of 21
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1 NEUROANESTHESIA AND INTENSIVE CARE
Fluid choice for resuscitation of the traumapatient: a review of the physiological, pharmaco-
logical, and clinical evidence[Le choix du liquide pour la ranimation du patient polytraumatis: une revue
des donnes physiologiques, pharmacologiques et cliniques]
Joachim Boldt MD PhD
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2 NEUR OANE STHE SIA AND INTENSIVE C ARE
Purpose : Volume replacement regimens are discussed very
emotionally. Interpretation of the literature is difficult due to variations
in study design, patient population, target for volume replacement,
endpoints, and type of fluids. Meta-analyses may not be very helpful
because all kinds of patients and very old studies are included. The
principles and options for volume replacement were reviewed
exclusively in trauma patients and studies from the literature focusing
on this problem were analyzed.
Source: Using a MEDLINE search, volume replacement therapy in
adult trauma patients published in the English language from 1985 to
the end of 2002 were identified and analyzed. Studies on pre- hospital
volume replacement, volume replacement in the emergency area or in
the operating room, and volume therapy in trauma intensive care unit
patients were included.
Principle findings: The age-old crystalloid/colloid controvery
has still not been resolved but has been enlarged to a colloid/colloid
debate. It is now widely accepted that human albumin could easily be
replaced by synthetic colloids for volume replacement in traumapatients. No superiority of a specific volume replacement strategy with
regard to outcome was found. However, in several studies outcome
was not the major endpoint. Although showing some promising results,
the importance of hypertonic solutions for volume replacement in the
trauma patient is not yet defined.
Conclusion: The choice of fluid therapy in trauma patients engen-
ders the most controversy and an examination of the body of literature
on this subject results in confusion. It is imperative to continue the
search for substances that are effective in avoiding the development of
post-trauma multi-organ dysfunction syndrome without detrimental
side-effects.
Objectif: Les doses de rem plissage vasculaire suscitent des discus-
sions trs motives. Linterprtation des publications est difficile
cause de la diversit des devis dtudes, des populations de patients,
des cibles de remplissage vasculaire, des paramtres tudis et des
types de liquides. Les mta-analyses ne sont peut-tre pas trs utiles
parce quelles comprennent tous les types de patients et danciennes
tudes. Les principes qui rgissent le remplissage vasculaire et les
options offertes ont t revus exclusivement chez les polytraumatiss
et les tudes qui mettent laccent sur ce problme ont t analyses.
Source : Les articles sur le remplissage vasculaire ralis chez les
patients polytraumatiss et rapports en anglais entre 1985 et la fin de
2002 ont t reprs dans MEDLINE et analyss. Les tudes sur le
remplissage vasculaire prhospitalier, sur le remplissage vasculaire
lurgence ou en salle dopration et sur le remplissage vasculaire chez
les patients polytraumatiss de lunit des soins intensifs ont t
retenues.
Constatations principales : La sempiternelle controverse cristal-
lode/collode nest pas encore rsolue, et sest tendue au dbat col-
lode/collode. On accepte gnralement de remplacer lalbumine
humaine par des collodes synthtiques chez les polytraumatiss. Nous
navons trouv aucune stratgie de remplissage vasculaire qui soit
suprieure aux autres quant au rsultat. De toute manire, le rsultat
ntait pas toujours le paramtre principal. Mme si les solutions
hypertoniques ont prsent quelques rsultats prometteurs, leur
importance dans le rem plissage vasculaire chez les polytraumatiss
nest pas encore dfinie.
Conclusion : Le choix dune fluidothrapie chez les polytraumatiss
engendre la plus grande controverse. Lexamen des publications sur le
sujet napporte que confusion. Il faut poursuivre la recherche de sub-
stances efficaces, qui noccasionnent pas de dficiences polyviscrales
post-traumatiques et qui soient sans effets secondaires nocifs.
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3 NEUR OANE STHE SIA AND INTENSIVE C ARE
From the Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen,
Germany.
Address correspondence to: Prof. Dr. Joachim Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum
der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Fax: 0621-503-3024;E-mail: [email protected]
Manuscript assessed May 20, 2003.Accepted for publication September 16, 2003.
Revision accepted February 13, 2004.
CAN J ANESTH 2004 / 51: 5 / pp 500513
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Boldt: VOLUME REPLACEMENT IN TRAUMA PATIENTS 4
RAUMA is the fourth-leading cause of death in the USA.1 Volume deficits are often present in trauma
patients and may result in the development of post-trauma
multiple organ failure on the intensive care unit (ICU). In addition to apparent blood loss, fluid deficits may
also occur secondary to generalized alterations of the endothelial barrier resulting in diffuse capillary
leakage and fluid shift from the intravascular to the interstitial compartment.
Adequate volume therapy appears to be a cornerstone of managing the trauma patient. In a prospective review of 111
consecutive patients who died in hospital after admission for treatment of injuries, the most common defects in patients
management were related to inadequate fluid resuscitation.2
Besides (hypo-, iso-, and hypertonic) crystalloids, human albumin (HA) and various synthetic colloids [e.g.,
dextrans, gelatins, hydroxyethyl starch (HES) preparations] are available to treat trauma-related volume deficits. In
recent years, the crystalloid/colloid dispute has been enlarged to a colloid/colloid debate because, aside from the natural
colloid albumin, several synthetic colloids are increasingly used as plasma substitutes in the trauma patient.
Aggressive pre-hospital fluid administration (in the field) has been common practice for more than 25 years in
trauma patients. Some recent studies, however, have shown that early volume restoration before definite hemostasis has
been performed may result in accelerated blood loss, hypothermia, and dilutional coagulopathy in certain types of
trauma.3 Thus it has been recommended that volume replacement should not be started early (concept of permissive
hypotension; scoop and run principle).4 This review is not designed to intensify the controversy between delayed
fluid resuscitation and early (field) volume replacement, nor to suggest new guidelines for appropriate volume therapy
in the trauma patient, but to recall the options for volume replacement and to analyze the literature according to
different volume replacement regimens in trauma patients exclusively. Trauma patients are definitely different from
cardiac surgery patients, patients with malignancies undergoing surgery or septic patients and thus volume replacementstrategies should be reviewed separately for these patients.
Pathophysiology of shock in the trauma patient Trauma is often associated with blood loss. Hemorrhage-related
hypovolemic shock after trauma can be divided into three phases:5
-phase I is the period from injury to operation for control of bleeding (pre-definitive care);
- phase II is the period during and immediately after the operation;
- phase III is the period in the ICU (post-definitive care).
Trauma-related hypovolemia may be associated with flow alterations which are inadequate to fulfill the nutritive role
of the circulation. Many of the manifestations of organ failure after successful primary resuscitation after trauma may
result from peripheral (micro-) circulatory derangements. In spite of achieving normal systemic hemodynamics it is
not guaranteed that perfusion in all organs and tissues is maintained as well. During low output syndrome the organismtries to compensate perfusion deficits by redistribution of flow to vital organs (e.g., heart, brain) resulting in an
underperfusion of other organs (splanchnic bed, kidney). Various inflammatory mediators and vasopressors are released
in this situation and are of particular importance for the development of impaired perfusion.
Recent evidence suggests that the endothelium is not only a passive barrier between the circulating blood and the
tissues, but may also be markedly involved in the regulation of microcirculatory blood flow by producing important
regulators of the vascular tone (e.g., prostaglandins, nitric oxide, endothelins, angiotensin II).6 The regional regulation
of blood flow is likely due to a balance between systemic mechanisms (e.g., the autonomous nervous system) and other
more locally active blood flow regulators. One important approach to improve perfusion in this situation appears to be
the use of adequate volume. Our pathophysiologic knowledge on the importance of the endothelium in modulating
microcirculation and inflammation has increased, however, the influence of different volume replacement strategies on
endothelial function has still to be elucidated.
Goals of volume replacement in the trauma patient The primary goal of volume administration is to guarantee stable
systemic hemodynamics and microcirculation by rapidly restoring circulating plasma volume. Excessive fluid
accumulation, particularly in the interstitial tissue should be avoided. Blood or blood products should be avoided as far
as possible due to unwanted risks.79
The infused fluid may stay in the intravascular compartment or equilibrate with the interstitial/intracellular fluid
compartments. Different mechanisms are involved in the control of volume and composition of each compartment
including the antidiuretic-hormone (ADH) system and the renin-angiotensin systems (RAS). The principal action of
these systems is to
T
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Boldt: VOLUME REPLACEMENT IN TRAUMA PATIENTS 6
6% dextran 70 10% dextran
40Mean molecular weight 70,000 40,000
Volume effect (hr) 5 3-4
Volume efficacy (%) 100 175(200)
Maximum daily dose (gkg1) 1.5 1.5
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7 CANADIAN JOURNAL OF ANESTHESIA
Gelatins (Table II)Gelatins are modified beef collagens. Due to their low-
molecular weight (LMW) average (approximately 35 kD)
the intravascular half-life of gelatin infusions is short
(approximately two hours) and gelatins are supposed to
be the least effective colloids.16 This disadvantage is
balanced by the absence of a dose-limitation. Gelatins arelisted by the World Health Organization as an essential
drug. In the USA, however, gelatins were abandoned in
1978 due to a high incidence of hypersensitivity
reactions.17 Although the raw product is from beef,
gelatins are generally agreed to be free of risk of prion
transmission.18
HES (Table III)
HES is a high polymeric glucose compound that is
manufactured through hydrolysis and hydroxyethylation
from the highly branched starch amylopectin.
Polymerized D-glucose units are joined primarily by oneto four linkages with occasional one to six branching
linkages. The degree of branching is approximately 1:20,
which means that there is one to six branches for every
20 glucose monomer units. Natural starches cannot be
used as plasma substitutes because they are unstable and
rapidly hydrolyzed by circulating amylase. Substituting
hydroxyethyl for hydroxyl groups
TABLE II Characteristics of gelatin solutions
Urea-
crosslinked
Crosslinked Succinylatedgelatin gelatin
Concentration (%) 3.5 5.5 4.0
Meanmolecular
35,000 30,000 30,000
Volume effect (hr) 1-3 1-3 1-3
Volume efficacy 70-80 70-80 70-80
Osmolarit
y
301 296 274
results in a highly increased solubility and retards
hydrolysis of the compound by amylase, thereby delaying
its breakdown and elimination from the blood. The
hydroxyethyl groups are introduced mainly at carbon
position C2, C3, and C6 of the anhydroglucose
residues. The pharmacokinetics of HES preparations arefurther characterized by the pattern of
hydroxyethylation, in particular by the molar substitution
(MS) and by the degree of substitution (DS). The MS is
computed by counting the total number of hydroxyethyl
groups present and dividing the number by the quantity
of glucose molecules. The DS is determined by
measuring the number of substituted glucose molecules
and dividing this number by the total number of glucose
molecules present.
The available HES preparations are characterized by
concentration (low: 3%; medium: 6%; high: 10%), MS
(low: 0.4; medium: 0.5; high: 0.62 and 0.7), and the
mean-molecular weight [low-molecular weight (LMW)
HES: 70 kD; medium-molecular weight (MMW)- HES:
from 130 to 260 kD; high-molecular weight (HMW)-
HES: > 450 kD]. Current evidence indicates that the ratio
of the C2:C6 hydroxyethylation appears to be anotherimportant aspect for pharmacokinetic and side-effects
(e.g., accumulation, bleeding complications). Several
HES preparations are available commercially in Europe,
whereas in the USA only the first generation HMW-HES
(Hetastarch; concentration: 6%; Mw: 450 kD; MS: 0.7) is
approved for volume replacement, and in Canada only a
MMW-HES (HES 270/0.5; Pentastarch) was available
until recently.
Hypertonic solution (HS; Table IV)Enthusiasm has been expressed for HS or hypertonic-
hyperoncotic solutions in the treatment of hypovolemicshock in trauma patients. The concentration of sodium
ranges from 3% to 7.5% and HS appear to improve
cardiovascular function on multiple levels:
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Boldt: VOLUME REPLACE MENT IN TRAUMA PATIENTS 8
TABLE III Characteristics of different HES solutions
HES HES HES HES HES HES
70/0.5 130/0.4 200/0.5 200/0.5; 200/0.62 450/0.7
260/0.5 (Hetastarch)(Pentastarch
Concentration (%) 6 6 6 10 6 6
Volume efficacy (%) 80-90 100 100 130-150 100 100
Volume effect (hr) 1-2 3-4 3-4 3-4 5-6 5-6
Mean molecular weight (Mw) 70,000 130,000 200,000 200,000 200,000 450,000
(Daltons) 260,000
Degree of molar substitution (MS) 0.5 0.4 0.5 0.5 0.62 0.7
C2/C6 ratio 4:1 9:1 6:1 6:1 9:1 4.6:1
Max. dose (mLkg1) 33 33-50 33 20 33 20
HES = hydroxyethyl starch.
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9 CANADIAN JOURNAL OF ANESTHESIA
TABLE IV Characteristics of hypertonic-colloid solutions
HyperHaesTM RescueFlowTM
(Fresenius, (BioPhausia,Germany) Sweden)
Electrolyte concentration 7.2% NaCl 7.5% NaCl
Sodium 1,232 mmolL1 1,283
mmolL
1
Osmolarity 2,464 mosmolL1 2,567
mosmolL1
Colloid hydroxyethyl starch dextran
Colloid concentration 6% 6%
Mean molecular 200 70
weight (kD)
Indication severe volume severe volume
deficit deficit
- displacement of tissue fluid into the blood com-
partment;
- direct vasodilatory effects in the systemic andpulmonary circulations;
- reduction in venous capacitance;
- and positive inotropic effects through direct actions
on myocardial cells.
The main mechanism of action of HS is the rapid
mobilization of endogenous fluid and subsequent plasma
volume expansion. Due to the hypertonicity of the
solutions, only a small volume of fluid (approximately 4
mLkg1) is necessary to effectively restore
cardiovascular function (small volume resuscitation).
The initial improvement in cardiovascular function (e.g.,
increase in cardiac output) seems to be mediated by the
hypertonicity of the solution, whereas the solute
composition does not seem to be important. Beneficial
effects of hypertonic saline solution were reported to be
rather transient. Thus, HS are often mixed with colloids
(dextran or HES), and these solutions show a significant
prolongation of efficacy. The use of extreme HS (up to
2,400 mosmolL1) has been studied in a limited number
of clinical trials, mostly in trauma patients with severe
hypovolemia and burns.
Clinical considerations of volume replacement in the
trauma patient
All fluids used for volume replacement in the trauma
patient have merits and demerits. The most alarming
problems that have to be considered when using a spe-
cific fluid are anaphylactoid reactions, increased bleeding
tendency, development of tissue edema, renal
dysfunction, and possible alterations of the immune
function.
Allergic reactionsThe use of crystalloids is not associated with anaphy-
lactic reactions. Dextran-associated anaphylactic reac-
tions are widely known for their frequency and severity.19
Gelatins are at risk of producing a larger number of
anaphylactic reactions compared with starch preparations
as shown in a large trial including approximately 20,000patients.20 Gelatins were associated more often with
severe, life-threatening anaphylactic reactions, whereas
this was very rare after the infusion of HES.20
Influence on coagulation and increasedbleeding tendency
Coagulopathy is a common complication of hemorrhagic
shock. Additionally, resuscitation-associated
hemodilution may alter hemostasis by lowering the
concentration of clotting proteins. Use ofcrystalloids has
been thought to be without negative influence oncoagulation except for that attributable to hemodilution,
although recent studies have demonstrated an increased
coagulability during hemodilution with saline.21 Albuminis considered to be the colloid with the least negative
influence on coagulation, although procoagulatory or
anticoagulatory effects (e.g., inhibiting platelet
aggregation, enhancing the inhibition of factor Xa by
antithrombin III) have been described with albumin.22
Dextrans are the plasma substitutes with the most widelyaccepted negative effects on hemostasis i.e., increasing
bleeding tendency. Using dextran both VIIIR:Ag and
VIIIR:RCo levels decrease significantly.23 With reduced
VIIIR:RCo there is a reduced binding to plateletmembrane receptor proteins GPIb and GPIIb/IIIa that
results in decreased platelet adhesion.23 Gelatins havebeen thought to possess no negative effect on
coagulation. However in a study in which healthy
humans received either 1,000 mL of gelatin or saline
solution, de Jonge et al.24 found that the infusion ofgelatin resulted in a significant impairment of primary
hemostasis and thrombin generation. Changes in
coagulation have most often been reported with the use of
HES.25 However, the different HES preparations have tobe distinguished concerning their influence on the hemo-
static process.26,27 HMW-HES (hetastarch) diminishes
concentrations of VIIIR:Ag and VIIIR:RCo more than aLMW-HES.23 Platelet aggregation abnormalities have
also been observed after the infusion of HMW-HES,
whereas infusion of HES with a LMW did not change
platelet aggregation induced by adenosine diphosphate.28
A substantial body of evidence supports the concept that
HES with MMWHES: 130 kD, 200 kD and especially
low MS (0.4;
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Boldt: VOLUME REPLACEMENT IN TRAUMA PATIENTS 10
0.5) have significantly less negative effects on coagula-
tion and can be safely used with regard to hemostasis
in humans.27,28
Tissue edemaFactors contributing to tissue edema formation are
venous congestion, reduced COP, arteriolar vasodila-tion/venous vasoconstriction, disorganization of the
interstitial matrix, increased endothelial permeability, and
lymphatic dysfunction. COP appears to be an important
aspect in determining fluid shifts between the
intravascular and interstitial compartments. Manipulation
of COP appears to be promising to ensure adequate
intravascular volume. Controversy still exists whether the
choice of fluid for restoration of circulating volume is
able to limit development of tissue edema. Dilution of
serum proteins by the massive administration of
crystalloids lowers COP with the risk of progressive
expansion of the interstitial space. In a non-trauma
experimental peritonitis model, crystalloid infusionresulted in more pronounced endothelial cell swelling
and decreased systemic capillary cross-sectional area
compared with volume therapy with colloids.29
Maintenance of COP by the administration of albumin
has been postulated to be a desirable goal. The oncotic
force of concentrated albumin (e.g., HA 20%) has been
shown to reduce tissue edema (e.g., pulmonary edema). 30
In patients with impaired vascular endothelial integrity
(e.g., in trauma patients), albumin may pass into the
interstitial compartment and fluid will subsequently shift
from the intravascular to the interstitial space. A rapid
and profound increase in the transcapillary escape rate ofradio-labelled albumin has been described within six
hours of surgery.31 The endothelium may also swell and,
subsequently, microcirculatory perfusion is altered. In
severely ill patients it was shown that the addition of
albumin resulted in more signs of respiratory failure,
compared to patients who did not receive albumin. This
appears to be, most likely, due to increased leakage into
the interstitial space.32
In inflammatory-related capillary leaks, HES has been
reported to have occlusive effects on damaged
capillaries, subsequently limiting the extravasation of
fluid.33
LMW-HES may exert beneficial effects onendothelial function, e.g., by O2 free radical scavenging,
by stabilization of fragile cell membranes, or by avoiding
endothelial swelling. This may be of benefit, particularly
in those trauma patients suffering from severe endothelial
leakage syndrome.34
Renal functionRenal dysfunction in trauma patients may develop for
several reasons including insufficiently treated hypo-
volemia. Crystalloids have no specific negative effects on
renal function except that they may not restore blood
volume adequately. The effects of the different colloids
are controversial. In patients with excessive fluid deficits,
the glomerular filtration of hyperoncotic colloids
(dextrans, 10% HES, 20% or 25% albumin) causes a
hyperviscous urine and stasis of the tubular flow resulting
in obstruction of tubular lumen.35
Certain commerciallyavailable albumins are known to contain remarkable
quantities of ions from the preparation process resulting
in toxic concentrations of aluminium in patients with
acute renal failure.36 HES molecules and gelatin
molecules are eliminated by glomerular filtration.
Gelatins appear to be almost devoid of significant
damaging effects on the kidneys. In a retrospective
analysis of patients undergoing kidney transplantation
and in whom HES with a high DS (0.62) was infused,
osmotic-nephrosis-like lesions were documented.37
This phenomenon, however, did not have negative effects
on graft function three and six months after
transplantation. Use of 6% HES 200/0.62 (2,100 660mL) in brain-dead donors resulted in impaired renal
function in kidney transplant recipients.38 Patients treated
with this HES preparation with a high MS showed higher
serum creatinine concentrations and a more frequent need
for hemodialysis compared to a gelatin-treated group of
patients. In a multicentre study in intensive care patients,
HES (200/0.62) resulted in a significantly higher
incidence of renal failure compared to a comparable
group of patients who received a gelatin preparation.39
Fortunately, the authors distinguished between different
types of starches, and state that the results of the study
may not be applicable to more rapidly degradable HES
preparations (e.g., HES 200/0.5). Use of HES 200/0.5over five days in a study of critically ill ICU patients was
without negative effects on renal function compared to a
control group in whom albumin was administered. 40 In a
study in elderly patients (> 75 yr) administration of 6%
HES 200/0.5 undergoing major abdominal surgery was
not associated with relevant changes of markers of renal
function (e.g., alpha-1-microglobulin, N-acetylbeta-D-
glucosaminidase).41
Accumulation and dose limitationsStoring, accumulation, and dose limitations have to beconsidered only when using synthetic colloids. Gelatin
and dextrans are naturally occurring substances and both
are fully metabolized in man. Nevertheless, a dose-
limitation exists for dextrans (approximately 2,500
mLday1) most likely because higher doses are
associated with severe bleeding complications. All
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11 CANADIAN JOURNAL OF ANESTHESIA
available HES preparations are stored and may accu-
mulate depending on the preparation. The smaller
molecules are rapidly eliminated by glomerular filtration.
A varying proportion of the HES administered leaves the
vascular space and is taken up by the reticuloendothelial
system (RES). RES storage, however, appears to be
without detrimental consequences.42
Nevertheless, a doselimitation exists for all HES preparations ranging from 20
mLkg1 to 50 mLkg1.
Immune function
Traumatic injury is known to induce intense alterations in
circulatory hemostasis and cell-mediated or humoral
immunity.43 These sequelae of trauma predispose to the
development of post-trauma sepsis or systemic
inflammatory response syndrome (SIRS). The mediators
of immunosuppression secondary to trauma are not
definitely elucidated. Endotoxin, tissue metabolicproducts resulting from cellular hypoxia, shock proteins,
hormonal mediators (e.g., catecholamines) are suspected
to take part in this process. Polymorphonuclear cells are
supposed to be key mediators of tissue injury and organ
failure. While neutrophils are essential for bacterial
killing, they paradoxically have the capacity to injure
host tissue. The interactions of neutrophils with
endothelial cells are regulated by complementary
adhesion molecules, which are present on these cells
(e.g., the immunoglobulin superfamily [e.g., vascular cell
adhesion molecule-1 (VCAM-1), intercellular adhesion
molecule-1 (ICAM-1)]; the integrin family [e.g., lym-
phocyte function-associated antigen (e.g., LFA-1 =CD11a/CD18)]; the selectins [E-selectin = endothelial
leukocyte adhesion molecule (ELAM-1)]; Lselectin =
e.g., leukocyte endothelial cell adhesion molecule; P-
selectin = granule membrane protein 140 (= GMP-140).
The soluble forms of some of these adhesion molecules
appear to be excellent markers of inflammation and
endothelial activation or damage.44The influence of HES
on endothelial cell activation was studied experimentally
by Collis et al.45 using endothelial cell cultures (humanumbilical vein endothelial cells ). E-selectin expression
on lipopolysaccharide-stimulated endothelial cells was
not influenced by HES. The authors, however, suggested
a possible beneficial role of HES by inhibitingendothelial activation. Thrombin-stimulated von
Willebrand factor (vWF) release was significantly more
reduced in the presence of HES than in the presence of
HA. The authors concluded from their data that HES may
be able to inhibit endothelial activation with subsequent
damage of endothelial integrity and that, by this
mechanism, HES may be able to ameliorate
capillary leak secondary to inflammation. The effects of
10% HES 200/0.5 or 20% albumin for volume
replacement over five days in severely (non-septic)
traumatized patients on plasma levels of circulating
adhesion molecules were assessed in a prospective ran-
domized study.46 Soluble ELAM- 1, soluble ICAM- 1,
and soluble VCAM- 1 plasma levels did not differ
between HES- and HA-treated patients indicating no
negative effect of the synthetic colloid HES on
endothelial function.
Volume replacement in trauma patient: analysis of the
literature
In the Advanced Trauma Life Support guidelinesRingers lactate is recommended as part of the emer-
gency resuscitation of the trauma patient, proceeding to
blood products as required.47 The American College of
Surgeons Classes of Acute Hemorrhages specify fourclasses of acute hemorrhage using a blood loss ranging
from up to 750 mL to > 2,000 mL.48 Fluid replacement
should be performed with crystalloids exclusively (3:1
rule) - there is no place for infusing (synthetic) colloids in
their recommendations.
Analysis of the literature
Crystalloids vs colloids in trauma patients
PUBLISHED META-ANALYSES
We are living in times of meta-analyses and evidence
based medicine (EBM). Different volume replacement
regimens have been examined with the help of these
popular instruments:
- In a meta-analysis from 1989, a possible reduction in
mortality was documented when crystalloids were used in
traumatized patients.49 In this analysis, five trauma
studies were included, two were from 1981, one from
1979, one from 1978, and one from 1977.
- In a meta-analysis by Schierhout and Robertson in
1998,50 the use of colloids was associated with an
increased incidence of death. Seven trauma studies were
included in this meta-analysis - three of them used
hypertonic/colloidal solutions, two albumin, one dextran,
and another gelatin. Summarizing all 37 analyzed studies,
resuscitation with colloids was associated with an
increased absolute risk of mortality of 4% (or four extra
deaths for every 100 patients resuscitated).
- In the Cochrane EBM analysis on volume
replacement in 1998, four trauma studies were included -one was from 1977, two were from 1978, and one was
from 1983.51 The message of this EBM analysis was that
albumin kills our patients (for every 17 patients treated
with albumin there was one additional death).
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TABLE V Volume replacement in adult trauma patients: crystalloid/colloid controversy
Author/year Substance Pro/retro Area Kind of Aim Conclusion
(reference) no. of patients rand/d-b trauma
Modig dextran 70 n = 14 pro/rand post only over seven days dex: better hemodynamics;
1986 (56) crystalloids (RA) n = 17 trauma severe dex:0.5l renal, coagulation: no differences
ICU factures RA:1.0-1.5l outcome: no differences
Nagy HES 250 (PS) n = 21 pro/rand E blunt maintain hemostasis: no differences
1993 (57) crystalloids (RL) n = 20 penetr. hemodynamic renal system: no differences
stability outcome: no differences
Sinclair crystalloids n = 20 pro/rand OR proximal replace HES: more effective1997 (58) cryst + HES n = 20 femoral blood loss HES: reduced hospital stay
fracture outcome: no differences
Evans gelatin (H) n = 19 pro/rand E blunt ? gelatin: increased Ca++ levels
1997 (59) crystalloids n = 5 outcome: not shown
Younes HES 250 (PS) n = 12 pro/rand E blunt SBP hemodynamics: no differences1998 (60) crystalloids (NS) n = 11 penetr. >100 mmHg transfusion: no differences
stab 24 hr survival: similar
Wu gelatin n = 18 pros/rand E ? fixed dose gelatin: better hemodynamics
2001 (61) RL n = 16 1000 mL outcome: no differences
PS = pentastarch; RL = Ringers lactate; RA = Ringers acetate; NS = 0.9% NaCl; HA = human albumin; kD = kilo Daltons;E = emergency room; OR = operating room; H = Haemaccel; F = in the f ield; ICU = intensive care unit; pro = prospectively;
rand = randomized; blunt = blunt trauma; penetr. = penetrating trauma; SBP = systolic blood pressure; dex = dextran; HES =
hydroxethyl starch; d-b = double-blind.
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13 CANADIAN JOURNAL OF ANESTHESIA
- Only one meta-analysis distinguished between
trauma patients and other kinds of patients (e.g., cardiac
surgery, critical care patients).52 In this analysis from
1999 four trauma studies were included; all of them
were more than 17 years old. All kinds of colloids
were compared to crystalloid-based resuscitation. There
were no differences between the two volumereplacement strategies.
- The influence of an albumin-based volume therapy
on mortality compared to other less expensive volume
replacement strategies was compared in a meta-analysis
of randomized controlled trials in 2001.53 No study more
recent than 2000 was included. In one subgroup, studies
involving surgery and trauma (27 studies) were included.
None of the analyzed factors (outcome, mortality) were
significantly influenced by either volume replacement
regimens. There was, overall, no beneficial effect of
(expensive) albumin in comparison to other (cheaper)
plasma substitutes on mortality.
Meta-analyses have two fundamental problems:54
1)There may be a selection bias of included trials; and
2)the results of the analyses may be similar, but theycan be interpreted quite differently. Specific objections to
all meta-analyses on volume therapy are:
- The mixing of patients with different diseases;
- The use of different kinds of fluids that have been
infused;
- The physicochemical properties of the various
synthetic colloids have been neglected in all meta-
analyses. Because of the important differences between
individual colloids, it is not appropriate to summarize allcolloids in a colloid group.
- Most meta-analyses include studies more than 15
years old. Important innovative strategies have been
developed in managing the trauma patient in the last 15
years including improved monitoring techniques,
ventilation strategies, feeding, and others that may also
influence outcomes.
- Mortality was used as the endpoint for volume
replacement in all meta-analyses. However, mortality was
not the endpoint of most of the volume replacement
studies. None of the studies found a statistically
significant effect that favoured colloids. It is still unclear
whether mortality is helpful to determine the optimalvolume resuscitation strategy.55
Description of primary studiesWith the help of a MEDLINE search, recent studies
dealing with volume therapy in trauma patients were
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Boldt: VOLUME REPLAC EMENT IN TRAUM A PATIENTS 14
TABLE VI Volume replacement in adult tr auma patients: colloid/colloid controversy
Auth
/year
Substance
no. of patients
Pro/retro
rand/d-b
Area Kind
of
Aim
Boldt 10% HES 200 n = 15 pro/rand post blunt CVP
1995 (62) 20% HA n = 15 traum
a
penetr. 12-16
Boldt 10% HES 200/0.5 n = 15 pro/rand post- blunt PCWP
1996 (63) 20% albumin (n = 15) traum penetr. 10-15
ICU
Boldt 10% HES 200 n = 15 pro/rand post blunt CVP/PCW
1996 (46) 20% HA n = 15 trau
maIC
penetr. 12-
18mm
Boldt 10% HES 200 n = 15 pro/rand post blunt PCWP
1996 (64) 20% HA n = 15 trau
ma
penetr. 12-
18
Boldt 10% HES 200 n = 14 pro/rand post blunt CVP/PCW
1996 (28) 20% HA n = 14 trau
ma
penetr. 12-
16
Boldt 10% HES 200 n = 75 pro/rand post blunt PCWP
1998 (28) 20% HA n = 75 trau
maIC
penetr. 12-
15mm
Allison1999 (65)
HES 250/0.45 (PS) n = 24
gelatin n = 21
pro/rand E blunt ?
Conclusion
(endothelial) coagulation: no differences
outcome: no differences
albumin: lower CI and pHi HES: beneficial effects on regulators of circulation outcome: no differences
HES: lower levels of adhesion molecules than HA
outcome: no differences
HES: better hemodynamics HES: better VO2 and VO2outcome: no differences
platelet function: no differences blood use: no differences outcome: no differences
HES: better hemodynamics HES: no side-effects
outcome: no differences
HES: reduced capillary leak renal/blood use: no differences outcome: not shown
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Boldt: VOLUME REPLACE MENT IN TRAUMA PATIENTS 15
PS = pentastarch; RL = Ringers lactate ; RA = Ringers acetate; NS = 0.9% NaCl; HA = human albumin; kD = kilo Daltons;
E = emergency room; OR = operating room; F = in the field; ICU = intensive care unit; pro = prospectively; rand = randomized;
blunt = blunt trauma; penetr. = penetrating trauma; HES = hydroxethyl starch; d-b = double-blind; pts = patients; CVP = central
venous pressure; PCWP = pulmonary capillary wedge pressure; CI = confidence interval; pHi = gastric intramucosal pH.
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Boldt: VOLUME REPLACE MENT IN TRAUMA PATIENTS 16
identified. Only studies published in English in
adult patients on pre-hospital volume
replacement, volume replacement in the
emergency area or in the operating room (OR), and
volume therapy in the trauma ICU published in theperiod from January 1st 1985 to December 31st
2002 were included. Studies in head trauma
patients, in traumatized children, and in burned
trauma patients were not included. Only original
studies comparing different solutions for volume
therapy were analyzed. Published abstracts,
reviews, and letters were not included. Animal or
experimental studies were excluded because
animal models cannot completely mimic thehuman trauma situation.
A total of 13 studies were found and analyzed:
six of them compared a crystalloid- vs a colloid-
based volume replacement regimen5661
(Table V)and seven compared different colloids for volume
resuscitation28,40,46,6265 (Table VI). In none of the
studies were different volume regimens during
primary resuscita tion (in the field) studied. In six
studies different volumes were administered in the
emergency department (E) or in the OR,5761,65 and
another seven studies looked at different volume
therapies in the post- surgery period in theICU.28,40,46,56,6264 The study population in eachvolume group of the different studies differed
widely, ranging from five to 75 patients. The
amount of volume administered also differed
widely (from 500 to > 3,500 mL) or was not
mentioned.
Limitations of existing studies
GOALS FOR VOLUME THERAPY
What goals of volume therapy were used in the
studies to guide specific volume replacement?
Unfortunately, standardized protocols were used
only in a few studies. Volume replacement wasadapted with regard to hemodynamic data [tomaintain filling pressures e.g., central venous
pressure, pulmonary
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17 CANADIAN JOURNAL OF ANESTHESIA
capillary wedge pressure (PCWP), to keep systolic
blood pressure > 100 mmHg]. Other studies only used
fixed doses of the different solutions without use of a
specific protocol.
ENDPOINTS TO ASSESS THE EFFICACY OF VOLUME THERAPY
Most studies were not focused primarily on outcome andoutcome was not reported in some studies. Thus the
influence of different volume replacement regimens on
outcome in trauma patients cannot be determined by the
studies examined.
Some studies focused only on possible adverse events
(e.g., hemostasis, kidney/pulmonary function,
inflammation). Because coagulation abnormalities have
been reported, especially after the administration of HES,
some studies looked especially at alterations of
hemostasis after infusion ofHES.28,56,57,62 The general result
from these studies was that the use of modern HES
preparations is not associated with impaired hemostasis
or an increased bleeding tendency.
One study focused on capillary leakage.65 In 45
patients suffering from blunt trauma either HES [Mw 250
kD (PentaspanTM, Bristol-Myers Squibb, Montreal, Qc,
Canada)] or gelatin were given for the first 24 hr.
Resuscitation with HES resulted in significantly less
post-trauma capillary leak (measured by
microalbuminuria) than resuscitation with gelatin.
DURATION OF VOLUME THERAPY
Unfortunately, some trials only compared rather short-
term effects of different volume replacement strategies.At the end of the study period, no further strict infusion
protocols were implemented. A definitive evaluation of
the efficacy of different volume replacement regimens is
not possible with such a design. In a prospective ran-
domized study, long-term volume therapy using either
20% HA or 6% HES 200/0.5 in the ICU was studied in
trauma patients with an Injury Severity Score > 15
points.63 HA or HES exclusively were infused over five
days to keep PCWP between 10 and 15 mmHg. Besides
hemodynamic monitoring, liver function was assessed
using the monoethylglycinexylidide test. Gastric
intramucosal pH was monitored by tonometry to evaluate
splanchnic perfusion. Additionally, important regulatorsof circulation were measured from arterial blood samples.
Mean arterial pressure, heart rate, and PCWP did not
differ between the two groups, whereas confidence
interval increased significantly more in the HES than in
the HA group. Liver function and splanchnic perfusion
were also similar between HA- and HES-treated trauma
patients. Concentrations of all vasoactive regulators
showed an almost similar course in
both groups. Thus, in trauma patients, long-term volume
therapy with HA did not show any advantages over a
modern HES solution.
Volume replacement with HS
Treatment of trauma-related hypovolemia using
hypertonic (and hyperoncotic) solutions should beassessed separately from the classic colloid/crystalloid
or colloid/colloid debate because this represents a special
issue. This strategy is mostly used in the early (field)
resuscitation of hemorrhagic hypovolemia.
PUBLISHED META-ANALYSES- In a meta-analysis of the efficacy of a hypertonic
7.5% saline/6% dextran solution in trauma patients from
1997, nine (original) studies were analyzed.66 The
analysis revealed no significant improvement in outcome
after the infusion of hypertonic saline solution, whereas
the use of hypertonic saline plus dextran (HSD) may be
superior compared to isotonic fluid resuscitation.
- In a recently published meta-analysis (Cochrane
review) from 2002, the use of crystalloids was compared
with HS. Five studies in trauma patients were included.
No beneficial influence of HS on outcome was found.67
MEDLINE-ANALYSIS
In our MEDLINE analysis on HS, 12 studies were found
and analyzed (Table VII, available as Additional Material
at www.cja-jca.org).6877 Either hypertonic saline solution
(HS; 7.5% NaCl) or a combination of HS with colloid
(6% dextran 70; HSD) were used (Table IV). All studies
used crystalloids [mostly normal saline solution (NS)] asa control group. The use of colloids was not compared.
Six studies used HS in the field, five in the E, and one in
the OR. Patient populations ranged from seven to 211
patients per group. The studies analyzed have several
problems.
GOALS AND ENDPOINTS FOR VOLUME THERAPY
In most of the studies analyzed, a fixed volume of either
fluid was given (250 mL). It is doubtful that 250 mL of
an isotonic crystalloid (e.g., NS) was adequate to treat
hypovolemia in trauma patients in the control groups.
Systemic hemodynamics were either improved or withoutdifferences compared to the use of crystalloids. No
negative influence on hemostasis, bleeding or use of
packed red cells was documented. Outcome was not
affected beneficially by the use of a hypertonic volume
replacement strategy.
ConclusionsIn the severely hypovolemic trauma patient adequate
volume restoration appears to be essential to treat non-
compensatory, irreversible shock. Lengthy uncorrected
hypovolemia will jeopardize survival by the continuous
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Boldt: VOLUME REPLACEMENT IN TRAUMA PATIENTS 18
stimulation of various vasopressive and immune
cascades. Prolonged under-resuscitation of the
hypovolemic trauma patient may have fatal consequences
for organ function. Thus, vigorous optimization of the
circulation - at least when surgical hemostasis has been
achieved - is a prerequisite to avoid development of
multiple organ dysfunction syndrome in the traumapatient. 78 This maneuver is aimed at assuring stable
macro- and microhemodynamics while avoiding
excessive fluid accumulation in the interstitial tissue.
Blood volume is restored more rapidly with colloids than
with crystalloids, colloids are more efficient resuscitative
fluids than crystalloids,79 and colloids are a more efficient
regimen to ensure adequate microcirculatory flow than
crystalloids.11,80 Especially hypotonic solutions (e.g.,
Ringers lactate, hypotonic colloids) should be avoided
due to the risk of (interstitial) fluid overload. Use of
balanced colloids is a promising alternative to avoid
electrolyte imbalances and overflow into the interstitial
compartment in this situation.
What endpoints should be chosen to assess the ideal
volume replacement strategy? Although often used,
clinical signs of hypovolemia are non-specific and
insensitive. Most studies on volume replacement in
trauma patients were not focused on outcome. It remains
unclear whether mortality is an appropriate endpoint
when comparing different volume replacement
strategies.55 New concepts on trauma, the development of
SIRS, and post-trauma organ dysfunction (e.g., renal or
pulmonary insufficiency) should change this point of
view.
Very few studies are available comparing different
volume replacement protocols exclusively in trauma
patients. Based on these limited data, the publication of
strict recommendations on the best volume
replacement strategy in the hypovolemic trauma patient
comes as a surprise. Further studies are necessary to
distinguish different types (e.g., with/without head injury,
blunt trauma, penetrating trauma) and severity of trauma.
We should not only consider young, strong male victims
but also - especially in highly industrialized countries -
the > 70-yr-old trauma patient who presents with several
comorbid states. It is time to leave emotions aside when
discussing the most appropriate volume replacement
strategy in trauma patients and to concentrate on the
available scientific evidence. We need improved
monitoring technologies that will help us guide volume
therapy and better point-of-care markers that will help
us assess when volume therapy is appropriate in the trau-
ma patient.
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