The Stress Response to Trauma and Surgery

Br J Anaesth 2000; 85: 109–17 The stress response is the name given to the hormonal and metabolic changes which follow injury or trauma. This is part of the systemic reaction to injury which encompasses a wide range of endocrinological, immunological and haematological effects (Table 1). The responses to surgery have been of interest to scientists for many years. In 1932, Cuthbertson described in detail the metabolic responses of four patients with lower limb injuries.10Cuthbertson DP Observations on the disturbance of metabolism produced by injury to the limbs.Q J Med. 1932; 1: 233-246Google Scholar He documented and quantified the time course of the changes. The terms ‘ebb’ and ‘flow’ were introduced to describe an initial decrease and subsequent increase in metabolic activity. The description of the ‘ebb’ phase was based partly on work in experimental animals and the estimations of increases in metabolic rate in the ‘flow’ phase were exaggerated. These descriptions have been perpetuated and are still quoted, but have been redefined29Little RA Girolami A Trauma metabolism—ebb and flow revisited.Br J Intensive Care. 1999; 9: 142-146Google Scholar and are perhaps not critical to an understanding of the actual changes which occur.Table 1Systemic responses to surgerySympathetic nervous system activationEndocrine ‘stress response’ pituitary hormone secretion insulin resistanceImmunological and haematological changes cytokine production acute phase reaction neutrophil leucocytosis lymphocyte proliferation Open table in a new tab After the early work on the stress response to accidental injury, attention turned to surgical trauma, and responses to most types of surgery were reported. Following on from this, the ability of anaesthetic agents and neural blockade to modify the endocrine and metabolic responses has been studied enthusiastically. Although it seems that the stress response developed to allow injured animals to survive by catabolizing their own stored body fuels, it has been argued 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, the potential benefits of regional anaesthesia on surgical outcome are still under scrutiny. Over the past 10 yr, the role of cytokines in the response to surgery, and the interaction between the immunological and neuroendocrine systems, has furthered interest in the subject. This review describes the endocrine and metabolic changes which occur during surgery, and the effects of anaesthetic and analgesic regimens upon the responses. The stress response to surgery is characterized by increased secretion of pituitary hormones and activation of the sympathetic nervous system.13Desborough JP Hall GM Endocrine response to surgery.in: Kaufman L Anaesthesia Review. Vol. 10. Churchill Livingstone, Edinburgh1993: 131-148Google Scholar The changes in pituitary secretion have secondary effects on hormone secretion from target organs (Table 2). For example, release of corticotrophin from the pituitary stimulates cortisol secretion from the adrenal cortex. Arginine vasopressin is secreted from the posterior pituitary and has effects on the kidney. In the pancreas, glucagon is released and insulin secretion may be diminished. The overall metabolic effect of the hormonal changes is increased catabolism which mobilizes substrates to provide energy sources, and a mechanism to retain salt and water and maintain fluid volume and cardiovascular homeostasis.Table 2Principal hormonal responses to surgery. ACTH, adreno-corticotrophic hormone (corticotrophin); AVP, arginine vasopressin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Based on Desborough and Hall13Endocrine glandHormonesChange in secretionAnterior pituitaryACTHIncreasesGrowth hormoneIncreasesTSHMay increase or decreaseFSH and LHMay increase or decreasePosterior pituitaryAVPIncreasesAdrenal cortexCortisolIncreasesAldosteroneIncreasesPancreasInsulinOften decreasesGlucagonUsually small increasesThyroidThyroxine, tri-iodothyronineDecrease Open table in a new tab Hypothalamic activation of the sympathetic autonomic nervous system results in increased secretion of catecholamines from the adrenal medulla and release of norepinephrine from presynaptic nerve terminals. Norepinephrine is primarily a neurotransmitter, but there is some spillover of norepinephrine released from nerve terminals into the circulation. The increased sympathetic activity results in the well recognized cardiovascular effects of tachycardia and hypertension. In addition, the function of certain visceral organs, including the liver, pancreas and kidney, is modified directly by efferent sympathetic stimulation and/or circulating catecholamines. Anterior pituitary hormone secretion is stimulated by hypothalamic releasing factors.32Lyons FM Meeran K The physiology of the endocrine system.Int Anesthesiol Clin. 1997; 35: 1-21Crossref PubMed Scopus (12) Google Scholar The pituitary synthesizes corticotrophin or adrenocorticotrophic hormone (ACTH) as part of a larger precursor molecule, pro-opiomelanocortin. The precursor is metabolized within the pituitary into ACTH, β-endorphin and an N-terminal precursor. Growth hormone and prolactin are also secreted in increased amounts from the pituitary in response to a surgical stimulus. Concentrations of the other anterior pituitary hormones, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) do not change markedly during surgery. The posterior pituitary produces arginine vasopressin which has a major role as an antidiuretic hormone. It also has an endocrine function, acting with corticotrophin-releasing factor in stimulating the secretion of pro-opiomelanocortin from the anterior pituitary. Corticotrophin (ACTH) is a 39 amino acid peptide, produced in the pituitary from the larger molecule, pro-opiomelanocortin. ACTH stimulates the adrenal cortical secretion of glucocorticoids so that circulating concentrations of cortisol are increased. Surgery is one of the most potent activators of ACTH and cortisol secretion, and increased plasma concentrations of both hormones can be measured within minutes of the start of surgery. Growth hormone is a protein of 191 amino acids secreted from the anterior pituitary.13Desborough JP Hall GM Endocrine response to surgery.in: Kaufman L Anaesthesia Review. Vol. 10. Churchill Livingstone, Edinburgh1993: 131-148Google Scholar Its release is stimulated by growth hormone releasing factor from the hypothalamus. Growth hormone, also known as somatotrophin, has a major role in growth regulation, particularly in the perinatal period and in childhood. Many of its actions are mediated through small protein hormones called insulin-like growth factors (IGFs), notably IGF-1, which is produced in liver, muscle and other tissues in response to stimulation by growth hormone. In addition to the regulation of growth, growth hormone has many effects on metabolism. It stimulates protein synthesis and inhibits protein breakdown, promotes lipolysis (the breakdown of triglycerides into fatty acids and glycerol) and has an anti-insulin effect. This means that growth hormone inhibits glucose uptake and use by cells, which spares glucose for use by neurones in situations of glucose scarcity. Growth hormone may also stimulate 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. β-Endorphin is an opioid peptide of 31 amino acids produced from the precursor molecule proopiomelanocortin. Increased β-endorphin concentrations in the circulation after surgery reflect increased pituitary hormone secretion. The hormone has no major metabolic activity. Prolactin is a protein hormone of 199 amino acids with a structure similar to that of growth hormone. Secretion of prolactin is increased as part of the stress reponse to surgery and also during exercise. It has little metabolic activity. Prolactin production increases during pregnancy and stimulates milk secretion from the breast. Cortisol secretion from the adrenal cortex increases rapidly following the start of surgery, as a result of stimulation by ACTH. From baseline values of around 400 nmol litre−1, 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.38Nicholson G Hall GM Burrin JM Peri-operative steroid supplementation.Anaesthesia. 1998; 53: 1091-1094Crossref PubMed Scopus (133) Google Scholar The cortisol response can be modified by anaesthetic intervention (see below). Usually, a feedback mechanism operates so that increased concentrations of circulating cortisol inhibit further secretion of ACTH. This control mechanism appears to be ineffective after surgery so that concentrations of both hormones remain high. Cortisol has complex metabolic effects on carbohydrate, fat and protein. It promotes protein breakdown and gluconeogenesis in the liver. Glucose use by cells is inhibited, so that blood glucose concentrations are increased. Cortisol promotes lipolysis, which increases the production of gluconeogenic precursors from the breakdown of triglyceride into glycerol and fatty acids. Cortisol has other glucocorticoid effects, notably those associated with anti-inflammatory activity. Corticosteroids inhibit the accumulation of macrophages and neutrophils into areas of inflammation and can interfere with the synthesis of inflammatory mediators, particularly prostaglandins. Insulin is the key anabolic hormone.13Desborough JP Hall GM Endocrine response to surgery.in: Kaufman L Anaesthesia Review. Vol. 10. Churchill Livingstone, Edinburgh1993: 131-148Google Scholar It is a polypeptide with two chains (of 21 and 30 amino acids) linked by two disulphide bridges. Insulin is synthesized and secreted by the β cells of the pancreas. It is released after food intake, when blood glucose and amino acid concentrations increase. Insulin promotes the uptake of glucose into muscle and adipose tissue and the conversion of glucose into glycogen and triglycerides. It also stimulates the formation of glycogen from glucose in the liver. Protein catabolism and lipolysis are inhibited by insulin. Insulin concentrations may decrease after the induction of anaesthesia, and during surgery there is a failure of insulin secretion to match the catabolic, hyperglycaemic response. This may be caused partly by α-adrenergic inhibition of β cell secretion. In addition, there is a failure of the usual cellular response to insulin, the so-called ‘insulin resistance’, which occurs in the perioperative period. Glucagon is produced in the α cells of the pancreas. This hormone promotes hepatic glycogenolysis. It also increases gluconeogenesis from amino acids in the liver and has lipolytic activity. Although plasma glucagon concentrations increase transiently after major surgery, this does not make a major contribution to the hyperglycaemic response. Thyroxine (T4) and tri-iodothyronine (T3) are secreted into the circulation from the thyroid gland under the influence of thyroid-stimulating hormone (TSH). Small amounts of inactive, reverse T3 (rT3) are produced from the thyroid. T3 is formed in the tissues by the monodeiodination of T4. T3 is three to five times more active metabolically than T4. The hormones are bound extensively to their binding proteins, albumin, thyroxine-binding pre-albumin and thyroid-binding globulin (TBG). The free thyroid hormones in the plasma are metabolically active. Very low concentrations of free T3 and T4 are present in the circulation and are in equilibrium with bound hormone in the plasma and the tissues.15Edwards R Thyroid and parathyroid disease.Int Anesthesiol Clin. 1997; 35: 63-83Crossref PubMed Scopus (8) Google Scholar Thyroid hormones stimulate the oxygen consumption of most of the metabolically active tissues of the body. Notable exceptions are the brain, spleen and the anterior part of the pituitary gland. As a result of thyroid hormone activity, metabolic rate and heat production is increased. The other principal actions of thyroid hormones are to increase carbohydrate absorption from the gut, to stimulate both the central and peripheral nervous systems and, in the longer term, to influence growth and development. There is a close association between the activity of thyroid hormones and the catecholamines. In general terms, epinephrine and norepinephrine increase the metabolic rate and stimulate the nervous system. The thyroid hormones increase the number and affininty of β-adrenoceptors in the heart and, ultimately, increase the sensitivity of the heart to the actions of catecholamines. Concentrations of total and free T3 decrease after surgery and return to normal after several days. TSH concentrations decrease during the first 2 h and then return to preoperative levels. The reason for the changes remains unclear, but may be influenced by the close relationship between thyroid hormones, catecholamines and cortisol. Exogenous steroids suppress T3, so hypercortisolaemia after surgery may also depress T3 concentrations.11Desborough JP Physiological responses to surgery and trauma.in: Hemmings Jr, HC Hopkins PM Foundations of Anaesthesia. Mosby, London1999: 713-720Google Scholar The gondotrophins, LH and FSH, are secreted from the anterior pituitary. FSH is responsible for the development of ovarian follicles in females. In males, FSH maintains the spermatic epithelium. LH stimulates growth and development of the Leydig cells of the testis which produce testosterone. In females, LH promotes maturation of the ovarian follicles and the secretion of oestrogen. It also stimulates the formation of the corpus luteum from the follicles after ovulation. Testosterone is a steroid manufactured from cholesterol in the Leydig cells of the testis. It has a negative feedback 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 significance of changes in pituitary gonadotrophins following surgery requires further study. Testosterone concentrations are decreased for several days, while LH concentrations show variable changes.51Woolf PD Hamill RW McDonald JV et al.Transient hypogonadotrophic hypogonadism caused by ctitical illness.J Clin Endocrinol Metab. 1985; 60: 444-450Crossref PubMed Scopus (278) Google Scholar In female subjects, oestradiol concentrations decrease for up to 5 days postoperatively.50Wang C Chan V Yeung RT Effects of surgical stress on pituitary testicular function.Clin Endocrinol. 1978; 9: 255-266Crossref PubMed Scopus (92) Google Scholar The net effect of the endocrine response to surgery is an increased secretion of catabolic hormones. This promotes the provision of food substrates from the catabolism of carbohydrate, fat and protein. In evolutionary terms, it seems likely that the stress response developed as a survival mechanism which allowed injured animals to sustain themselves until their injuries were healed. By using stored body fuels and retaining salt and water, the animal had a chance to survive without food until healing and repair had taken place. In current surgical and anaesthetic practice, it is questionable whether the stress response is necessary. Blood glucose concentrations increase after surgery begins. Cortisol and catecholamines facilitate glucose production as a result of increased hepatic glycogenolysis and gluconeogenesis. In addition, peripheral use of glucose is decreased. Blood glucose concentrations are related to the intensity of the surgical injury; the changes follow closely the increases in catecholamines. In cardiac surgery, blood glucose concentrations can increase up to 10–12 mmol litre−1 and remain elevated for >24 h after surgery. The changes are less marked with minor surgery. The usual mechanisms that maintain glucose homeostasis are ineffective in the perioperative period. Hyperglycaemia persists because catabolic hormones promote glucose production and there is a relative lack of insulin together with peripheral insulin resistance. In diabetic subjects it is now established that poor glycaemic control is associated with an increase in diabetic complications, which can be avoided with tight control of blood glucose47UKPDS group Effect of intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risks of complications in patients with type 2 diabetes.Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18982) Google Scholar (see paper by Halls). The risks of prolonged perioperative hyperglycaemia are less well established, although potential risks include wound infection and impaired wound healing. An increased incidence of wound infection and mediastinitis was found in diabetics and non-diabetics in whom blood glucose concentrations were >200 mg dl−1 after cardiac surgery.49Wallace LK Starr NJ Leventhal MJ Estafanous FG Hyperglycaemia on ICU admission after CABG is associated with increased risk of mediastinitis or wound infection.Anesthesiology. 1996; 85: A286Google Scholar Protein catabolism is stimulated by increased cortisol concentrations. Predominantly skeletal muscle is broken down, but some visceral muscle protein is also catabolized 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, fatty acids or ketone bodies. Protein catabolism results in marked weight loss and muscle wasting in patients after major surgical and traumatic injury. The loss of protein can be measured indirectly by increased nitrogen excretion in the urine. There has been much interest in the provision of nutritional supplements for patients with critical illness and those undergoing major surgery. Certain nutrients may have a beneficial influence on the immune status of stressed patients. Glutamine, arginine, glycine, ω-3 polyunsaturated fatty acids and nucleotides have been studied most extensively.44Tepaske R Immunonutrition.Curr Opin Anaesthesiol. 1997; 10: 86-91Crossref Scopus (3) Google Scholar Glutamine and arginine are semi-essential amino acids with multiplicity of functions including stimulation of immune activity. Studies of patients given enteral nutrition supplemented with arginine or glycine after major surgery benefited from a faster recovery of immunological parameters, fewer infectious complications and a shorter hospital stay.44Tepaske R Immunonutrition.Curr Opin Anaesthesiol. 1997; 10: 86-91Crossref Scopus (3) Google Scholar As a result of hormonal changes during surgery, fats stored as triglycerides are converted by lipolysis to glycerol and fatty acids. Lipolytic activity is stimulated by cortisol, catecholamines and growth hormone and is inhibited in the presence of insulin. The net result is increased mobilization of triglyceride, although plasma concentrations of glycerol and fatty acids may not change markedly. The glycerol produced by lipolysis is a substrate for gluconeogenesis in the liver. Fatty acids enter a ‘pool’ from which they may be oxidized in the liver and in muscle, converted to ketone bodies or re-esterified. A number of hormonal changes occur in response to surgery which influence salt and water metabolism. These changes support the preservation of adequate body fluid volumes. Arginine vasopressin, which is released from the posterior pituitary, promotes water retention and the production of concentrated urine by direct action on the kidney. Increased vasopressin secretion may continue for 3–5 days, depending on the severity of the surgical injury and the development of complications. 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 stimulates the release of aldosterone from the adrenal cortex, which in turn leads to Na+ and water reabsorption from the distal tubules in the kidney.11Desborough JP Physiological responses to surgery and trauma.in: Hemmings Jr, HC Hopkins PM Foundations of Anaesthesia. Mosby, London1999: 713-720Google Scholar The endocrine response is activated by afferent neuronal impulses from the site of injury. These travel along sensory nerve roots through the dorsal root of the spinal cord, up the spinal cord to the medulla to activate the hypothalamus. In the 1950s it was postulated that there might be ‘wound hormones’ produced in injured tissues which activated the pituitary–adrenal axis. In classical experiments, Egdahl demonstrated the role of the nervous system in the activation of the stress response.16Egdahl RH Pituitary–adrenal response following trauma to the isolated leg.Surgery. 1959; 6: 9-21Google Scholar He studied the adrenocortical responses to limb injury in dogs with innervated and denervated extremities. Blood samples were collected from the adrenal vein for assay of adrenal corticosteroid concentration. In animals with an intact sciatic nerve, operative injury and burns to the limb resulted in an immediate and sustained increase in adrenal hormone concentration in samples from the adrenal vein. If the nerve was cut after the 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 which stimulated the pituitary–adrenal axis. The idea that local substances might influence some of the changes associated with surgery was advanced by the discovery of the cytokines. Cytokines are a group of low-molecular-weight proteins which include the interleukins and interferons. They are produced from activated leucocytes, fibroblasts and endothelial cells as an early response to tissue injury and have a major role in mediating immunity and inflammation.42Sheeran P Hall GM Cytokines in anaesthesia.Br J Anaesth. 1997; 78: 201-219Crossref PubMed Scopus (191) Google Scholar The cytokines act on surface receptors on many different target cells and their effects are produced ultimately by influencing protein synthesis within these cells. Details of the cytokine network and the activation of cytokines in response to surgery have been reviewed recently.19Helmy SAK Wahby MAM El-Nawaway M The effect of anaesthesia and surgery on plasma cytokine production.Anaesthesia. 1999; 54: 733-738Crossref PubMed Scopus (125) Google Scholar 42Sheeran P Hall GM Cytokines in anaesthesia.Br J Anaesth. 1997; 78: 201-219Crossref PubMed Scopus (191) Google Scholar The effects of chronic stimulation of the cytokine network, for example, in sepsis, has also been reviewed.6Blackwell TS Christman JW Sepsis and cytokines: current status.Br J Anaesth. 1996; 77: 110-117Crossref PubMed Scopus (380) Google Scholar The cytokines have a major role in the inflammatory response to surgery and trauma. They have local effects of mediating and maintaining the inflammatory response to tissue injury, and also initiate some of the systemic changes which occur. After major surgery, the main cytokines released are interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α) and IL-6. The initial reaction is the release of IL-1 and TNF-α from activated macrophages and monocytes in the damaged tissues. This stimulates the production and release of more cytokines, in particular, IL-6, the main cytokine responsible for inducing the systemic changes known as the acute phase response.42Sheeran P Hall GM Cytokines in anaesthesia.Br J Anaesth. 1997; 78: 201-219Crossref PubMed Scopus (191) Google Scholar This is a 26 kDa protein. Concentrations of circulating cytokines are normally low and may be undetectable. Within 30–60 min after the start of surgery, IL-6 concentration increases; the change in concentration becomes significant after 2–4 h. Cytokine production reflects the degree of tissue trauma, so cytokine release is lowest with the least invasive and traumatic procedures, for example, laparoscopic surgery. The largest increases in IL-6 occur after major procedures such as joint replacement, major vascular and colorectal surgery. After these operations, cytokine concentrations are maximal at about 24 h and remain elevated for 48–72 h postoperatively. A number of changes occur following tissue injury which are stimulated by cytokines, particularly IL-6. This is known 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 inflammatory mediators, anti-proteinases and scavengers and in tissue repair. They include C-reactive protein (CRP), fibrinogen, α2-macroglobulin and other anti-proteinases. The increase in serum concentrations of CRP follows the changes in IL-6. Production of other proteins in the liver, for example, albumin and transferrin, decreases during the acute phase response. Concentrations of circulating cations such as zinc and iron decrease, partly as a consequence of the changes in the production of the transport proteins.42Sheeran P Hall GM Cytokines in anaesthesia.Br J Anaesth. 1997; 78: 201-219Crossref PubMed Scopus (191) Google ScholarTable 3Features of the acute phase response. C, C-reactive protein. Based on Sheeran and Hall42FeverGranulocytosisProduction of acute phase proteins in liver CRP fibrinogen α2-macroglobulinChanges in serum concentrations of transport proteins increase in ceruloplasmin decrease in transferrin, albumin and α2-macroglobulinChanges in serum concentrations of divalent cations copper increases zinc and iron decrease Open table in a new tab The cytokines IL-1and IL-6 can stimulate secretion of ACTH from isolated pituitary cells in vitro. In patients after surgery, cytokines may augment pituitary ACTH secretion and subsequently increase the release of cortisol. A negative feedback system exists, so that glucocorticoids inhibit cytokine production. The cortisol response to surgery is sufficient to depress IL-6 concentrations.20Jameson P Desborough JP Bryant AE Hall GM The effect of cortisol suppression on the interleukin-6 and white cell responses to surgery.Acta Anaesthesiol Scand. 1997; 40: 123-126Google Scholar Laparoscopic surgery causes less tissue injury than conventional procedures, so the increase in concentrations of biochemical markers of inflammation, such as IL-6 and the acute phase protein, CRP, is not as great.21Kehlet H Multimodal approach to control postoperative pathophysiology and rehabilitation.Br J Anaesth. 1997; 78: 606-617Crossref PubMed Scopus (1794) Google Scholar The classical stress responses (catecholamines, cortisol and glucose) to abdominal surgery such as cholecystectomy, are not changed greatly by reducing surgical trauma. This suggests that stimuli for the stress response arise from visceral and peritoneal afferent nerve fibres in addition to those from the abdominal wall. Anaesthesia has little effect on the cytokine response to surgery because it cannot influence tissue trauma. Although regional anaesthesia inhibits the stress response to surgery, it has no significant effect on cytokine production. Combined analgesic regimens which included high-dose steroids showed a small decline in IL-6 concentrations and the acute phase response because of the interaction of glucocorticoids and cytokines.41Schulze S Sommer P Bigler D et al.Effect of combined prednisolone, epidural analgesia, and indomethacin on the systemic response to surgery.Arch Surg. 1992; 127: 325-331Crossref PubMed Scopus (88) Google Scholar The technique was accompanied by unwanted side-effects, including wound breakdown. It has been known for many years that opioids suppress hypothalamic and pituitary hormone secretion. McDonald and colleagues demonstrated the suppressant effect of therapeutic doses of morphine on the hypothalamic– pituitary–adrenal axis in humans.33McDonald RK Evans FT Weise VK et al.Effect of morphine and nalorphine on plasma hydrocortisone levels in man.J Pharmacol Exp Ther. 1959; 125: 241-247PubMed Google Scholar Morphine suppressed the release of corticotrophin and, consequently, cortisol in normal and stress conditions, although the adrenals were found to respond to exogenous administration of ACTH. The inhibitory effects of morphine occur at the hypothalamic level. In cardiac surgery, the effects of morphine and other opioids on the stress response to surgery have been well documented.12Desborough JP Hall GM Modification of the hormonal and metabolic response to surgery by narcotics and general anaesthesia.Clin Anaesthesiol. 1989; 3: 317-334Scopus (25) Google Scholar Large doses of morphine (4 mg kg−1) block the secretion of growth hormone and inhibit cortisol release until the onset of cardiopulmonary bypass (CPB). Fentanyl (50–100 μg kg−1), sufentanil (20 μg kg−1) and alfentanil (1.4 mg kg−1) suppress pituitary hormone secretion until CPB.12Desborough JP Hall GM Modification of the hormonal and metabolic response to surgery by narcotics and general anaesthesia.Clin Anaesthesiol. 1989; 3: 317-334Scopus (25) Google Scholar After the onset of CPB, the physiological changes are so profound that the hypothalamic and pituitary responses cannot be completely inhibited by opi