Accepted Manuscript

Choice of fluid type:Physiological concepts and perioperative indications

C. Boer, S.M. Bossers, N.J. Koning

PII: S0007-0912(17)54071-4
DOI: 10.1016/j.bja.2017.10.022
Reference: BJA 63

To appear in: British Journal of Anaesthesia

Received Date: 15 September 2017

Revised Date: 22 October 2017
Accepted Date: 25 October 2017

Please cite this article as: Boer C, Bossers SM, Koning NJ, Choice of fluid type:Physiological concepts
and perioperative indications, British Journal of Anaesthesia (2017), doi: 10.1016/j.bja.2017.10.022.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Choice of fluid type:Physiological concepts and

perioperative indications

C. Boer1*, S.M. Bossers1, N.J. Koning1

PT
RI
Department of Anaesthesiology, Amsterdam Cardiovascular Sciences, VU University

Medical Centre, Amsterdam, the Netherlands.

SC
Running title: Choice of fluid type in the perioperative setting

U
AN
*Corresponding author. Email: c.boer@vumc.nl
M
D
TE
C EP
AC

1
 ACCEPTED MANUSCRIPT
SUMMARY

The consensus that intravenous resuscitation fluids should be considered as drugs with

specific dose recommendations, contra-indications and side-effects resulted in an increased

attention for the choice of fluid during perioperative care. In particular, the debate concerning

possible adverse effects of unbalanced fluids and hydroxyethyl starches resulted in a re-

PT
evaluation of the roles of different fluid types in the perioperative setting. This review

provides a concise overview of the current knowledge regarding the efficacy and safety of

RI
distinct fluid types for perioperative use. First, basic physiological aspects and possible side-

effects are explained. Second, we focus on considerations regarding fluid choice for specific

SC
perioperative indications based on an analysis of available randomised controlled trials.

U
MESH KEY WORDS: Fluid therapy; Colloids; Surgical Procedures
AN
M

Intravenous fluid administration to maintain tissue perfusion, electrolyte concentrations or to

infuse drugs is daily routine during anaesthesia and surgery. Intravenous fluids are
D

increasingly considered as drugs with dose recommendations, indications, contraindications,

TE

and side effects.1-3 This has resulted in new approaches to avoid unnecessary preoperative

fasting and fluid-related morbidity, and the institution of goal-directed fluid therapy to
EP

rationalize the use of fluids in the perioperative period.4, 5

In parallel, vigorous debate

developed regarding choice of fluid type, mainly focusing on the importance of avoiding
C

hyperchloraemic metabolic acidosis induced by unbalanced fluids and the unfavourable

AC

association of hydroxyethyl starches (HES) with haemostasis and renal function.

However the scientific evidence to guide fluid choice and dosing in the perioperative setting

is limited, and most guidelines refer to physiological experiments rather than comparative

clinical trials. Moreover, data from septic and critically ill patients are translated to the

surgical patient without clear rationale, irrespective of the differences in inflammatory state

between these distinct populations. This review is restricted to the use of different fluid types

2
 ACCEPTED MANUSCRIPT
in the perioperative setting, and their impact on basic physiology, including microvascular

perfusion, glycocalyx integrity, colloid osmotic pressure and haemostasis. Additionally, we

summarize considerations for choosing a fluid for specific surgical indications, including a

semi-structured analysis of the available studies that focus on fluid type and their association

with clinically relevant outcomes.

PT
TYPE OF FLUIDS

Composition

RI
The first types of physiological fluids were developed in the 19th century, including a fluid

SC
developed by Sydney Ringer to mimic blood plasma for ex vivo experiments with frog

hearts.6 In 1932, Alexis Hartmann added the buffer lactate to Ringer’s solution, and created

U
the first balanced crystalloid.7 In parallel, Jacob Hamburger developed normal saline
AN
solution.8

The use of colloids started with the infusion of albumin in trauma victims during World War II,
M

followed by the development of artificial colloidal solutions containing dextran, gelatin or

D

hydroxyethyl starch (HES). Table 1 gives an overview of commonly used fluids in the

perioperative setting with their main components, osmolarity and pH range. Unbalanced
TE

crystalloids (normal saline) and colloids (hetastarch, pentastarch, Voluven®, Gelofusin®, 5%

human albumin and Hyperhaes®) contain higher chloride concentrations, while in balanced
EP

solutions (Ringer’s lactate/acetate, Plasma-lyte 148, Hextend®, Tetraspan®, Gelaspan® and

Volulyte®) chloride concentrations are partially replaced with alternative anions and contain
C
AC

more potassium compared to unbalanced solutions. Gelatin- and albumin-containing colloids

are commonly used alternatives for HES, especially since the use of HES was abandoned in

specific patient populations. Gelatin and albumin are considered to be safe for surgical

patients, but the lack of large comparative studies prohibits an extensive analysis of this

colloid in view of perioperative care.

Side-effects

3
 ACCEPTED MANUSCRIPT
Infusion solutions for fluid therapy may have side-effects and are contraindicated in specific

populations. All solutions are therefore registered as pharmaceutical products by local

authorities, the US Food and Drug Administration and European Medicines Agency. While

large volumes of crystalloid and colloid solutions can lead to hypervolaemia, most solutions

can also cause an imbalance in electrolytes, including hyponatraemia, hyperchloraemia,

PT
hyperkalaemia and hypocalcaemia.5,9 The volume load and electrolyte disturbance can be of

particular impact in severe renal, cardiac or hepatic disease.10 Here we describe current

RI
knowledge on hyperchloraemia and hyperkalaemia as side-effects of infusion fluids, and

provide a concise overview of the association of HES with renal function and haemostatic

SC
abnormalities.

U
Normal saline and hyperchloraemic acidosis
AN
Normal saline (0.9%) contains supraphysiological concentrations of sodium (154 mmol l-1)

and chloride (154 mmol l-1). Excessive and long-term administration of saline can therefore
M

lead to hyperchloraemic metabolic acidosis when chloride levels exceed the serum

concentration (100-110 mmol l-1).4 In a systematic review and meta-analysis it was shown
D

that resuscitation with high-chloride fluids (chloride concentration > 111 mmol l-1) is
TE

associated with a higher risk of acute kidney injury (AKI; relative risk (RR) 1.64, 95%

confidence interval (CI) 1.27-2.13; P<0.001) and hyperchloraemia (RR 2.87, 95% CI 1.95-
EP

4.21; P<0.001), while mortality was not affected.11 A limitation of this meta-analysis was the
C

lack of data regarding the volume of crystalloids administered during the perioperative

period.11 A propensity-matched comparison of patients with or without acute postoperative

AC

hyperchloraemia (>110 mmol l-1) showed that hyperchloraemia was an independent

predictor of 30-day mortality (odds ratio (OR) 2.05; 95% CI 1.62-2.59).12 Moreover, patients

with subarachnoid haemorrhage and postoperative AKI had a 3-times higher increase in the

serum chloride concentration than patients without AKI.13 In open abdominal surgery,

perioperative balanced crystalloid resuscitation was associated with fewer complications

(OR 0.79; 95% CI 0.66-0.97) compared to normal saline in a propensity-matched cohort.14

4
 ACCEPTED MANUSCRIPT
In children undergoing major surgery, the increase in plasma chloride concentration was

higher in the normal saline group compared to a balanced crystalloid.15 However, when large

volumes were involved (>46.7 ml kg-1), both crystalloids resulted in comparable elevations of

plasma chloride concentration without affecting outcome.15 In the SPLIT trial, normal saline

was compared to a Plasma-Lyte 148 (chloride concentration 98 mmol l-1) in critically ill

PT
patients admitted to the ICU, more than 70% of which were postoperative patients.16

Although hyperchloraemic acidosis occurred more frequently with normal saline, the study

RI
was too small to show beneficial or harmful effects of balanced crystalloids on clinically

relevant outcomes.16 During renal transplantation, Ringer’s lactate or Plasma-Lyte 148

SC
reduced the incidence of metabolic acidosis compared to saline, but do not lead to better

postoperative renal function.17, 18

U
In summary, use of normal saline can increase risk for hyperchloraemic metabolic acidosis
AN
in large volume administration. Whether balanced solutions are associated with a favourable

profile in view of postoperative morbidity when compared to normal saline needs to be

M

elucidated in large comparative studies.

D

Hypokalaemia and hyperkalaemia

TE

In contrast to normal saline and colloids, balanced intravenous fluids contain potassium at a

concentration similar to that of the extracellular fluid (4-5 mmol l-1). Potassium is a
EP

predominantly intracellular ion, and supplemental potassium has a large volume of

C

distribution. It is currently unclear whether balanced intravenous fluids reduce the incidence
AC

of hypokalaemia, and the incidence of related complications like arrhythmias or cardiac

arrest. However, direct potassium supplementation did not reduce postoperative atrial

fibrillation in cardiac surgery.19 In renal transplantation, the use of balanced crystalloids

instead of normal saline reduces the risk for hyperkalaemia.17,18 This is attributed to the

transcellular potassium shift due to a hyperchloraemic acidosis with normal saline, which is

more significant than the low levels of potassium present in balanced intravenous fluids.

5
 ACCEPTED MANUSCRIPT
Hydroxyethyl starches and renal function

The use of HES has become controversial in the last two decades after an increasing

number of studies in critically ill patients, showing that its administration was associated with

an increased incidence of AKI or even mortality.20 20a Although the discussion on the use of

HES in critically ill patients is beyond the scope of the current review, in some of these trials

PT
there were substantial concerns regarding methodology.21 For example, in some studies

HES was administered before randomisation, the assessment of hypovolaemia was

RI
insufficient, there was prolonged administration of HES, or the administered volume

SC
surpassed the maximum dose.21

Use of HES 130/0.4 was studied in several small RCTs involving abdominal, orthopaedic or

U
vascular surgery.22-28 In all studies, HES 130/0.4 did not increase the risk for AKI compared
AN
to crystalloids or gelatin. Two RCTs in liver transplantation showed no deleterious effect of

HES 130/0.4 on renal function compared to 5% albumin or 4% gelatin.29,30 Notably, in most

M

of the abovementioned studies, the total dose of HES surpassed the maximum dose

currently recommended by the European Medicine Agency.25-30 Moreover, none of the RCTa
D

were powered to detect a difference in AKI between modern generation HES and
TE

crystalloids in the surgical patient. The quality and level of evidence of the available literature

is too low to conclude whether HES has a favourable or unfavourable profile in the treatment
EP

of acute perioperative hypovolaemia. When HES is used, the recommended dose should not

be surpassed and its use should be restricted to non-septic patients without pre-existent
C

renal failure.
AC

6
 ACCEPTED MANUSCRIPT

Effect of fluids on haemostasis

Haemodilution is associated with dilution of coagulation factors. Moreover, experiments in

vitro suggest that haemodilution with colloids has a greater effect on haemostatic

parameters, such as clotting time and clot firmness, than haemodilution with crystalloid

PT
solutions. Indeed experiments in vivo showed that 30% haemodilution by unbalanced HES

130/0.4 resulted in a relatively high reduction in fibrinogen and thrombin levels (44%),31 and

RI
HES also seems to have a greater impact on in vitro coagulation parameters than gelatin

and albumin containing solutions.32 Several studies have investigated the effect of distinct

SC
fluid types on coagulation parameters in surgical patients, including laboratory coagulation

tests like activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count

U
and fibrinogen levels,29,33-37 or the point-of-care thromboelastographic R and maximum
AN
amplitude (MA)38,39 or the thromboelastometric EXTEM clotting time (CT) and EXTEM and

FIBTEM maximum clot firmness (MCF).40-42 For detailed information see Supplemental
M

Table 1. Most studies did not show a difference in coagulation parameters between different
D

fluid types, except for the older generation HES 670/0.75, which was associated with

deterioration of coagulation parameters compared to Plasma-Lyte 14840 or HES 130/0.4.35,38

TE

Most of these studies were limited by a small sample size and had different dosing

strategies.
EP

Table 2 shows RCTs comparing different fluid types with perioperative blood loss as primary

endpoint.43-51 The majority of studies were performed in the cardiac surgical setting and did
C
AC

not show a difference in 24-hr blood loss between HES, albumin, gelatin or crystalloid

solutions. The only study showing a difference in postoperative blood loss was performed in

cystectomy, with a favourable haemostatic profile for Ringer’s lactate compared to HES

130/0.4 (blood loss 1370 ± 603 vs. 2181 ± 1190 ml; P=0.038).47 However the same authors

could not repeat these findings in two comparative studies in a similar population when

comparing Dextran 70 or 5% albumin with Ringer’s lactate.48,49 In conclusion, the majority of

studies do not show a difference in blood loss between fluid types. These data should be

7
 ACCEPTED MANUSCRIPT
viewed in light of different dosing strategies and populations among studies. Moreover, in

most studies comparing colloids and crystalloids as resuscitation fluids, the total volume of

fluids administered is different between groups, and paralleled by maintenance infusion of a

crystalloid. It is therefore difficult to differentiate between the direct effects of a fluid type on

haemostasis and the dilution component of fluid resuscitation.

PT
The use of HES as main component of the priming solution for extracorporeal circulation

during cardiac surgery was compared to gelatin52 or albumin.53,54 In these studies, the

RI
secondary endpoints postoperative bleeding and allogeneic blood transfusion were not

different between groups. In an RCT, there were no differences in blood coagulation

SC
parameters or postoperative bleeding between the use of Ringer’s acetate or balanced HES

130/0.4 as priming solution.55 The HES group required more postoperative blood

U
transfusion, albeit the study was not powered to prove this effect.55 Moreover, a large dose
AN
of HES 130/0.4 did not reveal differences in postoperative blood loss and bleeding following

cardiopulmonary bypass compared to a 200/0.5 starch.43 The level of evidence that is

M

available to support the choice of fluid type in priming solution is low. However, based on the
D

unfavourable profile of HES in critically ill patients or patients with renal failure, HES is
TE

decreasingly used for cardiopulmonary bypass prime solutions.

PHYSIOLOGY
EP

Viscosity and microvascular perfusion

C

The reduction in haematocrit after high volume fluid resuscitation with crystalloids or colloids
AC

leads to a decrease in whole blood viscosity. In addition to their effect on colloid osmotic

pressure, colloids were designed to mimic plasma viscosity after dilution with blood during

fluid resuscitation, with a target viscosity of 1.0-1.2 cP.56 Although gelatin has a lower

intrinsic viscosity than HES, its effect on red blood cell aggregation leads to increased

viscosity in vivo compared to HES.57

In the microcirculation, relative viscosity is lower than in larger vessels, the so-called

Fåhraeus-Lindquist effect, and a reduction in haematocrit can therefore be of particular

8
 ACCEPTED MANUSCRIPT
influence on capillary blood flow and capillary density (Figure 1).58, 59 Most studies focusing

on the effects of different fluid types on viscosity and microcirculatory function are limited to

experimental animal studies. In a hamster model, an increase in blood viscosity by highly

viscous colloids attenuated impairment of capillary perfusion induced by extreme

haemodilution.60 The benefit of high-viscosity colloids on capillary perfusion during

PT
haemodilution is attributed to the preservation of intra-capillary pressure that is needed to

maintain perfusion.59 A comparison of polyethylene glycol-conjugated bovine serum

RI
albumin61 or human haemoglobin62 with HES during resuscitation following haemorrhage in

hamsters revealed that, in contrast to HES, the conjugated albumin provided a prolonged

SC
restoration of microcirculatory function, suggesting a different impact of colloid solutions on

the microcirculation.61, 62 A recent systematic review summarizing the experimental evidence

U
for optimal fluid choices in post-haemorrhagic shock resuscitation suggests that fluids with a
AN
high viscosity, high colloid osmotic pressure and restorative capacities for the endothelial

glycocalyx have the most favourable profile to restore microcirculatory function.63 From a
M

clinical perspective, the evidence for the most effective fluid resuscitation strategy to improve
D

microcirculatory perfusion is however limited, and until now, the available evidence only
TE

suggests that artificial colloids are inferior in the restoration of microcirculatory oxygenation

when compared to packed red blood cell (PRBC) transfusion.64

EP

Endothelial glycocalyx
C

The glycocalyx resides on surface of the vascular endothelium, and consists of a layer of
AC

proteoglycans, e.g. syndecan and receptor-bound hyaluronan. The glycocalyx is negatively

charged and contributes to the natural barrier of the vessel wall.65 It has a fragile structure

and can be released by multiple stimuli, for instance ischaemia and reperfusion, sepsis,

hypoxia, inflammatory activation, hyperglycaemia and hypervolaemia.66 Since the total

volume of the endothelial glycocalyx is estimated at 700 ml, glycocalyx shedding can

significantly influence fluid shifts, even independently from its function in the endothelial

9
 ACCEPTED MANUSCRIPT
barrier. Moreover, the glycocalyx plays a role in the mechanical transduction of shear stress

to the endothelium, and inhibition of leukocyte or platelet adhesion to the vascular wall.65

In a systematic review of preclinical studies it was concluded that fresh frozen plasma (FFP),

but not Ringer’s lactate, normal saline or HES, partially restores glycocalyx thickness, with

concomitant benefits for microcirculatory perfusion, after haemorrhagic shock.63 In a more

PT
recent publication, it was suggested that the larger plasma volume expansion by FFP or

albumin compared to crystalloids after haemorrhagic shock could account for most of the

RI
favourable effects on outcome, since plasma levels of endothelial glycocalyx components
67
were similar between groups. However, the better volume effects of FFP or albumin

SC
compared to Ringer’s acetate suggest that FFP and albumin increase glycocalyx restoration

rather than prevent its degradation. Others showed that albumin appears to be more

U
effective than HES for glycocalyx restoration.68, 69 Studies in guinea pig heart preparations
AN
found that artificial colloids were less damaging to the endothelial glycocalyx than normal

saline.68, 70
M

The number of comparative clinical studies evaluating different fluid types and their effect on
D

glycocalyx integrity are limited, and mostly focus on glycocalyx shedding products. In an
TE

observational study a prophylactic bolus of 750 ml warmed lactated Ringer’s solution before

spinal anaesthesia for caesarean delivery was associated with a minor protein-adjusted
EP

median rise in heparin sulphate (from 600 (372-753) ng/mg to 651 (424-895) ng/mg) and

syndecan-1 (from 11 (8.4-16.1) ng/mg to 12 (9.6-19.2) ng/mg).71 In the only available RCT, it
C

was hypothesised that older generation HES (670/0.75) would lead to less endothelial
AC

damage and glycocalyx shedding that an equal dose of a balanced salt solution in off-pump

cardiac surgery.40 Median serum syndecan-1 levels were higher in the HES than in the

crystalloid group after fluid infusion (79.9 (46.6-176.6) ng ml-1 vs. 62.7 (30.1-103.0) ng ml-1;

P=0.030), but this difference disappeared in the postoperative period.40

From these data, it can be concluded that the current literature lacks evidence with respect

to the clinical impact of fluids on glycocalyx integrity. It is unclear whether a change in

glycocalyx integrity has a clinically relevant impact on the final intravascular volume effect of

10
 ACCEPTED MANUSCRIPT
distinct fluids. Moreover, it is unknown how this volume effect differs between healthy

individuals and patients with dysfunction of the endothelial barrier. Further studies should

reveal whether glycocalyx integrity is involved in the regulation of intravascular volume

during fluid resuscitation, and not just a surrogate marker for a disease state.

Effect on colloid osmotic pressure

PT
Colloid osmotic pressure is the osmotic pressure exerted by plasma proteins, and serves to

RI
attract fluid to the intravascular compartment. Although the absolute colloid osmotic pressure

in plasma (~25 mmHg) is low relative to the total osmotic pressure (~5500 mmHg), it has a

SC
major contribution in fluid distribution due to the large difference between the intravascular

and extravascular compartment. Starling’s equation describes the forces involved in fluid

U
shifts between the intravascular and extravascular space as:72
AN
F = (Pc – Pi) – σ ( Πp – Πi)

where F is capillary filtration force, Pc is capillary blood pressure, Pi is interstitial pressure, σ

M

is the osmotic reflection component, Πp is the plasma colloid osmotic pressure and Πi is the
D

interstitial colloid osmotic pressure (Figure 2).

TE

More recently, it has become clear that the endothelial glycocalyx plays an important role in

maintaining fluid in the intravascular compartment. The observations that there is no end-
EP

capillary fluid absorption from the interstitium at steady-state and that filtration is relatively
C

independent of the interstitial colloid osmotic pressure have led to a revised Starling

equation (Figure 2), which has been reviewed extensively:73, 74

AC

F = (Pc – Pi) – σ ( Πp – Πg)

where Πg is subglycocalyx colloid osmotic pressure.

In the revised Starling equation, there is an important role for the intact endothelial

glycocalyx and the sub-glycocalyx space in the endothelial intercellular clefts. Experimental

studies have shown that this space has a very low protein concentration and thus a low

11
 ACCEPTED MANUSCRIPT
osmotic pressure, reducing the filtration of fluid from the capillaries.73,74 Moreover, the

presence of this low-protein space explains the absence of absorption at the venous end of

the capillary, where the colloid osmotic pressure is higher in the interstitium than in the sub-

glycocalyx space. Since the endothelial glycocalyx has an osmotic reflection coefficient

close to 1, indicating a low level of protein leakage through the endothelial barrier, the force

PT
opposing capillary blood pressure (σ (Πp – Πg)) roughly equals plasma colloid osmotic

pressure.73, 74
The importance of plasma colloid osmotic pressure in the revised Starling

RI
equation is in line with early observations that low plasma colloid osmotic pressure is

associated with tissue oedema.75

SC
All intravenous fluids influence colloid osmotic pressure and fluid extravasation. Crystalloids

lower plasma colloid osmotic pressure, whereas albumin, gelatin and HES solutions

U
increase plasma colloid osmotic pressure and intravascular volume. Hypertonic saline is an
AN
exception in the crystalloid group. It increases extracellular osmotic pressure, but lowers

colloid osmotic pressure, therefore attracting water from the intracellular compartment into
M

the extracellular space, but not specifically into the intravascular compartment. Hypertonic
D

saline has been used extensively to reduce intracranial pressure in traumatic brain injury,
TE

but no survival benefits were observed in comparison with other fluids.76

In an animal model, albumin was more effective than HES in reducing extravasation of fluids
EP

for a similar colloid osmotic pressure, which is attributed to the incorporation of albumin in

the endothelial glycocalyx.68 In acute inflammation, tissue oedema develops as a

C

consequence of a reduced osmotic reflection coefficient through increased endothelial

AC

permeability and glycocalyx shedding. Consequently, the efficacy of colloids for intravascular

volume expansion is reduced during inflammatory conditions.68

Intravascular volume effects

Crystalloids can freely pass the glycocalyx, while colloids are largely retained within the

vasculature in case of an intact glycocalyx.77, 78

Many studies have investigated the

intravascular volume effect of fluid therapy in hypervolaemic conditions, such as volume

12
 ACCEPTED MANUSCRIPT
loading, but have low clinical relevance. For instance, atrial natriuretic peptide is released

during hypervolaemia which leads to endothelial glycocalyx shedding and thus reduces the

intravascular volume effect of intravenous fluids, particularly for colloids.79

In acute normovolaemic haemodilution experiments in human subjects as a model for acute

blood loss, 17% of infused Ringer’s lactate remained intravascular.80 Plasma volume was

PT
subsequently restored and interstitial oedema that developed following Ringer’s lactate

infusion was reduced by infusing 20% albumin. It remains unknown whether this could be

RI
attributed to increased competence of the endothelial glycocalyx, increased plasma colloid

osmotic pressure, or both.80 In contrast to changes in plasma volume after infusion of

SC
Ringer’s lactate, acute normovolaemic haemodilution with 5% albumin resulted in a

comparable blood volume to preoperative values.78 In healthy volunteers, replacement of

U
900 ml of blood by 5% albumin or Ringer’s lactate resulted in better maintenance of cardiac
AN
output and blood volume in the albumin group compared to the Ringer’s lactate group.81

Similarly, almost the entire volume of 6% HES 130/0.4 remained in the intravascular space
M

during acute normovolaemic haemodilution.82

D

From these results, it follows that restoration of intravascular volume following acute
TE

hypovolaemia is most effective using colloids, whereas maintenance or restoration of the

entire extracellular volume is best performed with crystalloids. This is the approach to fluid
EP

therapy that is most often used in perioperative goal-directed therapy protocols.83 83a

Moreover, the Cristal Trial showed that colloids were not more harmful than crystalloids
C

when was used for restoration of hypovolaemia.84 These findings are difficult to translate to
AC

the perioperative setting however, as only critically ill patients with hypovolaemic shock were

included. Due to pragmatic reasons the study was not blinded and physicians were allowed

to use any crystalloid or colloid available in their institution, leaving the study open to bias.84

More randomised clinical trials that evaluate this strategy in the perioperative setting are

awaited, particularly whether the efficacy of colloids in restoration of intravascular volume

during acute hypovolaemia outweigh their potential side effects in surgical patients.

13
 ACCEPTED MANUSCRIPT
SPECIFIC CLINICAL INDICATIONS

We performed a semi-structured literature search in Pubmed with the MESh search terms

[Surgical Procedures], [Fluid Therapy] and [Colloids] (112727 hits). All fluid types

summarized in Table 1 were included (unbalanced and balanced crystalloids, HES-, gelatin-

and albumin-containing colloids). This search was narrowed for the years 1997-2017 (69411

PT
hits) and Clinical Trials and Humans, and excluding [SEPSIS] (5020 hits). The search was

combined with specific clinical indications or endpoints, including cardiac surgery, renal

RI
transplantation, neurosurgery, traumatic brain injury, major abdominal surgery, paediatric

surgery and major haemorrhage to provide an overview of the clinical trials in this area. The

SC
search was mainly limited to RCTs (Supplemental table 2 and 3, respectively) that were

graded for quality based on the Oxford Centre for Evidence-based Medicine Levels of

U
Evidence definitions. Clinically relevant endpoints included major adverse cardiac events
AN
(MACE), AKI, blood loss, length of stay (LOS) in the intensive care unit (ICU), length of

hospital stay (LOHS) and mortality. Studies that only reported blood loss as relevant clinical
M

endpoint are described in table 2.

D

Cardiac surgery
TE

Eleven RCTs in cardiac surgery were identified with other primary clinically relevant

endpoints than postoperative bleeding (Supplemental table 2). In studies were HES was
EP

compared to a crystalloid solution, no differences were found in the length of stay in the ICU

or total length of hospital stay between groups.40,45,51,85-87. Among studies including HES and
C
AC

crystalloid fluid resuscitation, there was only one study reporting increased 24-hr blood loss

in the HES group compared to the crystalloid group.40 There were no indications of higher

rate of MACE or AKI in patients exposed to HES compared to crystalloid.40,45,51 In two

studies, distinct HES fluids were compared, reporting similar mortality rates between a

balanced and unbalanced HES88 and comparable length of hospital stay between HES

130/0.4 and HES 200/0.5.43 In a small study a comparison of 4% albumin with Ringer’s

lactate in the priming solution revealed no difference in length of ICU stay.89 Two studies

14
 ACCEPTED MANUSCRIPT
comparing a gelatin fluid with either Ringer’s lactate90 or HES 130/0.450 did not demonstrate

differences in atrial fibrillation rates or length of stay.

From the aforementioned studies, we cannot conclude that there is a difference in the

number of cardiovascular complications, AKI rates or length of hospital stay among fluid

resuscitation strategies. However, most studies included in this review have a small sample

PT
sizes based on power calculations using clinically irrelevant endpoints, and are rated as low-

quality studies with respect to their level of evidence.

RI
Renal transplantation

SC
Renal transplantation requires optimal hydration and perfusion of the kidney to ensure

normal function and prevent acute tubular necrosis. Crystalloid fluid therapy is the first

U
choice in renal transplantation procedures, but infusion of large volumes of normal saline is
AN
associated with development of hyperchloraemia. Three RCTs investigated the differences

in acid-base balance and rates of hyperchloraemia and hyperkalaemia between normal

M

saline or Ringer’s lactate during renal transplantation.17, 91, 92 Normal saline increases serum
D

chloride and potassium levels and alters base excess compared to Ringer’s lactate, while

Ringer’s lactate was associated with increased lactate levels, but without differences in
TE

creatinine clearance levels.17, 91

The number of patients requiring dialysis following renal

transplantation did not differ between normal saline and Ringer’s lactate groups rates.17, 91
EP

Three studies compared normal saline with Plasma-Lyte 148 or an alternative balanced

crystalloid in renal transplantation surgery.18, 91, 93, 94

C

Plasma-Lyte 148 fluid resuscitation

AC

resulted in maintenance of the acid-base balance and potassium levels, but without
18, 91, 93
differences in postoperative renal function or graft rejection among groups. In

addition, the use of 20% albumin as alterative of normal saline did not show any benefit

regarding graft function following surgery.95

All aforementioned studies were small in size, and larger RCTs are required to show

whether there is a benefit of a balanced crystalloid solution with respect to clinically relevant

outcome measures like renal function and graft rejection.

15
 ACCEPTED MANUSCRIPT
Neurosurgery

Maintenance of the plasma osmotic pressure during neurosurgical procedures could

contribute to reduced complications, including cerebral oedema and intracranial

hypertension. Consequently, neurosurgical procedures, which generally have a relatively

long duration, are preferably performed using isotonic crystalloid solutions that reduce the

PT
risk for hyperchloraemia and metabolic acidosis.12

Administration of a balanced crystalloid with colloid was associated with lower serum

RI
chloride levels and maintenance of acid-base balance compared to unbalanced crystalloid in

SC
combination with unbalanced colloid.96 A comparative study of isotonic and hypertonic HES

130/0.4 solutions in brain tumour surgery revealed reduced fluid load with lower dural

U
tension scores and better brain relaxation in the hypertonic group.97 Two RCTs in patients
AN
undergoing neurosurgery in the prone position showed that use of HES 130/0.4 resulted in

lower fluid requirements compared to Ringer’s acetate.42, 98

M

In patients with traumatic brain injury, special attention should be paid to the effect of

intravenous fluids on intracranial pressure. Hypertonic saline and mannitol are frequently
D

used to reduce intracranial pressure by increasing plasma osmotic and colloid osmotic
TE

pressures, respectively. A recent meta-analysis showed no difference in the effectiveness in

lowering intracranial pressure between hypertonic saline and mannitol, while hypertonic
EP

saline had fewer side-effects than mannitol.99,100 A subgroup of brain injured patients was

included in a post-hoc analysis of the SAFE trial, in which 4% albumin was compared with
C

normal saline in the intensive care setting, with less favourable outcome in patients
AC

resuscitated with albumin.101 This might be attributed to the effect of albumin crossing the

damaged blood-brain barrier, or to the hypo-osmolarity of 4% albumin (260-266 mOsmol kg-

1
), leading to increased intracranial pressure.102 Since most balanced crystalloids are hypo-

osmolar, they are not suitable for use in traumatic brain injury.103 The effect of albumin or

artificial colloids in isotonic fluids on outcome in traumatic brain injuryhas not been

investigated.

16
 ACCEPTED MANUSCRIPT
The number of studies focusing on intraoperative fluid therapy in neurosurgical procedures

is small, and none of the studies was designed to show differences in clinically relevant

endpoints. However, the abovementioned studies suggest that use of hypertonic fluids or

artificial colloids contributes to reduced fluid load and maintenance of cerebral physiology

during surgery.

PT
Major abdominal surgery

RI
Twelve studies in major abdominal surgery were identified, in which effects of intravenous

fluids were compared on clinically relevant outcomes (Supplemental table 3). Artificial

SC
colloids (HES and dextrans) were compared to crystalloids (both balanced and unbalanced)

in seven of the selected studies.25, 26, 29, 47, 48, 104, 105 In two studies, blood loss was increased

U
in the HES group compared to the crystalloid group, albeit that blood loss was only a primary
AN
endpoint in the cystectomy study.25, 47 The use of dextrans was associated with more major

blood loss (>1500 ml) compared to Ringer’s lactate.48

M

None of the studies detected a difference in cardiovascular or renal complications between

D

artificial colloids and crystalloid fluid resuscitation in major abdominal surgery. Length of ICU

stay was 2 hr longer in patients undergoing gastro-intestinal surgery with HES 70/0.5 versus
TE

Ringers acetate, which might be considered a clinically irrelevant difference.104 In a study

where HES 130/0.4 was compared to normal saline in cytoreductive ovarian cancer surgery,
EP

a trend towards increased 3-month mortality in the HES group was observed (n=5 vs. n=0,

respectively; P=0.051).105 However, all deaths were assessed as being unrelated to the
C
AC

study intervention before study subject unblinding.

Albumin 5% was compared to Ringer’s lactate in radical cystectomy and to HES 130/0.4

during liver transplantations.29, 49 Albumin did not lead to altered outcome in terms of blood

loss, AKI or length of hospital stay compared to Ringer’s lactate in either study.29, 49 In the

study focusing on renal function during liver transplantation, one out of 20 patients in both

HES and albumin groups required renal replacement therapy. Assessment of renal failure as

well as ICU and hospital stay and mortality was similar between groups.29

17
 ACCEPTED MANUSCRIPT
One study assessed the effects of Ringer’s lactate and normal saline in abdominal aortic

surgery.106 Normal saline led to increased incidence of hyperchloraemic acidosis and a trend

towards more blood loss, although this did not lead to an increased incidence of

cardiovascular or renal morbidity.106 Also a comparison of hypertonic saline with Ringer’s

lactate in pancreaticoduodenectomy did not reveal any differences in postoperative

PT
complications.107 In contrast, a comparison of Plasma-Lyte 148 and Ringer’s lactate in liver

resection surgery, with HES 130/0.4 as additional fluid, showed more blood loss in the

RI
Ringer’s lactate group (500 (300-638 vs. 300 (200-413) ml; P=0.03), but without reporting

other clinically relevant differences in outcome.34

SC
In conclusion, only blood loss might be increased by HES or dextran administration during

major abdominal surgery, but no other clinically relevant outcome parameters were affected

U
by intravenous fluid choice in major abdominal surgery. However, our conclusion should be
AN
handled cautious, since almost all existing studies were small and not powered to detect a

difference in clinical outcome.

M

Paediatric surgery
D

Fluid resuscitation with albumin solutions is still a preferred practice in major paediatric
TE

surgery. In particular, unbalanced synthetic colloids contribute to metabolic acidosis, as

shown in children of 0-12 years undergoing major surgery.108 In order to evaluate whether
EP

use of synthetic colloids is associated with adverse outcomes compared to albumin

C

solutions, four studies compared use of HES 130/0.4 with albumin for intraoperative volume

replacement therapy in children aging 5-46 months46, 3-15 months109, 0-2 years110 and 2-12
AC

years.111 All studies showed an equivalent efficacy for both colloid solutions, without

reporting differences in adverse effects.46, 109-111

Two studies reported that albumin was

associated with higher blood transfusion requirements.46, 109 A propensity-matched analysis

later confirmed that HES during paediatric cardiac surgery is as safe as albumin, probably

with less fluid accumulation.112 The effect of HES 70/0.5 Ringer’s lactate on haemoglobin

levels was further measured in infants and toddlers (1-38 months) undergoing urologic

18
 ACCEPTED MANUSCRIPT
surgery, showing that HES was a more effective volume expander than Ringer’s lactate,

without reporting a difference in adverse effects among groups.113

Unfortunately, the number of studies focusing on the choice of fluid type in children is small.

Current data suggest no superiority of one fluid over the other, but unbalanced fluids that

alter the acid-base balance in children should be avoided, while HES is considered as safe

PT
alternative for albumin.

Acute major bleeding

RI
Large volume resuscitation can contribute to prolonged bleeding in major traumatic bleeding

SC
or obstetric haemorrhage. In particular, the acidosis associated with unbalanced crystalloids

might further contribute to the lethal triad of coagulopathy during major bleeding.114 In the

U
prehospital treatment of traumatic hypovolaemic shock, two small studies showed that
AN
hypertonic fluid resuscitation does not improve outcome compared to other crystalloids, and

can even worsen coagulation status.115,116 In a propensity-matched analysis of women

M

receiving HES 130/0.4 or balanced crystalloids, no association was observed between HES

use and perioperative blood loss during caesarean delivery.117

D

The 4th edition of The European guideline on management of major bleeding and
TE

coagulopathy following trauma recommends that isotonic crystalloid solutions are the first

choice in fluid resuscitation in hypotensive trauma, and colloids should be avoided due to
EP

their adverse effects of haemostasis.118 However, the latter is mainly based on studies in
C

intensive care or septic patients, and novel RCTs are required to support the right choice of
AC

resuscitation fluids in acute traumatic bleeding.

19
 ACCEPTED MANUSCRIPT
CONCLUSIONS

Patient-tailored fluid management can contribute to improved outcomes in the perioperative

setting. The majority of studies in this field focus on goal-directed approaches, thereby

tailoring the need for volume to individual requirements.4, 5 83a

The choice of fluid type is of particular interest with the increasing number of reports

PT
showing higher rates of hyperchloraemia, hyperkalaemia and metabolic acidosis associated

with use of large volumes of normal saline, and the association of HES with bleeding

RI
disorders and renal complications in the critically ill. The unfavourable observations that

were attributed to HES in the critically ill were also of impact on the perioperative setting. In

SC
particular, in some institutions HES was replaced by gelatin or Ringer’s lactate, which

narrowed the available therapeutic strategies to treat perioperative hypovolaemia.

U
In the present review, we limitd the available evidence for choice of fluid type to the
AN
perioperative setting, and focused on relevant clinical endpoints including bleeding and

transfusion, AKI and length of hospital stay. From this analysis, we conclude that large
M

volumes of normal saline are associated with disturbance in the acid-base balance, which
D

can be detrimental in particular populations, including neurosurgery, acute major bleeding

TE

and children. Only a few studies included in this review report deleterious effects of HES on

the bleeding status of the patient, without revealing unfavourable effects on cardiac or renal
EP

function.

These findings should be considered in view of the low quality and small sample size of
C

most available studies. The publication of two ongoing RCTs focusing on clinically relevant
AC

endpoints in the perioperative setting119-121 may shed (some) light on our knowledge and

improve the available level of evidence regarding the efficacy and safety of different fluid

types in the surgical patient.

20
 ACCEPTED MANUSCRIPT

Author’s contributions

All authors (CB, SMB, NJ) contributed to the literature search, drafting and revising of the

article, final approval of the version to be published and agreed to be accountable for all

aspects of the work.

PT
Declaration of interests

RI
CB is member of the editorial board of the British Journal of Anaesthesia and has received

SC
honoraria for lectures for Medtronic and LivaNova. The other authors have no interests to

declare.

U
AN
Funding

This work was supported by the department of Anaesthesiology of VU University Medical

M

Centre, Amsterdam, the Netherlands.

D
TE
C EP
AC

21
 ACCEPTED MANUSCRIPT
REFERENCES

1. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid

restriction on postoperative complications: comparison of two perioperative fluid
regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003; 238: 641-
8
2. Bouwman RA, Boer C. Minimal invasive cardiac output monitoring: get the dose of

PT
fluid right. Br J Anaesth 2012; 109: 299-302
3. Reddy S, Weinberg L, Young P. Crystalloid fluid therapy. Crit Care 2016; 20: 59
4. Myles PS, Andrews S, Nicholson J, Lobo DN, Mythen M. Contemporary Approaches

RI
to Perioperative IV Fluid Therapy. World J Surg 2017
5. Doherty M, Buggy DJ. Intraoperative fluids: how much is too much? Br J Anaesth

SC
2012; 109: 69-79
6. Ringer S. Regarding the Action of Hydrate of Soda, Hydrate of Ammonia, and
Hydrate of Potash on the Ventricle of the Frog's Heart. J Physiol 1882; 3: 195-202.6
7.
U
Hartmann AF, Senn MJ. Studies in the metabolism of sodium r-lactate. I. Response
AN
of normal human subjects to the intravenous injection of sodium r-lactate. J Clin
Invest 1932; 11: 327-35
8. Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr 2008; 27: 179-88
M

9. Van Regenmortel N, De Weerdt T, Van Craenenbroeck AH, et al. Effect of isotonic

versus hypotonic maintenance fluid therapy on urine output, fluid balance, and
D

electrolyte homeostasis: a crossover study in fasting adult volunteers. Br J Anaesth

TE

2017; 118: 892-900

10. Orbegozo Cortes D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a
structured review of the literature. Br J Anaesth 2014; 112: 968-81
EP

11. Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-
analysis of high- versus low-chloride content in perioperative and critical care fluid
C

resuscitation. Br J Surg 2015; 102: 24-36

12. McCluskey SA, Karkouti K, Wijeysundera D, Minkovich L, Tait G, Beattie WS.
AC

Hyperchloremia after noncardiac surgery is independently associated with increased

morbidity and mortality: a propensity-matched cohort study. Anesth Analg 2013; 117:
412-21
13. Sadan O, Singbartl K, Kandiah PA, Martin KS, Samuels OB. Hyperchloremia Is
Associated With Acute Kidney Injury in Patients With Subarachnoid Hemorrhage. Crit
Care Med 2017; 45: 1382-8

22
 ACCEPTED MANUSCRIPT
14. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and
resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-
Lyte. Ann Surg 2012; 255: 821-9
15. Disma N, Mameli L, Pistorio A, et al. A novel balanced isotonic sodium solution vs
normal saline during major surgery in children up to 36 months: a multicenter RCT.
Paed Anaesth 2014; 24: 980-6
16. Young P, Bailey M, Beasley R, et al. Effect of a Buffered Crystalloid Solution vs

PT
Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT
Randomized Clinical Trial. JAMA 2015; 314: 1701-10

RI
17. O'Malley CM, Frumento RJ, Hardy MA, et al. A randomized, double-blind comparison
of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesth

SC
Analg 2005; 100: 1518-24
18. Weinberg L, Harris L, Bellomo R, et al. Effects of intraoperative and early
postoperative normal saline or Plasma-Lyte 148® on hyperkalaemia in deceased

U
donor renal transplantation: a double-blind randomized trial. Br J Anaesth 2017
AN
[update citation]
19. Lancaster TS, Schill MR, Greenberg JW, et al. Potassium and Magnesium
Supplementation Do Not Protect Against Atrial Fibrillation After Cardiac Operation: A
M

Time-Matched Analysis. Ann Thorac Surg 2016; 102: 1181-8

20. Zazzeron L, Gattinoni L, Caironi P. Role of albumin, starches and gelatins versus
D

crystalloids in volume resuscitation of critically ill patients. Curr Op Crit Care 2016;
22: 428-36
TE

20a.
BJA-2017-01163- Intravenous Fluids and Their Effects on Renal Outcomes] BJA in this issue; update
HH407.R2 citation; renumber references accordingly
EP

21. Meybohm P, Van Aken H, De Gasperi A, et al. Re-evaluating currently available data
C

and suggestions for planning randomised controlled studies regarding the use of
hydroxyethyl starch in critically ill patients - a multidisciplinary statement. Crit Care
AC

2013; 17: R166

22. Raiman M, Mitchell CG, Biccard BM, Rodseth RN. Comparison of hydroxyethyl
starch colloids with crystalloids for surgical patients: A systematic review and meta-
analysis. Eur J Anaesth 2016; 33: 42-8
23. Gillies MA, Habicher M, Jhanji S, et al. Incidence of postoperative death and acute
kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and
meta-analysis. Br J Anaesth 2014; 112: 25-34

23
 ACCEPTED MANUSCRIPT
24. Kancir AS, Pleckaitiene L, Hansen TB, Ekelof NP, Pedersen EB. Lack of
nephrotoxicity by 6% hydroxyethyl starch 130/0.4 during hip arthroplasty: a
randomized controlled trial. Anesthesiology 2014; 121: 948-58
25. Kancir AS, Johansen JK, Ekeloef NP, Pedersen EB. The effect of 6% hydroxyethyl
starch 130/0.4 on renal function, arterial blood pressure, and vasoactive hormones
during radical prostatectomy: a randomized controlled trial. Anesth Analg 2015; 120:
608-18

PT
26. Yates DR, Davies SJ, Milner HE, Wilson RJ. Crystalloid or colloid for goal-directed
fluid therapy in colorectal surgery. Br J Anaesth 2014; 112: 281-9

RI
27. Godet G, Lehot JJ, Janvier G, Steib A, De Castro V, Coriat P. Safety of HES 130/0.4
(Voluven(R)) in patients with preoperative renal dysfunction undergoing abdominal

SC
aortic surgery: a prospective, randomized, controlled, parallel-group multicentre trial.
Eur J Anaesth 2008; 25: 986-94
28. Mahmood A, Gosling P, Vohra RK. Randomized clinical trial comparing the effects on

U
renal function of hydroxyethyl starch or gelatine during aortic aneurysm surgery. The
AN
Br J Surg 2007; 94: 427-33
29. Mukhtar A, Aboulfetouh F, Obayah G, et al. The safety of modern hydroxyethyl
starch in living donor liver transplantation: a comparison with human albumin. Anesth
M

Analg 2009; 109: 924-30

30. Demir A, Aydinli B, Toprak HI, et al. Impact of 6% Starch 130/0.4 and 4% Gelatin
D

Infusion on Kidney Function in Living-Donor Liver Transplantation. Transpl Proc

2015; 47: 1883-9
TE

31. Fenger-Eriksen C, Tonnesen E, Ingerslev J, Sorensen B. Mechanisms of

hydroxyethyl starch-induced dilutional coagulopathy. J Thromb Haemost 2009; 7:
EP

1099-105
32. Niemi TT, Kuitunen AH. Artificial colloids impair haemostasis. An in vitro study using
thromboelastometry coagulation analysis. Acta Anaesth Scand 2005; 49: 373-8
C

33. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically

AC

balanced plasma expander for large volume use in major surgery: a randomized
phase III clinical trial. Hextend Study Group. Anesth Analg 1999; 88: 992-8
34. Weinberg L, Pearce B, Sullivan R, et al. The effects of plasmalyte-148 vs.
Hartmann's solution during major liver resection: a multicentre, double-blind,
randomized controlled trial. Minerva Anest 2015; 81: 1288-97
35. Gandhi SD, Weiskopf RB, Jungheinrich C, et al. Volume replacement therapy during
major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch.
Anesthesiology 2007; 106: 1120-7

24
 ACCEPTED MANUSCRIPT
36. Helmy A, Mukhtar A, Ahmed A, Sief NE, Hussein A. The intraoperative therapeutic
equivalence of balanced vs saline-based 6% hydroxyethyl starch 130/0.4 and their
influence on perioperative acid-base status and renal functions. J Clin Anesth 2016;
32: 267-73
37. Mercier FJ, Diemunsch P, Ducloy-Bouthors AS, et al. 6% Hydroxyethyl starch
(130/0.4) vs Ringer's lactate preloading before spinal anaesthesia for Caesarean
delivery: the randomized, double-blind, multicentre CAESAR trial. Br J Anaesth 2014;

PT
113: 459-67
38. Ahn HJ, Yang M, Gwak MS, et al. Coagulation and biochemical effects of balanced

RI
salt-based high molecular weight vs saline-based low molecular weight hydroxyethyl
starch solutions during the anhepatic period of liver transplantation. Anaesthesia

SC
2008; 63: 235-42
39. Martin G, Bennett-Guerrero E, Wakeling H, et al. A prospective, randomized
comparison of thromboelastographic coagulation profile in patients receiving lactated

U
Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in
AN
saline during major surgery. J Cardiothorac Vasc Anesth 2002; 16: 441-6
40. Kim TK, Nam K, Cho YJ, et al. Microvascular reactivity and endothelial glycocalyx
degradation when administering hydroxyethyl starch or crystalloid during off-pump
M

coronary artery bypass graft surgery: a randomised trial. Anaesthesia 2017; 72: 204-
13
D

41. Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T.

Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac
TE

surgery: a prospective randomized trial. Br J Anaesth 2010; 104: 691-7

42. Lindroos AC, Niiya T, Randell T, Niemi TT. Stroke volume-directed administration of
EP

hydroxyethyl starch (HES 130/0.4) and Ringer's acetate in prone position during
neurosurgery: a randomized controlled trial. J Anesth 2014; 28: 189-97
43. Kasper SM, Meinert P, Kampe S, et al. Large-dose hydroxyethyl starch 130/0.4 does
C

not increase blood loss and transfusion requirements in coronary artery bypass
AC

surgery compared with hydroxyethyl starch 200/0.5 at recommended doses.

Anesthesiology 2003; 99: 42-7
44. Kimenai DM, Bastianen GW, Daane CR, et al. Effect of the colloids gelatin and HES
130/0.4 on blood coagulation in cardiac surgery patients: a randomized controlled
trial. Perfusion 2013; 28: 512-9
45. Skhirtladze K, Base EM, Lassnigg A, et al. 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

25
 ACCEPTED MANUSCRIPT
46. Hanart C, Khalife M, De Ville A, Otte F, De Hert S, Van der Linden P. Perioperative
volume replacement in children undergoing cardiac surgery: albumin versus
hydroxyethyl starch 130/0.4. Crit Care Med 2009; 37: 696-701
47. Rasmussen KC, Johansson PI, Hojskov M, et al. Hydroxyethyl starch reduces
coagulation competence and increases blood loss during major surgery: results from
a randomized controlled trial. Ann Surg 2014; 259: 249-54
48. Rasmussen KC, Hoejskov M, Johansson PI, et al. Coagulation competence for

PT
predicting perioperative hemorrhage in patients treated with lactated Ringer's vs.
Dextran--a randomized controlled trial. BMC Anesth 2015; 15: 178

RI
49. Rasmussen KC, Hojskov M, Johansson PI, et al. Impact of Albumin on Coagulation
Competence and Hemorrhage During Major Surgery: A Randomized Controlled Trial.

SC
Medicine 2016; 95: e2720
50. Van der Linden PJ, De Hert SG, Deraedt D, et al. Hydroxyethyl starch 130/0.4 versus
modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on

U
perioperative bleeding and transfusion needs. Anesth Analg 2005; 101: 629-34, table
AN
of contents
51. Lee JS, Ahn SW, Song JW, Shim JK, Yoo KJ, Kwak YL. Effect of hydroxyethyl starch
130/0.4 on blood loss and coagulation in patients with recent exposure to dual
M

antiplatelet therapy undergoing off-pump coronary artery bypass graft surgery.

Circulation J 2011; 75: 2397-402
D

52. Bethlehem I, Wierda K, Visser C, Jekel L, Koopmans M, Kuiper MA. Influence of Two
Colloidal Extracorporeal Primes on Coagulation of Cardiac Surgical Patients: A
TE

Prospectively Randomized Open-Label Pilot Trial. J Extracorp Techn 2014; 46: 293-9
53. Cho JE, Shim JK, Song JW, Lee HW, Kim DH, Kwak YL. Effect of 6% hydroxyethyl
EP

starch 130/0.4 as a priming solution on coagulation and inflammation following

complex heart surgery. Yonsei Med J 2014; 55: 625-34
54. Kuitunen AH, Hynynen MJ, Vahtera E, Salmenpera MT. Hydroxyethyl starch as a
C

priming solution for cardiopulmonary bypass impairs hemostasis after cardiac

AC

surgery. Anesth Analg 2004; 98: 291-7, table of contents

55. Schramko A, Suojaranta-Ylinen R, Niemi T, et al. The use of balanced HES 130/0.42
during complex cardiac surgery; effect on blood coagulation and fluid balance: a
randomized controlled trial. Perfusion 2015; 30: 224-32
56. Villela NR, Salazar Vazquez BY, Intaglietta M. Microcirculatory effects of intravenous
fluids in critical illness: plasma expansion beyond crystalloids and colloids. Curr Op
Anesth 2009; 22: 163-7
57. Chen G, Zhao J, Li P, et al. Effects of synthetic colloid and crystalloid solutions on
hemorheology in vitro and in hemorrhagic shock. Eur J Med Res 2015; 20: 13

26
 ACCEPTED MANUSCRIPT
58. Paut O, Bissonnette B. Effects of temperature and haematocrit on the relationships
between blood flow velocity and blood flow in a vessel of fixed diameter. Br J
Anaesth 2002; 88: 277-9
59. Cabrales P, Tsai AG, Intaglietta M. Microvascular pressure and functional capillary
density in extreme hemodilution with low- and high-viscosity dextran and a low-
viscosity Hb-based O2 carrier. Am J Physiol Heart Circ Physiol 2004; 287: H363-73
60. Cabrales P, Tsai AG, Intaglietta M. Increased plasma viscosity prolongs

PT
microhemodynamic conditions during small volume resuscitation from hemorrhagic
shock. Resuscitation 2008; 77: 379-86

RI
61. Cabrales P, Nacharaju P, Manjula BN, Tsai AG, Acharya SA, Intaglietta M. Early
difference in tissue pH and microvascular hemodynamics in hemorrhagic shock

SC
resuscitation using polyethylene glycol-albumin- and hydroxyethyl starch-based
plasma expanders. Shock 2005; 24: 66-73
62. Wettstein R, Tsai AG, Erni D, Winslow RM, Intaglietta M. Resuscitation with

U
polyethylene glycol-modified human hemoglobin improves microcirculatory blood flow
AN
and tissue oxygenation after hemorrhagic shock in awake hamsters. Crit Care Med
2003; 31: 1824-30
63. Naumann DN, Beaven A, Dretzke J, Hutchings S, Midwinter MJ. Searching For the
M

Optimal Fluid to Restore Microcirculatory Flow Dynamics After Haemorrhagic Shock:

A Systematic Review of Preclinical Studies. Shock 2016; 46: 609-22
D

64. Atasever B, van der Kuil M, Boer C, et al. Red blood cell transfusion compared with
gelatin solution and no infusion after cardiac surgery: effect on microvascular
TE

perfusion, vascular density, hemoglobin, and oxygen saturation. Transfusion 2012;

52: 2452-8
EP

65. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial
glycocalyx: composition, functions, and visualization. Pflugers Archiv Eur J Physiol
2007; 454: 345-59
C

66. Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of the
AC

endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin

Pharmacol 2015; 80: 389-402
67. Nelson A, Statkevicius S, Schott U, Johansson PI, Bentzer P. Effects of fresh frozen
plasma, Ringer's acetate and albumin on plasma volume and on circulating
glycocalyx components following haemorrhagic shock in rats. Intens Care Med Exp
2016; 4: 6
68. Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects
of colloid and crystalloid resuscitation fluids on cardiac vascular permeability.
Anesthesiology 2006; 104: 1223-31

27
 ACCEPTED MANUSCRIPT
69. Torres Filho IP, Torres LN, Salgado C, Dubick MA. Plasma syndecan-1 and heparan
sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after
different resuscitation fluids. Am J Physiol Heart Circ Physiol 2016; 310: H1468-78
70. Zausig YA, Chappell D, Becker BF, et al. The impact of crystalloidal and colloidal
infusion preparations on coronary vascular integrity, interstitial oedema and cardiac
performance in isolated hearts. Crit Care 2013; 17: R203
71. Powell M, Mathru M, Brandon A, Patel R, Frolich M. Assessment of endothelial

PT
glycocalyx disruption in term parturients receiving a fluid bolus before spinal
anesthesia: a prospective observational study. Int J Obstet Anesth 2014; 23: 330-4

RI
72. Starling EH. On the Absorption of Fluids from the Connective Tissue Spaces. J
Physiol 1896; 19: 312-26

SC
73. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling
principle. Cardiovasc Res 2010; 87: 198-210
74. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of

U
transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid
AN
therapy. Br J Anaesth 2012; 108: 384-94
75. Rackow EC, Fein IA, Leppo J. Colloid osmotic pressure as a prognostic indicator of
pulmonary edema and mortality in the critically ill. Chest 1977; 72: 709-13
M

76. de Crescenzo C, Gorouhi F, Salcedo ES, Galante JM. Prehospital hypertonic fluid
resuscitation for trauma patients: A systematic review and meta-analysis. J Trauma
D

Acute Care Surg 2017; 82: 956-62

77. Chappell D, Jacob M. Role of the glycocalyx in fluid management: Small things
TE

matter. Best Pract Res Clin Anaesth 2014; 28: 227-34

78. Rehm M, Orth V, Kreimeier U, et al. Changes in intravascular volume during acute
EP

normovolemic hemodilution and intraoperative retransfusion in patients with radical

hysterectomy. Anesthesiology 2000; 92: 657-64
79. Chappell D, Bruegger D, Potzel J, et al. Hypervolemia increases release of atrial
C

natriuretic peptide and shedding of the endothelial glycocalyx. Crit Care 2014; 18:
AC

538
80. Jacob M, Chappell D, Hofmann-Kiefer K, et al. The intravascular volume effect of
Ringer's lactate is below 20%: a prospective study in humans. Crit Care 2012; 16:
R86
81. Riddez L, Hahn RG, Brismar B, Strandberg A, Svensen C, Hedenstierna G. Central
and regional hemodynamics during acute hypovolemia and volume substitution in
volunteers. Crit Care Med 1997; 25: 635-40

28
 ACCEPTED MANUSCRIPT
82. Jacob M, Rehm M, Orth V, et al. Exact measurement of the volume effect of 6%
hydoxyethyl starch 130/0.4 (Voluven) during acute preoperative normovolemic
hemodilution]. Anaesthesist 2003; 52: 896-904
83. Pearse RM, Harrison DA, MacDonald N, et al. Effect of a perioperative, cardiac
output-guided hemodynamic therapy algorithm on outcomes following major
gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA
2014; 311: 2181-90

PT
83a

RI
84. A
n

SC
n
a BJA-2017-01166-HH419.R1
n

U
e
AN
D
, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on
M

mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL
randomized trial. JAMA 2013; 310: 1809-17
D

85. Iriz E, Kolbakir F, Akar H, Adam B, Keceligil HT. Comparison of hydroxyethyl starch
and ringer lactate as a prime solution regarding S-100beta protein levels and
TE

informative cognitive tests in cerebral injury. Ann Thorac Surg 2005; 79: 666-71
86. Sirvinskas E, Sneider E, Svagzdiene M, et al. Hypertonic hydroxyethyl starch solution
EP

for hypovolaemia correction following heart surgery. Perfusion 2007; 22: 121-7
87. Tiryakioglu O, Yildiz G, Vural H, Goncu T, Ozyazicioglu A, Yavuz S. Hydroxyethyl
starch versus Ringer solution in cardiopulmonary bypass prime solutions (a
C

randomized controlled trial). J Cardiothor Surg 2008; 3: 45

AC

88. Base EM, Standl T, Lassnigg A, et al. Efficacy and safety of hydroxyethyl starch 6%
130/0.4 in a balanced electrolyte solution (Volulyte) during cardiac surgery. J
Cardiothorac Vasc Anesth 2011; 25: 407-14
89. Rex S, Scholz M, Weyland A, Busch T, Schorn B, Buhre W. Intra- and extravascular
volume status in patients undergoing mitral valve replacement: crystalloid vs. colloid
priming of cardiopulmonary bypass. Eur J Anaesth 2006; 23: 1-9
90. Tamayo E, Alvarez FJ, Alonso O, et al. The inflammatory response to colloids and
crystalloids used for pump priming during cardiopulmonary bypass. Acta Anaesth
Scand 2008; 52: 1204-12

29
 ACCEPTED MANUSCRIPT
91. Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different
crystalloid solutions on acid-base balance and early kidney function after kidney
transplantation. Anesth Analg 2008; 107: 264-9
92. Khajavi MR, Etezadi F, Moharari RS, et al. Effects of normal saline vs. lactated
ringer's during renal transplantation. Ren Fail 2008; 30: 535-9
93. Kim SY, Huh KH, Lee JR, Kim SH, Jeong SH, Choi YS. Comparison of the effects of
normal saline versus Plasmalyte on acid-base balance during living donor kidney

PT
transplantation using the Stewart and base excess methods. Transplantation
proceedings 2013; 45: 2191-6

RI
94. Potura E, Lindner G, Biesenbach P, et al. An acetate-buffered balanced crystalloid
versus 0.9% saline in patients with end-stage renal disease undergoing cadaveric

SC
renal transplantation: a prospective randomized controlled trial. Anesth Analg 2015;
120: 123-9
95. Abdallah E, El-Shishtawy S, Mosbah O, Zeidan M. Comparison between the effects

U
of intraoperative human albumin and normal saline on early graft function in renal
AN
transplantation. Int Urol Nephrol 2014; 46: 2221-6
96. Hafizah M, Liu CY, Ooi JS. Normal saline versus balanced-salt solution as
intravenous fluid therapy during neurosurgery: effects on acid-base balance and
M

electrolytes. J Neurosurg Sci 2017; 61: 263-70

97. Shao L, Wang B, Wang S, Mu F, Gu K. Comparison of 7.2% hypertonic saline - 6%
D

hydroxyethyl starch solution and 6% hydroxyethyl starch solution after the induction
of anesthesia in patients undergoing elective neurosurgical procedures. Clinics 2013;
TE

68: 323-8
98. Lindroos AC, Niiya T, Silvasti-Lundell M, Randell T, Hernesniemi J, Niemi TT. Stroke
EP

volume-directed administration of hydroxyethyl starch or Ringer's acetate in sitting

position during craniotomy. Acta Anaesth Scand 2013; 57: 729-36
99. Rickard AC, Smith JE, Newell P, Bailey A, Kehoe A, Mann C. Salt or sugar for your
C

injured brain? A meta-analysis of randomised controlled trials of mannitol versus

AC

hypertonic sodium solutions to manage raised intracranial pressure in traumatic brain

injury. Emerg Med J 2014; 31: 679-83
100. Gantner D, Moore EM, Cooper DJ. Intravenous fluids in traumatic brain injury: what's
the solution? Curr Op Crit Care 2014; 20: 385-9
101. Myburgh J, Cooper DJ, Finfer S, et al. Saline or albumin for fluid resuscitation in
patients with traumatic brain injury. New Engl J Med 2007; 357: 874-84
102. Van Aken HK, Kampmeier TG, Ertmer C, Westphal M. Fluid resuscitation in patients
with traumatic brain injury: what is a SAFE approach? Curr Op Anaesth 2012; 25:
563-5

30
 ACCEPTED MANUSCRIPT
103. Ertmer C, Van Aken H. Fluid therapy in patients with brain injury: what does
physiology tell us? Crit Care 2014; 18: 119
104. Ando Y, Terao Y, Fukusaki M, et al. Influence of low-molecular-weight hydroxyethyl
starch on microvascular permeability in patients undergoing abdominal surgery:
comparison with crystalloid. J Anesth 2008; 22: 391-6
105. Feldheiser A, Pavlova V, Bonomo T, et al. Balanced crystalloid compared with
balanced colloid solution using a goal-directed haemodynamic algorithm. Br J

PT
Anaesth 2013; 110: 231-40
106. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal

RI
saline versus lactated Ringer's solution for intraoperative fluid management in
patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth

SC
Analg 2001; 93: 817-22
107. Lavu H, Sell NM, Carter TI, et al. The HYSLAR trial: a prospective randomized
controlled trial of the use of a restrictive fluid regimen with 3% hypertonic saline

U
versus lactated Ringers in patients undergoing pancreaticoduodenectomy. Ann Surg
AN
2014; 260: 445-53
108. Witt L, Osthaus WA, Juttner B, Heimbucher C, Sumpelmann R. Alteration of anion
gap and strong ion difference caused by hydroxyethyl starch 6% (130/0.42) and
M

gelatin 4% in children. Paed Anaesth 2008; 18: 934-9

109. Miao N, Yang J, Du Z, et al. Comparison of low molecular weight hydroxyethyl starch
D

and human albumin as priming solutions in children undergoing cardiac surgery.

Perfusion 2014; 29: 462-8
TE

110. Standl T, Lochbuehler H, Galli C, Reich A, Dietrich G, Hagemann H. HES 130/0.4

(Voluven) or human albumin in children younger than 2 yr undergoing non-cardiac
EP

surgery. A prospective, randomized, open label, multicentre trial. Eur J Anaesth

2008; 25: 437-45
111. Van der Linden P, De Ville A, Hofer A, Heschl M, Gombotz H. Six percent
C

hydroxyethyl starch 130/0.4 (Voluven(R)) versus 5% human serum albumin for

AC

volume replacement therapy during elective open-heart surgery in pediatric patients.

Anesthesiology 2013; 119: 1296-309
112. Van der Linden P, Dumoulin M, Van Lerberghe C, Torres CS, Willems A, Faraoni D.
Efficacy and safety of 6% hydroxyethyl starch 130/0.4 (Voluven) for perioperative
volume replacement in children undergoing cardiac surgery: a propensity-matched
analysis. Crit Care 2015; 19: 87
113. Paul M, Dueck M, Joachim Herrmann H, Holzki J. A randomized, controlled study of
fluid management in infants and toddlers during surgery: hydroxyethyl starch 6%
(HES 70/0.5) vs lactated Ringer's solution. Paed Anaesth 2003; 13: 603-8

31
 ACCEPTED MANUSCRIPT
114. Ross SW, Christmas AB, Fischer PE, et al. Impact of common crystalloid solutions
on resuscitation markers following Class I hemorrhage: A randomized control trial. J
Trauma Acute Care Surg 2015; 79: 732-40
115. Delano MJ, Rizoli SB, Rhind SG, et al. Prehospital Resuscitation of Traumatic
Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and
Hyperfibrinolysis. Shock 2015; 44: 25-31
116. Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after

PT
traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg 2011;
253: 431-41

RI
117. Terkawi AS, Larkin SK, Tsang S, Sheeran JS, Tiouririne M. Effects of hydroxyethyl
starch 6 % (130/0.4) on blood loss during cesarean delivery: a propensity-matched

SC
analysis. J Anesth 2016; 30: 796-802
118. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of
major bleeding and coagulopathy following trauma: fourth edition. Crit Care 2016; 20:

U
100
AN
119. Futier E, Biais M, Godet T, et al. Fluid loading in abdominal surgery - saline versus
hydroxyethyl starch (FLASH Trial): study protocol for a randomized controlled trial.
Trials 2015; 16: 582
M

120. Kammerer T, Klug F, Schwarz M, et al. Comparison of 6% hydroxyethyl starch and

5% albumin for volume replacement therapy in patients undergoing cystectomy
D

(CHART): study protocol for a randomized controlled trial. Trials 2015; 16: 384
121. Loffel LM, Burkhard FC, Takala J, Wuethrich PY. Impact of a Potassium-enriched,
TE

Chloride-depleted 5% Glucose Solution on Gastrointestinal Function after Major

Abdominopelvic Surgery: Results of a Randomized Controlled Trial. Anesthesiology
EP

2016; 125: 678-89

C
AC

32
 ACCEPTED MANUSCRIPT
Figure legends

Figure 1. Schematic representation of the Fåhraeus-Lindquist effect in the microcirculation.

Figure 2. Schematic representation of the classical and revised Starling equations. Pc =

PT
capillary blood pressure; Pi = interstitial pressure; Πp = plasma colloid osmotic pressure; Πi

= interstitial colloid osmotic pressure; Πg = sub-glycocalyx colloid osmotic pressure.

RI
U SC
AN
M
D
TE
C EP
AC

33
 ACCEPTED MANUSCRIPT

Table 1: Overview of crystalloid and colloid fluids commonly used in the perioperative setting.

Main components Na+ Cl- K+ Osmolarity pH

(mmol l-1) (mmol l-1) (mmol l-1) (mOsm l-1)

PT
Crystalloids
Normal saline Na+, Cl- 154 154 0 308 4.5-7.0

RI
Ringer’s lactate Na+, Cl-, K+. lactate 130 109 4 273 6.0-7.5
Na+, Cl-, K+, acetate

SC
Ringer’s acetate 130 112 5 276 6.0-8.0
Plasma-lyte 148 Na+, Cl-, K+, acetate 140 98 5 294 6.5-8.0

U
5% Dextrose Dextrose 0 0 0 278 3.5-5.5

AN
Colloids
HES

M
6% 670/0.75 Na+, Cl-, poly(O-2-HE) starch (hetastarch) 154 154 0 308 3.5-7.0
6% 200/0.50 Na+, Cl-, poly(O-2-HE) starch (pentastarch) 154 154 0 326 5.0

D
6% 130/0.40 Na+, Cl-, poly(O-2-HE) starch (Voluven®) 154 154 0 308 4.0-5.5

TE
Gelatin Na+, Cl-, gelatin 154 120 0 274 7.1-7.7
5% Albumin Na+, Cl-, albumin 130-160 130-160 <2 309 6.4-7.4
EP
Hyperhaes® Na+, Cl-, poly(O-2-HE) starch 1232 1232 0 2464 3.5-6.0
Balanced HES 287 5.7-6.5
C

6% 670/0.75 Na+, Cl-, poly(O-2-HE) starch, lactate (Hextend®) 143 124 3 308 5.9
AC

6% 130/0.42 Na+, Cl-, poly(O-2-HE) starch, acetate (Tetraspan®) 140 118 4 297 5.6-6.4
6% 130/0.42 Na+, Cl-, poly(O-2-HE) starch, acetate (Volulyte®) 137 110 4 287 5.7-6.5
HE: Hydroxylethyl; HES: Hydroxylethyl starch. Electrolyte concentrations, osmolarity and pH may be subject to small differences with other
reports.
 ACCEPTED MANUSCRIPT

Table 2: Overview of randomised controlled studies with perioperative blood loss as primary endpoint

Author Fluids compared Procedure In vitro parameters Clinical Parameters Conclusion

(during/end of surgery)

PT
Primary endpoint: Perioperative blood loss
46
Hanart 1: 4% albumin Paediatric aPTT (s): 44 (41-49) vs. 44 (40-52) 24-hr blood loss (ml): 53 (36-74) vs. No difference in 24-

RI
2009 2: HES 130/0.4 cardiac surgery PT (%): 60 (52-65) vs. 55 (50-64) 53 (34-73) hour blood loss
-1
(n=100) Fibrinogen (mg dl ): 160 (138-185) Total transfusion rate: 78% vs. 57%; between 4% albumin
vs. 144 (120-165) P=0.0188) and HES 130/0.4.
9 -1
Platelets (x 10 l ): 171 (136-205)

SC
vs. 151 (111-183)
43 -1
Kasper 1: HES 130/0.4 (<50 ml kg ) CABG aPTT (s): 65 ± 29 vs. 69 ± 27 24-hr blood loss: 660 (380–1440) vs. No difference in 24-
-1
2003 2: HES 200/0.5 (<30 ml kg ) (n=120) PT (INR): 1.2 ± 1.0 vs. 1.2 ± 1.0 705 (330-1750) ml, P=0.60 hour blood loss

U
-1
(+ Gelatin*) Fibrinogen (g l ): 2.3 ± 0.8 vs. 2.2 ± 24-hr PRBC transfusion: 0 (0-3) vs. 0 between HES 130/0.4
0.8 (0-4) units; P=0.17 and HES 200/0.5.

AN
9 -1
Platelets (x 10 l ): 139 ± 43 vs. 127
± 39
44 -1
Kimenai 1: HES 130/0.4 (<50 ml kg ) CABG EXTEM MCF (mm): 61 ± 5 vs. 61 ± 24-hr blood loss: 500 ± 420 vs. 465 ± No difference in 24-
2013 2: Gelatin (n=60) 6 (P=0.47) 390 ml; P =0.48 hour blood loss

M
(+ Saline or Ringer’s lactate*) FIBTEM MCF (mm): 12 ± 5 vs. 11 ± between HES 130/0.4
3 (P=0.93) and gelatin.

D
51
Lee 1: Balanced crystalloid CABG TEG R (min): 22.6 ± 15.6 vs. 28.4 ± 24-hr blood loss: 810±322 vs. No difference in 24-
-1
2011 2: HES 130/0.4 (<30 ml kg ) (n=106) 19.8; P=0.163 753±313; P=0.353 hour blood loss

TE
(+ Balanced crystalloid) TEG MA (mm): 43.6 ± 10.4 vs. 40.0 24-hr PRBC transfusion: 0.9 ± 1.0 vs. between a balanced
± 10.8; P=0.147 0.6 ± 1.1; 0.508 crystalloid and HES
130/0.4.
47 -1
Rasmussen 1: HES 130/0.4 (35 ml kg ) Cystectomy TEG MA (mm): 52.1 ± 7.5 vs. 63.6 ± Blood loss (ml): 2181 ± 1190 vs. 1370 More blood loss in
EP
-1
2014 2: Ringer’s lactate (35 ml kg ) (n=33) 5.3; P=0.001 ± 603; P=0.038 the HES 130/0.4
-1
Fibrinogen (micromol l ): 5.09 ± PRBC transfusion (ml): 286 ± 380 vs. group compared to
1.79 vs. 7.68 ± 2.11; P=0.001 62 ± 169; P=0.041 the Ringer’s lactate
C

9 -1
Platelets (x 10 l ): 154 ± 31 vs. 217 group.
± 49; P=0.02
AC

48 -1
Rasmussen 1: Dextran 70 (25 ml kg ) Cystectomy TEG MA (mm): 48.9 (44.6-53.2) vs. Blood loss (ml): 2339 ± 1470 vs. 1822 No difference in blood
2015 2: Ringer’s lactate (n=37) 62.1 (58.9-65.3); P=0.001 ± 1240; P=0.27 loss between Dextran
PRBC transfusion (ml): 597 ± 613 vs. 70 and Ringer’s
313 ± 545; P=0.14 lactate.
49 -1
Rasmussen 1: 5% Albumin (25 ml kg ) Cystectomy TEG MA (mm): 60 ± 7 vs. 68 ± 6); Blood loss (ml): 1658 (800–3300) vs. No difference in blood
2016 2: Ringer’s lactate (n=39) P<0.002 1472 (700–4330); P=0.45 loss between 5%
PRBC transfusion (ml): 235 (0-980) albumin and Ringer’s
vs. 80 (0-1100); P=0.14 lactate.

35
 ACCEPTED MANUSCRIPT

45 -1
Skhirtladze 1: 5% albumin (<50 ml kg ) Cardiac surgery FIBTEM MCF (mm): 10 (9-13) vs. 7 24- hr blood loss (ml): 835 (545-1253) No difference in 24-
-1
2014 2: HES 130/0.4 (<50 ml kg ) N=240 (6-10) vs. 13 (11-17); P<0.0001 vs. 700 (540-1090) vs. 670 (455- hour blood loss
-1
3: Ringer’s lactate (<50 ml kg ) 1015); P=0.085 between 5% albumin,
(+ Ringer’s lactate*) PRBC transfusion rate: 58% vs. 61% HES 130/0.4 and
vs. 34%; P=0.0013 Ringer’s lactate.

PT
-1 -1
Van der 1: HES 130/0.4 (<50 ml kg ) CABG Unavailable Total blood loss (ml kg ): 19.4 ± 12.3 No difference in blood
50 -1
Linden 2: Gelatin (<50 ml kg ) (n=132) vs. 19.2 ± 14.5 loss between HES
2005 (+ Plasma-Lyte 148*) Total PRBC transfusion: 0 (0-6) vs. 0 130/0.4 and gelatin.

RI
(0-6) units
aPTT = activated partial thromboplastin time; CABG = coronary artery bypass graft surgery; CT = clotting time; HES = hydroxyethyl starch; INR =
international normalized ratio; MA = maximum amplitude; MCF = maximum clot firmness; PT = prothrombin time; TEG = thromboelastography; TEM =

SC
thromboelastometry. * maintenance fluid

U
AN
M
D
TE
C EP
AC

36
 ACCEPTED MANUSCRIPT

Supplemental table 1: Overview of randomised controlled studies with coagulation or metabolic parameters as primary endpoint

Author Fluids compared Procedure In vitro parameters Clinical Parameters

(during/end of surgery)

PT
Primary endpoint: Coagulation or metabolic parameters
38
Ahn 1: HES 670/0.75 (500 ml) Liver transplant TEG R (min): 28.7 ± 14.7 vs. 26.6 ± 10.8 Unavailable

RI
2008 2: HES 130/0.4 (500 ml) (n=74) TEG MA (mm): 32.6 ± 8.8 vs. 27.2 ± 10.8; P<0.05
(+ Saline*)
33
Gan 1: Balanced HES 670/0.75 Major elective surgery aPTT (s): 44 ± 30 vs. 43 ± 31 Blood loss: 1278 ± 1616 vs. 1024 ± 949

SC
1999 2: Unbalanced HES 670/0.75 (n=120) PT (s): 17 ± 7 vs. 16 ± 4 ml
-1
Fibrinogen (IU l ): 1.8 ± 1.4 vs. 1.8 ± 1.6 PRBC transfusion: 642 ± 1174 vs. 538 ±
9 -1
Platelets (x 10 l ): 175 ± 75 vs. 160 ± 72 694 ml
35 -1
Gandhi 1: HES 130/0.4 Orthopaedic surgery aPTT (s): 29.8 ± 4.3 vs. 33.7 ± 7.7; P=0.0004 PRBC transfusion (ml kg ): 10.6 ± 8.8

U
2007 2: HES 670/0.75 (n=100) PT (s): 12.8 ± 1.7 vs. 14.1 ± 2.6; P<0.0001 vs. 14.1 ± 12.4

AN
36
Helmy 1: Balanced HES 130/0.4 (<50 ml Urology surgery PT (INR): 1.6 ± 0.3 vs. 1.5 ± 0.2 Blood loss (ml): 2219 ± 994 vs. 2195 ±
-1
2016 kg ) (n=40) 1290
2: Unbalanced HES 130/0.4 (<50 PRBC transfusion (units): 3 (0-6) vs. 2.5
-1
ml kg ) (0-6)

M
(+Ringer’s lactate*)
40 -1
Kim 1: HES 670/0.75 (<20 ml kg ) Off-pump CABG EXTEM CT (s): 72.6 ± 20.4 vs. 57.5 ± 11.6 8-hr blood loss: 504 (395-699) vs. 316
2017 2: Plasma-Lyte 148 (n=120) EXTEM MCF (mm): 52.3 ± 7.8 vs. 59.1 ± 6.9 (220-433) ml; P<0.001

D
(+ Plasma-Lyte 148*) FIBTEM MCF (mm): 9.2 ± 4.6 vs. 14.6 ± 5.1 PRBC transfusion rate: 63.3% vs.
(all P<0.001) 66.7%; P=0.702

TE
39
Martin 1: Unbalanced HES 670/0.75 Major surgery Mean change TEG R (mm): 6.2 ± 8.5 vs. -0.3 ± Blood loss (ml): 550 (175-1250) vs. 388
2002 2: Balanced HES 670/0.75 (n=90) 4.1 vs. -3.7 ± 6.7 (200-1000) vs. 725 (350-1700)
3: Ringer’s lactate Mean change TEG MA (mm): -8.0 ± 9.8 vs. -5.4 ± PRBC transfusion (ml): 348 ± 801 vs.
(+ Ringer’s lactate*) 12.3 vs. no data 281 ± 488 vs. 303 ± 518
EP
37
Mercier 1: HES 130/0.4 (500 ml) Spinal anaesthesia aPTT (s): 36.2 ± 3.9 vs. 36.4 ± 3.5; P=0.47 Not available
2014 2: Ringer’s lactate (1000 ml) (n=167) PT (INR): 1.0 ± 0.1 ± 1.0 ± 0.1; P=0.32
9 -1
Platelets (x 10 l ): 219 ± 58 vs. 216 ± 57; P=0.67
C

29 -1
Mukhtar 1: 5% albumin (<50 ml kg ) Liver transplantation PT (INR): 2.6 ± 1.4 vs. 2.1 ± 0.2 PRBC transfusion (units): 4 (0-8) vs. 2
AC

-1
2009 2: HES 130/0.4 (<50 ml kg ) (n=40) (0-8)
(+ Ringer’s acetate*)
41 -1
Schramko 1: HES 130/0.4 (21 ml kg ) CABG & valve surgery EXTEM MCF (mm): 51.1±6.2 vs. 52.3±3.9 vs. 61.4 Unavailable
-1
2010 2: Gelatin (21 ml kg ) (n=45) ± 3.4; P<0.05
-1
3: Ringer’s acetate (21 ml kg ) FIBTEM MCF (mm): 9.5±3.6 vs. 9.9±2.9 vs.
16.4±3.8; P<0.05

37
 ACCEPTED MANUSCRIPT

34
Weinberg 1: Plasma-Lyte 148 Liver resection aPTT (s): 27 ± 3.4 vs. 29 ± 6.6; P=0.15 Blood loss: 300 (200-413) vs. 500 (300-
2015 2: Ringer’s lactate (n=60) PT (s): 11.0 ± 3.1 vs. 11.6 ± 3.2; P=0.46 638); P=0.03
-1
(+ HES 130/0.4) Fibrinogen (g l ): 3.8 ± 0.97 vs. 3.7 ± 1.65; P=0.76 PRBC transfusion rate: 3% vs. 10%;
9 -1
Platelets (x 10 l ): 236 ± 83 vs. 205 ± 98; P=0.19 P=0.19
aPTT = activated partial thromboplastin time; CABG = coronary artery bypass graft surgery; CT = clotting time; HES = hydroxyethyl starch; INR =

PT
international normalized ratio; MA = maximum amplitude; MCF = maximum clot firmness; PT = prothrombin time; TEG = thromboelastography; TEM =
thromboelastometry. * maintenance fluid

RI
U SC
AN
M
D
TE
C EP
AC

38
 ACCEPTED MANUSCRIPT

Supplemental table 2: Overview of randomised controlled studies with clinically relevant endpoints in cardiac surgery.

Author, year Study design & Fluids compared Surgery Study conclusion Additional outcomes
quality
Cardiac surgery

PT
88
Base Randomised, 1: Balanced HES CABG & valve Less acidosis in the balanced HES Mortality: 4.7% vs. 2.6%
2011 double-blinded 130/0.4 surgery group.
study 2: Unbalanced HES (n=81)

RI
Quality: 1B 130/0.4
85
Iriz RCT 1: HES 450/0.7 CABG No differences in clinical endpoints Total blood loss (ml): 1342 ± 105 vs. 1282 ± 144;

SC
2005 Quality: 2B 2: Ringer’s lactate (n=30) between groups. P=0.90
LOS ICU (days): 1.13 ± 0.09 days vs. 1.66 ± 0.33
43
Kasper Randomised, 1: HES 130/0.4 CABG No differences in clinical endpoints 24-hr blood loss: 660 (380–1440) vs. 705 (330-
2003 semi*-double- 2: HES 200/0.5 (n=120) between groups. 1750) ml, P=0.60

U
blinded study LOS ICU (days): 2 ± 1 vs. 2 ± 1
Quality: 1B LOHS (days): 9 ± 3 vs. 8 ± 3

AN
40
Kim Randomised, 1: HES 670/0.75 Off-pump CABG The use of hydroxyethyl starch 670/0.75 MACE: Myocardial infarction n=1 vs. n=0;
2017 double-blinded 2: Plasma-Lyte 148 (n=120) did not result in differences in P>0.999); AKI n=10 vs. n=12; P=0.637); Stroke
study microvascular reactivity or endothelial n=1 vs. n=0; P>0.999); Atrial fibrillation n=16 vs.

M
Quality: 1B glycocalyx degradation. No differences in n=12; P=0.333;
clinical endpoints between groups. 8-hr blood loss: 504 (395-699) vs. 316 (220-433)
ml; P<0.001

D
LOS ICU (days): 3 (2-5) vs. 3 (2-5); P=0.435
LOHS (days): 10 (8-14) vs. 9 (8-13) days;

TE
P=0.633)
51
Lee RCT 1: HES 130/0.4 CABG No differences in clinical endpoints AKI: n=1 vs. n=0; P=0.315
2011 Quality: 2B 2: Balanced (n=106) between groups. 24-hr blood loss: 810±322 vs. 753±313; P=0.353
Crystalloid LOS ICU (days): 2.7 ± 0.8 vs. 2.7 ± 1.1; P=0.916
EP
LOHS (days): 10.9 ± 5.7 vs. 10.3 ± 3.7; P=0.484
89
Rex Randomised 1: Ringer’s lactate Mitral valve More fluid was accumulated in the Cell saver (ml): 650 ± 613 vs. 833 ± 464
2006 controlled, 2: 4% albumin surgery extravascular space in the crystalloid LOS ICU (hr): 36 ± 12 vs. 40 ± 14
C

double-blind (n=22) arm, while the stroke volume index (SVI)

study was decreased in the immediate
AC

Quality: 2B postoperative period

39
 ACCEPTED MANUSCRIPT

86
Sirvinskas RCT 1: Hyperhaes CABG HyperHaes® solution had a positive 24-hr blood loss (ml): 531.0 ± 268.4 vs. 565.0 ±
2007 Quality: 2B 2: Ringer’s acetate (n=80) effect on haemodynamic parameters and 297.4; P=0.664
microcirculation. Oxygen transport was 24-hr diuresis (ml): 3640 ± 1123 vs. 2736 ± 901;
more effective after HyperHaes® solution P=0.01
infusion. Higher diuresis, lower need for

PT
the infusion therapy for the first 24 hours
and lower total fluid balance were
determined in the HyperHaes® group.
45

RI
Skhirtladze Randomised 1: 5% albumin CABG & valve No differences in clinical endpoints AKI: need for RRT n=2 vs. n=1 vs. n=0
2014 controlled, 2: HES 130/0.4 surgery between groups. 24-hr blood loss: 835 (545-1253) vs. 700 (540-
double-blind, 3: Ringer’s lactate (n=240) 1090) vs. 670 (455-1015); P=0.085

SC
single-centre LOS ICU (days): 1 (1-16) vs. 1 (1-48) vs. 1 (1-16)
trial LOHS (days): 14 (7-66) vs. 14 (8-55) vs. 13 (6-
Quality: 1B 164)
Mortality: n=2 vs. n=1 vs. n=1

U
90
Tamayo Semi-blinded 1: Ringer’s lactate CABG No differences in the inflammatory MACE: Atrial fibrillation n=0 vs. n=1
2008 RCT 2: Gelatin (n=44) response or clinical endpoints between 24-hr blood loss (ml): 946 ± 538 vs. 995 ± 497;

AN
Quality: 1B groups. P=0.76
LOS ICU (days): 2.1 ± 1.8 vs. 2.6 ± 2.2; P=0.388
Mortality: n=0 vs. n=0

M
87
Tiryakioglu RCT 1: Ringer’s lactate CABG No differences in clinical endpoints Total blood loss (ml): 460 ± 140 vs. 430 ± 150
2008 Quality: 2B 2: HES 130/0.4 (n=140) between groups. LOS ICU (hr): 47 ± 12 vs. 45 ± 10
LOHS (days): 9 ± 3 vs. 8 ± 3

D
Van der RCT 1: HES 130/0.4 CABG No differences in clinical endpoints Total blood loss (ml): 19.4 ± 12.3 vs. 19.2 ± 14.5
50 -1
Linden Quality: 2B 2: Gelatin (n=132) between groups. ml kg

TE
2005 LOS ICU (hr): 24 (20-73) vs. 43 (22-100)
LOHS (days): 98 (6-24) vs. 9 (7-35)
Mortality: n=0 vs. n=1
EP
Quality interpretation: http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009; 1B if randomised controlled trial (RCT) well
performed (large groups, double blinded, >80% follow-up); 2B if RCT of less quality (Small groups, single or not blinded, <80% follow-up). AKI = acute kidney
C

injury; CABG = coronary artery bypass graft; FFP = fresh frozen plasma; ICU = intensive care unit; MACE = Major Adverse Cardiovascular Events (e.g.
myocardial infarction, arrhythmia, symptomatic pulmonary embolism, pulmonary oedema, stroke); LOS = length of stay; LOHS = length of hospital stay; RRT
AC

= renal replacement therapy. When no P-values are reported data did not reach a significant statistical difference.

40
 ACCEPTED MANUSCRIPT

Supplemental table 3: Overview of randomised controlled studies with clinically relevant endpoints in abdominal surgery.

Author, year Study design & Fluids compared Surgery Study conclusion Additional outcomes
quality
Major Abdominal

PT
106
Ando RCT 1: HES 70/0.5 Abdominal Low-molecular-weight HES does not MACE: Arrhythmia: n=1 vs. n=1
2008 Quality: 2B 2: Ringer’s acetate surgery improve microvascular AKI: No difference in creatinine levels
(n=21) hyperpermeability, it does result in Blood loss (ml): 115 (90-200) vs. 110 (93- 193)

RI
higher urinary output in the ICU LOS (hr): 20 (18-20) vs. 22 (20-23); P=0.02
postoperative period. LOHS (days): 124 (21- 25) vs. 31 (23-37)

SC
107
Feldheiser Double-blind pilot 1: Balanced Cytoreductive Balanced HES solution is associated AKI: None
2013 study crystalloid ovarian cancer with better haemodynamic stability and Blood loss (ml): 820 (500-2200) vs. 1500 (700-
Quality: 2B 2: Balanced HES surgery reduced FFP need. No signs of renal 2650); P=0.313
130/0.4 (n=48) impairment by colloid solutions when LOHS (days): 13(11-17) vs. 13 (10-15); P= 0.401

U
fluid administration is targeted to In-hospital mortality: n=0 vs. n=1; P= 1.000
optimize cardiac preload. 3-Month mortality: n=0 vs. n=5; P= 0.051

AN
25
Kancir Randomised, 1: HES 130/0.4 Radical HES does not lead to nephrotoxicity in AKI: No difference in creatinine levels
2015 double-blinded, 2: Saline 0.9% prostatectomy patients with normal preoperative renal Blood loss (ml): 1256 ± 669 vs. 747 ± 331;
placebo- (n=36) function. Hemodynamic stability and P=0.008

M
controlled infused fluid volume were the same in LOHS (days): 2.5 (2.5-2.8) vs. 2.5 (2.5-2.5); P=
Quality: 1B both groups. There is increased blood 0.338
loss in the HES group.

D
109
Lavu Single-centre, 1: Hypertonic Pancreatico- There was a 25% reduction in MACE: No difference in cardiac complications
2014 prospective, saline duodenectomy complications when adjusted for age, AKI: No difference in renal complications

TE
RCT, parallel 2: Ringer’s lactate weight, and pancreatic texture in the Blood loss (ml): 350 (45-2250) vs. 400 (50-6900)
design hypertonic saline group LOHS (days): 7 (5-61) vs. 7 (4-41)
Quality: 2B 90-Day mortality: n=4 vs. n=3
EP
123
Loffel Randomised, 1: Chloride- Open radical Perioperative administration of G5K did MACE: 5 (22.7) vs. 2 (9.1)
2016 parallel-group, depleted 5% cystectomy, not enhance first defecation, but may AKI: No difference in renal complications
single-centre glucose solution pelvic lymph accelerate recovery of normal Blood loss (ml): 880 (200-1800) vs. 1200 (200-
double-blind trial (G5K) node dissection, gastrointestinal function, and reduces 2200)
C

Quality: 1B 2: Ringer’s maleate urinary potassium and magnesium substitution. LOS (days): 14.5 (10-23) vs. 15.5 (11-26)
solution diversion.
AC

(n=44)
29
Mukhtar RCT 1: HES 130/0.4 Liver The use of HES 130/0.4 as an AKI: Need for RRT: n=1 vs. n=1; No differences in
2009 Quality: 2B 2: 5% albumin transplantation alternative to human albumin resulted creatinine
(n=40) in equivalent renal outcome and LOS ICU (days): 5 ± 0.2 vs. 4.5 ± 0.5
mortality after liver transplantation LOHS (days): 23 ± 4 vs. 27 ± 3
Mortality: n=1 vs. n=1

41
 ACCEPTED MANUSCRIPT

47
Rasmussen RCT 1: HES 130/0.4 Cystectomy Administration of lactated Ringer’s AKI: No differences in renal complications
2014 Quality: 2B 2: Ringer’s lactate (n=33) solution provoked an approximately 2.5 Blood loss (ml): 2181 ± 1190 vs. 1370 ± 603;
times greater positive volume balance P=0.038
at the end of surgery.
48
Rasmussen RCT 1: Dextran 70 Radical No differences in clinical endpoints AKI: No differences in renal complications

PT
2015 Quality: 2B 2: Ringer’s lactate cystectomy between groups >1500 ml blood loss: n= 11 vs. n= 4; P=0.04
(n=37) LOHS (days): 9 (5-24) vs. 7 (6-92) P=0.69
49
Rasmussen RCT 1: 5% Albumin Radical No difference in the incidence of AKI: No difference in renal complications

RI
2016 Quality: 2B 2: Ringer’s lactate cystectomy postoperative complications or LOHS Blood loss (ml): 1658 (800–3300) vs. 1472 (700–
(n=39) between groups. 4330); P=0.45
LOHS (days): 8 (5-90) vs. 7 (3-20) Days; P=0.27

SC
108
Waters RCT 1: Ringer’s lactate Abdominal The use of saline was associated with MACE: Cardiac arrhythmia n=3 vs. n=3
2001 Quality: 2B 2: 0.9% normal Aortic Aneurysm more acidosis compared to the Ringer’s AKI: n=4 vs. n=5
saline Repair lactate group, but with no differences in Blood loss (ml): 705 (335-1649) vs. 1095 (430-

U
(n=66) clinical outcome. 1745)
Mortality: n=1 vs. n=1

AN
34
Weinberg Multicentre, 1: Plasmalyte 148 Major liver No differences in base excess values, MACE: Myocardial infarction n=0 vs. n=4; Cardiac
2015 double-blind, 2: Hartmann’s resection but different postoperative plasma arrhythmia n=2 vs. n=3
RCT solution (n=60) biochemistry and haemostasis values. AKI: No difference in renal complications

M
Quality: 1B Blood loss (ml): 300 (200-413) vs. 500 ml (300-
638); P=0.03
LOHS (days): 5.9 vs. 7.8; P=0,04.

D
30-Day mortality: n=0 vs. n=2; P=0,.9
26
Yates Single-centre, 1: HES 130/0.4 Colorectal There is no difference in clinical MACE: Acute coronary syndrome : n=11 vs. n=4;

TE
2014 double-blind, 2: Hartmann’s surgery endpoints between groups; HES was Pulmonary oedema: n=5 vs. n=2; Stroke: n=0 vs.
RCT solution (n=202) associated with a lower 24 h fluid n=0; Ventricular arrhythmias: n=0 vs. n=0
Quality: 1B balance. AKI: Need for RRT n=4 vs. n=0
EP
Blood loss (ml): 250 (50-700) vs. 200 ml (100-620)
LOHS (days): 9 vs. 8; P=0.74
Mortality: n=5 vs. n=2
Quality interpretation: http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009; 1B if randomised controlled trial (RCT) well
C

performed (large groups, double blinded, >80% follow-up); 2B if RCT of less quality (Small groups, single or not blinded, <80% follow-up). AKI = acute kidney
AC

injury; FFP = fresh frozen plasma; ICU = intensive care unit; MACE = Major Adverse Cardiovascular Events (e.g. myocardial infarction, arrhythmia,
symptomatic pulmonary embolism, pulmonary oedema, stroke); LOS = length of stay; LOHS = length of hospital stay; RRT = renal replacement therapy.
When no P-values are reported data did not reach a significant statistical difference.

42
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC