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National Heart, Lung, and Blood Institute (NHLBI) and Food and Drug Administration (FDA) Public Workshop: Risks and Benefits of Hydroxyethyl Starch Solutions

September 6-7, 2012 National Institutes of Health Bethesda, MD

Executive Summary FINAL DRAFT

Executive Summary

The workshop on the Risks and Benefits of Hydroxyethyl Starch Solutions (HES) was convened on September 6-7, 2012. Experts from the National Institutes of Health (NIH), Department of Defense (DoD), U.S. Food and Drug Administration (FDA), Department of Veterans Affairs (VA), academia, and industry attended the workshop to discuss new findings on the risks and benefits of FDA-approved HES, as well as the barriers to the development and use of resuscitation fluids in general. The purpose was to aid in planning future clinical studies in this area. Key areas discussed were the:

  • Use of HES in clinical practice, the risks and benefits of HES, and alternative intravenous resuscitation fluids, including normal saline, lactated Ringer's, and albumin;
  • Published evidence and practice regarding HES and other alternative fluid based resuscitation strategies in traumatic, septic, and peri-operative clinical settings;
  • Pathophysiology of hypovolemia and metabolic, inflammatory, coagulation, and other effects associated with fluid resuscitation in the setting of severe traumatic injury, sepsis, and peri-operative blood loss; and
  • Opportunities to elucidate future research directions for the role of fluid-oriented resuscitation strategies in traumatic shock with severe blood loss, septic shock, and intra-postoperative blood loss.

Discussion

HES are synthetic colloids composed almost entirely of amylopectin obtained from corn or potatoes. They are licensed as plasma volume expanders for the treatment of hypovolemic shock due to sepsis, acute hemorrhage (trauma), and burns. HES vary in their molecular weight, hydroxyethyl moieties, and in the ratio of C2 to C6 substitutions. Although a causal relationship has not been firmly established, large volumes of HES used in resuscitation may dilute plasma proteins and are associated with coagulation abnormalities that cannot be attributed solely to hemodilution and result in bleeding and/or anemia with possible compromised platelet function.

In reviewing the relevant basic and clinical science, including clinical research studies focusing on the incidence of related adverse events associated with the use of HES, the workshop participants noted that there have been many published clinical studies and trials using HES as a resuscitation fluid over the past 25 years. These studies have demonstrated no clear benefits of HES over other available IV resuscitation solutions with respect to risks for increased bleeding and renal toxicity. In addition, these studies have generally lacked a good definition of hypovolemia and information regarding bleeding characteristics. Two very large recently completed randomized trials (6S and CHEST) conducted in patients with sepsis and hypovolemia were described and discussed. Based on the available data, the group agreed that HES behaved as a class in terms of their toxic effects on bleeding and renal failure, which means that results from studies with one HES may be extrapolated to other HESs. They believed that studies performed with HES in elective surgery suggest some benefit, but harm was not ruled out because follow-up of patients was too short. Although some participants suggested that HES studies in elective surgery patients with long-term follow-up could be helpful in identifying long-term risks and benefits, others indicated that these did not warrant public funding. The group believed that these fluids are frequently overused in potentially hypovolemic conditions.

Recommendations:

  1. HES assessment: based on available evidence there is no clear benefit of HES over other available IV resuscitation solutions with potential risks for increased bleeding and renal toxicity; HES behaved as a class in terms of their toxic effects on bleeding and renal failure.
  2. Data review: Support a review of currently available data on HES and other products so this information may be appropriately used in clinical practice.
  3. Basic/translational/clinical research: To increase understanding of the use of resuscitation fluids in general, support is needed for fundamental, translational, and clinical research to elucidate the physiological effects and toxicity of their use across the full spectrum of their use in the treatment of hypovolemic states.
  4. Methods for accurate assessment and monitoring of hypovolemic states: New, accurate methods are needed to be developed for early detection and monitoring of hypovolemia to optimize HES and other solutions fluid management strategies of hypovolemic states.
  5. Physician education and clinical practice guidelines: To assure proper fluid management based on the evidence, education and training opportunities need to be promoted for both physicians in training and practitioners.

Publication Plans:

The Workshop Steering Committee plans to submit a summary of the meeting for publication in a peer-reviewed journal.

Participating Agencies, Divisions, and Institutes

Center for Biologics Evaluation and Researchimage of external icon (CBER), FDA
US Army Medical Research and Materiel Command, Department of Defense (DoD)
Division of Cardiovascular Sciences (DCVS), Division of Blood Diseases and Resources (DBDR), NHLBI

Workshop Steering Committee

  • Hasan Alam, MD; Harvard Medical School
  • Jerrold Levy, MD; Emory University School of Medicine
  • Michael Murray, MD; Mayo Clinic
  • Carol Schermer, MD, MPH; University of California - Davis
  • Martin Schreiber, MD; Oregon Health & Science University
  • Andrew Shaw, MD; Duke University
  • Donald Trunkey, MD; Oregon Health & Science University

Other Speakers and Discussants

  • Nicolai RS Haase, MD; Rigshospitalet Blegdamsvej 9 (Copenhagen, Denmark)
  • Sheldon Magder, MD; McGill University (Montreal, Canada)
  • Anders Perner, MD, PhD; Rigshospitalet Blegdamsvej 9 (Copenhagen, Denmark)
  • Konrad Rinehart, MD; Jena University Hospital; Chairman Global Sepsis Alliance (Jena, Germany)
  • Richard Weiskopf, MD; University of California, San Francisco
  • Lakhmir Chawla, MD; George Washington University Medical Center
  • John Kellum, MD; University of Pittsburgh

NHLBI Staff

  • George Sopko, MD, MPH; DCVS
  • Andrei Kindzelski, MD, PhD; DBDR

FDA Staff

  • Mitchell Berger, MPH; CBER
  • Nisha Jain, MD; CBER
  • Laurence Landow, MD; CBER
  • John Scott, PhD; CBER

DoD Staff

  • Anthony Pusateri, PhD; US Army Medical Research and Materiel Command, DOD

Contact staff

Last Updated: December 2012

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