TRAUMA
The metabolic and
endocrine response to
trauma
Amy Krepska
Jennifer Hastings
Owen Roodenburg
Abstract
Metabolic and endocrine pathways are central to the body’s compen-
satory response to trauma. They drive mobilization of energy sub-
strates, volume conservation and haemostasis via activation of the
hypothalamic pituitary adrenal axis, the sympathetic nervous system
and an inflammatory response. As clinicians, we can intervene in
these pathways, however optimal management of anaesthesia, fluids,
transfusion, nutrition and the use of steroids remains controversial and
to be determined.
Keywords Catecholamines; coagulation; cortisol; enhanced recov-
ery pathway; fibrinogen; gluconeogenesis; glutamine; hypothalamic
pituitary axis; inflammatory mediators; regional anaesthesia; renin
angiotensin aldosterone system; transfusion
Royal College of Anaesthetists CPD Matrix: 3A10
Introduction
Prior to the modern era of resuscitation, humans have long
developed crucial physiological responses to survive traumatic
insults. As many insults and conditions elicit similar physiologic
responses to those in trauma, for the anaesthetist ‘trauma’ is a
broad term just as readily encompassing surgery as well as
burns, traumatic brain injury, chest and abdominal injuries. All
these circumstances result in significant physiological changes,
essentially via metabolic and endocrine pathways but also
intrinsically involving the inflammatory and autonomic systems,
all with the ultimate aim of optimizing tissue repair.
To achieve this, it is vital to maintain perfusion and energy
supplies to vital organs. Hence the metabolic and endocrine
Amy Krepska MA MB BChir MPhil MRCP FRCA FFICM is a Registrar in
Anaesthesia at the Royal Brisbane and Women’s Hospital, Brisbane,
Australia. Conflicts of interest: none declared.
Jennifer Hastings MB BCh BAO MRCPI FCARCSI JFICMI is a Consultant in
Intensive Care Medicine and Anaesthesia at the Mater Misericordiae
University Hospital, Dublin, Ireland. Conflicts of interest: none
declared.
Owen Roodenburg MBBS (Hons) FRACP FCICM Grad Cert HSM is Director
of Intensive Care Services, Eastern Health, Melbourne, Australia.
Adjunct Clinical Associate Professor e Monash University, School of
Public Health and Preventative Medicine. Conflicts of interest: none
declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:8
Learning objectives
After reading this article, you should be able to:
C describe the response of the hypothalamic-pituitary-adrenal
axis to trauma
C describe how this response results in volume conservation,
mobilization of fuel sources and improved haemostasis
C outline the current controversies surrounding the management
of trauma patients
responses focus on mobilizing fuel sources, conserving volume
and minimizing blood loss. There is a complex interaction be-
tween these pathways with a surge in hypermetabolism and
catabolism.
Despite a robust design, these pathways are so complex there
is potential for failure of negative feedback with overshooting of
the response to actually lead to detriment. It is vital for the
anaesthetist to have a sound understanding of these mechanisms
to minimize the consequences of injury and to optimize and
support the body’s physiological responses.
The hypothalamic pituitary axis plays a central role in coor-
dinating these endocrine and metabolic responses. The hypo-
thalamus receives multiple inputs including from baroreceptors,
volureceptors and pain fibres stimulated during trauma; in
response a number of vital pathways are activated via the pitu-
itary and adrenal glands, and sympathetic nervous system.
Mobilization of energy resources
Corticotrophin releasing hormone (CRH) from the hypothalamus
results in release of adrenal corticotrophin hormone (ACTH)
from the anterior pituitary into the blood. This acts on the ad-
renal cortex resulting in a surge of cortisol. The key aim of
cortisol is to mobilize energy stores and hence it induces gluco-
neogenesis. Cortisol serum levels should result in negative
feedback into the hypothalamic pituitary axis, decreasing release
of further corticotrophin releasing hormone. This can fail in
trauma leading to a persistently high ACTH and cortisol resulting
in catabolism, with protein and, ultimately, muscle breakdown.
The latter is particularly detrimental to patients.
There is also a release of growth-hormone releasing hormone
(GHRH) from the hypothalamus leading to a release of growth
hormone (GH) from the anterior pituitary. This acts via insulin
like growth factors to increase catabolism, but to a lesser extent
than cortisol.
The pancreas also plays a role by decreasing the secretion of
insulin while increasing the secretion of glucagon. There is also a
state of relative insulin resistance, which when combined with
decreased insulin secretion, leads to decreased glucose uptake by
cells and increased circulating blood glucose levels.
These pathways all result in an increase in gluconeogenesis
via glycogenolysis, lipolysis and proteolysis. Overall this increase
in circulating glucose increases the supply of glucose at cellular
level. This is important in generating ATP via aerobic respiration
in the processes of glycolysis, the Krebs cycle and ultimately
oxidative phosphorylation to support the body post trauma.
414 Ó 2017 Published by Elsevier Ltd.
 TRAUMA
Volume conservation and redistribution
Trauma often results in a shocked state with hypoperfusion of
vital organs. In an attempt to maintain organ perfusion several
physiological responses occur, with the overall aim of ensuring
redistribution of blood flow to vital organs, volume conservation
and optimal haemostasis.
Hypothalamic stimulation results in increased sympathetic
outflow leading to two important effector responses. Firstly, the
preganglionic fibres synapsing with the adrenal medulla cause an
increased release of catecholamines into the circulation. Sec-
ondly, there is an increase in output down all postganglionic
sympathetic fibres. Those most important during trauma are the
cardioacceleratory fibres and those to the smooth muscle of the
vasculature. These postganglionic fibre outputs, together with
increased circulating catecholamines, mediate their effects via
the alpha and beta adrenoreceptors of the end organs leading to
the essential ‘flight or fight responses’.
Increased sympathetic outflow leads to positive cardiac ino-
tropy and chronotropy. Sympathetically mediated peripheral
venoconstriction mobilizes blood from reservoirs, such as mus-
cle, to increase venous return. Arteriolar vasoconstriction re-
distributes blood flow from peripheral to central structures.
In an attempt to correct volume loss, various compensatory
processes are activated, namely the renin angiotensin aldosterone
system (RAAS) and ADH release from the posterior pituitary.
Renin is secreted from juxtaglomerular cells in the kidney as a
result of increased sympathetic activity, renal hypoperfusion and
reduced sodium delivery to the macula densa. Renin converts
angiotensinogen to angiotensin I, which is further cleaved via
angiotensin converting enzyme (ACE), to angiotensin II (AT II).
AT II has multiple effects. Primarily, it stimulates the release of
aldosterone from the zona glomerulosa of the adrenal cortex and
via its actions on the hypothalamus, results in thirst and additional
ADH secretion. It is also a potent peripheral vasoconstrictor. At the
glomerulus, it causes preferential efferent arteriole constriction in
an attempt to conserve glomerular filtration rate (GFR). ACTH and
hyperkalaemia stimulate aldosterone release to a lesser extent.
Aldosterone acts predominantly on the distal convoluted tu-
bule of the nephron resulting in reabsorption of sodium and loss
of potassium and hydrogen ions. This increases water reab-
sorption and hence volume conservation. This is further accen-
tuated by the aldosterone like effect of circulating cortisol.
From the posterior pituitary, ADH is released and acting via V2
receptors in the kidney, results in an increase in aquaporins into
the collecting duct and hence water reabsorption into the systemic
circulation, to support the circulation during this time of injury.
The immunological response
Trauma induced tissue damage activates the complement
pathway. This results in neutrophil and macrophage activation
with subsequent release of inflammatory mediators including
interleukin-1, TNF-alpha and platelet activating factor. Conse-
quently there is upregulation of other acute phase proteins
including fibrinogen, oxygen free radicals and proteases as well
as arachidonic acid metabolites including thromboxanes and
prostaglandins. The end result of this earliest phase of tissue
trauma is propagation of the coagulation cascade, neutrophil
accumulation at the site of injury and a lymphocytosis with
ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:8
induction of both cell mediated and humoral pathways, all with
the aim of limiting further tissue damage and promoting repair.
However, there is a delicate balance between these pro- and anti-
inflammatory pathways and interfering with these in an attempt
to optimize outcomes in trauma patients, for example by
administration of steroids, is complex.
Haemostasis
In an attempt to prevent ongoing blood loss and conserve vol-
ume, various haemostatic mechanisms are activated. These
include vasoconstriction and platelet adhesion and aggregation,
ultimately leading to clot formation. These processes are
augmented by the inflammatory response to trauma, namely
elevated arachidonic acid metabolites such as thromboxane A2,
which acts as a potent vasoconstrictor and increases platelet
activation and aggregation. Serum levels of acute phase proteins,
such as the procoagulant fibrinogen, are also elevated whilst
others such as the anticoagulant, protein C are decreased altering
the balance between pro- and anticoagulant factors. The ultimate
aim of these pathways is a hypercoagulable state.
Management of the metabolic and endocrine pathways
activated in trauma: current controversies
All these processes seek to preserve vital organ functions and
allow survival following traumatic insult. However, without
appropriate management these compensatory mechanisms can
become overwhelmed resulting in death.
The hypermetabolic state associated with trauma increases
tissue oxygen demand. If cardiac output fails to increase suffi-
ciently, inadequate oxygen delivery to the tissues occurs. This
can be further compromised by peripheral vasoconstriction and
anaemia. Overall this will result in cellular hypoxia, lactic
acidosis and multiorgan failure. Equally, the compensatory
mechanisms of the coagulation system can become overwhelmed
resulting in disseminated intravascular coagulopathy (DIC) and
uncontrolled haemorrhage.
There are numerous interventions utilized in the management
of trauma patients, some augment the natural physiological re-
sponses but some interfere with these responses and can lead to
poorer patient outcomes. It is important that we understand how
our actions interfere with these processes so we can continue to
optimize our management and improve patient outcomes.
It is always difficult to demonstrate clear benefits of in-
terventions in the perioperative period. In particular, multi trauma
patients are a very heterogeneous group. Furthermore, it is
impossible to study and intervene in this group before their injury
and hence it is difficult to elicit the true benefit or detriment of
physiological responses and how best to modulate these. However,
nonetheless there has been much work looking at interventions in
the perioperative period of general surgical and burns patients, and
some of these findings can be extrapolated and applied to influence
interventions more specifically for trauma patients.
Choice of anaesthesia agent
Induction of anaesthesia in these patients can be difficult and there
is a constant debate about the competing interests to minimize the
risk of aspiration and a surge in intracranial pressure but to main-
tain haemodynamic stability. Overall the aim is to maintain the
415 Ó 2017 Published by Elsevier Ltd.
 TRAUMA
generated vasoconstrictive effect, whilst minimizing a surge in
hypertension at laryngoscopy, which could potentially cause car-
diac ischaemia and worsen bleeding at the site of injury.
Etomidate was traditionally used as an induction agent in this
setting but there have been specific concerns regarding the resul-
tant adrenal suppression and its potential impact on survival
studies despite the lack of a definitive link to negative outcomes.1
Opioids are known to suppress the hypothalamic pituitary axis to a
varying extent and clonidine has sympatholytic activity via central
activation of alpha 2 adrenergic receptors.2 No clear benefit of
using any of these agents has been shown and in general, a com-
bination of agents are used, increasingly including ketamine, with
invasive blood pressure monitoring to ensure targets are main-
tained both during induction and maintenance of anaesthesia.
Regional anaesthesia
Regional anaesthetic techniques have been used to improve
analgesia, attenuate the sympathetic response and to minimize
the development of chronic pain. There is increasing evidence to
support the safety of regional anaesthesia in trauma despite prior
concerns regarding risks associated with coagulopathy and con-
cealed compartment syndrome.3 It has been particularly used for
combat casualties with faster recovery and improved morale.
Fluid management
Traditionally, trauma patients have received large volume fluid
resuscitation in an attempt to reverse their hypovolaemic state and
improve organ perfusion. However, it has been increasingly sug-
gested that large volume resuscitation can lead to dilution of
coagulation factors, hypothermia and increased blood pressure
resulting in clot dislodgement, coagulopathy and poor organ
perfusion. Unsurprisingly, as the neurohumoral responses that
demand water and sodium retention have evolved over millennia,
the recent century of intravenous administration of sodium rich
water has not been so physiologically adapted to. Evidence now
suggests a link between increased volume of fluid resuscitation
and mortality. NICE now recommends a restrictive approach to
volume resuscitation until definitive control of bleeding has been
achieved, with the focus on haemorrhage control.4 The principle of
damage control resuscitation (DCR) is increasingly being used,
with permissive hypovolaemia, hypotension, haemostatic trans-
fusion and damage control surgery (see also Management of Shock
in Trauma on pp 386e389 of this issue).
There is ongoing controversy over blood pressure targets in
trauma resuscitation. There is some evidence that targeting a
lower blood pressure in penetrating trauma has a mortality
benefit but other studies, especially of blunt trauma, have failed
to show benefit. European guidelines now recommend a target
systolic blood pressure of 80e90 mmHg in the initial phase of
resuscitation until major bleeding has been controlled with an
overall restricted volume replacement strategy.5 In patients with
severe TBI, a mean arterial pressure of at least 80 mmHg should
be targeted. If severe hypotension they recommend the use of
vasopressors in addition to fluids.5
Blood product management
Blood product administration is a controversial topic in trauma
resuscitation. Initially, as a consequence of the stress response,
ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:8
acute phase proteins such as fibrinogen increase, which together
with coexisting hypovolaemia, results in a hypercoaguable pic-
ture. However it is becoming evident that the coagulation picture
is far more complex, with varying phases of hypo- and hyper-
coagulability, with a vast number of factors influencing this.
It is increasingly felt that traditional laboratory tests do not
sufficiently reflect the coagulation picture accurately and hence
there has been a move towards using viscoelastogram testing as
a point of care test to determine blood product administration
and optmization of the coagulation picture.5,6
Traditionally, trauma resuscitation focused on administration
of large volumes of packed red cells with a small volume of
plasma. However, there has been much work looking at the
optimal combination of blood products with ratios of plasma,
platelets and red blood cells much debated with some evidence
from severe trauma that increased plasma to red cell ratio might
lead to an improved coagulation profile.7 NICE currently rec-
ommends a one to one ratio of red blood cells to plasma.4
Fibrinogen consumption is felt to be central to the coagulopathy
and hence there is a drive towards using fibrinogen earlier to cor-
rect coagulopathy aided by the increased availability of fibrinogen
concentrate.6,8,9 Administration of tranexamic acid within three
hours of injury to treat the exaggerated fibrinolysis has been shown
to decrease morbidity and mortality and this is now recommended
in many guidelines and has become accepted practice.5,10
Steroids
Steroid use in trauma remains controversial. The initial hyper-
inflammatory response, aimed at limiting tissue damage, is fol-
lowed by a hypoinflammatory phase. During this latter phase the
body is susceptible to infection which can worsen tissue damage,
the so-called ‘two hit hypothesis’. The use of steroids in trau-
matic head injury have been shown to increase mortality.11
In hypotensive septic patients, it has been shown that the
administration of steroids increases the rate of shock reversal but
it is unclear if this can be translated to trauma patients. Overall
understanding of the HPA axis in critical illness remains limited
with recent evidence suggesting that cortisol levels appear to be
independent of ACTH.12 This leads to further uncertainty
regarding the role of steroids in critical care, including their role
in trauma patients.
Glucose control
Insulin therapy with optimum glucose levels have been long
debated.13 Many studies have suggested that tight control, although
optimizing wound healing and decreasing the incidence of in-
fections, can be detrimental as it risks hypoglycaemia. Nonetheless
it continues to be studied, with suggestions that subgroups of pa-
tients such as those with severe trauma, should have tighter control.
Enhanced recovery pathways
There has been a surge of interest in recent years in anaesthesia
and surgery, reviewing the management of patients in the peri-
operative period, to develop multimodal perioperative care
pathways, the so called ‘enhanced recovery’ programmes.14 The
concept is to optimize recovery and rehabilitation, with many of
the interventions aiming to minimize the stress response of
surgery through optimal nutrition, management of analgesia and
physiotherapy. Initially the focus was on colorectal surgery but
416 Ó 2017 Published by Elsevier Ltd.
 TRAUMA
now this has been expanded into multiple other areas including
orthopaedic and upper gastrointestinal surgery.
Nutrition
The hypercatabolic state associated with trauma can lead to muscle
atrophy and a resultant negative nitrogen balance. If inadequate
fuel sources are available ketogenesis occurs which can exacerbate
any existing acidaemia. Early feeding is a long debated issue in
critical care and it has been difficult to show a clear benefit. How-
ever proponents argue that nutritional supplementation is neces-
sary to enable a supply of amino acids for regeneration of protein
and requirements are potentially higher in burn and multitrauma
patients.15 Early feeding in critically ill patients is recommended
enterally if possible but if injuries do not allow, parenterally. The
necessity to supply micronutrients as well as glutamine is a hotly
debated issue, with large trials not demonstrating a clear benefit,
but in general they are included in most preparations.
Other innovative approaches
Burns patients are a subgroup of trauma patients which have
been described as being in a particularly marked hypermetabolic
and catabolic state for even up to 3 years post injury with sus-
tained levels of catecholamines, glucagon and glucocorticoid
with insulin resistance. Increasingly, a significant amount of
research is being done in this group of patients especially in
regards to analgesia, nutrition and fluid management.16
Innovative approaches include using propranolol to not only
manage the persistent tachycardia, and development of a cate-
cholamine induced cardiomyopathy, but to reduce resting energy
expenditure.16,17
Exercise and rehabilitation in the perioperative period can
improve lean body mass, energy expenditure and overall
mobility. Again this has been extensively studied in burns pa-
tients, but even post cardiothoracic and vascular surgery, it has
been safely implemented.
Conclusions
Severe trauma results in immense physiological derangement,
impacting metabolic, endocrine, autonomic and immune path-
ways. To survive traumatic insults the human body has evolved
compensatory responses. The interventions needed to optimize
these responses are still being determined.
As understanding and management of these patients has
improved in recent years, so too has survival. Nonetheless, John
Hunter, a military surgeon, as early as 1794, summed up the
body’s innate ability to survive trauma and reminds us of the
need to manage these patients with caution, to support rather
than hinder these metabolic and endocrine responses:
‘There is a circumstance attending accidental injury which
does not belong to disease e namely, that the injury done has in
all cases a tendency to produce both the disposition and the means
of cure’.18 A 17 Herndon DN, Rodriguez NA, Diaz EC, et al. Long-term propranolol
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