Acta Anaesthesiol Scand 2002; 46: 625–638 Copyright C Acta Anaesthesiol Scand 2002

Printed in Denmark. All rights reserved

ACTA ANAESTHESIOLOGICA SCANDINAVICA
0001-5172

Review Article

Small-volume resuscitation: from experimental evidence

to clinical routine. Advantages and disadvantages of
hypertonic solutions

U. KREIMEIER1,2 and K. MESSMER2

1
Department of Anesthesiology and 2Institute for Surgical Research, Ludwig-Maximilian University Munich, Munich, Germany

Background: The concept of small-volume resuscitatioin
(SVR) using hypertonic solutions encompasses the rapid in-
fusion of a small dose (4 ml per kg body weight, i.e. approxi-
mately 250 ml in an adult patient) of 7.2–7.5% NaCl/colloid
solution. Originally, SVR was aimed for initial therapy of severe
hypovolemia and shock associated with trauma.
Methods: The present review focusses on the findings con-
cerning the working mechanisms responsible for the rapid onset
of the circulatory effect, the impact of the colloid component on
microcirculatory resuscitation, and describes the indications for
its application in the preclinical scenario as well as perioperat-
ively and in intensive care medicine.
Results: With respect to the actual data base of clinical trials
SVR seems to be superior to conventional volume therapy with
regard to faster normalization of microvascular perfusion dur-
ing shock phases and early resumption of organ function. Par-
ticularly patients with head trauma in association with systemic
hypotension appear to benefit. Besides, potential indications for
this concept include cardiac and cardiovascular surgery (attenu-
ation of reperfusion injury during declamping phase) and burn
injury. The review also describes disadvantaages and potential
adverse effects of SVR:
Conclusion: Small-volume resuscitation by means of hyper-
tonic NaCl/colloid solutions stands for one of the most innova-
tive concepts for primary resuscitation from trauma and shock
established in the past decade. Today the spectrum of potential
indications envolves not only prehospital trauma care, but also
perioperative and intensive care therapy.
Received 17 July 2001, accepted for publication 6 February 2002
Key words: dextran; endothelial interaction, hydroxyethyl
starch; hypertonic solutions; intraoperative use; ischemia; leuko-
cyte; microcirculation; primary resuscitation shock; reperfusion
injury; small-volume resuscitation; trauma care.
c Acta Anaesthesiologica Scandinavica 46 (2002)

T HE CONCEPT of small-volume resuscitation, the

rapid infusion of a small dose (4 ml/kg b.w.) of
7.2–7.5% NaCl/colloid solution, was advocated as the
plasma volume rapidly increased 3- to 4-fold the vol-
ume infused (see later); second, by normalising the en-
dothelial cell volume the luminal diameter of the
initial therapy for severe hypovolemia and shock al-
most two decades ago (1). This therapy is based on the
instantaneous mobilization of endogenous fluid along
the osmotic gradient from the intracellular to the intra-
vascular compartment. For instances of primary vol-
ume resuscitation from severe hypovolemia and shock,
this method is attractive because of its rapid mobiliza-
tion of endogenous water; especially from the intra-
cellular compartment which represents a huge reser-
voir amounting to 25 l of fluid (Fig. 1; 2). In addition,
during shock and ischemia the endothelial cell volume
in particular increases because of cell adenoline tri-
phosphate (ATP) loss and cell membrane exchange
dysfunction, leading to an accumulation of water in the Fig. 1. Body fluids, causes of hypovolemia, and the impact of bolus
cells. Thus, any mobilization of water from this intra- infusions of hypertonic saline solution on mobilization from the intra-
cellular site has two important advantages: first, cellular compartment modified from Guyton (2).

625
U. Kreimeier and K. Messmer

Table 1

Product characteristics of hypertonic solutions used in clinical routine. The right column indicates the amount of sodium administered with 250
ml of infusion volume.

Product name Main substance Content of Osmolarity Naπ content with

container (mOsmol/l) 250 ml infusion volume

Isotonic (0.9%) NaCl Sodium chloride 9 g/l 500 ml 309 39 mmol

Glucosteril 20% Glucose 200 g/l 500 ml 1110 None
Glucosteril 40% Glucose 400 g/l 500 ml 2220 None
Osmosteril 20% Mannitol 200 g/l 250 ml 1100 None
Sorbitol 40% Sorbitol 400 g/l 500 ml 2200 None
Sodium bicarbonate 8.4% NaHCO3 1000 mmol/l 250 ml 2000 250 mmol
RescueFlowTM 7.5% NaCl/6% dextran 70 250 ml 2567 321 mmol
HyperHAESA 7.2% NaCl/6% hydroxyethyl starch 200,000 250 ml 2264 308 mmol

microvessels is rectified, and consequently microcircul-
atory blood flow increases.
In the preclinical scenario this is attractive when con-
sidering the small-infusion volume needed to elicit an
instantaneous cardiovascular effect without the risk of
fluid overload. Moreover, this concept is unique when
taking into account the specific mode of action at the
microvascular level that provides prompt restoration
of the nutritional blood flow (3). During the 1980s vari-
ous research groups were able to demonstrate, in clin-
ically relevant animals models of hemorrhagic as well
as traumatic shock, that even in the presence of a 50%
blood loss a volume as small as 4 ml/kg of 7.2–7.5% so-
dium chloride is sufficient to restore cardiac output and
regional organ blood flow to preshock values almost in-
stantaneously, while at the same time systemic arterial
pressure is significantly increased (4). In prehospital tri-
als, small-volume resuscitation by means of hypertonic
saline colloid solutions has shown favorable results in
hypotensive trauma patients (5); both in cases of severe
trauma requiring immediate surgery (6) and in patients
with head trauma with a Glasgow Coma Scale score of
8 or less in the presence of hypotension (systolic blood
pressure ⬍90 mmHg) (7,8).
Characteristics of hypertonic solutions
In general, hypertonic solutions are characterized by
a high crystalloid concentration, i.e. sodium, glucose
or mannitol. In clinical routine, sodium bicarbonate
8.4% (for correction of tissue acidosis reflected by a
lowered pH and a negative base excess measured in
serum), glucose 20% and 40% (for correction of severe
hypoglycemia, hypoglycemic shock) or mannitol 20%
(for treatment of increased intracranial pressure) are
slowly administered via an i.v. route (Table 1). Upon
infusion, these solutions increase plasma osmolality,
96% of which is determined by electrolytes such as
sodium chloride, bicarbonate, potassium, calcium,
magnesium and phosphate.
The normal range of plasma osmolality is 280–295
mOsmol/kg in healthy persons. In pathophysiolog-
ical states, e.g. hyperosmolar coma diabeticum, ex-
treme dehydration, alcohol intoxication, ketoacidosis
or hyperlactaemia, plasma osmolality may reach very
high values, which, if allowed to persist, are associ-
ated with unfavorable outcomes. In contrast, an i.v.
bolus infusion of small volumes of hypertonic solu-
tions is aimed at producing a substantial but short-
lasting rise of plasma osmolality in order to achieve a
high osmotic gradient across the cellular membranes.
For instance, in patients with signs of increased intra-
cranial pressure (ICP), mannitol is recommended in a
dose of 0.3–1.5 g/kg b.w., given as 1.5–7.5 ml/kg b.w.
mannitol 20% over 15 min.
Medical terms used in context with
small-volume resuscitation
After the first systematic studies in the 1960s, the re-
naissance in hypertonic solution use for initial therapy
of hypovolemic shock began in 1980 (9). The term
‘small-volume resuscitation’ was coined by Nakaya-
ma and coworkers (1), who, in a hemorrhagic shock
model in sheep, showed that cardiac output was re-
stored and systemic pressure significantly increased
immediately after an infusion of hypertonic saline
(2400 mOsm/l Ω7.5% NaCl), even when given in an
amount as small as 10% of actual blood loss. During
the following years, experimental and clinical studies
were performed, investigating different hypertonic
solutions (NaCl, glucose, mannitol, NaHCO3, sodium
acetate, lactated saline, urea, lithium-Cl, Tris-Cl) and
doses (4–6 ml/kg b.w.), different sodium chloride con-
centrations (1.5–30% NaCl), infusion speeds (2–15
min) and routes (i.v., intraosseous) of administration.

626
 Small-volume resuscitation in clinical routine

Also, their efficacy with respect to restoration of
macro- and microcirculatory parameters, organ func-
tion and ultimate survival (9).
The short duration of the circulatory effects, which
are elicited by the sharp increase in plasma osmolality,
has been attributed to the rapid equilibration of the hy-
pertonic solute between extracellular and intracellular
compartments. As many authors were concerned
about the short-lasting cardiovascular response after
small-volume resuscitation using hypertonic saline
alone, 7.2–7.5% saline solution has been combined with
a colloid containing a high water-binding capacity, i.e.
4.2–24% dextran 60/70 or 6–20% hydroxyethyl starch
200,000 and 450,000, respectively, in order to preserve
the intravascular volume gain. Therefore, one should
obtain a synergistic effect by increasing plasma osmol-
ality with the result of mobilizing intracellular water,
and providing high plasma oncotic pressure to con-
serve the volume effect. In fact, animal studies have re-
vealed that compared with hypertonic sodium chloride
alone the addition of a colloid indeed results in a sus-
tained circulatory response and increases survival (10).
Consequently, in recent years the meaning of ‘small-
volume resuscitation’ or ‘small-volume hypertonic re-
suscitation’ was modified, i.e. this concept now de-
notes primary resuscitation from hypovolemia and
shock by means of hypertonic saline colloid solution
(Table 2). With respect to the fact that also for other
indicators apart from hypovolemia and shock due to
trauma, e.g. intraoperative administration, beneficial
effects have been shown (see below), the concept has
been increasingly accepted in the past few years. Most
importantly, however, is the mode of administration,
i.e. the short-term administration of a small amount
of concentrated salt solution for prevention or treat-
ment of pathophysiologic alterations induced by se-
vere hypovolemia and shock. The application of hy-
pertonic sodium colloid solution in euvolemic pa-
tients to lower increased intracranial pressure shows
positive effects, and an identical solution may be used
(7.2–7.5% sodium colloid solution). Nevertheless, it
does not belong to this primary resuscitation category.
Small-volume resuscitation by means of
hypertonic saline colloid solution
The first authors who applied this concept to preclini-
cal trauma care were Holcroft et al. (11). In the mid
1980s they used 7.5% saline mixed with 6% dextran
70, giving a final concentration of 7.5% NaCl/4.2%
dextran 70 solution. This was the first prospective,
randomized study in trauma patients, and the data
showed a higher systemic pressure and higher sur-
vival rate after an initial small-volume resuscitation
using hypertonic saline colloid solution compared
with isotonic crystalloid resuscitation only. As one
manufacturer provided a hypertonic colloid contain-
ing solution (7.5% saline/6% dextran 70; Pharmacia
AB, Uppsala, Sweden), Holcroft and Vassar, Univer-
sity of California Davis Medical School, analyzed the
necessity of the colloid component in a multicenter
trial, in which hypotensive trauma patients from six
trauma systems served by helicopter transport were
investigated (7). The four treatment groups included

Table 2
Definition of terms used in the small-volume resuscitation context.

Medical term Definition Therapeutic options and

first described by

Small-volume resuscitation
Small-volume hypertonic resuscitation
(or small-volume hyper osmolar
resuscitation)
Small-volume resuscitation by means
of hypertonic-hyperoncontic
solutions
Small-volume resuscitation
by means of hypertonic colloid
solution
Primary resuscitation from severe hypovolemia and Nakayama et al. (1)
shock by means of bolus infusion of a small amount
(approx. 4 ml/kg b.w.) of hypertonic saline (7.2–7.5%
NaCl)
Primary resuscitation from hemorrhage by means of Prist et al. (106)
a small amount of hypertonic solutions of any sort,
alone or in combination with a colloid
Primary resuscitation from hemorrhagic hypotension Kreimeier et al. (107)
by means of bolus application (within 2–5 min) of a
small volume
(approx. 4 ml/kg b.w., i.e. 250 ml in an adult) of 7.2–7.5%
saline solution in combination with a hyperoncotic colloid
(6–10% dextran 60/70, 10% hydroxyethyl starch
200,000/0.62)
Primary resuscitation from hypovolemia and shock by means of a
bolus infusion (2–5 min) of a small volume of hypertonic saline colloid
solution (7.2–7.5% saline) (6–10% dextran 60/70, 6–10%
hydroxyethyl starch solution).

627
U. Kreimeier and K. Messmer
lactated Ringer’s solution, 7.5% sodium chloride, 7.5%
sodium chloride combined with 6% dextran 70, and
7.5% sodium chloride combined with 12% dextran 70;
each of the solutions were given in a quantity of 250
ml and followed by conventional isotonic volume
support. Only the 7.5% sodium chloride solution was
associated with an increase in blood pressure and en-
hanced survival to hospital discharge compared with
survival as predicted by the Major Trauma Outcome
Study. However, the impact of this study was limited
because it was terminated prematurely when only 194
instead of the 600 planned patients were included in
the final analysis; confounding factors were infusion
of a considerable amount of isotonic solutions and, in
almost a third of the patients, medical antishock
trousers were inflated at a time when the infusion of
the test solution had not yet been started.
Until 1994, evidence for the superiority of hyper-
tonic saline colloid solution in contrast to hypertonic
salt was provided from experimental data (12–14).
Wade et al. then performed a meta-analysis of all clin-
ical studies that had been designed prospectively and
randomized for analysis of the efficacy of hyperosmo-
lar saline or hyperosmolar saline dextran application
for the treatment of traumatic injury (15). Nine trials
with a total number of 1889 patients were analyzed.
Inclusion criterion was a systolic blood pressure of be-
low 100 mmHg. The data revealed no significant dif-
ference between hyperosmolar (7.5%) saline alone vs.
lactated Ringer’s solution; in contrast, the hyperosmo-
lar saline dextran solution (7.5% NaCl/6% dextran 70)
yielded a 5.1% higher survival rate when compared
with Ringer’s lactate (15), thus supporting the experi-
mental data of enhanced efficacy.
Impact of the colloid content
Small-volume resuscitation is intended for primary re-
suscitation from trauma and shock. By establishing a
high osmotic gradient across cellular membranes, en-
dogenous water is shifted into the intravascular com-
partment. When used simultaneously (hypertonic col-
loid solution) the colloid not only serves to preserve the
gained volume, but exhibits an additive acute circul-
atory effect. Walsh and coworkers demonstrated in hy-
povolemic sheep treated by small-volume resuscitation
that the dextran component (either 0%, 12% or 24%
dextran 70 were used) exerts an additive effect on
plasma volume and cardiac output increase (12).
In our own experiments in Beagles with severe, pro-
tracted traumatic-hemorrhagic hypotension (mean ar-
terial pressure Ω 40 mmHg for 75 min) employing the
radioactive microspheres method for quantification of
628
regional organ blood flow, we have demonstrated that
the nutritional blood flow in the kidneys and the gas-
trointestinal tract increased instantaneously and sig-
nificantly more pronounced when 10% dextran 60
was given in addition to 7.2 NaCl for small-volume
resuscitation (16). In this model, 10% of the shed
blood given as hypertonic saline colloid solution (ap-
proximately 4 ml/kg b.w. compensating a 50% blood
loss) proved sufficient to completely restore the nu-
tritional blood flow.
Following bolus infusion of 7.5% NaCl, rapid
plasma volume expansion occurs, amounting to 8–12
ml/kg, as measured by Smith and coworkers in
studies on conscious sheep subjected to hemorrhagic
shock (17). As 1 g dextran binds ⬃20 ml water, 6%
dextran 60/70 solution will bind ⬃5 ml/kg when
given in a dose of 4 ml/kg body weight. Conventional
dextran 60/70 therefore has a limited oncotic power
in keeping all the mobilized water within the intra-
vascular compartment. Higher concentrated dextran
solutions, particularly the 10% dextran 60/7.2% saline
solution we used in our experimental studies
(13,16,18), would theoretically seem preferable in
terms of pharmacologic properties.
Advantages of small-volume
resuscitation proven effects in the
experimental (laboratory) setting
On the basis of the experimental data obtained in the
case of hemorrhagic and traumatic shock, the estab-
lished effects of primary resuscitation by means of hy-
pertonic saline either alone or in combination with hy-
peroncotic dextran can be summarized as follows (4,
19):
1 Immediate increase of systemic pressure and car-
diac output, while peripheral vascular resistance is
reduced.
2 Instantaneous increase of nutritional blood flow
and reduction of postischemic reperfusion injury.
3 Resumption of organ function as indicated by in-
crease of urinary output.
4 Increased survival rate.
Moreover, hypertonic saline resuscitation has been
shown to reduce bacterial translocation in Sprague-
Dawley rats subjected to hemorrhagic shock, which
has been attributed to the prevention of gut hypoper-
fusion (20). Small-volume resuscitation therefore may
also be useful in ICU patients known to be at risk of
developing multiple systems organ failure (MSOF) on
the basis of compromised gut mucosa blood flow;
however, clinical data are missing. It has been sug-

gested that hypertonic saline dextran is of benefit for
the improvement of postburn microcirculatory dis-
turbances and attenuating postburn oxidant-induced
systemic and mesenteric lipid peroxidation (21). The
latter effect might be linked to the alterations of intra-
cellular sodium and water content developing in the
course of experimental burn injury (22).
Specific effect of hypertonic saline
colloid solution on postischemic
leukocyte/endothelial interaction
Chemotactic accumulation of circulating leukocytes
and their adhesion to the endothelial lining of post-
capillary venules have long been recognized as key
features of postischemic reperfusion injury (23,24).
The molecular mechanisms of leukocyte adhesion to
endothelial cells in response to hyperosmolarity have
been investigated by Thiel et al. (25) in vitro. Incuba-
tion of isolated leukocytes in buffer solutions with in-
creasing osmolarity seems to counteract the famyl-
methionyl-leucyl-phenyalamine (FMLP)-induced up-
regulation of b2-integrins in a dose-dependent man-
ner. At the same time FMLP-induced shedding of L-
selectin is reduced, suggesting that these changes are
not the result of a non-specific artifact, such as the
effects of the hypertonic medium on epitope-antibody
recognition (26). When compared with physiologic os-
molarity (290 mM), FMLP-induced CD18 up-regula-
tion and L-selectin shedding were significantly re-
duced at osmolarities typically found in humans and
animals after resuscitation with hypertonic solutions.
Special pharmacologic properties exist and suggest
the prefered use of hypertonic saline together with dex-
tran as a colloid: Nolte et al. published their data on the
leukocyte/endothelial interaction of hypertonic-hy-
peroncotic dextran solution after ischemia/reperfusion
injury in the hamster dorsal skinfold model (14). The
authors demonstrated that after 4 h of ischemia and re-
perfusion of striated skin muscle the number of leuko-
cytes adhering to the endothelium of postcapillary ven-
ules was significantly reduced for 24 h after bolus in-
fusion of 7.2% NaCl/10% dextran 60, and hypertonic
saline dextran effectively attenuated macromolecular
leakage and reduced capillary endothelial swelling as
assessed by capillary lumenal diameter measurements.
The hypertonic saline alone was significantly less ef-
ficient in protecting from postischemic leukocyte/en-
dothelial interaction and its sequelae.
The impact of the synthetic colloid dextran is also
known from hemodilution experiments: already very
small amounts of dextran have been shown to be cap-
able of reducing reperfusion injury after a period of
Small-volume resuscitation in clinical routine
shock and low/no flow in the microcirculation (27–29).
In the dorsal skinfold model in the hamster, postische-
mic leukocyte accumulation and adherence were found
to be significantly attenuated following prophylactic
isovolemic hemodilution with 6% dextran 60 to a hem-
atcrit of 30% (a clinically relevant value in the trauma
patient) when compared with controls (30). This effect
was absent when using 6% hydroxyethyl starch, and
the authors postulated a compound-specific pharmac-
ologic effect of dextran. The favorable effects of dextran
have been confirmed in a rat model of hemorrhagic
shock and resuscitation by dextran given either alone
(6% dextran 60, 100% shed blood volume) or as small-
volume resuscitation in combination with 7.2% saline
(7.2% NaCl/10% dextran 60, 10% shed blood volume)
(31): both regimens attenuated leukocyte stagnation in
sinusoids and leukocyte adherence in postsinusoidal
venules significantly more than did lactated Ringer’s
solution the latter administered four times the amount
of shed blood volume.
These findings, together with data from studies by
Junger et al. (32,33) and Rizoli et al. (34,35), support
the concept that hypertonic solutions might interfere
with neutrophil–endothelial cell interactions, sug-
gesting the possibility that this resuscitation strategy
appears applicable to a broad range of disease pro-
cesses in which neutrophil–endothelial cell interac-
tions are crucial in initiating organ injury.
Evidence from clinical trials
The concept of applying small volumes of hypertonic
saline/dextran solution for primary resuscitation from
severe hypovolemia proved effective in a prospective,
randomized study of trauma patients. As compared to
Ringer’s lactate, the bolus infusion of 250 ml 7.5%
NaCl/4.2% dextran 70 at the accident site resulted in a
higher systemic pressure increase (49 mmHg vs. 19
mmHg) and a higher survival rate (8/10 patients vs. 3/
10 patients) (36). In an extension of their first study, in
1989 Holcroft et al. reported on 60 trauma patients
entered in a randomized, prospective double-blind
trial (37). Administration of 7.5% saline/6% dextran 70
resulted in a higher blood pressure when the patients
reached the emergency room compared with Ringer’s
lactate given in the same amount (250 ml) and followed
by conventional fluid therapy. The 30-day survival rate
was significantly higher after small-volume resusci-
tation using hypertonic saline/dextran.
Also the data from the U.S. multicenter trial on pre-
hospital hypertonic saline/dextran infusion for post-
traumatic hypotension yielded positive results (6).
The 359 patients analyzed had a mean injury severity
629
U. Kreimeier and K. Messmer
score of 19, and received either 250 ml of 7.5% saline
in 6% dextran 70 or Ringer’s lactate, followed by con-
ventional therapy. There was no difference in overall
survival within the first 24 h; however, in the sub-
group of patients requiring surgery and those with a
penetrating injury, hypertonic saline/dextran infusion
proved superior to Ringer’s lactate (P⬍0.02 and
P⬍0.01, respectively). In addition, there were fewer
complications (ARDS, renal failure, coagulopathy)
compared with the standard treatment group.
The application of hypertonic saline/dextran solu-
tions has proven safe in patients, and in none of the
controlled clinical trials have adverse effects been
attributed to the colloid component, nor have anaphy-
lactoid reactions been observed (10). In an attempt to
gain access to a more representative database, Kramer
and Wade performed a meta-analysis of studies in
which hypertonic saline/dextran or hypertonic saline
alone had been used for primary volume therapy after
traumatic injury (15,38). Finally, eight trials were in-
cluded, yielding a total number of 1170 patients. In-
clusion criterion was a systolic blood pressure below
100 mmHg in combination with trauma. No signifi-
cant difference regarding 30-days survival could be
established between hypertonic (7.5%) saline alone vs.
lactated Ringer’s solution (15), whereas the hyper-
tonic saline dextran solution (7.5% NaCl/6% dextran
70) yielded a 5.1% higher survival rate (38). This result
stresses the necessity and impact of the colloid com-
ponent used for small-volume resuscitation.
Preclinical use and efficacy
In view of data from diverse controlled clinical trials
the concept of small-volume resuscitation has been
demonstrated to be feasible and effective with respect
to conventional fluid therapy for primary resusci-
tation of trauma patients (39,40), as well as in the
emergency room (41,42). Prehospital trials in particu-
lar have shown favorable results in cases of severe
trauma requiring immediate surgery (6).
The incidence of mortality and morbidity resulting
from severe head trauma is strongly related to elev-
ated intracranial pressure and hypotension (43). Pre-
clinical administration of small volumes (250 ml) of
7.5% NaCl/dextran 70, increased the blood pressure
of severely injured patients more efficiently than did
lactated Ringer’s solution, and showed a tendency to-
ward improving survival in the patients with severe
head injury (39). The data from the latest multicenter
trial (7) suggest that hypotensive trauma patients with
baseline Glasgow Coma Scale scores of 8 or less will
benefit most from 7.5% saline resuscitation.
630
In contrast, a recent review according to evidence-
based medicine provided by the Cochrane Library re-
veals the problem of demonstrating efficacy in pre-
clinical care traumatized patients: in an attempt to de-
termine whether hypertonic crystalloid decreases
mortality in patients with hypovolemia with and
without head injuries, Medline, EMBASE, The
Cochrane Controlled Trials Register and the Special-
ized Register of the Injuries Group were reviewed
(44). Sixteen trials were identified with a total of 837
patients. Data on mortality were obtained in 12 of the
studies. The pooled relative risk for death in trauma
patients was 0.84 (95% CI 0.61–1.16), in patients with
burns 1.49 (95% CI 0.56–3.95), and in patients under-
going surgery 0.62 (95% CI 0.08–4.57). The reviewers
concluded that this comprises insufficient data for de-
ciding whether hypertonic crystalloids are better than
isotonic crystalloids for the resuscitation of patients
with trauma, burns or those undergoing surgery (44).
A main reason for these findings may be seen in the
heterogeneity of injury pattern, pre-existing diseases,
and the armentarium of general therapy in trauma
victims included into preclinical trials: this issue was
already discussed among the participants of the SALT
V Conference in Galveston in 1992, where, taking
‘mortality’ as the endpoint, statisticians anticipated a
cohort of approximately 7000 patients required to
prove the efficacy of primary volume therapy by
means of small-volume resuscitation.
For use aside from the original indication (primary
resuscitation from trauma and shock), benefits and
potential side-effects (see later) must be considered. A
list of potential indications for small-volume resusci-
tation in emergency care, perioperative use and in
critically ill patients is given in Table 3.
Disadvantages and potential adverse
effects
In the experimental setting hypertonic solutions with
a sodium chloride concentration up to 30% have been
studied for use in primary resuscitation from hemor-
rhagic shock. Bolus infusion of hypertonic NaCl-solu-
tion into a peripheral vein with concentrations above
10% resulted in significant hemolysis, whereas hyper-
tonic solutions of 7–7.5% NaCl are regarded as safe
(45). The efficacy and safety of 7.2–7.5% NaCl in com-
bination with 6% dextran 60/70, respectively, has
been demonstrated in nearly 2000 patients enrolled in
controlled clinical trials (8,38,46,47). At the injection
site, which in most cases was the cubital vein, no
phlebitis occurred (48).
Although the concept involves infusion of a small
 Small-volume resuscitation in clinical routine

volume (250 ml or approximately 4 ml/kg), there is a
considerable osmolar load. In a controlled clinical trial
short-lasting osmolalities above 350 mOsmol/kg have
been reported in 12 out of 55 patients after infusion
of 250 ml 7.5% NaCl/4–6% dextran 70 and in 8/51 pa-
tients of the control group receiving Ringer’s lactate
(50). However, most of these trauma patients (18/20)
had serum ethanol concentrations ⱖ 39 nmol/l, ac-
counting for at least 36 mOsmol of the total serum
osmolality measured. None of these patients pre-
sented with any acute clinical signs of hyperosmolal-
ity (49). Serum osmolality decreased within the first
4–8 h after bolus infusion, and after 24 h there was
no difference between those patients having received
hypertonic saline and the control group (6,49).
Infusion of hypertonic solutions of any solute may
provoke electrolyte imbalance. The increase of the
aforementioned serum osmolality is due to sodium
load. In a controlled clinical study in trauma patients
mean serum sodium concentration was 9 mEq/l
higher in the treatment group as compared to the con-
trol group at the time of arrival in the emergency
room (6). In the first blood sample taken after bolus
infusion of 250 ml 7.5% NaCl/6% dextran hypernatre-
mia above 160 mEq/l occurred in 2 out of 55 patients,
without neurological symptoms (49). Neuropatholog-
ical signs of central pontine myelolysis have not been
found in any of the patients who died.
Aside from the increase in serum sodium also chlor-
ide levels increase and may be associated with aci-
dosis (hyperchloremic acidosis). Although the general
concept of hyperchloremic acidosis was seldomly dis-
cussed in the anesthesiology literature until approxi-
mately a decade ago, the recent publication from
Scheingraber et al. (50) has demonstrated that infusion
of approximately 30 ml/kg/h saline (total amount 70
ml/kg b.w.) during anesthesia and surgery inevitably
leads to metabolic acidosis, which is associated with
hyperchloremia. However, this dose is approximately
double the sodium load administered contained in 4
ml/kg b.w. 7.5% saline, and even under the condition
of rapid infusion and thus eliciting higher initial
serum chloride concentrations, seems reasonable and
should not be responsible for acidosis observed in
critically ill patients. It seems more appropriate to as-
sume that by bolus infusion of hypertonic sodium
chloride solutions and improvement of nutritional
blood flow, a wash-out of acidic substances and meta-
bolites occurs in the sense of demasking so-called
‘hidden acidosis’ (51).

Table 3

Field of potential indication for small-volume hypertonic therapy.

Type of derangement/shock Phase Impact

Trauma Prehospital setting Volume substitution, microcirculatory resuscitation

Emergency room Microcirculatory resuscitation
Intraoperatively Volume substitution
Head trauma Increased intracranial pressure Lowering intracranial pressure, improvement of CBF
Hypovolemic shock Anaphylaxis Volume refill
Intraoperatively Volume substitution (in cases of sudden bleeding)
Septic shock Hyperdynamic state Volume substitution, microcirculatory resuscitation,
increase of tissue oxygen uptake
Hypodynamic state Reopening of shock-narrowed capillaries,
microcirculatory resuscitation
Burn injury Initial phase Reduction of edema formation, microcirculatory
resuscitation, attenuation of bacterial translocation
Intensive care Multiple organ dysfunction syn- Improvement of organ blood flow and organ function,
drome (MODS), organ failure attenuation of bacterial translocation
Cardiogenic shock Myocardial infarction Volume replenishment without risk of fluid overload,
positive inotropic effect
Cardiovascular surgery Aortic aneurysm Volume support in the phase of ‘declamping shock’,
attenuation of reperfusion injury,
reduction of volume requirements aiming at less positive fluid balance
Cardiac surgery Decrease of volume requirements, reduction of volume
requirements aiming at less positive fluid balance
Anesthesiological management Epidural anesthesia In general: no indication (for reasons of existing
alternatives working as well)
Physiological volume replacement In general: no indication (cf. above)

The term ‘small-volume resuscitation’ by means of hypertonic sodium colloid refers to the prevention or therapy of symptoms in combination
with severe hypovolemia and shock.
Fast i.v. infusion of hypertonic solutions may lead to short-lasting hypotension, which may be harmful in patients with compromised myocardial
function.

631
U. Kreimeier and K. Messmer
Further concerns of safety and potential compli-
cations have been addressed in experimental studies,
but their clinical relevance appears controversial (52–
55). This holds true for small-volume resuscitation as
the cause of aggravating blood loss in cases of uncon-
trolled hemorrhage (56–58, see later), risks of hyper-
natremia and hypokalemia, particularly in cases of
pre-existing dehydration (59), hemolysis and hemo-
globinuria (60), altered clotting times and platelet ag-
gregation (61) as a result of hypertonic saline itself,
and also the possibility of anaphylactic/anaphylacto-
id reactions (62), coagulation disorders (63), and tissue
storage (64) linked to the colloid component (see also
‘Possible adverse reactions due to the colloid compo-
nent’).
Of clinical importance, particularly in the prehospi-
tal trauma scenario, is the potential adverse effect of
hypertonic saline on blood loss in cases of uncon-
trolled hemorrhage: in the clinical studies, including
large numbers of patients with penetrating trauma,
increased bleeding has not been encountered. In con-
trast, those patients severely traumatized and needing
immediate surgery because of large blood losses have
benefited from small-volume resuscitation by means
of hypertonic saline dextran (46).
The user should be aware of the fact that bolus in-
fusion (i.e. application of 250 ml hypertonic solution
within 2 min) may be accompanied by an initial and
substantial, however very short-lasting drop in ar-
terial pressure (65,66), which might be harmful for pa-
tients with compromised myocardial function or coro-
nary heart disease who are incapable of compensating
for reduced coronary perfusion pression. However,
first, the period of hypotensive response usually lasts
less than 1 min, during which endogenous fluid mo-
bilization leads to an increase of cardiac preload and
thus enhancement of cardiac output, and second, car-
diac afterload is reduced at the same time because of
peripheral vasodilation resulting in reduced cardiac
work.
Although the use of a colloid solution seems intuit-
ively logical for the preservation of the circulatory
volume, it also means facing a double-edged sword:
besides a potential benefit with regard to sustained
circulatory stability, the colloid component bears the
risk of anaphylactoid reactions and thus increases the
risk of unwanted side-effects possibly elicited by the
hypertonic component per se (Table 4). It should be
noted that the application of hyperosmolar saline/
dextran solution proved safe in patients, and in none
of the controlled clinical trials have adverse effects
been attributed to the colloid component, nor have
anaphylactoid reactions been observed (4,8).
632
Possible adverse reactions as a result of
the colloid component
With the renaissance of dextran through the concept of
small-volume resuscitation, the discussion on possible
anaphylactoid reactions was again re-emerging. Al-
though relevant during application in cases of elective
surgery (e.g. when used for acute hemodilution under
normotension and stable circulation), where the prein-
jection of monovalent hapten dextran (PromitA, Phar-
malink, Spaånga, Sweden) is mandatory (so-called
hapten prophylaxis), it has to be stressed that so far
none of the severe DIARs in context with the appli-
cation of dextran occurring in patients with shock.
Therefore Laubenthal et al., based on the pathophysi-
ological mechanisms responsible for dextran anaphyl-
axis as well as on a survey about the safety of Dextran
in Central Europe (67), stated already in 1987 that ‘Pa-
tients in shock do not need the hapten prophylaxis.’
(68). Consequently, in the clinical trials where hyper-
tonic saline dextran solutions were used, no hapten
prophylaxis was applied, except for the patients en-
rolled in the first trial of Holcroft et al. (11).
Adverse reactions may occur with all synthetic col-
loids, even with human albumin (69,70). Most import-
antly, because of the nature of anaphylactoid reactions
these are independent from the amount of colloid ad-
ministered. In a prospective French multicenter trial
Laxenaire et al. (71) recorded 43 anaphylactoid reac-
tions, 20% of which were severe (grades III and IV), in
19,593 patients after the administration of different col-
loids. Among the diverse synthetic volume substitutes,
gelatins are the least effective with regard to their short
intravascular volume effect, which does not last for
more than 2–3 h. The major advantage is that there is no
dose limitation, unlike the restrictions placed on each
of the two other synthetic colloids. However, it was
suggested that gelatine in particular affects the func-
tionality of the von Willebrand factor and partly in-
hibits platelet adhesion (72). In addition, gelatine-
Table 4
Potential side-effects associated with small-volume resuscitation.
Hyperosmolar coma
Hypernatremia
Hypokalemia
Cerebral or peripheral seizures
Arrhythmia
Negative-inotropic effect (following rapid infusion)
Tissue necrosis (in cases of paravasation)
Hemolysis (at the injection site)
Enhanced bleeding (under uncontrolled hemorrhage)
Anaphylactoid reaction (linked to the colloid component)

based products seem to become incorporated into de-
veloping clots and reduce the function of fibronectin in
forming covalent cross-linkages and normal covalent
associations with fibrin, thus interfering with the poly-
merization of fibrin monomers and reducing the qual-
ity of clot formation (73). Moreover, both urea-linked
and modified fluid gelatins carry a comparably high
risk of adverse reactions, as reported by Lorenz et al.
(74) and Laxenaire et al. (71). Following induction of
general anesthesia and volume loading with 500 ml
Haemaccel-35, Lorenz et al. reported clinically relevant
or even life-threatening cardiorespiratory side-effects
related to histamine release in 15 of 57 patients (26%),
in contrast to only 8% in controls receiving Ringer solu-
tion (74). Finally, the discussion about vCJD revealed
additional uncertainty on the safety of gelatins. Both,
the low oncotic property and the higher risk of possible
adverse effects were reasons why gelatins have not
been considered as colloid components in the concept
of small-volume resuscitation by means of hypertonic
colloid solutions.
It is argued that dextrans, superior plasma substi-
tutes, in particular are associated with anaphylactic/
anaphylactoid reactions (which may occur with any
colloid; 71), coagulation abnormalities (if used in a dose
exceeding 1.5 g/kg/day) and impaired blood cross-
matching (also, if used in great amounts). Through the
implementation of the hapten prophylaxis, however,
the incidence of severe dextran-induced anaphylatic
reactions (DIAR; grade III–V) has been reduced from
1:2000 patients (1975–79) to 1:70,000 patients (1983–92)
in Sweden, where reporting of severe adverse drug re-
actions is mandatory (75).
An essential argument in favor of the hydroxyethyl
starch solution has long been the lack of evidence for
the existence of preformed antibodies against hydroxy-
ethyl starch (HES). However, in 1995 a patient treated
in our institution for blood analysis unequivocally re-
vealed preformed hydroxyethyl starch-reactive anti-
bodies (76). Blood samples had been taken during aor-
tic aneurysm surgery when severe hemodynamic insta-
bility occurred, and an adverse reaction was suspected.
A HES antibody titre assay based on the highly sensi-
tive ELISA technique on both pre- and post-reaction
serum samples revealed the neutralization of pre-
formed antibody titres upon exposure to HES and the
reappearance of specific antibodies within 4–8 weeks,
suggesting anaphylaxis as described by Richter et al.
(77). Moreover, it has been shown that medium mol-
ecular weight hydroxyethyl starch in particular lowers
factor VIII:C concentration (78), which may prove haz-
ardous to patients who need full hemostatic com-
petence. At this point it seems reasonable to assume
Small-volume resuscitation in clinical routine
that HES reduces the levels of fibrinogen coagulation
factors, factor VIII, and von Willebrand factor, and re-
duces platelet function.
The new hydroxyethyl starch HES 130,000/0.4 was
designed to provide more oncotically effective small
molecules, and to enhance metabolism and renal elim-
ination of the substance. In addition, HES 130,000/0.4
has been reported to be associated with lower intra-
operative blood loss, less transfusion requirements of
packed red blood cells, and a more pronounced in-
crease of von Willebrand factor in the postoperative
period as compared to HES 200,000/0.5, when both
substances were administered in identical amounts
(79).
6% Hydroxyethyl starch 200,000 is a perioperatively
widely used plasma substitute with a recommended
dose limit of 2 g/kg b.w./24 h. The same holds true for
dextran, which has a recommended daily dose limit of
1.5 g/kg b.w. (i.e. about 1750 ml in a 75-kg patient).
Principally, these limits have been set to avoid poten-
tial interference with the coagulation system, primar-
ily as a result of the dilution of coagulation factors
and associated depression of thrombocyte counts.
During small-volume resuscitation, however, only
very low amounts of a colloid are administered, so
that the issue of maximum dose of the specific colloid
used with the hypertonic colloid solution per se is of
no clinical relevance. However, we have to bear in
mind that small-volume resuscitation is intended as
first line therapy, followed by conventional fluid ther-
apy as needed to achieve stable hemodynamics.
Clinical use and spectrum of indications
There are several infusion solutions available that
contain hypertonic saline in combination with a col-
loid (Table 5). Austria was the first European country
in which small-volume resuscitation by means of a
hypertonic saline colloid solution became clinical rou-
tine for resuscitation from severe trauma and shock:
OsmohesTM (Laevosan, Linz) was authorized in July
1994, and 3 years later HyperhesTM (Fresenius Kabi
Austria, Graz) was registered and became clinically
available. According to the manufacturer’s data, the
use of 56,000 units has so far been documented in Au-
stria. In their survey from Austria, Schimetta et al. (80)
give important insight into drug safety of small-vol-
ume resuscitation by means of hypertonic saline
starch solution. They calculate the incidence of ad-
verse reactions to be of the order 8–16 in 100,000 pa-
tients treated (80).
The therapeutic indication essentially is primary re-
suscitation from severe hypovolemia and shock. It
633
U. Kreimeier and K. Messmer

should be noted, however, that according to the manu-
facturer’s specifications, the product profile differs be-
tween the indication for RescueFlowTM (BioPhausia
AB, Uppsala, Sweden) and HyperHAESTM (Fresenius
Kabi Deutschland GmbH, Bad Homburg, Germany),
both of which are available in Germany. These solu-
tions have been registered in 1999 (RescueFlowTM in
eight European countries) and 2000 (HyperHAESTM in
Germany only), respectively. Table 6 gives a summary
of the pharmacologic properties and indication for
their use. It can clearly be seen that the focus of indi-
cation is the preclinical treatment of severe hypovolem-
ia and shock. However, likewise in the perioperative
setting their use may be considered (81) (Table 3) – al-
though not specifically listed in the manufacturer’s
specifications. Thus beneficial effects of this concept
could be demonstrated in clinical trials in patients un-
dergoing cardiac surgery (82–86) and vascular surgery
(87–91) as well as in critically ill patients with burn in-
jury (92,93), with increased intracranial pressure (94–
98) and sepsis syndrome (99,100). The positive effect on
increased intracranial pressure has been established in

Table 5

Commercially available solutions used for small-volume resuscitation from trauma and shock.

Name Content Country registered

Registered solutions:
Plasmadex-Hiper 7.5% NaCl/6% dextran 70 Brazil
Hiperton 7.5% NaCl/6% dextran 70 Mexico
Macrodex HT 7.5% NaCl/6% dextran 70 Argentina
Osmohes 7.2% NaCl/10% HES 200/0.5 Austria
Tensiton 7.5% NaCl/6% dextran 70 Czech Republic
Hyperhes 7.5% NaCl/6% HES 200/0.60–0.66 Austria
Osmohes 7.2% NaCl/10% HES 200/0.5 Hungary
RescueFlow 7.5% NaCl/6% dextran 70 European community (eight countries)
HyperHAES 7.2% NaCl/6% HES 200/0.5 Germany
Registration pending:
RescueFlow 7.5% NaCl/6% dextran 70 U.S.A.
HyperHAES 7.2% NaCl/6% HES 200/0.5 European community

Table 6

Pharmacologic properties and indications for the use of RescueFlowTM and HyperHAESTM.

RescueFlowTM HyperHAESTM

Electrolyte concentration 7.5% NaCl 7.2% NaCl

Sodium content 1283 mmol/l 1232 mmol/l
Chloride content 1283 mmol/l 1232 mmol/l
Theoretical osmolarity 2567 mOsmol/l 2464 mOsmol/l
pH 3.5–7.0 3.5–6.0
Colloid Dextran Hydroxyethyl starch
Mean molecular weight 70,000 200,000
Degree of substitution – 0.40–0.55
Colloid concentration 6% 6%
Colloid content 60 g/l 60 g/l
Colloid osmotic pressure approx. 70 mmHg Approx. 36 mmHg
Container volume 250 ml 250 ml
Recommended dose Approx. 250 ml (4 ml/kg b.w.) Approx. 250 ml (4 ml/kg b.w.)
Indication* Initial treatment of hypovolemia Initial treatment of acute hypovo-
with hypotension induced by trau- lemiad and shock (so-called
matic injury ‘small-volume resuscitation’)
Special warnings* Pretreatment with hapten dextran Interference in the diagnosis
(PromitA) has been shown to of pancreatitis may be en-
reduce the risk of hypersensi- countered following administra-
tivity reactions during dextran tion of hydroxyethyl starch
usage
Manufacturer BioPhausia AB, Uppsala, Sweden Fresenius Kabi Deutschland
GmbH, Bad Homburg, Germany

*According to drug specifications from the manufacturers, RescueFlowTM and HyperHAESTM. In addition, HyperHESTM (7.5% NaCl/6% HES
200,000/0.62; Fresenius Kabi Austria) has been available in Austria since 1997.

634

patients with isolated head trauma or multiple trauma,
while in cases of existing capillary leak (burn injury,
sepsis) a short-lasting hemodynamic effect has been
shown (increase of cardiac output and DO2, reduction
of oxygen extraction rate).
A major difference among all these studies and the
acute, preclinical use (i.e. in cases of primary resusci-
tation from trauma and shock) is that nearly all inves-
tigators infused hypertonic solutions more slowly
(typically over 20 min) than suggested for resusci-
tation from hemorrhagic shock (2–5 min). Neverthe-
less, they still could demonstrate that the application
is efficient in terms of increase of cardiac filling press-
ure and a concomitant increase of cardiac output and
oxygen delivery (101). In some high-risk patients, it
seems advisable to closely monitor the cardiac re-
sponse to fluid loading with hypertonic solutions and
best to titrate the infused volume against the changes
of pulmonary capillary wedge pressure (102). Most
trials in cardiac and vascular surgery revealed less
positive perioperative fluid balance than after conven-
tional fluid therapy (101), and in our own intraopera-
tive study in patients with aortic aneurysm surgery
we observed improved hemodynamic stability and
pulmonary function (89).
Impact on patients with trauma
combined with head injury
In the beginning criticism has arisen from the poten-
tial risk of hypertonic saline solution in cases of severe
trauma together with head injury. When used for re-
suscitation from experimental hemorrhagic shock in
presence of intracranial hypertension, however, 7.2%
saline has been shown to reduce intracranial pressure
and improve regional cerebral blood flow (103,104).
These findings have been confirmed in polytraumatiz-
ed ICU patients with increased intracranial pressure,
non-responding to conventional therapy, in whom al-
ready 5 min post infusion of 4 ml/kg 7.5% NaCl/hy-
droxyethyl starch 200,000/0.6 (105). Intracranial
pressure had decreased significantly; this was paral-
leled by an increase of cerebral perfusion pressure
(CPP) by 19–43%.
Conclusion
Small-volume resuscitation is defined as bolus in-
fusion of 250 ml (i.e. approximately 4 ml/kg b.w) of
hypertonic saline colloid solution within 2–5 min
through a peripheral vein for primary resuscitation
from severe hypovolemia and shock, generally seen
after severe trauma and hemorrhage. Besides the
Small-volume resuscitation in clinical routine
rapid restoration of macrohemodynamics and preven-
tion of early death, this concept particularly aims at
the prevention of late complications (sepsis, MSOF)
resulting from protracted microcirculatory disturb-
ances. The most important mechanism of action at the
level of the microcirculation is the mobilization of en-
dogenous fluid primarily from edematous endothelial
cells, by which the rectification of shock-narrowed
capillaries and the restoration of nutritional blood
flow is efficiently promoted. By the combined use of
hypertonic saline together with a potent colloid (dex-
tran, hydroxyethyl starch) the circulating effect is not
only prolonged, but, in cases of higher concentrated
colloid content (10% dextran 60/70) it is also potenti-
ated. Apart from a beneficial specific pharmacologic
effect the colloid compound might lead to higher inci-
dence of side-effects: besides hyperosmolarity and
hypernatremia, which are both essential for provok-
ing the circulatory effect through establishment of an
osmotic gradient across cellular membrane, anaphyl-
actoid reactions linked to the colloid may occur. How-
ever, these seem to be negligible in the acute phase of
the preclinical scenario. One therefore should bear in
mind that small-volume resuscitation by means of hy-
pertonic colloid solution does not mean a given form
of simple volume therapy with a somewhat enhanced
volume effect, but resuscitation from trauma and
shock by means of a highly potent agent.
References
1. Nakayama S, Sibley L, Gunther RA, Holcroft JW, Kramer
GC. Small-volume resuscitation with hypertonic saline
(2,400 mosm/liter) during hemorrhagic shock. Circ Shock
1984: 13: 149–159.
2. Guyton AC. The body fluid compartments: extracellular and
intracellular fluids; interstitial fluid and edema. In: Guyton
AC, ed. Textbook of Medical Physiology. Philadelphia: W.B.
Saunders, 1991: 274–285.
3. Messmer K, Kreimeier U. Microcirculatory therapy in shock.
Resuscitation 1989: 18 (Suppl.): S51–S61.
4. Kreimeier U, Thiel M, Messmer K. Hypertonic-hyperoncotic
solutions. In: Risberg B, eds. Trauma Care – an Update. Stock-
holm: Pharmacia and Upjohn Sverige AB, 1996:142–153.
5. Younes RN, Aun F, Ching CT, Goldenberg DC, Franco MH,
Miura FK. et al. Prognostic factors to predict outocome fol-
lowing the administration of hypertonic/hyperoncotic solu-
tion in hypovolemic patients. Shock 1997: 7: 79–83.
6. Mattox KL, Maningas PA, Moore EE, Mateer JR, Marx JA,
Aprahamian C. et al. Prehospital hypertonic saline/dextran
infusion for post-traumatic hypotension – the U.S.A. multi-
center trial. Ann Surg 1991: 213: 482–491.
7. Vassar MJ, Fischer RP, O’Brien PE, Bachulis BL, Chambers
JA, Hoyt DB et al. A multicenter trial for resuscitation of
injured patients with 7.5% sodium chloride. The effect of
added dextran 70. Arch Surg 1993: 128: 1003–1013.
8. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN,
Efficacy of hypertonic 7. 5% saline and 6% dextran-70 in
635
U. Kreimeier and K. Messmer
treating trauma: a meta-analysis of controlled clinical
studies. Surgery 1997: 122: 609–616.
9. Kreimeier U, Messmer K. Small-volume resuscitation. In:
Kox WJ, Gamble J, eds. Fluid Resuscitation. Baillière’s Clin-
ical Anaesthesiology. Vol. 2. London: Baillière Tindall, 1988:
545–577.
10. Kreimeier U, Frey L, Messmer K. Small-volume resusci-
tation. Curr Opinion Anaesth 1993: 6: 400–408.
11. Holcroft JW, Vassar MJ, Turner JE, Derlet RW, Kramer GC.
3% NaCl and 7.5% NaCl/dextran 70 in the resuscitation of
severely injured patients. Ann Surg 1987: 206: 279–288.
12. Walsh JC, Kramer GC. Resuscitation of hypovolemic sheep
with hypertonic saline/dextran: the role of dextran. Circ
Shock 1991: 34: 336–343.
13. Kreimeier U, Brueckner UB, Schmidt J, Messmer K. Instan-
taneous restoration of regional organ blood flow after severe
hemorrhage: effect of small-volume resuscitation with hy-
pertonic-hyperoncotic solutions. J Surg Res 1990: 49: 493–503.
14. Nolte D, Bayer M, Lehr HA, Becker M, Krombach F, Kreime-
ier U. et al. Attenuation of postischemic microvascular dis-
turbances in striated muscle by hyperosmolar saline dex-
tran. Am J Physiol 1992: 263: H1411–H1416.
15. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN.
Efficacy of hypertonic saline/dextran (HSD) or hypertonic
saline (HS) on survival following traumatic injury: a meta-
analysis. Abstracts of the International Conference on Hy-
pertonic Resuscitation SALT 6, Teton Village, Wyoming,
June 2–3, 1994.
16. Kreimeier U, Brückner UB, Niemczyk S, Messmer K. Hyper-
osmotic saline dextran for resuscitation from traumatic-he-
morrhagic hypotension: effect on regional blood flow. Circ
Shock 1990: 32: 83–99.
17. Smith GJ, Kramer GC, Perron P, Nakayama S, Gunther RA,
Holcroft JW. A comparison of several hypertonic solutions
for resuscitation of bled sheep. J Surg Res 1985: 39: 517–
528.
18. Kreimeier U, Frey L, Dentz J, Herbel T, Messmer K. Hyper-
tonic saline dextran resuscitation during the initial phase of
acute endotoxemia: effect on regional blood flow. Crit Care
Med 1991: 19: 801–809.
19. Kreimeier U, Thiel M, Peter K, Messmer K. Small-volume
hyperosmolar resuscitation. Acta Anaesthesiol Scand 1997: 41
(Suppl. 111): 302–306.
20. Reed LL, Manglano R, Martin M, Hochman M, Kocka F,
Barrett J. The effect of hypertonic saline resuscitation on bac-
terial translocation after hemorrhagic shock in rats. Surgery
1991: 110: 685–690.
21. Tokyay R, Zeigler ST, Kramer GC, Rogers CS, Heggers JP,
Traber DL. et al. Effects of hypertonic saline dextran resusci-
tation on oxygen delivery, oxygen consumption, and lipid
peroxidation after burn injury. J Trauma 1992: 32: 704–713.
22. Chiao JJC, Jones WG, Shires GT, Barber AE. Effect of sepsis on
intracellular sodium activity, sodium concentration, and
water content in thermal injured rat. Circ Shock 1992: 38: 42–
49.
23. Hernandez LA, Grisham MB, Twohig B, Arfors K-E, Harlan
JM, Granger DN. Role of neutrophils in ischemia-reper-
fusion-induced microvascular injury. Am J Physiol 1987: 253:
H699–H703.
24. Granger DN, Benoit JN, Suzuki M, Grisham MB. Leukocyte
adherence to venular endothelium during ischemia-reper-
fusion. Am J Physiol 1989: 20: G683–G688.
25. Thiel M, Buessecker F, Eberhardt K, Chouker A, Setzer F,
Kreimeier U. et al. Effects of hypertonic saline on expression
of human polymorphonuclear leukocyte adhesion mol-
ecules. J Leukoc Biol 2001: 70: 261–273.
636
26. Lehr HA, Saetzler RK, Thiel M, Arfors KE. Microvascular
salvage by small volume resuscitation with hypertonic
fluids: concepts and facts. In: Messmer K, ed. Compromised
Perfusion. Prog Appl Microcirc Vol. 22. Basel: Karger-Verlag,
1996: 167–180.
27. Steinbauer M, Harris A, Hoffmann T, Messmer K. Pharma-
cological effects of dextrans on the postischemic leukocyte–
endothelial interaction. In: Messmer K, ed. Compromised
Perfusion. Prog Appl Microcirc Vol. 22. Basel: Karger-Verlag,
1996: 114–125.
28. Steinbauer M, Harris AG, Leiderer R, Abels C, Messmer K.
Impact of dextran on microvascular disturbances and tissue
injury following ischemia/reperfusion in striated muscle.
Shock 1998: 9: 345–351.
29. Nolte D, Lehr HA, Messmer K. Dextran and adenosine-
coupled dextran reduce postischemic leukocyte adhesion in
postcapillary venules of the hamster. Prog Appl Microcirc. Ba-
sel: Karger-Verlag, 1991: 18: 103–111.
30. Menger MD, Thierjung C, Hammersen F, Messmer K. Dex-
tran vs. hydroxyethylstarch in inhibition of postischemic
leukocyte adherence in striated muscle. Circ Shock 1993: 41:
248–255.
31. Corso CO, Okamoto S, Rüttinger D, Messmer K. Hypertonic
saline dextran attenuates leukocyte accumulation in the
liver after hemorrhagic shock and resuscitation. J Trauma
1999: 46: 417–423.
32. Angle N, Cabello-Passini R, Hoyt DB, Loomis WH, Shreve
A, Namiki S. et al. Hypertonic saline infusion: can it regulate
human neutrophil function? Shock 2000: 14: 503–508.
33. Junger WG, Coimbra R, Liu FC, Herdon-Remelius C, Junger
W, Junger H et al. Hypertonic saline resuscitation: a tool to
modulate immune function in trauma patients? Shock 1997:
8: 235–241.
34. Rizoli SB, Kapus A, Fan J, Li YH, Marshall JC, Rotstein OD.
Immunomodulatory effects of hypertonic resuscitation on
the development of lung inflammation following hemor-
rhagic shock. J Immunol 1998: 161: 6288–6296.
35. Rizoli SB, Kapus A, Parodo J, Rotstein OD. Hypertonicity
prevents lipopolysaccharide-stimulated CD11b/CD18 ex-
pression in human neutrophils in vitro: role for p38 inhi-
bition. J Trauma 1999: 46: 794–798.
36. Holcroft JW, Vassar MJ, Turner JE, Derlet RW, Kramer GC.
3% NaCl and 7.5% NaCl/Dextran 70 in the resuscitation of
severely injured patients. Ann Surg 1987: 206: 279–286.
37. Holcroft JW, Vassar MJ, Perry CA, Gannaway WL, Kramer
GC. Perspectives on clinical trials for hypertonic saline/dex-
tran solutions for the treatment of traumatic shock. Braz J
Med Biol Res 1989: 22: 291–293.
38. Kramer GC, Wade CE, Prough DS. Hypertonic saline dex-
tran: efficacy and regulatory approval [editorial]. Acta Anaes-
thesiol Scand 1998: 42: 141–144.
39. Vassar MJ, Perry CA, Gannaway WL, Holcroft JW. 7.5% so-
dium chloride/dextran for resuscitation of trauma patients
undergoing helicopter transport. Arch Surg 1991: 126: 1065–
1072.
40. Mols P, Robert P, Henry B, Fox A, Gillet JB, Flamand JP
et al. Study on the feasibility and hemodynamic efficacy of
intravenous administration of small 7.2% Nacl/6% hydroxy-
ethyl starch 200/0.5 in trauma patients during the prehospi-
tal period – a pilot study. JEUR 1999: 3: 99–104.
41. Holcroft JW, Vassar MJ, Perry CA, Gannaway WL, Kramer
GC. Use of a 7.5% NaCl/6% Dextran 70 solution in the re-
suscitation of injured patients in the emergency room. Prog
Clin Biol Res 1989: 299: 331–338.
42. Younes RN, Aun F, Accioly CQ, Casale LP, Szajnbok I, Biroli-
ni D. Hypertonic solutions in the treatment of hypovolemic

shock: a prospective, randomized study in patients admitted
to the emergency room. Surgery 1992: 111: 380–385.
43. Marmarou A, Anderson RL, Ward JD, Choi SC, Young HF,
Eisenberg HM. et al. Impact of ICP instability and hypoten-
sion on outcome in patients with severe head trauma. J Neu-
rosurg 1991: 75: S59–S66.
44. Bunn F, Roberts I, Tasker R, Akpa E. Hypertonic versus iso-
tonic crystalloid for fluid resuscitation in critically ill pa-
tients (Cochrane Review). Cochrane Library 2000: 4.
45. Rocha e Silva M, Velasco IT, Porfirio MF. Hypertonic saline
resuscitation: saturated salt-dextran solutions are equally ef-
fective, but induce hemolysis in dogs. Crit Care Med 1990:
18: 203–207.
46. Wade C, Grady J, Kramer G. Efficacy of hypertonic saline
dextran (HSD) in patients with traumatic hypotension:
meta-analysis of individual patient data. Acta Anaesthesiol
Scand Suppl 1997: 110: 77–79.
47. Rocha e Silva M, Poli de Figueiredo LF. Hypertonic solu-
tions. In: Baue AE, Faist E, Fry DE, eds. Multiple Organ Fail-
ure. Pathophysiology, Prevention, and Therapy. New York, Ber-
lin, Heidelberg: Springer, 2000: 605–612.
48. Vassar MJ, Holcroft JW. Use of hypertonic-hyperoncotic
fluids for resuscitation of trauma patients. J Intensive Care
Med 1992: 7: 189–198.
49. Vassar MJ, Perry CA, Holcroft JW. Analysis of potential risks
associated with 7.5% sodium chloride resuscitation of trau-
matic shock. Arch Surg 1990: 125: 1309–1315.
50. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid
saline infusion produces hyperchloremic acidosis in patients
undergoing gynecologic surgery. Anesthesiology 1999: 90:
1265–1270.
51. Bergentz SE, Carlsten A, Gelin LE, Kreps J. ‘Hidden acidosis’
in experimental shock. Ann Surg 1969: 169: 227–232.
52. Krausz MM, Kablan M, Rabinovici R, Klin B, Sherman Y,
Gross D. Effect of injured vessel size on bleeding following
hypertonic saline infusion in uncontrolled hemorrhagic
shock in anesthetized rats. Circ Shock 1991: 35: 9–13.
53. Krausz MM, Landau EH, Klin B, Gross D. Hypertonic saline
treatment of uncontrolled hemorrhagic shock at different
periods from bleeding. Arch Surg 1992: 127: 93–96.
54. Prist R, Rocha e Silva M, Velasco IT, Loureiro MI. Press-
ure-driven hemorrhage: a new experimental design for
the study of crystalloid and small-volume hypertonic re-
suscitation in anesthetized dogs. Circ Shock 1992: 36: 13–
20.
55. Bilynskyj MCV, Errington ML, Velasco IT, Rocha e Silva M.
Effect of hypertonic sodium chloride (7.5%) on uncontrolled
hemorrhage in rats and its interaction with different anes-
thetic procedures. Circ Shock 1992: 36: 68–73.
56. Rabinovici R, Yue TL, Krausz MM, Sellers TS, Lynch KM,
Feuerstein G. Hemodynamic, hematologic and eicosanoid
mediated mechanisms in 7.5 percent sodium chloride treat-
ment of uncontrolled hemorrhagic shock. Surg Gynecol Ob-
stet 1992: 175: 341–354.
57. Krausz MM, Horn Y, Gross D. The combined effect of small
volume hypertonic saline and normal saline solutions in un-
controlled hemorrhagic shock. Surg Gynecol Obstet 1992: 174:
363–368.
58. Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade
CE. Use of hypertonic saline/dextran versus lactated
Ringer’s solution as a resuscitation fluid after uncontrolled
aortic hemorrhage in anesthetized swine. Ann Emerg Med
1992: 21: 1077–1085.
59. Wade CE, Tillman FJ, Loveday JA, Blackmon A, Potanko E,
Hunt MM. et al. Effect of dehydration on cardiovascular re-
sponses and electrolytes after hypertonic saline/dextran
Small-volume resuscitation in clinical routine
treatment for moderate hemorrhage. Lab Invest 1992: 21: 113–
119.
60. Moon PF, Snyder JR, Haskins SC, Perron PR, Kramer GC.
Effects of a highly concentrated hypertonic saline-dextran
volume expander on cardiopulmonary function in anesthet-
ized normovolemic horses. Am J Vet Res 1991: 52: 1611–
1618.
61. Reed RL, Johnston JD, Chen Y, Fischer RP. Hypertonic saline
alters plasma clotting times and platelet aggregation. J
Trauma 1991: 31: 8–14.
62. Summary JJ, Dubick MA, Zaucha GM, Kilani AF, Korte DW,
Wade CE. Acute and subacute toxicity of 7.5% hypertonic
saline/6% dextran-70 (HSD) in dogs 1. Serum immunoglob-
ulin and complement responses. J Appl Toxicol 1992: 12: 261–
266.
63. Hess JR, Dubick MA, Summary JJ, Bangal NR, Wade CE. The
effects of 7.5% NaCl/6% Dextran 70 on coagulation
and platelet aggregation in humans. J Trauma 1992: 32: 40–
44.
64. Dubick MA, Ryan BA, Summary JJ, Wade CE. Dextran met-
abolism following infusion of 7.5% NaCl/6% Dextran-70 to
euvolemic and hemorrhaged rabbits. Drug Dev Res 1992: 25:
29–38.
65. Kien ND, Kramer GC, White DA. Acute hypotension caused
by rapid hypertonic saline infusion in anesthetized dogs.
Anesth Analg 1991: 73: 597–602.
66. Frey L, Kesel K, Prückner S, Pacheco A, Welte M, Messmer
K. Is sodium acetate dextran superior to sodium chloride
dextran for small volume resuscitation from traumatic he-
morrhagic shock? Anesth Analg 1994: 79: 517–524.
67. Laubenthal H. Dextrananaphylaxie, Pathomechanismus und
Prophylaxe. Anaesthesiologie und Intensivmedizin. 1986:
169: 1–129.
68. Laubenthal H, Peter K, Messmer K. Dextran for traumatic
shock patients in spite of possible anaphylactic reactions?
Circ Shock 1987: 21: 372.
69. Messmer KFW. The use of plasma substitutes with special
attention to their side effects. World J Surg 1987: 11: 69–74.
70. Ring J. Anaphylactoid reactions to intravenous solutions
used for Volume substitution. Clin Rev Allergy 1991: 9: 397–
414.
71. Laxenaire MC, Charpentier C, Feldman L, Group Francais
d’Etude de la Tolérance des Substituts Plasmatiques. Ana-
phylactoid reactions to colloid plasma substitutes: frequency,
risk factors, mechanisms. A French prospective multicentre
inquiry. Ann Fr Anesth Réanim 1994: 13: 301–310.
72. Tabuchi N, de Haan J, Huet RCGG, Boonstra PW, van
Oeveren W. Gelatin use impairs platelet adhesion during
cardiac surgery. Thromb Haemost 1995: 74: 1447–1451.
73. Mardel SN, Saunders F, Ollerenshaw L, Edwards C, Badde-
ley D. Reduced quality of in-vitro clot formation with gela-
tin-based plasma substitutes (letter to the editor). Lancet
1996: 347: 825.
74. Lorenz W, Duda D, Dick W, Sitter H, Doenicke A, Black
A. et al. Incidence and clinical importance of perioperative
histamine-release: randomized study of volume loading and
antihistamines after induction of anesthesia. Lancet 1994:
343: 933–940.
75. Ljungström KG. Safety of dextran in relation to other col-
loids – ten years experience with hapten inhibition. In-
fusionsther Transfusionsmed 1993: 20: 206–210.
76. Kreimeier U, Christ F, Kraft D, Lauterjung L, Niklas M, Peter
K. et al. Anaphylaxis due to hydroxyethyl-starch-reactive
antibodies. Lancet 1995: 346: 49–50.
77. Richter AW, Hedin HI. Dextran hypersensitivity. Immunol
Today 1982: 3: 132–138.
637
U. Kreimeier and K. Messmer
78. Kapiotis S, Quehenberger P, Eichler HG, Schwarzinger I,
Partan C, Schneider B. et al. Effect of hydroxyethyl starch on
the activity of blood coagulation and fibrinolysis in healthy
volunteers: comparison with albumin. Crit Care Med 1994:
22: 606–612.
79. Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-But-
ijn WT, Haagenaars JA, van Oeveren W et al. A novel hydro-
xyethyl starch (Voluven) for effective perioperative plasma
volume substitution in cardiac surgery. Can J Anaesth 2000:
47: 1207–1215.
80. Schimetta W, Schöchl H, Kröll W, Pölz W, Pölz G, Mauritz
W. Safety of hypertonic hyperoncotic solutions – a survey
from Austria. Wien Klin Wochenschr 2002: 114: 89–95.
81. Tollofsrud S, Kramer GC. Intra-operative use of hypertonic
solutions. In: Vincent J-L, ed. Yearbook of Intensive Care and
Emergency Medicine 2000. Berlin Heidelberg: Springer, 2000:
476–485.
82. Boldt J, Knothe C, Zickmann B, Hammermann H, Stertmann
WA, Hempelmann G. Volume loading with hypertonic sa-
line solution: endocrinologic and circulatory responses. J
Cardiothorac Vasc Anesth 1994: 8: 317–323.
83. Boldt J, Hammermann H, Hempelmann G. Kolloidhaltige
hypertone Lösungen in der Kardiochirurgie. Zentralbl Chir
1993: 118: 250–256.
84. Sirieix D, Hongnat JM, Delayance S, D’Attellis N, Vicaut E,
Berrebi A. et al. Comparison of the acute hemodynamic ef-
fects of hypertonic or colloid infusions immediately after mi-
tral valve repair. Crit Care Med 1999: 27: 2159–2165.
85. Prien T, Thülig B, Wüsten R, Schoofs J, Weyand M, Lawin
P. Hyperton-Hyperonkotischer Volume Nersatz (7.5%
NaCl/10 % Hydroxyethylstärke 200000/605) bei Patienten
mit Koronararterienstenosen. Zentralbl Chir 1993: 118: 257–
266.
86. Tollofsrud S, Noddeland H. Hypertonic saline and dextran
after coronary artery surgery mobilises fluid excess and im-
proves cardiorespiratory functions. Acta Anaesthesiol Scand
1998: 42: 154–161.
87. Shackford SR, Sise MJ, Fridlund PH, Rowley WR, Peters
RM, Virgilio RW et al. Hypertonic sodium lactate versus lac-
tated Ringer’s solution for intravenous fluid therapy in op-
erations on the abdominal aorta. Surgery 1983: 94: 41–51.
88. Christ F, Niklas M, Kreimeier U, Lauterjung L, Peter K,
Messmer K. Hyperosmotic-hyperoncotic solutions during
abdominal aortic aneurysm (AAA) resection. Acta Anaes-
thesiol Scand 1997: 41: 62–70.
89. Auler JOC, Pereira MHC, Gomide-Amaral RV, Stolf NG, Jat-
ene AD, Rocha e Silva M. Hemodynamic effects of hyper-
tonic sodium chloride during surgical treatment of aortic
aneurysms. Surgery 1987: 101: 594–601.
90. Ragaller M, Müller M, Bleyl JU, Strecker A, Segiet TW, El-
linger K et al. Hemodynamic effects of hypertonic hydroxye-
thyl starch 6% solution and isotonic hydroxyethyl starch 6%
solution after declamping during abdominal aortic aneu-
rysm repair. Shock 2000: 13: 367–373.
91. Albrecht MD, Schroth M, Fähnle M, Ellinger K. Effects of
hypertonic-hyperoncotic infusion on the human atrial natri-
uretic factor in a standardized clinical trial. Shock 1995: 3:
152–156.
92. Bowser BH, Caldwell FTJ. The effects of resuscitation with
hypertonic vs. hypotonic vs. colloid on wound and urine
fluid and electrolyte losses in severely burned children. J
Trauma 1983: 23: 916–923.
93. Monafo WW, Halverson JD, Schechtman K. The role of con-
centrated sodium solutions in the resuscitation of patients
with severe burns. Surgery 1984: 95: 129–135.
638
94. Worthley LIG, Cooper DJ, Jones N. Treatment of resistant
intracranial hypertension with hypertonic saline. J Neurosurg
1988: 68: 478–481.
95. Härtl R, Ghajar J, Hochleuthner H, Mauritz W. Hypertonic/
hyperoncotic saline reliably reduces ICP in severely head-
injured patients with intracranial hypertension. Acta Neuro-
chir (Wien) 1997: 70 (Suppl.): 126–129.
96. Weinstabl C, Hammerle AF. Hypertone, hyperonkotische
Hydroxyäthylstärke-Lösung zur Senkung des intrakraniel-
len Druckes. Fortschr Anaesth 1992: 6: 105–107.
97. Hannemann L, Meyer-Hellmann A, Kuss B, Brock M, Rein-
hart K. Reduction of therapy-resistant intracranial pressure
by application of hypertonic saline (7.5%). Crit Care Med
1990: 18: S205.
98. Horn P, Munch E, Vajkoczy P, Herrmann P, Quintel M,
Schilling L. et al. Hypertonic saline solution for control of
elevated intracranial pressure in patients with exhausted
response to mannitol and barbiturates. Neurol Res 1999: 21:
758–764.
99. Hannemann L, Korell R, Kuss B, Reinhart K. Effects of hy-
pertonic saline on hemodynamic and oxygen transport- re-
lated variables in critically ill patients. Eur Surg Res 1990:
22: 313.
100. Hannemann L, Reinhart K, Korell R, Spies C, Bredle DL.
Hypertonic saline in stabilized hyperdynamic sepsis. Shock
1996: 5: 130–134.
101. Christ F. Hyperosmotic saline solutions in clinical patient
care. Curr Opin Crit Care 1999: 5: 293–299.
102. Ellinger K, Fähnle M, Schroth M, Albrecht DM. Optimal
preoperative titrated dosage of hypertonic-hyperoncotic
solutions in cardiac risk patients. Shock 1995: 3: 167–172.
103. Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS.
Regional cerebral blood flow following resuscitation from
hemorrhagic shock with hypertonic saline – influence of a
subdural mass. Anesthesiology 1991: 75: 319–327.
104. Schürer L, Dautermann C, Härtl R, Murr R, Berger S,
Röhrich F. et al. Treatment of hemorrhagic hypotension
with hypertonic/hyperoncotic solutions: effects on regional
cerebral blood flow and brain surface oxygen tension. Eur
Surg Res 1992: 24: 1–12.
105. Hammerle AF, Weinstabl C, Mayer N, Germann P, Steltzer
H. Decrease of intracranial pressure following a combi-
nation of hypertonic saline and hydroxyethyl starch. In:
Baron JF, ed. Plasma Volume Expansion. Paris: Arnette
Blackwell, 1992: 231–233.
106. Prist R, Rocha e Silva M, Velasco IT, Loureiro MI. Pressure-
driven hemorrhage: a new experimental design for the
study of crystalloid and small-volume hypertonic resusci-
tation in anesthetized dogs. Circ Shock 1992: 36: 13–20.
107. Kreimeier U, Schmidt J, Brückner UB, Schoenberg M,
Messmer K. Hypertonic-hyperoncotic solution (HHS) for
effective treatment of hemorrhagic hypotension. Eur Surg
Res 1987: 19: S44.
Address:
Priv.-Doz. Dr. Uwe Kreimeier
Department of Anesthesiology
Ludwig-Maximilian University
Munich
Grosshadern
Marchioninistrasse 15
D-81366 Munich
Germany
e-mail: kreimeier/ana.med.uni-muenchen.de