Trauma

Hormonal and metabolic The stress response and potential effects

responses to trauma Stress response Potential effect

Tod Guest Hyperglycaemia Impaired immune response and

tissue healing, osmotic diuresis,
organ dysfunction
Hypokalaemia and other Muscle weakness, arrhythmias,
electrolyte disturbances ileus
Fluid overload/tissue oedema Ileus, impaired wound healing
(excessive fluid administration (including anastomoses),
Abstract with increased ADH activity) congestive cardiac failure
The stress response is the result of integrated endocrine, metabolic and Hypertension and tachycardia Myocardial stress and ischaemia
immune mechanisms which promote tissue healing and restore physi- Procoagulant state DVT/PE, coronary artery
ological homeostasis after tissue damage. The two activated and inter- thrombosis or ischaemic stroke
acting limbs of the response are the hypothalamic–pituitary–adrenal axis Impaired gastrointestinal Failure of enteral nutrition,
and the cytokine cascade. The resultant state is characterized by ca- motility nausea, vomiting, diarrhoea,
tabolism (proteolysis, lipolysis and glycogenolysis), production of energy constipation
substrates and water and sodium retention with increased sympathetic Immunosuppression Infection, impaired wound
tone. Together with an activated immune system the body’s reserves healing
focus on combating pathogens and tissue repair, whilst maintaining vital
ADH, antidiuretic hormone; DVT, deep vein thrombosis; PE, pulmonary
organ function. embolism

Keywords catabolism; cortisol; cytokines; hormones; hypothalamic– Table 1

­pituitary–adrenal axis
Definition
The stress response is a cascade of endocrine, metabolic and
immunological interactions that has evolved to preserve tissue
and organ perfusion and energy substrate availability whilst
promoting healing. In a modern medical context aspects of the
response may become maladaptive (Table 1), especially if pro-
longed. Increasing age, comorbidity, use of invasive treatments
and immune-system modulation all result in a pathogenic imbal-
ance in the response. There continues to be great interest in the
detail and response to intervention due to the belief that improve-
ments in outcome can be made.
Stimuli
The stress response is not ‘all or none’ in nature. A graded
response occurs, depending on the degree of tissue damage. Sur-
gery, trauma, burns, infection and inflammatory processes all
elicit a stress response. Pain and even perceived potential injury
may activate parts of the stress system.
Initiation mechanism
Somatic and visceral afferent neuronal signals are transmitted
from the site of tissue damage (via ascending spinal pathways)
to the CNS. These signals stimulate the catecholaminergic- and
corticotrophin-releasing hormone (CRH) neuronal systems. In
turn the hypothalamic-pituitary–adrenal (HPA) axis is activated.
Tissue damage also results in local release of chemical mediators
Tod Guest, FRCA, is a Specialist Registrar in Intensive Care Medicine and
Anaesthesia at Derriford Hospital, Plymouth.
(cytokines). These then activate a system-wide cascade of events,
including the acute-phase response as well as the characteristic
pattern of local inflammation. There is considerable interaction
between these two processes.
Structure and function
The anatomic components are the central norepinephrinergic
nuclei (e.g. the locus ceruleus), corticotrophin-releasing hormone
(CRH) and arginine vasopressin (AVP)-producing paraventricu-
lar nuclei and the central and peripheral limbs of the hypotha-
lamic-pituitary axis (Figure 1). There are multiple peripheral
target organs and tissues for the hormones produced in the stress
response.
Catecholamines: norepinephrine released from the central and
peripheral autonomic nervous system and epinephrine released
from the adrenal glands result in the sympathetic response of
tachycardia and hypertension. Catecholamine-mediated effects on
other organs include suppression of insulin release, increased glu-
cagon release, stimulation of glycolysis and lipolysis in liver and
muscle and release of renin from the renal juxtaglomerular cells.
An inhibitory effect on upper gastrointestinal motility is also seen.
Pituitary hormones: the hypothalamus produces releasing fac-
tors, stimulating release of the respective anterior pituitary hor-
mones. Levels of adrenocorticotrophic hormone (ACTH), growth
hormone and prolactin are increased. The release of other ante-
rior pituitary hormones (luteinizing hormone, follicle-­stimulating
hormone and thyroid-stimulating hormone is varied whilst
their roles are less well understood. AVP is synthesized in the
­paraventricular nuclei and exerts a stimulatory paracrine effect
on ACTH release synergistically with CRH. Systemic (endocrine)
AVP is stored and released by the posterior pituitary. Levels rise

ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:9 398 Crown Copyright © 2008 Published by Elsevier Ltd. All rights reserved.

Structure and function of the stress response
Hypothalamus
↑NE
↑TSH
↑/↓LH/FSH
↑Prolactin
↓Insulin
↑Glucagon
↑Cortisol
↑ACTH
Pancreas
Adrenal gland
Angiotensin
↑Aldosterone
↑Renin
↑Epinephrine Kidney
ACTH, adrenocorticotrophic hormone; AP, anterior pituitary; AVP, arginine vasopressin; CRH, corticotrophin-releasing hormone; FSH, follicle-stimulating hormone;
GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; NE, norepinephrine; PP, posterior pituitary;
TSH, thyroid-stimulating hormone.
Figure 1
as part of the stress response, promoting water reabsorption in
the kidney by increasing water channels (aquaporins) in cells
that line the distal collecting system.
Cortisol has a major immunosuppressive role, inhibiting the
release and production of cytokines, the function and move-
ments of leukocytes and the effects of these on target tissues.
Its anti-inflammatory effect is part of the overall immunomodu-
lation of the stress response. An appropriate immune response
depends on a balance of the anti-inflammatory effects of cortisol
and certain cytokines and the immuno-enhancing effects of other
cytokines. The catabolic effects of cortisol (proteolysis, lipolysis
and hepatic gluconeogenesis) are also key, and have potential
maladaptive effects such as hyperglycaemia as well as maintain-
ing energy substrate levels. Cortisol also antagonises the anabolic
effects of growth hormone and insulin. Cortisol exerts a negative
feedback effect on CRH production by the hypothalamus and on
ACTH production by the anterior pituitary.
Growth hormone stimulates protein synthesis and acts via inter-
mediate molecules known as somatomedins or insulin-like growth
factors that are produced mainly by the liver. Growth hormone
stimulates glycolysis, lipolysis and reduces tissue ­glucose uptake.
Cytokines are glycopeptides whose role is signalling between
cells of the immune and haematopoietic systems.1 They are
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:9
Trauma
Spinal pain
pathways
CRH
GHRH
AP PP Tissue injury
↑GH
↑AVP Local inflammation
Cytokines
Liver
Acute phase
proteins
IGFs
­ roduced by activated macrophages, fibroblasts and endothelial
p
cells, and include interleukins (IL), tumour necrosis factor (TNF)
and interferon (INF). Pro-inflammatory cytokines include IL-1β,
IL-2, IL-6 and TNF-α. Anti-inflammatory cytokines include IL-4,
IL-10 and transforming growth factor-β.
Chemokines are a subgroup of cytokines that act as attrac-
tants to leukocytes, leading to migration and extravasation into
damaged tissues. Signalling occurs between cells via cell surface
cytokine receptors, signal transduction and gene transcription,
resulting in a targeted cytokine response that depends on the
initiating event. Excessive or inappropriate cytokine production
has been associated with various disease processes (e.g. menin-
gococcal septicaemia and autoimmune diseases). The effects of
haemofiltration and adsorption therapies on excessive cytokine
levels in conditions such as sepsis are being studied. Immuno-
suppression following trauma is at least in part related to a dys-
regulated cytokine response.
Acute-phase response is the response, predominantly by the
liver, to the cytokines produced in the stress response, and in
particular to IL-6. The acute-phase response comprises increased
hepatic synthesis of acute-phase proteins (e.g. C-reactive protein,
D-dimer, ferritin and complement factors and caeruloplasmin).
Synthesis of other proteins (e.g. albumin and transferrin) is
reduced. Increased plasma copper levels and hepatic sequestra-
tion of iron and zinc occur partly as a result of these changes.
399 Crown Copyright © 2008 Published by Elsevier Ltd. All rights reserved.
 Trauma
Pyrexia due to raised prostaglandin-E2 levels, further HPA
axis activation, increased vascular permeability and leukocyte
activation are all features of this response.
Modulation of the stress response
Steroids: the level of endogenous cortisol present in response
to surgery can significantly down regulate IL-6 production. The
effects of therapeutic steroids given perioperatively have not
been encouraging. In major abdominal surgery steroids sup-
pressed the cytokine response, but resulted in worse outcome
through complications such as wound breakdown.
Opioids: injected opioids have been shown to block ACTH release
through reduced CRH release at the hypothalamic level. Alfent-
anil has been shown to reduce cytokine levels after abdominal
surgery. However, improved outcome has not been well dem-
onstrated, and the relatively large doses of fentanyl (100 μg/kg)
given to suppress cortisol and glucose responses to open chole-
cystectomy in one study resulted in profound respiratory depres-
sion postoperatively.
Anaesthetic induction/sedative agents: etomidate blocks 11-
β-hydroxylase and the cholesterol side-chain cleavage enzyme
critical to the biosynthesis of cortisol. This occurs for 8 hours
after a single induction dose and prolonged infusion as a sedative
on the ICU is associated with a significant increase in mortality.
Benzodiazepines also block steroid release but at the hypotha-
lamic level, the effect of which is unclear.
Regional anaesthesia: the HPA-axis response is known to be
attenuated by neuraxial (epidural or spinal) blockade. This
occurs by blocking both afferent (spinal ascending pain path-
way) activation of the hypothalamus and efferent (sympathetic
autonomic nervous system) stimulation of the adrenals, liver and
pancreas. Regional anaesthesia has no effect on cytokine levels
because initiation of this response is by direct tissue damage.
Findings from a systematic review2 suggested that regardless of
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:9
surgery type and whether or not general anaesthesia was used,
neuraxial (epidural and spinal) anaesthesia reduced mortality by
one-third. Morbidity was also found to be reduced (deep vein
thrombosis, pulmonary embolism, transfusion requirements,
pneumonia, myocardial infarctions, renal failure) when neur-
axial block was used. A subsequent randomized controlled trail
in patients undergoing major abdominal surgery demonstrated
improved morbidity and analgesia but no mortality benefit.3
β-blockers: beneficial effects of β-blockade have been demon-
strated for high-risk cardiac patients. The rationale of dampen-
ing the adverse sympathetic effects is attractive, yet definitive
evidence as to which treatment regimens are most effective are
still awaited.
Hormonal: the use of insulin to achieve tight glycaemic control
has been shown to have some beneficial effects in critically ill
patients. This is likely to be due in part to an anti-inflammatory
effect. Small studies of exogenous growth hormone in burns and
surgical patients have shown some promise with improved grip
strength, nitrogen balance and wound healing. A large random-
ized controlled trial of growth hormone supplementation in criti-
cally ill patients demonstrated increased mortality.4 ◆
References
1 Sheeran P, Hall GM. Cytokines in anaesthesia. Br J Anaesthesia
1997; 78: 201–19.
2 Rodgers A, Walker N, Schug S, et al. Reduction of postoperative
mortality and morbidity with epidural or spinal anaesthesia: results
from overview of randomised trials. Br Med J 2000; 321: 1493.
3 Rigg JR, Jamrozik K, Myles PS, et al. Epidural anaesthesia and
analgesia and outcome of major surgery: a randomised trial. Lancet
2002; 359: 1276–82.
4 Takala J, Ruokonen E, Webster NR, et al. Increased mortality
associated with growth hormone treatment in critically ill adults.
N Engl J Med 1999; 341: 785–92.
400 Crown Copyright © 2008 Published by Elsevier Ltd. All rights reserved.