Top

Published in:

Open Access 01-10-2018 | Original

Adrenocortical function during prolonged critical illness and beyond: a prospective observational study

Authors: Bram Peeters, Philippe Meersseman, Sarah Vander Perre, Pieter J. Wouters, Dimitri Vanmarcke, Yves Debaveye, Jaak Billen, Pieter Vermeersch, Lies Langouche, Greet Van den Berghe

Published in: Intensive Care Medicine | Issue 10/2018

Abstract

Purpose

For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus–pituitary–adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.

Methods

Patients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.

Results

In all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.

Conclusions

Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.

Available only for authorised users

Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander PS, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G (2013) Reduced cortisol metabolism during critical illness. N Engl J Med 368:1477–1488CrossRef

Vermes I, Beishuizen A, Hampsink RM, Haanen C (1995) Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 80:1238–1242PubMed

Peeters B, Guiza F, Boonen E, Meersseman P, Langouche L, Van den Berghe G (2017) Drug-induced HPA axis alterations during acute critical illness: a multivariable association study. Clin Endocrinol (Oxf) 86:26–36CrossRef

Polito A, Sonneville R, Guidoux C, Barrett L, Viltart O, Mattot V, Siami S, de la Grandmaison GL, Chretien F, Singer M, Gray F, Annane D, Brouland JP, Sharshar T (2011) Changes in CRH and ACTH synthesis during experimental and human septic shock. PLoS One 6:e25905CrossRef

Bornstein SR (2009) Predisposing factors for adrenal insufficiency. N Engl J Med 360:2328–2339CrossRef

Boonen E, Bornstein SR, Van den Berghe G (2015) New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol 3:805–815CrossRef

Annane D, Pastores SM, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Meduri GU, Olsen KM, Rochwerg B, Rodgers SC, Russell JA, Van den Berghe G (2017) Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 43:1781–1792CrossRef

Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E (2000) A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038–1045CrossRef

Barquist E, Kirton O (1997) Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 42:27–31CrossRef

10.

Van den Berghe G (2016) On the neuroendocrinopathy of critical illness. Perspectives for feeding and novel treatments. Am J Respir Crit Care Med 194:1337–1348CrossRef

11.

Peeters B, Langouche L, Van den Berghe G (2017) Adrenocortical stress response during the course of critical illness. Compr Physiol 8:283–298CrossRef

12.

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 (2017) 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 43:1751–1763CrossRef

13.

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 SC, Russell JA, Van den Berghe G (2017) 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. Crit Care Med 45:2078–2088CrossRef

14.

Peeters B, Meersseman P, Vander Perre S, Wouters P, Vanmarcke D, Langouche L, Van den Berghe G (2018) The HPA-axis responses to prolonged critical illness: when do these normalize again, if at all?. Poster presented at the Annual Meeting of the Endocrine Society, Chicago

15.

Boonen E, Meersseman P, Vervenne H, Meyfroidt G, Guiza F, Wouters PJ, Veldhuis JD, Van den Berghe G (2014) Reduced nocturnal ACTH-driven cortisol secretion during critical illness. Am J Physiol Endocrinol Metab 306:E883–E892CrossRef

16.

Vanhorebeek I, Peeters RP, Vander Perre S, Jans I, Wouters PJ, Skogstrand K, Hansen TK, Bouillon R, Van den Berghe G (2006) Cortisol response to critical illness: effect of intensive insulin therapy. J Clin Endocrinol Metab 91:3803–3813CrossRef

17.

Boonen E, Langouche L, Janssens T, Meersseman P, Vervenne H, De Samblanx E, Pironet Z, Van Dijck L, Vander Perre S, Derese I, Van den Berghe G (2014) Impact of duration of critical illness on the adrenal glands of human intensive care patients. J Clin Endocrinol Metab 99:4214–4222CrossRef

18.

Deutschman CS, Raj NR, McGuire EO, Kelz MB (2013) Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit Care Med 41:e368–e375CrossRef

19.

Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K (1999) Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 27:723–732CrossRef

20.

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871CrossRef

21.

Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124CrossRef

22.

Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, Keh D, Kupfer Y, Oppert M, Meduri GU (2009) Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 301:2362–2375CrossRef

23.

Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, Winzeler B, Bingisser R, Elsaesser H, Drozdov D, Arici B, Urwyler SA, Refardt J, Tarr P, Wirz S, Thomann R, Baumgartner C, Duplain H, Burki D, Zimmerli W, Rodondi N, Mueller B, Christ-Crain M (2015) Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 385:1511–1518CrossRef

24.

Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RA, Kocak M (2016) Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med 42:829–840CrossRef

25.

Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J, ADRENAL Trial Investigators, Australian-New Zealand Intensive Care Society Clinical Trials Group (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378:797–808CrossRef

26.

Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E, CRICS-TRIGGERSEP Network (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378:809–818CrossRef

27.

Gibbison B (2018) Diagnosing adrenal insufficiency in critical illness: time to go back to the start. Resuscitation 129:A11–A12CrossRef

28.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829CrossRef

29.

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655CrossRef

30.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810CrossRef

Title: Adrenocortical function during prolonged critical illness and beyond: a prospective observational study
Authors: Bram Peeters
Philippe Meersseman
Sarah Vander Perre
Pieter J. Wouters
Dimitri Vanmarcke
Yves Debaveye
Jaak Billen
Pieter Vermeersch
Lies Langouche
Greet Van den Berghe
Publication date: 01-10-2018
Publisher: Springer Berlin Heidelberg
Published in: Intensive Care Medicine / Issue 10/2018
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-018-5366-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Adrenocortical function during prolonged critical illness and beyond: a prospective observational study

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2018

Unilateral pulmonary venous occlusion caused by a localized pericardial clot

Industry-funded versus non-profit-funded critical care research: a meta-epidemiological overview

Conflicts of interest and the patient–doctor covenant

Gastric perforation following cardiopulmonary resuscitation

Do I have a conflict of interest? No

Association of conflicts of interest with the results and conclusions of goal-directed hemodynamic therapy research: a systematic review with meta-analysis