (DUMC) and The Mount Sinai Medical Center. Patients with coagulopathy, significant hepatic (liver enzymes >50% upper limit of normal values) or renal (creatinine > 50% upper limit of normal values) dysfunction, congestive heart failure; those who had received an investigational drug within the last 30 days; or with known hypersensitivity to hydroxyethyl starches were excluded.
Patients were premedicated with midazolam and fentanyl. Before the induction of anesthesia, an IV bolus of 7 mL/kg lactated Ringer's solution was administered, followed by an IV infusion of lactated Ringer's solution at a rate of 5 mL · kg-1 · h-1, which was continued for the duration of anesthesia. Anesthesia was induced by an IV technique and maintained with a balanced inhalational technique incorporating isoflurane, nitrous oxide, and oxygen with neuromuscular blockade supplied by IV vecuronium. Ventilation was adjusted to maintain PaCO2 at 35–40 mm Hg, and temperature was maintained >35.5°C throughout surgery. If an epidural catheter was placed as part of the patient's postoperative care, a 3-mL test dose consisting of lidocaine 1.5% with 1:200,000 epinephrine was administered, and no epidural local anesthetic drugs were administered intraoperatively. Anesthesia was maintained at a constant level as judged by standard clinical criteria.
In addition to the standard monitoring, direct arterial and central venous pressures were also monitored. All cardiovascular variables and urine flow were monitored and recorded during general anesthesia. Postoperatively, heart rate (HR), blood pressure, and urinary volumes were recorded every hour for 4 h, then every 4 h until 24 h after surgery. Types and volumes of all fluids administered intra- and postoperatively (including but not limited to crystalloid solutions, blood, and blood products) were recorded, as were the volumes and doses of any drugs given during general anesthesia and an estimation of blood loss.
Laboratory tests including hematocrit, platelet count, serum electrolytes and creatinine, colloid oncotic pressure, coagulation tests (e.g., prothrombin time, activated partial thromboplastin time), Factor VIIIc, and von Willebrand factors were measured before induction, at the end of surgery, and on the day after surgery.
Patients at one center (DUMC) had a blood sample drawn before induction and at the end of the surgical procedure for thromboelastographic (TEG) analysis, which provides a bedside dynamic measure of clot formation and takes into account the presence of coagulation factors and cofactors (e.g., calcium) (14). Whole blood is placed in a cuvette, which is rotated back and forth. A piston is suspended in the blood, and as coagulation proceeds, fibrin strands form between the walls of the cuvette and the piston. The piston thus becomes increasingly coupled to the motion of the cuvette; hence, the shearing elasticity of the evolving blood clot is detected to yield the TEG trace. The TEG variables for patients receiving <20 mL/kg or 
20 mL/kg of study solution are described in Figure 1.
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- - = 6% hetastarch <20 mL/kg, –Patients received either 6% hetastarch in saline or Hextend® for the treatment of hypovolemia according to a hypovolemia algorithm (Figure 2). The intraoperative use of albumin was prohibited. The study solutions were prepared by the pharmacy in similar glass bottles to maintain blinding of groups. According to this algorithm, hemodynamic targets included maintenance of arterial blood pressure, HR, and urine output within a predefined range. Hemodynamic variables triggering colloid dosing involved a urine output <0.5 mL · kg-1 · h-1, a HR >20% above baseline or a HR >110 bpm, and systolic blood pressure (BP) <20% below baseline or systolic BP <90 mm Hg. If the central venous pressure (CVP) was < 15 mm Hg and the hematocrit was greater than 21% then a dose of colloid (either Hextend® or 6% hetastarch in saline) was administered until the hemodynamic target was met. If the CVP was
15 mm Hg, hypovolemia was a less likely cause of the abnormal hemodynamics; thus, consideration was given to further monitoring (i.e., inserting a pulmonary artery catheter) or circulatory support with vasoactive drugs. In addition, patients received 6% hetastarch in saline or Hextend® in volumes equivalent to that judged to be lost as a result of surgical hemorrhage. If the hematocrit was 
21%, then blood was administered for the treatment of hypovolemia instead of 6% hetastarch in saline or Hextend®. However, the clinicians administered blood to a patient with a hematocrit >21% if clinically indicated; for example, if there was evidence of myocardial ischemia and anemia was thought to be a contributory cause.
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After the administration of blood, the hematocrit was rechecked, and blood was given until the hematocrit exceeded 21%. After the administration of each colloid dose, an assessment was made to determine whether the hemodynamic goals had been met. If so, then the algorithm called for continued hemodynamic monitoring. If a colloid dose did not result in restoration of the hemodynamic targets, then the CVP was measured again to determine which limb of the algorithm was followed.
For the treatment of bleeding of a nonsurgical etiology, the protocol called for the administration of blood products (platelets, fresh-frozen plasma, cryoprecipitate, or fibrinogen) when clinically indicated and supported by the laboratory evidence of abnormal coagulation: platelet count <100,000/L, prothrombin time >1.5 times control, activated partial thrombin time >1.5 times control, and/or fibrinogen <100 mg/dL. Patients were extubated, either in the operating room or postoperatively, when they fulfilled standard clinical criteria. They were visited daily in the immediate postoperative period for a maximum of 5 days, until discharge or death. Patients who remained in the hospital for >5 days were visited again on the day of discharge. All adverse events and postoperative length of stay were recorded. In addition, adverse events were deemed coagulation-related if, in the judgement of the investigators, abnormal laboratory values were associated with a nonsurgical bleeding.
Data were analyzed to compare all patients in the protocol group with all patients in the control group on an intent to treat basis. The groups were compared using a t-test or Wilcoxon rank-sum test as appropriate. The volumes of IV colloid and calcium administered to the two groups were compared by using a one-way analysis of covariance adjusted for each patient's estimated blood loss. Incidence of adverse events and intraoperative calcium administration were compared using a two-tailed Fisher's exact test. A P value <0.05 was considered statistically significant.
For estimation of sample size, the total volume of colloid (Hextend® or 6% hetastarch in saline) administered by the end of surgery was taken as the primary outcome. Analysis of data from 207 patients undergoing similar types of surgery and anesthesia revealed a mean ± SD colloid equivalent volume transfused during surgery of 1821 ± 540 mL. A sample size of 60 in each group was calculated to have at least 80% power to detect a difference in means of 30% given a common standard deviation of 540 mL using a two-group t-test with a 0.05 two-sided significance.
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Results |
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One hundred twenty patients were enrolled. Three patients did not receive study solution (one did not require colloid treatment, one failed to have a central venous catheter inserted, and one rescheduled surgery at short notice). The two groups were well matched with regard to demographics, preexisting disease, duration of anesthesia, and type of surgery (Table 1). Patients in both groups received similar volumes of study drug (1596 mL of Hextend® versus 1428 mL of 6% hetastarch) (Table 2). Twenty-one (35%) patients in the 6% hetastarch group and 25 (42%) patients in the Hextend® group received >20 mL/kg study solution, with a maximal volume infused of 5000 mL in each group. No study patient received albumin intraoperatively.
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Baseline hemodynamic variables were similar between the two groups (Table 3). Although there was no statistically significant difference in the change in HR, BP, and CVP between the two groups from baseline to end of surgery, there was a trend toward slower HR at the end of surgery (78 vs 82 bpm) and a greater increase in CVP (1.9 vs -0.4 mm Hg) in Hextend®-treated patients. The difference in mean HR became statistically significant in a subset of patients who received blood transfusion (78 vs 85 bpm; P = 0.049). Hemodynamic goals as specified in the algorithm were achieved 63% (38 of 60) of the time in the 6% hetastarch in saline group and 65% (39 of 60) of the time in the Hextend® group. Postoperative hemodynamics and urine output were similar between the groups, and there was no difference in the postoperative administration of fluids, blood, and blood products.
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There were no overall differences in the laboratory-measured hematological, biochemical and coagulation (Table 4) variables. Only one patient received parenteral calcium supplementation intraoperatively in the Hextend® group versus six patients in the control group (mean intraoperative calcium 4.2 vs 220 mg; P < 0.05). Four patients experienced massive blood loss (>70 mL/kg) during the procedure. Three of these four patients were in the 6% hetastarch in saline group. There was no difference between the two groups in the incidence of overall adverse events. One death that occurred on Day 34 in the Hextend® group but was not drug-related. The Hextend® patients' length of hospital stay averaged 7.5 days (versus 8.4 days in the control group).
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The percentage of patients who received blood transfusions intraoperatively and postoperatively were similar: Hextend® 35 of 59 (59%), 6% hetastarch in saline 34 of 58 (59%). In a retrospective subgroup analysis of patients who received a blood transfusion intraoperatively, estimated blood loss was significantly less in the Hextend® group (1560 mL vs 2516 mL; P = 0.02), and the number of patients requiring calcium administration intraoperatively (1 of 31 vs 6 of 25; P = 0.04) was also significantly smaller. Consistent with reduced blood loss, the Hextend® group seemed to require less blood and blood products (Table 5).
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Patients who received 6% hetastarch in saline exhibited an overall significant slowing of the onset of clot formation (r time) during surgery, compared with those receiving Hextend® (P < 0.05). When TEG tracings were analyzed with respect to the volume of test solutions administered (<20 mL/kg and
20 mL/kg), this difference was more pronounced in the 6% hetastarch group (Figure 1). Other TEG variables were similar between the two groups. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We designed this study to determine the efficacy and safety of Hextend® compared with 6% hetastarch in saline. The results of this study demonstrate that Hextend® is effective for the treatment of hypovolemia. Furthermore, numerous findings from this study suggest that Hextend® is a safe alternative.
The administration of colloid as plasma volume expander during the intraoperative period may be associated with an improved outcome. Mythen and Webb (3) demonstrated a reduction in the incidence of major complications and hospital stay in elective cardiac surgery patients who received perioperative plasma volume expansion with colloid. Similar results were shown by Sinclair et al. (4), who studied the effect of fluid optimization with colloid in elderly patients undergoing repair of a proximal femoral fracture. There was a 39% reduction in hospital stay in the colloid treatment group.
Although 6% hetastarch in saline is effective in expanding plasma volume, its use has been associated with side effects, notably coagulation abnormalities, when large volumes are used (15,16). This prompted a labeling statement cautioning the use of >20 mL · kg-1 · d-1. In this study, 35% of patients in the 6% hetastarch group and 42% of patients in the Hextend® group received more than the 20-mL/kg recommendation.
Numerous findings in this study suggest that Hextend® has a favorable side effect profile. Only one patient received parenteral calcium supplementation intraoperatively in the Hextend® group, versus six patients in the control group. There were trends toward there being less bleeding in the Hextend® group, as judged by estimated blood loss and the requirement for blood products. These trends were observed at both study sites for red blood cell, platelets, fresh-frozen plasma, and cryoprecipitate transfusions. Several of these differences became more pronounced in the subset of patients in which one would expect to observe a larger drug effect, i.e., patients receiving intraoperative blood transfusions and patients receiving >20 mL/kg study fluid. The Hextend®-treated group demonstrated a significantly better TEG dynamic clot formation (P < 0.05), which was more marked in the subgroup who received 20 mL/kg.
Based on the laboratory coagulation tests, there is no obvious explanation for the decreased blood loss, need for blood products, and coagulation-related adverse events noted in Hextend® patients. The difference in dose-dependent changes in factor VIII and von Willebrand factor previously observed with higher molecular weight starches (7) were not seen in either group. One possible explanation may lie in the differences in ionized calcium, as calcium is essential to the pathways underlying effective clot formation. Hextend® contains calcium levels similar to those normally found in blood (10 mg/dL), whereas 6% hetastarch in saline contains none. Moreover, this supposition is supported by the observation that, in patients who received red blood cell transfusions, there was a mean difference in estimated blood loss of approximately 1 L. The transfusion of citrated red blood cells may have been associated with a more profound but transient reduction in plasma calcium levels in the patients receiving large amounts of calcium-free 6% hetastarch in saline as opposed to Hextend® (17). A rapid (within 5 min) infusion of 750 mL of citrated red blood cells has been shown to induce up to a 41% acute decline in ionized calcium (18). This transient reduction in ionized calcium may have lead to less effective clotting at the cut tissue edge. Because Hextend® is also lower in chloride (which therefore reduces acidosis secondary to this chloride burden) and is buffered with lactate, a more favorable localized and acute acid-base balance may also prevail in these patients relative to controls, further facilitating clotting (19).
The TEG studies conducted at DUMC provided further evidence consistent with coagulation-related abnormalities in the patients given 6% hetastarch in saline. The r times were significantly increased during surgery in these patients compared with the Hextend® patients, which suggests that the onset of clot formation became delayed in the 6% hetastarch in saline group. This difference became more pronounced in the subgroup who received 20 mL/kg. The r time correlates with initial fibrin formation and is related to overall activity of clotting factors, which could be influenced by local calcium concentration (14).
Our findings in this study indicate that Hextend® is as effective as 6% hetastarch in saline when used for the treatment of hypovolemia. Numerous findings suggest that Hextend® has a favorable side effects profile. Furthermore, there were no serious adverse events related to the administration of Hextend® in volumes of up to 5 L. With its buffered, balanced electrolyte formulation, Hextend® seems to be a safe alternative to 6% hetastarch in saline.
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Acknowledgments |
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This study was supported in part by a grant from BioTime, Inc.
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Footnotes |
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The results of this study were presented in part at the American Society of Anesthesiologists meeting, October 17–21, 1998, Orlando, FL.
1 J. V. Booth, MB, FRCA, D.S. Bronheim, MD, C. Robertson, MD, D. E. Feierman, MD, D. Kucmeroski, BS, G. V. Gabrielson, S. Dufore, RN, I. H. Sampson, MD, K. M. Robertson, MD, S. B. Scarola, MD, A. B. Hilton, MD, W. J. Winfree, BSN, R. L. Woolf, MB, FRCA, and I. J. Mackie, MRCPath. 
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- Mythen MG, Webb AR. Intra-operative gut mucosal hypoperfusion is associated with increased post-operative complications and cost. Intensive Care Med 1994;20:99–104.[Web of Science][Medline]
- Mythen MG, Webb AR. The role of gut mucosal hypoperfusion in the pathogenesis of post-operative organ dysfunction. Intensive Care Med 1994;20:203–9.[Web of Science][Medline]
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Mythen MG, Webb AR. Perioperative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg 1995;130:423–9.
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Sinclair S, James S, Singer M. Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture : randomised controlled trial. BMJ 1997;315:909–12.
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Gan TJ, Arrowsmith JE. The oesophageal Doppler monitor [editorial]. BMJ 1997;315:893–4.
[Free Full Text] - Cope JT, Banks D, Mauney MC, et al. Intraoperative hetastarch infusion impairs hemostasis after cardiac operations. Surg 1997;63:78–82.
- Kuitunen A, Hynynen M, Salmenpera M, et al. Hydroxyethyl starch as a prime for cardiopulmonary bypass : effects of two different solutions on haemostasis. Scand 1993;37:652–8.
- Macintyre E, Bullen C, Machin SJ. Fluid replacement in hypovolaemia. Intensive Care Med 1985;11:231–3.[Web of Science][Medline]
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Offringa M. Excess mortality after human albumin administration in critically ill patients. BMJ 1998;317:223–4.
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Reviewers CIGA.Human albumin administration in critically ill patients : systemic review of randomised controlled trials. BMJ 1998;317:235–40.
[Abstract/Free Full Text] - Nielsen VG, Tan S, Brix AE, et al. Hextend (hetastarch solution) decreases multiple organ injury and xanthine oxidase release after hepatoenteric ischemia-reperfusion in rabbits. Med 1997;25:1565–74.
- Bick RL. Evaluation of a new hydroxyethyl starch preparation (Hextend) on selected coagulation parameters. Clin Appl Thrombos Hemostas 1995;1:215–29.
- Woolf R, Gan TJ, Cooper A, et al. An open label study of Hextend®, a new physiologically balanced colloid. In: Proceedings of the Association of Cardiothoracic Anaesthetists, 1997.
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Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307–13.
[Free Full Text] - Stump DC, Strauss RG, Henriksen RA, et al. Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion 1985;25:349–54.[Web of Science][Medline]
- Lockwood DN, Bullen C, Machin SJ. A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehovah's Witness. Anaesthesia 1988;43:391–3.[Web of Science][Medline]
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H. E. Manspeizer, M. Imai, R. J. Frumento, M. K. Parides, B. Mets, and E. Bennett-Guerrero Arterial and Venous Thrombelastograph(R) Variables Differ During Cardiac Surgery Anesth. Analg., August 1, 2001; 93(2): 277 - 281. [Abstract] [Full Text] [PDF]
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R. Protheroe and J. Nolan Which fluid to give? Trauma, July 1, 2001; 3(3): 151 - 160. [Abstract] [PDF]
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V. G. Nielsen, B. T. Geary, and M. S. Baird Evaluation of the Contribution of Platelets to Clot Strength by Thromboelastography in Rabbits: The Role of Tissue Factor and Cytochalasin D Anesth. Analg., July 1, 2000; 91(1): 35 - 39. [Abstract] [Full Text] [PDF]
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G. R. Haynes, M. K. Bailey, T. J. Gan, E. Bennett-Guerrero, and M. G. Mythen Excessive Use of Hetastarch: An Iatrogenic Cause of Bleeding and Hypocalcemia? Response Anesth. Analg., June 1, 2000; 90(6): 1455 - 1456. [Full Text] [PDF]
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V. G. Nielsen and M. S. Baird Extreme Hemodilution in Rabbits: An In Vitro and In Vivo Thrombelastographic(R) Analysis Anesth. Analg., March 1, 2000; 90(3): 541 - 545. [Abstract] [Full Text] [PDF]
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