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A 3-Level Prognostic Classification in Septic Shock Based on Cortisol Levels and Cortisol Response to Corticotropin
Abstract
CONTEXT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. OBJECTIVE: To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. DESIGN AND SETTING: Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. PARTICIPANTS: A total of 189 consecutive patients who met clinical criteria for septic shock. INTERVENTION: A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. MAIN OUTCOME MEASURES: Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). RESULTS: The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). CONCLUSION: Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.
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“Short-term hormone dysfunction could also be explained by acute phase inflammation and stress49505152.”
From Endocrine dysfunction following traumatic brain injury: a 5-year follow-up nationwide-based study (2016) · cites this paper as [51]
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“Pulmonary artery catheterization 107 (47) 37 (57)† 60 (36) 39 (62)† Mechanical ventilation 117 (52) 47 (72)† 78 (47) 41 (65)† Median admission blood glucose level, mg/dL (range) 130 (100-173) 149 (100-229)† 128 (100-180) 142 (100-186)† Admission SOFA score‡ 8 (3-12) 10 (4-15)† 6 (3-11) 10 (5-14)† Maximal daily SOFA sc…”
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InfluentialSerum cytokines and critical illness-related corticosteroid insufficiency
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“(19) identified that patients with septic shock frequently had relative adrenal insufficiency and that their response to corticotropin predicted survival.”
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“%) was seen in the approximately 20% of patients who had a baseline cortisol of at least 34 mg/dL and a post-ACTH increase in cortisol of up to 9mg/dL.”
BackgroundInfluentialEFFECTS OF DEXAMETHASONE ON MACROPHAGE MIGRATION INHIBITORY FACTOR PRODUCTION IN SEPSIS
Bruhn, A. R., Verdant, C. L., Vercruysse, V., Su, F., Vray, B., & Vincent, J. (2006) · Shock · doi:10.1097/01.shk.0000225416.27742.cb · Cited by 24
“Sepsis and other inflammatory states activate the hypothalamic-pituitary-adrenal axis, resulting in increased blood levels of glucocorticoids (2).”
BackgroundDickerson, H. A., Cooper, D. S., Checchia, P. A., & Nelson, D. P. (2008) · Cardiology in the Young · doi:10.1017/s1047951108002990 · Cited by 24
“Although conflicting data exist, previous studies in adult patients with sepsis support steroid treatment in patients with both relative adrenal insufficiency and insufficient basal cortisol.(11,12,21) Much of the data on the hypothalamic-pituitaryadrenal axis in critical illness stems from research in patients with s…”
BackgroundResultLuce, J. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-141-1-200407060-00019 · Cited by 25
Zhao, T., Li, Y., Bronson, R. T., Liu, B., Velmahos, G. C., & Alam, H. B. (2014) · Surgery · doi:10.1016/j.surg.2014.03.033 · Cited by 23
Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders
Kondo, T., Okada, Y., Saika, S., Yamaguchi, N., Hatakeyama, S., & Maruyama, K. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151418 · Cited by 24
Advantages and Disadvantages of Etomidate Use for Intubation of Patients with Sepsis
Cherfan, A. J., Arabi, Y. M., Al‐Dorzi, H. M., & Kenny, L. P. (2012) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/j.1875-9114.2012.01027.x · Cited by 24
“Although reflecting on the definition or the clinical consequences of relative adrenal insufficiency is well beyond the scope of this review, there is evidence to show significant association between this condition and poor patient outcomes.(8) More alarming are the findings that link single-dose etomidate to an incre…”
BackgroundVenkatesh, B., & Cohen, J. (2014) · Clinical Endocrinology · doi:10.1111/cen.12702 · Cited by 23
Annane, D., Brun‐Buisson, C., Cariou, A., Martin, C., Misset, B., Renault, A., Lehmann, B., Millul, V., Maxime, V., & Bellissant, É. (2016) · Annals of Intensive Care · doi:10.1186/s13613-016-0147-3 · Cited by 23
“Finally, non-responders [16] were an a priori defined subgroup in analyzing corticosteroids effects.”
BackgroundSelf-citationCarlson, D. E., Chiu, W. C., & Scalea, T. M. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000207340.24290.3c · Cited by 23
Hypothalamic–pituitary hormones during critical illness
Langouche, L., & den Berghe, G. V. (2014) · Handbook of clinical neurology · doi:10.1016/b978-0-444-59602-4.00008-3 · Cited by 23
Bondanelli, M., Zatelli, M. C., Ambrosio, M. R., & Uberti, E. C. D. (2008) · Pituitary · doi:10.1007/s11102-008-0112-8 · Cited by 23
“The cortisol response to high-dose ACTH test may have prognostic implications, since an inadequate rise \9 lg/dl (250 nmol/l) may be associated with an increased risk of death [40, 41].”
BackgroundLumbar puncture and cerebrospinal fluid analysis
Welch, H., & Hasbun, R. (2010) · Handbook of clinical neurology · doi:10.1016/s0072-9752(09)96003-1 · Cited by 24
Experimental and emerging therapies for sepsis and septic shock
Añel, R., & Kumar, A. (2001) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.10.8.1471 · Cited by 23
“However, available evidence suggests that stress response to cortisol may also be impaired in sepsis and septic shock [6,7].”
BackgroundThe metabolic and nutritional response to critical illness
Lavery, G. G., & Glover, P. (2000) · Current Opinion in Critical Care · doi:10.1097/00075198-200008000-00001 · Cited by 23
Reduced cortisol metabolism during critical illness.
(2013) · New England Journal of Medicine · doi:10.1056/nejmc1306703 · Cited by 23
Elevated Circulating Leukemia Inhibitory Factor in Patients With Extensive Burns
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“higher basal cortisol level and less maximal responsiveness to short ACTH testing.(26) Not all of our cases”
BackgroundAdrenal function in sepsis and septic shock.
Pizarro, C. F., & Troster, E. (2007) · Jornal de Pediatria · doi:10.2223/jped.1708 · Cited by 22
“Incidence of adrenal insufficiency ranges according to population and criteria used to define this condition.(5,8,9,13,17-26)”
BackgroundCorticosteroids in Pediatric Heart Surgery: Myth or Reality
Fudulu, D. P., Gibbison, B., Upton, T. J., Stoica, S. C., Caputo, M., Lightman, S. L., & Angelini, G. D. (2018) · Frontiers in Pediatrics · doi:10.3389/fped.2018.00112 · Cited by 22
“In 189 consecutive adult patients with septic shock, the authors found that an incremental cortisol response to ACTH (defined as the difference between the basal cortisol and the highest value between cortisol measured at 30 and 60min) of <9 μg/dL or a high baseline cortisol concentration (>34 μg/dL) were of good prog…”
BackgroundSerum cortisol levels in children with acute bacterial and aseptic meningitis
Singhi, S. C., & Bansal, A. (2005) · Pediatric Critical Care Medicine · doi:10.1097/01.pcc.0000192317.90862.44 · Cited by 22
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Treatment of impaired perfusion in septic shock
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“There is a recent study which showed that mortality was associated with baseline and stimulated concentrations of cortisol in patients with septic shock (57).”
BackgroundAdmission hypoglycaemia is associated with adverse outcome in community-acquired pneumonia
Singanayagam, A., Chalmers, J. D., & Hill, A. T. (2009) · European Respiratory Journal · doi:10.1183/09031936.00197008 · Cited by 22
“In addition, studies have shown the presence of relative adrenal insufficiency in a proportion of patients with septicaemia [19-22] and this finding has been shown to correlate with adverse outcome [23].”
BackgroundCorticosteroids in sepsis: a new concept for an old drug.
Klaitman, V., & Almog, Y. (2003) · PubMed · Cited by 22
Corticosteroids for treating sepsis in children and adults
Annane, D., Briegel, J., Granton, D., Bellissant, É., Bollaert, P., Keh, D., Kupfer, Y. Y., Pirracchio, R., & Rochwerg, B. N. (2025) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002243.pub5 · Cited by 23
Self-citationAcute Adrenal Insufficiency May Affect Outcome in the Trauma Patient
Guillamondegui, O. D., Gunter, O. L., Patel, S. H., Fleming, S. B., Cotton, B. A., & Morris, J. A. (2009) · The American Surgeon · doi:10.1177/000313480907500404 · Cited by 21
Prognostic Value of Relative Adrenal Insufficiency During Cardiogenic Shock
Bagate, F., Lellouche, N., Lim, P., Moutereau, S., Razazi, K., Carteaux, G., de Prost, N., Dubois‐Randé, J., Brun‐Buisson, C., & Dessap, A. M. (2016) · Shock · doi:10.1097/shk.0000000000000710 · Cited by 21
“4%); in the second one, analysis was restricted to hospital mortality instead of long-term mortality; in the third one, classification of patients was based on thresholds commonly used during SS (13), that is, 938 nmol/L (34 mg/dL) for T0, and 248 nmol/L (9 mg/dL) for Dmax; with the latter thresholds, adrenal response…”
Metadata
- Authors
- Annane, D.
- Affiliations
- Hôpital Raymond-Poincaré (FR)
- Corresponding author
- Annane, Djillali
- ORCID
- Annane, Djillali
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2000-02-23
- Volume
- 283
- Issue
- 8
- Pages
- 1038
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2156618518
- Cited by
- 1,000
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 15 · 2023: 19 · 2022: 15 · 2021: 13 · 2020: 19 · 2019: 22 · 2018: 27 · 2017: 27 · 2016: 27 · 2015: 26 · 2014: 44 · 2013: 35 · 2012: 38
- FWCI
- 38.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Keywords
- septic shock, cortisol, ACTH stimulation test, tetracosactrin, hypothalamic-pituitary-adrenal axis, prognostic stratification, 28-day mortality, stress response, organ failure, lactate, PaO2/FiO2 ratio, intensive care unit patients, corticosteroid therapy, sepsis
- MeSH terms
- Adult, Cosyntropin, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Middle Aged, Pituitary-Adrenal System, Prognosis, Prospective Studies, Severity of Illness Index, Shock, Septic, Biomarkers, Multivariate Analysis, Proportional Hazards Models, Survival Analysis
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