535667

research-article2014
SCVXXX10.1177/1089253214535667Seminars in Cardiothoracic and Vascular AnesthesiaMoret et al

Review
Seminars in Cardiothoracic and

Albumin—Beyond Fluid Replacement in

Vascular Anesthesia
2014, Vol. 18(3) 252­–259
© The Author(s) 2014
Cardiopulmonary Bypass Surgery: Why, Reprints and permissions:
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How, and When? DOI: 10.1177/1089253214535667

scv.sagepub.com

Enrique Moret, MD, PhD1, Matthias W. Jacob, MD, PhD2,

Marco Ranucci, MD, FESC3, and Alexey A. Schramko, MD, PhD4

Abstract
Maintaining vascular barrier competence, preventing interstitial edema, and keeping microcirculation intact is crucial to
achieve an optimal outcome in cardiopulmonary bypass surgery (CPB). Blood contact with roller pumps and foreign
surfaces during CPB induces shear stress and a pressure drop across the pump boot that leads to transient systemic
activation of the inflammatory and hemostatic systems. Moreover, patients after CPB often need volume resuscitation
using the smallest possible amount of colloid solution because of fluid overload. For this purpose, human-derived albumin
may be preferred over synthetic colloids because CPB priming with albumin preserves oncotic pressure, prevents
platelet adhesion, and likely induces less consumption of coagulation factors. In patients with increased bleeding or renal
failure, albumin is a safe alternative because of its minimal side effects. Large, randomized clinical trials comparing the
benefit of albumin versus other fluids are warranted in the future to define albumin’s distinct role in select high-risk
surgical populations.

Keywords
albumin, colloid, crystalloid, cardiopulmonary bypass

Introduction assessment of volume responsiveness). This is achieved by

Intravenous fluid infusions to increase intravascular volume
are often required during cardiac surgery, but the choice of
the resuscitation fluid remains controversial. Awareness that
fluids are drugs with indications, contraindications, and side
effects is essential. A good understanding of their physiol-
ogy and pharmacology as well as the clinical context is cru-
cial to achieve an optimal outcome.1,2
During cardiopulmonary bypass surgery (CPB), a tran-
sient systemic activation of the inflammatory and hemo-
static systems (fibrin formation, platelet activation/
consumption, and endothelial damage) takes place because
of the action of roller pumps that generates blood contact
with foreign surfaces, shear stress, and a pressure drop
across the pump boot.3 Five percent albumin priming pre-
serves oncotic pressure, prevents fibrinogen, and platelet
adhesion, and has a protective effect on endothelial glyco-
calyx, maintaining vascular barrier competence, prevent-
ing interstitial edema, and keeping microcirculation
intact.4-7 Fluid shifts caused by multiple factors are inher-
ent in this patient population. After CPB, the majority of
surgery patients are fluid overloaded, but at the same time,
they present a strong fluid extravasation. Meticulous care
is needed to achieve optimal hemostasis and to maintain
an adequate volume status and hemodynamics (repeated
giving the right amount of the right fluid at the right time
to the right patient in order to compensate for surgical
blood loss.
Colloids have better volume effect and stay longer in the
intravascular space than crystalloids.8 However, the safety
and efficacy of synthetic colloids for fluid replacement
have not been fully evaluated. Some adverse effects on sur-
vival and renal function have been reported, such that the
use of synthetic colloids requires caution.9 Recently, Canet
et al10 using propensity score analysis described that the
administration of intraoperative colloids (mainly third-gen-
eration hydroxyethyl starch [HES]) in a population-based
general surgical cohort is associated with higher rates of
diverse major postoperative complications and longer
hospital stay.
1
Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
2
Munich University Hospital, Munich, Germany
3
San Donato Hospital, Milan, Italy
4
Helsinki University Hospital, Helsinki, Finland
Corresponding Author:
Enrique Moret, Department of Anesthesiology, Hospital Universitari
Germans Trias i Pujol, Ctra. del Canyet s/n, E-08916 Badalona,
Barcelona, Spain.
Email: emoret.germanstrias@gencat.cat

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Moret et al 253
Albumin is the ideal colloid because it is human derived,
has minimal side effects, does not alter renal function,11 has
less effect on platelet count drop, and consequently, may
reduce the risk of bleeding after CPB compared with syn-
thetic colloids.12 Additionally, hypoalbuminemia has been
associated with poor long-term survival after coronary
artery bypass graft surgery in a prospective review of nearly
600 patients.13 On the other side, anticoagulant and anti-
thrombotic effect of albumin have been described, indepen-
dently of being the result of hemodilution. Although these
effects are poorly understood, albumin probably exerts a
heparin-like action and a nitric oxide radicals binding
capacity that impairs platelet aggregation.14,15 As in all ther-
apeutic products made from human blood, a number of
measures are put in place to prevent transmission of patho-
gens.16,17 Effectiveness is evidenced by the absence of
cases of transmission of viral or prionic diseases ever iden-
tified for albumin during several decades of use.
Unfortunately, adequately powered, randomized trials
with clinically useful endpoints investigating synthetic
colloid solutions versus albumin have not been completed
to date. In the future, it will be important to design large,
randomized clinical trials comparing albumin with other
fluids after cardiac surgery to define the role of albumin in
selected high-risk surgical populations.18
Why and How? Albumin Properties
and Benefits for Microcirculation
To understand the importance of the intravascular pres-
ence of the albumin molecule for microcirculatory steady
state it is necessary to know some basic physiological prin-
ciples, as well as the latest scientific developments around
compartments and barriers.
The Physiology of Microcirculation: The
Classical View
Intra- and extracellular spaces are separated by the cellular
membrane. This lipid bilayer is not resistant against hydro-
static pressure, but largely impermeable to electrolytes and
proteins. By contrast, the vascular barrier permits hydro-
static pressure gradients to be established but does not
retain electrolytes and is largely impermeable to proteins.
Thus, water distributes passively over the compartments,
following pressure gradients and the distribution of osmot-
ically and oncotically active substances.
Historical concepts of vascular permeability are based on
Ernest Starling’s principle of 1896,19 schematically opposing
an inward-directed oncotic gradient between a presumably
protein-poor interstitial space and the protein-rich plasma to
the outward-directed hydrostatic force generated across the
vascular wall by external heart work. This is outlined math-
ematically by the corresponding Starling’s equation, presum-
ing net filtration per unit area per time (F/A/T) to be driven
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by the hydrostatic pressure difference between the vascular
lumen and the interstitial space (PV − PI) and limited by the
opposing oncotic pressure within the vascular lumen, suc-
tioning fluid from the presumably protein-low interstitial
compartment (πV − πI). The effective fluid flux resulting
from these 2 opposing forces is determined by hydraulic
conductivity (HC), a primary property of the barrier:
Starling equation:
F / A / T = HC x ([ PV − PI] )
− [ πV − πI ] .
Following Starling’s approach, it is presumed that at the
arterial side of the circulation, fluid in peripheral tissue can
be filtered from the blood to the interstitial space because
of a hydrostatic gradient clearly outweighing the inwardly
directed force. In contrast, at the venous side, the filtered
fluid should be largely reabsorbed due to decreased blood
pressure and excess fluid being removed by the lymphatic
system. When the lymphatic drainage capacity is over-
whelmed, tissue edema arises.
It was reported more than 350 years ago by physiologist
Olaus Rudbeck that lymphatic fluid contains all coagulation
factors and is, therefore, potentially able to coagulate.20
Tissue factor, a potent starter of coagulation, is tightly packed
around arterioles,21 forming a “hemostatic envelope” to stop
bleeding immediately if there is a problem within this high-
pressure segment.22 Accordingly, any kind of fluid-bypass
from arteriolar to venular for reabsorption, as suggested by
Starling, is not possible. In addition, it has been repeatedly
demonstrated in various experimental models that tissue
albumin concentration does not account for vascular barrier
competence. Rather, the interstitial space is filled up with
plasma proteins, making any potent oncotic gradient across
the whole vessel wall unlikely.23,24 Nevertheless, the barrier
works and how this could be possible remains a question.
A Timely Model of Vascular Barrier Functioning
A modern sight of the vascular barrier includes a small,
seemingly insignificant structure attached to the endothe-
lial surface termed the “endothelial glycocalyx.” It consists
of membrane-bound proteoglycans and glycosaminogly-
cans carrying negatively charged side chains. In vivo, these
negative charges lead to a strong binding of plasma con-
stituents, mainly albumin, forming the endothelial surface
layer.25 Its total volume amounts up to 1000 mL in humans,
with a thickness of more than 1 µm. While the hydrostati-
cally outward-driven plasma (Figure 1, light gray arrow) is
retained within the endothelial surface layer, a small space
beneath remains free of protein, allowing an inward
directed oncotic force to be developed completely at the
luminal side of the endothelial cell line (Figure 1, dark gray
arrow).26 The endothelial surface layer rather than the
endothelial cell line is the decisive structure accounting for
vascular barrier competence.
254 Seminars in Cardiothoracic and Vascular Anesthesia 18(3)
Figure 1.  Schematic view toward the endothelial glycocalyx
(adapted from Becker et al26). While the hydrostatically
outward-driven plasma (light gray arrow) is retained within the
endothelial surface layer, a small space beneath remains free
of protein, allowing an inward-directed oncotic force to be
developed completely at the luminal side of the endothelial cell
line (dark gray arrow).
The Functional Role of Albumin: Experimental
Insights
Experimental evidence introduced during the last 10 years
confirmed this model, ascribing an important functional
role to albumin as a natural plasma protein. In the isolated
guinea pig heart model, prepared and perfused in a modi-
fied, nonworking Langendorff mode, pressure-dependent
transudate formation can be quantified.24 The result is a
linear relationship; the slope of the graph (Figure 2, gray
graph, angle α) represents hydraulic conductivity, a pri-
mary property of the barrier.
As long as no other forces are active, the graph comes
from the origin. If additional forces would be active, for
example, an oncotic gradient as presumed by Starling, the
slope would remain the same but the graph would be
shifted toward the right side (Figure 2, black graph). In
fact, such a model would theoretically enable reabsorption
in a segment of the vasculature where the inward-directed
force is lower than the hydrostatic pressure. These condi-
tions would be present on the left hand side of the intersec-
tion (Figure 2, dotted black line).27
The Role of Macromolecules for Vascular
Barrier Competence
In the first set of experiments to derive net hydraulic con-
ductivity of a whole organ vascular system, the coronary
systems of isolated guinea pig hearts were perfused at dif-
ferent perfusion pressures with pure crystalloidal buffer,
buffer augmented with 2 g/100 mL HES, and buffer aug-
mented with 2 different concentrations of human albumin
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Figure 2.  Pressure-dependent fluid filtration at the vascular
barrier (adapted from Jacob and Chappell27). Slope of the gray
line (angle α) represents hydraulic conductivity, a primary
property of the barrier. If additional forces would be active,
the slope would remain the same, but the line would be shifted
toward the right side (black line; the new intersection “i” with
the abscissa stands for its amount). This would theoretically
enable reabsorption in a segment of the vasculature where the
inward directed force is lower than the hydrostatic pressure
(dotted black line).
(1.67 and 0.83 g/100 mL28). The resulting measured intra-
vascular colloid osmotic pressures were 0.0, 5.45, 2.95,
and 1.40 mm Hg, respectively. Surprisingly, adding these
macromolecules did not primarily lead to shifting the
graph rightward, which would have indicated an additional
inward-directed force. Human albumin led in these
extremely subphysiological colloid osmotic pressure
ranges to a marked flattening of the curve, indicating a
decrease in hydraulic conductivity, that is, an improve-
ment of intrinsic vascular barrier competence.
An intravascular concentration of less than 1 g/100 mL
(equal to roughly one fourth of the physiological concen-
tration) is enough to make the system work. Additional
experiments showed that the system reliably collapses at
an albumin concentration of 0.5 g/100 mL.
A large part of the effect of adding macromolecules to a
vascular system, at least in low concentrations, is the result
of an interaction with the endothelial glycocalyx. The
properties of human albumin are superior to those of HES
in this context.28
Dilution of the Intravascular Albumin
Concentration Below the Functional Threshold
In the second set of experiments, the effects on vascular bar-
rier competence when diluting a critical intravascular albu-
min concentration with artificial solutions was investigated.7
Moret et al 255
Primarily, the guinea pig hearts were prepared, and pressure
(80 cm H2O) constantly perfused with crystalloidal buffer
augmented with 1 g/100 mL human albumin over 30 min-
utes. Then, the perfusion mode was switched to replacement
of half of the buffer with artificial, commercially available
infusion solutions (0.9% saline, Ringer’s acetate, 6% and
10% HES, or 4% gelatin). As confirmed by electron micros-
copy and quantitative analyses of the coronary effluent,
these solutions did not cause any shedding of the endothelial
glycocalyx. Therefore, it can be assumed that the observed
effects are functional ones, exclusively caused by the inter-
action of the glycocalyx with the intravascular macromole-
cules. After switching the perfusion mode, transvascular
fluid filtration and interstitial edema markedly increased in
all groups versus control conditions. This effect was greatest
with crystalloids and significantly decreased with artificial
colloids. However, none of them were able to restore the
conditions toward basal levels.
Currently, none of the commercially available crystal-
loid or colloid preparations appear able to maintain vascu-
lar barrier competence below a functional threshold
concentration of albumin.
When? Perioperative Administration
of Albumin and Pump Priming
Albumin for Pump Priming in Pediatric Heart
Surgery
Because of the small body surface area of newborns and
infants, CPB priming volume exerts a strong hemodilu-
tional effect on the circulatory blood volume of the patient.
The decreased content of red blood cells may be compen-
sated, when required, by the use of packed red cells in the
priming volume; conversely, the decrease in colloid
osmotic pressure due to plasma protein (albumin) dilution
requires additional corrective measures.
The usual approach to this problem is based on fresh
frozen plasma (FFP) or 4% to 5% albumin. The main dif-
ference between the 2 is the presence of fibrinogen and
coagulation factors in FFP with a better preservation of
fibrinogen levels.29 There are few comparative studies on
these alternative strategies. In 2003, Oliver et al30 com-
pared 5% albumin priming with FFP-based priming in
pediatric patients. They found no differences in blood loss
in simple procedures and noncyanotic patients, whereas
patients had a larger blood loss in the complex and cya-
notic groups. Patients in the 5% albumin group had a sig-
nificantly lower administration of blood products.
From a theoretical point of view, using FFP or 5% albu-
min in the priming volume means following 2 different
strategies of coagulation factors management. When FFP
is used, coagulation factors are added simultaneously
to CPB initiation; therefore they are less diluted during
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CPB.31 However, thrombin generation is probably enhan­
ced during CPB, more heparin is needed, and more con-
sumption of coagulation factors is triggered. When using
albumin for the priming volume, a dilution of coagulation
factors is accepted during CPB, and this will lead to less
thrombin generation and consumption of coagulation fac-
tors (“anesthesia of the hemostatic system”). When this
second strategy is adopted, coagulation factors (FFP)
should be supplemented after protamine administration.
Albumin for Pump Priming in Adult Heart
Surgery
The main advantage offered by albumin for CPB priming
is represented by its properties of “natural coating” of the
circuit and oxygenator. Once blood comes in contact with
foreign surfaces, a protein layer is bound onto the surface.
The main component of this layer is fibrinogen, and once
fibrinogen is bound, this will lead, in turn, to platelet adhe-
sion on fibrinogen via the glycoprotein IIb/IIIa receptor.
This is actually the first step leading to fibrin deposition on
the surface and fibrinogen and platelet consumption.
However, albumin may compete with fibrinogen in the
formation of the protein layer, and pre-adsorption of albu-
min prevents fibrinogen adsorption and platelet adhesion.
In a meta-analysis from Russell et al,32 it was demonstrated
that albumin, compared with crystalloids as a priming
solution, exerts a number of beneficial effects, including
platelet count and colloid osmotic pressure preservation.
Albumin for Plasma Volume Substitution
At present, there are different possible solutions for intra-
vascular fluid replacement, belonging to the groups of iso-
tonic crystalloids, hypertonic crystalloids, artificial
colloids (gelatins and HES), and 4% to 5% albumin. In the
assessment of the clinical properties of these solutions, the
main issues are efficacy and safety.
In general, colloids guarantee a greater response than
crystalloids in terms of preload changes and fluid replace-
ment in cardiac surgery patients.33 Hypertonic saline
induces a greater increase in systemic blood pressure ver-
sus normal saline after coronary revascularization.34
Albumin preserves colloid osmotic pressure to a similar
degree as artificial colloids. However, artificial colloids
may induce a number of adverse effects, which have been
pointed out in recent years.35-38
Safety Issues
Both HES and gelatins exert a certain degree of deleterious
effects on the hemostatic system. When compared with 4%
albumin, HES 120 and HES 400 were associated with a pro-
longed time to clot formation, decreased clot firmness, and
256 Seminars in Cardiothoracic and Vascular Anesthesia 18(3)
a larger chest drain blood loss in cardiac surgery patients.39
In a recent study, HES was compared with albumin in off-
pump coronary patients, and was associated with a larger
use of allogeneic blood products.36
It is well established that albumin is associated with a
lower degree of hemostatic system imbalance than syn-
thetic colloids,40 and a recent meta-analysis confirmed that
albumin versus HES 120 and HES 400 is associated with
less bleeding, less allogeneic blood products transfusions,
and a lower rate of surgical reoperation in the setting of
cardiac surgery.41
Additionally, there is a wide body of evidence linking
the use of HES to renal dysfunction in various types of
critically ill patients. The recently released Consensus
Statement of the European Society of Intensive Care
Medicine Task Force on colloid volume therapy in criti-
cally ill patients42 provides a number of recommendations
that exclude the use of HES with molecular weight ≥200
kDa in patients at risk for renal failure and strongly limit
the use of HES 130. Conversely, the same document
quotes the existence of a retrospective study on greater
than 20 000 coronary surgery patients, where the use of
albumin versus HES was associated with a 20% reduction
of the relative risk of death.43
When? Postoperative Administration
of Albumin
After CPB, patients have often several problems.
Myocardial stunning and vasoplegic syndrome are widely
described, and in the early postoperative period, a signifi-
cant number of patients (up to 50%) need inotropic support
and/or vasopressors because of a hypotension.44 The use of
priming solution, transfusions, and large fluid transfers
during cardiac surgery predisposes patients to a fluid over-
load. Despite intraoperative fluid accumulation, patients
have often intravascular volume deficit because of fluid
shifting from intra- to the extravascular space due to sys-
temic inflammatory response reaction and damage of the
endothelial glycocalyx. In contrast to general surgery
patients, the number of complications correlates with the
volume of fluids administered intra- and postoperatively.
Additionally, CPB predisposes patients to anemia, hypoal-
buminemia, and coagulation disturbances. Therefore after
CPB, rapid volume resuscitation with the smallest possible
amount of fluid without side effects is needed. Several
studies show that colloid solutions have a better (up to
2-fold) volume expansion effect than crystalloids 45;46.
Albumin is the most common protein in plasma. The
discussion about multiple functions of albumin in humans
is still open. Albumin solution is the only available colloid
of biological origin indicated for CPB. Albumin has
replaced less pure preparations such as plasma protein
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fraction because of its better side-effect profile and less
contraindications such as possible induction of severe
hypotension in patients on cardiopulmonary bypass.47,48
Albumin solution has been successfully used for volume
replacement therapy for more than 50 years in various
patient groups. Several albumin solutions are available at
this time: slightly hypooncotic 4%, normooncotic 5% with
the volume effect between 80% and 100%, and a strongly
hyperoncotic 20% or 25% solution with the volume effect
up to 300%.49 Therefore, in some cases, it is possible to
significantly increase the intravascular volume using a
very small amount (only 100-200 mL) of this fluid.
Additionally, albumin has a potential protective effect on
endothelial glycocalyx, and theoretically its use could
improve microcirculation, which is altered after CPB.
There are no large randomized controlled trials in car-
diac surgery patients comparing albumin to any other
fluid. However, Fritz et al50 in 2003 demonstrated that the
presence of postoperative hypoalbuminemia predicts mor-
tality after cardiac surgery even better than EUROscore. In
this study, cutoff for hypoalbuminemia was 18 g/L.
In 2006, Niemi et al38 demonstrated that the use of both
old HES and gelatin solutions correlates with the amount
of postoperative bleeding after cardiac surgery, but the use
of 4% albumin solution does not. Schramko et al51 in 2009
compared the postoperative infusion of 2 HES solutions
(HES 200/0.5 and HES 130/0.4) to 4% albumin. Albumin
did not cause any changes in maximum clot firmness, but
both HES solutions decreased thromboelastometry
slightly, but significantly. Onorati et al52 retrospectively
compared the low dose of albumin priming with a pure
crystalloid one in 377 patients. Patients receiving albumin
needed less blood transfusions and had lower blood loss
postoperatively. Additionally, the resternotomy rate was
significantly lower in the albumin group. Navickis et al41
published a meta-analysis comparing the use of HES solu-
tions with albumin: Hemodynamics were similar in both
groups, but the use of albumin decreased blood loss, the
amount of blood products transfusions, and the need for
reoperation postoperatively. However, this meta-analysis
has insufficient data about the use of tetrastarch HES
130/0.4. Interestingly, some investigators reported that
when the use of albumin solution was compared with other
colloids of nonbiological origin or to crystalloids, the
platelet counts in the albumin group was significantly
higher postoperatively than in the other fluids groups.51,52
This “platelet preservation” effect of albumin has been dis-
cussed in several forums; however the mechanism of this
effect is still unclear. Some studies reported slight hypoco-
agulation after albumin use, but these changes are caused
more by hemodilution effect. Based on these findings, the
use of albumin solution after cardiac surgery is also safe in
patients who already have increased blood loss.
Moret et al 257
In 2012, HES 130/0.4 has been reported to impair renal
function in patients with severe sepsis.53 Despite the fact
that sepsis pathophysiology completely differs from the
events taking place in the patients after cardiac surgery,
and the recent meta-analysis reports a benefit from the use
of modern HES compared with other fluids in surgical
patients,54 the use of HES—especially in patients with
altered renal function—is decreased. The use of albumin
solutions in patients with renal dysfunction or with risk for
acute kidney injury is an attractive alternative to the use of
other colloids because 4% or 5% albumin solutions have
no effect on renal function.
Conclusions
Human albumin is an important part of the vascular bar-
rier, functionally active via a strong interaction with the
endothelial glycocalyx. Dilution of the physiological
plasma albumin concentration to one fourth of the physi-
ological concentration of approximately 4 g/100 mL
appears to be a major functional problem. However, reach-
ing 0.5 g/100 mL experimentally caused a collapse of the
system which could not be prevented by artificial colloids.
While providing colloid osmotic pressure, the interaction
of artificial colloids with the endothelial glycocalyx is too
low to maintain physiological conditions at the vascular
barrier. Therefore, the natural colloid, albumin, may be the
preferable choice to treat a massive volume deficit.
Human albumin may, from a physiological standpoint,
be the best choice in critically ill patients to replace a defi-
cit in cardiac preload if, at the same time, we target at
maintaining vascular barrier competence, preventing inter-
stitial edema, and keeping the microcirculation intact. In
pediatric cardiac surgery patients, the use of FFP in the
priming may lead to a higher degree of thrombin genera-
tion during CPB with a greater need for heparin and higher
consumption of coagulation factors, while priming with
human albumin preserves oncotic pressure, prevents plate-
let adhesion, and likely induces less coagulation factor
consumption.
After cardiac surgery, patients often need volume resus-
citation using the smallest possible amount of colloid solu-
tion because of fluid overloading. Albumin maintains
hemodynamics as effectively as other colloids. For patients
with hypoalbuminemia, albumin solution should be the
drug of choice. Additionally, in patients with risk for
increased bleeding or renal failure, albumin is a safe alter-
native because of its minimal side effects. The role of albu-
min in plasma is multifunctional, and at this time we do
not know all the possible benefits from the use of this drug.
Some functions, such as platelet or endothelial glycocalyx
preservation are already described. It is hoped that in the
near future the results from large randomized controlled
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trials comparing the use of albumin with other fluids in
cardiac surgery patients will be available.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of inter-
est with respect to the research, authorship, and/or publication of
this article: Enrique Moret received speaker honoraria from
Grifols. Matthias W. Jacob received lecture fees from Fresenius
Kabi, Grifols, B. Braun, Baxter, and Serumwerk Bernburg; and
research grants from Serumwerk Bernburg, CSL Behring, and
Grifols. Mathias W. Jacob is member of the Grifols Albumin
Advisory Board. Marco Ranucci received honoraria and speak-
er’s fees from Grifols SA, Medtronic, Sorin Group, CSL,
Behring, Novo Nordisk, and Roche Diagnostics. Alexey A.
Schramko received honoraria for lectures and travel reimburse-
ments from B. Braun, Fresenius Kabi, TEM international, CLS
Behring, and Grifols.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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