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Hypothalamic–pituitary–adrenal function: anaesthetic implications
PHARMACOLOGY
Hypothalamicepituitarye adrenal function: anaesthetic implications
Learning objectives After reading this article you should understand the: C hormonal aspects of the stress response to trauma or surgery C inflammatory response to injury and how this is related to the hormonal response C role of anaesthetic agents and techniques in modifying this response C role of steroid supplementation in critical illness
Grainne Nicholson George M Hall
Abstract Surgery, trauma and critical illness evoke a series of hormonal and metabolic changes commonly referred to as the stress response. Activation of the hypothalamicepituitaryeadrenal axis results in increased secretion of hormones such as cortisol. Anaesthesia can suppress adrenocortical secretion either by an effect at the hypothalamus, for example by a decrease in neural input with regional anaesthesia, or by a direct effect on the adrenal cortex, for example by etomidate. For patients undergoing routine surgery an increase in cortisol secretion is unnecessary, uneventful recovery occurs in the presence of circulating cortisol concentrations within the normal range. Patients often present for surgery taking corticosteroids for a variety of medical conditions, but excessive supplementation with hydrocortisone is unnecessary, and can cause side effects. The use of steroids in critically ill patients remains contentious. Furthermore, the immune system and neuroendocrine system are closely related and the metabolic response to surgery involves both hormonal and inflammatory processes. Attempts have also been made to obtund the perioperative inflammatory response.
pituitary to inhibit release of CRF and ACTH, respectively, so restoring circulating cortisol levels to normal physiological values. These feedback control mechanisms fail in surgery, trauma and critical illness, resulting in abnormal endocrine function. The hypothalamus is part of the anterior diencephalon and contributes to the floor and lateral wall of the third ventricle (Figure 1). There are vascular connections between the hypothalamus and the anterior lobe of the pituitary, the portal hypophysial vessels, whereas the posterior pituitary is linked to the hypothalamus by neural connections, the hypothalamohypophysial tract, arising from cell bodies in the supraoptic and paraventricular nuclei. The key difference between the anterior and posterior pituitary results from their embryological origins. The anterior pituitary is derived from Rathke’s pouch, an evagination from the roof of the pharynx, while the posterior lobe arises from an evagination of the third ventricle. Other than neuroendocrine control, the hypothalamus has important functions in temperature regulation, appetite control and sexual behaviour. The anterior pituitary secretes six hormones in response to releasing factors secreted into the hypophysial vessels in the hypothalamus: adrenocorticotropic hormone growth hormone (GH) prolactin (PRL) thyroid-stimulating hormone (TSH) luteinizing stimulating hormone (LSH) follicle-stimulating hormone (FSH). The posterior pituitary secretes arginine vasopressin (AVP) and oxytocin. The stress response to surgery or injury is a combination of not just hormonal, but also inflammatory changes. The systemic inflammatory response is mediated primarily by cytokines synthesized at the site of injury. Cytokines are low molecular weight (<80 kDa), heterogeneous glycoproteins, which include interleukins, interferons and tumour necrosis factor. They are synthesized by activated macrophages, fibroblasts, endothelial and glial cells in response to tissue injury from surgery or trauma. Cytokines are present locally at high concentrations when they isolate and destroy infective organisms, prevent further tissue damage and activate wound healing. Some inflammatory mediators are released into the circulation, particularly interleukin (IL)-6, and act on distant organs to stimulate the acute-phase response. This response is characterized by acute-phase protein synthesis in the liver, neutrophil mobilization from the bone marrow,
Keywords Cortisol; cytokines; etomidate; sepsis; surgery Royal College of Anaesthetists CPD matrix: 1A02
Surgery evokes a series of hormonal and metabolic changes commonly referred to as the stress response. Afferent neuronal input, both somatic and autonomic from the surgical site, activates the hypothalamicepituitary axis and the sympathetic nervous system. In addition to a marked increase in catabolic hormone secretion there is suppression of the important anabolic hormones insulin and testosterone. The hypothalamicepituitary axis is the major neuroendocrine organ of the body. Regulation of hormone secretion is undertaken by feedback loops, both positive and negative. A typical pathway involves secretion of a releasing factor from the hypothalamus, such as a corticotrophinreleasing factor or hormone (CRF or CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH) into the circulation. In turn, this acts on the target organ, the adrenal cortex, to secrete cortisol. An increase in the circulating concentration of cortisol acts on the hypothalamus and
Grainne Nicholson MD FFARCSI is a Senior Lecturer and Honorary Consultant at St George’s Hospital, University of London, UK. Conflicts of interest: none declared. George M Hall FRCA PhD is Professor of Anaesthesia at St George’s Hospital, University of London, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
473
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
precursor molecule, pro-opiomelanocortin (POMC) which undergoes considerable post-translational processing. The main stimulus to ACTH secretion is corticotrophin-releasing hormone (CRH), a 41-amino acid-peptide produced in the hypothalamus and secreted into the hypophyseal portal system. Arginine vasopressin (AVP) also plays an important role in the control of ACTH secretion during stress, by directly stimulating the release of ACTH and acting synergistically with CRH, as well as regulating pituitary CRH receptor expression. ACTH acts on the adrenal gland through a specific cell surface receptor, a member of the G-protein-coupled receptor family to stimulate cortisol secretion. Normally feedback inhibition by cortisol then prevents any further increases in CRH or ACTH production. Cortisol is a C21 corticosteroid with both glucocorticoid and mineralocorticoid activity. Endogenous cortisol production is between 25 and 30 mg per day, circulating concentrations vary in a circadian pattern and the half-life of cortisol in the circulation is between 60 and 90 minutes. Plasma cortisol concentrations increase rapidly in response to surgical stimulation and remain elevated for a variable time following surgery. Peak values are achieved within 4e6 hours after surgery or injury and return towards baseline after 24 hours; this increase in plasma cortisol may, however, be sustained for up to 48e72 hours following major surgery, such as cardiac surgery. The amount of cortisol secreted following major surgery, such as abdominal or thoracic surgery, is between 75 and 100 mg on the first day. Minor surgery, such as herniorrhaphy, induces less than 50 mg cortisol secretion during the first 24 hours. Increased cortisol production is secondary to ACTH secretion, but the plasma ACTH concentration is far greater than that required to produce a maximal adrenocortical response. Furthermore, the normal pituitary adrenocortical feedback mechanism is no longer effective, as both hormones remain increased simultaneously. Cortisol has complex effects on intermediate metabolism of carbohydrate, fat and protein. It causes an increase in blood glucose concentrations by stimulating protein catabolism and promoting glucose production in the liver by gluconeogenesis. Cortisol reduces peripheral glucose utilisation by an anti-insulin effect. Glucocorticoids inhibit the recruitment of neutrophils and monocyte-macrophages into the area of inflammation and also have well-described anti-inflammatory actions, mediated by a decrease in the production of inflammatory mediators such as leukotrienes and prostaglandins. In addition there is immunoregulatory feedback between the glucocorticoid hormones and IL-6; the production and action of IL-6 is inhibited by ACTH and cortisol. Activation of the hypothalamicepituitaryeadrenal axis in response to surgery may be modified by anaesthesia. Regional anaesthesia can prevent an increase in ACTH and cortisol secretion but only if autonomic afferent fibre activity is blocked as well as somatic afferent fibre activity. There are a limited number of operative sites at which this can be achieved: pelvis, limb and eye. For pelvic surgery an extensive afferent blockade from dermatomes T4 to S5 is necessary to prevent pituitary hormone secretion. This upper dermatomal limit is often higher than required for surgery, but is essential if sympathetic afferent blockade is to be achieved. It is presumed that complete afferent blockade of the surgical site markedly decreases the neural input to the hypothalamus.
Negative feedback control of the hypothalamic–pituitary axis Hypothalamus
Negative feedback
Releasing factor Anterior pituitary Posterior pituitary Stimulatory hormone
Negative feedback
Stimulatory hormone released into systemic circulation
Target gland
Active hormone Negative feedback Target tissue
Figure 1
immunosuppression from altered T-lymphocyte differentiation, increased body temperature by affecting hypothalamic control and adrenocorticotrophic hormone secretion from the anterior pituitary. These widespread changes are usually considered essential for recovery from injury, although some aspects of the acute-phase response are potentially detrimental. For example, the increased synthesis of fibrinogen in the liver, peaking several days after injury, increases the risk of thromboembolism and is accompanied by a decrease in albumin synthesis. The immune and the neuroendocrine systems are closely interconnected. Interleukin-1 and IL-6 have been shown to stimulate secretion from isolated pituitary cells. In surgical patients, circulating cytokines may augment pituitary ACTH secretion and consequently increase the release of cortisol sustaining the glucocorticoid response to injury for several days. A negative feedback system exists whereby glucocorticoids decrease cytokine production by inhibiting gene expression. Thus, the cortisol response to surgery limits the severity of the inflammatory response. It has been suggested that increased intracerebral IL-6 results in the enhanced cortisol secretion found after cerebral haemorrhage.
Effects of surgery and anaesthesia The onset of surgery is associated with the rapid secretion of hormones derived from the anterior and posterior pituitary gland. Adrenocorticotropic hormone (ACTH) is secreted by corticotroph cells in the anterior lobe of the pituitary gland. ACTH contains 39 amino acids and is synthesized as part of a large
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
474
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
The release of CRH in the hypothalamus is influenced by a variety of neurotransmitters. It is not surprising, therefore, that several anaesthetic drugs have been shown to inhibit ACTH release during surgery. Large doses of m-opioid analgesics have been shown repeatedly to block the ACTH/cortisol response to surgery, but only at the expense of postoperative respiratory depression. Similarly, large doses of midazolam have been found to partially inhibit ACTH secretion, presumably as a consequence of activating g-aminobutyric acid (GABA) receptors in the hypothalamus. Although this is unlikely to be relevant clinically when midazolam is used for short-term sedation, suppression of cortisol will occur if it is infused for several days. The a2 agonist dexmedetomidine has an interesting biphasic effect on hypothalamicepituitary function. It decreases ACTH secretion while stimulating GH release. In addition to the opioid receptors, a2adrenoceptors and GABA receptors, other neurotransmitters that have been shown to be involved in controlling CRH release in animals include acetylcholine and 5-hydroxytryptamine. Etomidate achieved notoriety in the early 1980s when used for prolonged sedation in critically ill patients in intensive care units. Mortality was increased significantly and this was shown to be associated with severe adrenocortical suppression. Subsequently, etomidate was withdrawn in many countries, although it is still available for use as a single-dose induction agent in UK. The mechanism underlying the adrenal suppression has been well described; inhibition of 11b-hydroxylase with a lesser effect on other b-hydroxylases and cholesterol cleavage enzyme (Figure 2). Other commonly administered induction agents such as propofol and thiopentone are approximately 1000 times less potent than etomidate in inhibiting 11b-hydroxylase. Etomidate is an imidazole derivative, and it is this moiety that is responsible for enzyme inhibition. Indeed, etomidate is such a potent inhibitor of adrenal steroidogenesis that it has been used to treat inoperable malignant adrenocortical tumours. A low-dose infusion markedly decreased cortisol secretion with only minimal sedation.
In spite of the profound endocrinological effects of etomidate this compound is still occasionally used for induction of anaesthesia. Because of its safety profile e a 30-fold difference between the anaesthetic dose and the lethal dose e and the minimal depressant effects on the cardiovascular system, etomidate is often administered to physiologically unstable patients undergoing elective surgery, for example major vascular surgery. It has been shown repeatedly that a single induction dose of etomidate inhibits cortisol and aldosterone secretion for about 8 hours. Circulating cortisol concentrations are usually in the low enormal range during this time (250e300 nmol/litre). Despite the absence of the typical cortisol response to surgery these patients show no increase in mortality or major morbidity. The inference, therefore, is that for patients undergoing routine elective surgery, cortisol is necessary only in normal concentrations at least intraoperatively and for the first hours after surgery.
Inflammatory changes It is well known that the severity of injury correlates with the magnitude of the inflammatory changes. Endoscopic surgical techniques cause a much lower stress response than open techniques and are associated with improved outcomes in terms of less pain, less morbidity and shorter hospital stays. However, concerns had been expressed about its suitability for the treatment of malignant disease, particularly because of port-site recurrences when used in the treatment of colorectal cancer. These fears have not been realised and laparoscopic resection of rectosigmoid carcinoma actually improves survival and disease control of patients. The mechanism for this is unknown but it has been suggested that better immune function and reduced tumour manipulation may both contribute. There is, however, considerable inter-individual variability in terms of the inflammatory response. In vitro research indicates this may be genetic in origin, with some individuals being more prone
Inhibitors of aldosterone production Mineralocorticoid pathway ACTH +
Glucocorticoid pathway
Androgen pathway
17 -Hydroxypregnenolone
Dehydroepiandrosterone
17 -Hydroxylase
Pregnenolone
Cholesterol Angiotensin II +
Trilostane –
3 -Dehydrogenase
3 -Dehydrogenase
Progesterone
17 -Hydroxylase
17 -Hydroxyprogesterone
Etomidate –
Corticosterone Angiotensin II +
17 -Hydroxylase
11 -Hydroxylase 17 -Hydroxylase
Androstenedione
21 -Hydroxylase
21 -Hydroxylase 11-Deoxycorticosterone
3 Dehydrogenase
11-Deoxycortisol
Etomidate –
11 -Hydroxylase
Hydrocortisone (cortisol)
18-Hydroxylase
Aldosterone Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
475
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
surgical patients taking glucocorticoids is now well established. In critically ill patients in the intensive care unit the appropriateness of the observed cortisol changes is unclear. Plasma cortisol values tend to be increased in the early stages of critical illness and correlate with the severity of other physiological scoring systems and hence predict outcome. However, there is much confusion about the magnitude of the cortisol response necessary to maintain normal cardiovascular function in such patients. Attempts have been made to assess adrenocortical function by the short synacthen test, but interpretation of the results has been difficult. There have been disputes about whether to use an absolute threshold value after ACTH, such as 550 nmol/litre cortisol, or to use an incremental increase. The problem with the latter approach is that the size of the increment is inversely related to the magnitude of the concentration of cortisol before ACTH. It is not surprising that attempts to assess adrenocortical function in patients in intensive care units have proved difficult. Nevertheless, there may be a group of patients who have adrenocortical insufficiency and in whom outcome may be improved by the administration of hydrocortisone. Glucocorticoids have a key role in maintaining the responsiveness of the vasculature to catecholamines so that adrenocortical insufficiency may result in the failure to respond to infusions of adrenergic drugs. Steroids have been given to critically ill patients for several decades, particularly those with sepsis, and enthusiasm for this approach has waxed and waned. Recommendations produced by the Surviving Sepsis Campaign in 2004 stated that patients with septic shock who, despite adequate fluid replacement, required inotropes to maintain blood pressure should be given a ‘low-dose’ daily replacement with 200e300 mg hydrocortisone. The study followed up more than 15,000 patients and in 2010 reported that compliance with the entire ‘management bundle’ was associated with reduced mortality rates. Since steroid supplementation was only one factor, it is likely that there will continue to be confusion about the role of hydrocortisone in critically ill patients until the pathophysiological changes in hypothalamicepituitaryeadrenal function have been elucidated. A
than others to be ‘pro-inflammatory’. Clinical work suggests that such individuals may be at more risk of perioperative complications. Pharmacological manoeuvres to reduce the inflammatory response include the use of glucocorticoids, volatile anaesthetics and regional anaesthesia, but no single agent has been shown to be effective. Moreover, neuraxial blockade has been shown to be more effective when clonidine and dexmedetomidine are added to the local anaesthetic, suggesting that central sympathetic pathways have a role in modifying the systemic inflammatory response. Neuraxial blockade with local anaesthetics alone has little effect on the inflammatory response. Intravenous lignocaine has an anti-inflammatory effect, but only after abdominal surgery. Future work will focus on cytokine receptor antagonists, to limit local inflammation following surgery or trauma.
Therapeutic use of steroids and anaesthesia Corticosteroids are used widely in medicine, and after prolonged administration there is failure of endogenous cortisol secretion as a result of the negative feedback on ACTH and CRH. It is now at least half a century since the notion was introduced that patients taking steroids needed large doses of steroid cover to survive surgery. This practice, however, is illogical and unnecessary. There are two principal arguments against the administration of large doses of steroids perioperatively. First, work with etomidate has shown that only normal circulating values of cortisol and aldosterone are necessary for routine surgery. Furthermore, primate studies have confirmed that the normal daily cortisol output, 25 mg/day in man, is sufficient for major upper abdominal surgery. Second, even if the anaesthetist wished to mimic the usual cortisol response to surgery, the total secretion in the first 24 hours after surgery rarely exceeds 100 mg. Thus, the current recommendations for steroid cover are based on these underlying physiological principles. The key points to note are that if the patient is taking less than 10 mg prednisolone/ day (or an equivalent dose of another steroid) then additional hydrocortisone is unnecessary; if the patient has not taken steroids in the past 3 months again hydrocortisone is not required perioperatively; and if high-dose steroids are being given for immunosuppression then these must be maintained perioperatively. Old regimens of 200e300 mg/day of hydrocortisone are of historical interest only. Patients with Addison’s disease, on low maintenance doses of steroids, will have no response to surgery and will need appropriate supplementation, which may include fludrocortisone. The excessive administration of steroids perioperatively is associated with the following complications: hypertension from fluid retention, hyperglycaemia, immunosuppression, failure of wound healing, gastric erosions and psychological disturbances. Perioperative hypotension in a patient taking steroids is not uncommon. It has been shown that this is only rarely associated with low circulating cortisol values and is commonly the result of hypovolaemia. If hypotension persists after fluid administration then 25 mg intravenous hydrocortisone may be given. Ideally, a blood sample should be taken for cortisol estimation before the hydrocortisone bolus so that suspected steroid deficiency can be confirmed or refuted.
FURTHER READING Dellinger RP, Carelet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and shock. Crit Care Med 2004; 32: 858e73. Gibbison B, Angelini GD, Lightman SL. Dynamic output and control of the hypothalamic-pituitary-adrenal axis in critical illness and major surgery. Br J Anaesth 2013; 111: 347e60. Kennedy BC, Hall GM. Neuroendocrine and inflammatory aspects of surgery; do they affect outcome? Acta Anaesthesiol Belg 1999; 50: 205e9. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010; 38: 683e4. Nicholson G. The hormonal and metabolic responses to trauma. Anaesth Intensive Care Med 2005; 6: 313e4. Nicholson G, Hall GM. Effects of anaesthesia on the inflammatory response to injury. Curr Opin Anesthesiol 2011; 24: 370e4. Nicholson G, Burrin JM, Hall GM. Peri-operative steroid supplementation. Anaesthesia 1998; 53: 1091e104.
Steroids and the critically ill The ACTH/cortisol response to elective surgery has been well defined and the rationale for hydrocortisone supplementation in
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
476
Ó 2014 Elsevier Ltd. All rights reserved.
Hypothalamicepituitarye adrenal function: anaesthetic implications
Learning objectives After reading this article you should understand the: C hormonal aspects of the stress response to trauma or surgery C inflammatory response to injury and how this is related to the hormonal response C role of anaesthetic agents and techniques in modifying this response C role of steroid supplementation in critical illness
Grainne Nicholson George M Hall
Abstract Surgery, trauma and critical illness evoke a series of hormonal and metabolic changes commonly referred to as the stress response. Activation of the hypothalamicepituitaryeadrenal axis results in increased secretion of hormones such as cortisol. Anaesthesia can suppress adrenocortical secretion either by an effect at the hypothalamus, for example by a decrease in neural input with regional anaesthesia, or by a direct effect on the adrenal cortex, for example by etomidate. For patients undergoing routine surgery an increase in cortisol secretion is unnecessary, uneventful recovery occurs in the presence of circulating cortisol concentrations within the normal range. Patients often present for surgery taking corticosteroids for a variety of medical conditions, but excessive supplementation with hydrocortisone is unnecessary, and can cause side effects. The use of steroids in critically ill patients remains contentious. Furthermore, the immune system and neuroendocrine system are closely related and the metabolic response to surgery involves both hormonal and inflammatory processes. Attempts have also been made to obtund the perioperative inflammatory response.
pituitary to inhibit release of CRF and ACTH, respectively, so restoring circulating cortisol levels to normal physiological values. These feedback control mechanisms fail in surgery, trauma and critical illness, resulting in abnormal endocrine function. The hypothalamus is part of the anterior diencephalon and contributes to the floor and lateral wall of the third ventricle (Figure 1). There are vascular connections between the hypothalamus and the anterior lobe of the pituitary, the portal hypophysial vessels, whereas the posterior pituitary is linked to the hypothalamus by neural connections, the hypothalamohypophysial tract, arising from cell bodies in the supraoptic and paraventricular nuclei. The key difference between the anterior and posterior pituitary results from their embryological origins. The anterior pituitary is derived from Rathke’s pouch, an evagination from the roof of the pharynx, while the posterior lobe arises from an evagination of the third ventricle. Other than neuroendocrine control, the hypothalamus has important functions in temperature regulation, appetite control and sexual behaviour. The anterior pituitary secretes six hormones in response to releasing factors secreted into the hypophysial vessels in the hypothalamus: adrenocorticotropic hormone growth hormone (GH) prolactin (PRL) thyroid-stimulating hormone (TSH) luteinizing stimulating hormone (LSH) follicle-stimulating hormone (FSH). The posterior pituitary secretes arginine vasopressin (AVP) and oxytocin. The stress response to surgery or injury is a combination of not just hormonal, but also inflammatory changes. The systemic inflammatory response is mediated primarily by cytokines synthesized at the site of injury. Cytokines are low molecular weight (<80 kDa), heterogeneous glycoproteins, which include interleukins, interferons and tumour necrosis factor. They are synthesized by activated macrophages, fibroblasts, endothelial and glial cells in response to tissue injury from surgery or trauma. Cytokines are present locally at high concentrations when they isolate and destroy infective organisms, prevent further tissue damage and activate wound healing. Some inflammatory mediators are released into the circulation, particularly interleukin (IL)-6, and act on distant organs to stimulate the acute-phase response. This response is characterized by acute-phase protein synthesis in the liver, neutrophil mobilization from the bone marrow,
Keywords Cortisol; cytokines; etomidate; sepsis; surgery Royal College of Anaesthetists CPD matrix: 1A02
Surgery evokes a series of hormonal and metabolic changes commonly referred to as the stress response. Afferent neuronal input, both somatic and autonomic from the surgical site, activates the hypothalamicepituitary axis and the sympathetic nervous system. In addition to a marked increase in catabolic hormone secretion there is suppression of the important anabolic hormones insulin and testosterone. The hypothalamicepituitary axis is the major neuroendocrine organ of the body. Regulation of hormone secretion is undertaken by feedback loops, both positive and negative. A typical pathway involves secretion of a releasing factor from the hypothalamus, such as a corticotrophinreleasing factor or hormone (CRF or CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH) into the circulation. In turn, this acts on the target organ, the adrenal cortex, to secrete cortisol. An increase in the circulating concentration of cortisol acts on the hypothalamus and
Grainne Nicholson MD FFARCSI is a Senior Lecturer and Honorary Consultant at St George’s Hospital, University of London, UK. Conflicts of interest: none declared. George M Hall FRCA PhD is Professor of Anaesthesia at St George’s Hospital, University of London, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
473
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
precursor molecule, pro-opiomelanocortin (POMC) which undergoes considerable post-translational processing. The main stimulus to ACTH secretion is corticotrophin-releasing hormone (CRH), a 41-amino acid-peptide produced in the hypothalamus and secreted into the hypophyseal portal system. Arginine vasopressin (AVP) also plays an important role in the control of ACTH secretion during stress, by directly stimulating the release of ACTH and acting synergistically with CRH, as well as regulating pituitary CRH receptor expression. ACTH acts on the adrenal gland through a specific cell surface receptor, a member of the G-protein-coupled receptor family to stimulate cortisol secretion. Normally feedback inhibition by cortisol then prevents any further increases in CRH or ACTH production. Cortisol is a C21 corticosteroid with both glucocorticoid and mineralocorticoid activity. Endogenous cortisol production is between 25 and 30 mg per day, circulating concentrations vary in a circadian pattern and the half-life of cortisol in the circulation is between 60 and 90 minutes. Plasma cortisol concentrations increase rapidly in response to surgical stimulation and remain elevated for a variable time following surgery. Peak values are achieved within 4e6 hours after surgery or injury and return towards baseline after 24 hours; this increase in plasma cortisol may, however, be sustained for up to 48e72 hours following major surgery, such as cardiac surgery. The amount of cortisol secreted following major surgery, such as abdominal or thoracic surgery, is between 75 and 100 mg on the first day. Minor surgery, such as herniorrhaphy, induces less than 50 mg cortisol secretion during the first 24 hours. Increased cortisol production is secondary to ACTH secretion, but the plasma ACTH concentration is far greater than that required to produce a maximal adrenocortical response. Furthermore, the normal pituitary adrenocortical feedback mechanism is no longer effective, as both hormones remain increased simultaneously. Cortisol has complex effects on intermediate metabolism of carbohydrate, fat and protein. It causes an increase in blood glucose concentrations by stimulating protein catabolism and promoting glucose production in the liver by gluconeogenesis. Cortisol reduces peripheral glucose utilisation by an anti-insulin effect. Glucocorticoids inhibit the recruitment of neutrophils and monocyte-macrophages into the area of inflammation and also have well-described anti-inflammatory actions, mediated by a decrease in the production of inflammatory mediators such as leukotrienes and prostaglandins. In addition there is immunoregulatory feedback between the glucocorticoid hormones and IL-6; the production and action of IL-6 is inhibited by ACTH and cortisol. Activation of the hypothalamicepituitaryeadrenal axis in response to surgery may be modified by anaesthesia. Regional anaesthesia can prevent an increase in ACTH and cortisol secretion but only if autonomic afferent fibre activity is blocked as well as somatic afferent fibre activity. There are a limited number of operative sites at which this can be achieved: pelvis, limb and eye. For pelvic surgery an extensive afferent blockade from dermatomes T4 to S5 is necessary to prevent pituitary hormone secretion. This upper dermatomal limit is often higher than required for surgery, but is essential if sympathetic afferent blockade is to be achieved. It is presumed that complete afferent blockade of the surgical site markedly decreases the neural input to the hypothalamus.
Negative feedback control of the hypothalamic–pituitary axis Hypothalamus
Negative feedback
Releasing factor Anterior pituitary Posterior pituitary Stimulatory hormone
Negative feedback
Stimulatory hormone released into systemic circulation
Target gland
Active hormone Negative feedback Target tissue
Figure 1
immunosuppression from altered T-lymphocyte differentiation, increased body temperature by affecting hypothalamic control and adrenocorticotrophic hormone secretion from the anterior pituitary. These widespread changes are usually considered essential for recovery from injury, although some aspects of the acute-phase response are potentially detrimental. For example, the increased synthesis of fibrinogen in the liver, peaking several days after injury, increases the risk of thromboembolism and is accompanied by a decrease in albumin synthesis. The immune and the neuroendocrine systems are closely interconnected. Interleukin-1 and IL-6 have been shown to stimulate secretion from isolated pituitary cells. In surgical patients, circulating cytokines may augment pituitary ACTH secretion and consequently increase the release of cortisol sustaining the glucocorticoid response to injury for several days. A negative feedback system exists whereby glucocorticoids decrease cytokine production by inhibiting gene expression. Thus, the cortisol response to surgery limits the severity of the inflammatory response. It has been suggested that increased intracerebral IL-6 results in the enhanced cortisol secretion found after cerebral haemorrhage.
Effects of surgery and anaesthesia The onset of surgery is associated with the rapid secretion of hormones derived from the anterior and posterior pituitary gland. Adrenocorticotropic hormone (ACTH) is secreted by corticotroph cells in the anterior lobe of the pituitary gland. ACTH contains 39 amino acids and is synthesized as part of a large
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
474
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
The release of CRH in the hypothalamus is influenced by a variety of neurotransmitters. It is not surprising, therefore, that several anaesthetic drugs have been shown to inhibit ACTH release during surgery. Large doses of m-opioid analgesics have been shown repeatedly to block the ACTH/cortisol response to surgery, but only at the expense of postoperative respiratory depression. Similarly, large doses of midazolam have been found to partially inhibit ACTH secretion, presumably as a consequence of activating g-aminobutyric acid (GABA) receptors in the hypothalamus. Although this is unlikely to be relevant clinically when midazolam is used for short-term sedation, suppression of cortisol will occur if it is infused for several days. The a2 agonist dexmedetomidine has an interesting biphasic effect on hypothalamicepituitary function. It decreases ACTH secretion while stimulating GH release. In addition to the opioid receptors, a2adrenoceptors and GABA receptors, other neurotransmitters that have been shown to be involved in controlling CRH release in animals include acetylcholine and 5-hydroxytryptamine. Etomidate achieved notoriety in the early 1980s when used for prolonged sedation in critically ill patients in intensive care units. Mortality was increased significantly and this was shown to be associated with severe adrenocortical suppression. Subsequently, etomidate was withdrawn in many countries, although it is still available for use as a single-dose induction agent in UK. The mechanism underlying the adrenal suppression has been well described; inhibition of 11b-hydroxylase with a lesser effect on other b-hydroxylases and cholesterol cleavage enzyme (Figure 2). Other commonly administered induction agents such as propofol and thiopentone are approximately 1000 times less potent than etomidate in inhibiting 11b-hydroxylase. Etomidate is an imidazole derivative, and it is this moiety that is responsible for enzyme inhibition. Indeed, etomidate is such a potent inhibitor of adrenal steroidogenesis that it has been used to treat inoperable malignant adrenocortical tumours. A low-dose infusion markedly decreased cortisol secretion with only minimal sedation.
In spite of the profound endocrinological effects of etomidate this compound is still occasionally used for induction of anaesthesia. Because of its safety profile e a 30-fold difference between the anaesthetic dose and the lethal dose e and the minimal depressant effects on the cardiovascular system, etomidate is often administered to physiologically unstable patients undergoing elective surgery, for example major vascular surgery. It has been shown repeatedly that a single induction dose of etomidate inhibits cortisol and aldosterone secretion for about 8 hours. Circulating cortisol concentrations are usually in the low enormal range during this time (250e300 nmol/litre). Despite the absence of the typical cortisol response to surgery these patients show no increase in mortality or major morbidity. The inference, therefore, is that for patients undergoing routine elective surgery, cortisol is necessary only in normal concentrations at least intraoperatively and for the first hours after surgery.
Inflammatory changes It is well known that the severity of injury correlates with the magnitude of the inflammatory changes. Endoscopic surgical techniques cause a much lower stress response than open techniques and are associated with improved outcomes in terms of less pain, less morbidity and shorter hospital stays. However, concerns had been expressed about its suitability for the treatment of malignant disease, particularly because of port-site recurrences when used in the treatment of colorectal cancer. These fears have not been realised and laparoscopic resection of rectosigmoid carcinoma actually improves survival and disease control of patients. The mechanism for this is unknown but it has been suggested that better immune function and reduced tumour manipulation may both contribute. There is, however, considerable inter-individual variability in terms of the inflammatory response. In vitro research indicates this may be genetic in origin, with some individuals being more prone
Inhibitors of aldosterone production Mineralocorticoid pathway ACTH +
Glucocorticoid pathway
Androgen pathway
17 -Hydroxypregnenolone
Dehydroepiandrosterone
17 -Hydroxylase
Pregnenolone
Cholesterol Angiotensin II +
Trilostane –
3 -Dehydrogenase
3 -Dehydrogenase
Progesterone
17 -Hydroxylase
17 -Hydroxyprogesterone
Etomidate –
Corticosterone Angiotensin II +
17 -Hydroxylase
11 -Hydroxylase 17 -Hydroxylase
Androstenedione
21 -Hydroxylase
21 -Hydroxylase 11-Deoxycorticosterone
3 Dehydrogenase
11-Deoxycortisol
Etomidate –
11 -Hydroxylase
Hydrocortisone (cortisol)
18-Hydroxylase
Aldosterone Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:10
475
Ó 2014 Elsevier Ltd. All rights reserved.
PHARMACOLOGY
surgical patients taking glucocorticoids is now well established. In critically ill patients in the intensive care unit the appropriateness of the observed cortisol changes is unclear. Plasma cortisol values tend to be increased in the early stages of critical illness and correlate with the severity of other physiological scoring systems and hence predict outcome. However, there is much confusion about the magnitude of the cortisol response necessary to maintain normal cardiovascular function in such patients. Attempts have been made to assess adrenocortical function by the short synacthen test, but interpretation of the results has been difficult. There have been disputes about whether to use an absolute threshold value after ACTH, such as 550 nmol/litre cortisol, or to use an incremental increase. The problem with the latter approach is that the size of the increment is inversely related to the magnitude of the concentration of cortisol before ACTH. It is not surprising that attempts to assess adrenocortical function in patients in intensive care units have proved difficult. Nevertheless, there may be a group of patients who have adrenocortical insufficiency and in whom outcome may be improved by the administration of hydrocortisone. Glucocorticoids have a key role in maintaining the responsiveness of the vasculature to catecholamines so that adrenocortical insufficiency may result in the failure to respond to infusions of adrenergic drugs. Steroids have been given to critically ill patients for several decades, particularly those with sepsis, and enthusiasm for this approach has waxed and waned. Recommendations produced by the Surviving Sepsis Campaign in 2004 stated that patients with septic shock who, despite adequate fluid replacement, required inotropes to maintain blood pressure should be given a ‘low-dose’ daily replacement with 200e300 mg hydrocortisone. The study followed up more than 15,000 patients and in 2010 reported that compliance with the entire ‘management bundle’ was associated with reduced mortality rates. Since steroid supplementation was only one factor, it is likely that there will continue to be confusion about the role of hydrocortisone in critically ill patients until the pathophysiological changes in hypothalamicepituitaryeadrenal function have been elucidated. A
than others to be ‘pro-inflammatory’. Clinical work suggests that such individuals may be at more risk of perioperative complications. Pharmacological manoeuvres to reduce the inflammatory response include the use of glucocorticoids, volatile anaesthetics and regional anaesthesia, but no single agent has been shown to be effective. Moreover, neuraxial blockade has been shown to be more effective when clonidine and dexmedetomidine are added to the local anaesthetic, suggesting that central sympathetic pathways have a role in modifying the systemic inflammatory response. Neuraxial blockade with local anaesthetics alone has little effect on the inflammatory response. Intravenous lignocaine has an anti-inflammatory effect, but only after abdominal surgery. Future work will focus on cytokine receptor antagonists, to limit local inflammation following surgery or trauma.
Therapeutic use of steroids and anaesthesia Corticosteroids are used widely in medicine, and after prolonged administration there is failure of endogenous cortisol secretion as a result of the negative feedback on ACTH and CRH. It is now at least half a century since the notion was introduced that patients taking steroids needed large doses of steroid cover to survive surgery. This practice, however, is illogical and unnecessary. There are two principal arguments against the administration of large doses of steroids perioperatively. First, work with etomidate has shown that only normal circulating values of cortisol and aldosterone are necessary for routine surgery. Furthermore, primate studies have confirmed that the normal daily cortisol output, 25 mg/day in man, is sufficient for major upper abdominal surgery. Second, even if the anaesthetist wished to mimic the usual cortisol response to surgery, the total secretion in the first 24 hours after surgery rarely exceeds 100 mg. Thus, the current recommendations for steroid cover are based on these underlying physiological principles. The key points to note are that if the patient is taking less than 10 mg prednisolone/ day (or an equivalent dose of another steroid) then additional hydrocortisone is unnecessary; if the patient has not taken steroids in the past 3 months again hydrocortisone is not required perioperatively; and if high-dose steroids are being given for immunosuppression then these must be maintained perioperatively. Old regimens of 200e300 mg/day of hydrocortisone are of historical interest only. Patients with Addison’s disease, on low maintenance doses of steroids, will have no response to surgery and will need appropriate supplementation, which may include fludrocortisone. The excessive administration of steroids perioperatively is associated with the following complications: hypertension from fluid retention, hyperglycaemia, immunosuppression, failure of wound healing, gastric erosions and psychological disturbances. Perioperative hypotension in a patient taking steroids is not uncommon. It has been shown that this is only rarely associated with low circulating cortisol values and is commonly the result of hypovolaemia. If hypotension persists after fluid administration then 25 mg intravenous hydrocortisone may be given. Ideally, a blood sample should be taken for cortisol estimation before the hydrocortisone bolus so that suspected steroid deficiency can be confirmed or refuted.
FURTHER READING Dellinger RP, Carelet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and shock. Crit Care Med 2004; 32: 858e73. Gibbison B, Angelini GD, Lightman SL. Dynamic output and control of the hypothalamic-pituitary-adrenal axis in critical illness and major surgery. Br J Anaesth 2013; 111: 347e60. Kennedy BC, Hall GM. Neuroendocrine and inflammatory aspects of surgery; do they affect outcome? Acta Anaesthesiol Belg 1999; 50: 205e9. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010; 38: 683e4. Nicholson G. The hormonal and metabolic responses to trauma. Anaesth Intensive Care Med 2005; 6: 313e4. Nicholson G, Hall GM. Effects of anaesthesia on the inflammatory response to injury. Curr Opin Anesthesiol 2011; 24: 370e4. Nicholson G, Burrin JM, Hall GM. Peri-operative steroid supplementation. Anaesthesia 1998; 53: 1091e104.
Steroids and the critically ill The ACTH/cortisol response to elective surgery has been well defined and the rationale for hydrocortisone supplementation in
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