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TRAUMA III
1988 THE LANCET Vol 363 June 12, 2004 www.thelancet.com
Advances in shock resuscitation have occurred during
military conflict because of concentrated experience with
patients. With other clashes around the world that will
probably involve both military personnel and civilians,
what further advances should we expect in the next several
years? Shock resuscitation is an obligatory intervention that
with refinement has changed the epidemiology of deaths
from trauma (table 1). During World War I, as a result of
the wound toxin hypothesis, no preoperative resuscitation
was administered and many soldiers died. In World War II
and the Korean conflict, due to the misconception over
haemoconcentration, colloid was administered and
eventually banked blood resuscitation became standard
care. Early survival improved, but many casualties later
died of acute renal failure. During the Vietnam conflict,
with the recognition that the extracellular fluid space had
to be repleted, large volume isotonic crystalloid solutions
replaced colloids for initial shock resuscitation. Mortality
rates and the incidence of acute renal failure decreased but
adult respiratory distress syndrome emerged as a major
source of morbidity and mortality. Through the 1970s and
early 1980s, intensive care units (ICUs) were developed,
where advanced technology and improved care allowed
patients with single organ failure to survive for long
periods. Patients no longer died of acute renal failure or
adult respiratory distress syndrome, but developed
multiple organ failure, which, at that time, was usually
fatal.
From the mid-1980s to the present, regional trauma
systems have been implemented, in which the most
severely injured patients are rapidly triaged to high volume,
level 1 trauma centres where rapid intervention and
Lancet 2004; 363: 198896
Department of Surgery, University of TexasHouston Medical
School, Houston, TX, USA (Prof F A Moore MD, B A McKinley PhD); and
Department of Surgery, University of ColoradoDenver Health
Medical Center, Denver, CO USA (Prof E E Moore MD)
Correspondence to: Dr Frederick A Moore, Department of Surgery,
University of TexasHouston Medical School, 6431 Fannin Street,
Suite 4264, Houston, TX 77030, USA
(e-mail: Frederick.A.Moore@uth.tmc.edu)
prompt definitive care are given.
1
Consequently, the
epidemiology of death from trauma has changed.
2
Rates of
early hospital death from blood-loss have been reduced
with the introduction of damage control surgery. For
example, damage control laparotomy is well established in
the initial surgical care of patients with severe torso injury,
and consistent results have been achieved in the USA and
Europe.
3
These patients, however, remain at high risk of
multiple organ failure.
4
Although mortality rate from
multiple organ failure is decreasing, it remains the major
cause of prolonged ICU stays. As we learn more about the
relations between the initial traumatic shock insult, the
obligatory resuscitation, and the dysfunctional inflamma-
tory response that causes multiple organ failure, some
The next generation in shock resuscitation
Frederick A Moore, Bruce A McKinley, Ernest E Moore
Search strategy
For this review we drew on a continuously updated collection
of references on shock resuscitation, maintained at the
Trauma Research Center, University of Texas-Houston
Medical School, supplemented by a PubMed search using the
keywords shock, trauma, and resuscitation.
Resuscitation of the severely injured patient who presents in shock has improved greatly, following focused wartime
experience and insight from laboratory and clinical studies. Further benefit is probable from technologies that are being
brought into clinical use, especially hypertonic saline dextran, haemoglobin-based oxygen carriers, less invasive early
monitors, and medical informatics. These technologies could improve the potential of prehospital and early hospital care
to pre-empt or more rapidly reverse hypoxaemia, hypovolaemia, and onset of shock. Damage control surgery and
definitive interventional radiology will probably combine with more real-time detection and intervention for hypothermia,
coagulopathy, and acidosis, to avoid extreme pathophysiology and the bloody vicious cycle. Although now widely
practised as standard of care in the USA and Europe, shock resuscitation strategies involving haemoglobin replacement
and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centres. One of the difficulties
is the scarcity of published evidence for or against seemingly basic intervention strategies, such as early or large-
volume fluid loading. Standardised protocols for resuscitation, representing the best and most current knowledge of the
clinical process, could be devised and widely implemented as interactive computerised applications among trauma
centres in the USA and Europe. Prevention of injury is preferable and feasible, but early care of the severely injured
patient and modulation of exaggerated systemic inflammatory response due to transfusion and other complications of
traditional strategies will probably provide the next generation of improvements in shock resuscitation.
Era Focus Resuscitation Outcome
World War I Wound toxins None Early death
World War II, Intravascular Colloids, blood Early survival
Korean war repletion ARF death
Vietnam war Intravascular Crystalloids, Early survival
and extracellular banked blood ARF
fluid repletion ARDS death
1970s80s ICUs, organ PA catheters, ARF
failure, metabolic endpoints of ARDS ? MOF
support resuscitation MOF deaths
Mid-1980s Trauma centres, Rapid triage, Early survival
to present trauma systems damage control, ARDS/MOF
shock and ARDS/MOF deaths
trauma ICUs
ARF=acute renal failure. ARDS=adult respiratory distress syndrome.
MOF=multiple organ failure.
Table 1: Improvements in resuscitation and the changing
epidemiology of trauma deaths over time
Trauma III
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Transfusion trigger
Banked red blood cells have been widely available since
World War II, but the indications for administration
continue to be debated. Animals with haemorrhagic shock
show improved survival with haemoglobin concentration
maintained in the range 120130 g/L.
24,25
Animal models of
isovolaemic haemodilution suggest that the optimum
haemoglobin concentration for maintaining systemic
oxygen delivery (DO
2
) is 100 g/L, but in healthy human
volunteers isovolaemic haemodilution is tolerated at
concentrations as low as 50 g/L.
26
Until recently, clinical
studies in critically ill patients concluded that 100 g/L
haemoglobin was optimum for shock resuscitation,
27
but
more recent consensus panels have judged that a lower
concentration is adequate. The American Society of
Anesthesiology recommends maintaining haemoglobin at
greater than 60 g/L, whereas the National Institutes of
Health recommends a concentration of greater than
70 g/L.
28,29
A prospective randomised controlled trial has
shown that ICU patients randomised to restrictive blood
transfusions (transfuse if haemoglobin concentration
<70 g/L and maintain between 70 and 90 g/L) did as well
and possibly better than patients who were liberally
transfused (transfuse if <100 g/L and maintain between
100 and 120 g/L).
30
This study was done in a select group
of euvolaemic patients. Malone and colleagues report
blood transfusion as a risk factor, independent of shock
severity, for poor outcome in patients with trauma.
31
Short-term improvement in survival is believed to be
due to reduction of the adverse immunological
consequences of transfusion of banked red blood cells.
The concept of transfusion-related immunosuppression
dates from the early 1970s with the observation that
greater pretransplant transfusion was associated with
improved renal allograft survival.
32
Subsequently,
perioperative transfusion was associated with cell-mediated
immunosuppression, tumour recurrence, and
postoperative infections.
3336
The capacity of banked red
blood cells to provoke neutrophil cytotoxicity is a key
mechanism in multiple organ failure.
5,37
In epidemiological
studies, early transfusion has been shown to be a strong
independent risk factor for multiple organ failure.
4,8
Focused clinical studies have shown that severely injured
patients at high risk of multiple organ failure have
circulating neutrophils that are primed for cytotoxicity
within the first 6 h after injury, increased expression of
adhesion receptors, activation of p38 mitogen-activated
protein kinase, and delayed apoptosis.
6,38,39
The precise
mechanisms linking red blood cell transfusion and
neutrophil priming remain to be established, but it is
generally believed that passenger leucocytes accompanying
red blood cells in storage are important in the generation of
proinflammatory agents and progressively increase from 14
to 42 days of storage.
4042
Some investigators have
implicated cytokines (tumour necrosis factor , interleukin
1, interleukin 6, interleukin 8), but our focus has been on
proinflammatory lipids presumably generated from the
degradation of the red blood cell membrane.
4345
Although
pre-storage leucoreduction of red blood cells decreases the
generation of cytokines, this process does not eliminate
neutrophil priming.
46
Another emerging concern regarding
stored cells is that substantial shape changes and impaired
deformability occur by the second week of storage and
progress during further preservation.
47
The effects of
decreased deformability on microcirculation have been
documented experimentally, and include impaired tissue
access and entrapment resulting in microvascular
obstruction.
48
These findings might account for the
observation that blood transfusion failed to improve
TRAUMA III
THE LANCET Vol 363 June 12, 2004 www.thelancet.com 1989
disconcerting observations indicate that our fundamental
approach to resuscitation needs to be reassessed.
510
The
purpose of this report is to briefly review traditional
resuscitation, discuss its inherent flaws in view of our
current understanding of the pathogenesis of multiple
organ failure, and identify alternative methods of fluid
resuscitation, haemorrhage control, and monitoring
techniques that could be used in the near future to
improve outcome.
Traditional resuscitation
Crystalloid versus colloid debate
Since the early 1940s, when restoration of circulatory
blood volume was embraced as pivotal in shock
resuscitation, controversy has existed as to which fluid to
use for this purpose.
11
A review article from that era
concluded that saline and glucose solutions were
unsuitable because they were quickly lost from the
intravascular space. Plasma and serum were considered
the best substitutes for whole bloodand in some cases,
better than blood itself.
12
This was the resuscitation
strategy used in World War II. Isotonic crystalloids
became the standard of care in the late 1960s based on the
laboratory work of Moyer, Shires, Moss, and others,
1315
which showed that: (1) large-volume resuscitation with
isotonic crystalloids provided the best survival; (2)
extracellular fluid was redistributed during shock into
both the intravascular and intracellular spaces; (3)
optimal resuscitation corrected this extracellular fluid
deficit, required infusion of isotonic crystalloid fluid, and
shed blood in a ratio of three volumes of crystalloid to one
of blood; and (4) in severe shock, this ratio increased up
to eight to one.
Isotonic crystalloid fluids were used in the Vietnam
conflict. For various reasons, mortality and acute renal
failure decreased, but a new entity called shock lung
emerged. This complication was soon described in civilian
publications as adult respiratory distress syndrome, and
was shown to be the major source of morbidity and
mortality in the ICU. The pathogenesis was not known,
but controversy existed over whether adult respiratory
distress syndrome was an iatrogenic complication of
resuscitation with crystalloids.
16,17
Beginning in the mid-
1970s, prospective randomised controlled trials were done
to compare crystalloids with colloids in resuscitation, with
pulmonary dysfunction as the primary endpoint.
1820
Results conflicted because of shortcomings in study
design, which included small numbers of patients,
heterogeneous populations, and different resuscitation
endpoints and sodium loads, and difficulty in defining
pulmonary dysfunction. These data have been assessed by
meta-analysis,
19,20
and no difference in the incidence of
pulmonary dysfunction has been found. However, when
mortality is used as the endpoint and the data are
subgrouped, the use of crystalloids in trauma patients is
associated with improved survival. Although these data
are not definitive, this finding does lend support to the
current common use of crystalloids in US trauma centres.
The type of crystalloid fluid used in resuscitation
engenders less controversy. Normal saline and lactated
Ringers are the two balanced salt solutions that are com-
monly used. Although important theoretical differences
favour lactated Ringers, laboratory investigators have had
difficulty demonstrating substantial differences in
outcome.
21,22
Results of one study showed that the two
solutions were equivalent in moderate haemorrhagic
shock, but that with massive haemorrhage normal saline
was associated with greater physiological derangement
and greater mortality rate, compared with Ringers.
23
For personal use. Only reproduce with permission from The Lancet Publishing Group.
TRAUMA III
1990 THE LANCET Vol 363 June 12, 2004 www.thelancet.com
oxygen consumption in critically ill and injured patients
and, in one study, seemed to induce splanchnic
ischaemia.
49,50
Endpoints of resuscitation
Initial care
Initial care of severely injured patients presenting in shock
is prioritised to ensure survival (ie, advanced trauma life
support), and empiric volume loading is an emphasised
early intervention.
1
The response of blood pressure and
heart rate to volume loading defines stability. For patients
who do not respond appropriately, diagnostic testing is
focused on identifying sources of uncontrolled haemor-
rhage, which need prompt attention in the operating room
or interventional radiology suite. Controversy exists as to
whether blood pressure and heart rate should be restored
to normal at this point.
51,52
One recent prospective trial in
penetrating torso trauma showed worse survival in
patients who were volume loaded before definitive
vascular control was obtained in the operating room,
although subgroup analysis showed this effect to be
significant only in those with pericardial tamponade.
53
Whether this finding applies to patients with blunt trauma
is not clear.
53,54
Furthermore, 20% of patients with major
torso trauma will have a serious concomitant closed head
injury and, if the patient is under-resuscitated, decreased
cerebral perfusion pressure can result in devastating
secondary brain injury.
55
Fortunately, in most patients,
there is time to obtain additional information.
Measurement of arterial blood gases with base deficit
determination indicates the severity of shock, and serial
haemoglobin measurements assess ongoing bleeding.
Additional monitoring should include central venous
pressure (via central venous line), urine output rate (via
Foley catheter), and arterial haemoglobin oxygen
saturation (via pulse oximetry). The current goal is to
return blood pressure and heart rate to normal, and
establish urine output while maintaining central venous
pressure in a moderate range (815 mm Hg).
Oxygen delivery and optimisation
Once operating room and interventional radiology
procedures are complete, severely injured patients are
transferred to the ICU where attention is focused on
optimising resuscitation. The use of pulmonary artery
catheters is controversial, but most trauma centres in the
USA use them in most patients with evidence of ongoing
haemorrhagic shock.
56
Prospective studies in the 1980s
showed that high-risk surgical patients had improved
survival when subjected to resuscitation protocols aimed
at optimising DO
2
57
These findings gave rise to the
hypothesis that unrecognised flow-dependent oxygen
consumption (VO
2
) was an important cause of multiple
organ failure and could be eliminated by maximising DO
2
.
Although the physiological argument and epidemiological
data supporting this concept are enticing, investigators
have failed in several prospective randomised trials to
document consistent outcome advantages, and one
multicentre European study concluded that maximising
DO
2
is harmful.
5860
These disparate results could be due to
a number of confounding variables, including different
inclusion criteria, variable timing of the intervention, and
different types of intervention. The original studies were
designed to optimise DO
2
before a major operative insult
and to maintain DO
2
perioperatively. Studies in nonsur-
gical ICUs were primarily done in patients with
established sepsis, septic shock, or adult respiratory
distress syndrome. At the time of enrolment, these
patients already had organ failure, and prolonged
resuscitation with high dose inotrope and vasopressor
agents might well have been harmful. On the other hand,
earlier intervention with less aggressive interventions
remain an attractive approach in patients with major torso
trauma. High risk trauma patients can have unrecognised
early myocardial dysfunction, which is greatly improved by
volume loading.
The primary goal of shock resuscitation is the
establishment of adequate DO
2
. The definition of
adequate, however, remains controversial. The three
primary determinants are arterial haemoglobin concen-
tration, oxygen saturation, and cardiac output. In acute
shock, high oxygen saturation is easily maintained by
increasing the fraction of inspired oxygen concentration
(FIO
2
), and haemoglobin concentration is maintained by
liberal blood transfusion, but cardiac output is more
difficult to manipulate and monitor. Continuous cardiac
output monitoring by pulmonary artery catheter
thermodilution technology is the standard of care.
Traditionally, thermodilution has been used to measure
cardiac output because it was more convenient than
alternative indicator dilution methods (direct Fick, dye
dilution). The process has become even more convenient
with the introduction of continuous cardiac output
technology, which has proven to be as accurate as the
bolus technique and provides a real-time response to
resuscitation. Less invasive techniques of measuring
cardiac output include transthoracic electrical bioimped-
ance, transoesophageal echocardiography, Doppler
ultrasound, combined indicator dilution, and arterial
pressure waveform analysis and analysis of carbon dioxide
rebreathing. These technologies continue to be refined and
have replaced thermodilution in some ICUs, but
unfortunately have not been systematically tested in
trauma resuscitation. The pulmonary artery catheter also
provides essential information about preload assessment
(ie, pulmonary artery capillary wedge pressure, or, more
recently, right ventricular end diastolic volume index). To
optimise cardiac output, preload often needs to be pushed
to relatively high pressures and, if this does not work,
vasoactive drugs need to be administered.
How far to increase DO
2
is a clinical dilemma. Driving
DO
2
until VO
2
reaches a plateau makes sense intuitively,
but is not clinically practical. Cardiac output has
substantial variability and since both DO
2
and VO
2
are
derived from cardiac output, it is virtually impossible to
obtain a stable plateau. Shoemaker and colleagues
57
have
simplified this dilemma. In an analysis of the physiological
response in survivors and non-survivors, they showed that
a DO
2
index of greater than 600 mL/min per m
2
was
associated with survival. They then showed in prospective
trials that patients maintained at such a DO
2
index had
improved survival. Most other investigators have not
succeeded in reproducing these results. Our current
experience is that a DO
2
index of greater than 500 mL/min
per m
2
obtains a similar response with less need for volume
loading and blood transfusions.
61
An alternative is to maintain increased DO
2
until lactate
concentration returns to normal. In our experience VO
2
fails to increase, despite increased DO
2
, in a substantial
subset of patients, and lactate concentration remains
persistently increased. This finding probably represents a
defect in mitochondrial function in peripheral tissues, and
these patients often develop multiple organ failure.
7
Conceptually, this response is similar to that of
resuscitating patients with advanced septic shock. Early
volume loading has been shown to be beneficial, but
aggressive resuscitation in the later stages does not improve
outcome and a persistently increased lactate is highly
For personal use. Only reproduce with permission from The Lancet Publishing Group.
observation that blood transfusions contain pro-
inflammatory mediators that both prime and activate
neutrophils.
4045
The next generation
Fluid resuscitation
Crystalloid versus colloid debate revisited
Unfortunately, the prospective randomised controlled trials
comparing crystalloid and colloid resuscitation were done
in the 1970s and 1980s, before the recognition of
abdominal compartment syndrome as an important clinical
entity. Additionally, albumin was the principal colloid used,
but other types of colloid (starches and gelatins) are
available. Because of their higher molecular weights, these
colloids are confined to the intravascular space and their
infusion results in more efficient plasma volume expansion.
In severe haemorrhagic shock, however, the permeability of
capillary membranes increases, allowing colloids to enter
the interstitial space, which can then worsen oedema and
impair tissue oxygenation. The theory that these high-
molecular-weight agents plug capillary leaks that occur
during neutrophil-mediated organ injury has not been
established.
70,71
Furthermore, Lucas and colleagues
72,73
propose that resuscitation with albumin induces renal
failure and even impairs pulmonary function. Similarly,
hetastarch has been shown to induce renal dysfunction in
patients with septic shock and in recipients of kidneys from
brain-dead donors.
7476
Hetastarch also has a limited role in
massive resuscitation because it causes a coagulopathy and
hyperchloraemic acidosis due to its high chloride content. A
new hydroxyethyl starch preparation (Hextend)
purportedly does not cause these adverse effects, but has
not been studied in massive resuscitation.
77
We share the
belief that colloids might reduce the incidence of abdominal
compartment syndrome, but this possible benefit must be
weighed against the potentially detrimental effects of
colloids already reported. Additionally, alternative
crystalloid solutions are being developed that not only
expand the intravascular space and replete the extracellular
fluid, but also have anti-inflammatory properties (eg,
Ringers ethyl pyruvate).
78
Hypertonic saline
A provocative report by Velasco and colleagues in 1980
79
spurred research interest in hypertonic saline. Small-
volume hypertonic saline was shown to be as effective as
large-volume crystalloids in expanding plasma volume and
enhancing cardiac output in haemorrhagic shock in
animals.
80
Furthermore, hypertonic saline increased
perfusion of the microcirculation, presumably by selective
arteriolar vasodilation and by decreasing swelling of red
blood cells and of the endothelium.
81
This improved
microcirculation, however, could lead to increased
bleeding. Consequently, hypertonic saline was tested in
animal models of uncontrolled haemorrhagic shock and
was shown to increase bleeding, but mortality was model-
dependent and the best survival was obtained when saline
was given with high-volume crystalloids.
82,83
Additionally,
the resuscitative effectiveness of hypertonic saline was
found to be enhanced by combination with dextran
(hypertonic saline dextran [HSD])
84
In view of the small
volume needed to achieve these effects, there was great
interest in the use of these fluids in resuscitation in the field
for both military and civilian use. From the late 1980s
through the early 1990s, several trials were done.
Individually, these trials found survival outcome to be
inconsistently improved, but did document that a bolus of
hypertonic saline or HSD was safe.
85,86
Meta-analysis of
these data suggests that hypertonic saline is no better than
TRAUMA III
THE LANCET Vol 363 June 12, 2004 www.thelancet.com 1991
predictive of death. An alternative explanation is that high
lactate concentration occurs following severe insults
because excessive mobilised substrates cannot be
processed through the Krebs cycle.
62,63
As a result, there is
a build up of intracellular pyruvate that is converted to
lactate, which then exits the cell and is taken back to the
liver to be converted into glucose (the Cori cycle). Thus, a
high lactate concentration at the end of resuscitation
simply reflects a more severe stress response.
Why change resuscitation?
Over the last decade, epidemiological studies of patients
with torso trauma have revealed several disturbing
observations that have led us to conclude that
fundamental changes in current resuscitation strategies are
needed. Although now widely practised as standard of care
in the US and Europe, shock resuscitation strategies
involving haemoglobin replacement and fluid volume
loading to regain tissue perfusion and oxygenation are
quite variable among trauma centres, and published
evidence for or against seemingly basic intervention
strategies (eg, early or large volume fluid loading
6466
) is
scant.
First, the clinical trajectory of patients who develop
multiple organ failure is set early in the resuscitation
process (ie, within 6 h of injury).
5,9
Many patients at high
risk require emergency surgery or interventional radiology,
and arrive in the ICU after this time window.
9
Although
resuscitation efforts in the ICU can clearly modify the
subsequent clinical course, even highly refined and
individually tailored resuscitation cannot reverse the
dysfunctional response that has already occurred.
10
To
substantially reduce the incidence of multiple organ
failure, interventions before ICU admission will need to be
modified. Unfortunately, this will need to be accomplished
in chaotic clinical situations such as damage control
surgery, and in environments not traditionally focused on
monitoring resuscitation.
Second, although initial crystalloid volume loading is
valuable in defining haemodynamic stability, to continue
this process in the face of ongoing haemorrhage promotes
further bleeding, haemodilutes the patient, and sets the
stage for the so-called bloody vicious cycle of
hypothermia, acidosis, and coagulopathy.
10
This syndrome
is particularly problematic in patients with blunt trauma,
who often have sources of bleeding that are not amenable
to direct control. Failure to resuscitate these patients will,
however, ultimately lead to irreversible shock.
Third, although crystalloid resuscitation is efficacious in
most patients, it produces problematic tissue oedema in
patients who arrive in severe shock. These patients
typically need massive fluid resuscitation to maintain
intravascular volume and many develop the abdominal
compartment syndrome, which seems to be a second hit
for multiple organ failure.
10,67
Patients with severe torso
trauma who are admitted with shock and an associated
severe closed head injury are in a precarious situation.
Under-resuscitation decreases cerebral perfusion pressure,
which causes secondary brain injury. Excessive crystalloid
administration promotes cerebral oedema, which increases
intracranial pressure and further decreases cerebral
perfusion pressure.
Fourth, shock initiates dysfunctional inflammation that
causes multiple organ failure. Resuscitation is an
obligatory intervention to decrease the severity of the
shock insult, but the current strategy is not directed at
modulating inflammationin fact, it may worsen it.
Laboratory studies show that lactated Ringers solution
activates neutrophils.
68,69
Even more disturbing is the
For personal use. Only reproduce with permission from The Lancet Publishing Group.
TRAUMA III
1992 THE LANCET Vol 363 June 12, 2004 www.thelancet.com
standard of care isotonic crystalloid fluids, but that HSD
might be better.
87
Subgroup analysis showed that patients
who presented with shock and concomitant severe closed
head injury benefited most from HSD.
88
This observation
was consistent with laboratory data showing that,
compared with isotonic crystalloid, hypertonic saline or
HSD increases cerebral perfusion pressure, decreases
intracranial pressure, and decreases brain oedema, in
combined head injury and haemorrhagic shock.
89
This
finding has led some authorities to recommend that
hypertonic saline should replace mannitol in the
management of intracranial hypertension in patients with
severe closed head injury.
90,91
The argument in favour of
hypertonic saline is even more compelling with the recent
recognition that hypertonic saline resuscitation markedly
decreases the inflammatory response (specifically neutro-
phil cytotoxicity) in animal models of haemorrhagic shock,
ischaemia and reperfusion, and sepsis.
9294
Blood substitutes
Another potential avenue to decrease the need for massive
crystalloid administration could be earlier administration of
bloodspecifically, packed red blood cells. For reasons
described earlier, the Advanced Trauma Life Support
guidelines recommendation to initiate resuscitation of class
IV haemorrhagic shock with lactated Ringers may not be
optimal. However, the present limited supply of stored
blood and potential adverse effects make the option of
earlier administration of packed red blood cells (or other
blood components) logistically impractical and probably
harmful. Haemoglobin-based oxygen carriers for trauma
resuscitation may provide a workable compromise, and
their development has an interesting history (table 2). The
most clinically successful of these carriers are polymerised
haemoglobin solutions.
105
Interest in haemoglobin-based
oxygen carriers dates from the 1933 report of Amberson
and colleagues
95
who showed that haemolysates could
transport oxygen in mammals. Unfortunately, when
infused into humans, these solutions had excessively toxic
effectsvasoconstriction, acute renal failure, and
abdominal painwhich were attributed to stromal
contamination.
96
The next generation of carrier solutions
were stroma-free, but toxicity persisted and was attributed
to instability of the haemoglobin tetramer, which
spontaneously dissociates into dimers and monomers. One
formulation of stabilised tetramer, diaspirin cross-linked
haemoglobin, was authorised for a phase III study in
trauma patients.
101
This product, however, failed and the
trial was prematurely stopped due to unexpectedly high
mortality in the treatment group (24 of 52 [46%] vs eight of
46 [17%]). Although this event was judged a major setback
for clinical implementation of haemoglobin-based oxygen
carriers, the product used was a solution of diaspirin cross
linked haemglobin, which had previously been shown to
markedly increase pulmonary and systemic vascular
resistance in animals. Tetrameric haemoglobin extravasates
from the vascular space, binds nitric oxide within the vessel
wall and, thereby, results in unopposed vasoconstriction.
This issue was addressed in another product by
polymerising the haemoglobin tetramer.
102
The additional
benefit of these larger moieties is that they exert less colloid
osmotic activity and therefore a higher dose can be
administered. A further limitation of earlier haemoglobin-
based oxygen carriers was that, because of the loss of 2,3
diphosphoglycerate, oxygen affinity was greatly increased
(normal P50 of 26 mm Hg decreased to 12 mm Hg). This
problem was addressed by pyroxidilation of the
haemoglobin tetramer, which increased P50 to 29 mm Hg.
One such polymerised haemoglobin solution has been
tested extensively in phase I and phase II trials in patients
with trauma and has been shown to be safe and
effective.
106108
A phase III pre-hospital trial is underway.
Haemorrhage control
The combination of hypothermia, coagulopathy, and
acidosis is a syndrome that accelerates its effects in a cycle
that is rapidly fatal unless interrupted.
109
In addition to
rewarming, coagulation factor replacement or enhanced
haemostasis via intravenous infusion of procoagulants or
antifibrinolytics might have a role in recalcitrant
coagulopathy. Recombinant activated factor VII (rFVIIa)
is an attractive candidate. When administered, it ostensibly
binds only to exposed subendothelial tissue factor. This
complex then activates the extrinsic clotting system at the
injury site without causing systemic hypercoagulability.
rFVIIa is approved in many countries for treatment of
bleeding in haemophilia patients with inhibitors. In various
animal models, rFVIIa has been shown to be an effective
procoagulant adjunct for haemorrhage control.
110,111
In
these models, rFVIIa does not activate the systemic
clotting system or cause diffuse microthrombosis. Case
reports document variable effectiveness of rFVIIa in
patients with acquired coagulopathy including trauma,
cirrhosis, gastrointestinal bleeding, bone-marrow
transplant, and heart-valve replacement.
112,113
No adverse
effects have been attributed to administration of the drug.
However, patients with major torso trauma who survive
massive resuscitation are at high risk of multiple organ
failure, and the potential that rFVIIa might contribute to
its pathogenesis is an unresolved concern.
Informatics and monitoring technology
Over the past decade, damage-control surgical techniques,
presumptive embolisation by interventional radiology, and
refined ICU resuscitation have saved many lives. To
further improve outcome, future efforts need to be
directed at better control of pre-ICU resuscitation. The
first challenge will be to accurately identify high-risk
bleeding patients in the field so that their early
resuscitation can be optimised and novel treatments tested.
Since the early 1970s, there has been a great interest in
developing trauma centre triage instruments, such as the
Glasgow coma score, trauma score, and revised trauma
score. By necessity, these scores were designed to be easy
to calculate to reduce distraction of pre-hospital staff from
Carrier Developments
Haemolysates 1933Bovine haemolysates into dogs/cats:
preservation of neurological function, maintenance of
oxygen consumption
95
1949Human haemolysates into patients: transport
oxygen, observed pressor effect
96
Modified 1951Human filtered haemolysates into humans: renal
haemolysates dysfunction
97
Tetrameric Hb 1967Human Hb tetramer into dogs: no renal
dysfunction
98
1978Human Hb tetramer into humans: renal toxicity,
hypertension, abdominal pain
99
Modified 1993Human modified Hb into animals: improved
tetrameric Hb survival as low-volume resuscitation agent, but concern
about systemic and pulmonary vasoconstriction
100
1999Human modified Hb into trauma patients:
increased mortality
101
Polymerised Hb 1984 Human glutaraldehyde polymerised Hb
102
1989Bovine glutaraldehyde polymerised Hb
103
2000Human o-raffinose polymerised Hb
104
Hb=haemoglobin.
Table 2: History of haemoglobin-based oxygen carriers
For personal use. Only reproduce with permission from The Lancet Publishing Group.
continuous monitoring.
116,117
We have shown the pH of
skeletal muscle to be a variable indicative of metabolic
status that is useful to track resuscitation.
115
A third
possibility is a commercially available fibre-optic sensor of
sublingual carbon dioxide.
118
This monitor is based on the
principle that hypoperfusion leads to increased PCO
2
in
tissue (interstitial fluid).
Once a patient has arrived in the emergency
department, more complex monitoring is feasible. Of the
available technology, monitoring of transcutaneous O
2
(PtcO
2
) has been shown to be valuable in shock
resuscitation.
119121
This is a time-honoured monitoring
technique in neonatal ICUs and, in stable patients, PtcO
2
correlates well with PaO
2
.
122124
If PtcO
2
decreases below
normal, then either PaO
2
has decreased (poor
oxygenation) or cardiac output has decreased (poor
perfusion). These two alternatives can be differentiated
easily by obtaining an arterial blood gas analysis.
Limitations of PtcO
2
monitoring in the emergency
department include a calibration time of roughly 10 min
and instability with patient movement. Another more
invasive alternative is to place a central venous line in the
superior vena cava to monitor central venous haemoglobin
oxygen saturation (ScvO
2
). The same fibre-optic reflective
spectroscopy technology that is used to measure mixed
venous haemoglobin O
2
saturation (SmvO
2
) in pulmonary
artery catheters has been incorporated into a standard
central venous catheter. Although ScvO
2
is not the same as
SmvO
2
, the principle that these variables reflect the
balance between DO
2
and VO
2
is familiar to most clini-
cians. This technology is known to provide an accurate,
stable measurement, and a trial in which ScvO
2
was used
as the endpoint in resuscitation of patients with septic
shock in the emergency department has shown improved
survival compared with routine care.
125
Because un-
TRAUMA III
THE LANCET Vol 363 June 12, 2004 www.thelancet.com 1993
providing vital care. With advanced informatics
technology, monitored variables can now be automatically
obtained and assessed for trend responses to initial
interventions.
114
This information, combined with
demographics and injury description, has the potential to
accurately identify patients who are actively bleeding and at
high risk early, before arrival in hospital.
The second challenge will be to monitor the early
resuscitation of bleeding patients in environments not
traditionally equipped for advanced monitoringie, from
the field to the emergency department to the interventional
radiology suite. The ideal monitor for these environments
would be one that senses an essential variable, provides
accurate, stable, and continuous measurement and trend
analysis, and, furthermore, is easily used, easily understood,
noninvasive, small in size and transportable. Some potential
monitors are described in table 3. For resuscitation in the
field, a simple monitor of the adequacy of tissue perfusion is
needed. This should be done in an easily accessible tissue
that undergoes disproportionate vasoconstriction during
shock, such as skin, subcutaneous fat, muscle, and oral
mucosa. If perfusion in this tissue can be normalised with
resuscitation, then perfusion in other tissues will be
adequate. Near infrared spectroscopy is a method that can
quantitatively monitor oxygen saturation of haemoglobin in
skeletal muscle and subcutaneous tissue (StO
2
), and that
can function as an index of tissue perfusion. In a recent
study, we used this method to monitor StO
2
over the
deltoid region during active shock resuscitation and found
that StO
2
correlated closely with DO
2
.
115
Near infrared
spectroscopy also has the potential to simultaneously
monitor the aa
3
redox state, which reflects mitochondrial
oxygen consumption.
7
Another alternative is placement of
very small probes, electrodes, or fibre-optic sensors for PO
2
,
PCO
2
, and pH directly into the tissue of interest for
Monitor Variable Manufacturer/supplier Placement Sensor technology Advantages; disadvantages
Pulmonary artery CCO, CVP, Edwards Lifesciences (Irvine, PA via right Catheter tip thermistor, Standard of care for haemodynamic
catheter* PAP, PAWP, USA), Abbott Critical heart foil heater element; instability; invasive, ICU placement
SmvO
2
(SVRI) Care (Morgan Hill, USA) fibre-optic hemoximetry procedure
Bedside Hb* Blood Hb HemoCue AB (Angelholm, N/A Disposable reagent Easy, accurate; quality control check to
concentration Sweden) cuvette, optical read verify calibration needed before use (nurse
time, material storage)
Impedance CCO Cardiodynamics International Chest, neck AC microcurrent Noninvasive CCO, HR; imprecision with
cardiography (San Diego, USA) adhesive injection, measurement tachycardia
(thoracic electrodes
bioimpedance)*
Central venous ScvO
2
, CVP Edwards Lifesciences SVC via CV Fibre-optic hemoximetry Less invasive than PAC; CO needed if
oximetry* non-resolving haemodynamic instability
Transcutaneous PtcO
2
Radiometer AG (Copenhagen, Skin surface Polarographic PO
2
Non-invasive blood gas, continuous; nurse
blood gas, PO
2
* Denmark) (shoulder, electrode, skin surface intensive (calibration time, site
chest) heater, thermistor maintenance)
Near infrared StO
2
Hutchinson Technology Shoulder Fibre-optic skin surface Non-invasive tissue SO
2
, continuous;
spectrometry* (Minneapolis, USA) (deltoid) probe, NIR light source efficacy for diagnosis of shock unproven
in clinical trial
Tissue gas* PtO
2
, PtCO
2
, pHt Diametrics Medical Subcutaneous, Fibre-optic optode Low invasiveness, continuous tissue gas,
(Minneapolis, USA) skeletal (fluorescent, absorption pH; efficacy for diagnosis of shock unproven
muscle indicator chemistry) in clinical trial
Gastrointestinal PslCO
2
CapnoProbe, Nellcor Sublingual Fibre-optic optode Non-invasive; single measurement per
tract mucosal (Pleasanton, USA) sensor (not continuous)
PCO
2
* PgCO
2
Tonocap, Datex Ohmeda Nasogastric CO
2
gas analysis Combined PCO
2
monitor and nasogastric
(Helsinki, Finland) tube tube, continuous; non-specific
(PgCO
2
increasewith severe hypotension,
peritoneal hypertension)
CCO=continuous cardiac output. CVP=central venous pressure. PAP=pulmonary artery pressure. PAWP=pulmonary artery wedge pressure. SmvO
2
=mixed venous Hb O
2
saturation. SVRI=systemic vascular resistance index. Hb=haemoglobin. ScvO
2
=central venous Hb oxygen saturation. PtcO
2
=transcutaneous O
2
. StO
2
=subcutaneous
tissue O
2
saturation. PtO
2
, PtCO
2
, pHt=tissue (interstitial fluid) PO
2
, PCO
2
, pH. PslCO
2
=sublingual mucosa PCO
2
. PgCO
2
=gastric mucosa PCO
2
. PA=pulmonary artery.
N/A=not applicable. SVC=superior vena cava. NIR=near infrared spectroscopy. HR=heart rate. PAC=pulmonary artery catheter. CO=cardiac output. SO
2
=O
2
saturation.
*Commercially available. Frequently used, or with US Food and Drug Administration clearance for indication of shock, or both.
Table 3: Pre-ICU resuscitation monitors
For personal use. Only reproduce with permission from The Lancet Publishing Group.
TRAUMA III
1994 THE LANCET Vol 363 June 12, 2004 www.thelancet.com
recognised myocardial dysfunction is a substantial problem
after major trauma, a monitor of cardiac output in the
emergency department would be valuable. Transthoracic
electrical bioimpedance best meets the specifications for
pre-ICU monitoring.
126
Early bioimpedance systems
provided continuous cardiac output measurements that
correlated well with discrete measurements made by pul-
monary artery catheter thermodilution in stable patients,
but did not perform well in critically ill patients, especially
those who were tachycardic. Newer bioimpedance
technology has been used to successfully direct trauma
resuscitation in the emergency department.
127
The third and perhaps the most difficult challenge in
controlling pre-ICU resuscitation is the early
identification of patients who are unresponsive to
treatment, and implementation of alternative interven-
tions to alter their poor clinical trajectory before it
becomes irreversible. Here again, informatics technology
will be invaluable. The intensity of data from
physiological monitors, laboratory analyses, radiological
imaging, life-support devices, and ongoing physical
examinations can overwhelm the bedside clinician,
especially those with less expertise. Hospital wide
electronic medical records are being implemented in
most medical centres.
128
The ability to rapidly transmit,
record, recall, and review represents a tremendous
advance in patient care. The association of measurements
and observations with specific template care processes
ie, decision support protocolsis the next step, and has
been done successfully for care processes in the ICU,
including fluid and electrolyte management, mechanical
ventilation, and diagnosis and treatment of nosocomial
infections.
129,130
We have developed and implemented a
bedside computerised shock resuscitation protocol in our
ICU.
61
This standardised process has improved our ability
to direct and monitor an aspect of care that is often
controversial, variable among patients, and confusing to
bedside personnel. With ongoing review and analysis, we
have been able to identify interventions that work best
and can now accurately predict, at admission to ICU,
whether a patient will or will not respond, so that
alternative strategies can be employed. This
standardised, rule-based, data-driven approach is being
extended to the very early clinical course in the
emergency department at our institution using mobile
workstation and wireless technology to facilitate
communication. Further extension of communication
with field rescue personnel is currently the subject of
military and civilian study in the USA, with implemen-
tation of computer, wireless, and satellite technologies,
including video, voice, text, and data.
131
The developments described in the present report may
improve the ability of prehospital and early hospital care to
pre-empt or more rapidly reverse hypoxaemia,
hypovolaemia and onset of shock. Such advances are of
particular interest for the initial management in the field of
military or civilian casualties of combat.
132,133
Prevention of
the first hit is preferable and feasible,
134
but prehospital
care of severely injured patients
135
and modulation of
exaggerated systemic inflammatory response due to
transfusion and other second hit complications of
traditional strategies will probably provide the next
generation of improvements in shock resuscitation.
Conflict of interest statement
None declared.
Acknowledgments
The authors are funded by grants P50-GM4922, P50 GM38529, and U54
GM62119.
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