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Correspondence  |   August 2004
Why the Food and Drug Administration Changed the Warning Label for Hetastarch
Author Affiliations & Notes
  • Gary R. Haynes, Ph.D., M.D.
    *
  • * Medical University of South Carolina, Charleston, South Carolina.
Article Information
Correspondence
Correspondence   |   August 2004
Why the Food and Drug Administration Changed the Warning Label for Hetastarch
Anesthesiology 8 2004, Vol.101, 560-561. doi:
Anesthesiology 8 2004, Vol.101, 560-561. doi:
To the Editor:—
The United States Food and Drug Administration (FDA) recently approved a major change in the labeling of 6% hetastarch in saline, applying specifically to cardiopulmonary bypass surgeries. This synthetic colloid is commonly used in place of 5% human albumin as a plasma volume expander in a variety of surgical and critical care settings.
In August 2003, the following warning statement was added: HESPAN is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired  .1 The change follows a recommendation of the Blood Products Advisory Committee, Center for Biologics Evaluation and Research, Rockville, Maryland, made to the FDA in June 2002.1
The interference by hetastarch with coagulation has been documented repeatedly over the last three decades. These effects were described in the early 1960s when preclinical research on hetastarch demonstrated prolonged bleeding times.2 Hetastarch infusion mediates a dose-dependent decrease of factor VIII and von Willebrand factor and interferes with platelet function by absorption to their surface.3–5 Although coagulation measures and anecdotal reports of hetastarch-associated hemorrhage have been reviewed extensively, controversy regarding the clinical relevance of these effects has persisted in the absence of adequate data.6 
Because of this controversy a useful approach is to evaluate studies of a well-defined group, such as patients requiring cardiopulmonary bypass. Postoperative bleeding in this group is a very significant complication because the need for surgical reexploration increases the risk to patients with greater mortality, prolonged intensive care unit stay, and increased cost.
Early studies of hetastarch used during cardiac surgery failed to document any difference in postoperative blood loss between hetastarch or albumin given for volume replacement.7–9 Three studies showed modestly higher blood loss when patients received hetastarch but none of these reached statistical significance.10–12 These reports were limited by small sample sizes (n < 200), and these reports are no longer useful because patient selection, surgical technique, and perioperative management have changed greatly in the years since they were published.
Two studies in cardiac surgery patients and an epidemiological study from the current literature prompted the FDA to ask if hetastarch mediates increased bleeding in patients on cardiopulmonary bypass. Both surgical studies examined the effect of intraoperative hetastarch administration on postoperative blood loss. The studies are significant because their study populations approach or exceed the threshold (200 patients in each arm of a comparative study) suggested by Warren and Durieux to achieve adequate statistical power.13 Herwalt et al.  14 examined the risk factors associated with increased postoperative bleeding when hetastarch was substituted for albumin in cardiopulmonary bypass pump priming solution. They found an increase in the transfusion of blood products, increased costs, and two risk factors: age greater than 60 yr and the use of more than 5 ml/kg hetastarch were associated with postoperative bleeding in their study of 500 patients.
Cope et al.  15 reviewed 189 consecutive coronary artery bypass graft surgeries. They reported a significant increase in blood loss and use of hemostatic agents when hetastarch was used in the operating room. Increased postoperative chest tube drainage, transfusion requirements, and a greater risk of surgical reexploration were documented in patients who received hetastarch during surgery, and five patients (7.4%) receiving hetastarch intraoperatively required surgical reexploration as opposed to one (1.6%) in the group that did not.
A large review from the Mayo Clinic, Rochester, Minnesota, reported the experience of 444 consecutive cases, all performed by the same surgeon when the routine practice of using hetastarch for volume expansion during surgery was discontinued as a result of the Cope publication.16 The retrospective study examining postoperative bleeding found the mean blood loss was about 40% higher in patients receiving hetastarch. Like Cope et al.  ,15 they also noted that it appeared to increase in a dose-dependent manner.
The value of these studies comes from limiting the use of hetastarch to the intraoperative period and examining the postoperative result of that practice. They are retrospective studies but the complete change in hetastarch use minimizes the risk of treatment bias. No important between-group biases were evident and the studies included patient numbers to warrant acceptance of most of the major findings.
The advisory committee also heard the report of Canver and Nichols17 that supported the use of hetastarch. That study compared crystalloid, albumin, hetastarch, and a combination of albumin and hetastarch for cardiopulmonary bypass pump priming in nearly 900 coronary artery bypass graft patients. The study failed to find any difference in postoperative bleeding or reoperation. The committee did not agree with the conclusion because patients in each arm of the study were dissimilar. Patients given a hetastarch-based priming solution had much shorter cross-clamp times than did those in the other groups. Because the duration of cardiopulmonary bypass influences bleeding, it is noteworthy that even with the shorter cross-clamp time; Canver and Nichols’ data shows the highest mean consumption of platelets and fresh frozen plasma was in the hetastarch group.
On a unanimous vote (with two abstentions), the Blood Products Advisory Committee recommended changing the labeling of 6% hetastarch in saline to warn users of the risk of excessive bleeding associated with its use in bypass surgery.
There are additional reports not used by the Blood Products Advisory Committee in reaching their decision that support their action. Wilkes et al.  18 conducted a meta-analysis examining 16 studies encompassing 653 patients in whom hetastarch was used during cardiopulmonary bypass. When compared with albumin administration, patients receiving hetastarch had greater blood loss and the proportion of patients with blood loss greater than 1 l was 19% for patients receiving albumin versus  33% for patients receiving hetastarch. Two reports published since the FDA decision provide additional evidence supporting that action. Sedrakyan et al.  19 examined mortality as a clinical outcome in more than 19,000 patients that had coronary artery bypass surgery. Patients receiving albumin or nonprotein colloids (dextran, hetastarch) were compared, and albumin administration was associated with lower mortality (2.47% versus  . 3.03%). This represents 25% lower odds of mortality compared to nonprotein colloid use. This result is consistent with Knutson et al.,  16 who also found a small increase in mortality of 3% in the hetastarch treatment group. Avorn et al.  20 performed a case-controlled study of 238 bypass cases examining patients receiving three or more units of blood products within 72 h of surgery or who returned to the operating room for bleeding. A multivariate analysis found those receiving one unit of hetastarch had more than twice the risk of bleeding than control group patients and the risk increased to more than four times that of the control group when patients received 2 or 3 units of hetastarch.
Significant randomized clinical trials of the 6% hetastarch product in lactated electrolyte solution (Hextend®; BioTime, Inc, Berkeley, California) are lacking. The only clinical trial evaluating this material compared the treatment group and a control group that received hetastarch in saline.21 Resuscitation fluids in both arms of the study were given to maintain a target urine output, heart rate, and systolic blood pressure without regard to a maximum dose. As a result, some patients in both the control and treatment groups received up to 5 l of hetastarch. This is far in excess of the recommended dosing guidelines for this product. At the present time there are no robust clinical data to support the manufacturer’s assertion that 6% hetastarch in electrolyte solution is not associated with similar bleeding-related complications in cardiac surgery cases.
* Medical University of South Carolina, Charleston, South Carolina.
References
HESPAN®[production labeling]. Irvine, California: B. Braun Medical, Inc.; March, 2003
Thompson WL, Gadsden RH: Prolonged bleeding times and hypofibrinogenemia in dogs after infusion of hydroxyethyl starch and dextran. Transfusion 1965; 5:440–6Thompson, WL Gadsden, RH
Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 1981; 21:299–301Strauss, RG
Strauss RG, Stump DC, Henricksen RA: Effects of hydroxyethyl starch on fibrinogen, fibrin clot formation, and fibrinolysis. Transfusion 1985; 25:230–4Strauss, RG Stump, DC Henricksen, RA
Kuitunen A, Hynynen M, Salmenpera M, Heinonen J, Valetera E, Verkkala K, Myllyla G: Hydroxyethyl starch as a prime for cardiopulmonary bypass: Effects of two different solutions on hemostasis. Acta Anaesthesiol Scand 1993; 37:652–58Kuitunen, A Hynynen, M Salmenpera, M Heinonen, J Valetera, E Verkkala, K Myllyla, G
Blaicher AM, Reiter WJ, Blaicher W, Kettner SC, Felfevnig M, Grabner CM, Simpfer M: The effect of hydroxyethyl starch on platelet aggregation in vitro  . Anesth Analg 1998; 86:1318–21Blaicher, AM Reiter, WJ Blaicher, W Kettner, SC Felfevnig, M Grabner, CM Simpfer, M
Saunders CR, Carlisle L, Bick RL: Hydroxyethyl starch versus albumin in cardiopulmonary bypass prime solutions. Ann Thorac Surg. 1983 36:532–9Saunders, CR Carlisle, L Bick, RL
Sade RM, Stroud MR, Crawford FA, Kratz JM, Deering JP, Bartles DM: A prospective randomized study of hydroxyethyl starch, albumin, and lactated Ringer’s solution as priming fluid for cardiopulmonary bypass. J Thorac Cardiovasc Surg 1985; 89:713–22Sade, RM Stroud, MR Crawford, FA Kratz, JM Deering, JP Bartles, DM
Boldt J, Knothe C, Zickermann B, Andres P, Dapper F, Hempelmann G: Influence of different intravascular volume therapies on platelet function in patients undergoing cardiopulmonary bypass. Anesth Analg 1993; 76:1185–90Boldt, J Knothe, C Zickermann, B Andres, P Dapper, F Hempelmann, G
Diehl JT, Lester JL 3rd, Cosgrove DM: Clinical comparison of hetastarch and albumin in postoperative cardiac patients. Ann Thorac Surg 1982; 34:674–9Diehl, JT Lester, JL Cosgrove, DM
Moggio RA, Rha CC, Somberg ED, Prager PI, Pooley RW, Reed GE: Hemodynamic comparison of albumin and hydroxyethyl starch in postoperative cardiac surgery patients. Crit Care Med 1983; 11:943–5Moggio, RA Rha, CC Somberg, ED Prager, PI Pooley, RW Reed, GE
Kirkin JK, Lell WA, Kouchoukos NT: Hydroxyethyl starch versus albumin for colloid infusion following cardiopulmonary bypass in patients undergoing myocardial revascularization. Ann Thorac Surg 1984; 37:40–6Kirkin, JK Lell, WA Kouchoukos, NT
Warren BB, Durieux ME: Hydroxyethyl starch: Safe or not? Anesth Analg 1997; 84:206–12Warren, BB Durieux, ME
Herwaldt LA, Swartzendruber SK, Edmond MB, Embrey RP, Wilkerson KR, Wenezel RP, Perl TM: The epidemiology of hemorrhage related to cardiothoracic operations. Infect Control Hosp Epidemiol 1998; 19:9–16Herwaldt, LA Swartzendruber, SK Edmond, MB Embrey, RP Wilkerson, KR Wenezel, RP Perl, TM
Cope JT, Banks D, Mauney MC, Lucktong T, Shockey KS, Kron IL, Tribble CG: Intraoperative hetastarch infusion impairs hemostasis after cardiac operations. Ann Thorac Surg 1997; 63:87–93Cope, JT Banks, D Mauney, MC Lucktong, T Shockey, KS Kron, IL Tribble, CG
Knutson JE, Deering JA, Hall FW, Nuttall GA, Schroeder DR, White RD, Bullany CJ: Does intraoperative hetastarch administration increase blood loss and transfusion requirements after cardiac surgery? Anesth Analg 2000; 90:801–7Knutson, JE Deering, JA Hall, FW Nuttall, GA Schroeder, DR White, RD Bullany, CJ
Canver CC, Nichols RD: Use of intraoperative hetastarch priming during coronary artery bypass. Chest 2000; 118:1616–20Canver, CC Nichols, RD
Wilkes MM, Navickis RJ, Sibbald WJ: Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: A meta-analysis of postoperative bleeding. Ann Thorac Surg 2001; 72:527–34Wilkes, MM Navickis, RJ Sibbald, WJ
Sedrakyan A, Gondek K, Paltiel D, Elefteriades JA: Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest 2003; 123:1853–7Sedrakyan, A Gondek, K Paltiel, D Elefteriades, JA
Avorn J, Patel P, Levin R, Winkelmayer WC: Hetastarch and bleeding complications after coronary artery surgery. Chest 2003; 124:1437–42Avorn, J Patel, P Levin, R Winkelmayer, WC
Gan TJ, Bennett-Guerrero E, Phillips-Bute B, Wakeling H, Moskowitz DM, Olufolabi Y, Konstadt SN, Bradford C, Glass PS, Machin SJ, Mythen MG: Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Anesth Analg 1999; 88:992–8Gan, TJ Bennett-Guerrero, E Phillips-Bute, B Wakeling, H Moskowitz, DM Olufolabi, Y Konstadt, SN Bradford, C Glass, PS Machin, SJ Mythen, MG