Anesth Analg 2000;90:1455-1456
© 2000 International Anesthesia Research Society
LETTERS TO THE EDITOR
Excessive Use of Hetastarch: An Iatrogenic Cause of Bleeding and Hypocalcemia?
Gary R. Haynes, MD, PhD, and
Melinda K. Bailey, MD
Department of Anesthesiology Medical University of South Carolina Charleston, SC 29425
In comparing two hetastarch preparations for volume replacement, Gan et al. (1) administered either 6% hetastarch in saline or 6% hetastarch in a physiological salt solution (Hextend®; BioTime, Inc., Berkely, CA) to restore homeostasis when triggers of hypotension, tachycardia, low urine output, or low central venous pressure were reached. The report shows similar estimated blood losses (EBL) in the standard hetastarch (1278 ± 1616 mL) and Hextend® (1024 ± 949 ml) groups.
Disturbingly, the investigators defined a dosing limit of up to 5 L of both hetastarch solutions, far in excess of the safe limit of 20 mL/kg recommended in the 6% hetastarch labeling (2). Fully 35% of patients given hetastarch received more than the 20 mL/kg limit (up to 5 L in several cases), as did 42% of the Hextend®-treated subjects.
Hetastarch interferes with platelet function and coagulation factors, particularly factor VIII (3,4). Infusion in gross excess introduces the real possibility that the investigators may have exacerbated bleeding. In this distorted context, the authors’ suggestion that reduced EBL—itself a dubious measure—was a distinguishing outcome in the treatment group is not valid.
Table 4 data suggest that there were no coagulation function differences between these groups. As all patients received continuous administration of lactated Ringer’s solution, one would not expect frequent instances of calcium deficit. However, as a massive excess of hetastarch may have mediated iatrogenic hemorrhage in several patients, multiple units of citrated red cells could have transiently decreased serum calcium levels in the standard hetastarch group, as the authors suggest. Thus, the instances of transient hypocalcemia may ultimately have been attributable to excessive bleeding induced by massive hetastarch overdose.
Finally, in a study intent on maximizing colloid administration for shed blood volume replacement, why were subjects not switched to albumin once the safe hetastarch limit of 20 mL/kg was reached? Also, to be answered is why the authors chose to dismiss this prevailing practice standard on the basis of unfounded and misleading criticisms of albumin safety in the elective surgical setting.
References
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Gan TJ, Bennett-Guerroro E, Phillips-Bute B, et al. Hextend®, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Anesth Analg 1999;88:992–8.[Abstract/Free Full Text]
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6% Hetastarch in 0.9% sodium chloride injection [package insert]. North Chicago, IL:Abbott Laboratories, 1998.
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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]
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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]
Response
T. J. Gan, MB, FRCA,
E. Bennett-Guerrero, MD, and
M. G. Mythen, MD, FRCA
Duke University Medical Center Durham, NC 27710
College of Physicians and Surgeons Columbia University New York, NY 10032
University College London Hospitals London, UK
We appreciate Drs. Haynes and Bailey’s interest in our study (1). However, we would like to address a number of inaccuracies in their letter.
Haynes and Bailey were incorrect when they cited that 20 mL/kg was the safe limit recommended in the 6% hetastarch in saline (HS) labeling. There is no volume limit. The package insert states that "Doses of more than 1500 mL per day for the typical 70 kg patient (approximately 20 mL per kg of body weight) are usually not required, although higher doses have been reported in postoperative and trauma patients where severe blood loss has occurred" (2).
In our study, there was no volume limit for colloid administration. It was coincidental that in both groups (Hextend® [HX; BioTime, Inc., Berkeley, CA] and HS), the maximum volume of study solutions infused was 5 L. There was a trend that the HX group had less blood loss compared with the HS group, and on subset (red blood cell transfused patients) analysis, this difference was statistically significant (P = 0.02). In the transfused HX patients, there were also strong trends showing a reduced need for blood and blood products. The HX patients required significantly less IV calcium, and this became more significant in those transfused. The HX patients showed less clinically significant coagulation-related adverse events compared with the HS patients (4 versus 12). In another analysis at Duke, the estimated blood loss in the HX group was comparable to a similar group who received lactated Ringer’s [LR] (HX versus LR: 1418 ± 938 vs 1378 ± 1043 mL [mean ± SD]), which was significantly less than the HS group (1918 ± 1753 mL; P = 0.01) (3). These results, although not conclusive, suggest that HX may offer advantages over HS, especially when large volumes are infused.
HX is currently in use in numerous major medical centers around the country. The package insert states: "Doses of more than 1500 ml are usually not required although doses of isotonic solutions containing 6% hetastarch up to 1500 mL have been used during major surgery generally without a need for blood or blood products. Volumes in excess of 1500 mL per day have been used where severe blood loss has occurred, although generally only in conjunction with the administration of blood and blood products." Since the product has been available for clinical use, larger volumes of HX than those used in the clinical trial have been administered without major complications.
Haynes and Bailey stated that there is a prevailing practice standard that albumin should be substituted once 20 mL/kg of hetastarch is administered. However, there is no reported study to show that the administration of large volumes of albumin solution is devoid of coagulation abnormality. Indeed, there is evidence to suggest the contrary. Egli et al. (4) demonstrated that hemodilution (60%) with albumin resulted in compromised k time, alpha angle, and maximum amplitude (MA) of the thromboelastogram, and these changes were similar to patients administered hetastarch or gelatin (4). Other investigators have used hetastarch solutions as plasma volume expanders well above 20 mL/kg without significant coagulation problems. Falk et al. (5) and Rackow et al. (6) each used an average beyond 4.5 L of HS in comparison with albumin and found no relative differences in bleeding or blood requirements.
The use of albumin as a plasma volume expander has been cautioned. In a systematic review of 30 prospective, randomized trials of human albumin administration in critically ill patients, the Cochrane Injuries Group found that for each patient category when albumin was used for hypovolemia, hypoalbuminemia or burns, the relative risk of death was 1.46, 1.69, and 2.40, respectively (7). They concluded that "the use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of rigorously conducted, randomized controlled trials" (7).
Haynes and Bailey agree with us that transient hypocalcemia may partly account for the difference in estimated blood loss and blood use observed in a subgroup of patients who received red cell transfusion. The role of calcium in the coagulation process is well established. Laboratory evidence suggests that some colloid macromolecules may bind with Factor VIII-vWF and, hence, be unavailable for the coagulation process. This could be affected by the lack of calcium. It has been demonstrated that FVIII-vWF needs to be exposed to Ca++ to obtain its optimal biologic activity in supporting platelet adherence (8). The thromboelastographic coagulation difference in our study may be related to the presence of calcium in HX.
Another explanation could be the difference in chloride level between HX and HS. Scheingraber et al. (9) investigated the effects of either saline or lactated Ringer’s solution on acid-base balance during gynecological surgery. They demonstrated a significant difference between the two groups in serum chloride 30 min after the infusion. There was a trend in the saline group to more blood loss (962 ± 332 vs 704 ± 447 mL) and to less urine production after 120 min (717 ± 459 vs 1075 ± 799 mL) although the study was not powered to show a difference. In the discussion, they suggested that hyperchloremic metabolic acidosis caused by large infusions of 0.9% saline may not be benign.
References
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Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend®, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Anesth Analg 1999;88:992–8.
-
6% hetastarch in 0.9% sodium chloride injection [package insert]. North Chicago, IL:Abbott Laboratories, 1998.
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Martin G, El-Moalem H, Bennett-Guerrero E, et al. Comparison of intraoperative blood loss in patients undergoing major surgery using Hextend, Hespan and lactated Ringer’s solution [abstract]. Anesthesiology 1999;91:A166.
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Egli GA, Zollinger A, Seifert B, et al. Effect of progressive haemodilution with hydroxyethyl starch, gelatin and albumin on blood coagulation. Br J Anaesth 1997;78:684–9.[Abstract/Free Full Text]
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Falk JL, Rackow EC, Astiz ME, et al. Effects of hetastarch and albumin on coagulation in patients with septic shock. J Clin Pharm 1988;28:412–5.
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Rackow EC, Falk JL, Fein IA, et al. Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med 1983;11:839–50.[Web of Science][Medline]
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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]
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Sakariassen KS, Ottenhof-Rovers M, Sixma JJ. Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence. Blood 1984;63:996–1003.[Abstract/Free Full Text]
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Scheingraber S, Rehm M, Sehmisch C, et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999;90:1265–70.[Web of Science][Medline]
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