Hetastarch is a synthetic colloid fluid used primarily to expand blood volume in patients who have lost significant amounts of fluid from surgery, trauma, burns, or critical illness. Derived from waxy maize starch and chemically modified to resist rapid breakdown, it works by pulling water into the bloodstream and holding it there. For decades it was one of the most widely used plasma expanders in hospitals, but large clinical trials beginning around 2008 revealed serious kidney and bleeding risks in critically ill patients, prompting regulatory agencies to sharply restrict its use. Today, hetastarch occupies a much narrower clinical role than it once did, and understanding where it still fits requires knowing both its benefits and its well-documented harms.
How Hetastarch Expands Blood Volume
When someone loses blood or fluid rapidly, the immediate danger is that the heart has too little volume to pump effectively. Hetastarch addresses this by behaving like a sponge inside blood vessels. Its large starch molecules cannot easily pass through vessel walls, so when infused intravenously, they raise the oncotic pressure of the blood plasma. That pressure difference draws water from surrounding tissues back into the bloodstream. In animal studies, hetastarch infusions raised plasma oncotic pressure by roughly 6 mm Hg, significantly widening the pressure gradient between plasma and the fluid in lung and soft tissue.1PubMed. Effects of pentafraction and hetastarch plasma expansion on lung and soft tissue transvascular fluid filtration The practical result is that a relatively modest infusion volume produces a larger and longer-lasting increase in circulating blood volume than an equivalent amount of saline would.
Hetastarch’s molecular weight averages around 450,000 daltons, and it has a high degree of chemical substitution (a molar substitution ratio of about 0.70). Those two features slow its breakdown by enzymes in the blood, giving it a long intravascular half-life compared with other hydroxyethyl starch products. In fact, pharmacokinetic data show that HES 450/0.7 has an elimination half-life of roughly 48 days, and only about 40 to 65 percent of an infused dose is eventually recovered in urine, meaning a substantial fraction gets stored in body tissues.2PubMed Central. Clinical pharmacokinetic considerations in the use of plasma expanders This tissue storage is one reason newer, lower-molecular-weight starch products were developed, and it is central to several of hetastarch’s side effects.
Resuscitation in Hypovolemia and Trauma
The oldest and most straightforward use of hetastarch is emergency volume resuscitation when a patient is in hypovolemic shock, meaning dangerously low blood volume from hemorrhage, dehydration, or fluid loss. In an early prospective study of 14 patients, infusing 500 mL of hetastarch raised cardiac output, increased mean arterial blood pressure, and improved oxygen delivery, leading the investigators to conclude it was an effective resuscitation fluid for hypovolemic patients.3PubMed. Hydroxyethyl starch for resuscitation of patients with hypovolemia and shock A pilot study in multisystem trauma patients similarly found that large-volume hetastarch infusions were safe and effective compared with plasma protein fraction, a blood-derived colloid.4JAMA Surgery. Efficacy of Hetastarch in the Resuscitation of Patients With Multisystem Trauma and Shock
These early studies, mostly from the 1980s, established hetastarch’s reputation as a reliable alternative to albumin (a natural human protein that is expensive and sometimes in short supply). The appeal was obvious: hetastarch was cheaper, did not carry the theoretical risk of transmitting blood-borne infections, and seemed to work just as well for restoring hemodynamic stability in acute settings. Much of the enthusiasm for hetastarch in trauma and surgical resuscitation was built on this generation of evidence. The complications that would eventually reshape its use profile came to light primarily in sicker patient populations studied decades later.
Postoperative Volume Replacement
After major surgery, patients routinely need intravenous fluids to replace blood and fluid lost during the procedure. Hetastarch became a common choice for this role, particularly in cardiac surgery. In a trial comparing hetastarch to albumin in patients recovering from coronary artery bypass grafting, the two fluids produced essentially identical results across liver, kidney, and lung function markers, as well as coagulation lab values. Chest tube drainage, a proxy for postoperative bleeding, did not differ between groups, and the authors noted that hetastarch offered substantial cost savings.5PubMed. Clinical comparison of hetastarch and albumin in postoperative cardiac patients
In children who had undergone cardiopulmonary bypass, hetastarch at doses of 20 mL per kilogram or less was also comparable to albumin, with no differences in fluid requirements, bleeding, or blood product use. At higher doses, however, clotting times began to lengthen in the hetastarch group, hinting at the coagulation effects that would be better characterized in later research.6PubMed. Comparison of hetastarch with albumin for postoperative volume expansion in children after cardiopulmonary bypass This dose-dependent bleeding signal became one of the recurring themes in hetastarch safety literature.
A large randomized trial published in 2020 looked at whether HES offered any advantage over saline in high-risk patients undergoing major abdominal surgery. By postoperative day 14, about 36 percent of HES patients and 32 percent of saline patients had died or developed major complications, a difference that was not statistically significant.7JAMA. Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial The result essentially showed no benefit to using HES over cheap, widely available saline in this population, further eroding the clinical case for starch-based fluids in elective surgery.
Granulocyte Collection by Leukapheresis
One use of hetastarch that sits outside the world of fluid resuscitation entirely is its role in granulocyte collection. Granulocytes are white blood cells needed by patients with severely compromised immune systems, and they are collected from healthy donors through a process called leukapheresis. Hetastarch is added to the donor’s blood during the procedure to speed up red blood cell sedimentation, which in turn increases the yield of granulocytes. For over a decade it has been the preferred sedimenting agent for this purpose because it consistently enhances granulocyte recovery, is generally well tolerated in the short term, and has few side effects at the doses used.8Blood. A Controlled Comparison of the Efficacy of Hetastarch and Pentastarch in Granulocyte Collections by Centrifugal Leukapheresis This application is one of the few areas where hetastarch remains in routine clinical use without major controversy, partly because the doses involved are small and the exposure is brief.
Effects on Blood Clotting
Hetastarch does not simply dilute clotting factors the way any large-volume infusion would. It has an independent, direct effect on the coagulation system. Studies have shown that it prolongs partial thromboplastin time and prothrombin time, lowers fibrinogen levels, and reduces clotting factor VIII activity beyond what simple dilution would explain.9PubMed. Pentastarch may cause fewer effects on coagulation than hetastarch In at least one reported case, prolonged hetastarch use produced a bleeding disorder resembling severe type I von Willebrand disease, with marked drops in factor VIII, von Willebrand factor antigen, and ristocetin cofactor activity. Once the hetastarch was stopped, the levels normalized over about 17 days.10PubMed. Development of a von Willebrand-like syndrome after prolonged use of hydroxyethyl starch
This bleeding tendency is dose-dependent and more pronounced with hetastarch than with lower-molecular-weight starch products, because hetastarch lingers in the blood longer and accumulates with repeated dosing. Pentastarch, a related product with a lower molecular weight (about 264,000 versus 450,000 for hetastarch) and fewer hydroxyethyl groups, is cleared from the bloodstream far faster and has less effect on coagulation.11PubMed. A randomized clinical trial of 10% pentastarch (low molecular weight hydroxyethyl starch) versus 5% albumin for plasma volume expansion after cardiac operations In severely septic patients treated with HES, post hoc analyses found that the starch increased bleeding risk, and that bleeding was itself associated with a higher risk of death.12PubMed. Bleeding and risk of death with hydroxyethyl starch in severe sepsis: post hoc analyses of a randomized clinical trial
Kidney Risks and the ICU Controversy
The most consequential safety findings about hydroxyethyl starch came from critically ill patients in intensive care units. The CHEST trial, a large Australian study enrolling over 7,000 ICU patients, compared 6% HES 130/0.4 (a newer, lower-molecular-weight formulation than traditional hetastarch) with saline. Mortality did not differ significantly between groups, but patients given HES were more likely to require dialysis: about 7.0 percent versus 5.8 percent for saline. HES was also associated with significantly more adverse events overall (5.3 percent versus 2.8 percent).13New England Journal of Medicine. Hydroxyethyl starch or saline for fluid resuscitation in intensive care
The picture was even grimmer in patients with sepsis. The 6S trial randomized patients with severe sepsis to HES 130/0.42 or Ringer’s acetate and found that 51 percent of HES patients had died by 90 days, compared with 43 percent receiving the crystalloid, a statistically significant increase. Renal replacement therapy was needed in 22 percent of the HES group versus 16 percent of the crystalloid group.14PubMed Central. Hydroxyethyl starch in severe sepsis: end of starch era? These results were not quirks of a single formulation. The underlying kidney damage appears to involve osmotic injury to the tubular cells of the kidney, where starch molecules are taken up and cause swelling and dysfunction. Experimental work in isolated kidney models has confirmed that HES triggers interstitial inflammation, macrophage infiltration, and tubular damage, with higher-molecular-weight and higher-substitution products causing more harm than newer low-molecular-weight versions.15PubMed Central. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model
These findings reshaped clinical practice. The critical care community’s confidence in all HES products, hetastarch included, eroded rapidly once the CHEST and 6S results were published. The fact that even the supposedly “improved” lower-molecular-weight starches caused kidney damage and excess mortality in septic patients made it clear that the problem was not limited to older formulations.
Regulatory Restrictions
In 2013, both the U.S. Food and Drug Administration and the European Medicines Agency issued warnings against using HES products in critically ill patients, including those with sepsis. The EMA went further than the FDA, imposing generally more restrictive guidance on HES usage overall.16PubMed Central. Comparison of hydroxyethyl starch regulatory summaries from the Food and Drug Administration and the European Medicines Agency The FDA added a black box warning, the most serious type of label warning, to all HES products marketed in the United States. The warning contraindicates HES in critically ill adults, patients with pre-existing kidney dysfunction, and patients with severe liver disease or coagulation disorders. It also advises avoiding HES in patients undergoing open heart surgery with cardiopulmonary bypass, given the heightened bleeding risk.
Several European countries and health systems have gone further still, effectively banning HES from hospital formularies entirely. The debate continues in some surgical and anesthesia communities, where practitioners argue that the risks demonstrated in septic ICU patients do not necessarily apply to otherwise healthy patients undergoing elective surgery. The FLASH trial’s finding of no clear harm (but also no benefit) in major abdominal surgery patients has not exactly rallied support for continued use, though, and the practical trend has been toward crystalloid-only resuscitation strategies in most settings.
Tissue Storage and Pruritus
One of the more unusual side effects of hetastarch is severe, treatment-resistant itching. Unlike typical drug-induced itching, this pruritus does not respond to antihistamines. Skin biopsies from affected patients reveal hetastarch deposits in dermal macrophages, endothelial cells of blood and lymph vessels, nerve-associated cells, and even keratinocytes. Importantly, there are no signs of histamine release from mast cells, which explains why antihistamines do nothing.17PubMed. Hydroxyethylstarch deposits in human skin–a model for pruritus? The itching can persist for weeks or months after the infusion and is thought to result from direct irritation of cutaneous nerve endings by the stored starch molecules.
This tissue storage phenomenon is not limited to skin. Hetastarch accumulates in the liver, spleen, kidneys, and lymph nodes, and the higher its molecular weight and degree of substitution, the more it accumulates. Newer HES products (like HES 130/0.4) show significantly reduced tissue storage compared with traditional hetastarch (HES 670/0.75 or 450/0.70), which is one reason the industry shifted toward lower-molecular-weight formulations.18Transfusion Alternatives in Transfusion Medicine. The starch family: are they all equal? Pharmacokinetics and pharmacodynamics of hydroxyethyl starches Whether this long-term tissue deposition causes harm beyond pruritus remains unclear, but it is a feature unique to starch-based volume expanders and does not occur with crystalloid fluids or albumin.
Allergic and Anaphylactic Reactions
True anaphylaxis from hetastarch is rare. When large numbers of patients were screened for HES-reactive antibodies using sensitive laboratory techniques, antibodies turned up in only one patient at a low titer, and that patient tolerated repeated HES infusions without any clinical reaction.19Anesthesia & Analgesia. Hydroxyethyl Starch Antibodies in Humans: Incidence and Clinical Relevance The incidence of anaphylactic reactions to HES is lower than that seen with dextran or gelatin, two other colloid volume expanders.
That said, severe reactions do occur. Case reports describe sudden hypotension, bronchospasm, and skin rashes within minutes of HES infusion, sometimes requiring extended intensive care management.20PubMed. Severe anaphylactoid reaction to hydroxyethyl starch In one case during general anesthesia, a patient developed hypotension, agitation, and rash five minutes after HES administration, with elevated serum tryptase and immunoglobulin E levels confirming an allergic mechanism.21PubMed Central. Anaphylactic reaction with hydroxyethyl starch during anesthesia – A case report Intradermal skin testing in at least one case produced a delayed positive response, suggesting complement-mediated pathways rather than classical IgE-mediated allergy may sometimes be involved. Because these reactions are unpredictable, any clinician infusing HES should have resuscitation equipment immediately available, though the overall risk is quite low compared with other colloids.
Use in Burn Resuscitation
Severe burns trigger massive fluid shifts out of the bloodstream and into damaged tissues, and burn patients often need enormous volumes of intravenous fluid in the first 24 to 72 hours. There has been longstanding interest in whether colloids like hetastarch could reduce the total fluid volume needed, potentially limiting the tissue swelling and lung complications that accompany very large crystalloid infusions. A randomized, double-blind trial comparing HES 130/0.4 with lactated Ringer’s solution in severe burn patients found no significant difference in total fluid volumes administered over three days, no difference in kidney function, and no difference in the rate of acute respiratory distress syndrome or 28-day mortality.22BioMed Central / Critical Care. Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: a randomized, controlled, double-blind clinical trial In other words, the hoped-for fluid-sparing effect did not materialize, and HES offered no clinical advantage in this setting. Given the known risks, most burn centers have moved away from routine HES use.
Veterinary Applications
Hetastarch has been used in veterinary emergency medicine in much the same way as in human medicine, primarily as a volume expander in dogs and cats with acute hemorrhage, surgical blood loss, or conditions causing low blood protein levels. Veterinary reports indicate that bolus and continuous-rate infusions of 6% hetastarch at moderate doses are generally well tolerated in dogs and cats.23PubMed. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use However, the veterinary evidence base is thin. Most studies involve small patient numbers and short-term follow-up, and there are no consensus recommendations for HES use in veterinary medicine.24PubMed. Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care
Case reports have documented osmotic nephrosis, a form of kidney injury caused by starch uptake in tubular cells, in dogs receiving HES.25PubMed Central. Rapid exacerbation of renal function after administration of hydroxyethyl starch in a dog The parallels with human renal toxicity have made many veterinary critical care specialists cautious, and some have adopted the same skepticism toward HES that now prevails in human ICU practice. As with human medicine, the trend in veterinary emergency care has been shifting toward crystalloid-based protocols, though hetastarch remains available and is still used in situations where rapid plasma expansion is needed and the patient does not have pre-existing kidney disease.
How Hetastarch Compares With Newer Starch Products
Hetastarch is sometimes called a “first-generation” hydroxyethyl starch, and its molecular characteristics sit at one end of a spectrum. Pentastarch, with a molecular weight about half that of hetastarch and a lower substitution ratio (0.45 versus 0.70), is cleared from the bloodstream dramatically faster. One trial measured an initial intravascular half-life of 2.5 hours for pentastarch compared with 25.5 hours for hetastarch, along with reduced coagulation effects.26PubMed. A randomized clinical trial of 10% pentastarch (low molecular weight hydroxyethyl starch) versus 5% albumin for plasma volume expansion after cardiac operations The third-generation product, HES 130/0.4 (sometimes sold as Voluven), was designed to minimize the tissue accumulation and coagulation problems associated with hetastarch. And tissue storage is indeed significantly reduced with the newer product compared with hetastarch.27Transfusion Alternatives in Transfusion Medicine. The starch family: are they all equal? Pharmacokinetics and pharmacodynamics of hydroxyethyl starches
Yet the kidney and mortality signals in the CHEST and 6S trials were found using these newer products, not hetastarch itself. That is a point worth sitting with: the harms that triggered regulatory crackdowns were demonstrated with the formulations specifically engineered to be safer than hetastarch. If HES 130/0.4 causes excess kidney injury and death in septic patients, traditional hetastarch, with its much longer persistence in the body, would be expected to perform at least as badly in the same population. The practical conclusion most clinicians have drawn is that the entire product class is problematic in critically ill patients, regardless of which generation of starch is used.