Cortisol levels associated with mortality in children with critical illness:  a systematic review

Restu Triwulandani Tolibin; Septin Widiretnani; Annang Giri Moelyo

doi:10.14238/pi63.6.2023.472-82

Restu Triwulandani Tolibin Department of Child Health, Faculty of Medicine, Universitas Sebelas Maret/Dr. Moewardi Hospital, Surakarta, Central Java
Septin Widiretnani Department of Child Health, Faculty of Medicine, Universitas Sebelas Maret/Dr. Moewardi Hospital, Surakarta, Central Java
Annang Giri Moelyo Department of Child Health, Faculty of Medicine, Universitas Sebelas Maret/Dr. Moewardi Hospital, Surakarta, Central Java

DOI: https://doi.org/10.14238/pi63.6.2023.472-82

Keywords: cortisol; mortality; sepsis

Abstract

Background Critically ill patients, including those with sepsis, have increased cortisol levels due to activation of the hypothalamic-pituitary-adrenal (HPA) axis or critical illness-related corticosteroid insufficiency (CIRCI).

Objective To evaluate for a possible association between cortisol levels and mortality from sepsis in pediatric patients by systematic review of the literature.

Methods A systematic review was conducted on studies involving critically ill children, including those with sepsis. We included studies published between 2011-2020 analyzing data on cortisol levels (total serum cortisol, serum-free cortisol, salivary cortisol, real-time free cortisol, basal serum cortisol and post-adrenocorticotropin hormone (ACTH) stimulation test, or basal salivary cortisol and post-ACTH stimulation test), the predictive score for mortality (Pediatric Logistic Organ Dysfunction/PELOD), Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM), Vasotropic Inotropic Score (VIS), or Pediatric Critical Illness Score (PCIS)], mortality (non-survivor percentage), and CIRCI percentage as an outcome in patients with critical illness, sepsis, and septic shock.

Results Twenty-one observational studies were included in our systematic review, with a total of 2,212 subjects, 916 of whom had sepsis. Nineteen studies indicated a positive association between elevated cortisol levels and mortality in critically ill children, but 2 studies stated that there was no association with the CIRCI percentage of 32.3 and 84.3% respectively. The mortality percentage of critically ill patients with elevated cortisol levels and sepsis were 25.81 (2.7-60)% and 35.31 (6-60)%, respectively. The percentages of CIRCI in critically ill and sepsis patients were 21.91 (0-84.3)% and 21.35 (0-84.3)%, respectively.

Conclusion Cortisol levels may increase or decrease in critically ill children. Elevated cortisol levels are associated with mortality in septic children. The effect of CIRCI on mortality in critically ill children cannot be concluded.

References

1. Marik PE. Endocrinology of the stress response during critical illness. The stress response of critical illness: metabolic and hormonal aspects. Switzerland: Springer International Publishing; 2016. p. 446-454. PMID: 24970271.
2. Annane D, Pastores SM, Arlt W, Balk RA, Beishuizen A, Briegel J, 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;45:2078-88.. Intensive Care Med. 2017;17:4919. DOI: https://doi.org/10.1097/CCM.0000000000002737.
3. Téblick A, Peeters B, Langouche L, Van den Berghe G. Adrenal function and dysfunction in critically ill patients. Nature Rev Endocrinol. 2019; 15:417–2719:185. DOI: https://doi.org/10.1038/s41574-019-0185-7.
4. Elbuken G, Karaca Z, Tanriverdi F, Unluhizarci K, Sungur M, Doganay M, et al. Comparison of total, salivary, and calculated free cortisol levels in patients with severe sepsis. J Intensive Care. 2016;4:3. DOI: https://doi.org/10.1186/s40560-015-0125-0.
5. Bekhit OE, Mohamed SA, Yousef RM, AbdelRasol HA, Khalaf NA, Salah F. Relation between baseline total serum cortisol level and outcome in pediatric intensive care unit. Sci Rep. 2019;9:6008. DOI: https://doi.org/10.1038/s41598-019-42443-z.
6. Zabidi L, Supriatna M, Mexitalia M. Kadar kortisol serum sebagai indikator prognosis sepsis pada anak. Sari Pediatri. 2015;17:101-6.
7. Pertiwi N, Suryawan W, Arimbawa I, Suparyatha I. Association between serum cortisol levels and Pediatric Logistic Organ Dysfunction score in critically ill patients. Medicina. 2017;48:128-32. DOI: https://doi.org/10.15562/medi.v48i2.41.
8. Patki V, Khilnani P, Zimmerman J. Adrenal dysfunction in critical care settings. Journal of Pediatric Critical Care. 2017;4:52-63214. DOI: https://doi.org/10.21304/2017.0403.00214.
9. Uçar A, Ba? F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr. 2016;12:261-74. DOI: https://doi.org/10.1007/s12519-016-0018-x.
10. Soto-Rivera CL, Schwartz SM, Sawyer JE, Macrae DJ, Agus M. Endocrinologic diseases in pediatric cardiac intensive care. Pediatr Crit Care Med. 2016;17:S296–S301. DOI: https://doi.org/10.1097/PCC.0000000000000827.
11. Huang X, Hu W, He X, Zhang G. A potential diagnostic protocol for critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients. J Emerg Crit Care Med. 2018;2:86. DOI: https://doi.org/10.21037/jeccm.2018.10.11.
12. Wells GA, Shea B, O’Connell D, Peterson JD, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. The Ottawa Hospital. 2020.E17-18. Corpus ID: 79550924.
13. Rady H, Aly Y, Hafez M, Bazaraa H. Adrenocortical status in infants and children with sepsis and septic shock. 2014;62:18-23. DOI: : https://doi.org/10.1016/j.epag.2014.02.001.
14. Iyer P, Harrington B, Fadrowski J, Sibinga E, Amankwah E. 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;89:31-7. DOI: https://doi.org/10.1159/000484561.
15. Lin M, Zhang B, Lin H, Sun P, Wang S, Guo R, et al. Dynamic changes in serum cortisol and ACTH levels and lymphocyte subset counts in children with septic shock. Preprint (version 1) Research Square. 2020;(7):1-21. DOI: https://doi.org/10.21203/rs.3.rs-39009/v1.
16. Jacobs A, Derese I, Vander Perre S, Wouters P, Verbruggen S, Billen J, et al. Dynamics and prognostic value of the hypothalamus–pituitary–adrenal axis responses to pediatric critical illness and association with corticosteroid treatment: a prospective observational study. Intensive Care Med. 2020;46:70-81. DOI: https://doi.org/10.1007/s00134-019-05854-0.
17. Levy-Shraga Y, Pinhas-Hamiel O, Molina-Hazan V, Tamir-Hostovsky L, Eini ZM, Lerner-Geva L, et al. Elevated baseline cortisol levels are predictive of bad outcomes in critically ill children. Pediatr Emer Care. 2018;34:613-7. DOI: https://doi.org/10.1097/PEC.0000000000000784.
18. Balbao V, Costa M, Castro M, Carlotti A. Evaluation of adrenal function in critically ill children. Clin Endocrinol. 2014;81:559-65. DOI: 10.1111/cen.12444.
19. Aydin B, Demirkol D, Bas F, Turkoglu U, Kumral A, Karabocuoglu M, et al. Evaluation of endocrine function in children admitted to pediatric intensive care unit. Pediatrics International. 2014;56:349-53. DOI: https://doi.org/10.1111/ped.12269.
20. Demiral M, Kiral E, Dinleyici EC, Simsek E. Evaluation of the hypothalamic-pituitary-adrenal axis in a paediatric intensive care unit. Acta Endo (Buc) 2019;15:466-71. DOI: https://doi.org/10.4183/aeb.2019.466.
21. Menon K, McNally D, Acharya A, O’Hearn K, Choong K, Wong HR, et al. Random serum free cortisol and total cortisol measurements in pediatric septic shock. J Pediatr Endocrinol Metab. 2018;31:757–62. DOI: https://doi.org/10.1515/jpem-2018-0027.
22. Zimmerman J, Donaldson A, Barker R, Meert K, Harrison R, Carcillo J, et al. Real-time free cortisol quantification among critically ill children. Pediatr Crit Care Med. 2011;12:525-31. DOI: https://doi.org/10.1097/PCC.0b013e3181fe4474.
23. Singh S, Rathia S, Awasthi S, Singh, A, Bhatia V. Salivary cortisol estimation to assess adrenal status in children with fluid unresponsive septic shock. Indian Pediatr. 2013;15:681-4. DOI: https://doi.org/10.1007/s13312-013-0190-1.
24. Karaguzel G, Atay S, Deger O, Imamoglu M, Okten A, Karaguzel G. The effects of three specific conditions related to critical care on adrenal function in children. Intensive Care Med. 2012;38:1689-96. DOI: https://doi.org/10.1007/s00134-012-2662-5.
25. Alder M, Opoka A, Wong H. The glucocorticoid receptor and cortisol levels in pediatric septic shock. Crit Care. 2018;22:244. DOI: https://doi.org/10.1186/s13054-018-2177-8.
26. Nguyen T, Doan T, Tran D. The role of blood cortisol levels in the prognosis for pediatrics septic shock. Arch Pharma Pract. 2019;10:10-14.
27. Yehya N, Vogiatzi M, Thomas N, Srinivasan V. Cortisol correlates with severity of illness and poorly reflects adrenal function in pediatric acute respiratory distress syndrome. J Pediatr. 2016; 177: 212-8.1-7. DOI: https://doi.org/10.1016/j.jpeds.2016.05.020.
28. Elbaih A, Elkilany A, Enany M. Salivary cortisol level as a marker of adrenal function in children with systemic inflammatory response syndrome in Egypt. Ann Paediatr Rheum. 2017;6:28-33. DOI: https://doi.org/10.5455/apr.022720171311.
29. Rachmawati R, Widodo D, Tridjaja B, Pudjiaji A. Fungsi adrenal pada sepsis di unit perawatan intensif pediatrik. Sari Pediatri. 2011;12:426-32.
30. Wani WA, Dar SA, Mir MN, Ahmad QI, Ali SW, Charoo BA. Prognostic significance of serum cortisol in catecholamine-resistant pediatric shock. Int J Applied Res. 2019;5:142-8. DOI:10.22271/allresearch.2019.v5.i3c.01.
31. Weiss S, Peters M, Alhazzani W, Agus M, Flori H, Inwald D, et al. Surviving Sepsis Campaign International Guidelines for the management of septic shock and sepsis-associated organ dysfunction in children part II. Intensive Care Med. 2020;46:s10-s57. DOI: https://doi.org/10.1007/s00134-019-05878-6.