Prevention of adrenal crisis: cortisol responses to major stress ...€¦ · 08/02/2020 ·...

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Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose 1

hydrocortisone delivery in adrenal insufficiency 2

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Alessandro Prete MD*, Angela E Taylor PhD*, Irina Bancos MD, David J Smith PhD, Mark A 4

Foster PhD, Sibylle Kohler MD, Violet Fazal-Sanderson BSc, John Komninos MD, Donna M 5

O’Neil PhD, Dimitra A Vassiliadi MD, Christopher J Mowatt MD, Radu Mihai PhD, Joanne L 6

Fallowfield PhD, Djillali Annane PhD, Janet M Lord FMedSci, Brian G Keevil PhD, John AH 7

Wass MD#, Niki Karavitaki PhD#, and Wiebke Arlt FMedSci# (corresponding author). 8

* Joint first authors # Equal senior authors 9

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Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 11

2TT, UK (AP, AET, DJS, DMO’N, IB, NK, WA); Centre for Endocrinology, Diabetes and 12

Metabolism, Birmingham Health Partners, Birmingham, B15 2GW, UK (AP, AET, NK, WA); 13

Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Mayo 14

Clinic, Rochester, MN 55905, USA (IB); School of Mathematics, University of Birmingham, 15

Birmingham, B15 2TT, UK (DJS); Institute of Inflammation and Ageing, University of 16

Birmingham, Birmingham, B15 2WB, UK (MAF, JML); NIHR Surgical Reconstruction and 17

Microbiology Research Centre, Queen Elizabeth Hospital, Birmingham, B15 2GW, UK (MAF, 18

JML); Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, B15 2GW, 19

UK (MAF); Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, 20

Oxford, OX3 7LE, UK (SK, VFS, JK, JAHW); Department of Endocrinology, Diabetes and 21

Metabolism, Evangelismos Hospital, Athens, Greece (DAV); Department of Anaesthesiology, 22

Royal Shrewsbury Hospital, The Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK 23

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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(CJM); Department of Endocrine Surgery, Churchill Hospital, Oxford, UK (RM); Institute of 24

Naval Medicine, Alverstoke, PO12 2DL, UK (JLF); Critical Care Department, Hôpital 25

Raymond-Poincaré, Laboratory of Infection & Inflammation U1173 INSERM/University Paris 26

Saclay-UVSQ, Garches, 92380, France (DA); Department of Clinical Biochemistry, University 27

Hospital of South Manchester, Manchester Academic Health Science Centre, The University of 28

Manchester, Manchester, UK (BGK); NIHR Birmingham Biomedical Research Centre (JML, 29

WA), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, 30

Birmingham, B15 2TH, UK. 31

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Short title: Prevention of adrenal crisis in stress. 33

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Keywords: stress; surgery; hydrocortisone; cortisol; glucocorticoids; mass spectrometry. 35

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Corresponding author: 37

Professor Wiebke Arlt MD DSc FRCP FMedSci 38

Institute of Metabolism and Systems Research 39

College of Medical and Dental Sciences 40

University of Birmingham, 41

Birmingham, B15 2TT, UK. 42

Email: [email protected] 43

Telephone: +44(0)1214158811 44

Fax: +44(0)1214158712 45

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Funding: This work was supported by the Medical Research Council UK (program grant 47

G0900567, to WA), the Oxfordshire Health Services Research Committee (NK), and the 48

National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the 49

University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham 50

(grant reference number BRC-1215-2009, to WA and JML). AP is a Diabetes UK Sir George 51

Alberti Research Training Fellow (grant reference number 18/0005782). IB is the recipient of a 52

Robert and Elizabeth Strickland Career Development Award, the James A Ruppe Career 53

Development Award in Endocrinology, and the Mayo Clinic Catalyst Award for Advancing in 54

Academics. 55

The views expressed are those of the authors and not necessarily those of the NIHR or the 56

Department of Health and Social Care UK. The funders of the study had no role in the: design 57

and conduct of the study; collection, management, analysis, and interpretation of the data; 58

preparation, review, or approval of the manuscript; decision to submit the manuscript for 59

publication. 60

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Disclosure summary: All authors declare: no support from any organization for the submitted 62

work other than that described above; no financial relationships with any organizations that 63

might have an interest in the submitted work; no other relationships or activities that could 64

appear to have influenced the submitted work. 65



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ABSTRACT 66

Context: Patients with adrenal insufficiency require increased hydrocortisone cover during major 67

stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are 68

not evidence-based. 69

Objective: To identify the most appropriate mode of hydrocortisone delivery in patients with 70

adrenal insufficiency exposed to major stress. 71

Design and Participants: Cross-sectional study: 122 unstressed healthy subjects and 288 72

subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress 73

[N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective 74

surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing 75

administration of 200mg hydrocortisone over 24 hours in four different delivery modes 76

(continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus 77

administration). 78

Main Outcome Measure: We measured total serum cortisol and cortisone, free serum cortisol 79

and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic 80

modelling was used to determine the most appropriate mode and dose of hydrocortisone 81

administration in patients with adrenal insufficiency exposed to major stress. 82

Results: Serum cortisol was increased in all stress conditions, with the highest values observed 83

in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode 84

persistently achieving median cortisol concentrations in the range observed during major stress. 85

Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg 86

hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best 87

suited for maintaining cortisol concentrations in the required range. 88



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Conclusions: Continuous intravenous hydrocortisone infusion should be favored over 89

intermittent bolus administration in the prevention and treatment of adrenal crisis during major 90

stress. 91

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INTRODUCTION 93

The activation of the hypothalamic-pituitary-adrenal axis in response to stressful stimuli elicits 94

increased glucocorticoid output, aiming at restoring homeostasis. Cortisol is the major 95

glucocorticoid produced by the human adrenal glands and is a key component of the 96

physiological stress response (1). 97

Adrenal insufficiency is caused by failure of the adrenal cortex to produce cortisol, which can be 98

caused by loss of function of the adrenal itself or its hypothalamic-pituitary regulatory center or, 99

most commonly, long-term exogenous glucocorticoid treatment for other conditions. Patients 100

with adrenal insufficiency are unable to produce adequate amounts of cortisol in response to 101

stress and, therefore, require increased hydrocortisone replacement doses to avoid life-102

threatening adrenal crisis during surgery, trauma or severe infection (2-4). Prevention of adrenal 103

crisis is challenging (5,6), and studies investigating the optimal dose and mode of steroid cover 104

during major stress are lacking. Currently, administered hydrocortisone doses are chosen 105

empirically rather than based on evidence. There is considerable variability in recommended 106

administration modes, total doses, and dosing intervals (7). The lack of evidence-based 107

recommendations for dose and mode of glucocorticoid replacement in major stress sends a 108

confusing message to healthcare staff, which regularly exposes patients to harm (8). 109

This study was designed to determine the most appropriate hydrocortisone dose and delivery 110

mode for patients with adrenal insufficiency during major stress. We employed tandem mass 111

spectrometry to measure glucocorticoid concentrations in subjects with preserved adrenal 112

function exposed to various conditions of stress, and compared them to concentrations achieved 113

after administration of stress dose hydrocortisone by a range of currently used delivery modes in 114

patients with adrenal insufficiency. 115



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MATERIALS AND METHODS 116

Study design, participants, and procedures 117

Three clinical studies were undertaken (Figure 1), with patient demographics and outcome 118

measures summarized in Table 1. 119

First, in a cross-sectional study, we measured circulating glucocorticoid concentrations in 122 120

healthy, non-stressed controls and 288 subjects with distinct and defined states of stress at the 121

time of blood sampling. These conditions of stress included: 105 otherwise healthy subjects 122

under combat stress (blood samples taken within four weeks of their deployment to the 123

Afghanistan conflict) (9); 83 prospectively recruited subjects with acute major trauma (estimated 124

new injury severity score [NISS] (10) >15; blood samples taken within 24 hours of acute injury, 125

excluding brain injury); 100 consecutively recruited patients with sepsis (blood samples 126

collected within 24 hours of fulfilling the criteria for sepsis (11) in the Intensive Care Unit 127

setting). At the time of sampling, none of the subjects had an established diagnosis of adrenal 128

insufficiency or were receiving treatment with glucocorticoids or other medications with major 129

impact on steroid synthesis or metabolism. 130

Second, we prospectively recruited 22 patients with normal adrenal function who underwent 131

repeated longitudinal serum sample collection over a 24-hour period whilst undergoing elective 132

surgery with general anesthesia (Suppl. Table 1). Blood samples were drawn at the following 133

time points: 0 (=knife-to-skin, KTS), 0.5, 1, 2, 3, 4, 5, 6, 12, and 24 hours. 134

Third, we undertook a randomized, open-label study in 10 patients with an established diagnosis 135

of primary adrenal insufficiency and on stable steroid replacement therapy for at least six months 136

(Suppl. Table 2). All patients attended the Clinical Research Facility for a 24-hour study period 137

on four occasions separated by at least one week. On each study day, they were admitted at 138



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08:00h after an overnight fast and last intake of their regular steroid replacement at 12:00h the 139

preceding day; standardized meals were served at 10:00h, 14:00h, and 18:00h. On each of the 140

study days, subjects received 200mg hydrocortisone over 24 hours administered by one of four 141

different administration modes: oral tablets (ORAL; 50mg at 09:00h, 15:00h, 21:00h, and 142

03:00h); intramuscular bolus injection (IM; 50mg at 09:00h, 15:00h, 21:00h, and 03:00h); 143

intravenous bolus injection (IVI; 50mg at 09:00h, 15:00h, 21:00h, and 03:00h); continuous 144

intravenous infusion (CIV) of 200mg hydrocortisone over 24 hours (diluted in 50 ml glucose 5% 145

and administered via perfusor at a rate of 4 ml/h). The four different administration modes were 146

administered to each patient in random order (Suppl. Table 2). Blood sampling was carried out 147

every 30 min from 9:00h-11:00h, 15:00h-17:00h, 21:00h-23:00h, and 03:00h-05:00h and 148

otherwise in hourly intervals throughout the 24-hour study period. 149

Ethics approval 150

All study participants provided written informed consent prior to inclusion and all study 151

procedures underwent Ethics Committee approval prior to recruitment (combat stress: MOD 152

REC 116/Gen/10; major trauma: NRES Committee South West – Frenchay 11/SW/0177; sepsis: 153

Comité de Protection des Personnes de Saint-Germain-en-Laye – COITTSS trial NCT00320099; 154

elective surgery and adrenal insufficiency: South Birmingham REC Ref 07/H1207/22). 155

Glucocorticoid measurements 156

Serum concentrations of total cortisol and its inactive metabolite cortisone were measured by 157

liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described (12). 158

For measurement of serum free cortisol concentrations, the unbound cortisol fraction was 159

separated by temperature-controlled ultrafiltration, centrifuged in preconditioned ultrafiltration 160

devices and then measured with LC-MS/MS, as previously described (13). Measurement of 24-161



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hour urinary glucocorticoid excretion was carried out by gas chromatography/mass spectrometry, 162

as previously described (14). For further details on the mass spectrometry analysis, see Suppl. 163

Methods. 164

Statistical analysis 165

Medians with 5th to 95th centile ranges and interquartile ranges were calculated for continuous 166

variables. The area under the concentration-time curve (AUC) was calculated by means of 167

trapezoidal integration. Serum cortisol concentrations between the various groups were 168

compared by Kruskal-Wallis and Mann-Whitney U tests. The level of significance was set at 169

p<0.05. Statistical analyses were performed by SPSS 178 21.0 for Windows (SPSS, Inc., 170

Chicago, IL, USA) and MATLAB (Mathworks, Natick MA, USA). 171

Pharmacokinetic modelling analysis 172

The serum cortisol time course response �� was modelled relative to intravenous 173

hydrocortisone via linear pharmacokinetics, ��

�� , ��0� � �, where � is clearance rate, 174

� is initial response (representing intravenous bolus [IVI] delivery), and is rate of continuous 175

intravenous (CIV) delivery of hydrocortisone. This model has the exact solution, �� 176

� ��

��1 � ��. IVI 50mg data over 6-12 hours was used to fit the parameters � and � 177

(with � 0) using a mixed effects model implemented in MATLAB (Mathworks, Natick MA, 178

USA) and the function nlmefit. This approach enabled the estimation of population average 179

(fixed effects) and between-patient heterogeneity (random effects). Responses to other modes of 180

administration were predicted by plotting model solutions with appropriately modified 181

parameters � and �� ; for example IVI 100mg was modelled by taking �� 2� and � � 0; CIV 182

200mg/24h was modelled by taking � � �/6 and �� 0. 183



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RESULTS 184

Glucocorticoid concentrations in different conditions of stress 185

Serum total cortisol concentrations were highest and most variable in patients with sepsis, 186

followed by patients undergoing elective surgery with general anesthesia, patients with combat 187

stress, and patients with acute major trauma (Figure 2a). Pairwise comparisons showed 188

significant differences between unstressed controls vs. all stressed groups, except for patients 189

with major trauma. 190

When analyzing the inactive cortisol metabolite cortisone, pairwise comparisons to levels 191

observed in unstressed controls showed significantly higher serum cortisone in combat stress, 192

whilst circulating cortisone was significantly lower in elective surgery and sepsis patients; serum 193

cortisone concentrations in patients after major trauma did not differ from unstressed controls 194

(Figure 2b). The serum cortisol/cortisone ratio showed a significant increase, favoring active 195

cortisol in all stress conditions, with the highest increase in sepsis (Figure 2c). 196

Free serum cortisol concentrations were higher than in unstressed controls in all stressed groups, 197

with the highest concentrations observed in sepsis (Figure 2d). 198

24-hour urinary excretion of cortisol, cortisone and their major metabolites was significantly 199

increased in major trauma, whilst glucocorticoid excretion in patients undergoing elective 200

surgery did not significantly differ from unstressed controls (Figure 2e). 201

Glucocorticoid dynamics during elective surgery 202

We separately analyzed circulating glucocorticoid concentrations in patients undergoing 203

surgeries of short duration (median duration 60 min, range 25-85 min; n=11) from those who 204

underwent longer-lasting surgery (median duration 175 min, range 100-295 min; n=11). In both 205

groups, serum cortisol decreased within an hour of induction of anesthesia, followed by a gradual 206



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increase. In the group with shorter surgery, maximum serum cortisol concentrations (Cmax) were 207

observed after a median of 3 hours post-KTS, while in the group with longer duration surgery, 208

Cmax were observed after a median of 5 hours post-KTS (Table 2 and Suppl. Fig. 1), i.e. during 209

the wake-up phase after general anesthesia. 210

After reaching Cmax, both serum cortisol and cortisone concentrations gradually decreased back 211

to pre-surgical baseline levels in the patients with short duration surgery, while circulating 212

glucocorticoid concentrations remained increased in the group with longer-lasting surgery 213

(Suppl. Fig. 1). The serum cortisol/cortisone ratio followed a similar pattern, with no difference 214

between the two groups after 24 hours (Suppl. Fig. 1). 215

Pharmacokinetics of stress dose hydrocortisone in patients with primary adrenal 216

insufficiency 217

After administration of bolus hydrocortisone, Cmax were achieved after a median time of 30 min 218

(ORAL and IVI) or 60 min (IM), followed by a decrease to minimum concentrations (Cmin) after 219

a median time of 360 min, i.e. before the administration of the next 6-hourly dose (Figure 3a-c 220

and Table 2). By contrast, CIV administration of hydrocortisone led to serum cortisol 221

concentrations persistently within the same range from around 2 hours after the commencement 222

of infusion, without distinct peak and trough concentrations after achievement of steady state 223

(Figure 3d). Serum cortisone concentrations remained stable throughout, with no notable 224

differences between the four hydrocortisone delivery modes (Suppl. Fig. 2). 225

For all four hydrocortisone administration regimens, serum free cortisol concentrations at Tmax 226

(i.e. when Cmax were observed) were significantly higher than those observed in patients exposed 227

to different stress conditions, except for sepsis, where free cortisol tended to be higher (Suppl. 228

Fig. 3a). Free cortisol during CIV at Tmin (i.e. when Cmin were observed) was significantly higher 229



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than in surgical patients at KTS and 4 hours into surgery, and after acute trauma, but 230

significantly lower than in sepsis (Suppl. Fig. 3a). Free cortisol concentrations at Tmin of the 231

other hydrocortisone administration protocols were significantly lower than in sepsis, but did not 232

differ from those observed during other stress conditions. 233

The pattern of 24-hour urinary glucocorticoid metabolite excretion was similar in patients 234

receiving hydrocortisone in the IM, IV, and CIV administration modes while after oral 235

hydrocortisone administration urine cortisol excretion was lower but cortisol metabolite 236

excretion was higher (Suppl. Fig. 3b), indicative of a first-pass effect with rapid metabolism of 237

cortisol to downstream tetrahydro-metabolites in the liver. Glucocorticoid metabolite excretion 238

after exogenous hydrocortisone administration resembled the pattern observed in major trauma 239

while patients with elective surgery and unstressed controls had a much higher proportion of 240

cortisone metabolites (Suppl. Fig. 3b). 241

Serum cortisol after hydrocortisone administration vs. serum cortisol during elective 242

surgery 243

Serum cortisol concentrations observed in the 10 patients with primary adrenal insufficiency 244

after hydrocortisone administration were plotted against the cortisol response of patients 245

undergoing surgery of longer (N=11; Figure 4a-d) and shorter duration (N=11; Figure 4e-h). 246

Initial peak cortisol concentrations after hydrocortisone administration in the primary adrenal 247

insufficiency patients exceeded the concentrations observed during elective surgery in patients 248

with preserved adrenal function. However, median cortisol concentrations after ORAL, IM, and 249

IVI hydrocortisone administration decreased to trough levels below the median observed in 250

patients undergoing longer-lasting surgery several hours before the scheduled repeat 251

administration of bolus hydrocortisone (Figure 4a-c). By contrast, CIV hydrocortisone 252



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administration persistently maintained serum cortisol concentrations above the median of 253

concentrations observed in patients undergoing elective surgery (Figure 4d). 254

Serum cortisone concentrations in primary adrenal insufficiency and surgical patients showed a 255

similar pattern; again, only CIV hydrocortisone administration achieved concentrations 256

consistently above those observed in subjects undergoing elective surgery (Suppl. Fig. 4). 257

Linear pharmacokinetic modelling of stress dose hydrocortisone administration 258

Next, we used the pharmacokinetic data obtained in the primary adrenal insufficiency patients 259

undergoing exogenous hydrocortisone administration to model the most appropriate dose and 260

mode of hydrocortisone delivery for raising cortisol concentrations quickly and sustain 261

concentrations within the desired range, defined as above the median observed during elective 262

longer-lasting surgery. Fitting to IVI, serum total cortisol concentrations yielded parameter 263

estimates for the fixed effect (average) of initial response Q = 1,347nmol/L (SE 70nmol/L) and 264

clearance rate k = 0.27 h-1 (SE 0.016 h-1). Random effect variances were calculated as 265

(158nmol/L)2 and approximately 0, respectively. 266

Figure 5a depicts the 5th and 95th percentile range modelled on the serum cortisol concentrations 267

observed after IV bolus injection of 50mg hydrocortisone dose; Figure 5b shows the predicted 268

24-hour serum cortisol concentrations. The model and fitted parameters were used to predict the 269

serum cortisol responses to three alternative modes: 100mg hydrocortisone IV bolus injection 270

(Figure 5c-d); initial 50mg (Figure 5e) and initial 100mg (Figure 5f) IV bolus injections, both 271

followed by CIV infusion of 200mg/24h hydrocortisone. Modelling of these two regimens 272

predicted that both would achieve the serum cortisol concentration range observed for longer-273

lasting elective surgery, with a near-instantaneous initial increase in serum cortisol 274

concentration. 275



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DISCUSSION 276

Patients with adrenal insufficiency are unable to mount a cortisol response to counteract a 277

stressful event and, therefore, their regular replacement dose needs to be increased during major 278

stress to avoid adrenal crisis (15). Nevertheless, no consensus exists regarding the optimal dose 279

and hydrocortisone delivery mode during major stress, and current recommendations are 280

empirical rather than evidence-based (7,16). This study is the first systematic dose-response 281

study comparing the cortisol dynamics after administration of stress doses of hydrocortisone in 282

patients with adrenal insufficiency to the acute cortisol response induced by surgery and other 283

conditions of major stress. Our aim was to define the most clinically appropriate but still 284

practically feasible regimen of hydrocortisone administration during major stress in patients with 285

adrenal insufficiency, based on state-of-the-art tandem mass spectrometry measurements of 286

circulating glucocorticoids. We found that continuous intravenous hydrocortisone was the only 287

delivery mode that steadily maintained circulating cortisol in the range observed during major 288

stress, while intermittent bolus administration of hydrocortisone resulted in frequent troughs with 289

lower concentrations, thereby potentially exposing patients with adrenal insufficiency to periods 290

of under-replacement, and hence the possibility of adrenal crisis, a life-threatening complication 291

of cortisol deficiency. 292

In line with previously reported findings (17-19), we documented that serum total cortisol 293

concentrations in all examined conditions of psychological and physical stress were increased 294

above those observed in healthy, unstressed controls. The only exception was major trauma, with 295

relatively lower total serum cortisol concentrations but increased serum free cortisol and 24-hour 296

urinary cortisol, likely explained by the impact of blood loss in these patients. 297



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Consistent with our previous systematic review and meta-analysis of the cortisol response to 298

surgery (19), we observed an initial decrease in serum cortisol during elective surgery, which is 299

likely to be linked to the induction of anesthesia. We observed higher cortisol concentrations 300

during longer-lasting surgery, using reference standard tandem mass spectrometry for serum 301

glucocorticoid analysis. This was also observed in a recent study in 93 patients undergoing 302

elective surgery (20), with serum cortisol measurements carried out by immunoassay. In a 303

previous meta-analysis of studies investigating the serum cortisol response to surgery (19) we 304

did not find an impact of the duration of surgery on peri- and postoperative serum cortisol 305

concentrations, likely explained by the heterogeneity of the studies included, which were also 306

limited by the near exclusive use of immunoassays and lack of measurement of free cortisol. 307

Linear pharmacokinetic modelling of stress dose hydrocortisone administration modes and doses 308

combined with mixed effects regression identified continuous intravenous infusion of 200mg 309

hydrocortisone over 24 hours as the most appropriate replacement regiment in patients with 310

adrenal insufficiency exposed to major stress. Modelling indicated that this should be preceded 311

by a one-off initial intravenous bolus of 50-100mg hydrocortisone to rapidly increase serum 312

cortisol and shorten the time to steady state. We found that continuous intravenous 313

hydrocortisone infusion was the only delivery mode to maintain cortisol concentrations 314

persistently in the range observed during major stress including longer-lasting surgery. This 315

regimen did not result in significant peaks and troughs in circulating cortisol, which were 316

observed with the three hydrocortisone bolus administration modes (ORAL, IM, and IVI). 317

Significant troughs potentially expose patients with adrenal insufficiency to under-replacement 318

and the risk of life-threatening adrenal crisis, while supraphysiologic peaks might come with 319



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adverse side effects, as previously shown in the context of sepsis with an increased rate of 320

hyperglycemic episodes (21). 321

A major strength of the present study is the use of reference standard tandem mass spectrometry 322

for the measurement of circulating glucocorticoid concentrations, with all samples measured 323

contemporaneously and with the same assay. Traditional immunoassays are associated with 324

considerable inter-assay variation and potential cross-reactivity with other steroids, which may 325

lead to over- and underestimations of true levels in critically ill patients with stress-induced 326

stimulation of the hypothalamic-pituitary-adrenal axis (22,23). We also used mass spectrometry 327

for the direct measurement of serum free cortisol, an important strength in comparison to studies 328

who only employed indirect calculation of serum free cortisol utilizing cortisol-binding globulin, 329

which is often inaccurate in the context of acute surgery and critical illness (19,24,25). Our 330

previous systematic review and meta-analysis (19), only identified two studies measuring 331

perioperative glucocorticoids by tandem mass spectrometry (26,27) and two studies directly 332

measuring serum free cortisol in patients undergoing surgery (27,28). 333

One of the limitations of the present study is that, whilst serum cortisol was measured during 334

elective surgery repeatedly over a 24-hour period, concentrations for the other stress conditions 335

were measured at a single time point only. In the acute phase, sepsis causes a surge of circulating 336

cortisol to persistently raised concentrations (17). Though we observed the highest serum cortisol 337

concentrations in sepsis, it is unlikely that hydrocortisone doses higher than 200mg/24h would be 338

required to cover patients with adrenal insufficiency in that situation, as critical illness results in 339

a decrease in cortisol inactivation (29). Moreover, in the context of patients with sepsis but 340

normal adrenal function prior to illness, an increase from hydrocortisone 200mg/24h to 341

300mg/24h did not impact on morbidity or mortality (30). In the present study, we did not assess 342



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the dynamics of cortisol metabolism during surgery and major stress. The previously reported 343

reduced cortisol clearance during critical illness (29) may affect the requirements of 344

hydrocortisone in patients with adrenal insufficiency and should be taken into consideration 345

when interpreting our findings. A recent study reported that 100mg hydrocortisone/24h might be 346

sufficient, though this was based on data collected in mostly secondary AI patients with likely 347

residual cortisol biosynthetic capacity, with measurements carried out by immunoassays (31), 348

Another limitation of our study is that the surgical group comprised mostly patients undergoing 349

moderately invasive procedures. Thus, we cannot exclude that more invasive and longer-lasting 350

surgeries could yield even higher serum cortisol concentrations. However, maximum cortisol 351

concentrations were usually observed after the end of surgery in our patients, likely coinciding 352

with withdrawal of general anesthesia and more invasive surgeries will be undertaken with the 353

appropriately anesthesia and pain control regimens, thus not necessarily eliciting a higher 354

cortisol response. 355

In conclusion, our data provide evidence that hydrocortisone stress dose cover during surgery, 356

trauma, and major illness in patients with adrenal insufficiency should be provided by continuous 357

intravenous infusion of 200mg hydrocortisone over 24 hours, following the administration of an 358

initial intravenous hydrocortisone bolus of 50-100mg. 359

DATA AVAILABILITY 360

The datasets generated during and/or analyzed during the current study are not publicly available 361

but are available from the corresponding author on reasonable request. 362



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endocrinology and metabolism 2020; 466

467



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FIGURE LEGENDS 468

469

Figure 1 – Summary of the studies performed 470

Assessment of the circulating and urinary glucocorticoid concentrations in response to different 471

stress conditions and to stress dose hydrocortisone administration. Abbreviations: IM, 472

intramuscular injection; IVI, intravenous injection; CIV, continuous intravenous infusion. 473

474

Figure 2 – Circulating glucocorticoids during major stress 475

Serum concentrations of (a) total cortisol (nmol/L), (b) total cortisone (nmol/L), and (c) cortisol 476

(F)/cortisone (E) ratio in healthy controls (N=122), during combat stress (N=105), during 477

elective surgery (N=22), after major trauma (N=83), and during sepsis (N=100). In the patients 478

undergoing elective surgery, the maximum serum cortisol levels (and corresponding serum 479

cortisone levels) were used for the calculations. Panel d reports serum free cortisol 480

concentrations in nmol/L in healthy controls (N=11), during elective surgery at knife-to-skin 481

(KTS, N=21) and 4 hours after start of operation (N=21), after major trauma (N=18), and during 482

sepsis (N=17). Panel e reports the 24-hour urinary excretion of cortisol, cortisol metabolites, 483

cortisone, and cortisone metabolites in healthy controls (N=122), following elective surgery 484

(N=21), and after major trauma (N=23). Boxes show median and interquartile range, whiskers 485

are 5th to 95th percentile. Symbols: n.s., p>0.05; *, p≤0.05; **, p≤0.01; ***, p≤0.001. 486

487

Figure 3 – Serum total cortisol following hydrocortisone administration 488

Serum total cortisol (nmol/L) in 10 patients with adrenal insufficiency after hydrocortisone 489

administered orally (ORAL), intramuscularly (IM), as intravenous boluses (IVI), and as 490



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continuous intravenous infusion (CIV). Data are presented as median (black line) and range 491

(shaded grey area). 492

493

Figure 4 – Comparison of serum total cortisol during elective surgery of longer duration 494

and following hydrocortisone administration 495

Serum total cortisol concentrations (nmol/L) in 10 patients with adrenal insufficiency after the 496

administration of 50mg hydrocortisone over 6 hours (black line: median, whiskers: range) in four 497

different modes (orally [ORAL], via intramuscular [IM] or intravenous bolus injection [IVI], or 498

as continuous intravenous infusion [CIV]) projected onto serum cortisol concentrations observed 499

in patients undergoing elective surgery (Panels a-d, serum cortisol in 11 patients undergoing 500

elective surgery of longer duration [red line: median; red shaded area: range]; Panels e-h, serum 501

cortisol in 11 patients undergoing elective surgery of shorter duration [blue line: median; blue 502

shaded area: range]) from time point knife-to-skin (KTS; 0 hours) to 6 hours post-KTS. All 503

measurements were carried out by tandem mass spectrometry. 504

505

Figure 5 – Linear pharmacokinetic modelling of stress dose hydrocortisone administration 506

Mixed effects linear pharmacokinetic modelling of serum cortisol in response to intravenous 507

hydrocortisone administration modes. Serum cortisol concentrations are presented in nmol/L; the 508

black lines show the fixed effect (central tendency) kinetics, the shaded gray area indicates 90% 509

of between-patient variability. Panels a and b show cortisol measurements (circles) following 510

50mg IV bolus injection and the fitted model over 6 and 24 hours, respectively. The 511

pharmacokinetic modelling was also used to predict the serum cortisol response to 100mg IV 512

bolus injection over 6 and 24 hours (panels c and d, respectively), as well as initial 50mg (Panel 513



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e) and 100mg (Panel f) IV bolus injections followed by CIV infusion of 200mg/24h 514

hydrocortisone. 515



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Table 1 – Clinical characteristics of study participants and sampling regimen. 516

517

Cohort Number of subjects

Number of females (%)

Age, median (range) years

Time of collection

Serum total cortisol/cortisone Healthy controls 122 58 (47.5%) 29 (20-69) Between 09:00h and 11:00h (single time point)

Subjects under combat stress 105 0 27 (19-47) Between 06:00h and 09:00h (single ime point)

Patients with major trauma a 83 9 (10.8%) 28 (18-85) Within 24 hours of admission for major trauma (single time point)

Patients with sepsis 100 30 (30%) 71 (28-101) Within 24 hours of fulfilling the criteria of sepsis (single time point)

Patients undergoing elective surgery b 22 14 (63.6%) 49 (21-60) 24-hour profile from knife-to-skin onwards

Patients with primary adrenal insufficiency 10 8 (80%) 56 (40-64) 24-hour profile from 09:00h to 09:00h

Serum free cortisol Patients with major trauma a 18 4 (22.2%) 35 (19-75) Within 3 days of admission (single time point)

Patients with sepsis 17 1 (5.9%) 63 (31-101) Within 24 hours of fulfilling the criteria of sepsis (single time point)

Patients undergoing elective surgery b 21 13 (61.9%) 49 (21-60) At knife-to-skin and 4h after the initiation of surgery

Patients with primary adrenal insufficiency 10 8 (80%) 56 (40-64) Two time points (Tmin and Tmax) c

24-hour urine glucocorticoid excretion Healthy controls 122 58 (47.5%) 29 (20-69) During the day and night preceding the serum sample collection

Patients with major trauma a 23 3 (13.0%) 41 (20-78) Within 3 days of admission (24-hour collection)

Patients undergoing elective surgery b 21 13 (61.9%) 49 (21-60) 24-hour collection from knife-to-skin onwards

Patients with primary adrenal insufficiency 10 8 (80%) 56 (40-64) 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: Tmin: time when the minimum serum total cortisol levels were observed after hydrocortisone administration; Tmax: time when the maximum serum total cortisol levels were observed after hydrocortisone administration.

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Table 2 - Pharmacokinetic parameters of serum total cortisol concentrations observed during elective surgery in patients with 520

preserved adrenal function (N=22) and after hydrocortisone administration via four different modes in patients with primary adrenal 521

insufficiency (N=10). 522

Elective surgery

0-24h 0-6h 6-12h 12-24h

Cmax

(nmol/L) Tmax (h) Cmin

(nmol/L) Tmin (h) ΔCmax-Cmin AUC

(nmol*h/L) AUC

(nmol*h/L) AUC

(nmol*h/L) AUC (nmol*h/L)

Patients with normal baseline adrenal function undergoing elective surgery with general anesthesia

All patients (N=22)

522 (261-1379)

4 (0-12)

60 (17-320)

2 (0-24)

423 (220-1287)

5,295 (1,191-22,274)

1,812 (285-5,687)

1,329 (324-7,221)

2,154 (582-9,366)

Surgery of longer duration (N=11)

611 (261-1379)

5 (0-12)

66 (17-320)

2 (0-24)

499 (235-1287)

8,026 (1,343-22,061)

2,107 (338-5,474)

2,433 (393-7,221)

3,486 (612-9,366)

Surgery of shorter duration (N=11)

431 (261-1379)

3 (0-12)

56 (17-320)

1 (0-24)

375 (235-1287)

3,922 (1,492-10,807)

1,681 (502-3,517)

807 (324-2,718)

1,434 (666-4,572)

Primary adrenal insufficiency

0-24h 0-6h 6-12h 12-18h 18-24h

Cmax

(nmol/L) Tmax (h) Cmin

(nmol/L) Tmin (h) ΔCmax-Cmin AUC

(nmol*h/L) AUC

(nmol*h/L) AUC

(nmol*h/L) AUC

(nmol*h/L) AUC

(nmol*h/L)

Patients with primary adrenal insufficiency (N=10) receiving 200mg hydrocortisone over 24 hours in four different delivery modes ORAL (50mg/6h)

1423 (1083-2457)

0.5 (0.5-1.5)

277 (64-398)

6 (0.5-6)

1089 (834-2393)

15,267 (8,591-22,417)

3,807 (2,471-5,731)

4,056 (1,839-6,348)

4,200 (2,539-5,700)

3,944 (2,208-5,600)

IM (50mg/6h)

1152 (830-1345)

1 (0.5-2)

289 (148-453)

6 (6-6)

844 (581-1151)

14,950 (10,383-20,102)

3,887 (2,864-5,200)

4,055 (2,429-5,296)

3,781 (2,789-5,135)

3,866 (2,711-5,305)

IVI (50mg/6h)

1449 (1072-2432)

0.5 (0.5-6)

171 (0-375)

6 (6-6)

1239 (954-2261)

13,413 (9,412-20,220)

3,577 (2,415-4,852)

3,466 (2,623-4,815)

3,453 (2,440-6,084)

3,425 (2,310-5,253)

CIV (200mg/24h)

836 (661-1073)

7 (2-18)

520 (388-617)

20 (12.5-23.0)

329 (232-551)

14,649 (10,934-19,082)

3,582 (2,685-5,025)

4,067 (2,938-5,112)

4,004 (3,033-5,069)

3,712 (2,796-4,766)

The table reports pharmacokinetic parameters determined from circulating serum total cortisol concentrations observed in 22 patients undergoing elective surgery with general anesthesia (knife-to-skin = 0h), and after administration of 200mg hydrocortisone over 24 hours to 10 patients with primary adrenal insufficiency.

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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; Cmax: maximum serum total cortisol concentration observed; Cmin: minimum serum total cortisol concentration observed; IM: intramuscular; IVI: intravenous injection; Tmax: time when the maximum serum total cortisol concentrations (Cmax) were observed; Tmin: time when the minimum serum total cortisol concentrations (Cmin) 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


concentrations over a 24-

hour period including

elective surgery


concentrations over a 24-

hour period following

administration of stress

dose hydrocortisone

Healthy

subjects

(N=122) a

Combat

stress

(N=105)

Major

trauma

(N=83) a

Sepsis

(N=100)

Elective surgery

with general anaesthesia

(N=22) a

Primary adrenal insufficiency

patients receiving

hydrocortisone (200mg over 24

hours) with four administration

modes (N=10) a

Integrated data analysis

Repeated blood sampling

over 24 hoursRepeated blood sampling

over 24 hours

Blood sampling at a single time point

Oral IM IVI CIV

a These patients were also asked to collect 24-hour urines for the measurement of urinary glucocorticoid excretion.



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Fig.

(a) (b)

(c) (d)

(e)



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(a) (b)

(c) (d)CIV

Oral

IVI

IM



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Fig.

0 1 2 3 4 5 6

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1 0 0 0

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l (n

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C IV

I

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IV I

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ortis

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C IV

(a) (b)

(c) (d)

(e) (f)

(g) (h)

CIV

Oral

CIV

Oral

IVI

IM

IVI

IM



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(a) (b)

(c) (d)

(e) (f)



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