Tobias Lyngeraa Wulff, Peter Buhl Hjortrup, Tine Sylvest Meyhoff, Claus Larsen Feltoft, Maureen Smith, Lars H Lundstrøm
To evaluate the effect and harms of perioperative glucocorticoid stress dose for patients with known or suspected adrenal insufficiency for prevention of serious adverse events.
Description of the condition
The adrenal cortex produces glucocorticoids and mineralocorticoids to maintain homeostasis. Glucocorticoids, mainly cortisol, are an integral part of the regulation of metabolism, the immune system, cardiovascular function, growth, and reproduction. Cortisol secretion is increased in response to stress through the hypothalamus‐pituitary‐adrenal (HPA) axis (Bancos 2015). Cortisol mobilises glucose by promoting gluconeogenesis and reduces glucose uptake in peripheral tissue. This increases blood glucose levels in an effort to ensure supply to vital organs and tissues. Furthermore, cortisol helps regulate blood pressure by increasing the sensitivity of vascular smooth muscle to vasoconstrictors and by suppressing the release of vasodilators such as nitrous oxide (Dutt 2022). Mineralocorticoid (predominantly aldosterone) secretion is regulated by the renin‐angiotensin‐aldosterone system (RAAS) and potassium levels and acts to increase sodium and water reabsorption and potassium excretion in the kidneys, thereby directly influencing circulating blood volume and blood pressure (Hahner 2021).
Cortisol secretion rates have been found to vary throughout the day and follow a circadian rhythm that varies from 5 mg/m2 to 10 mg/m2, equivalent to an oral administration of 15 mg to 25 mg of hydrocortisone (Brandon 1999; Esteban 1991). The level of cortisol production increases up to six‐fold in response to stress, trauma, anxiety, illness or surgery (Cooper 2003).
Adrenal insufficiency is the failure of the adrenal cortex to secrete sufficient amounts of corticosteroids in response to a relevant stimulus; it can be broadly divided into either primary or secondary adrenal insufficiency. Primary adrenal insufficiency (Addison's disease) is rare with a prevalence of 0.8 to 1.4 per 10,000 people (Chabre 2017; Laureti 1999; Løvås 2002). It is characterised by pathologies of the adrenal cortex, mainly of an autoimmune nature (autoimmune Addison's disease). Other causes of primary adrenal insufficiency include infections such as HIV, cytomegalovirus, tuberculosis, adrenalectomy, haemorrhage, and sepsis (Bancos 2015). Secondary adrenal insufficiency is due to a disease process that affects the anterior pituitary (adrenocorticotropic hormone (ACTH) secretion) or hypothalamus (corticotropin‐releasing hormone (CRH) secretion) with an estimated prevalence of 1.4 to 2.8 per 10,000 people (Regal 2001; Tomlinson 2001), or can result from exogenous corticosteroid therapy (Bancos 2015). Although the incidence and prevalence of adrenal insufficiency due to exogenous corticosteroid therapy is largely unknown, the number of people at risk may be high given that perhaps 0.5% to 1% of the adult population is estimated to use glucocorticoids (Gudbjornsson 2002; van Staa 2000; Walsh 1996), and a significant proportion exhibit insufficient adrenal function (Broersen 2015).
For primary adrenal insufficiency, the entire cortex can be involved and the production of both glucocorticoids and mineralocorticoids is affected. Physiological replacement doses of corticosteroids with both glucocorticoid and mineralocorticoid activity are needed. For secondary adrenal insufficiency, mineralocorticoid (aldosterone) production is usually preserved since aldosterone is primarily regulated by RAAS, so replacement with corticosteroids with mineralocorticoid activity is unnecessary.
Several tests are available to diagnose adrenal insufficiency: basal plasma cortisol and ACTH level, ACTH test, insulin tolerance test (ITT), CRH and metyrapone stimulation tests. The two latter tests are rarely used in daily clinical practice. The type of test used depends on the clinical context. To determine whether cortisol deficiency is due to primary or secondary adrenal insufficiency, one could for instance assess the HPA‐axis integrity with the ITT through induction of hypoglycaemia (secondary adrenal insufficiency). Alternatively, the short ACTH stimulation test is carried out by injecting cosyntropin, a synthetic ACTH, to test the direct adrenal response to stimuli (primary adrenal insufficiency). To some extent, the choice of diagnostic test depends upon whether the patient is ambulatory, hospitalised, or critically ill and the level of monitoring available (Nicolaides 2017).
Ultimately, adrenal insufficiency can lead to adrenal crisis when an individual is exposed to a stressor (e.g. trauma, disease, surgery). Adrenal crisis is a condition that occurs when there is haemodynamic instability in an individual with inadequate adrenal function or reserve. This crisis usually evolves over a few hours and, if untreated, the patient may develop severe hypotension, hypothermia, hypoglycaemia, confusion, or circulatory collapse leading to death (Hahner 2015; Miller 2001).
Surgery causes a physiological stress response that results in a significant increase in cortisol secretion. The extent of the stress response depends on the invasiveness of surgery and type of anaesthesia (Prete 2018; Prete 2020), and may serve as a trigger for developing adrenal crisis.
Currently, surgical patients with known or suspected adrenal insufficiency receive supplemental glucocorticoids to avoid developing adrenal crisis. Both UK and US Society guidelines recommend a differentiated approach to patients depending on whether the patients have primary or secondary adrenal insufficiency and the extent of the surgery (Bornstein 2016; Woodcock 2020). Furthermore, Woodcock 2020 states that intravenous dexamethasone (6 mg to 8 mg) will suffice for glucocorticoid coverage for the first 24 hours in people receiving adrenosuppressive doses of steroids. However, different recommendations exist in the literature (Liu 2017), with varying stress doses of hydrocortisone in the perioperative period.
Description of the intervention
Corticosteroids are frequently used therapeutically for their anti‐inflammatory and immunosuppressive properties. Common types of corticosteroids used include prednisolone, hydrocortisone, fludrocortisone, betamethasone, and dexamethasone (Nicolaides 2018). The relative potency of corticosteroids is shown in Table 1. Chronic use of corticosteroids given in supraphysiologic doses leads to the development of secondary adrenal insufficiency. Other side effects from prolonged administration of corticosteroids include hypertension, delayed wound healing, water retention, diabetes, osteoporosis, and psychological changes (Schlaghecke 1992). The risk of adrenal suppression from the use of corticosteroid therapy depends on the specific corticosteroid dose, duration, and route of administration (Broersen 2015). The onset of adrenal suppression can occur as early as one week after commencing corticosteroid therapy (Salem 1994). Patients who receive the equivalent of 5 mg prednisolone a day may have suppression of the HPA axis (Borresen 2017). Adrenal insufficiency may persist for a long duration after discontinuation of corticosteroid therapy (Broersen 2015; Jamilloux 2013)
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