Biblio AA Mars 2015

1. March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 519
Copyright © 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000465
H
ydroxyethyl starch (HES) has been used for >40
years as an intravascular volume expander.1
As a
result, much of the pharmacology of HES has since
been determined, including coagulopathic,2
anaphylactoid
side effects,3
and the size-dependent retention of HES mol-
ecules in liver, skin, and nervous tissue.4
To address these
issues, more modern HES formulations have progressively
smaller molecular weights and molar substitutions (aver-
age number of hydroxyethyl residues per glucose subunit),
a change known to facilitate faster clearance from the body.5
Because so much is already known about HES solu-
tions, the possibility of increased nephrotoxicity with IV
HES administration in acute care medicine has been sur-
prising. Beginning with nephrosis-type lesions observed in
transplanted kidneys from donors given HES,6
researchers
have proceeded to identify associations between HES and
renal failure in critically ill patients,7
and (most recently) a
causal relationship in large scale trials of HES 130/0.4 ver-
sus crystalloids in septic patients.8,9
This line of inquiry has
been sufficiently convincing that in 2013 both the European
Medicines Agency and the United States Food and Drug
Administration (FDA) issued warnings against HES use in
septic patients in the intensive care unit (ICU).a,b
The FDA
further warned providers about the potential for excessive
bleeding in cardiac surgical patients with the use of HES.a
The possibility that a similar nephrotoxic effect may
exist with perioperative HES use has stirred considerable
controversy among anesthesiologists. In the September
issue of this journal alone, 2 of The Open Mind articles10,11
and 1 Editorial12
extensively reviewed the complex mix of
physiological data, clinical experience, and large outcome
trials that currently inform the safety of perioperative HES
use. Together, these well-written analyses are an excellent
primer for anesthesiologists interested in the >40-year his-
tory of HES use in clinical medicine and 20-year history of
renal toxicity. Not unsurprisingly, they also come to dif-
ferent conclusions with one concluding that a blanket ban
on HES use is not justified,10
and another accepting the
potential perioperative nephrotoxicity of HES but calling
for more research to better define risk/benefit ratios.11
To a non-HES user, this controversy is fascinating. How
can clinicians use a drug for almost half a century and not
already have clearly identified a perioperative complication
acute kidney injury (AKI) that can more than double postop-
erative mortality?13
With an ostensibly simple question (drug
versus control), a defined period (perioperative), a clear end
point (AKI), and >3000 citations in PubMed alone,c
how can
we know so much about a drug and yet not know enough
to decide whether a patient undergoing a radical cystec-
tomy should receive crystalloid or HES when acute bleeding
causes hypotension? To the many thoughtful points raised
by The Open Mind articles of Irwin et al. and Raghunathan
et al., we add the ongoing and related controversy regarding
perioperative hemodynamic optimization. Arguments that
we give too much fluid perioperatively14
coexist uneasily
with observations that preemptive perioperative hemody-
namic optimization utilizing more advanced monitors leads
to both more fluid administration and better outcomes.15
If
perioperative clinicians cannot agree regarding the optimal
fluid state for surgery, how can we distinguish between
resuscitation and maintenance use of HES? Furthermore, in
the absence of agreed-upon optimal end points for resusci-
tation, will any therapy (HES, crystalloid, or other colloids)
consistently result in a positive outcome?
What both Irwin et al. and Raghunathan et al. do agree
on is more research to better assess the risk of periopera-
tive HES use. In this month’s issue of Anesthesia & Analgesia,
2 studies shed more light on this question. Kancir et al.16
measured creatinine clearance, urinary NGAL (a protein
released into the urine during renal injury), and urine out-
put in 40 patients randomized to receive either HES 130/0.4
or 0.9 normal saline for perioperative fluid therapy. No
difference in any measure of renal function was observed
for 15 postoperative days. Kancir et al. did find indirect
evidence of better volume expansion with HES (versus 0.9
normal saline), reflected in lower plasma concentrations of
renin, angiotensin, and vasopressin. Patients receiving HES
in this group also showed a trend toward higher blood loss.
In the second paper,17
Hand et al. report the results of
a hospital-mandated switch from albumin to 6% HES
(130/0.4) for fluid therapy during orthotopic liver trans-
plant. In 174 liver transplant recipients receiving albumin,
But Is It Safe? Hydroxyethyl Starch in Perioperative Care
Steven Greenberg, MD,* and Avery Tung, MD†
From the *Department of Anesthesiology, NorthShore University
HealthSystem, Evanston, Illinois; and †Department of Anesthesia and
Critical Care, University of Chicago, Chicago, Illinois.
Accepted for publication July 29, 2014.
Funding: Internal funding.
Conflict of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Avery Tung, MD, Department of Anesthesia
and Critical Care, University of Chicago, 5841 S. Maryland Ave., MC4028,
Chicago IL 60637. Address e-mail to atung@dacc.uchicago.edu.
EditorialE
a
Available at: http://www.fda.gov/biologicsbloodvaccines/safetyavailabil-
ity/ucm358271.htm. Accessed July 15, 2014.
b
Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medi-
cines/human/referrals/Hydroxyethyl_starch-containing_solutions/human_
referral_prac_000012.jsp&mid=WC0b01ac05805c516f. Accessed July 16, 2014.
c
Available at: www.pubmed.com, keyword “hetastarch.” Accessed July 27, 2014.

2. E Editorial
520 www.anesthesia-analgesia.org anesthesia analgesia
HES, or both, Hand et al. observed an odds ratio of 1.18
for AKI as measured by Risk Injury Failure Loss End-Stage
Kidney Disease (RIFLE) criteria for HES use (versus albu-
min). The authors also found a dose-dependent effect of
HES on the odds of renal injury, with the adjusted odds
ratio for renal failure in patients receiving HES only (2.94)
nearly 3 times that for patients receiving albumin only.
Although these 2 studies have apparently disparate
findings, they differ in ways that highlight why the safety
of HES is both controversial and difficult to establish.
While Kancir et al. studied patients undergoing radical
prostatectomy, Hand et al. focused on considerably sicker
liver transplant patients. Hand et al.’s patients were more
likely to be transfused (90% vs 2.5%), and at significantly
higher risk for renal injury (22% of patients that did not
receive HES sustained renal injury). Neither study distin-
guished between ongoing fluid maintenance (to replace
routine fluid loss) and volume resuscitation to treat acute
blood loss or other volume deficits. As some have argued,18
because HES was designed as a volume expander with
greater efficacy than crystalloid, its use should be limited
to acute hypovolemic resuscitation. By this logic, using
HES for maintenance fluid therapy merely increases the
toxicity of HES without any benefit. The small size of
Kancir et al.’s study (N = 40) and complex, retrospective
nature of Hand et al.’s study may also have limited their
ability to find an effect of HES on renal failure or to accu-
rately estimate the magnitude of any effect. After propen-
sity adjustment, for example, the odds ratio reported by
Hand et al. for HES use fell from 2.74 (using multivariate
logistical regression) to 1.18.
Although the patients in Kancir et al.’s study may not
have been at sufficiently high risk for renal failure to show a
difference between groups, Kancir et al. did find a (nonsig-
nificant) trend toward higher blood loss in the HES group.
This trend is consistent with the known coagulopathic
effects of HES and the recent FDA warning in cardiac sur-
gery patients. Hand et al. did not find that HES increased
bleeding, but their study was not powered to detect differ-
ences in bleeding, and any coagulopathic effect may have
been difficult to identify in a liver transplant population
with a 90% transfusion rate at baseline.
How should the clinician interpret these findings? One
possibility is that patients at high risk for renal failure are
more susceptible to the potential perioperative nephrotox-
icity of HES. Such an interpretation would mirror neph-
rotoxic effects of HES in septic ICU patients. As noted by
Raghunathan et al., the “Scandinavian Starch Severe Sepsis/
Septic Shock” or 6S trial studied patients in severe sepsis as
defined by a known focus of infection, at least 2 systemic
inflammatory response syndrome criteria, and at least 1
organ with a Sequential Organ Failure Assessment (SOFA)
score 2. Over a 90-day period, patients receiving HES had
a relative risk of 1.17 for the primary outcome of death or
dependence on dialysis. More patients in the HES group
also suffered severe bleeding (RR = 1.52) and required renal
replacement therapy (RRT) (RR = 1.35).
However, these results differ from those observed in
the CHEST study (Crystalloid versus Hydroxyethyl Starch
Trial) published 6 months later. Entry criteria for this trial
consisted of patients admitted to the ICU judged by the
treating clinician to require fluid resuscitation with one
accompanying physiological measurement. Patients in
CHEST may thus have been less critically ill (mean Acute
Physiology and Chronic Health Evaluation II [APACHE II]
score in 6S = 17; mean SOFA score in CHEST = 7).8,9
Unlike
6S, the CHEST trial found less nephrotoxicity with HES
(greater requirement for RRT in the HES group but no dif-
ference in mortality or renal failure). As with the 2 perioper-
ative studies in this month’s issue of Anesthesia Analgesia,
a greater degree of physiological stress appeared to enhance
the nephrotoxicity of HES in the ICU.
Is HES safe for perioperative use? As no large random-
ized trials comparable to 6S or CHEST exist for periopera-
tive use, a definitive answer is not possible, and existing
studies regarding the perioperative nephrotoxicity of HES
use are mixed.19–22
In fact, Hand et al. first conceived their
study in response to Mukhtar et al.23
who found no adverse
effect of HES in liver transplant.
Clinicians might consider some general observations.
First, the longevity of HES in clinical use suggests that for
most patients, the magnitude of any nephrotoxic risk is likely
to be small and a greater perioperative concern may be the
risk of coagulopathy or anaphylactoid reaction. Second, any
nephrotoxic effect is likely to be greater in patients at greater
risk for perioperative renal injury. Identifying preoperative
risk factors for nephrotoxicity might then assist in determin-
ing which patients, if any, might receive HES safely. Finally,
existing data suggest that the magnitude of any increased
overall risk attributable to HES alone (and not to factors
related to HES administration such as the need for acute
resuscitation) is small. Even in patients with severe sepsis8,9
or undergoing liver transplant,17,23
the attributable adjusted
or multivariate odds ratio for renal injury or RRT is 1.4.
Unanswered questions still remain regarding the periop-
erative use of HES. The deleterious effects of using HES for
patients undergoing higher risk procedures (pancreatic can-
cer, multilevel spinal fusion,) as compared with lower risk
procedures (hip arthroplasty, urologic procedures) remain
unclear. In addition, few data address outcome end points
beyond the immediate postoperative period when compar-
ing HES 130/0.4 versus other “real-world” options such as
crystalloids, blood, and albumin. Trials addressing these
issues face considerable methodological challenges. They
should distinguish between use of HES for acute volume
expansion and HES use for maintenance fluid therapy. They
should also address the potential confounding effect of
hyperchloremic versus balanced carrier solutions. We look
forward to such research in the future! E
DISCLOSURES
Name: Steven Greenberg, MD.
Contribution: This author helped design the study and write
the manuscript.
Attestation: Steven Greenberg approved the final manuscript.
Conflicts of Interest: Steven Greenberg reported no conflicts of
interest directly related to this manuscript. Steven Greenberg
has served as consultant to CASMED in 2013.
Name: Avery Tung, MD.
Contribution: This author helped design the study and write
the manuscript.

3. Hydroxyethyl Starch in Perioperative Care
March 2015 • Volume 120 • Number 3 www.anesthesia-analgesia.org 521
Attestation: Avery Tung approved the final manuscript.
Conflicts of Interest: This author declares no conflicts of
interest.
RECUSE NOTE
Dr. Avery Tung is the Section Editor for Critical Care, Trauma,
and Resuscitation for Anesthesia Analgesia. This manuscript
was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr.
Tung was not involved in any way with the editorial process
or decision.
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