Stress and Metabolic Response to Trauma

in Critical Illness

J. A r n o l d and R. A. Little

Introduction 'flow' to describe two distinct phases in the response

to injury. The initial ebb phase was reported to last
Trauma, whether it occurs through accident or
approximately 24h after injury, although it could be
elective surgery, elicits a wide ranging metabolic
considerably shorter or longer, and it was charac-
response that has traditionally been thought to be
terised by a depression in both cardiac output and
mediated largely by the neuroendocrine system.
metabolic rate. However, there is a growing body of
However, more recently, inflammatory mediators
clinical literature suggesting that metabolic i'ate is in
(e.g., cytokines) that are released from a variety of
fact elevated in the ebb phase. Nonetheless, a
cells, such as macrophages, and infiltrate the wound
number of other characteristics feature consistently
or septic focus, have been shown to act synergistically
in the ebb phase response to trauma and they include:
with the endocrine mediators in eliciting the meta-
1) stimulation of the sympathetic nervous system
bolic response to injury. The magnitude of the
(SNS), 2) increased release of 'counter-insulin'
response generally reflects the severity of the injury,
(counterregulatory) hormones such as glucagon and
thus although minor surgical procedures do not have
cortisol 3) glucose intolerance (hyperglycaemia) due
as great an effect as severe burns, or other serious
to insulin resistance in insulin-dependent tissues
injuries, they do, nonetheless influence whole-body
(e.g., skeletal muscle), 4) increased glycogenolysis
metabolism. This short review will focus largely on
and 5) breakdown and mobilisation of adipose tissue
the metabolic consequences of tissue injury because
lipid reserves.
simple haemorrhage, which is dominated mainly by
In contrast, the flow phase of trauma is charac-
inadequate tissue perfusion (anoxia/hypoxia), can
terised by increases in cardiac output and metabolic
generally be corrected rapidly by blood transfusion
rate and an overall enhancement of substrate utili-
and adequate ventilation. However, as many injuries
sation. For example, increased release of free fatty
involve both haemorrhage and tissue damage it is
acids from adipose tissue continues in the flow phase
inevitable that there will be some overlap between
when fat is the preferred substrate for oxidation.
the metabolic responses to injury-induced hypoxia
Some of the amino acids, liberated largely from
and the injury, itself. A more comprehensive review
skeletal muscle, are consumed in energy production
of the metabolic response to trauma has recently been
while others are directed towards the liver as precur-
published. 1
sors for the synthesis of acute phase proteins, includ-
A number of characteristic features make up the
ing C-reactive protein and others, that predominate
pattern of response to trauma and these have been in the acute-phase inflammatory response (for review
documented over many years from clinical and see 3). Despite alterations in protein synthetic rates,
experimental investigations. Cuthbertson, during the whole-body protein breakdown is augmented giving
Second World War 2 put forward the terms 'ebb' and rise to increased nitrogen excretion in the urine.
Glucose intolerance persists in the flow phase even
Dr J. Arnold, Professor R.A. Little, North Western Injury
Research Centre, Stopford Building, University of Manchester, though gluconeogenesis is stimulated. It should be
Oxford Road, Manchester M13 9PT, UK mentioned that sepsis causes much the same pattern

Current Anaesthesia and Critical Care (1991)2, 139-148

© 1991LongmanGroupUK Ltd 139
140 CURRENT ANAESTHESIA AND CRITICAL CARE
150
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INJURY S E V E R I T Y S C O R E
A B
Fig. 1 - - (A) Relationship between plasma adrenaline concentration (logarithmic scale) and severity of injury (assessed by
Injury Severity Score). O, patients with elevated plasma ethanol concentrations; ©, other patients; A, control, uninjured (ISS
= 0), subjects sampled by direct venepuncture. The least mean squares regression line for all injured subjects is shown (P <
0.001) (From: 23). (B) Relationship between plasma concentrations of insulin and adrenaline in injured patients; above an
adrenaline concentration of 2 nmol/I all insulin concentrations are below 20mU/l. (From:23).
of disturbance as the flow phase response to trauma
and its inclusion with trauma and injury will be
henceforth implied. The following sections will
discuss, in greater detail, the alterations in metabo-
lism that occur after trauma by distinguishing
between the ebb and flowphases. Thereafter, effects
of nutritional intervention will be examined briefly in
terms of modifying the patient's metabolic response
to injury.
Neuroendocrine and humoral response
As mentioned in the introduction, the sympathoadre-
nal system and the hypothalamic-pituitary axis are
stimulated during the ebb phase. The hormonal
responses tend to wane early on in the flow phase
although there are exceptions, such as cortisol, whose
concentration may remain elevated for 10-15 days
after severe injury, especially in the elderly. In
addition, many different cell types (e.g., monocytes
and macrophages) are activated at this time and may
secrete many different humoral factors. A brief
overview of some of these neuroendocrine and
humoral changes may prove beneficial in understand-
ing the concomitant modifications in substrate utili-
sation that also take place during the response to
injury. More details of the neuroendocrine response
to trauma are provided in two comprehensive
reviews.4,5
Soon after injury the SNS and the adrenal medulla
are stimulated and raised plasma concentrations of
noradrenaline, dopamine and adrenaline can be
120
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PLASMA ADRENALINE,
nmol/I
observed. The increase in plasma catecholamine
levels, which is directly related to the severity of the
injury, (e.g., Fig. 1A) is a very transient response and
concentrations usually return to pre-injury values
within 24-48 h. However, plasma catecholamine con-
centrations can remain elevated into the hypermeta-
bolic flow phase after severe burn and head injuries.
The rise in plasma catecholamines may influence
directly the release of hormones by the endocrine
pancreas. Inhibition of insulin secretion is seen
frequently after severe trauma, such as burns, where
catecholamine concentrations are greatly increased
(Fig. 1B). However, with less severe injuries plasma
insulin concentrations are very variable and bear no
relationship to the patient's glycaemic state. Gluca-
gon concentrations have been observed to increase
significantly within 12h of severe trauma. More
moderate injury also stimulates glucagon release
although, the response is more variable.
Nociceptive inputs appear to be partly responsible
for stimulating the release of adrenocorticotropic
hormone (ACTH) from the anterior pituitary
immediately after elective surgery or accidental
injury. Accordingly, increased release of cortisol by
the adrenal cortex occurs, although the response can
be variable and does not appear related to injury
severity in the ebb phase when reductions in adrenal
cortical blood flow may complicate the picture. In
contrast, cortisol concentration increases in accord-
ance with the severity of injury in the early flow phase
and it can take as long as 2 weeks or more before
 STRESS AND METABOLIC RESPONSE TO T R A U M A IN CRITICAL ILLNESS 141

near-normal levels are seen after, for example, severe generating processes, such as shivering. It has to be
thermal injuries or femur fracture in the elderly. The emphasised that only the thermoregulatory
role of cytokines, especially tumour necrosis factor component of heat production is affected and heat
(TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6), arising as the by-product of basal metabolic reactions,
in mediating the response to trauma, has received such as the maintenance of ionic gradients, is not
much attention in the last decade. There have been affected.
many isolated studies suggesting roles for IL-1 and The few clinical studies examining the ebb phase
TNF in elevating turnover of lipid and protein response have yielded little evidence to support
reserves although results have not been consistent. Cuthbertson's original observation of a reduction in
They are also involved in glucose homeostasis and the metabolic rate. In that work, Cuthbertson measured
activation of the pituitary-adrenal axis. There have 4 0 2 in four injured patients within 24h of accidental
been no systematic studies demonstrating increases in injury and in three patients undergoing elective
TNF and IL-1 after injury although recent work with orthopaedic surgery. Oxygen uptake, immediately
thermally injured and elective surgical patients has after injury, was lower than the values measured
revealed significant increases in plasma IL-6 concen- during the ensuing flow phase. However, when
trations shortly after trauma. The acute pyrexia seen measured upon recovery, VO2 was not significantly
in paediatric burn injury has been positively corre- different from that measured during the ebb phase.
lated with the IL-6 response. 6 Furthermore, a recent Little and colleagues 1° have since failed to demon-
study of elective surgical patients demonstrated a strate a reduction in metabolic rate in 43 traumatised
positive relationship between serum IL-6 concentra- patients, with different injury severity scores (ISS), at
tions and the severity of the surgical procedure; a approximately 6h after injury (Fig. 2). Another
peak IL-6 response was observed 6-12 h after the first recent study by Edwards and coworkers 11 used a
surgical incision. 7 It appears that IL-6 may have a reverse Fick equation to calculate "VO2in 16 recently
significant influence on the ebb phase response injured patients who required intensive monitoring.
although there can be little doubt that it acts synergis- Ten of the 16 patients showed an elevated VO2 while
tically with other hormonal and humoral mediators. only two patients, both of whom had a reduced core
temperature, demonstrated a reduction in metabolic
rate (Table 1).
Ebb phase Other studies have also reported increases in
Metabolic rate metabolic rate shortly after trauma. Core tem-
perature and oxygen uptake, measured serially in
Understandably, metabolic rate in the ebb phase of patients up to 24h after major surgical interventions,
injury is difficult to study in man. Hence, develop- were reported to be significantly raised at 12 and 16h,
ment of well-defined ebb phase injury models, such as respectively after surgery. 12 Work by the North
haemorrhage, bilateral hind limb ischaemia, femur Western Injury Research Centre has also demon-
fracture and scald injury have enabled carefully strated that paediatric burn patients show a rise in
controlled investigations to be carried out (for
reviews see: 8,9). Haemorrhage in experimental
animals results in a reduction in oxygen consumption Table 1 - - Oxygen consumption (VO2) calculated early (mean
(VO2) and an impairment of thermoregulation at low 1.6h, range 0.8-9.0h) after severe injury in man. All patients
ambient temperatures. However, reinfusion of whole received fluid replacement and arterial oxyhaemoglobin
saturation was maintained 395%. Ambient temperature 24°C.
blood combined with high concentrations of inspired (Data taken from Edwards, Redmond, Nightingale and Wilkins,
oxygen eliminates the suppression of thermoregu- 1988) *Patient died
lation. It has been suggested that anoxia/hypoxia and
Case No ISS V02
a failure of oxygen transport are the primary media-
tors affecting metabolic rate rather than the haemor- 1) Valueslessthan predicted:
4 32 105
rhage, per se. 12 34 94
The situation is more complicated in the presence 2) Values equalto predicted:
of tissue injury where the reduction in oxygen con- 1 25 145
sumption is not reversed by restoration of tissue 2 34* 119
3 34 155
oxygen delivery. Experimental studies using limb 7 24 110
ischaemia and scald injury in the rat have revealed an
3) Values higher than predicted:
inhibition of thermoregulatory heat production that 5 32 176
can, if left untreated, result in a fall in core body 6 32 176
temperature. However, the inhibition is rapidly 8 66* 308
9 38 175
reversible in the rat upon injection of noradrenaline, 10 48 176
a potent stimulator of thermogenesis. It has thus been 11 48 190
concluded that tissue injury results in a central 13 32* 238
14 34 198
impairment of thermoregulation rather than a 15 41" 186
decrease in thermogenic capacity of peripheral heat 16 16 190
142 CURRENT ANAESTHESIA AND CRITICAL CARE

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OXID'N OXID'N
Fig. 2 - Metabolic rate and substrate oxidation in acutely injured patients. Mean values _+ SEM; * p < 0.02; MR = metabolic
rate; RQ = respiratory quotient; CHO OXID'N = carbohydrate oxidation. Adapted from Little et al,l°; +standard values from
Fleisch. 24.

core temperature and heat content that reaches a
peak during the first 12h after injury. The increase in
metabolic rate can be modified pharmacologically
and it has thus been proposed that the underlying
mechanism involves an upward readjustment of
metabolic control, possibly in the hypothalamus. The
consensus today is that although injury in experimen-
tal animals may result in an inhibition of thermoregu-
lation, the opposite appears true for injured (treated)
man; metabolic rate and temperature seem to
increase immediately after injury.
Substrate turnover
Carbohydrate. Increased breakdown of hepatic
glycogen stores contributes initially to the elevated
blood glucose concentrations observed early after
trauma. In contrast, muscle glycogenolysis does not
occur acutely after elective surgery, although later
on, in the flow phase, muscle glycogen breakdown
contributes significantly to raising plasma concentra-
tions of lactate and pyruvate. The hyperglycaemic
response is linked to the severity of injury and the
highest blood glucose levels have been reported after
severe thermal and head injuries. Adrenaline and
glucagon appear to have the most stimulatory effect
on hepatic glycogenolysis at this time although activa-
tion of hepatic sympathetic innervation and other
hormonal and humoral mediators may also contri-
bute. It is of interest to note that hypoxia, a common
consequence of haemorrhage, is also a potent stimu-
lus of glycogenolysis. The suppressed or erratic
release of insulin during the ebb phase has little effect
at countering glycogen breakdown and the rising
blood glucose concentrations. Lastly, once plasma
levels of counterregulatory hormones have risen,
gluconeogenesis also contributes significantly to the
hyperglycaemic response.
The teleological benefit of the hyperglycaemic
response acutely after trauma may lie in the fact that
hepatic glycogenolysis ensures an adequate supply of
glucose for the initial defence reaction ('fight or
flight') of the organism. Physiologically the hypergly-
caemia would: 1) stimulate myocardial glucose
uptake and secure myocardial function by supplying
substrate for anaerobic glycolysis and 2) draw inter-
stitial fluid osmotically across microvascular endothe-
lia and hence compensate for intravascular fluid loss.
Lipid. The stimulus to mobilise lipid substrate from
fat depots is also strong during the ebb phase. The
hormonal milieu immediately after injury in man
favours lipolysis and causes a general rise in plasma
free fatty acid (FFA) and glycerol concentrations.
However, FFA release from adipose tissue is particu-
larly variable and does not appear to be related to
injury severity. Blood flow to adipose tissue may
decrease significantly acutely after injury and the
resulting unavailability of plasma-derived albumin to
bind FFA and transport it in the plasma may directly
affect FFA release. Furthermore, impaired tissue
perfusion causes hyperlactataemia, which is known to
enhance re-esterification of fatty acids to triacyl-
 STRESS A N D M E T A B O L I C R E S P O N S E T O T R A U M A IN C R I T I C A L ILLNESS
PERCENTAGE
-20 0 20
I I
starvation
postoperative m
peritonitis
long bone fracture
severe infection,
multiple trauma
burns
(body surface) (10z)
Fig. 3 - - Changes in resting metabolic rate during starvation and acute illness. Adapted from W i l m o r e ? s
glycerol. Glycerol release from adipose tissue is not
as restricted, however, as a consequence of its
hydrophyllic nature and better ability to cross the fat
cell membrane.
Similar to the situation for glycogen mobilisation,
significantly increased lipolysis in the ebb phase
would also suggest teleologically, an increase in lipid
utilisation. Little and colleagues 1° calculated whole-
body substrate utilisation from their indirect calo-
rimetry data of recently injured patients (Fig. 2) and
did indeed find fat oxidation to be enhanced signifi-
cantly in the most severely injured. However, fat
utilisation was increased at the expense of carbohy-
drate; glucose oxidation was markedly reduced in
patients with serious injuries. Ketone bodies,
although strongly linked to the rate of F F A oxidation,
do not appear to make a significant contribution to
the fuel requirements of the central nervous system
(CNS, including the brain), during the ebb phase.
Hence, a large proportion of the oxidized carbohy-
drate could be attributed to obligatory glucose utili-
sation by the CNS suggesting that a significant
inhibition of glucose uptake by insulin-sensitive
tissues, such as skeletal muscle, had occurred.
Flow phase
Metabolic rate
In contrast to the ebb phase, there is little debate
concerning the rise in metabolic rate that char-
143
CHANGE IN METABOLIC RATE
40 60 80 100 120
I I I I I
• • • ,
(2og) (30g) (5og)
acterises the flow or hypermetabolic phase of injury.
A rise in body temperature, that usually occurs at this
time, does not appear to be the driving stimulus
behind the generalised increase in metabolism.
Furthermore, the pyrexial response is observed both
in the presence and absence of infection.
The rise in metabolic rate is directly related to the
severity of the injury (Fig. 3). Minor elective opera-
tions may have little or no effect on resting energy
expenditure and increases above 5% are rarely
observed. Long bone fractures can have a greater
stimulatory effect and it is not uncommon to observe
increases of 25%. The largest and most prolonged
elevations in metabolic rate are experienced in severe
thermal injuries (i>50% body surface area burn)
where metabolic rate is frequently doubled for
upwards of 7-10 days. At the other end of the scale,
starvation or severe malnutrition may reduce energy
expenditure by nearly 15% and hence have a partial
masking effect on any increase in metabolic rate due
to injury. Thus the severity of illness, nutritional
status and length of immobility will all have an
influence on metabolic rate.
In terms of daily energy requirements, it is rare that
3000kcal (12.5MJ) per day will be exceeded by the
most severely ill patient (Table 2). In cachectic,
bedridden patients it is more common to observe
energy expenditures close to 1000kcal (4.2MJ) per
day. These values can be compared with the average
daily energy expenditure for a healthy 'control'
subject of 1500kcal (6.3M J).
144 CURRENT ANAESTHESIA AND CRITICAL CARE

Table 2 - - Energy expenditure calculated from respiratory gas have been inconsistent. One team of researchers
exchange measurements during the flow phase in a number of reported that raising the ambient temperature did
acute illness states
abolish the hypermetabolic response, 13 however,
Energy Expenditure another group was unable to find any effect of
(kcal/m2day) (kcal/day) increasing ambient temperature. 14
Median (range) Median(range)
The increase in metabolic rate seen in the flow
Sepsis 34.2 (22.3-57.4) 1642 (1070-2755) phase may be stimulated by the damaged and healing
(sepsis score 8-29)
Injury (day 5-10) tissues. In fact, Wilmore 15 has suggested that the
(i) non-head 43.1 (36.6-48.9) 2068 (1758-2284) wound can be thought of as an extra organ whose
(ISS 9-47) heterogeneous cell population demands a significant
(ii) head 39.4 (27.0-47.3) 1897 (1231-2157)
(ISS 25-35) fraction of the increase in cardiac output. Cells
Acute renal failure 43.6 (33.4-51.8) 2030 (1547-2399) involved in inflammatory and wound reparative pro-
control 37.7 (32.8-45.6) 1810 (1574-2139) cesses have been shown to consume preferentially
To convert kcal to kJ multiply by 4.187 large quantities of glucose, almost exclusively by
anaerobic glycolysis. The resulting lactate is
reconverted aerobically back to glucose (i.e., at a
As mentioned above, an increase in core metabolic cost) in the liver.
temperature normally accompanies the rise in meta- Alterations in other metabolic processes, when
bolic rate after injury. It is believed that an upward considered cumulatively, will also contribute signifi-
readjustment of the lateral hypothalamic setpoint cantly to the hypermetabolic response observed in
results in an increase in the thermoneutral the flow phase. The contribution made by increased
temperature (temperature at which the organism is in substrate cycling and turnover will be discussed in the
thermal balance with the environment). This central next section.
resetting may be initiated by any number of stimuli
(mediators), either foreign (e.g., bacterial pyrogens)
Substrate turnover
or endogenous (e.g., IL-1, IL-6 or TNF). Thus,
eliminating the stimulatory mediators or, perhaps Carbohydrate. During the flow phase plasma glucose
more feasibly, raising ambient temperature to the concentrations decrease to normal or near-normal
new thermoneutral zone of 30-32°C (thermoneutra- although the duration of the hyperglycaemic
lity for normal adult (nude) man is 27-29°C) might be response is directly related to the severity of the
expected to attenuate the increase in metabolic rate injury. The plasma insulin level is raised above that
and core temperature. This has been done for burned anticipated from the plasma glucose level, a feature
patients by a number of investigators and the results of insulin resistance. Studies employing a variety of

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Fig. 4 - - Dose-response curves for effect of insulin on forearm glucose uptake. • , injured patients; © uninjured subjects.
Each point represents the result of an individual euglycaemic clamp study. The glucose infusion rate and the insulin
concentration shown are each averaged over the last 80 min of the clamp experiment (From:27).
 STRESS A N D M E T A B O L I C R E S P O N S E T O T R A U M A IN C R I T I C A L ILLNESS 145

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POST-INJURY DAYS
Fig. 5 - - Respiratory quotient and substrate oxidation responses following m o d e r a t e l y severe injury (e.g., long bone
fracture). Adapted from Frayn et al? 6.

techniques such as infusion of isotopically-labelled oxidation as occurs normally in 'healthy' subjects.

substrates, glucose clamping and measurement of
arterio-venous differences in glucose concentration
across a limb have all demonstrated a reduced ability
of insulin to promote glucose disposal in insulin-sensi-
tive tissues of injured patients (Fig. 4). The underly-
ing mechanism explaining the insulin resistance is not
known although a post-receptor defect may be
involved. The increased plasma cortisol concentra-
tion observed at this time would also have an
inhibitory effect on glucose uptake.
Plasma gluconeogenic substrates, such as lactate
and pyruvate from muscle glycogenolysis and wound
metabolism, glycerol from adipose tissue breakdown
and alanine from enhanced proteolysis, are all
elevated in the flow phase. Gluconeogenesis is stimu-
lated accordingly, despite the elevated plasma glu-
cose concentration that would ordinarily inhibit the
process. Furthermore, hepatic glucose production
cannot be inhibited by the infusion of large amounts
of dextrose.
It is the consensus that glucose turnover rate is
increased after injury, although there is controversy
surrounding utilisation of the glucose taken up by the
tissues. The rate of glucose oxidation is normally
dependent on carbohydrate intake and the body's
glycogen reserves. Low carbohydrate intakes (5%
intravenous dextrose) do in fact stimulate glucose
oxidation to a degree in stressed patients, however,
larger intake s (hypertonic dextrose) fail to inhibit fat
The glucose not oxidised should either be converted
to fat or stored as glycogen. Indirect calorimetry
suggests that injured patients should theoretically
have larger glycogen stores than non-injured volun-
teer subjects receiving similar feeding regimens.
However, one would question whether the hormonal
imbalance of the injured patient would favour an
enhanced rate of glycogen synthesis during infusion
of dextrose.
Lipid. As mentioned above, one of the characteristic
features of the flow phase is the persistence of fat
oxidation in patients, especially the severely ill, who
are provided with dextrose-based parenteral nutri-
tion. In less severe trauma, the same phenomenon is
observed although there is a gradual rise in respira-
tory quotient and carbohydrate oxidation over 3-5
days post-injury as substrate preference gradually
reverts to glucose (Fig. 5). The mechanism explaining
the preferential fat oxidation is not totally clear. The
turnover of FFA is directly proportional to their
concentration in the plasma. However, plasma FFA
levels in patients with mild to moderate injuries
generally return to normal within a few days of injury
and the turnover-concentration relationship would
not appear to hold. Nonetheless, isotope studies
have demonstrated enhanced FFA turnover in rela-
tion to their concentration in injured patients and it
has been suggested that SNS activation may be
responsible. However, there is no explanation for the
146 CURRENT ANAESTHESIA AND CRITICAL CARE
increase in FFA clearance from the plasma. Inter-
estingly, Wolfe and colleagues 16 studied rates of
glycerol and FFA turnover simultaneously in burn
injured patients (60-95% body surface area burns)
and found an increase in triglyceride cycling (re-ester-
ification of FFA) that accounted for 10-15% of the
increase in total energy expenditure. Furthermore,
the rate of glycerol turnover in the latter study was
seen to treble in relation to its plasma concentration
and probably reflected increased re-esterification of
glycerol in adipose tissue. The increased cycling of
FFA and glycerol appeared to be stimulated by
enhanced sympathetic activation of lipoprotein lipase
and increased turnover of very low density lipo-
protein. Although turnover of triglyceride is
increased after trauma, the plasma triglyceride con-
centration is usually little changed during the flow
phase.
Lastly, one might expect an adaptive ketonaemic
response to trauma in the light of altered fat metabo-
lism during the flow phase. Clinical studies of severe
trauma have reported impaired synthesis of ketone
bodies, although, findings after more moderate
injury have been inconsistent.
Protein. Net loss of body protein, largely as urea, is
one of the most serious complications of critical
illness (for a comprehensive review see Rennie, 17). It
was believed originally that protein turnover in
organs such as the heart and lungs was not affected
during the flow phase. However, all tissues are
influenced in relation to their weight and protein
composition except the brain and other nervous
tissue. Skeletal muscle, containing the majority of the
body's nitrogen, accordingly, undergoes significant
net protein loss after trauma. It is the atrophy of
skeletal muscle that presents clinically such a marked
visual manifestation of the increase in protein
turnover.
The effects of injury on protein turnover is
extremely variable and, similar to many facets of the
metabolic response, it is dependent on the severity
and nature of the injury, together with the nutritional
status of the patient. Net negative nitrogen balance
may reflect: 1) a decreased rate of protein synthesis
with normal or slightly elevated catabolism as
observed in mild to moderately severe injury or
elective surgery or 2) increased protein catabolism
with or without a small enhancement of protein
synthetic rate as seen in severe thermal injury or
sepsis. Studies have estimated that enhanced rates of
protein turnover may make substantial contributions
to total energy expenditure in injured patients.
Increases in metabolic rate of 10% (425kJ) after
moderate injury or 20-30% (900-1325 kJ) following
more severe trauma or sepsis have been attributed to
increased protein cycling.
As mentioned above, skeletal muscle is the most
significant single source of amino acids in the body
and after injury both damaged and uninjured muscle
undergo net proteolysis. Glutamine and alanine can
constitute up to 45% of the amino acids (nitrogen)
released by skeletal muscle. Arteriovenous
difference in 3-methylhistidine, an amino acid
derived exclusively from breakdown of myofibrillar
proteins (i.e., actin and myosin), has been employed
to demonstrate increased catabolism of skeletal
muscle across a limb. Although 3-methylhistidine is
excreted unaltered in the urine, the reliability of
urinary measurements as an index of skeletal muscle
breakdown is questionable as other tissues, such as
smooth muscle, also contribute to the urinary concen-
tration.
Significant alterations in intracellular amino acid
metabolism occur after trauma; the concentration of
essential amino acids, especially the branched-chain
amino acids, rise whereas non-essential amino acids,
such as glutamine, the largest carrier of nitrogen,
decrease.
Amino acids released by muscle are utilised by
many tissues including the healing wound, kidney,
gut mucosa and white blood cells, including macro-
phages. However, the liver consumes the largest
quantity of amino acids as substrate for the increased
rate of gluconeogensis and in the synthesis of proteins
of the acute inflammatory response (e.g., C-reactive
protein). The rates of synthesis and degradation of
other plasma proteins, including albumin and trans-
ferrin, are also increased. The drop in plasma
albumin and transferrin concentrations observed
after injury is not due to inhibition of their synthesis,
but rather reflects the enhanced leakage of the
proteins across the microvascular endothelium into
extravascular spaces.
Nutritional state may influence protein turnover
and in many instances it compounds the effects of
injury. For example, malnourished patients have a
more negative nitrogen balance than normally nour-
ished patients when subjected to identical surgical
procedures. Furthermore, complete starvation
decreases both protein synthetic and catabolic rates.
Clague and coworkers is developed a generalised
model describing protein turnover after injury that
incorporated the contribution made by nutritional
intake. It was proposed that the rate of protein
synthesis could be enhanced by providing an ade-
quate intake of energy and nitrogen. Nutritional
intervention can favourably modify nitrogen balance
in many critically ill patients, however, certain 'obli-
gatory' net losses of protein are unavoidable.
Nitrogen balance of a patient having undergone an
elective surgical procedure of moderate severity
typically resembles that shown in Figure 6. In contrast
to the model of Clague and colleagues, the nitrogen
loss that occurs during the first few days after surgery
cannot be reversed or prevented by provision of
energy and nitrogen, even when given greatly in
excess of requirements. The same phenomenon
occurs in patients with more severe illness, such as
multiple organ failure and chronic sepsis, where net
 STRESS AND METABOLIC RESPONSE TO T R A U M A IN CRITICAL ILLNESS
10
o}
5
UJ
O
z 0
<
._J
<
-5
Z
LIJ
-10
O
tr-
~- - 1 5
Z
-20 I [
1 2
POST-INJURY
Fig. 6 - - Nitrogen balance following injury or elective surgery of moderate severity (unpublished results).
negative nitrogen balance may persist for weeks
despite the most 'aggressive' nutritional regimens.
Nutritional intervention. While uncomplicated injury
or elective surgery is associated with obligatory losses
of fat and, more importantly, lean body mass, once
convalescence is underway and nutritional intake is
normalised, body tissues are readily restored. Thus,
no special nutritional measures are usually taken with
these patients. However, the need for special atten-
tion to nutritional support in severely injured and
septic patients is universally accepted (for reviews see
19,20). The optimal nutritional regimen for such
patients is the subject of much debate and has
received much investigation since the introduction of
parenteral nutrition in the 1960s. While enteral
feeding is the preferred means of providing alimen-
tation, parenteral nutrition is frequently the only
alternative for the critically ill.
Clinicians are quick to appreciate that the alter-
ations in fuel utilisation that occur following trauma
are teleologically beneficial to the patient. However,
many parenteral nutritional regimens prescribed by
the clinician still provide the majority of energy as
dextrose, despite the indications that lipid, as an
energy substrate, is preferred.
Based on the respiratory gas exchange
measurements of many groups, it is the consensus
that the severely injured or septic patient generally
requires 160-190kJ/kg/day. Elegant studies exam-
ined the effects of varied nitrogen intakes in dietary
regimens matching energetic requirements in
critically ill patients, zl Nitrogen balance was
improved with nitrogen intakes up to 200mg/kg,
147
I I f I I
3 4 5 10 20
DAYS
however, at levels above that no improvement was
observed. Despite the fact that intravenous amino
acids stimulate protein synthetic rate, the increase is
never sufficient to eliminate net negative nitrogen
balance.
The effects of new amino acid formulations on
nitrogen balance in injured patients is presently very
topical. Experimental feeding studies using intrave-
nous solutions enriched in branched-chain amino
acids suggested that nitrogen balance was improved
with their administration. However, results from
clinical studies have been equivocal and unconvinc-
ing. Glutamine supplementation, when technology
ensures its stability in intravenous amino acid solu-
tions, may have the favourable effect on nitrogen
balance and intestinal integrity that clinicians
involved in critical care are seeking. Other
approaches to the prevention or reversal of post-trau-
matic muscle wasting might include the use of, for
example, growth hormone which may be of special
benefit in the elderly 22 and [3-adrenergic receptor
agonists which increase muscle mass.
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