Systemic responses to trauma

B A Foex
Emergency Medicine, University of Manchester, Hope Hospital, Salford, UK

The systemic responses to trauma can be divided into cardiovascular, immuno-

logical, and metabolic. The cardiovascular responses are seen immediately after a
traumatic insult. The pattern of response depends on whether the insult is mainly
haemorrhagic, tissue damage, or a combination of the two. The response may be
quite different for penetrating vascular trauma, compared with a crush injury to a
limb. The immunological, or inflammatory, consequences of trauma usually
become apparent several hours or days after the initial insult, although it is
increasingly clear that they may be triggered by the very early cardiovascular
changes. These have been implicated in the development of multiple organ
failure. The metabolic responses are of greatest importance in the longer term:
after successful resuscitation and after the definitive treatment of the patient's
injuries. The metabolic responses need to be taken into account during the
recovery from treatment and during the rehabilitation of the patient.

The aims of this chapter are to present an overview of the physiological

responses to trauma. These can be divided for practical purposes into
three: cardiovascular, immunological, and metabolic. This chapter will
cover the first two, while the third: the metabolic response to trauma is
covered in a separate volume of the British Medical Bulletin}.
In the 1970s and early 1980s, mortality from trauma was described as
following a trimodal distribution2-3. Deaths occurred either immediately,
or within the first few hours, or much later (days, even weeks, after the
accident). A better understanding of the early pathophysiology of
trauma and improvements in the early management of trauma patients
seems to have resulted in a reduction in the early deaths45. In some
areas, the trimodal distribution of deaths has been lost6-7. Continued
advances in the management of trauma depend on a good understanding
of the systemic responses.
Correspondence to Studying the response to trauma in a clinical setting is often difficult: the
Mr Bernard A FoSx, urgency of resuscitation makes extensive physiological assessment
Emergency Medicine, impossible and the resuscitation itself will alter the responses observed. For
Clinical Sciences
Building, Hope Hospital,
this reason, much of our understanding of the responses to trauma comes
Salford M6 8HD, UK from laboratory studies using human volunteers and animal models.

British Medical Bulletin 1999, 55 (No 4) 726-743 C The British Council 1999
 Systemic responses to trauma

The cardiovascular response to trauma

In a physiological sense, trauma is not a single insult: it is a combination
of haemorrhage, tissue injury, pain, and fear. To understand the physio-
logy of trauma these components have often been studied in isolation.

The cardiovascular response to haemorrhage

The biphasic response to haemorrhage

Systematic research into the cardiovascular responses to haemorrhage
began in the Second World War, when extensive blood donor programmes
were established. It was found that a small percentage of blood donors
lost consciousness following even a small haemorrhage, and that the
percentage increased as the volume of venesection increased. This
observation was studied by venesecting volunteers and monitoring heart
rate, blood pressure, cardiac output, right atrial pressure and fore-arm
blood flow8. Initially, the response to haemorrhage was an increase in
heart rate and total peripheral vascular resistance so that, despite a fall in
cardiac output, blood pressure was maintained (Fig. 1). However, once
about 1000 ml of blood had been removed, there was a sudden fall in
blood pressure associated with a bradycardia and syncope. This was
found to coincide with a profound increase in fore-arm blood flow and a
reduction in systemic vascular resistance. These changes could be largely
reversed by re-infusion of the shed blood.

BAROREFLEX DEPRESSOR
REFLEX
170%
Syncope

100% SVR (%)

Fig. 1 Biphasic HR(bpm)

response to haemor-
rhage. Faint induced 100 |
by venesection mmHg
showing the biphasic
response in heart rate
(HR), blood pressure SBP (mmHg)
(SBP) and systemic (1/min)
vascular resistance CO (1/min)
(SVR) with a gradual
reduction in cardiac
output (CO). Adapted 0 5 10 15
from Barcroft etal" Time (min) venesection

British Medical Bulletin 1999,55 (No 4) 727

Trauma

It appeared that the response to simple haemorrhage consisted of two

distinct phases: an initial phase of tachycardia and increased vascular
resistance maintaining arterial pressure, followed by a phase of decom-
pensation with hypotension and bradycardia. These observations have
been confirmed clinically9'10, in simulated hypovolaemia11'12, and in animal
experiments13"15. The bradycardia of haemorrhagic shock is reviewed by
Secher and Bie16. The precise mechanisms controlling this biphasic
response to simple haemorrhage have been extensively reviewed17. Only a
brief outline of two of the reflexes involved will be provided here.

The arterial baroreceptor reflex

A relatively small haemorrhage (up to 10-15% of total blood volume
(TBV)) results in an unloading of arterial baroreceptors located in the
aortic arch and carotid sinuses. The result is a reduction in cardiac vagal
activity and an increase in sympathetic stimulation of the heart. At the
same time, there is an increase in sympathetic vasoconstrictor tone and
an increase in total peripheral vascular resistance so that arterial blood
pressure and perfusion to tissues critically dependent on oxygen supply
are maintained despite a reduction in cardiac output.

The 'depressor" reflex

When blood loss exceeds a critical volume (usually around 20% TBV),
hypotension and bradycardia are seen. This is due to the activation of
another reflex, referred to as the 'depressor' reflex, which appears to over-
ride the baroreceptor reflex. The efferent limb of this 'depressor' reflex is
carried in the vagus (increased activation leading to bradycardia, which
can be blocked by atropine11) and the sympathetic vasoconstrictor nerves
(decreased activation leading to vasodilatation). The precise nature of the
afferent limb of the 'depressor' reflex is still unclear.

The triphasic response to haemorrhage

A recent animal study showed that after the bradycardic phase of
haemorrhage there was a massive increase in heart rate as blood loss
reached 44% of total blood volume. This was associated with a further
reduction in mean arterial pressure14.
Jacobsen and Secher observed a similar triphasic response in a series
of patients in haemorrhagic shock18. No patients in the bradycardic
phase died, suggesting that this phase of haemorrhagic shock is
reversible with prompt fluid resuscitation. However, once patients go
into a phase of tachycardia and hypotension, shock may be irreversible.
This third and potentially irreversible phase of haemorrhagic shock is
associated with increased sympathetic activity. The precise mechanisms

728 British Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

triggering this have not been clearly elucidated, but it may be related to
the development of cerebral hypoperfusion and cerebral hypoxia.

The cardiovascular response to tissue injury

The response to tissue injury consists mainly of a pressor response: an

increase in blood pressure mediated by an increase in sympathetic
vasoconstrictor tone producing an increase in peripheral vascular
resistance19. The tissue injury response is accompanied by a tachycardia:
there is a suppression of the baroreflex20 which would normally result in
a bradycardia.
A similar response is seen when the 'defence area' of the brain is
stimulated electrically21"22. Stimulation of the 'defence area' provokes the
'defence reaction' the features of which are: (i) a tachycardia (n) an
increase in blood pressure; (ni) an increase in sympathetic efferent
activity; and (iv) a relative vasodilatation to skeletal muscle with
vasoconstriction in the splanchmc vasculature. In contrast to the
response to haemorrhage, which preserves blood flow to vital organs,
the response to injury prepares the organism for 'fight or flight' and so
diverts blood away from the visceral organs to skeletal muscle. The
similarities between these two responses has resulted in the suggestion
that the response to tissue injury is mediated via the same pathways as
the defence reaction. A more detailed explanation of the central
pathways can be found in Kirkman and Little17.

The cardiovascular response to combined haemorrhage and tissue injury

Historically, haemorrhage was regarded as a complication of wound

shock. When Parsons and Phemister realised that blood loss could
account for wound shock they also noticed that a minor degree of
haemorrhage could be fatal if associated with tissue injury23. This
interaction was studied later by Wang et aP4. In a canine model of
haemorrhage and haemorrhage and soft tissue injury, there was a higher
mortality in the haemorrhage and soft tissue injury group. As the
circulating volume lost was the same in both groups they concluded that
another factor was involved. In further studies, they found similar
increases in mortality when sciatic nerve stimulation or soft tissue injury
were added to then" haemorrhage model25. From this, they deduced that
afferent nerve stimulation was an important factor in the increased
mortality of traumatic shock compared with simple haemorrhagic shock.
A variety of models has been used to study the interaction between
haemorrhage and tissue injury. Figure 2 compares the cardiovascular

British Medical Bulletin 1999,55 (No 4) 729

Trauma

response to haemorrhage with and without concomitant tissue injury,

modelled using hind-limb ischaemia13. A number of differences are
apparent. The background limb ischaemia results in a higher resting HR
and MAP. It appears that there is a re-setting of the baroreceptor reflex
to a higher MAP and there is also a reduction in the sensitivity of the
reflex. Coote et al showed that somatic afferent nerve stimulation can
modulate the baroreceptor reflex21-26.
A similar phenomenon has been recorded clinically by Anderson et
aP°, who found that patients suffering moderate injuries, such as long
bone fractures, showed a reduction in baroreflex receptor sensitivity
within a few hours of their injury. The reflex had not returned to its
normal sensitivity even after 14 days. Driscoll also suggested that there
was a reduction in baroreflex sensitivity and a right shift in baroreflex
setting in patients with significant tissue injury in addition to blood
loss10. Figure 2 also shows that, in those animals subjected to hind-limb
ischaemia, there is no bradycardia as haemorrhage progresses. Such a
bradycardia is normally mediated by the 'depressor' reflex and an
increased vagal tone to the heart. Thus, tissue injury also seems to
interfere with this reflex pathway.
It is clear that the cardiovascular responses to haemorrhage and tissue
injury are quite different. However, central integration of the various
reflex pathways is such that the cardiovascular response, when the two
conditions occur simultaneously, resembles the response to tissue injury
more than haemorrhage.

550

Fig. 2 Cardiovascular H+LI

R(bpm

response to haemor-
rhage and hind-limb 400
ischaemia. The figure
shows the effects of
progressive haemor- X Haem
rhage (Haem), and 250
the effects of
haemorrhage in the
presence of bilateral 'SB 130
hind-limb ischaemia
(H+LI), on heart rate
(HR), in the upper 90
panel, and mean
H+LI
arterial blood
pressure (MAP), in the
lower panel, in the
conscious rat. Values
1 50
H 1 1 1 1 1 1
Haem
are expressed as
means ± SE. Adapted 0 15 35
from Kirkman etaP1.
Haemorrhage (% TBV)

730 British Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

Consequences of haemorrhage and tissue injury: oxygen transport

The cardiovascular responses are accompanied by important changes in

oxygen transport. Rady et aP7 found that, in the anaesthetised pig,
oxygen delivery (DO2I) was halved by a 40% TBV haemorrhage while
oxygen consumption (VO2I) was maintained. This was achieved by an
increase in oxygen extraction ratio (OER) from 30% to 67% and a fall
in mixed venous oxygen saturation (SvO2) from 72% to 34%. When
haemorrhage occurred on a background of somatic afferent nerve
stimulation (SANS - to mimic tissue injury) DO2I was reduced to 27%.
At the same time, VO2I fell to 53% despite an increase in OER from
37% to 81% and a fall in SvO2 from 66% to 20%. Somatic afferent
nerve stimulation itself was found to have no effect on either DO2I or
VO2I, although it did produce the expected pressor response to tissue
injury (tachycardia, increase in arterial blood pressure andj increase in
systemic vascular resistance).
A later study28 showed that skeletal muscle injury (SMI) had a
qualitatively similar detrimental effect. The precise mechanism for the
deleterious effects of SANS and SMI are not clear. It may be that SANS
or tissue injury causes an increase in critical oxygen delivery (the level of
DO2 below which VO2 becomes supply-dependent) as has been
demonstrated by Kirkman et al29, which, in turn, may be dependent on
the redistribution of blood flow away from certain metabolically active
organs, such as the gut, towards more inactive skeletal muscle.

Consequences of haemorrhage and tissue injury: regional blood flows

It was apparent that, in the initial phase of haemorrhage, there was an

increase in systemic vascular resistance (SVR), which helped maintain
arterial blood pressure in the face of a fall in cardiac output8. Fore-arm
blood flow was unchanged, suggesting that the increase in SVR was
caused by vasoconstriction in other vascular beds.
Vatner found that, in conscious dogs, mild haemorrhage (resulting in a
tachycardia but no fall in blood pressure) resulted in increases in
mesenteric and iliac vascular resistance, but a reduction in renal vascular
resistance30. With moderate hypotensive haemorrhage, there was a greater
reduction in mesenteric blood flow than in coronary blood flow,
suggesting redistribution of flow in favour of the heart at the expense of
other internal organs.
When haemorrhage or hypovolaemia is taken further so that there is
profound hypotension, regional blood flows may alter again. Barcroft et
al found that when their volunteers became hypotensive and fainted,
there was a sudden fall in SVR and a sudden increase in fore-arm blood

British Medical Bulletin 1999,55 (No 4) 731

Trauma

flow, suggesting a sudden skeletal muscle vasodilatation8. A similar

skeletal muscle vasodilatation occurred when sheep were haemorrhaged
until an abrupt fall in blood pressure was seen31.
Regional vascular responses have also been studied using lower body
negative pressure (LBNP), in volunteers, to simulate hypovolaemia32'33.
The first study showed that splanchnic blood flow was more sensitive to
simulated hypovolaemia than renal blood flow32, while the second
showed that splanchnic blood flow remained depressed until the end of
the study period 60 min after reversal of LBNP33.
Another indication of the vulnerability of gut blood flow came from
an examination of microvascular blood flow following haemorrhage34.
Rats haemorrhaged to a MAP of 40 mmHg showed reductions in
microvascular blood flow in the liver, spleen, kidney, small intestine and
skeletal muscle, with the greatest reductions being seen in the small
intestine and the kidney. Volume replacement with Ringer's lactate
solution could only partially restore microvascular blood flow, which
continued to deteriorate in all organs, even after resuscitation.
Parallels have been drawn between the responses to injury and the
defence reaction26. The essential components of the regional vascular
changes during the 'defence reaction' are an increase in splanchnic
vasoconstrictor tone and a reduction in vasoconstrictor tone to skeletal
muscle, thus preparing the organism for 'fight or flight'22.
When haemorrhage, in a pig model, occurred on a background of
somatic afferent nerve stimulation (SANS, to mimic tissue injury) there
was an alteration in the pattern of vascular response35. In haemorrhage
alone (30% of TBV), vascular resistance in the femoral bed more than
doubled, while resistance in the splanchnic bed hardly changed. When
30% TBV haemorrhage was superimposed on SANS, there was a much
smaller increase in femoral resistance. Splanchnic resistance increased,
showing that with the additional insult of SANS (mimicking tissue injury),
there was a relative diversion of blood away from the gut towards skeletal
muscle (Fig. 3).

Consequences of haemorrhage and tissue injury: gut mucosa

Do the changes in gut blood flow, which are seen with both simple
haemorrhage and haemorrhage with tissue injury have any major
functional consequences? There now appears to be ample evidence that
reduced gut blood flow, or haemorrhagic shock, can result in mucosal
ischaemia and eventually to mucosal damage36-37. The gut mucosa plays
an important role as a barrier between the host and the gut microflora,
which contains potential pathogens and toxins. Even in resting conditions
the gut mucosa appears hypoxic compared to the serosa38. Gut mucosal

732 British Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

220
Fig. 3 Changes in
regional vascular
resistances in response
to haemorrhage and 120
P-H
somatic afferent nerve
stimulation. The
figure shows the
changes in femoral
vascular resistance
(upper panel), and gut
vascular resistance
150
(lower panel) before
and after a 30% TBV
I HNS
haemorrhage (Haem),
and after the same
haemorrhage in the
I
Gut^

presence of brachial
nerve stimulation r/^_______ ^ Haem
(HNS) Values are 100
expressed as means ± 1 1

SE. Adapted from

Mackway-Jones etaP1 Pre End haem
oxygen tension (PmO2) was found to be very sensitive to changes in
blood volume: there was a fall in PmO2 before any change in MAP or
serosal oxygen tension (PsO2). By the time blood loss reached 15%,
PmO2 had fallen by 40% with minimal changes in MAP and PsO r This
provides further evidence for potential hypoxia of the gut mucosa in the
face of haemorrhage.
Any ischaemic insult to the mucosa may result in a loss of this barrier
function and the translocation of organisms or toxins from the gut
lumen into the host lymphatics or circulation.

Consequences of haemorrhage and injury: translocation of bacteria and endotoxin

As early as 1952, the suggestion was made that: 'tissue anoxia of shock
might stimulate invasion of the liver by intestinal flora'39. It was not until
the 1970s that the term translocation was applied to the movement of
organisms from the gut lumen into either the systemic circulation, the
lymphatics, or the peritoneum. By the late 1980s, the gut had been heavily
implicated in the development of multiple organ failure (MOF)40-41.
Bacterial translocation is well documented in rodents, in which enteric
organisms have been cultured after haemorrhagic shock42"*6. Feeding
rats [14C]-labelled Escherichia colt showed that the organisms originated
in the gut47.

British Medical Bulletin 1999,55 (No 4) 733

Trauma

In large mammals, the evidence is mixed but a number of investigators

have demonstrated translocation in swine48'49, sheep5OrS1, and baboons52.
Other investigators found no evidence of translocation in swine53"54. A
direct link between gut blood flow and bacterial translocation has been
shown in pigs subjected to a 40% BSA burn55.
Translocation in humans remains controversial. Moore et al inserted
portal vein catheters in 20 trauma patients undergoing emergency laparo-
tomy to take serial portal venous blood samples56. Endotoxin assays
performed over the first 48 h were negative. Although 30% of these
patients went on to develop MOF, the investigators found no evidence
that MOF was caused by gut-derived organisms. In another study, no
evidence of bacterial translocation from mesenteric lymph nodes, excised
at laparotomy, was found in 25 blunt trauma patients, despite the fact that
28% suffered major infectious complications with enteric pathogens57.
In contrast, two studies, which used immunofluorescence to look for
evidence of the breakdown products of translocated organisms in
mesenteric lymph nodes of trauma patients, both gave positive results58*59.
Positive blood cultures were found m 13 of 50 trauma patients very shortly
after their injury. The incidence of positive cultures was related to blood
pressure on admission. For 10 of these, the average admission blood
pressure was 45 mmHg. Whether these patients provide evidence for
bacterial translocation as part of the pathophysiology of trauma is
debatable: bacterial translocation may simply have been an agonal event60.
If endotoxaemia is taken as an index of translocation, then it has been
shown to occur on the day of injury and to increase until day four in
burns patients 61 . No endotoxaemia was found in two series of trauma
patients56-62, while only 7% of patients in haemorrhagic shock had
raised endotoxin concentrations 63 .
There can be little doubt that bacterial translocation occurs in rodents.
From the evidence in man one may suggest that finding live organisms
in the circulation or the reticulo-endothelial system is a rare, possibly
agonal, event. Immunofluorescence and microscopy have suggested that
organisms may translocate across the gut mucosal barrier but that they
are then killed by the secondary defences.

Immunological consequences of trauma

Late deaths from trauma continue to be a problem6-7'64. Most of these
are the result of MOF. This late development of a systemic illness is not
a new phenomenon: after the battle of El Alamein, a surgeon wrote
that 65 : 'severe wounding was often followed by an illness, more or less
serious and lasting at least several days, in which many factors other

734 British Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

than blood-loss or its late effects operated'. The precise nature of the
'many factors' has been a source of debate ever since. The evolution of
this debate was summarised in 199666.
It is clear that the immune system is intimately involved in the
response to trauma. The production of various cytokines after trauma
will be used to illustrate this. It would be impossible to review all aspects
of the immune response to trauma in such a short review. Two books
will provide a very valuable introduction to this field67-68.

Consequences of haemorrhage and tissue injury: cytokine production

Inflammatory response
Inflammatory cytokine production has been described in models of
haemorrhagic and traumatic shock52'69"71. Ayala et al have suggested, as
a result of their studies with rodent models of haemorrhage and tissue
injury, that the two insults act as slightly different triggers for cytokine
production69. It seemed that tumour necrosis factor a (TNFa) was only
produced after haemorrhage, but that interleukin-6 (IL-6) production
could be stimulated by tissue injury before any haemorrhage70.
It is clear from a number of studies of elective surgery that the tissue
injury caused by surgery will stimulate the production of interleukin-1
(IL-1), and/or IL-672"80. Indeed, it appears that the production of EL-6 is
linked to the severity of the tissue injury inflicted73-77. In these studies,
IL-6 production was detectable within 2 h of the initial incision and the
peak was seen within a few hours, unlike the peak in C-reactive protein,
which tended to occur the following day75.
Deitch et al suggested that the gut acted as a cytokine-producing organ
since levels of TNFa and IL-6 were higher in portal venous blood than
in systemic blood71.
Thus, it appears that the vascular responses to haemorrhagic and
traumatic shock can result in functionally important reductions in gut
blood flow so that there is a breakdown of the gut mucosal barrier. Once
this has happened, bacterial or endotoxin translocation may occur with
potential triggering of the production of inflammatory mediators, such
as cytokines. This may represent the initiation of a chain of events
leading to a process of systemic inflammation which may ultimately
produce multiple organ failure.

Clinical studies
Studies of elective surgery have shown that there seems to be some
correlation between the degree of tissue injury and the production of EL-6.
This has been confirmed in several trauma series62-81, and in burns82.

British Medical Bulletin 1999,55 (No 4) 735

Trauma

Raised inflammatory cytokine concentrations were found on the day

of admission, after trauma, and then gradually declined over the next 48
h in patients making a good recovery62-81. However, there was good
evidence for a secondary increase in cytokine production, later, in those
patients developing septic complications62'81"83. Initial cytokine
concentrations were not predictive for those patients who would
develop septic complications.
The role of TNFa in the cytokine response to trauma remains very
unclear. Many studies have found that TNFa was either undetectable, or
only detectable in a minority of patients after trauma62-81'84"87.
It has been suggested that the TNFa response is too transient to be
detected in most studies. A study using blood taken at the scene of the
accident concluded that TNFa was active in the inflammatory response
due to trauma and that it might be activated early and may have
modulated subsequent cytokine activity88.
Raised plasma TNFa concentrations have been found in
haemorrhagic shock patients63. There was no correlation between TNFa
concentrations and the degree of haemorrhage (as assessed by the
volume of blood transfusion), nor was there a difference in TNFa
concentrations between those patients developing MOF and those who
did not. However, most studies have shown that TNFa concentrations
are higher in those patients who do become septic after trauma, than in
those who do not62-81"83-89.

Anti-inflammatory responses
Trauma not only results in the production of various inflammatory
cytokines. Interleukin-10 (EL-10) has been characterised as an anti-
inflammatory cytokine90"93, and its production has been measured in
trauma patients94. Plasma IL-10 was associated with hypotension on
admission, and the development of sepsis, but was not related to the
severity of injury. In contrast, in another study, higher IL-10
concentrations were seen in patients with an ISS greater than 25 than in
those with a lower ISS95. In this same group of 401 patients, higher IL-
10 concentrations were measured in those patients who became septic
and those who developed multiple organ dysfunction syndrome
(MODS). The authors suggested that IL-10 might actually be involved
in the pathogenesis of sepsis and MODS after injury. This seems to run
counter to the ideas generated by laboratory studies.
Other endogenous anti-inflammatory mediators have been examined.
There is good laboratory evidence for a protective effect of the
endogenous inhibitor of IL-1, interleukin-1 receptor antagonist (IL-lra),
in endotoxaemia96'97. Elective surgery has been shown to result in an
increase in IL-1 inhibitory activity over a 24 h period, but there was still

736 Bntish Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

an increase in IL-6 and in the C-reactive protein, mostly after IL-1

inhibitory activity had returned to baseline75. An increase in IL-lra was
seen in 22 trauma patients, but the concentration of EL-lra and other
soluble cytokine receptors, was higher in non-survivors than in
survivors98. The authors suggested that these receptors might be markers
of the severity of the insult, rather than contributors to the mortality.
Although inflammatory cytokines were undetectable, it does not appear
that the anti-inflammatory mechanisms had a very protective function.
Soluble TNF receptors (sTNF-Rs) are produced in trauma patients98-99,
but, in both studies, concentrations were higher in non-survivors than in
survivors. If they had a protective anti-inflammatory function one might
expect that the non-survivors would be those patients unable to produce
the receptors, rather than those who produced the most. Interestingly,
sTNF-R concentrations decreased during episodes of infection or
hypoxia in individual patients99. Maybe these reductions in sTNF-R
concentrations do indicate a loss of endogenous anti-inflammatory
activity during secondary episodes of sepsis. This may form part of the
basis of the 'two-hit' model for the development of MOF.

Activation of cytokine production

Bacterial and/or endotoxin translocation from the gastrointestinal tract
has been advanced as one possible mechanism for the activation of
cytokine production. Deitch et al have suggested that, even in the
absence of live translocating organisms or endotoxin in the portal and
systemic circulations, the gut can still act as a cytokine generator via the
activation of the gut associated lymphoid tissue71.
Alternatively, it could be that cytokine production is triggered directly
at the wound site. Evidence for this comes from both a rat model and a
clinical situation100. Raised levels of EL-6 were found in both wound
fluid and serum of rats subjected to polyvinyl alcohol sponge implant-
ation, and in fluid draining from mastectomy scars. This suggested that
cytokines found in the systemic circulation might have originated at the
wound site. Both IL-1 and IL-6 were found in the blisters of burned
children, although IL-1 was generally absent from the circulation, again
suggesting local production101.
It may be that two mechanisms act together or act independently on
different cytokines: IL-6 being triggered to a greater extent at the wound
site by tissue trauma while TNFa and IL-1 might be more sensitive to
changes in gut barrier function and activation of the gut associated
lymphoid tissue.
The question remains as to the exact trigger mechanism for the
cytokine production seen in trauma and burns patients. The macro-
phage hypothesis of activated macrophages producing cytokines and

British Medical Bulletin 1999,55 (No 4) 737

Trauma

other mediators which then result in systemic inflammation leaves the

question of what activates the macrophages unanswered102.

Models for the development of post-trauma multiple organ failure

A better understanding of the inflammatory responses after trauma has

resulted in interesting models for the development of MOF. Moore et al
have divided the inflammatory response into two phases: an initial
hyperinflammatory response (the systemic inflammatory response
syndrome - SIRS), followed by a phase of immunosuppression103'104.
This model was a response to several studies104'105, which showed that
there were two types of MOF patients: those who went into MOF
'early', and those who went into MOF 'late'.
The other model is that of the 'one-hit' or 'two-hit' insult resulting in
early MOF103'106. In this model, patients may go into MOF, either
because of one early and massive traumatic insult, which causes so much
inflammation that MOF ensues, or, if the initial insult is not massive,
then this inflammatory response may be triggered by a secondary insult
such as definitive surgery a few days after the trauma. Secondary surgery
has been reported as a trigger for MOF107. The validity of these ideas has
aroused some controversy108-109. Even if there is debate about this model
it does serve as a warning that there may be a risk to delaying definitive
surgery for orthopaedic injuries, for example. There may be an argu-
ment for either doing early "damage control surgery" or delaying for a
week or more, until after the worst of the hyperinflammation110'111.

Summary
In this review, I have tried to show that trauma elicits a variety of
cardiovascular responses. The responses to haemorrhage and to tissue
injury are different and the two insults interact to produce changes in
organ blood flow and oxygen delivery. These changes may have
important effects on the gut and gut mucosal integrity. The gut has been
heavily implicated in the development of MOF40-41.
Whether or not the gut and bacterial translocation are relevant in
man, it is now clear that there is an inflammatory response after trauma.
The development of that response seems to be responsible for the
development of MOF, either by a 'one-hit' or by a 'two-hit' process in
the early stages, or later as the result of immunosuppression.
By understanding these responses, attempts can be made to optimise
the resuscitation and later care of trauma patients. As a recent review

738 British Medical Bulletin 1999,55 (No 4)

 Systemic responses to trauma

stated112: 'patients in shock, if they are to survive the initial insult, are
still at risk of dying on a subacute basis from continuing global
hypoperfusion and the resultant multiple organ dysfunction, if they are
inadequately resuscitated...It is clear that adequate resuscitation goes
beyond the restoration of a normal blood pressure and urine output.'

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