A Starch Update
Avery Tung, M.D. FCCM
2014 SCA Annual meeting
New Orleans, LA
1. Introduction:
Although human albumin is used more commonly than starch in the United States as a volume expander
in cardiac surgery, starches and other colloids are preferentially used in place of albumin worldwide.
Arguments for use of starches over albumin and/or crystalloid for volume expansion are
straightforward. Because adverse effects of blood and blood product transfusion are increasingly well
recognized, the need for a non-blood colloid with similar volume expanding properties is increasing.
Starch solutions, formed most commonly as a 6% solution of hydroxyethyl starch in normal saline, have
a greater oncotic pressure than crystalloid fluids, and are significantly less expensive than albumin. In
hepatic and cardiac disease, where edema is an issue, the readily availability of such an agent would fill
an important clinical need.
The tantalizing possibility that synthetic, substituted hydroxyethyl starchs (HES) may solve the above
problem has led to an outpouring of research on clinical properties of starch administration. Studies
advocating use of HES for volume expansion have not only focused on its ability to expand intravascular
volume (versus crystalloids) but also on possible effects on inflammation, endothelial barrier
dysfunction, and intestinal function.
Set against these claims, however, are signals from outcome trials suggesting that HES use may have
toxic effects on renal function and even mortality when used in critically ill patients. Although the
mechanism of such an effect on renal function is unclear, animal studies suggest that HES is retained in
solid organs such as liver, kidney, lung, spleen, and lymph nodes.
This talk will review the physiology and rationale for hetastarch use in hemodynamically unstable
patients, evaluate and discuss recent large clinical trials of hetastarch use in critically ill patients, identify
challenges in performing and interpreting studies of hetastarch use, and discuss whether safe uses of
hetastarch are possible in critically ill patients
2. A (brief) introduction to Hetastarch solutions
Hetastarch is an artificial colloid derived from a highly branched glucose polymer (107-109 daltons) called
amylopectin. Although amylopectin itself is not soluble in water, it is modified via addition of
hydroxyethyl groups at the C2,C3, and C6 positions and hydrolyzed into smaller units. The resulting
molecules range in size from 20,000 to 2.5M Daltons which are water soluble.
Excretion depends on the size of the particular molecule. Hetastarch molecules < 50K daltons are
readily eliminated by renal excretion, and 33% of a single dose of 500cc hetastarch (30 gm of a 6%
solution) is eliminated in 24 hours. After 2 weeks, ~10% of administered Hetastarch remains in the
intravascular space. Hepatic clearance of Hetastarch is minimal.
Hydroxyethyl starch solutions can be subdivided based on the size of the starch polymer and degree of
molar substitution. Three hydroxyethyl starch solutions (Hespan, Hextend, and Voluven) are licensed in
the United States for intravascular administration. Hespan (licensed in 1972) has an average molecular
weight of 450,000D (with a range from 5000 to >1M) daltons, and a molar substitution fraction (number
of hydroxylethyl groups per glucose subunit) of 0.7. Hextend (licensed in 1999) is slightly larger (~670D)
with a similar molar substitution. The newest hetastarch solution, named Voluven (licensed 2007), uses
a considerably smaller average molecular weight (130KD) with a molar substitution ratio of 0.4. All
solutions are made up as a 6% solution in either 0.9NS (Hespan or Voluven) or balanced electrolyte
solution (Hextend). Outside the United States, other formulations are available including Hesteril
(200KD, 0.5% substitution). In the literature, these starches are thus often referred to by their %
concentration, average molecular weight, and % substitution with (occasionally) the ratio of C2 to C6
carbons substituted with hydroxyethyl groups. Thus, Hespan is often referred to as “6% HES
650/0.5/5:1”.
3. The problem
Although hetastarch solutions have been in use since 1978, side effects of hetastarch were widely
considered limited to pruritis and a mild coagulopathic effect. An association between osmotic
nephrotic lesions on renal transplant recipients and hetastarch use was first published in 1993. No renal
dysfunction was reported, but in 1996 a randomized trial involving up to 33 cc/kg of hydroxyethyl starch
resulted in a 33% incidence of posttransplant renal failure when compared to gelatin solutions. In 2001
a prospective randomized trial in septic patients found use of hydroxyethylstarch as an independent risk
factor for acute renal failure.
The mechanism of renal failure associated with hetastarch infusion is unclear. An increased
inflammatory response in the renal tubules, and hyperviscous urine resulting from renal filtration of
smaller hetastarch fragments (50kD) are two hypotheses. Since 2001, multiple trials (including three in
the New England Journal of Medicine: code named VISEP, 6S and CHEST) have compared hetastarch
with crystalloid infusions to clarify the extent and clinical relevance of renal injury associated with HES
use. None have found benefit to hetastarch use. VISEP found an increased rate of renal failure and
renal replacement therapy (RRT), 6S found an increased risk of RRT and 90 day mortality, and CHEST
likewise found an increase in RRT use.
In light of accumulating evidence that renal dysfunction may be a consequence of hetastarch use, and
bolstered by high profile reviews in JAMA and the Cochrane group, the European Medicines Agency
Pharmacovigilance Risk Assessment committee reviewed the safety of HES and initially concluded in
June 2013 that HES should be suspended in all patient populations before choosing in October to allow
it for hypovolemic patients where crystalloid alone was felt to be insufficient and specifically not for
patients with sepsis, burns, or critical illness.
Hetastarch solutions also adversely affect coagulation via an unclear mechanism. Both Hespan and
Hextend carry label warnings against use in cardiopulmonary bypass due to increased bleeding. Studies
suggest several mechanisms, ranging from hetastarch effects on fibrinogen binding sites on platelets to
impaired fibrin polymerization, and hetastarch-induced decreases in Factors VIII, vWF, and XIII. The
coagulation effect appears to be a function of larger polymer size and higher molar substitution ratios,
suggesting that newer hetastarches (such as Voluven) may not have as large an effect.
Finally, hetastarch solutions are more likely to cause anaphylactic reactions than crystalloid, and induce
a lingering pruritis due to starch deposition into liver, skin, and cutaneous nerves. Unlike the
anticoagulation effect, pruritis appears to be molecular size independent.
4. Challenges to clarifying the effect of hetastarch on renal function
Several factors have contributed to the difficulty in clarifying the relationship between hetastarch
administration and renal injury. The first of these is the heterogeneity of starch types used in the
different studies. Because of data suggesting that smaller hetastarch polymer sizes leads to fewer
coagulation complications, less renal dysfunction, less itching, and less tissue accumulation, newer
formulations have smaller average molecular weights. As a result, meta-analyses have combined
studies with 6% HES 200/0.5 and 6% HES 130/0.4 together, leading critics to argue that adverse effects
on renal function are overstated.
The second problem is the distortion in the literature caused by Dr. Joachim Boldt. An aggressive
supporter of hydroxyethyl starch solutions, Boldt’s work (>80 papers) consistently showed not only
minimal to no harm to renal function with hetastarch, but also beneficial effects on inflammation,
hemodynamic stability, and coagulation. Although by now his work has all been retracted (and is
adjusted for in current meta-analyses, its indirect effects on subsequent research protocols and on
overall clinical use is more difficult to adjust for.
The last (and most difficult) issue complicating interpretation of hetastarch trials is determining how
best to study the use of hetastarch in clinical environments. In principle, the advantage of a synthetic
colloid is its ability to rapidly reestablish preload in patients who require augmentation of cardiac output
or blood pressure to preserve end-organ function. The increased oncotic pressure of hetastarch over
crystalloid allows it to more rapidly and efficiently expand intravascular volume. Hetastarch solutions
should thus be studied in the way they are intended to be used.
Viewed in this way, a study protocol designed to maximize benefit from hetastarch would only give it
when the patient was hypotensive or in circulatory shock, and/or when volume loss was present. In
contrast, a hemodynamically stable patient receiving hetastarch as a continuous infusion (rather than
crystalloid) per protocol would be less likely to reap any benefit from hetastarch (as no volume
expansion is indicated) and more likely to incur harm. A study of hetastarch vs crystalloid for nonurgent
fluid maintenance, would thus make as little sense as comparing blood to crystalloid.
Unfortunately, protocols in most large scale studies could be interpreted to reflect more routine use of
fluid than suggested above. In both the 6S and CHEST trials, for example, all patients were stabilized
with a mixture of colloid (up to 1000cc) and crystalloid before being randomized to receive only
crystalloid or colloid. Colloid or crystalloid was then given whenever the treating physician felt a bolus
was necessary. As many patients had already reached resuscitation goals by this time, the indication for
colloids was less strong. This lack of an explicit indication for acute resuscitation has led some to argue
that, absent a clear indication for aggressive, urgent volume expansion, putative advantages of colloids
are being missed. Evidence also exists that trials driven by “appropriate” clinical indications find greater
benefit to colloid use. In fact, the 2013 CRISTAL study, which compared crystalloids and colloids in
patients in hypovolemic shock (vs sepsis) and included the initial 6 hours of resuscitation found
improved 90 day survival. Critics have also argued that because colloid resuscitates more efficiently
than crystalloid, patients in the colloid group were at higher risk of overresuscitation (volume
administration in the absence of volume responsiveness), potentially contributing to worsened
outcomes.
In the same vein, critics of current large scale colloid/crystalloid trials argue that critically ill septic
patients often have baseline renal insufficiency, and that use of colloids in those patients is already
contraindicated by the manufacturer. In the 6S trial, for example, 36% of patients had acute kidney
injury prior to randomization to colloid or control. Since such patients should not be getting colloid
anyway, an effect of colloid on renal function in such a high risk group is clinically irrelevant.
Going forward, such difficulties are likely to be difficult to resolve. Worldwide, older hetastarch
formulations continue to be used, and enough circumstantial evidence currently exists that further large
studies excluding such formulations are unlikely. Even more difficult would be future trials designed to
study hetastarch in paradigms where volume expansion is more acutely needed. Tremendous variability
in fluid resuscitation practices, and hemodynamic monitoring and management exist. Set against that
background, any attempt to standardize an acute volume expansion protocol is vulnerable to criticism
that the protocol is clinically atypical or incorrect.
5. What about cardiac surgery?
Critics of existing hetastarch trials argue that its use for non-bleeding, non-hypovolemic septic patients
with preexisting renal injury is already inappropriate. Such arguments, however, leave open the
question of whether hetastarch use may reduce blood transfusion and improve outcomes after cardiac
surgery. In such patients, massive variability in blood transfusion practice exists, with unclear clinical
consequences. More than one study finds that policies of restrictive transfusion and lower hematocrits
do not harm cardiac surgery patients and may even improve outcomes. In addition, hypovolemia during
cardiac surgery and cardiopulmonary bypass may be easier to recognize, thus reducing criticisms that
colloid administration is being given for non-hypovolemic reasons.
Evidence for or against use of hetastarch solutions in cardiac surgery are mixed. Trials are complicated
by the choice of control fluid (albumin vs crystalloid), older hetastarch formulations (particularly HES
200/0.5), variable endpoints (bleeding vs TEG parameters vs transfusion requrirements, mortality and
renal failure), and study protocol (routine administration vs acute volume expansion only). Against this
complex background, a typical result is that of one large recent trial that compared Hetastarch 130/0.4,
albumin, and crystalloid and found increased transfusion requirements with both colloid solutions, a
smaller positive fluid balance with albumin (vs hetastarch and crystalloid), weakening of clot integrity
with both albumin and HES (as measured by TEG), and small rises in creatinine in both colloid groups
without clinically relevant changes in renal function.
Taken together, existing literature in cardiac surgery suggests that hetastarch (vs albumin) results in no
clear benefit with respect to blood trnasfusion or renal function, and that colloids result in a small,
clinically unclear advantage with respect to fluid balance. Given that the most likely goal of hetastarch
use in cardiac surgery would be to reduce transfusion requirements, these data suggest that use of
hetastarch is unlikely to increase dramatically in the future.
6. References:
1. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation
Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H.
Lancet 1993;342:248-9
2. Crittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P.
Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant
recipients. Lancet 1996;348:1620–22
3. Skhirtladze K, Base EM, Lassnigg A, Kaider A, LInke S, Dworschak M, Hiesmayr MJ.
Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate on blood
loss and coagulation after cardiac surgery
Br J Anaesth 2014;112:255–64
4. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, Du B, McArthur C, Myburgh J. Resuscitation fluid
use in critically ill adults: an international cross-sectional study in 391intensive care units. Crit Care 2010;
14: R185.
5. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH,
Elkjaer JM, Poulsen LM, et al: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N
Engl J Med 2012,367:124-34.
6. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, Preiser JC, Outin H, Troché G,
Charpentier C, et al: Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill
patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013,
310:1809–17.
7. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M,
Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E,
Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K. Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J Med 2008;358:125-39
8. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6%
hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The
CRYSTMAS study. Crit Care 2012; 16: R94.
9. Myburgh JA, Finfer S, Bellomo R, Billot L. Cass A, Gattas D, Glass P, Lipman, J, Liu, B, Colin McArthur,
McGuinness, S, Rajbhandari, D, Taylor, C, Webb, S for the CHEST Investigators and the Australian and
New Zealand Intensive Care Society Clinical Trials Group*. Hydroxyethyl starch or saline for fluid
resuscitation in intensive care. N Engl J Med 2012; 367: 1901-11.
10. Chong C, Greco EF, Stothart D, Maziak DE, Sundaresan S, Shamji F, neilipovitz D, McIntyre L, Hebert
P, Seely A. Substantial variation of both opinions and practice regarding perioperative fluid resuscitation.
Can J Surg 2009;52:207-14
11. Pattakos G, Koch CG, Brizzio ME, Batizy LH, Sabik JF, Blackstone EH, Lauer MS. Outcome of Patients
Who Refuse Transfusion After Cardiac Surgery A Natural Experiment With Severe Blood Conservation.
Arch Intern Med. 2012;172:1154-60.
12. Glance LG, Dick AW, Mukamel DB, Fleming FJ, Zollo RA, Wissler R, Salloum R, Meredith UW, Osler
TM. Association between Intraoperative Blood Transfusion and Mortality and Morbidity in Patients
Undergoing Noncardiac Surgery. Anesthesiology 2011; 114: 283–92