British Journal of Anaesthesia 85 (1): 109±17 (2000) The stress response to trauma and surgery J. P. Desborough Department of Anaesthesia, Epsom General Hospital, Dorking Road, Epsom KT18 7EG, UK Br J Anaesth 2000; 85: 109±17 Keywords: surgery; hormones, cortisol; sympathetic nervous system, catecholamines; anaesthetic techniques, epidural 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 Endocrine gland Hormones Change in secretion Table 1 Systemic responses to surgery Anterior pituitary ACTH Increases Sympathetic nervous system activation Growth hormone Increases Endocrine `stress response' TSH May increase or decrease pituitary hormone secretion FSH and LH May increase or decrease insulin resistance Posterior pituitary AVP Increases Immunological and haematological changes Adrenal cortex Cortisol Increases cytokine production Aldosterone Increases acute phase reaction Pancreas Insulin Often decreases neutrophil leucocytosis Glucagon Usually small increases lymphocyte proliferation Thyroid Thyroxine, tri-iodothyronine Decrease Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000 Desborough Sympathoadrenal response 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 or circulating catecholamines. 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 and prolactin Anterior pituitary b-Endorphin is an opioid peptide of 31 amino acids Anterior pituitary hormone secretion is stimulated by produced from the precursor molecule proopiomelanocor- 32 hypothalamic releasing factors. 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. Cortisol Posterior pituitary 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 ±1 endocrine function, acting with corticotrophin-releasing ACTH. From baseline values of around 400 nmol litre , factor in stimulating the secretion of pro-opiomelanocortin cortisol concentrations increase to a maximum at about ±1 from the anterior pituitary. 4±6 h, and may reach >1500 nmol litre depending on the severity of the surgical trauma.38 The cortisol response can be modi®ed by anaesthetic intervention (see below). Corticotrophin 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- Growth hormone 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. 110 Stress response to trauma and surgery Insulin and glucagon heart and, ultimately, increase the sensitivity of the