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Hydroxyethyl starch

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Hydroxyethyl starch
Clinical data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life1.4 hrs
ExcretionRenal
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.120.749 Edit this at Wikidata
Chemical and physical data
Molar mass130 - 200 kDa (typical)
3D model (JSmol)
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  • InChI=1S/C16H32O11.C6H12O6/c17-1-6-22-11-12-13(23-7-2-18)14(24-8-3-19)15(25-9-4-20)16(27-12)26-10-5-21;7-1-2-3(8)4(9)5(10)6(11)12-2/h12-21H,1-11H2;2-11H,1H2/t12-,13-,14+,15-,16+;2-,3-,4+,5-,6+/m11/s1 checkY
  • Key:DNZMDASEFMLYBU-RNBXVSKKSA-N checkY
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Hydroxyethyl starch (HES/HAES) is a nonionic starch derivative. It is one of the most frequently used volume expanders under the trade names Hespan by B. Braun Medical Inc. and Voluven or Volulyte by Fresenius Kabi. HES is a general term and can be sub-classified according to average molecular weight, molar substitution, concentration, C2/C6 ratio and Maximum Daily Dose.[2]

Its use in those who are very ill is associated with an increased risk of death and kidney problems.[3] The European Medicines Agency in June 2013 is discussing removing it from the market.[4] The companies B Braun and Fresenius Kabi were ordered to recall all HES solutions within 48 hours in UK on June 27th 2013.[5] FDA issued a black box warning for HES in June of 2013 advising that side effects are a class effect, that it should not be used in the ICU due to increased mortality and need of dialysis.[6]

Medical uses

A hydroxyethyl starch solution ready for intravenous infusion.

An intravenous solution of hydroxyethyl starch is used to prevent shock following severe blood loss caused by trauma, surgery, or other problem. It however appears to have greater risk of a poor outcome compared to other intravenous solutions[3] and may increase the risk of death.[7]

Adverse effects

Anaphylactoid reactions: hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm and non-cardiogenic pulmonary edema. Decrease in hematocrit and disturbances in coagulation. One liter of 6% solution (Hespan) reduces factor VIII level by 50% and will prolong aPTT.[8]

HES derivatives have been demonstrated to have increased rates of acute renal failure and need for renal replacement therapy and to decrease long-term survival when used alone in cases of severe sepsis compared with Ringer lactate solution.[9] The effects were tested recently on HES 130kDa/0.42 in people with severe sepsis, and showed increased rates of renal failure and increased mortality when compared to LR. It has been recommended that, since medium-MW HES solutions may be associated with harm, these solutions should not be used routinely for patients with septic shock.[10]

During 2010/11 a large number of research papers associated with a single author were retracted for ethical reasons and this may have an impact on clinical guidelines referring to HES preparations prepared before this date.[11]

FDA Recommendations for Health Care Professionals referring to HES due to class effects [12] Do not use HES solutions in critically ill adult patients including those with sepsis, and those admitted to the ICU. Avoid use in patients with pre-existing renal dysfunction. Discontinue use of HES at the first sign of renal injury. Need for renal replacement therapy has been reported up to 90 days after HES administration. Continue to monitor renal function for at least 90 days in all patients. Avoid use in patients undergoing open heart surgery in association with cardiopulmonary bypass due to excess bleeding. Discontinue use of HES at the first sign of coagulopathy.

Contraindications

  • This product should not be used in people who are hypersensitive or allergic to hydroxyethyl starch.
  • Patients with kidney failure not related to low blood volume and patients on dialysis should avoid this product in high doses which are used for volume expansion.
  • Use of hydroxyethyl starch with normal saline in its preparation is contraindicated in people with severe increases in blood levels of sodium or chloride.
  • Patients with intracranial bleeds should not use this product.

Safety concerns

High molecular weight HES has been linked to coagulopathy, pruritus, as well as nephrotoxicity, acute renal failure and mortality.[13][14] On the other hand, low molecular weight HES seems not to demonstrate such adverse effects.[2] However, some suggest that low molecular weight HES poses significant safety concerns. They posit that studies concluding otherwise are not reliable for a number of reasons including “unsuitable comparators, too short observation periods, low cumulative dose and low-risk patients.” (Hartog & Reinhart, 2009, p 1340).[13] Recent results of 6S trial seem to confirm these concerns (see below).

In June 2012 6S paper was published in the New England Journal of Medicine raising concerns regarding the use of hydroxyethyl starch in sepsis - specifically, resuscitation with hydroxyethyl starch (as opposed to Ringer's acetate) resulted in an increased risk of death or end stage renal failure.[15] This study used Tetraspan (HES 130/0.42) of the pharmaceutical company B.Braun but the original version of the publication contained the product specification HES 130/0.4.[15] The pharmaceutical company, Fresenius Kabi, that makes a similar product but with the specification HES 130/0.4 is threatening to bring legal action against the author, Anders Perner, as they wanted the misleading use of their product specification to be corrected.[16] The academic community has raised concerns regarding this sort of behavior by a corporation although Fresenius Kabi did not doubt the results of the study.[16] The Chest study compared Hes130/0.40 with Saline in 7000 patients. The study was performed in patients that were less sick than in 6s; however, the increase in mortality was similar to 6s. There has also been a significant increase in dialysis rate overall. The increase in creatinine confirmed the pathophysiological rationale. Furthermore, the patients needed more blood products, had significant more liver failure and itching. The study has been published in the NEJM Oct 2012.[17]

As a consequence, the European Regulatory Agency (EMA)has started an Official Procedure to Assess the Safety of all HES Products(Nov 2012). The FDA in Sept 2012 conducted a Public Workshop addressing Safety concerns of HES, which according to the Majority of participants should be addressed by regulators.[18] The surviving Sepsis Campaign Decided to ban HES from treatment in Sepsis patients. [19]

On June 14th, 2013, PRAC, which is the safety committee of EMA, the European regulatory agency, published on their official website the recommendation to suspend the marketing autorisation of all HES products in Europe. The risk benefit ratio is negative based on results of 3 megatrials (VISEP, 6S, CHEST). A clinical benefit could not be demonstrated in any patient population, and there is ample evidence of harm, especially kidney failure due to long-term storage of the product in vital organs.[20] The FDA followed on June 24th.MHRA recalled the HES products on June 27th as the risks outweigh potential benefits and safer and cheaper alternatives are available.[5][6]

Pharmacokinetics

Different types of hydroxyethyl starches are typically described by their average molecular weight, typically around 130 to 200 kDa (bearing in mind that there will be a range of different-sized molecules in any given solution); and their degree of molar substitution (what proportion of the glucose units on the starch molecule have been replaced by hydroxyethyl units), typically around 0.35 to 0.5. A solution of hydroxyethyl starch may further be described by its concentration in % (i.e. grams per 100ml). So for example, one commercially available hydroxyethyl starch (Voluven) is described as 6% HES 130 / 0.4.

The elimination depends on molar substitution degree. Molecules smaller than the renal threshold (60–70 kDa) are readily excreted in the urine while a small part of the larger ones are metabolized by plasma α–amylase before those degradation products are renally excreted. However HES is only partly degraded and excreted, while for a large amount the metabolism remains unclear. Approximately one-third to two-thirds of administered HES cannot be accounted for by 24-h urinary excretion. In one study the cumulative excretion over 72 h was 50% of the administered dose. HES has remained detectable in plasma 4 months after infusion, and in skin tissue up to 54 months after HES infusion. Administered HES accumulates in large quantities within diverse tissues where it can persist for periods of several years.[21] Therefore HES should not be administered for longer than 24 hours [22]

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b Westphal, M., James, M., Kozek-Langenecker, S., Stocker, R., Guidet, B., & Van Aken, H. (2009). Hydroxyethyl starches: different products--different effects. [Review] [140 refs]" Anesthesiology 111(1), 187–202.
  3. ^ a b Zarychanski, R (2013 Feb 20). "Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis". JAMA: the Journal of the American Medical Association. 309 (7): 678–88. doi:10.1001/jama.2013.430. PMID 23423413. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001814.jsp&mid=WC0b01ac058004d5c1 PRAC recommends suspending marketing authorizations for infusion solutions containing hydroxyethyl starch
  5. ^ a b http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON287028
  6. ^ a b http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm
  7. ^ Perel, P (2013 Feb 28). "Colloids versus crystalloids for fluid resuscitation in critically ill patients". The Cochrane database of systematic reviews. 2: CD000567. doi:10.1002/14651858.CD000567.pub6. PMID 23450531. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Miller: Anesthesia, 6th ed, p 1787
  9. ^ Brunkhorst FM; Engel C; Bloos F; et al. (2008). "Intensive insulin therapy and pentastarch resuscitation in severe sepsis". N. Engl. J. Med. 358 (2): 125–39. doi:10.1056/NEJMoa070716. PMID 18184958. {{cite journal}}: Unknown parameter |author-separator= ignored (help); Unknown parameter |month= ignored (help)
  10. ^ James Downar, Stephen E Lapinsky. Pro/con debate: Should synthetic colloids be used in patients with septic shock? Critical Care 2009, 13:203 (29 January 2009)
  11. ^ Statement Regarding Published Clinical Trials Conducted without IRB Approval by Joachim Boldt. March 4, 2011
  12. ^ http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm
  13. ^ a b Hartog, C., & Reinhart, K. (2009). CONTRA: Hydroxyethyl starch solutions are unsafe in critically ill patients. Intensive Care Medicine, 35(8), 1337–42. doi:10.1007/s00134-009-1521-5
  14. ^ Perner, A., Haase, N., Wetterslev, J., Åneman, A., Tenhunen, J., Guttormsen, A. B., Klemenzson, G., et al. (2011). Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S - Scandinavian Starch for Severe Sepsis/Septic Shock trial): Study protocol, design and rationale for a double-blinded, randomised clinical trial. Trials, 12, 24. doi:10.1186/1745-6215-12-24
  15. ^ a b Perner, A (2012 Jul 12). "Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis". The New England Journal of Medicine. 367 (2): 124–34. doi:10.1056/NEJMoa1204242. PMID 22738085. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ a b Wojcik, Jeppe (July 24, 2012). "Pharma giant threatens Danish scientist". ScienceNordic. Retrieved 13 August 2012.
  17. ^ Myburgh, John A.; et al. 2012. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care" N Engl J Med 367:1901-1911.
  18. ^ http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm313370.htm
  19. ^ http://journals.lww.com/ccmjournal/pages/articleviewer.aspx?year=2013&issue=02000&article=00024&type=abstract
  20. ^ Medicines Agency: Solutions for infusion containing hydroxyethyl starch
  21. ^ http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2004.06272.x/abstract
  22. ^ PRAC (Pharmacovigilance Risk Assessment Committee) confirms that hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients. October 11th, 2013, Pressemitteilung, PDF
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