ICU · first-part-physiology
Endocrine Physiology in Critical Illness — Comprehensive
Also known as Endocrine physiology · Stress response · HPA axis · Cortisol · Critical illness-related corticosteroid insufficiency · CIRCI · Sick euthyroid syndrome · Nonthyroidal illness syndrome · Stress hyperglycaemia · ADH vasopressin · SIADH · RAAS · Counter-regulatory hormones
Endocrine physiology applied to critical illness: cortisol actions and CIRCI (2008 and 2017 task forces), glucocorticoid evidence in septic shock, steroid-treated patients and peri-operative stress dosing, non-thyroidal illness syndrome, glucose-control trials, vasopressin, severe hyponatraemia correction and osmotic demyelination risk, and the RAAS.
Checked against its sources on 8 Oct 2026
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- CIRCI: vasopressor-refractory septic shock with inappropriately low cortisol for the degree of stress — treat with hydrocortisone 200 mg/day, do NOT use ACTH stimulation test to decide treatment in septic shock
- Sick euthyroid syndrome: low T3 in critical illness is ADAPTIVE — do NOT treat with levothyroxine unless intrinsic thyroid disease coexists
- Intensive glucose control (4.5-6.0 mmol/L) increased 90-day mortality with more severe hypoglycaemia (NICE-SUGAR) — target 10.0 mmol/L or less (180 mg/dL or less)
- Non-osmotic ADH release in critical illness causes dilutional hyponatraemia (SIADH pattern) — fluid restrict, do not correct rapidly
A 58-year-old on long-term prednisolone for rheumatoid arthritis is admitted with faecal peritonitis and becomes hypotensive despite fluids and noradrenaline. Two endocrine problems overlap: chronic exogenous glucocorticoids suppress the HPA axis, and critical illness itself can produce CIRCI.[5][1]
Cortisol in critical illness
Cortisol antagonises the migration of inflammatory cells and the synthesis or action of virtually all pro-inflammatory mediators, promotes anti-inflammatory components, and mediates cardiovascular tolerance to endotoxin and the maintenance of vascular sensitivity to catecholamines.[3] In the adrenal cortex the zona fasciculata produces glucocorticoids, and ACTH and cortisol follow a diurnal rhythm with a morning peak.[17]
Adrenal insufficiency (cortisol increment below 9 μg/dL after 250 μg corticotropin) is present in about half of patients with septic shock and is associated with more refractory hypotension and higher mortality.[3]
CIRCI — definition and diagnosis
The 2008 task force defined CIRCI as HPA dysfunction during critical illness from adrenal insufficiency plus tissue corticosteroid resistance, to be suspected in hypotension poorly responsive to fluids and vasopressors, particularly in sepsis.[1] It recommended diagnosis by a delta total cortisol below 9 μg/dL after 250 μg ACTH or a random total cortisol below 10 μg/dL, but advised that the ACTH test should not be used to select patients for glucocorticoids.[1] The 2017 update could not agree on a single reliable test and suggested total over free or salivary cortisol.[2]
Who gets hydrocortisone
| Source | Finding |
|---|---|
| Boyer 2006 review | Low doses (about 300 mg daily for 5 days or more) increase vasoconstrictor response; prolonged low-dose regimens reduced 28-day mortality (RR 0.76) without heterogeneity; high doses should not be given |
| Sprung 2008 (499 patients) | 28-day mortality 34.3% hydrocortisone vs 31.5% placebo; no difference in corticotropin non-responders (39.2% vs 36.1%) |
| Marik 2008 | Hydrocortisone 200 mg/day in four doses or 240 mg/day infusion for 7 days or more in septic shock; wean, do not stop abruptly |
| Annane 2017 | Hydrocortisone below 400 mg/day for 3 days or more in septic shock unresponsive to fluid and moderate-to-high-dose vasopressors; not for sepsis without shock |
Steroid-treated patients and surgery
Primary adrenal insufficiency is failure of the gland; secondary is deficient ACTH or CRH secretion. Patients on physiological replacement for either are at significant risk of adrenal crisis and must receive stress doses of hydrocortisone peri-operatively.[5] Prednisolone 5 mg or more daily in adults for 1 month or more, by oral, inhaled, intranasal, intra-articular or topical routes, may suppress the HPA axis — chronic glucocorticoid administration is the commonest cause of secondary adrenal suppression — and stress dosing is in addition to the usual steroid.[5]
References17ShowHide
- [1]Marik 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. Critical care medicine, 2008.PMID 18496365
- [2]Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Critical care medicine, 2017.PMID 28938253
- [3]Boyer A, Chadda K, Salah A, et al. Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality. International journal of clinical pharmacology and therapeutics, 2006.PMID 16961159
- [4]Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. The New England journal of medicine, 2008.PMID 18184957
- [5]Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia, 2020.PMID 32017012
- [6]Fliers E, Bianco AC, Langouche L, et al. Thyroid function in critically ill patients. The lancet. Diabetes & endocrinology, 2015.PMID 26071885
- [7]Ganesan K, Anastasopoulou C, Wadud K Euthyroid Sick Syndrome. 2022.PMID 29489255
- [8]van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. The New England journal of medicine, 2001.PMID 11794168
- [9]NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. The New England journal of medicine, 2009.PMID 19318384
- [10]Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study. Critical care (London, England), 2013.PMID 23452622
- [11]Cuzzo B, Padala SA, Lappin SL Physiology, Vasopressin. 2023.PMID 30252325
- [12]Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. The New England journal of medicine, 2008.PMID 18305265
- [13]Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. European journal of endocrinology, 2014.PMID 24569125
- [14]Tandukar S, Sterns RH, Rondon-Berrios H Osmotic Demyelination Syndrome following Correction of Hyponatremia by ≤10 mEq/L per Day. Kidney360, 2021.PMID 35373113
- [15]Baek SH, Jo YH, Ahn S, et al. Risk of Overcorrection in Rapid Intermittent Bolus vs Slow Continuous Infusion Therapies of Hypertonic Saline for Patients With Symptomatic Hyponatremia: The SALSA Randomized Clinical Trial. JAMA internal medicine, 2021.PMID 33104189
- [16]Kaur J, Rout P Physiology, Renin Angiotensin System. 2026.PMID 29261862
- [17]Dutt M, Wehrle CJ, Jialal I Physiology, Adrenal Gland. 2023.PMID 30725945