Abstract
Adrenal insufficiency (AI) is a life-threatening disorder. Defects at any level of the hypothalamic-pituitary-adrenal axis can impair adrenal function. It is difficult to make a diagnosis of AI in the newborn because during the neonatal period clinical findings are not specific and range from insidious, nonspecific complaints to circulatorycollapse due to hypovolemic shock. Another condition when is difficult to make a diagnosis of AI is in critically ill patients. There is no consensus on which patients to test for AI, which tests to use and how to interpret them. In this evidence-based review we aim to provideinformation for the evaluation of adrenal function results and findings in both the neonatal period and critical illness in childhood and adolescence.
Keywords: Adrenal functions, neonatal, critical illness
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References
Sperling MA, Joseph A Mojzoub, Kumar MR, Constantine AS. Sperling pediatric endocrinology. 5th ed. Philadelphia, Elsevier, 2021;436-441.
Hyman SJ, Novoa Y, Holzman I. Perinatal endocrinology: common endocrine disorders in the sick and premature newborn. Pediatr Clin North Am. 2011;58:1083-1098.
Ng PC. Effect of stress on the hypothalamic-pituitary-adrenal axis in the fetus and newborn. J Pediatr. 2011;158(2 Suppl):41-43.
Enver EO, Vatansever P, Guran O, Bilgin L, Boran P, Turan S, Haklar G, Bereket A, Guran T. Adrenal steroids reference ranges in infancy determined by LC-MS/MS. Pediatr Res. 2022;92:265-274. Epub 2021 Sep 23
Rauh M. Steroid measurement with LC-MS/MS. Application examples in pediatrics. J Steroid Biochem Mol Biol. 2010;121:520-527. Epub 2009 Dec 28
Taylor AE, Keevil B, Huhtaniemi IT. Mass spectrometry and immunoassay: how to measure steroid hormones today and tomorrow. Eur J Endocrinol. 2015;173:1-12. Epub 2015 Apr 15
Stanczyk FZ, Clarke NJ. Advantages and challenges of mass spectrometry assays for steroid hormones. J Steroid Biochem Mol Biol. 2010;121:491-495. Epub 2010 May 12
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365:2125-2136.
Nomura S. Immature adrenal steroidogenesis in preterm infants. Early Hum Dev. 1997;49:225-233.
Gidlöf S, Wedell A, Guthenberg C, von Döbeln U, Nordenström A. Nationwide neonatal screening for congenital adrenal hyperplasia in sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr. 2014;168:567-574.
Allen DB, Hoffman GL, Fitzpatrick P, Laessig R, Maby S, Slyper A. Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr. 1997;130:128-133.
Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics. 1998;101:583-590.
Jiang X, Tang F, Feng Y, Li B, Jia X, Tang C, Liu S, Huang Y. The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling. J Pediatr Endocrinol Metab. 2019;32:1253-1258.
Chan CL, McFann K, Taylor L, Wright D, Zeitler PS, Barker JM. Congenital adrenal hyperplasia and the second newborn screen. J Pediatr. 2013;163:109-113. Epub 2013 Feb 12. Erratum in: J Pediatr. 2013;163:308.
Clayton PE, Miller WL, Oberfield SE, Ritzén EM, Sippell WG, Speiser PW; ESPE/ LWPES CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res. 2002;58:188-195
Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101:427-434. Epub 2015 Dec 9
Soliman AT, Taman KH, Rizk MM, Nasr IS, Alrimawy H, Hamido MS. Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate-for-gestational-age newborns versus those with sepsis and respiratory distress: Cortisol response to low-dose and standard-dose ACTH tests. Metabolism. 2004;53:209-214.
LeDrew R, Bariciak E, Webster R, Barrowman N, Ahmet A. Evaluating the low-dose ACTH stimulation test in neonates: ideal times for cortisol measurement. J Clin Endocrinol Metab. 2020;105:dgaa635.
Ranke MB, Mullis PE. Diagnostics of Endocrine Function in Children and Adolescents 4th ed. Basel, Karger, 2011;361-362.
Karlsson R, Kallio J, Irjala K, Ekblad S, Toppari J, Kero P. Adrenocorticotropin and corticotropin-releasing hormone tests in preterm infants. J Clin Endocrinol Metab. 2000;85:4592-4595.
Balbão VM, Costa MM, Castro M, Carlotti AP. Evaluation of adrenal function in critically ill children. Clin Endocrinol (Oxf). 2014;81:559-565. Epub 2014 Mar 24
Levy-Shraga Y, Pinhas-Hamiel O. Critical illness-related corticosteroid insufficiency in children. Horm Res Paediatr. 2013;80:309-317. Epub 2013 Nov 7
Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers S, Russell JA, Van den Berghe G. 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. Intensive Care Med. 2017;43:1751-1763. Epub 2017 Sep 21. Erratum in: Intensive Care Med. 2018;44:401-402.
Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M; American College of Critical Care Medicine. 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;36:1937-1949.
Hebbar KB, Stockwell JA, Leong T, Fortenberry JD. Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock. Crit Care Med. 2011;39:1145-1150.
Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350:1629-1638.
Zimmerman JJ, Donaldson A, Barker RM, Meert KL, Harrison R, Carcillo JA, Anand KJ, Newth CJ, Berger J, Willson DF, Jack R, Nicholson C, Dean JM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Real-time free cortisol quantification among critically ill children. Pediatr Crit Care Med. 2011;12:525-531.
Stewart PM. The Adrenal Cortex. In: Williams Textbook of Endocrinology, Polonsky KS (ed) Saunders, Philadelphiai, 2002;491.
Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477. Epub 2013 Mar
Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med. 2001;27:1584-1591.
Hammond GL, Smith CL, Paterson NA, Sibbald WJ. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab. 1990;71:34-39.
Cooper MS, Bujalska I, Rabbitt E, Walker EA, Bland R, Sheppard MC, Hewison M, Stewart PM. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res. 2001;16:1037-1044.
Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, Geenen V. Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab. 1999;84:2834-2839.
Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, Lévy B, Bollaert PE. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med. 2005;31:388-392. Epub 2005 Feb 10
Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, Bertrand L, Beltramini A, Gamand P, Albizzati S, Perdrizet D, Lebail G, Chollet-Xemard C, Maxime V, Brun-Buisson C, Lefrant JY, Bollaert PE, Megarbane B, Ricard JD, Anguel N, Vicaut E, Adnet F; KETASED Collaborative Study Group. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009;374:293-300. Epub 2009 Jul 1
Cohen J, Pretorius CJ, Ungerer JP, Cardinal J, Blumenthal A, Presneill J, Gatica-Andrades M, Jarrett P, Lassig-Smith M, Stuart J, Dunlop R, Starr T, Venkatesh B. Glucocorticoid sensitivity is highly variable in critically ill patients with septic shock and is associated with disease severity. Crit Care Med. 2016;44:1034-1041.
Kaufman D. Glucocorticoid therapy in septic shock in adults. Up To Date, 21 Jun. 2022.
Hauser GJ. Early goal-directed therapy of pediatric septic shock in the emergency department. Isr J Emerg Med. 2007;7:5.
Langer M, Modi BP, Agus M. Adrenal insufficiency in the critically ill neonate and child. Curr Opin Pediatr. 2006;18:448-453.
Menon K, Ward RE, Lawson ML, Gaboury I, Hutchison JS, Hébert PC; Canadian Critical Care Trials Group. A prospective multicenter study of adrenal function in critically ill children. Am J Respir Crit Care Med. 2010;182:246-251. Epub 2010 Mar 18
Moran JL, Chapman MJ, O’Fathartaigh MS, Peisach AR, Pannall PR, Leppard P. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock. Intensive Care Med. 1994;20:489-495.
Briegel J, Schelling G, Haller M, Mraz W, Forst H, Peter K. A comparison of the adrenocortical response during septic shock and after complete recovery. Intensive Care Med. 1996;22:894-899.
Bouachour G, Roy PM, Guiraud MP. The repetitive short corticotropin stimulation test in patients with septic shock. Ann Intern Med. 1995;123:962-963.
Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med. 2006;174:1319-1326. Epub 2006 Sep 14
Span LF, Hermus AR, Bartelink AK, Hoitsma AJ, Gimbrère JS, Smals AG, Kloppenborg PW. Adrenocortical function: an indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med. 1992;18:93-96.
Heckmann M, Wudy SA, Haack D, Pohlandt F. Serum cortisol concentrations in ill preterm infants less than 30 weeks gestational age. Acta Paediatr. 2000;89:1098-1103.
Uçar A, Baş F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr. 2016;12:261-274. Epub 2016 Apr 8
Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine parameters. Crit Cared. 1995;23:78-83.
Demiral M, Kiral E, Dinleyici EC, Simsek E. Evaluation of the hypothalamic-pituitary-adrenal axisin a paediatrıc intensive care unit. Acta Endocrinol (Buchar). 2019;15:466-471.
Aydın BK, Demirkol D, Baş F, Türkoğlu U, Kumral A, Karaböcüoğlu M, Cıtak A, Darendeliler F. Evaluation of endocrine function in children admitted to pediatric intensive care unit. Pediatr Int. 2014;56:349-353. Epub 2014 Apr 1
IyerP, Harrington B, Fadrowski JJ, Sibinga E, Amankwah EK. Correlation between cosyntropin stimulation study and disease severity in children with fluid- and catecholamine -refractory shock in the pediatric and cardiovascular Intensive care unit. Horm Res Paediatr. 2018; 89: 31-37. Epub 2017 Nov 17
Gunnala V, Guo R, Minutti C, Durazo-Arvizu R, Laporte C, Mathews H, Kliethermis S, Bhatia R. Measurement of salivary cortisol level for the diagnosis of critical illness-related corticosteroid insufficiency in children. Pediatr Crit Care Med. 2015;16:101-106.
Venkatesh B, Mortimer RH, Couchman B, Hall J. Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: a prospective study. Anaesth Intensive Care. 2005;33:201-209.
Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000;283:1038-1045.
Lipiner-Friedman D, Sprung CL, Laterre PF, Weiss Y, Goodman SV, Vogeser M, Briegel J, Keh D, Singer M, Moreno R, Bellissant E, Annane D; Corticus Study Group. Adrenal function in sepsis: the retrospective Corticus cohort study. Crit Care Med. 2007;35:1012-1018.
Siraux V, De Backer D, Yalavatti G, Mélot C, Gervy C, Mockel J, Vincent JL. Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests. Crit Care Med. 2005;33:2479-2486.
Asare K. Diagnosis and treatment of adrenal insufficiency in the critically ill patient. Pharmacotherapy. 2007;27:1512-1528.
Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31:141-145.
Soliman AT, Taman KH, Rizk MM, Nasr IS, Alrimawy H, Hamido MS. Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate-for-gestational-age newborns versus those with sepsis and respiratory distress: Cortisol response to low-dose and standard-dose ACTH tests. Metabolism. 2004;53:209-214.
Agwu JC, Bissenden J. The low dose synacthen test: experience in well preterm infants. J Pediatr Endocrinol Metab. 2004;17:1607-1612.
Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, Allolio B, Annane D, Stewart PM. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab. 2006;91:2548-2554. Epub 2006 Apr 11
Beishuizen A, Thijs LG, Vermes I. Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care. 2002;6:434-438. Epub 2002 Jul 9
Sayyed Kassem L, El Sibai K, Chaiban J, Abdelmannan D, Arafah BM. Measurements of serum DHEA and DHEA sulphate levels improve the accuracy of the low-dose cosyntropin test in the diagnosis of central adrenal insufficiency. J Clin Endocrinol Metab. 2012;97:3655-3662. Epub 2012 Jul 31
Odabaşı Güneş S, Peltek Kendirci HN, Ünal E, Buluş AD, Dündar İ, Şıklar Z. Clinical, biochemical and molecular characteristics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Res Pediatr Endocrinol. 2025;17(Suppl 1):3-11.
Yavaş Abalı Z, Kurnaz E, Güran T. Antenatal diagnosis and treatment in congenital adrenal hyperplasia due to 21- hydroxylase deficiency and congenital adrenal hyperplasia screening in newborns. J Clin Res Pediatr Endocrinol. 2025;17(Suppl 1):33-43.
