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 Consultant 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; Adjunct Clinical Associate
Professor, Monash University, School of Public Health and
Preventative Medicine, Melbourne, Australia. Conflicts of interest:
none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
Please cite this article as: Krepska A et al., The metabolic and endocrine response to trauma, Anaesthesia and intensive care medicine, https://
doi.org/10.1016/j.mpaic.2020.04.011
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 which can lead to harmful effects. 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-adrenal axis plays a central role in
coordinating these endocrine and metabolic responses. The hy-
pothalamus receives multiple inputs including from barorecep-
tors, 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 CRH. This can fail in trauma, leading to a persistently
high ACTH and cortisol that results 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
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 in-
crease in circulating glucose increases the supply of glucose at a
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.
1 Ó 2020 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 aldoste-
rone system (RAAS) and ADH release from the posterior pitui-
tary. 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 con-
verts 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 vaso-
constrictor. At the glomerulus, it causes preferential efferent
arteriole constriction in an attempt to conserve glomerular
filtration rate (GFR). ACTH and hyperkalaemia stimulate aldo-
sterone 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,
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
Please cite this article as: Krepska A et al., The metabolic and endocrine response to trauma, Anaesthesia and intensive care medicine, https://
doi.org/10.1016/j.mpaic.2020.04.011
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 induction of both cell-medi-
ated 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 opti-
mize outcomes in trauma patients, for example by adminis-
tration of steroids, is complex.
Haemostasis
In an attempt to prevent ongoing blood loss and conserve
volume, 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 while others such as the anticoagulant, protein C are
decreased, altering the balance between procoagulant 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 over-
whelmed, 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, there has been much work looking at in-
terventions in the perioperative period of general surgical and
burns patients, and some of these findings can be extrapolated
2 Ó 2020 Published by Elsevier Ltd.
 TRAUMA
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 pres-
sure but to maintain haemodynamic stability. Overall, the aim is
to maintain the generated vasoconstrictive effect while mini-
mizing a surge in hypertension at laryngoscopy, which could
potentially cause cardiac 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
resultant adrenal suppression and its potential impact on sur-
vival 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 combination of agents are used, increasingly including
ketamine, with invasive blood pressure monitoring to ensure
targets are maintained 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
suggested 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, hypo-
tension, haemostatic transfusion and damage control surgery
(see also Management of Shock in Trauma on pp 000-000 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
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
Please cite this article as: Krepska A et al., The metabolic and endocrine response to trauma, Anaesthesia and intensive care medicine, https://
doi.org/10.1016/j.mpaic.2020.04.011
systolic blood pressure of 80e90 mmHg in the initial phase of
resuscitation in a trauma patient without brain trauma 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,
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 coagulop-
athy and hence there is a drive towards using fibrinogen earlier
to correct coagulopathy aided by the increased availability of
fibrinogen concentrate.6,8,9 Administration of tranexamic acid
within 3 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
without a mortality benefit but it is unclear if this can be trans-
lated to trauma patients.12,13 Overall understanding of the HPA
axis in critical illness remains limited, with recent evidence
suggesting that cortisol levels appear to be independent of
ACTH.14 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.15 Many studies have suggested that tight control,
although optimizing wound healing and decreasing the incidence
3 Ó 2020 Published by Elsevier Ltd.
 TRAUMA
of infections, can be detrimental as it risks hypoglycaemia.
Nonetheless it continues to be studied, with suggestions that
subgroups of patients 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.16 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
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. Nutritional supplemen-
tation is necessary to enable a supply of amino acids for regen-
eration of protein and requirements are potentially higher in burn
and multitrauma patients.17 ESPEN guidelines recommend that
all trauma patients should preferentially receive early enteral
nutrition instead of early parenteral nutrition where possible and
a higher protein intake should be considered due to high protein
losses.18 The necessity to supply micronutrients as well as
glutamine is a hotly debated issue, with large trials not demon-
strating a clear benefit.
Other innovative approaches
Burns patients are a subgroup of trauma patients that have been
described as being in a particularly marked hypermetabolic and
catabolic state for even up to 3 years post injury with sustained
levels of catecholamines, glucagon and glucocorticoid with in-
sulin resistance. Increasingly, a significant amount of research is
being done in this group of patients, especially in regards to
analgesia, nutrition and fluid management.19
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.19,20
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
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
Please cite this article as: Krepska A et al., The metabolic and endocrine response to trauma, Anaesthesia and intensive care medicine, https://
doi.org/10.1016/j.mpaic.2020.04.011
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’.21 A
REFERENCES
1 Flynn G, Shehabi Y. Pro/con debate: is etomidate safe in hemo-
dynamically unstable critically ill patients? Crit Care 2012; 16(4):
227.
2 Desborough JP. The stress response to trauma and surgery. Br J
Anaesth 2000; 85: 109e17. https://doi.org/10.1093/bja/85.1.109.
3 Fleming I, Egeler C. Regional anaesthesia for trauma: an update.
Contin Educ Anaesth Crit Care Pain 2014; 14(3): 136e41. https://
doi.org/10.1093/bjaceaccp/mkt048.
4 https://www.nice.org.uk/guidance/ng39/evidence/full-guideline-
2308122833 ‘NICE guideline NG39 Major trauma: assessment
and initial management February 2016’
5 Rossaint R, Bouillon B, Cerny V, et al. The European guideline on
management of major bleeding and coagulopathy following
trauma: fourth edition. Crit Care, 2016; 1e55. https://doi.org/10.
1186/s13054-016-1265-x.
6 Hagemo JS, Christiaans SC, Stanworth SJ, et al. Detection of
acute traumatic coagulopathy and massive transfusion re-
quirements by means of rotational thromboelastometry: an inter-
national prospective validation study. Crit Care 2015; 19. https://
doi.org/10.1186/s13054-015-0823-y.
7 Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma,
platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mor-
tality in patients with severe trauma. JAMA 2015; 313: 471.
https://doi.org/10.1001/jama.2015.12.
8 Khan S, Davenport R, Raza I, et al. Damage control resuscitation
using blood component therapy in standard doses has a limited
effect on coagulopathy during trauma hemorrhage. Intensive Care
Med 2015; 41: 239e47. https://doi.org/10.1007/
s00134-014-3584-1.
9 Hagemo JS, Stanworth S, Juffermans NP, et al. Prevalence,
predictors and outcome of hypofibrinogenaemia in trauma: a
multicentre observational study. Crit Care, 2014; 18. https://doi.
org/10.1186/cc13798.
10 Moulton JP. The importance of early treatment with tranexamic
acid in bleeding trauma patients: an exploratory analysis of the
CRASH-2 randomised controlled trial, 2011. https://doi.org/10.
1016/S0140-6736(11)60278-X. 6736.
11 CRASH trial collaborators. Effect of intravenous corticosteroids
on death within 14 days in 10008 adults with clinically significant
head injury ( MRC CRASH trial): randomised placebo-controlled
trial. Lancet, 2004; 1321e8.
12 Sprung C, Annane D, Keh D, et al. Hydrocortisone therapy for
patients with septic shock. N Engl J Med 2008; 358: 111e24.
13 Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid
therapy in patients with septic shock. N Engl J Med 2018; 378:
797e808.
14 Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol
metabolism during critical illness. N Engl J Med 2013; 368:
1477e88.
4 Ó 2020 Published by Elsevier Ltd.
 TRAUMA

15 Kalfon P, Giraudeau B, Ichai C, et al. Tight computerized versus
conventional glucose control in the ICU: a randomized controlled
trial. Intensive Care Med 2014; 40: 171e81. https://doi.org/10.
1007/s00134-013-3189-0.
16 Taylor M. Enhanced recovery after surgery protocols. Annu
Queenst Updat Anaethesia, 2012; 71e5.
17 McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the
provision and assessment of nutrition support therapy in the adult
critically ill patient: society of critical care medicine (SCCM) and
American society for parenteral and enteral nutrition (A.S.P.E.N.
J Parenter Enter Nutr 2016; 40: 159e211. https://doi.org/10.1177/
0148607115621863.
18 Singer P, Blaser AR, Berger M, et al. ESPEN guideline on clinical
nutrition in the intensive care unit. Clin Nutr 2019; 38: 48e79.
19 Finnerty C, Tapiwa Mabvuure N, Arham A, et al. NIH public ac-
cess. JPEN 2013; 37: 1e14. https://doi.org/10.1177/
0148607113496117.The.
20 Herndon DN, Rodriguez NA, Diaz EC, et al. Long-term propranolol
use in severely burned pediatric patients: a randomized controlled
study. Ann Surg 2012; 256: 402e11. https://doi.org/10.1097/SLA.
0b013e318265427e.
21 Turk JL. Inflammation: John Hunter’s a treatise on the blood,
inflammation and gun-shot wounds. Int J Exp Pathol 1994; 75:
385e95.

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx 5 Ó 2020 Published by Elsevier Ltd.

Please cite this article as: Krepska A et al., The metabolic and endocrine response to trauma, Anaesthesia and intensive care medicine, https://
doi.org/10.1016/j.mpaic.2020.04.011