Measurement of serum free cortisol shows discordant responsivity to stress and dynamic evaluation

CONTEXT: Routinely available assays of adrenal function measure serum total cortisol (TC) and not the biologically active free cortisol (FC). However, there are few data on FC levels during surgical stress and in response to standard pharmacological tests. OBJECTIVE: Our objective was to evaluate TC and FC levels in different states of physical stress. DESIGN AND SETTING: We conducted a prospective observational study in a university hospital. PARTICIPANTS AND MAIN OUTCOME MEASURES: We measured TC and FC levels in 64 patients: group A, 17 healthy controls without stress; group B, 23 medical patients with moderate stress; and group C, 24 surgical patients undergoing coronary bypass grafting. Cortisol levels in group C were measured basally and at several time points thereafter and were compared with responsivity to a pharmacological dose of ACTH. FC was measured using equilibrium dialysis. RESULTS: In group C patients after extubation, the relative increase above basal FC was higher than the increase in TC levels (399 +/- 266 vs. 247 +/- 132% of initial values, respectively; mean +/- sd; P = 0.02) and then fell more markedly, FC levels falling to 67 +/- 49% and TC levels to 79 +/- 36% (P = 0.04). After ACTH stimulation, TC levels increased to 680 +/- 168 nmol/liter, which was similar to the increase with major stress (811 +/- 268 nmol/liter). In contrast, FC levels increased to 55 +/- 16 nmol/liter after ACTH stimulation but significantly greater with surgical stress to 108 +/- 56 nmol/liter (P > 0.001). CONCLUSION: The more pronounced increase in FC seen during stress as compared with the ACTH test suggests that this test does not adequately anticipate the FC levels needed during severe stress.