Pituitary-adrenal function in patients with acute subarachnoid haemorrhage: a prospective cohort study

Stepani Bendel, Timo Koivisto, Esko Ruokonen, Jaakko Rinne, Jarkko Romppanen, Ilkka Vauhkonen, Vesa Kiviniemi, Ari Uusaro, Stepani Bendel, Timo Koivisto, Esko Ruokonen, Jaakko Rinne, Jarkko Romppanen, Ilkka Vauhkonen, Vesa Kiviniemi, Ari Uusaro

Abstract

Introduction: Subarachnoid haemorrhage (SAH) may damage the hypothalamo-pituitary-adrenal gland (HPA) axis and disturb cortisol metabolism. There are no available data that relates to the response of the HPA axis in the acute phase of SAH. We aimed to characterise the behavior of serum adrenocorticotropic hormone (ACTH), total cortisol, stimulated total cortisol and free cortisol concentrations in acute aneurysmal SAH.

Methods: A prospective cohort study was conducted of patients with acute aneurysmal SAH (n = 30) admitted to a tertiary university hospital. Patients admitted for elective aneurysmal surgery (n = 16) served as the control group. An ACTH stimulation test was performed twice during the first week and at three months. The main outcome measure was description of the ACTH-cortisol response by calculating serum free cortisol and measuring total cortisol and ACTH concentrations. A mixed models method was used for testing between the groups, allowing heterogeneity between the groups.

Results: Patients with SAH had higher initial serum total cortisol (mean +/- SD; 793 +/- 312 nmol/L) and free cortisol concentrations (83 +/- 55 nmol/L) than control patients (535 +/- 193 nmol/L, p = 0.001 and 33 +/- 18 nmol/L, p < 0.001, respectively). Thereafter, there were no differences in this respect. Serum free and total cortisol concentrations correlated but were unaffected by the severity of SAH. ACTH concentrations were comparable between SAH and control groups. Patients with Hunt-Hess grades IV to V had higher ACTH concentrations at day one (10.7 +/- 7.1 pmol/l/L) and day five (8.2 +/- 7.7 pmol/L) than patients with grade I-III (day one: 3.8 +/- 2.0 pmol/L, p = 0.002; day five: 4.7 +/- 1.8 pmol/L, p = 0.04).

Conclusions: Calculation of serum free cortisol concentration was not helpful in identifying patients with potential hypocortisolism. SAH severity did not affect cortisol concentrations, possibly indicating relative pituitary-adrenal insufficiency in patients with more severe bleeding.

Trial registration: ClinicalTrials.gov Identifier NCT00614887.

Figures

Figure 1
Figure 1
Flow chart of patients with (a) subarchnoid haemorrhage (SAH) and (b) control patients.
Figure 2
Figure 2
Serum free and total cortisol concentrations. Patients with subarchnoid haemorrhage (SAH) had higher initial (a) serum total cortisol (p = 0.001) and (b) free cortisol concentrations (p < 0.001) than control patients. At later time points, there were no differences between the groups in this respect. Data are presented as median, interquartile ranges and outliers.
Figure 3
Figure 3
Pooled data and quadratic regression analysis. Equation from quadratic regression analysis for serum free cortisol concentration = 0.024 × serum total cortisol concentration + 0.0000772 × total cortisol concentration2. Pearson correlation coefficient 0.88, p < 0.001.
Figure 4
Figure 4
Percentage of patients with baseline serum free cortisol concentration less than 55 nmol/L or serum total cortisol concentration less than 500 nmol/L. * = difference between the groups at day one, p = 0.046. ** = difference between the groups at day one, p < 0.001.
Figure 5
Figure 5
Response to exogenous adrenocorticotropic hormone (ACTH) in patients with subarachnoid haemorrhage (SAH) and control patients. There were no statistically significant differences between the groups. The percentage of patients with a serum cortisol response less than 248 nmol/L also was not different between the groups. Test one = day one; test two = day five (control) and day seven (SAH); test three = three months. Data are presented as median, interquartile ranges and outliers.
Figure 6
Figure 6
Evolution of corticoid-binding globulin (CBG) concentration in patients with subarachnoid haemorrhage (SAH) and control patients. There were no between-group differences, but CBG concentration changed significantly over time in both groups, p = 0.008. Data are presented as mean ± standard deviation.

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