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

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.

Keywords: Adrenal insufficiency; CIRCI; Glucocorticoids; HPA axis; Sepsis; Septic shock.

Fig. 1

Adrenocortical function parameters from day 7 in ICU until ICU discharge or death—and 7 days after ICU discharge—for patients who did not receive glucocorticoids. a Time courses for the 347 ICU patients, divided into the four cohorts based on the duration of ICU stay, as compared with 20 matched healthy subjects. b Last assessment in ICU and assessment 7 days after ICU discharge for all patients. Data are shown as mean ± SEM on a logarithmic scale. ICU intensive care unit, d day, w week. Circles during ICU stay denote data points for all patients included within each time cohort, triangles denote data points of a decreasing numbers of patients. The horizontal blue-shaded area represents the mean ± SEM of results from the 20 healthy subjects. *P ≤ 0.05 for the comparison with healthy subjects

Fig. 2

Estimated activity of the cortisol-metabolizing enzymes 11β-HSD2 (a), 5α-reductase (b,c) and 5β-reductase (d,e) from day 7 in ICU until ICU discharge or death among the 64 long-stay (ICU ≥ 4w) patients who did not receive glucocorticoids. Results for the patients are shown as mean ± SEM on a logarithmic scale. ICU intensive care unit. Circles during ICU stay denote data points for all patients in ICU for at least 4 weeks, triangles denote data points of a decreasing numbers of patients thereafter. The horizontal blue-shaded areas represent the mean ± SEM of results from the 20 healthy subjects. *P < 0.001 for the comparisons with healthy subjects

Fig. 3

Adrenocortical function parameters from day 7 in ICU until ICU discharge or death in long-stay (ICU ≥ 4w) patients who did not receive glucocorticoids, a compared for the presence or absence of sepsis, b compared for the presence or absence of septic shock, and c compared for survivors and non-survivors. Data are shown as mean ± SEM on a logarithmic scale. ICU intensive care unit. The horizontal blue-shaded areas represent the mean ± SEM of results from the 20 healthy subjects. The numerical P values are those for the comparisons between patient groups

Fig. 4

Adrenocortical function parameters for patients on the last pre-glucocorticoid treatment assessment and for patients who did not receive glucocorticoids, matched for risk factors and day of assessment. a plasma ACTH, b total cortisol, c free cortisol, d incremental total cortisol response, e incremental free cortisol response. Data are shown as mean ± SEM on a logarithmic scale. The horizontal blue-shaded areas represent the mean ± SEM of results from the 20 healthy subjects. The numerical P values are those for the comparisons between patient groups and *P ≤ 0.01 for the comparisons with healthy subjects