BETHESDA, MD 11 October 2012—FDA's September 6–7 public workshop on the risks and benefits of hydroxyethyl starch (HES) solutions was, in part, an indictment of the practice of routinely administering i.v. fluids without acknowledging that they can cause adverse events.
"Fluid is a drug. And I don't think, in my training . . . that that was ever brought home for me. We just call them maintenance fluids," said Lakhmir Chawla, kidney specialist at the George Washington University Medical Center in Washington, D.C.
"You can take whatever fluid you want," Chawla said. "If you give enough, . . . you get toxicity."
FDA convened the workshop to discuss recent data on the risks and benefits of HES solutions and their effects on homeostasis and kidney function. The workshop was cosponsored by the Department of Defense, the National Heart, Lung and Blood Institute of the National Institutes of Health, and the Department of Health and Human Services Office of the Assistant Secretary for Health.
Workshop participants discussed the merits and drawbacks of HES, other colloid solutions, and crystalloid preparations such as 0.9% sodium chloride solution and lactated Ringer's solution.
Fluid replacement. Carol Schermer, a trauma surgeon at the University of California Davis Medical Center, said the rationale for giving i.v. fluids is to replace blood loss and maintain an adequate circulating blood volume. The goal is to prevent organ failure from hypoperfusion.
Schermer said research indicates that administering fluids to patients with sepsis in the first hours of the illness appears to improve survival, but the practice is probably harmful later on.
And, she said, once clinicians start administering i.v. fluids, they tend to continue the therapy over time, potentially leading to fluid overload. Consequences of the condition include hypertension, breathing abnormalities, edema, electrolyte imbalances, and kidney injury.
Schermer said studies have shown that fluid overload in hospitalized patients with a variety of conditions is associated with an increased risk of death.
I.V. fluid replacement can also interfere with blood clotting, an undesirable effect in patients who are receiving the fluids to make up for blood loss.
"There is no question that if you give any kind of fluid in large amounts, it will cause coagulopathy," Schermer said.
John Kellum, professor of clinical care medicine at the University of Pittsburgh, said it's a knee-jerk reaction in North American intensive care units to give a saline bolus when a patient's blood pressure drops, even though the practice is "almost completely unstudied."
"We say it's worse to be hypotensive than to get a liter of saline. I'm not sure that's true anymore," he said.
HES solutions. HES solutions are synthetic colloids indicated for the treatment of hypovolemia resulting from trauma, sepsis, burns, or anaphylaxis. Three FDA-approved HES solutions are currently available in the United States. Two products—B. Braun Medical Inc.'s Hespan, licensed in 1972, and Biotime Inc.'s Hextend, licensed in 1999—are hetastarches. The newest product, Fresenius Kabi's Voluven, is a tetrastarch. This nomenclature refers to the percentage of hydroxyethyl groups per glucose unit, which affects the amount of time an HES product persists in the body.
For example, said FDA Medical Officer Laurence Landow, the hetastarches Hespan and Hextend have half-lives of about 46 hours, but Voluven has a half-life of 12 hours. Several speakers at the meeting noted that longer half lives may lead to greater HES toxicity.
Hasan Alam, a trauma surgeon at Massachusetts General Hospital in Boston, said recent clinical data indicate that HES solutions cause inflammation, impair coagulation, and result in dose-dependent organ injury, especially kidney injury. He said studies have shown an increase in the risk of bleeding and death associated with the use of HES solutions in comparison with crystalloids.
Those findings hold true for older HES products and newer ones, he said.
"You want to believe that this is a safer fluid, . . . but the data is not there," Alam said. "There is really no good data out there to show that the newer starches are safer."
And, he said, studies examining the efficacy of HES solutions have generally shown "either a wash or no proof of benefit."
Alam favors the use of balanced salt solutions for resuscitation, and he did not recall ever using an HES product for the treatment of trauma or sepsis.
"There's no place for it," he said.
Some speakers said HES solutions should not be considered "top-shelf" resuscitation fluids, but the products should remain available to clinicians.
"It should not be the first thing you go to, . . . given the rather persistent signal for harm," Chawla said. He said there may be situations when it is appropriate to use HES solutions.
"But I haven't seen any identified," he noted.
According to clinical practice guidelines from the U.S. Army Institute of Surgical Research, the HES product Hextend is commonly used as a resuscitation fluid in soldiers injured in combat. The guidelines note that studies have shown that the product may interfere with hemostasis.
Martin Schreiber, a lieutenant colonel in the U.S. Army Reserves and chief of trauma, critical care, and acute care surgery at the Oregon Health & Science University in Portland, said Hextend is given to injured soldiers as a single 500- to 1000-mL bolus.
Schreiber, who has served as director of the Defense Department's Joint Theater Trauma System, said the military chose Hextend because it appeared to be the best available FDA-approved product for the aggressive replacement of interstitial fluid.
Like other workshop attendees, Schreiber called for the judicious use of resuscitation fluids and said research increasingly supports the concept that "if you give less fluids, you get better results."
The workshop speakers agreed that additional research on the use of resuscitation fluids would be beneficial but had mixed opinions about how extensive any new clinical trials should be.
Nishia Jain of FDA's Office of Blood Research and Review said the agency has "taken a lot of take-home messages" about the safety and benefits of resuscitation fluids. She said FDA is looking forward to new data from ongoing clinical trials of HES solutions and may make labeling changes on the basis of new findings.