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• W2470536415 abstract "Key points•The circadian rhythm of the hypothalamic–pituitary–adrenal (HPA) axis is composed of 45–60 min pulses of cortisol, known as an ultradian rhythm.•The corresponding pulsatility in cortisol-receptor binding is important for normal functioning with varying effects on gene transcription.•Cortisol-binding globulin acts as a reservoir and effectively delivers free cortisol to inflammatory sites.•The value of point assessments of HPA axis function in the intensive care unit is therefore probably of minimal use other than to diagnose absolute deficiency. •The circadian rhythm of the hypothalamic–pituitary–adrenal (HPA) axis is composed of 45–60 min pulses of cortisol, known as an ultradian rhythm.•The corresponding pulsatility in cortisol-receptor binding is important for normal functioning with varying effects on gene transcription.•Cortisol-binding globulin acts as a reservoir and effectively delivers free cortisol to inflammatory sites.•The value of point assessments of HPA axis function in the intensive care unit is therefore probably of minimal use other than to diagnose absolute deficiency. The basic constituents of the hypothalamic–pituitary–adrenal (HPA) axis will be familiar to most physicians because the ‘stress response’ is seen after any significant illness, injury, or surgery. However, this article seeks to highlight the substantial advances in understanding that have been made in the last decade and how these may alter treatment and guide future research. A simple schematic of the HPA axis can be seen in Figure 1.1Gibbison 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: 347-360Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The paraventricular nucleus (PVN) of the hypothalamus is the ‘control centre’ of the HPA axis. It receives input from multiple other centres: •Suprachiasmatic nucleus: the body's ‘biological clock’ provides diurnal information, modulating inhibitory gain to the PVN, resulting in low activation during periods of sleep, increasing in anticipation of awakening and peaking in the morning, the basis of the circadian rhythm.•Brainstem nuclei: delivers information from physiological changes such as hypotension or inflammation.•Limbic region: provides stimulation from cognitive or emotional stressors.•Sympathetic/sensory: in addition to higher centre inputs at the hypothalamus, there is also extensive sensory and sympathetic innervation to the end target, the adrenal glands, via the splanchnic nerves. Both cholinergic pre-ganglionic and catecholaminergic post-ganglionic sympathetic fibres synapse at the adrenal gland and appear to sensitize it to adrenocorticotrophic hormone (ACTH), increasing cortisol release. This is probably an indirect effect'vasodilation leads to a higher adrenal blood flow which in turn means more cortisol output. Furthermore, the adrenal gland has autonomous clock genes exerting additional circadian control on steroidogenesis and ACTH sensitivity. This effect may be modulated directly by light and possibly via splanchnic innervation.•The PVN contains two types of neuroendocrine cells:•Magnocellular neurones synthesize arginine vasopressin (AVP'also known as anti-diuretic hormone, ADH), which is then transported to the posterior pituitary (an embryological down-growth from the hypothalamus), for storage and subsequent release.•Parvocellular neurones synthesize corticotrophin-releasing hormone (CRH), which is secreted from the median eminence of the hypothalamus into the hypophyseal portal circulation. CRH acts upon corticotrophs in the anterior pituitary prompting secretion of ACTH into the systemic circulation, which in turn stimulates cortisol release from the zona fasciculata of the adrenal cortex. Cortisol is synthesized de novo, secreted, and circulating free cortisol then exerts a negative feedback effect at the pituitary to reduce ACTH secretion and inhibit CRH release at the PVN. ‘Normal’ people under unstressed conditions normally produce the equivalent of about 20–25 mg hydrocortisone per day. The familiar circadian rhythm of cortisol and ACTH (high in the early morning and low in the late afternoon and evening) is in fact composed of an ultradian rhythm of pulses lasting around 45–60 min.2Henley DE Leendertz JA Russell GM et al.Development of an automated blood sampling system for use in humans.J Med Eng Technol. 2009; 33: 199-208Crossref PubMed Scopus (75) Google Scholar The peaks of the circadian rhythm are generated by high amplitude pulses and the troughs by smaller pulses, or non-pulsatile activity (see Fig. 2). The term ultradian refers to any biological cycle that repeats more frequently than daily, whereas circadian rhythms follow a 1 day cycle. This pulsatility used to be considered to come from a pulse generator within the hypothalamus, but recent studies have concluded that it is more likely generated from the positive feed-forward from the pituitary (ACTH) and negative feed-back relationship from the adrenal (cortisol).3Walker JJ Terry JR Lightman SLL Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis.Proc Biol Sci. 2010; 277: 1627-1633Crossref PubMed Scopus (172) Google Scholar The driver ‘pushing’ the system is the hypothalamic CRH. It may be imagined on a simple level like a ‘Newton's Cradle’ system; where ACTH and cortisol are two balls oscillating at alternative ends and CRH is the driving force to maintain and vary propulsion. Ultradian rhythms are relatively commonplace in neurological and other neuroendocrine pathways responsible for maintaining homeostasis. Pulsatile signalling affords many benefits including greater signal control, higher energy efficiency, and enables receptor recovery between pulses, which is essential for maintaining target responsiveness. Since pulses can vary in amplitude, duration, shape, and frequency, pulsatile signalling also transmits much greater information to the target receptor when compared with continuous signalling. This can be illustrated by comparing a colour television image (where each pixel can vary in frequency and amplitude) with that of a black and white television (where pixels may only vary in amplitude). Since the ultradian pattern of ACTH and cortisol release is relatively newly determined, much of the research seeking to accurately quantify HPA activity in health and after injury or surgery may be inaccurate due to insufficient sampling frequency. Pulsatility is important'patients with absolute cortisol deficiency (Addison's disease), who take physiological cortisol replacement but lack the pulses, are twice as likely to die as their peers.4Bergthorsdottir R Leonsson-Zachrisson M Odén A Johannsson G Premature mortality in patients with Addison's disease: a population-based study.J Clin Endocrinol Metab. 2006; 91: 4849-4853Crossref PubMed Scopus (382) Google Scholar Pulses of cortisol also exhibit characteristics of an effective refractory period'the same stressor applied at different phases of the ultradian cycle appears to elicit differing magnitudes of cortisol response. An exaggerated response occurs if the stressor is applied during the increasing cortisol phase, whereas a much smaller or no response is generated when the same stimulus is applied during the falling phase of the cycle. Whether this also applies to humans during sepsis or after surgery remains as yet unstudied. Like the other endogenous steroid hormones, cortisol is synthesized from cholesterol. Since cortisol is lipophilic and will readily pass through membranes, it cannot be packaged in vesicles, but instead must be rapidly manufactured de novo. Cortisol steroidogenesis begins with the binding of ACTH to the membrane-bound G-protein-coupled receptor (the melanocortin 2 receptor'MC2-R) on the surface of zona fasciculata cells. This triggers the cAMP–protein kinase A cascade which in turn activates steroidogenic acute regulatory protein (StAR) in the mitochondria. StAR protein is important since it orchestrates the transportation of cholesterol from the outer to the inner mitochondrial membrane and is the rate-limiting step in steroidogenesis. Once inside the mitochondrion, cholesterol is converted into the steroid precursor, pregnenolone, by side chain cleavage enzyme (CYP450SCC). Cortisol is then constructed via a series of enzyme-catalysed steps within the mitochondrion and endoplasmic reticulum, before being released into the circulation. Cortisol clearance occurs principally by hepatic metabolism via 5α- and 5β-reductases and is eliminated by the kidneys via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2. This is balanced by regeneration of cortisol from cortisone in the liver and adipose tissue by 11β-HSD type 1. As a steroid hormone, cortisol is fat soluble and thus relatively insoluble in plasma. As a result, it is highly protein-bound; 80–90% to cortisol-binding globulin (CBG), 10–15% to albumin, with only 5% remaining unbound and free to cross cell membranes and bind to receptors. CBG is a 50–60 kDa protein, part of the serpin (serine proteinase inhibitor) family, and is synthesized mainly in the liver. CBG is also found in small amounts in the lung, kidney, and testes tissue where it may have a role in regulating local cortisol levels within each organ. CBG is important because as a transporter and reservoir of cortisol in the blood, it plays a significant role in the fraction of free cortisol available to pass into cells. Each CBG molecule binds to one cortisol molecule and thus binding is saturable with a finite binding capacity. This characteristic of the system means it is extremely efficient, since any large pulse of cortisol exceeding the CBG binding capacity or physiological decrease in the CBG level will result in a significant increase in the free fraction of cortisol in the blood, amplifying the signal to the tissues. Serum CBG levels have a diurnal fluctuation, decreasing slightly in the day and increasing at night and thus accentuating the overall circadian rhythm of cortisol. Cortisol is preferentially delivered to sites of inflammation by CBG. CBG behaves as a ‘thermocouple’, showing marked decline in affinity for cortisol at higher temperatures, such as during fever.5Henley DE Lightman SL New insights into corticosteroid-binding globulin and glucocorticoid delivery.Neuroscience. 2011; 180: 1-8Crossref PubMed Scopus (82) Google Scholar Cortisol is also liberated from CBG by activated neutrophils which release elastase, an enzyme that cleaves and irreversibly destroys CBG. Local inflammatory changes in pH do not affect CBG affinity, but do reduce the affinity of albumin to cortisol and therefore further enhance the effect. Since glucocorticoids are lipophilic, they readily cross the phospholipid bilayer of cell membranes and bind to intracellular glucocorticoid receptors (GRs). Stabilizer proteins aid the GR–ligand complex formation and cause dimerization of two GR–ligand complexes. The dimerized GR–ligand complexes can then be transported into the cell nucleus, where they transiently bind to deoxyribonucleic acid (DNA), acting as effective transcription factors. The GR complex oscillates on and off the DNA, with each interaction lasting 10–20 s. It is this rapid oscillation that allows HPA output to respond quickly to stressors. Although GR follows a ‘saturable’ pharmacokinetic pattern, we do not know at what concentration of cortisol the receptors are saturated in different tissues. The interaction of the ultradian rhythm with receptor binding is important for physiological functioning. Transcription of glucocorticoid-responsive genes occurs in pulses that tracks the pulses of cortisol'that is, pulsatile receptor binding leads to pulsatile gene expression.6Conway-Campbell BL Sarabdjitsingh RA McKenna MA et al.Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene period 1 in rat hippocampus.J Neuroendocrinol. 2010; 22: 1093-1100Crossref PubMed Scopus (114) Google Scholar The genetic output of glucocorticoids can be both positive (cause transcription) and negative (repress transcription) and be transient or continuous. The characteristics of this output is exquisitely sensitive to patterns, with pulsatile glucocorticoid exposure exerting a greater control over certain target genes and a smaller effect on others in comparison with constant presentation as is seen in glucocorticoid-based therapeutics. Some effects of glucocorticoids are too fast to be the result of transcription, with effects seen in seconds or minutes (transcription takes 20–40 min). Thus, some GRs are membrane-bound and act via ion channels and secondary messenger systems. These can cause T-cell inhibition in the immune system and activation of endothelial nitric oxide synthase in neurovascular tissue. Significant stressors, such as major surgery or critical injury or illness, pose significant challenges to the body's homeostasis. They trigger compensatory autonomic and neuroendocrine mechanisms, some of which are fairly primitive in evolutionary terms. The HPA axis is pivotal to the body's homeostatic response and has evolved to react rapidly, with an amplification of effect: increased cortisol production, reduced circulating CBG and albumin levels, with a reduced affinity for cortisol, all leads to a net increase in both total and free serum cortisol. Cortisol clearance also seems to be reduced during major stress, such as severe sepsis.7Boonen E Vervenne H Meersseman P et al.Reduced cortisol metabolism during critical illness.N Engl J Med. 2013; 368: 1477-1488Crossref PubMed Scopus (322) Google Scholar This is possibly as a result of the accumulation of circulating bile salts inhibiting the enzymes that breakdown cortisol or a reduction in liver and kidney perfusion. CBG cleavage by neutrophil activity ensures cortisol is optimally targeted at areas of inflammation. In addition to stimulation of the higher inputs to the hypothalamus, production of pro-inflammatory cytokines, tumour necrosis factor α (TNF-α), and interleukins −1 and −6 (IL-1 and IL-6) cause direct stimulation of CRH and ACTH. Over the first 24 h, ultradian pulses in ACTH and cortisol are seen to be significantly magnified8Gibbison B Spiga F Walker JJ et al.Dynamic pituitary–adrenal interactions in response to cardiac surgery.Crit Care Med. 2015; 43: 791-800Crossref PubMed Scopus (58) Google Scholar (Fig. 3). However, by the first postoperative day, ACTH levels typically return to normal, whereas cortisol pulses remain elevated. This suggests that the mechanisms controlling the adrenal output may be different or sensitized differently in acute systemic inflammation. The inflammatory cytokines TNF-α, IL-1, and IL-6 have varied effects on the adrenal gland. There is a high density of IL-6 receptors in the zona fasciculata of the adrenal gland and the corticotroph cells of the pituitary. They increase cortisol production in cell culture, in animal models, and in humans. IL-1 also increases cortisol synthesis, but to a lesser extent. TNF-α has different effects on cortisol synthesis depending on the concentration; at low concentrations, inhibitory effects appear to dominate and at higher concentrations, stimulatory effects predominate. HPA axis activation and elevated cortisol levels should be regarded as a response to the inflammation rather than a driver. Therefore, in broad terms, the greater the tissue damage, the greater the levels of activation of the HPA axis and the higher the cortisol level. However, this is a rather one-dimensional way of looking at the HPA axis after surgery'the timing of the increase and patterns are also important. For example, laparoscopic cholecystectomies have an earlier increase in cortisol than open cholecystectomy, although overall levels are higher and persist longer in the open cholecystectomies. Multiple strategies have been tried to modulate HPA axis activity around the time of surgery, although it is difficult to see what benefit reducing cortisol production in response to the same operation brings. An appropriate amount of corticosteroid is required to protect the body from uncontrolled inflammation at one end of the spectrum and circulatory failure at the other'high-dose corticosteroids are associated with a poor outcome, as is too little. It must be remembered that the high-dose exogenous steroids associated with poor outcomes (methylprednisolone in sepsis9Sprung CL Caralis PV Marcial EH et al.The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study.N Engl J Med. 1984; 311: 1137-1143Crossref PubMed Scopus (557) Google Scholar and head injury)10Edwards P Arango M Balica L et al.Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.Lancet. 2005; 365: 1957-1959Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar have potencies many times more than is physiologically possible. Effective neuraxial anaesthesia can block the somatic and autonomic innervation to both the hypothalamus and directly at the adrenals, and so could potentially reduce HPA activation. Systemic analgesics can directly and indirectly affect the HPA axis'for example, opioids suppress the hypothalamic–pituitary–gonadal–adrenal pathway. Chronic opioid use is well recognized to cause hypogonadism and occasionally adrenal suppression. The use of non-steroidal anti-inflammatory drugs before surgery can reduce levels of inflammatory mediators, but has no direct effect on the HPA axis. Reducing the inflammatory response to surgery is best achieved by adjusting surgical technique to minimize tissue damage, for example, by using minimally invasive surgery. The link between adrenal dysfunction and circulatory failure has been recognized for over a century. In patients with septic shock who are resistant to standard treatment (antibiotics, fluids, vasopressors, and inotropes), a syndrome of relative adrenal insufficiency has been postulated'critical illness-related corticosteroid insufficiency. This has also been postulated to exist in many other syndromes of systemic inflammation, such as burns. However, crystallization of this phenomenon has proved elusive, with measurements of serum, urine, and salivary cortisol, ACTH responsiveness, and eosinophil count all seeming of little value. This was reflected in the consensus guidelines produced by the American College of Critical Care Medicine in 2008.11Marik PE Pastores SM Annane D et al.Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine.Crit Care Med. 2008; 36: 1937-1949Crossref PubMed Scopus (683) Google Scholar Given that cortisol (and ACTH) may vary by up to 600 nmol litre−1 during the ultradian pulse, any test involving infrequent cortisol measurement or ACTH responsiveness is unlikely to be useful in this set of patients. Whether in fact this group of patients does really exist and how to diagnose and treat them is yet to be established. The use of exogenous corticosteroids during critical illness and their benefits is a different and equally contested debate. The use of high-dose corticosteroids (>400 mg hydrocortisone or equivalent per day) at immunosuppressive doses in sepsis has been discarded since the mid-1990s when multiple studies and two meta-analyses revealed no outcome improvement and a potential increase in the incidence of superinfection. Over the last two decades, attention has focused on lower doses of corticosteroids (<400 mg hydrocortisone or equivalent per day). The first major randomized controlled trial was published by Annane and colleagues12Annane D Sebille V Charpentier C et al.Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.J Am Med Assoc. 2002; 288: 862-871Crossref PubMed Scopus (2520) Google Scholar in 2002. It concluded that there was no overall mortality benefit with the use of corticosteroids in sepsis, although perhaps there was a benefit in those failing an ACTH stimulation test. CORTICUS, the largest randomized control trial to date, recruited 600 patients and showed no mortality benefit with corticosteroid use even in that cohort of patients considered to have ‘adrenal insufficiency’.13Sprung CL Annane D Keh D et al.Hydrocortisone therapy for patients with septic shock.N Engl J Med. 2008; 358: 111-124Crossref PubMed Scopus (1639) Google Scholar The use of random cortisol levels or the ACTH stimulation test as a marker of adrenal insufficiency in sepsis has subsequently been discredited and is no longer advocated. The latest and largest RCT to compare hydrocortisone with placebo in septic shock, called ADRENAL (www.clinicaltrials.gov NCT01448109), aims to recruit 3800 patients and started in 2012, with a proposed completion date of late 2016. Large-scale reviews and meta-analyses have regularly been undertaken to assess the role of steroids in sepsis of which the latest, the Cochrane review was published in December 2015.14Annane D Bellissant E Bollaert PE Briegel J Keh D Kupfer Y Corticosteroids for treating sepsis.Cochrane Database Syst Rev. 2015; 12: CD002243Google Scholar All have included a disparate collection of smaller studies, which have used different synthetic corticosteroids, at a variety of doses and treatment durations, by bolus and continuous infusion'all factors which may result in very different physiological and transcriptional effects and outcome. Overall, the use of low-dose corticosteroids in sepsis may only have a small positive impact on all-cause mortality, but they do consistently appear to reverse shock more rapidly, reduce the number of ventilation days, and length of stay on the intensive care unit. Cardiac surgery evokes a significant acute inflammatory response both from the use of cardiopulmonary bypass and tissue destruction from the surgery itself. There is a theoretical benefit of supplemental corticosteroids to obviate some of the inflammatory response. However, since survival rates after cardiac surgery are >98%, extremely large trials are required to be of adequate power to demonstrate statistically significant changes in mortality. The vast majority of studies have looked at large, immunosuppressive doses of methylprednisolone and dexamethasone rather than the low-dose hydrocortisone predominant in sepsis. The two largest placebo controlled randomized trials have only recently been published; the DECS trial15Dieleman JM Nierich AP Rosseel PM et al.Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial.J Am Med Assoc. 2012; 308: 1761-1767Crossref PubMed Scopus (301) Google Scholar in 2012, using a single dose of dexamethasone (n=4494 patients) and the SIRS trial16Whitlock RP Devereaux PJ Teoh KH et al.Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial.Lancet. 2015; 386: 1243-1253Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar in 2015, using methylprednisolone (n=7507 patients). Neither study has revealed any significant difference in mortality or major morbidity and thus the routine use of corticosteroids in adult cardiac surgery is currently not justified. There is no evidence that anything other than absolute corticosteroid deficiency is associated with circulatory failure after surgery. Traditionally, surgical patients likely to have a suppressed HPA axis from long-term steroid therapy would receive an increased dose of steroid during the perioperative period'the theory being to replicate the endogenous stress response after surgery. However, converting patients’ regular steroids to an i.v. equivalent (Table 1) while they are not eating and drinking is probably all that is required, although many guidelines do not yet reflect this. The caveat to this are patients with Addison's disease, who are unable to produce ANY endogenous cortisol and thus do require larger steroid doses during the surgical period.17Marik PE Varon J Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature.Arch Surg. 2008; 143: 1222-1226Crossref PubMed Scopus (126) Google ScholarTable 1Dose equivalency of corticosteroidsCorticosteroidEquivalent dose (mg)Hydrocortisone40Prednisolone10Triamcinolone8Methylprednisolone8Dexamethasone1.5Betamethasone1.2 Open table in a new tab The HPA axis is a dynamic system that has evolved to rapidly respond to stressors. Cortisol secretion is pulsatile and this pulsatility has a real impact on physiological functioning in both health and disease. Normal function and control of the HPA axis after major surgery and critical illness is still not yet fully understood'nor is its place as an avenue of therapy for these conditions. Too much corticosteroid is associated with an excess mortality and morbidity, too little is associated with circulatory failure and death. Where the transition points are, we are still to find out." @default.
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• W2470536415 title "Hypothalamic–pituitary–adrenal function during health, major surgery, and critical illness" @default.
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