Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery in adrenal insufficiency

Context: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. Objective: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress. Design and Participants: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration). Main Outcome Measure: We measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. Results: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. Conclusions: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

. First, in a cross-sectional study, we measured circulating glucocorticoid concentrations in 122 1 2 0 healthy, non-stressed controls and 288 subjects with distinct and defined states of stress at the Afghanistan conflict) (9); 83 prospectively recruited subjects with acute major trauma (estimated   Table 1). Blood samples were drawn at the following 1 3 3 time points: 0 (=knife-to-skin, KTS), 0.5, 1, 2, 3, 4, 5, 6, 12, and 24 hours. Third, we undertook a randomized, open-label study in 10 patients with an established diagnosis 1 3 5 of primary adrenal insufficiency and on stable steroid replacement therapy for at least six months 1 3 6 (Suppl. Table 2). All patients attended the Clinical Research Facility for a 24-hour study period 1 3 7 on four occasions separated by at least one week. On each study day, they were admitted at 1 3 8 . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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Glucocorticoid concentrations in different conditions of stress 1 8 5 Serum total cortisol concentrations were highest and most variable in patients with sepsis,  When analyzing the inactive cortisol metabolite cortisone, pairwise comparisons to levels 1 9 1 observed in unstressed controls showed significantly higher serum cortisone in combat stress, 1 9 2 whilst circulating cortisone was significantly lower in elective surgery and sepsis patients; serum 1 9 3 cortisone concentrations in patients after major trauma did not differ from unstressed controls  Free serum cortisol concentrations were higher than in unstressed controls in all stressed groups,   We separately analyzed circulating glucocorticoid concentrations in patients undergoing . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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increase. In the group with shorter surgery, maximum serum cortisol concentrations (C max ) were 2 0 7 observed after a median of 3 hours post-KTS, while in the group with longer duration surgery, 2 0 8 C max were observed after a median of 5 hours post-KTS (Table 2 and Suppl. Fig. 1), i.e. during 2 0 9 the wake-up phase after general anesthesia. After reaching C max , both serum cortisol and cortisone concentrations gradually decreased back 2 1 1 to pre-surgical baseline levels in the patients with short duration surgery, while circulating 2 1 2 glucocorticoid concentrations remained increased in the group with longer-lasting surgery 2 1 3 (Suppl. Fig. 1). The serum cortisol/cortisone ratio followed a similar pattern, with no difference 2 1 4 between the two groups after 24 hours (Suppl. Fig. 1). After administration of bolus hydrocortisone, C max were achieved after a median time of 30 min 2 1 8 (ORAL and IVI) or 60 min (IM), followed by a decrease to minimum concentrations (C min ) after  Table 2). By contrast, CIV administration of hydrocortisone led to serum cortisol 2 2 1 concentrations persistently within the same range from around 2 hours after the commencement 2 2 2 of infusion, without distinct peak and trough concentrations after achievement of steady state differences between the four hydrocortisone delivery modes (Suppl. Fig. 2).

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For all four hydrocortisone administration regimens, serum free cortisol concentrations at T max 2 2 6 (i.e. when C max were observed) were significantly higher than those observed in patients exposed to different stress conditions, except for sepsis, where free cortisol tended to be higher (Suppl. . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint .
12 than in surgical patients at KTS and 4 hours into surgery, and after acute trauma, but 2 3 0 significantly lower than in sepsis (Suppl. Fig. 3a). Free cortisol concentrations at T min of the 2 3 1 other hydrocortisone administration protocols were significantly lower than in sepsis, but did not 2 3 2 differ from those observed during other stress conditions. The pattern of 24-hour urinary glucocorticoid metabolite excretion was similar in patients 2 3 4 receiving hydrocortisone in the IM, IV, and CIV administration modes while after oral 2 3 5 hydrocortisone administration urine cortisol excretion was lower but cortisol metabolite 2 3 6 excretion was higher (Suppl. Fig. 3b), indicative of a first-pass effect with rapid metabolism of   IVI hydrocortisone administration decreased to trough levels below the median observed in CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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13 administration persistently maintained serum cortisol concentrations above the median of consistently above those observed in subjects undergoing elective surgery (Suppl. Fig. 4).

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Linear pharmacokinetic modelling of stress dose hydrocortisone administration 2 5 8 Next, we used the pharmacokinetic data obtained in the primary adrenal insufficiency patients   predicted that both would achieve the serum cortisol concentration range observed for longer-  . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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14 DISCUSSION 2 7 6 Patients with adrenal insufficiency are unable to mount a cortisol response to counteract a 2 7 7 stressful event and, therefore, their regular replacement dose needs to be increased during major 2 7 8 stress to avoid adrenal crisis (15). Nevertheless, no consensus exists regarding the optimal dose 2 7 9 and hydrocortisone delivery mode during major stress, and current recommendations are 2 8 0 empirical rather than evidence-based (7,16). This study is the first systematic dose-response  In line with previously reported findings (17-19), we documented that serum total cortisol 2 9 3 concentrations in all examined conditions of psychological and physical stress were increased 2 9 4 above those observed in healthy, unstressed controls. The only exception was major trauma, with 2 9 5 relatively lower total serum cortisol concentrations but increased serum free cortisol and 24-hour 2 9 6 urinary cortisol, likely explained by the impact of blood loss in these patients. . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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15 Consistent with our previous systematic review and meta-analysis of the cortisol response to 2 9 8 surgery (19), we observed an initial decrease in serum cortisol during elective surgery, which is 2 9 9 likely to be linked to the induction of anesthesia. We observed higher cortisol concentrations 3 0 0 during longer-lasting surgery, using reference standard tandem mass spectrometry for serum 3 0 1 glucocorticoid analysis. This was also observed in a recent study in 93 patients undergoing   hydrocortisone over 24 hours as the most appropriate replacement regiment in patients with 3 1 0 adrenal insufficiency exposed to major stress. Modelling indicated that this should be preceded 3 1 1 by a one-off initial intravenous bolus of 50-100mg hydrocortisone to rapidly increase serum 3 1 2 cortisol and shorten the time to steady state. We found that continuous intravenous  . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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16 adverse side effects, as previously shown in the context of sepsis with an increased rate of Another limitation of our study is that the surgical group comprised mostly patients undergoing 3 4 9 moderately invasive procedures. Thus, we cannot exclude that more invasive and longer-lasting with withdrawal of general anesthesia and more invasive surgeries will be undertaken with the  In conclusion, our data provide evidence that hydrocortisone stress dose cover during surgery,  The datasets generated during and/or analyzed during the current study are not publicly available 3 6 1 but are available from the corresponding author on reasonable request. . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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9.
Hill NE, Fallowfield JL, Delves SK, Ardley C, Stacey M, Ghatei M, Bloom SR, Frost G, . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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13.
Perogamvros I, Owen LJ, Newell-Price J, Ray DW, Trainer PJ, Keevil BG. Simultaneous . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
is the (which was not peer-reviewed) The copyright holder for this preprint . 20 metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. The . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
is the (which was not peer-reviewed) The copyright holder for this preprint .

20.
Khoo B, Boshier PR, Freethy A, Tharakan G, Saeed S, Hill N, Williams EL, Moorthy K, . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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28.
Christ . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
is the (which was not peer-reviewed) The copyright holder for this preprint .  pharmacokinetic modelling was also used to predict the serum cortisol response to 100mg IV 5 1 2 bolus injection over 6 and 24 hours (panels c and d, respectively), as well as initial 50mg (Panel 5 1 3 . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint . . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
is the (which was not peer-reviewed) The copyright holder for this preprint . 24-hour collection from 09:00h to 09:00h a All patients underwent measurements of serum total cortisol and cortisone. A subgroup of patients provided samples to measure serum free cortisol and urinary glucocorticoids. b All patients underwent measurements of serum total cortisol and cortisone. All but one patient provided samples to measure serum free cortisol and urinary glucocorticoids. c Blood was collected at: T min : time when the minimum serum total cortisol levels were observed after hydrocortisone administration; T max : time when the maximum serum total cortisol levels were observed after hydrocortisone administration. . CC-BY 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
is the

(which was not peer-reviewed)
The copyright holder for this preprint  insufficiency (N=10).

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28 Hydrocortisone was administered either as six-hourly bolus injection (ORAL, IM, IVI) or by CIV. All data are presented as median (range); numbers for the three different hydrocortisone bolus administration modes represent averages of the observations made during the four consecutive 6-hour intervals, while CIV data refer to the time period 2-24h (steady state was achieved at 2h during CIV). Abbreviations: CIV: continuous intravenous infusion; C max : maximum serum total cortisol concentration observed; C min : minimum serum total cortisol concentration observed; IM: intramuscular; IVI: intravenous injection; T max : time when the maximum serum total cortisol concentrations (C max ) were observed; T min : time when the minimum serum total cortisol concentrations (C min ) were observed.

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Cross-sectional study
Longitudinal study (observational) Pharmacokinetic study (interventional, randomized, open-label) Circulating glucocorticoid concentrations during distinct states of stress, as compared to healthy, unstressed subjects