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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 ation of reperfusion injury during declamping phase) and burn
(SVR) using hypertonic solutions encompasses the rapid in- injury. The review also describes disadvantaages and potential
fusion of a small dose (4 ml per kg body weight, i.e. approxi- adverse effects of SVR:
mately 250 ml in an adult patient) of 7.2–7.5% NaCl/colloid Conclusion: Small-volume resuscitation by means of hyper-
solution. Originally, SVR was aimed for initial therapy of severe tonic NaCl/colloid solutions stands for one of the most innova-
hypovolemia and shock associated with trauma. tive concepts for primary resuscitation from trauma and shock
Methods: The present review focusses on the findings con- established in the past decade. Today the spectrum of potential
cerning the working mechanisms responsible for the rapid onset indications envolves not only prehospital trauma care, but also
of the circulatory effect, the impact of the colloid component on perioperative and intensive care therapy.
microcirculatory resuscitation, and describes the indications for
its application in the preclinical scenario as well as perioperat-
ively and in intensive care medicine. Received 17 July 2001, accepted for publication 6 February 2002
Results: With respect to the actual data base of clinical trials
SVR seems to be superior to conventional volume therapy with Key words: dextran; endothelial interaction, hydroxyethyl
regard to faster normalization of microvascular perfusion dur- starch; hypertonic solutions; intraoperative use; ischemia; leuko-
ing shock phases and early resumption of organ function. Par- cyte; microcirculation; primary resuscitation shock; reperfusion
ticularly patients with head trauma in association with systemic injury; small-volume resuscitation; trauma care.
hypotension appear to benefit. Besides, potential indications for
this concept include cardiac and cardiovascular surgery (attenu- 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- sodium chloride, bicarbonate, potassium, calcium,
atory blood flow increases. magnesium and phosphate.
In the preclinical scenario this is attractive when con- The normal range of plasma osmolality is 280–295
sidering the small-infusion volume needed to elicit an mOsmol/kg in healthy persons. In pathophysiolog-
instantaneous cardiovascular effect without the risk of ical states, e.g. hyperosmolar coma diabeticum, ex-
fluid overload. Moreover, this concept is unique when treme dehydration, alcohol intoxication, ketoacidosis
taking into account the specific mode of action at the or hyperlactaemia, plasma osmolality may reach very
microvascular level that provides prompt restoration high values, which, if allowed to persist, are associ-
of the nutritional blood flow (3). During the 1980s vari- ated with unfavorable outcomes. In contrast, an i.v.
ous research groups were able to demonstrate, in clin- bolus infusion of small volumes of hypertonic solu-
ically relevant animals models of hemorrhagic as well tions is aimed at producing a substantial but short-
as traumatic shock, that even in the presence of a 50% lasting rise of plasma osmolality in order to achieve a
blood loss a volume as small as 4 ml/kg of 7.2–7.5% so- high osmotic gradient across the cellular membranes.
dium chloride is sufficient to restore cardiac output and For instance, in patients with signs of increased intra-
regional organ blood flow to preshock values almost in- cranial pressure (ICP), mannitol is recommended in a
stantaneously, while at the same time systemic arterial dose of 0.3–1.5 g/kg b.w., given as 1.5–7.5 ml/kg b.w.
pressure is significantly increased (4). In prehospital tri- mannitol 20% over 15 min.
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 Medical terms used in context with
trauma requiring immediate surgery (6) and in patients small-volume resuscitation
with head trauma with a Glasgow Coma Scale score of After the first systematic studies in the 1960s, the re-
8 or less in the presence of hypotension (systolic blood naissance in hypertonic solution use for initial therapy
pressure ⬍90 mmHg) (7,8). 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
Characteristics of hypertonic solutions
model in sheep, showed that cardiac output was re-
In general, hypertonic solutions are characterized by stored and systemic pressure significantly increased
a high crystalloid concentration, i.e. sodium, glucose immediately after an infusion of hypertonic saline
or mannitol. In clinical routine, sodium bicarbonate (2400 mOsm/l Ω7.5% NaCl), even when given in an
8.4% (for correction of tissue acidosis reflected by a amount as small as 10% of actual blood loss. During
lowered pH and a negative base excess measured in the following years, experimental and clinical studies
serum), glucose 20% and 40% (for correction of severe were performed, investigating different hypertonic
hypoglycemia, hypoglycemic shock) or mannitol 20% solutions (NaCl, glucose, mannitol, NaHCO3, sodium
(for treatment of increased intracranial pressure) are acetate, lactated saline, urea, lithium-Cl, Tris-Cl) and
slowly administered via an i.v. route (Table 1). Upon doses (4–6 ml/kg b.w.), different sodium chloride con-
infusion, these solutions increase plasma osmolality, centrations (1.5–30% NaCl), infusion speeds (2–15
96% of which is determined by electrolytes such as min) and routes (i.v., intraosseous) of administration.

626
Small-volume resuscitation in clinical routine

Also, their efficacy with respect to restoration of importantly, however, is the mode of administration,
macro- and microcirculatory parameters, organ func- i.e. the short-term administration of a small amount
tion and ultimate survival (9). of concentrated salt solution for prevention or treat-
The short duration of the circulatory effects, which ment of pathophysiologic alterations induced by se-
are elicited by the sharp increase in plasma osmolality, vere hypovolemia and shock. The application of hy-
has been attributed to the rapid equilibration of the hy- pertonic sodium colloid solution in euvolemic pa-
pertonic solute between extracellular and intracellular tients to lower increased intracranial pressure shows
compartments. As many authors were concerned positive effects, and an identical solution may be used
about the short-lasting cardiovascular response after (7.2–7.5% sodium colloid solution). Nevertheless, it
small-volume resuscitation using hypertonic saline does not belong to this primary resuscitation category.
alone, 7.2–7.5% saline solution has been combined with
a colloid containing a high water-binding capacity, i.e.
Small-volume resuscitation by means of
4.2–24% dextran 60/70 or 6–20% hydroxyethyl starch
hypertonic saline colloid solution
200,000 and 450,000, respectively, in order to preserve
the intravascular volume gain. Therefore, one should The first authors who applied this concept to preclini-
obtain a synergistic effect by increasing plasma osmol- cal trauma care were Holcroft et al. (11). In the mid
ality with the result of mobilizing intracellular water, 1980s they used 7.5% saline mixed with 6% dextran
and providing high plasma oncotic pressure to con- 70, giving a final concentration of 7.5% NaCl/4.2%
serve the volume effect. In fact, animal studies have re- dextran 70 solution. This was the first prospective,
vealed that compared with hypertonic sodium chloride randomized study in trauma patients, and the data
alone the addition of a colloid indeed results in a sus- showed a higher systemic pressure and higher sur-
tained circulatory response and increases survival (10). vival rate after an initial small-volume resuscitation
Consequently, in recent years the meaning of ‘small- using hypertonic saline colloid solution compared
volume resuscitation’ or ‘small-volume hypertonic re- with isotonic crystalloid resuscitation only. As one
suscitation’ was modified, i.e. this concept now de- manufacturer provided a hypertonic colloid contain-
notes primary resuscitation from hypovolemia and ing solution (7.5% saline/6% dextran 70; Pharmacia
shock by means of hypertonic saline colloid solution AB, Uppsala, Sweden), Holcroft and Vassar, Univer-
(Table 2). With respect to the fact that also for other sity of California Davis Medical School, analyzed the
indicators apart from hypovolemia and shock due to necessity of the colloid component in a multicenter
trauma, e.g. intraoperative administration, beneficial trial, in which hypotensive trauma patients from six
effects have been shown (see below), the concept has trauma systems served by helicopter transport were
been increasingly accepted in the past few years. Most 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 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)
Small-volume hypertonic resuscitation Primary resuscitation from hemorrhage by means of Prist et al. (106)
(or small-volume hyper osmolar a small amount of hypertonic solutions of any sort,
resuscitation) alone or in combination with a colloid
Small-volume resuscitation by means Primary resuscitation from hemorrhagic hypotension Kreimeier et al. (107)
of hypertonic-hyperoncontic by means of bolus application (within 2–5 min) of a
solutions 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)
Small-volume resuscitation Primary resuscitation from hypovolemia and shock by means of a
by means of hypertonic colloid bolus infusion (2–5 min) of a small volume of hypertonic saline colloid
solution 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% regional organ blood flow, we have demonstrated that
sodium chloride combined with 6% dextran 70, and the nutritional blood flow in the kidneys and the gas-
7.5% sodium chloride combined with 12% dextran 70; trointestinal tract increased instantaneously and sig-
each of the solutions were given in a quantity of 250 nificantly more pronounced when 10% dextran 60
ml and followed by conventional isotonic volume was given in addition to 7.2 NaCl for small-volume
support. Only the 7.5% sodium chloride solution was resuscitation (16). In this model, 10% of the shed
associated with an increase in blood pressure and en- blood given as hypertonic saline colloid solution (ap-
hanced survival to hospital discharge compared with proximately 4 ml/kg b.w. compensating a 50% blood
survival as predicted by the Major Trauma Outcome loss) proved sufficient to completely restore the nu-
Study. However, the impact of this study was limited tritional blood flow.
because it was terminated prematurely when only 194 Following bolus infusion of 7.5% NaCl, rapid
instead of the 600 planned patients were included in plasma volume expansion occurs, amounting to 8–12
the final analysis; confounding factors were infusion ml/kg, as measured by Smith and coworkers in
of a considerable amount of isotonic solutions and, in studies on conscious sheep subjected to hemorrhagic
almost a third of the patients, medical antishock shock (17). As 1 g dextran binds ⬃20 ml water, 6%
trousers were inflated at a time when the infusion of dextran 60/70 solution will bind ⬃5 ml/kg when
the test solution had not yet been started. given in a dose of 4 ml/kg body weight. Conventional
Until 1994, evidence for the superiority of hyper- dextran 60/70 therefore has a limited oncotic power
tonic saline colloid solution in contrast to hypertonic in keeping all the mobilized water within the intra-
salt was provided from experimental data (12–14). vascular compartment. Higher concentrated dextran
Wade et al. then performed a meta-analysis of all clin- solutions, particularly the 10% dextran 60/7.2% saline
ical studies that had been designed prospectively and solution we used in our experimental studies
randomized for analysis of the efficacy of hyperosmo- (13,16,18), would theoretically seem preferable in
lar saline or hyperosmolar saline dextran application terms of pharmacologic properties.
for the treatment of traumatic injury (15). Nine trials
with a total number of 1889 patients were analyzed.
Advantages of small-volume
Inclusion criterion was a systolic blood pressure of be-
resuscitation proven effects in the
low 100 mmHg. The data revealed no significant dif-
experimental (laboratory) setting
ference between hyperosmolar (7.5%) saline alone vs.
lactated Ringer’s solution; in contrast, the hyperosmo- On the basis of the experimental data obtained in the
lar saline dextran solution (7.5% NaCl/6% dextran 70) case of hemorrhagic and traumatic shock, the estab-
yielded a 5.1% higher survival rate when compared lished effects of primary resuscitation by means of hy-
with Ringer’s lactate (15), thus supporting the experi- pertonic saline either alone or in combination with hy-
mental data of enhanced efficacy. peroncotic dextran can be summarized as follows (4,
19):
Impact of the colloid content 1 Immediate increase of systemic pressure and car-
diac output, while peripheral vascular resistance is
Small-volume resuscitation is intended for primary re-
reduced.
suscitation from trauma and shock. By establishing a
2 Instantaneous increase of nutritional blood flow
high osmotic gradient across cellular membranes, en-
and reduction of postischemic reperfusion injury.
dogenous water is shifted into the intravascular com-
3 Resumption of organ function as indicated by in-
partment. When used simultaneously (hypertonic col-
crease of urinary output.
loid solution) the colloid not only serves to preserve the
4 Increased survival rate.
gained volume, but exhibits an additive acute circul-
atory effect. Walsh and coworkers demonstrated in hy- Moreover, hypertonic saline resuscitation has been
povolemic sheep treated by small-volume resuscitation shown to reduce bacterial translocation in Sprague-
that the dextran component (either 0%, 12% or 24% Dawley rats subjected to hemorrhagic shock, which
dextran 70 were used) exerts an additive effect on has been attributed to the prevention of gut hypoper-
plasma volume and cardiac output increase (12). fusion (20). Small-volume resuscitation therefore may
In our own experiments in Beagles with severe, pro- also be useful in ICU patients known to be at risk of
tracted traumatic-hemorrhagic hypotension (mean ar- developing multiple systems organ failure (MSOF) on
terial pressure Ω 40 mmHg for 75 min) employing the the basis of compromised gut mucosa blood flow;
radioactive microspheres method for quantification of however, clinical data are missing. It has been sug-

628
Small-volume resuscitation in clinical routine

gested that hypertonic saline dextran is of benefit for shock and low/no flow in the microcirculation (27–29).
the improvement of postburn microcirculatory dis- In the dorsal skinfold model in the hamster, postische-
turbances and attenuating postburn oxidant-induced mic leukocyte accumulation and adherence were found
systemic and mesenteric lipid peroxidation (21). The to be significantly attenuated following prophylactic
latter effect might be linked to the alterations of intra- isovolemic hemodilution with 6% dextran 60 to a hem-
cellular sodium and water content developing in the atcrit of 30% (a clinically relevant value in the trauma
course of experimental burn injury (22). patient) when compared with controls (30). This effect
was absent when using 6% hydroxyethyl starch, and
the authors postulated a compound-specific pharmac-
Specific effect of hypertonic saline
ologic effect of dextran. The favorable effects of dextran
colloid solution on postischemic
have been confirmed in a rat model of hemorrhagic
leukocyte/endothelial interaction
shock and resuscitation by dextran given either alone
Chemotactic accumulation of circulating leukocytes (6% dextran 60, 100% shed blood volume) or as small-
and their adhesion to the endothelial lining of post- volume resuscitation in combination with 7.2% saline
capillary venules have long been recognized as key (7.2% NaCl/10% dextran 60, 10% shed blood volume)
features of postischemic reperfusion injury (23,24). (31): both regimens attenuated leukocyte stagnation in
The molecular mechanisms of leukocyte adhesion to sinusoids and leukocyte adherence in postsinusoidal
endothelial cells in response to hyperosmolarity have venules significantly more than did lactated Ringer’s
been investigated by Thiel et al. (25) in vitro. Incuba- solution the latter administered four times the amount
tion of isolated leukocytes in buffer solutions with in- of shed blood volume.
creasing osmolarity seems to counteract the famyl- These findings, together with data from studies by
methionyl-leucyl-phenyalamine (FMLP)-induced up- Junger et al. (32,33) and Rizoli et al. (34,35), support
regulation of b2-integrins in a dose-dependent man- the concept that hypertonic solutions might interfere
ner. At the same time FMLP-induced shedding of L- with neutrophil–endothelial cell interactions, sug-
selectin is reduced, suggesting that these changes are gesting the possibility that this resuscitation strategy
not the result of a non-specific artifact, such as the appears applicable to a broad range of disease pro-
effects of the hypertonic medium on epitope-antibody cesses in which neutrophil–endothelial cell interac-
recognition (26). When compared with physiologic os- tions are crucial in initiating organ injury.
molarity (290 mM), FMLP-induced CD18 up-regula-
tion and L-selectin shedding were significantly re-
Evidence from clinical trials
duced at osmolarities typically found in humans and
animals after resuscitation with hypertonic solutions. The concept of applying small volumes of hypertonic
Special pharmacologic properties exist and suggest saline/dextran solution for primary resuscitation from
the prefered use of hypertonic saline together with dex- severe hypovolemia proved effective in a prospective,
tran as a colloid: Nolte et al. published their data on the randomized study of trauma patients. As compared to
leukocyte/endothelial interaction of hypertonic-hy- Ringer’s lactate, the bolus infusion of 250 ml 7.5%
peroncotic dextran solution after ischemia/reperfusion NaCl/4.2% dextran 70 at the accident site resulted in a
injury in the hamster dorsal skinfold model (14). The higher systemic pressure increase (49 mmHg vs. 19
authors demonstrated that after 4 h of ischemia and re- mmHg) and a higher survival rate (8/10 patients vs. 3/
perfusion of striated skin muscle the number of leuko- 10 patients) (36). In an extension of their first study, in
cytes adhering to the endothelium of postcapillary ven- 1989 Holcroft et al. reported on 60 trauma patients
ules was significantly reduced for 24 h after bolus in- entered in a randomized, prospective double-blind
fusion of 7.2% NaCl/10% dextran 60, and hypertonic trial (37). Administration of 7.5% saline/6% dextran 70
saline dextran effectively attenuated macromolecular resulted in a higher blood pressure when the patients
leakage and reduced capillary endothelial swelling as reached the emergency room compared with Ringer’s
assessed by capillary lumenal diameter measurements. lactate given in the same amount (250 ml) and followed
The hypertonic saline alone was significantly less ef- by conventional fluid therapy. The 30-day survival rate
ficient in protecting from postischemic leukocyte/en- was significantly higher after small-volume resusci-
dothelial interaction and its sequelae. tation using hypertonic saline/dextran.
The impact of the synthetic colloid dextran is also Also the data from the U.S. multicenter trial on pre-
known from hemodilution experiments: already very hospital hypertonic saline/dextran infusion for post-
small amounts of dextran have been shown to be cap- traumatic hypotension yielded positive results (6).
able of reducing reperfusion injury after a period of 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 contrast, a recent review according to evidence-
in 6% dextran 70 or Ringer’s lactate, followed by con- based medicine provided by the Cochrane Library re-
ventional therapy. There was no difference in overall veals the problem of demonstrating efficacy in pre-
survival within the first 24 h; however, in the sub- clinical care traumatized patients: in an attempt to de-
group of patients requiring surgery and those with a termine whether hypertonic crystalloid decreases
penetrating injury, hypertonic saline/dextran infusion mortality in patients with hypovolemia with and
proved superior to Ringer’s lactate (P⬍0.02 and without head injuries, Medline, EMBASE, The
P⬍0.01, respectively). In addition, there were fewer Cochrane Controlled Trials Register and the Special-
complications (ARDS, renal failure, coagulopathy) ized Register of the Injuries Group were reviewed
compared with the standard treatment group. (44). Sixteen trials were identified with a total of 837
The application of hypertonic saline/dextran solu- patients. Data on mortality were obtained in 12 of the
tions has proven safe in patients, and in none of the studies. The pooled relative risk for death in trauma
controlled clinical trials have adverse effects been patients was 0.84 (95% CI 0.61–1.16), in patients with
attributed to the colloid component, nor have anaphy- burns 1.49 (95% CI 0.56–3.95), and in patients under-
lactoid reactions been observed (10). In an attempt to going surgery 0.62 (95% CI 0.08–4.57). The reviewers
gain access to a more representative database, Kramer concluded that this comprises insufficient data for de-
and Wade performed a meta-analysis of studies in ciding whether hypertonic crystalloids are better than
which hypertonic saline/dextran or hypertonic saline isotonic crystalloids for the resuscitation of patients
alone had been used for primary volume therapy after with trauma, burns or those undergoing surgery (44).
traumatic injury (15,38). Finally, eight trials were in- A main reason for these findings may be seen in the
cluded, yielding a total number of 1170 patients. In- heterogeneity of injury pattern, pre-existing diseases,
clusion criterion was a systolic blood pressure below and the armentarium of general therapy in trauma
100 mmHg in combination with trauma. No signifi- victims included into preclinical trials: this issue was
cant difference regarding 30-days survival could be already discussed among the participants of the SALT
established between hypertonic (7.5%) saline alone vs. V Conference in Galveston in 1992, where, taking
lactated Ringer’s solution (15), whereas the hyper- ‘mortality’ as the endpoint, statisticians anticipated a
tonic saline dextran solution (7.5% NaCl/6% dextran cohort of approximately 7000 patients required to
70) yielded a 5.1% higher survival rate (38). This result prove the efficacy of primary volume therapy by
stresses the necessity and impact of the colloid com- means of small-volume resuscitation.
ponent used for 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
Preclinical use and efficacy
list of potential indications for small-volume resusci-
In view of data from diverse controlled clinical trials tation in emergency care, perioperative use and in
the concept of small-volume resuscitation has been critically ill patients is given in Table 3.
demonstrated to be feasible and effective with respect
to conventional fluid therapy for primary resusci-
Disadvantages and potential adverse
tation of trauma patients (39,40), as well as in the
effects
emergency room (41,42). Prehospital trials in particu-
lar have shown favorable results in cases of severe In the experimental setting hypertonic solutions with
trauma requiring immediate surgery (6). a sodium chloride concentration up to 30% have been
The incidence of mortality and morbidity resulting studied for use in primary resuscitation from hemor-
from severe head trauma is strongly related to elev- rhagic shock. Bolus infusion of hypertonic NaCl-solu-
ated intracranial pressure and hypotension (43). Pre- tion into a peripheral vein with concentrations above
clinical administration of small volumes (250 ml) of 10% resulted in significant hemolysis, whereas hyper-
7.5% NaCl/dextran 70, increased the blood pressure tonic solutions of 7–7.5% NaCl are regarded as safe
of severely injured patients more efficiently than did (45). The efficacy and safety of 7.2–7.5% NaCl in com-
lactated Ringer’s solution, and showed a tendency to- bination with 6% dextran 60/70, respectively, has
ward improving survival in the patients with severe been demonstrated in nearly 2000 patients enrolled in
head injury (39). The data from the latest multicenter controlled clinical trials (8,38,46,47). At the injection
trial (7) suggest that hypotensive trauma patients with site, which in most cases was the cubital vein, no
baseline Glasgow Coma Scale scores of 8 or less will phlebitis occurred (48).
benefit most from 7.5% saline resuscitation. Although the concept involves infusion of a small

630
Small-volume resuscitation in clinical routine

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


Possible adverse reactions as a result of
cations have been addressed in experimental studies,
the colloid component
but their clinical relevance appears controversial (52–
55). This holds true for small-volume resuscitation as With the renaissance of dextran through the concept of
the cause of aggravating blood loss in cases of uncon- small-volume resuscitation, the discussion on possible
trolled hemorrhage (56–58, see later), risks of hyper- anaphylactoid reactions was again re-emerging. Al-
natremia and hypokalemia, particularly in cases of though relevant during application in cases of elective
pre-existing dehydration (59), hemolysis and hemo- surgery (e.g. when used for acute hemodilution under
globinuria (60), altered clotting times and platelet ag- normotension and stable circulation), where the prein-
gregation (61) as a result of hypertonic saline itself, jection of monovalent hapten dextran (PromitA, Phar-
and also the possibility of anaphylactic/anaphylacto- malink, Spaånga, Sweden) is mandatory (so-called
id reactions (62), coagulation disorders (63), and tissue hapten prophylaxis), it has to be stressed that so far
storage (64) linked to the colloid component (see also none of the severe DIARs in context with the appli-
‘Possible adverse reactions due to the colloid compo- cation of dextran occurring in patients with shock.
nent’). Therefore Laubenthal et al., based on the pathophysi-
Of clinical importance, particularly in the prehospi- ological mechanisms responsible for dextran anaphyl-
tal trauma scenario, is the potential adverse effect of axis as well as on a survey about the safety of Dextran
hypertonic saline on blood loss in cases of uncon- in Central Europe (67), stated already in 1987 that ‘Pa-
trolled hemorrhage: in the clinical studies, including tients in shock do not need the hapten prophylaxis.’
large numbers of patients with penetrating trauma, (68). Consequently, in the clinical trials where hyper-
increased bleeding has not been encountered. In con- tonic saline dextran solutions were used, no hapten
trast, those patients severely traumatized and needing prophylaxis was applied, except for the patients en-
immediate surgery because of large blood losses have rolled in the first trial of Holcroft et al. (11).
benefited from small-volume resuscitation by means Adverse reactions may occur with all synthetic col-
of hypertonic saline dextran (46). loids, even with human albumin (69,70). Most import-
The user should be aware of the fact that bolus in- antly, because of the nature of anaphylactoid reactions
fusion (i.e. application of 250 ml hypertonic solution these are independent from the amount of colloid ad-
within 2 min) may be accompanied by an initial and ministered. In a prospective French multicenter trial
substantial, however very short-lasting drop in ar- Laxenaire et al. (71) recorded 43 anaphylactoid reac-
terial pressure (65,66), which might be harmful for pa- tions, 20% of which were severe (grades III and IV), in
tients with compromised myocardial function or coro- 19,593 patients after the administration of different col-
nary heart disease who are incapable of compensating loids. Among the diverse synthetic volume substitutes,
for reduced coronary perfusion pression. However, gelatins are the least effective with regard to their short
first, the period of hypotensive response usually lasts intravascular volume effect, which does not last for
less than 1 min, during which endogenous fluid mo- more than 2–3 h. The major advantage is that there is no
bilization leads to an increase of cardiac preload and dose limitation, unlike the restrictions placed on each
thus enhancement of cardiac output, and second, car- of the two other synthetic colloids. However, it was
diac afterload is reduced at the same time because of suggested that gelatine in particular affects the func-
peripheral vasodilation resulting in reduced cardiac tionality of the von Willebrand factor and partly in-
work. hibits platelet adhesion (72). In addition, gelatine-
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: Table 4
besides a potential benefit with regard to sustained
Potential side-effects associated with small-volume resuscitation.
circulatory stability, the colloid component bears the
risk of anaphylactoid reactions and thus increases the Hyperosmolar coma
Hypernatremia
risk of unwanted side-effects possibly elicited by the Hypokalemia
hypertonic component per se (Table 4). It should be Cerebral or peripheral seizures
noted that the application of hyperosmolar saline/ Arrhythmia
Negative-inotropic effect (following rapid infusion)
dextran solution proved safe in patients, and in none Tissue necrosis (in cases of paravasation)
of the controlled clinical trials have adverse effects Hemolysis (at the injection site)
been attributed to the colloid component, nor have Enhanced bleeding (under uncontrolled hemorrhage)
Anaphylactoid reaction (linked to the colloid component)
anaphylactoid reactions been observed (4,8).

632
Small-volume resuscitation in clinical routine

based products seem to become incorporated into de- that HES reduces the levels of fibrinogen coagulation
veloping clots and reduce the function of fibronectin in factors, factor VIII, and von Willebrand factor, and re-
forming covalent cross-linkages and normal covalent duces platelet function.
associations with fibrin, thus interfering with the poly- The new hydroxyethyl starch HES 130,000/0.4 was
merization of fibrin monomers and reducing the qual- designed to provide more oncotically effective small
ity of clot formation (73). Moreover, both urea-linked molecules, and to enhance metabolism and renal elim-
and modified fluid gelatins carry a comparably high ination of the substance. In addition, HES 130,000/0.4
risk of adverse reactions, as reported by Lorenz et al. has been reported to be associated with lower intra-
(74) and Laxenaire et al. (71). Following induction of operative blood loss, less transfusion requirements of
general anesthesia and volume loading with 500 ml packed red blood cells, and a more pronounced in-
Haemaccel-35, Lorenz et al. reported clinically relevant crease of von Willebrand factor in the postoperative
or even life-threatening cardiorespiratory side-effects period as compared to HES 200,000/0.5, when both
related to histamine release in 15 of 57 patients (26%), substances were administered in identical amounts
in contrast to only 8% in controls receiving Ringer solu- (79).
tion (74). Finally, the discussion about vCJD revealed 6% Hydroxyethyl starch 200,000 is a perioperatively
additional uncertainty on the safety of gelatins. Both, widely used plasma substitute with a recommended
the low oncotic property and the higher risk of possible dose limit of 2 g/kg b.w./24 h. The same holds true for
adverse effects were reasons why gelatins have not dextran, which has a recommended daily dose limit of
been considered as colloid components in the concept 1.5 g/kg b.w. (i.e. about 1750 ml in a 75-kg patient).
of small-volume resuscitation by means of hypertonic Principally, these limits have been set to avoid poten-
colloid solutions. tial interference with the coagulation system, primar-
It is argued that dextrans, superior plasma substi- ily as a result of the dilution of coagulation factors
tutes, in particular are associated with anaphylactic/ and associated depression of thrombocyte counts.
anaphylactoid reactions (which may occur with any During small-volume resuscitation, however, only
colloid; 71), coagulation abnormalities (if used in a dose very low amounts of a colloid are administered, so
exceeding 1.5 g/kg/day) and impaired blood cross- that the issue of maximum dose of the specific colloid
matching (also, if used in great amounts). Through the used with the hypertonic colloid solution per se is of
implementation of the hapten prophylaxis, however, no clinical relevance. However, we have to bear in
the incidence of severe dextran-induced anaphylatic mind that small-volume resuscitation is intended as
reactions (DIAR; grade III–V) has been reduced from first line therapy, followed by conventional fluid ther-
1:2000 patients (1975–79) to 1:70,000 patients (1983–92) apy as needed to achieve stable hemodynamics.
in Sweden, where reporting of severe adverse drug re-
actions is mandatory (75).
Clinical use and spectrum of indications
An essential argument in favor of the hydroxyethyl
starch solution has long been the lack of evidence for There are several infusion solutions available that
the existence of preformed antibodies against hydroxy- contain hypertonic saline in combination with a col-
ethyl starch (HES). However, in 1995 a patient treated loid (Table 5). Austria was the first European country
in our institution for blood analysis unequivocally re- in which small-volume resuscitation by means of a
vealed preformed hydroxyethyl starch-reactive anti- hypertonic saline colloid solution became clinical rou-
bodies (76). Blood samples had been taken during aor- tine for resuscitation from severe trauma and shock:
tic aneurysm surgery when severe hemodynamic insta- OsmohesTM (Laevosan, Linz) was authorized in July
bility occurred, and an adverse reaction was suspected. 1994, and 3 years later HyperhesTM (Fresenius Kabi
A HES antibody titre assay based on the highly sensi- Austria, Graz) was registered and became clinically
tive ELISA technique on both pre- and post-reaction available. According to the manufacturer’s data, the
serum samples revealed the neutralization of pre- use of 56,000 units has so far been documented in Au-
formed antibody titres upon exposure to HES and the stria. In their survey from Austria, Schimetta et al. (80)
reappearance of specific antibodies within 4–8 weeks, give important insight into drug safety of small-vol-
suggesting anaphylaxis as described by Richter et al. ume resuscitation by means of hypertonic saline
(77). Moreover, it has been shown that medium mol- starch solution. They calculate the incidence of ad-
ecular weight hydroxyethyl starch in particular lowers verse reactions to be of the order 8–16 in 100,000 pa-
factor VIII:C concentration (78), which may prove haz- tients treated (80).
ardous to patients who need full hemostatic com- The therapeutic indication essentially is primary re-
petence. At this point it seems reasonable to assume suscitation from severe hypovolemia and shock. It

633
U. Kreimeier and K. Messmer

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

patients with isolated head trauma or multiple trauma, rapid restoration of macrohemodynamics and preven-
while in cases of existing capillary leak (burn injury, tion of early death, this concept particularly aims at
sepsis) a short-lasting hemodynamic effect has been the prevention of late complications (sepsis, MSOF)
shown (increase of cardiac output and DO2, reduction resulting from protracted microcirculatory disturb-
of oxygen extraction rate). ances. The most important mechanism of action at the
A major difference among all these studies and the level of the microcirculation is the mobilization of en-
acute, preclinical use (i.e. in cases of primary resusci- dogenous fluid primarily from edematous endothelial
tation from trauma and shock) is that nearly all inves- cells, by which the rectification of shock-narrowed
tigators infused hypertonic solutions more slowly capillaries and the restoration of nutritional blood
(typically over 20 min) than suggested for resusci- flow is efficiently promoted. By the combined use of
tation from hemorrhagic shock (2–5 min). Neverthe- hypertonic saline together with a potent colloid (dex-
less, they still could demonstrate that the application tran, hydroxyethyl starch) the circulating effect is not
is efficient in terms of increase of cardiac filling press- only prolonged, but, in cases of higher concentrated
ure and a concomitant increase of cardiac output and colloid content (10% dextran 60/70) it is also potenti-
oxygen delivery (101). In some high-risk patients, it ated. Apart from a beneficial specific pharmacologic
seems advisable to closely monitor the cardiac re- effect the colloid compound might lead to higher inci-
sponse to fluid loading with hypertonic solutions and dence of side-effects: besides hyperosmolarity and
best to titrate the infused volume against the changes hypernatremia, which are both essential for provok-
of pulmonary capillary wedge pressure (102). Most ing the circulatory effect through establishment of an
trials in cardiac and vascular surgery revealed less osmotic gradient across cellular membrane, anaphyl-
positive perioperative fluid balance than after conven- actoid reactions linked to the colloid may occur. How-
tional fluid therapy (101), and in our own intraopera- ever, these seem to be negligible in the acute phase of
tive study in patients with aortic aneurysm surgery the preclinical scenario. One therefore should bear in
we observed improved hemodynamic stability and mind that small-volume resuscitation by means of hy-
pulmonary function (89). pertonic colloid solution does not mean a given form
of simple volume therapy with a somewhat enhanced
volume effect, but resuscitation from trauma and
Impact on patients with trauma
shock by means of a highly potent agent.
combined with head injury
In the beginning criticism has arisen from the poten-
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