British Journal of Anaesthesia 85 (1): 109±17 (2000)
The stress response to trauma and surgery
Department of Anaesthesia, Epsom General Hospital, Dorking Road, Epsom KT18 7EG, UK
Br J Anaesth 2000; 85: 109±17Keywords: surgery; hormones, cortisol; sympathetic nervous system, catecholamines;
The stress response is the name given to the hormonal and outcome are still under scrutiny. Over the past 10 yr, the role
metabolic changes which follow injury or trauma. This is of cytokines in the response to surgery, and the interaction
part of the systemic reaction to injury which encompasses a between the immunological and neuroendocrine systems,
wide range of endocrinological, immunological and hae- has furthered interest in the subject. This review describes
matological effects (Table 1). The responses to surgery have the endocrine and metabolic changes which occur during
been of interest to scientists for many years. In 1932, surgery, and the effects of anaesthetic and analgesic
Cuthbertson described in detail the metabolic responses of regimens upon the responses.
four patients with lower limb injuries.10 He documented and
quanti®ed the time course of the changes. The terms `ebb'
and `¯ow' were introduced to describe an initial decrease
and subsequent increase in metabolic activity. The descrip- The endocrine response to surgery
tion of the `ebb' phase was based partly on work in The stress response to surgery is characterized by increased
experimental animals and the estimations of increases in secretion of pituitary hormones and activation of the
metabolic rate in the `¯ow' phase were exaggerated. These sympathetic nervous system.13 The changes in pituitary
descriptions have been perpetuated and are still quoted, but secretion have secondary effects on hormone secretion from
have been rede®ned29 and are perhaps not critical to an target organs (Table 2). For example, release of cortico-
understanding of the actual changes which occur.
trophin from the pituitary stimulates cortisol secretion from
After the early work on the stress response to accidental the adrenal cortex. Arginine vasopressin is secreted from the
injury, attention turned to surgical trauma, and responses to posterior pituitary and has effects on the kidney. In the
most types of surgery were reported. Following on from pancreas, glucagon is released and insulin secretion may be
this, the ability of anaesthetic agents and neural blockade to diminished. The overall metabolic effect of the hormonal
modify the endocrine and metabolic responses has been changes is increased catabolism which mobilizes substrates
studied enthusiastically. Although it seems that the stress to provide energy sources, and a mechanism to retain salt
response developed to allow injured animals to survive by and water and maintain ¯uid volume and cardiovascular
catabolizing their own stored body fuels, it has been argued homeostasis.
that the response is unnecessary in current surgical practice.
Strenuous efforts have been made to inhibit the stress
responses to surgery and evaluate the outcome. In particular, Table 2 Principal hormonal responses to surgery. ACTH, adreno-
the potential bene®ts of regional anaesthesia on surgical corticotrophic hormone (corticotrophin); AVP, arginine vasopressin; FSH,
follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-
stimulating hormone. Based on Desborough and Hall13
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000
small protein hormones called insulin-like growth factors
Hypothalamic activation of the sympathetic autonomic (IGFs), notably IGF-1, which is produced in liver, muscle
nervous system results in increased secretion of catechola- and other tissues in response to stimulation by growth
mines from the adrenal medulla and release of norepinephr- hormone. In addition to the regulation of growth, growth
ine from presynaptic nerve terminals. Norepinephrine is hormone has many effects on metabolism. It stimulates
primarily a neurotransmitter, but there is some spillover of protein synthesis and inhibits protein breakdown, promotes
norepinephrine released from nerve terminals into the lipolysis (the breakdown of triglycerides into fatty acids and
circulation. The increased sympathetic activity results in glycerol) and has an anti-insulin effect. This means that
the well recognized cardiovascular effects of tachycardia growth hormone inhibits glucose uptake and use by cells,
and hypertension. In addition, the function of certain which spares glucose for use by neurones in situations of
visceral organs, including the liver, pancreas and kidney, glucose scarcity. Growth hormone may also stimulate
is modi®ed directly by efferent sympathetic stimulation and/ glycogenolysis in the liver. Growth hormone secretion
from the pituitary increases in response to surgery and
trauma, in relation to the severity of the injury.
The hypothalamic±pituitary±adrenal axis
b-Endorphin is an opioid peptide of 31 amino acids
Anterior pituitary hormone secretion is stimulated by produced from the precursor molecule proopiomelanocor-
hypothalamic releasing factors.32 The pituitary synthesizes tin. Increased b-endorphin concentrations in the circulation
corticotrophin or adrenocorticotrophic hormone (ACTH) as after surgery re¯ect increased pituitary hormone secretion.
part of a larger precursor molecule, pro-opiomelanocortin. The hormone has no major metabolic activity.
The precursor is metabolized within the pituitary into
Prolactin is a protein hormone of 199 amino acids with a
ACTH, b-endorphin and an N-terminal precursor. Growth structure similar to that of growth hormone. Secretion of
hormone and prolactin are also secreted in increased prolactin is increased as part of the stress reponse to surgery
amounts from the pituitary in response to a surgical and also during exercise. It has little metabolic activity.
stimulus. Concentrations of the other anterior pituitary Prolactin production increases during pregnancy and stimu-
hormones, thyroid-stimulating hormone (TSH), follicle- lates milk secretion from the breast.
stimulating hormone (FSH) and luteinizing hormone (LH)
do not change markedly during surgery.
The posterior pituitary produces arginine vasopressin which Cortisol secretion from the adrenal cortex increases rapidly
has a major role as an antidiuretic hormone. It also has an following the start of surgery, as a result of stimulation by
endocrine function, acting with corticotrophin-releasing ACTH. From baseline values of around 400 nmol litre±1,
factor in stimulating the secretion of pro-opiomelanocortin cortisol concentrations increase to a maximum at about
4±6 h, and may reach >1500 nmol litre±1 depending on the
severity of the surgical trauma.38 The cortisol response can
be modi®ed by anaesthetic intervention (see below).
Usually, a feedback mechanism operates so that increased
Corticotrophin (ACTH) is a 39 amino acid peptide, concentrations of circulating cortisol inhibit further secre-
produced in the pituitary from the larger molecule, pro- tion of ACTH. This control mechanism appears to be
opiomelanocortin. ACTH stimulates the adrenal cortical ineffective after surgery so that concentrations of both
secretion of glucocorticoids so that circulating concentra- hormones remain high.
tions of cortisol are increased. Surgery is one of the most
Cortisol has complex metabolic effects on carbohydrate,
potent activators of ACTH and cortisol secretion, and fat and protein. It promotes protein breakdown and
increased plasma concentrations of both hormones can be gluconeogenesis in the liver. Glucose use by cells is
measured within minutes of the start of surgery.
inhibited, so that blood glucose concentrations are in-
creased. Cortisol promotes lipolysis, which increases the
production of gluconeogenic precursors from the break-
down of triglyceride into glycerol and fatty acids.
Growth hormone is a protein of 191 amino acids secreted
Cortisol has other glucocorticoid effects, notably those
from the anterior pituitary.13 Its release is stimulated by associated with anti-in¯ammatory activity. Corticosteroids
growth hormone releasing factor from the hypothalamus. inhibit the accumulation of macrophages and neutrophils
Growth hormone, also known as somatotrophin, has a major into areas of in¯ammation and can interfere with the
role in growth regulation, particularly in the perinatal period synthesis of in¯ammatory mediators, particularly prosta-
and in childhood. Many of its actions are mediated through glandins.
heart and, ultimately, increase the sensitivity of the heart to
Insulin is the key anabolic hormone.13 It is a polypeptide the actions of catecholamines.
with two chains (of 21 and 30 amino acids) linked by two
Concentrations of total and free T3 decrease after surgery
disulphide bridges. Insulin is synthesized and secreted by and return to normal after several days. TSH concentrations
the b cells of the pancreas. It is released after food intake, decrease during the ®rst 2 h and then return to preoperative
when blood glucose and amino acid concentrations increase. levels. The reason for the changes remains unclear, but may
Insulin promotes the uptake of glucose into muscle and be in¯uenced by the close relationship between thyroid
adipose tissue and the conversion of glucose into glycogen hormones, catecholamines and cortisol. Exogenous steroids
and triglycerides. It also stimulates the formation of suppress T3, so hypercortisolaemia after surgery may also
glycogen from glucose in the liver. Protein catabolism and depress T3 concentrations.11
Insulin concentrations may decrease after the induction of Gonadotrophins
anaesthesia, and during surgery there is a failure of insulin
secretion to match the catabolic, hyperglycaemic response. The gondotrophins, LH and FSH, are secreted from the
This may be caused partly by a-adrenergic inhibition of anterior pituitary. FSH is responsible for the development of
b cell secretion. In addition, there is a failure of the usual ovarian follicles in females. In males, FSH maintains the
cellular response to insulin, the so-called `insulin resist-
LH stimulates growth and development of the Leydig
ance', which occurs in the perioperative period.
cells of the testis which produce testosterone. In females,
Glucagon is produced in the a cells of the pancreas. This LH promotes maturation of the ovarian follicles and the
hormone promotes hepatic glycogenolysis. It also increases secretion of oestrogen. It also stimulates the formation of the
gluconeogenesis from amino acids in the liver and has corpus luteum from the follicles after ovulation.
lipolytic activity. Although plasma glucagon concentrations
Testosterone is a steroid manufactured from cholesterol
increase transiently after major surgery, this does not make a in the Leydig cells of the testis. It has a negative feedback
major contribution to the hyperglycaemic response.
effect on LH secretion from the anterior pituitary. It has
important effects on protein anabolism and on growth, in
addition to its well known role in the development and
maintainance of male secondary sexual characteristics.
The signi®cance of changes in pituitary gonadotrophins
4) and tri-iodothyronine (T3) are secreted into
the circulation from the thyroid gland under the in¯uence of following surgery requires further study. Testosterone
thyroid-stimulating hormone (TSH). Small amounts of concentrations are decreased for several days, while LH
concentrations show variable changes.51 In female subjects,
inactive, reverse T3 (rT3) are produced from the thyroid. oestradiol concentrations decrease for up to 5 days
T3 is formed in the tissues by the monodeiodination of T4. postoperatively.50
T3 is three to ®ve times more active metabolically than T4.
The hormones are bound extensively to their binding
proteins, albumin, thyroxine-binding pre-albumin and thy-
roid-binding globulin (TBG). The free thyroid hormones in Metabolic sequelae of the endocrine response
the plasma are metabolically active. Very low concentra- The net effect of the endocrine response to surgery is an
tions of free T3 and T4 are present in the circulation and are increased secretion of catabolic hormones. This promotes
in equilibrium with bound hormone in the plasma and the the provision of food substrates from the catabolism of
carbohydrate, fat and protein. In evolutionary terms, it
Thyroid hormones stimulate the oxygen consumption of seems likely that the stress response developed as a survival
most of the metabolically active tissues of the body. Notable mechanism which allowed injured animals to sustain
exceptions are the brain, spleen and the anterior part of the themselves until their injuries were healed. By using stored
pituitary gland. As a result of thyroid hormone activity, body fuels and retaining salt and water, the animal had a
metabolic rate and heat production is increased. The other chance to survive without food until healing and repair had
principal actions of thyroid hormones are to increase taken place. In current surgical and anaesthetic practice, it is
carbohydrate absorption from the gut, to stimulate both questionable whether the stress response is necessary.
the central and peripheral nervous systems and, in the longer
term, to in¯uence growth and development.
There is a close association between the activity of Carbohydrate metabolism
thyroid hormones and the catecholamines. In general terms, Blood glucose concentrations increase after surgery begins.
epinephrine and norepinephrine increase the metabolic rate Cortisol and catecholamines facilitate glucose production as
and stimulate the nervous system. The thyroid hormones a result of increased hepatic glycogenolysis and gluconeo-
increase the number and af®ninty of b-adrenoceptors in the genesis. In addition, peripheral use of glucose is decreased.
Blood glucose concentrations are related to the intensity presence of insulin. The net result is increased mobilization
of the surgical injury; the changes follow closely the of triglyceride, although plasma concentrations of glycerol
increases in catecholamines. In cardiac surgery, blood and fatty acids may not change markedly. The glycerol
glucose concentrations can increase up to 10±12 mmol produced by lipolysis is a substrate for gluconeogenesis in
litre±1 and remain elevated for >24 h after surgery. The the liver. Fatty acids enter a `pool' from which they may be
changes are less marked with minor surgery.
oxidized in the liver and in muscle, converted to ketone
The usual mechanisms that maintain glucose homeostasis bodies or re-esteri®ed.
are ineffective in the perioperative period. Hyperglycaemia
persists because catabolic hormones promote glucose
production and there is a relative lack of insulin together
In diabetic subjects it is now established that poor A number of hormonal changes occur in response to surgery
glycaemic control is associated with an increase in diabetic which in¯uence salt and water metabolism. These changes
complications, which can be avoided with tight control of support the preservation of adequate body ¯uid volumes.
blood glucose47 (see paper by Halls). The risks of prolonged Arginine vasopressin, which is released from the posterior
perioperative hyperglycaemia are less well established, pituitary, promotes water retention and the production of
although potential risks include wound infection and concentrated urine by direct action on the kidney. Increased
impaired wound healing. An increased incidence of vasopressin secretion may continue for 3±5 days, depending
wound infection and mediastinitis was found in diabetics on the severity of the surgical injury and the development of
and non-diabetics in whom blood glucose concentrations complications.
were >200 mg dl±1 after cardiac surgery.49
Renin is secreted from the juxtaglomerular cells of the
kidney, partly as a result of increased sympathetic efferent
activation. Renin stimulates the production of angiotensin II.
This has a number of important effects; in particular, it
Protein catabolism is stimulated by increased cortisol stimulates the release of aldosterone from the adrenal
concentrations. Predominantly skeletal muscle is broken cortex, which in turn leads to Na+ and water reabsorption
down, but some visceral muscle protein is also catabolized from the distal tubules in the kidney.11
to release the constituent amino acids. The amino acids may
be further catabolized for energy or used in the liver to form
new protein, particularly acute-phase proteins. The liver
also converts amino acids into other substrates, glucose, Activation of the stress response
fatty acids or ketone bodies. Protein catabolism results in The endocrine response is activated by afferent neuronal
marked weight loss and muscle wasting in patients after impulses from the site of injury. These travel along sensory
major surgical and traumatic injury. The loss of protein can nerve roots through the dorsal root of the spinal cord, up the
be measured indirectly by increased nitrogen excretion in spinal cord to the medulla to activate the hypothalamus.
In the 1950s it was postulated that there might be `wound
There has been much interest in the provision of hormones' produced in injured tissues which activated the
nutritional supplements for patients with critical illness pituitary±adrenal axis. In classical experiments, Egdahl
and those undergoing major surgery. Certain nutrients may demonstrated the role of the nervous system in the
have a bene®cial in¯uence on the immune status of stressed activation of the stress response.16 He studied the adreno-
patients. Glutamine, arginine, glycine, w-3polyunsaturated cortical responses to limb injury in dogs with innervated and
fatty acids and nucleotides have been studied most exten- denervated extremities. Blood samples were collected from
sively.44 Glutamine and arginine are semi-essential amino the adrenal vein for assay of adrenal corticosteroid concen-
acids with multiplicity of functions including stimulation of tration. In animals with an intact sciatic nerve, operative
immune activity. Studies of patients given enteral nutrition injury and burns to the limb resulted in an immediate and
supplemented with arginine or glycine after major surgery sustained increase in adrenal hormone concentration in
bene®ted from a faster recovery of immunological param- samples from the adrenal vein. If the nerve was cut after the
eters, fewer infectious complications and a shorter hospital injury, there was a rapid decline in the hormone response. In
those animals in which the sciatic nerve was transected
before operative or burn injury, there was no increase in
adrenal hormone after the trauma. This work did not provide
evidence that local substances were released after injury
As a result of hormonal changes during surgery, fats stored which stimulated the pituitary±adrenal axis. The idea that
as triglycerides are converted by lipolysis to glycerol and local substances might in¯uence some of the changes
fatty acids. Lipolytic activity is stimulated by cortisol, associated with surgery was advanced by the discovery of
catecholamines and growth hormone and is inhibited in the the cytokines.
Table 3 Features of the acute phase response. C, C-reactive protein. Based
Cytokines are a group of low-molecular-weight proteins
which include the interleukins and interferons. They are Fever
produced from activated leucocytes, ®broblasts and en- Production of acute phase proteins in liver
dothelial cells as an early response to tissue injury and have
a major role in mediating immunity and in¯ammation.42
The cytokines act on surface receptors on many different
Changes in serum concentrations of transport proteins
target cells and their effects are produced ultimately by
in¯uencing protein synthesis within these cells. Details of
decrease in transferrin, albumin and a2-macroglobulin
Changes in serum concentrations of divalent cations
the cytokine network and the activation of cytokines in
response to surgery have been reviewed recently.19 42 The
effects of chronic stimulation of the cytokine network, for
example, in sepsis, has also been reviewed.6
The cytokines have a major role in the in¯ammatory
response to surgery and trauma. They have local effects of as a consequence of the changes in the production of the
mediating and maintaining the in¯ammatory response to transport proteins.42
tissue injury, and also initiate some of the systemic changes Interaction between the immune system and the neuro-
which occur. After major surgery, the main cytokines endocrine system
released are interleukin-1 (IL-1), tumour necrosis factor-a The cytokines IL-1and IL-6 can stimulate secretion of
(TNF-a) and IL-6. The initial reaction is the release of IL-1 ACTH from isolated pituitary cells in vitro. In patients after
and TNF-a from activated macrophages and monocytes in surgery, cytokines may augment pituitary ACTH secretion
the damaged tissues. This stimulates the production and and subsequently increase the release of cortisol. A negative
release of more cytokines, in particular, IL-6, the main feedback system exists, so that glucocorticoids inhibit
cytokine responsible for inducing the systemic changes cytokine production. The cortisol response to surgery is
suf®cient to depress IL-6 concentrations.20Minimally invasive surgery
Laparoscopic surgery causes less tissue injury than con-
ventional procedures, so the increase in concentrations of
This is a 26 kDa protein. Concentrations of circulating biochemical markers of in¯ammation, such as IL-6 and the
cytokines are normally low and may be undetectable. acute phase protein, CRP, is not as great.21 The classical
Within 30±60 min after the start of surgery, IL-6 concen- stress responses (catecholamines, cortisol and glucose) to
tration increases; the change in concentration becomes abdominal surgery such as cholecystectomy, are not
signi®cant after 2±4 h. Cytokine production re¯ects the changed greatly by reducing surgical trauma. This suggests
degree of tissue trauma, so cytokine release is lowest with that stimuli for the stress response arise from visceral and
the least invasive and traumatic procedures, for example, peritoneal afferent nerve ®bres in addition to those from the
laparoscopic surgery. The largest increases in IL-6 occur abdominal wall. Anaesthesia has little effect on the cytokine
after major procedures such as joint replacement, major response to surgery because it cannot in¯uence tissue
vascular and colorectal surgery. After these operations, trauma. Although regional anaesthesia inhibits the stress
cytokine concentrations are maximal at about 24 h and response to surgery, it has no signi®cant effect on cytokine
remain elevated for 48±72 h postoperatively.
production. Combined analgesic regimens which included
high-dose steroids showed a small decline in IL-6 concen-
trations and the acute phase response because of the
interaction of glucocorticoids and cytokines.41 The tech-
A number of changes occur following tissue injury which nique was accompanied by unwanted side-effects, including
are stimulated by cytokines, particularly IL-6. This is known wound breakdown.
as the `acute phase response'; one of its features is the
production in the liver of acute phase proteins (Table 3).
These proteins act as in¯ammatory mediators, anti-protei- The effect of anaesthesia on the stress
nases and scavengers and in tissue repair. They include C- response to surgery
reactive protein (CRP), ®brinogen, a2-macroglobulin and
other anti-proteinases. The increase in serum concentrations General anaesthesia
of CRP follows the changes in IL-6. Production of other Opioids
proteins in the liver, for example, albumin and transferrin, It has been known for many years that opioids suppress
decreases during the acute phase response. Concentrations hypothalamic and pituitary hormone secretion. McDonald
of circulating cations such as zinc and iron decrease, partly and colleagues demonstrated the suppressant effect of
therapeutic doses of morphine on the hypothalamic± after induction of anaesthesia with etomidate or thiopental.3
pituitary±adrenal axis in humans.33 Morphine suppressed Pre-induction cortisol concentrations were measured and a
the release of corticotrophin and, consequently, cortisol in short ACTH stimulation test was performed at 24 h to assess
normal and stress conditions, although the adrenals were adrenal function. Cortisol concentrations before induction
found to respond to exogenous administration of ACTH. of anaesthesia were high, in keeping with other studies of
The inhibitory effects of morphine occur at the hypotha- adrenal function in critically ill patients. Those patients who
received etomidate tended to have a smaller cortisol
In cardiac surgery, the effects of morphine and other response to stimulation by ACTH than the control thiopental
opioids on the stress response to surgery have been well group. Although assessment of adrenocortical function in
documented.12 Large doses of morphine (4 mg kg±1) block critically ill patients using single cortisol concentrations and
the secretion of growth hormone and inhibit cortisol release ACTH stimulation tests is the subject of great controversy,34
until the onset of cardiopulmonary bypass (CPB). Fentanyl this study suggests that etomidate may interfere with
(50±100 mg kg±1), sufentanil (20 mg kg±1) and alfentanil (1.4 cortisol synthesis in these patients.3
mg kg±1) suppress pituitary hormone secretion until CPB.12
The benzodiazepine, midazolam, which has an imidazole
After the onset of CPB, the physiological changes are so ring in addition to the basic benzodiazepine structure,
profound that the hypothalamic and pituitary responses attenuates the cortisol responses to both peripheral and
cannot be completely inhibited by opioids. A high-dose upper abdominal surgery.9 14 Midazolam and diazepam both
opioid technique leads inevitably to respiratory depression inhibit cortisol production from isolated bovine adrenocor-
after surgery, which requires ventilatory support to be tical cells in vitro. Although Crozier and colleagues showed
provided for the patient in the postoperative period.
that subjects produced cortisol in response to exogenous
In lower abdominal surgery, fentanyl 50 mg kg±1 will ACTH,9 thus con®rming that the site of action of the
suppress the growth hormone, cortisol and glycaemic benzodiazepine is at the hypothalamic±pituitary level, a
changes found during pelvic surgery.18 In this study, the direct inhibitory effect on steroid production cannot be
opioid was administered during induction of anaesthesia. excluded.
When fentanyl 50 mg kg±1 was given 60 min after the start of
pelvic surgery, there was no signi®cant effect on the Clonidine
endocrine response which was already established.5 It was Clonidine is a centrally acting antihypertensive drug which
subsequently established that fentanyl 15 mg kg±1 was activates a2-adrenergic receptors.1 It provides haemody-
suf®cient to inhibit cortisol and glucose responses to lower namic stability through its sympatholytic activity, and can
reduce anaesthetic and analgesic requirements and provide
In upper abdominal surgery, systemic opioids are sedation. By reducing the sympathoadrenal and cardiovas-
relatively ineffective in preventing the stress response to cular responses caused by noxious surgical stimuli, the a2-
upper abdominal surgery. Fentanyl 100 mg kg±1 abolished agonists inhibit the stress responses mediated by the
completely the hormonal changes after conventional sympathetic nervous system.
cholecystectomy, but the technique resulted in respiratory
depression requiring ventilatory support in the postoperative
Regional anaesthesiaExtensive epidural analgesia with local anaesthetic agents
will prevent the endocrine and metabolic responses to
The anaesthetic induction agent etomidate is a carboxylated surgery in the pelvis and on the lower limbs. Epidural
imidazole that interferes with the production of steroids in blockade from dermatomal segment T4 to S5, established
the adrenal cortex by reversible inhibition of the enzyme before the start of surgery, prevented increases in cortisol
11b-hydroxylase and cholesterol side-chain cleavage en- and glucose concentrations in response to hysterectomy.17
zyme. The synthesis of both aldosterone and cortisol is Both afferent input from the operative site to the central
blocked. A single induction dose of the drug will suppress nervous system and the hypothalamic±pituitary axis, and
hormone production for 6±12 h,48 while infusion for 1±2 h efferent autonomic neuronal pathways to the liver and
blocks cortisol synthesis for up to 24 h.37 In healthy patients, adrenal medulla are blocked. Thus the adrenocortical and
there were no adverse cardiovascular effects from such an glycaemic responses to surgery are abolished. Less exten-
infusion during pelvic surgery, and the only metabolic result sive neural blockade will not completely abolish the
of cortisol inhibition was a decrease in the expected hormonal and metabolic changes.
In upper abdominal or thoracic surgery, it is not possible
The use of etomidate by infusion as part of intravenous to prevent pituitary hormone responses completely, even
sedation for critically ill patients was found to be associated with extensive epidural local anaesthetic blockade. In a
with increased mortality.27 As a result, the drug is no longer classical study by Bromage and colleagues, epidural block
licensed for use in long-term sedation. A recent study has up to the C6 dermatome inhibited glycaemic changes but
examined adrenocortical function in critically ill patients not the increases in cortisol concentrations in response to
upper abdominal and thoracic surgery.7 Other studies neural blockade in patients who are given anticoagulants
con®rm these ®ndings. Many suggestions have been made because of the risk of epidural haematoma formation.
to explain the failure to abolish completely the stress Procedural guidelines may be used to minimize the risk of
responses in these studies. Most of these centre around neurological complications.3 Thoracic epidural anaesthesia
inadequate or incomplete afferent somatic and sympathetic is not without potential side-effects, which include possible
neural blockade which allows pituitary activation and hence cranial spread of the epidural block. This may lead to arm
cortisol release from the adrenal cortex under the in¯uence weakness, and apnoea may occur if the diaphragm is
of ACTH, whilst efferent blockade of nerves to the adrenal affected by blockade of nerve roots C3±C5. Testing of arm
medulla and the liver inhibits hyperglycaemic responses. movements has been advocated to monitor cephalad spread
Attempts were made subsequently to improve on the of thoracic epidural anaesthesia.2
afferent blockade using vagal blockade, splanchnic nerve
block or continuous intraperitoneal local anaesthetic, but no
technique has abolished consistently the stress responses to The stress response and surgical outcome
upper abdominal or thoracic surgery.
There has been a great deal of interest in the modi®cation of
the stress response with respect to the potential bene®cial
effects on surgical outcome. The extent to which the
Perioperative thoracic epidural anaesthesia has been used responses are modi®ed depends on the choice of the
successfully in the management of patients undergoing analgesic techniques used. Inhibition of stress responses is
coronary artery bypass surgery.28 46 Investigators have greatest with neural blockade with local anaesthetics.
examined the effects of thoracic epidural analgesia on Therefore attention has focused largely on the effects of
neuroendocrine secretion and on physiological variables. It regional anaesthetic and analgesic regimens, particularly
is possible to prevent changes in catecholamine responses epidural blockade with local anaesthetic agents. Individual
during CPB and up to 24 h after the start of cardiac surgery studies show that provision of analgesia using neural
using thoracic epidural analgesia combined with general blockade leads to improvements in physiological variables
anaesthesia.36 This cannot be achieved using opioid anaes- in speci®c organ systems. Single investigations often cannot
thesia alone. The cortisol responses to CPB may also be show bene®ts in morbidity and mortality because the
attenuated using thoracic epidural analgesia, although incidence of serious complications after surgery is generally
low, and the numbers of patients studied is small. Meta-
Although there is no direct association between the analysis is being used increasingly to demonstrate that
attenuation of hormonal and metabolic responses and regional analgesia has bene®cial effects on surgical out-
postoperative outcome, the use of thoracic epidural anal- come.
gesia in cardiac surgery has many potential bene®ts in terms
of improvements in organ function. Thoracic epidural Bene®cial effects of regional analgesia
anaesthesia provides intense analgesia, avoids the use of
systemic opioids and improves postoperative pulmonary Thromboembolic complications
function.28 It may reduce the incidence of thrombotic It is well established that regional analgesic techniques
complications by decreasing the tendency towards hyper- reduce the incidence of thromboembolic complications
coagulability in the perioperative period.45
following surgery of the pelvis and lower limbs.31 In upper
The myocardium-speci®c contractile protein, troponin T, abdominal procedures, there is not quite the same bene®t in
is a highly speci®c biochemical marker of myocardial the incidence of thrombotic episodes.
injury. Measurement of serum concentrations of the protein
can be used to assess myocardial ischaemia. A recent study Pulmonary function
showed that thoracic epidural anaesthesia and general Although it might be assumed that good analgesia with
anaesthesia in cardiac surgery attenuated the myocardial regional techniques should lead to decreased postoperative
sympathetic response and was associated with decreased pulmonary complications, improvements in overall pul-
myocardial damage as determined by less release of monary outcome have not been demonstrated unequivo-
troponin T.30 In medical patients, thoracic epidural anal- cally. In single studies, pulmonary function has been shown
gesia has been used successfully to treat refractory angina. to improve, and meta-analysis has found that continuous
The sympatholytic effects of the blockade of cardiac administration of epidural local anaesthetic decreases the
sympathetic efferents and afferents may improve the incidence of pulmonary complications, whereas other
balance of oxygen delivery and consumption. The use of techniques, including the use of systemic or epidural
thoracic epidural anaesthesia in patients with heart disease opioids, were less effective.4
has been the subject of a recent review.35
Despite the potential bene®ts of thoracic epidural anaes- Regional analgesia is very effective in tempering some of
thesia, there are speci®c cautions about the use of regional the cardiovascular responses to surgery which result from
sympathetic activation. Whether neural blockade tech-
niques are more bene®cial in terms of overall cardiac Conclusions
morbidity and outcome compared with other methods of The stress response to surgery comprises a number of
pain relief has not been established.22 31
hormonal changes initiated by neuronal activation of the
hypothalamic±pituitary±adrenal axis. The overall metabolic
effect is one of catabolism of stored body fuels. In general,
Continuous epidural analgesia at the thoracic level the magnitude and duration of the response are proportional
decreases paralytic ileus following abdominal procedures.43 to the surgical injury and the development of complications
The use of local analgesia, or a combination of local and such as sepsis. Other changes also occur following surgery,
opioid analgesia, was more effective than either systemic or notably an increase in cytokine production which is
epidural opioids in preventing ileus. The elimination of ileus triggered locally as a tissue response to injury.
allows the early use of enteral nutrition which is an
Regional anaesthesia with local anaesthetic agents
important factor in reducing the risk of infectious compli- inhibits the stress response to surgery and can also in¯uence
postoperative outcome by bene®cial effects on organ
Despite evidence that regional analgesia confers bene®- function.
cial effects on organ function, improvements in overall
postoperative morbidity and length of hospital stay have not
been demonstrated conclusively. This is disappointing in
view of the widespread introduction of acute pain services References
which consume time and resources. Of course, analgesia is
1 Aantaa R, Scheinin M. Alpha2-adrenergic agents in anaesthesia.
provided for humanitarian reasons. Patient-controlled anal-
gesia is popular and accepted by many patients, but has
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For Management Useful Contact Numbers TB Control Programme Telephone National Manager Provincial Managers: Eastern Cape ofessionals Free State KwaZulu-Natal Mpumalanga Northern Cape North West For Health Pr Western Cape Useful References South African National Tuberculosis Guidelines . Churchyard, G.J. Tuberculosis and HIV. Chapter 26. 2007. National
SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE VETERINARY MEDICINAL PRODUCT QUALITATIVE AND QUANTITATIVE COMPOSITION Each film coated tablet contains: Doxycycline hyclate equivalent to 300 mg Doxycycline, 0.825mg, Titanium Dioxide (E171) and 7.181mg Ponceau 4R (E124) as colourant. For a full list of excipients, see section 6.1 3. PHARMACEUTICAL A red oblong film-coated tablet wit