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US Food and Drug Administration adds black boxed warning to Hydroxyethyl starch (HES)

Thursday, September 12, 2013  
Posted by: Lynsey Mellon
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US Food and Drug Administration adds black boxed warning to Hydroxyethyl starch (HES)

Summary of HES related Recommendations for ASFA members: 

I. Avoid the use of HES in critically ill patients, patients with renal insufficiency, patients with sepsis, and patients at risk of bleeding who are undergoing TPE.  HES use in these settings should be limited only to situations where the benefit of its use outweighs the risk.  Examples of such situations would include but are not be limited to:
a. Jehovah’s Witnesses with a life-threatening disease amenable to TPE who refuse albumin and plasma replacement fluids.
b. Patients with severe recurrent allergic reactions to albumin.
c. During severe albumin shortages, after assessment of the benefit of the therapy versus risk of replacement alternatives.

II. Avoid the use of HES or use with caution in critically ill patients, patients with renal insufficiency, and patients at risk of bleeding in the setting of leukocytapheresis.

III. Potential granulocyte donors should be questioned and/or screened for evidence of renal insufficiency and underlying renal disease. Consent for collection should include an explicit discussion of this potential risk and education on signs and symptoms to look for as outlined in the FDA black box warning document. 

Background:
Hydroxyethyl starch (HES) is a colloidal solution that is used predominantly for volume replacement in a number of clinical settings including sepsis, trauma, and cardiopulmonary bypass.  In apheresis, HES has rarely been used as a replacement fluid in plasma exchange (TPE) in patients who refuse albumin or plasma on religious or other grounds and as a partial replacement for albumin to minimize the costs of procedures as it is less expensive than human albumin.  In addition, it is also used as a sedimenting agent in the setting of therapeutic leukocytapheresis and the collection of granulocytes.  In these two uses, HES induces rouleaux formation which enhances the separation of granulocytes from the red cells.  The use of HES in the setting of granulocyte collections has been associated with increased granulocyte product yields.[1]  HES has a long half-life, being metabolized by α-amylase with the breakdown products being excreted by the kidneys.[2]

HES is associated with a number of dose dependent side-effects.  These side-effects include:
- Prolongation of the aPTT with development of a von Willebrand disease-like state and increased risk of bleeding – HES results in increased turnover of von Willebrand factor (vWF) with a resulting decline in factor VIII.  The decreased vWF results in decreased platelet function while a low factor VIII causes prolongation of the aPTT.[3]  This is dose-dependent, with a maximum dose of 20mL/kg/24-hour period being suggested in the setting of volume resuscitation.[4]
- Skin deposition with pruritus – Pruritus, sometimes severe, can occur with skin deposition and this is one of the most common side-effects reported with HES.[5, 6]
- Anaphylactoid reactions – HES can activate the alternative complement pathway resulting in the generation of C3a and C5a.  This can produce allergic type reactions ranging from urticaria (hives) to life-threatening anaphylaxis. [7, 8, 9]
- Tissue deposition with organ failure – There has been a single case report of a Jehovah’s Witness with myasthenia gravis who suffered from HES deposition in multiple organs after years of TPE using HES as the replacement fluid.  The organ deposition resulted in multisystem organ failure that subsequently resolved following discontinuation of TPE.[10]

On June 24 2013, the US Food and Drug Administration added a black boxed warning to HES.[11]  The black box warning deals with increased mortality and severe renal injury in critically ill adult patients as well as an increased risk of bleeding in the setting of HES use in cardiopulmonary bypass.  This was based upon the publication of three randomized controlled trials in 2012 indicating an increased risk of mortality and renal injury requiring renal replacement therapy in critically ill adult patients with sepsis and those admitted to the ICU.[12, 13, 14]  Additional evidence also included meta-analyses and observational studies demonstrating similar findings.  Finally, a meta-analysis of 18 randomized controlled trials also showed an increase in bleeding when HES was used in cardiopulmonary bypass.[15]

The FDA made the following recommendations:
- Do not use HES solutions in critically ill adult patients including those with sepsis and those admitted to the ICU.
- Avoid use of HES in patients with pre-existing renal dysfunction.
- Discontinue use of HES at the first sign of renal injury.
- Patients receiving HES should have their renal function monitored for at least 90 days as need for renal replacement therapy has been reported up to 90 days after HES.
- Avoid HES use in patients undergoing open heart surgery in association with cardiopulmonary bypass.
- Discontinue the use of HES at the first sign of coagulopathy.

Because of the FDA black box warnings, the European Medicines Agency has recommended the suspension of marketing of HES containing infusion solutions in Europe.  Unfortunately, an alternative sedimenting agent is not available for the collection of granulocytes as the side effects mentioned above as well as the studies cited by the FDA saw similar findings with high-molecular weight HES (Hetastarch) as well as low-molecular weight HES (Pentastarch).

The American Society for Apheresis (ASFA) is issuing this document to remind apheresis practitioners of the risks associated with the use of HES in volume replacement.  While the volume of HES administered during therapeutic apheresis procedures and granulocyte collection is less than that reported to be used in the trials cited by the FDA [12, 13, 14], coagulopathy and allergic type reactions have been reported in granulocyte donors.[3, 8]  In addition, an ASFA member has reported onset of oliguria in a granulocyte donor with undiagnosed renal insufficiency following exposure to HES.  


References
1. Iacone A, Di Bartolomeo P, Di Girolamo G, et al: Hydroxyethyl starch and steroid improved collection of normal granulocytes with continuous flow centrifugation gravity leukapheresis. Haematologica 1981; 66:645–655.
2. Yacobi A, Stoll RG, Sum CY, et al: Pharmacokinetics of hydroxyethyl starch in normal subjects. J Clin Pharmacol 1982; 22:206–212.
3. Strauss RG, Stansfield C, Henriksen RA, et al: Pentastarch may cause fewer effects on 
coagulation than hetastarch. Transfusion 1988; 28:257–260.
4. Nearman HS, Herman ML: Toxic effects of colloids in the intensive care unit. Crit Care Clin 1991; 7:713–723.
5. Sirtl C, Laubenthal H, Zumtobel V, et al: Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related. Br J Anaesth 1999; 82:510–515.
6. Stander S, Szepfalusi Z, Bohle B, et al: Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study. Cell Tissue Res 2001; 304:261–269.
7. Ring J, Messmer K: Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977; 1:466–469.
8. Dutcher JP, Aisner J, Hogge DE, et al: Donor reaction to hydroxyethyl starch during granulocytapheresis. Transfusion 1984; 24:66–67.
9. Kannan S, Milligan KR: Moderately severe anaphylactoid reaction to pentastarch (200/0.5) in a patient with acute severe asthma. Intensive Care Med 1999; 25:220–222.
10. Auwerda JJ, Wilson JH, Sonneveld P: Foamy macrophage syndrome due to hydroxyethyl starch replacement: a severe side effect in plasmapheresis. Ann Intern Med 2002; 137:1013–1014.
11. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm
12. Perner A, Haase N, Guttirmsen AB, et al. Hydroxyethyl starch 130/0.4 versus Ringer’s acetate in severe sepsis. N Engl Med 2012;367:124-34
13. Guildet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Critical Care 2012;16:R94.
14. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901-11.
15. Navicks RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: A meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2012;144:223-30.