Prevention of adrenal crisis in stress (The PACS Study): serum cortisol during elective surgery, acute trauma and sepsis in comparison to 'stress dose' hydrocortisone administration in adrenal insufficiency

ABSTRACTContextPatients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based.ObjectiveTo identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress.Design and ParticipantsCross-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 MeasureWe 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.ResultsSerum 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.ConclusionsContinuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

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Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa133 ◽

2020 ◽

Vol 105 (7) ◽

pp. 2262-2274 ◽

Cited By ~ 9

Author(s):

Alessandro Prete ◽

Angela E Taylor ◽

Irina Bancos ◽

David J Smith ◽

Mark A Foster ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Intravenous Infusion ◽

Elective Surgery ◽

Serum Cortisol ◽

Pharmacokinetic Modeling ◽

Total Serum ◽

Adrenal Crisis ◽

Bolus Administration ◽

Continuous Intravenous Infusion ◽

Linear Pharmacokinetic

Abstract Context Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a 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 who are 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 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-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 modeling 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 modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50–100 mg 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.

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EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Adrenal crisis

Acta Endocrinologica ◽

10.1530/eje-14-0824 ◽

2015 ◽

Vol 172 (3) ◽

pp. R115-R124 ◽

Cited By ~ 81

Author(s):

Bruno Allolio

Keyword(s):

Patient Education ◽

Adrenal Insufficiency ◽

Well Being ◽

Stressful Events ◽

Major Surgery ◽

Adrenal Crisis ◽

Self Administration ◽

Necrosis Factor Alpha ◽

Hydrocortisone Administration ◽

Glucocorticoid Deficiency

Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5–10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis.

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Hydrocortisone Administration for Prevention of Adrenal Crisis in Stress – Pharmacokinetics of Different Administration Modes in Adrenal Insufficiency and Comparison to Surgical Stress.

10.1210/endo-meetings.2010.part3.p13.p3-647 ◽

2010 ◽

pp. P3-647-P3-647

Author(s):

N Karavitaki ◽

AE Taylor ◽

S Kohler ◽

DA Vassiliadi ◽

DM Holmes ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Surgical Stress ◽

Adrenal Crisis ◽

Hydrocortisone Administration

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Steroid-Induced Iatrogenic Adrenal Insufficiency in Children: A Literature Review

Endocrines ◽

10.3390/endocrines1020012 ◽

2020 ◽

Vol 1 (2) ◽

pp. 125-137

Author(s):

Shogo Akahoshi ◽

Yukihiro Hasegawa

Keyword(s):

Adrenal Insufficiency ◽

Serum Cortisol ◽

Early Morning ◽

Serum Cortisol Level ◽

Adrenal Crisis ◽

Acth Stimulation ◽

Morning Serum Cortisol ◽

High Doses ◽

Loss Of Appetite ◽

Cortisol Suppression

The present review focuses on steroid-induced adrenal insufficiency (SIAI) in children and discusses the latest findings by surveying recent studies. SIAI is a condition involving adrenocorticotropic hormone (ACTH) and cortisol suppression due to high doses or prolonged administration of glucocorticoids. While its chronic symptoms, such as fatigue and loss of appetite, are nonspecific, exposure to physical stressors, such as infection and surgery, increases the risk of adrenal crisis development accompanied by hypoglycemia, hypotension, or shock. The low-dose ACTH stimulation test is generally used for diagnosis, and the early morning serum cortisol level has also been shown to be useful in screening for the condition. Medical management includes gradually reducing the amount of steroid treatment, continuing administration of hydrocortisone corresponding to the physiological range, and increasing the dosage when physical stressors are present.

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Spontaneous bilateral adrenal hemorrhage of pregnancy

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20170423 ◽

2017 ◽

Vol 6 (2) ◽

pp. 772 ◽

Cited By ~ 2

Author(s):

Kavya Jonnalagadda ◽

Nisha Bhavani ◽

Praveen V. Pavithran ◽

Harish Kumar ◽

Usha V. Menon ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Fetal Monitoring ◽

Serum Cortisol ◽

Adrenal Hemorrhage ◽

Normal Vaginal Delivery ◽

Adrenal Crisis ◽

Acute Hemorrhage ◽

Bilateral Adrenal Hemorrhage ◽

In Pregnancy

Spontaneous adrenal hemorrhage of pregnancy is an acute hemorrhage into the adrenal gland in pregnancy in the absence of trauma, tumor or decoagulant therapy. This can have catastrophic consequences on the mother and the baby and if the hemorrhage involves both the adrenal glands the risk is aggravated because of the high incidence of resulting adrenal insufficiency. We report a case of spontaneous bilateral adrenal hemorrhage in pregnancy resulting in adrenal crisis. A 26 year old primigravida presented at 32 weeks of gestation initially with right sided infrascapular pain and one month later with similar pain in the left side associated with high blood pressure. Imaging with ultrasound and MRI was suggestive of bilateral adrenal mass probably hemorrhage; 2 days following the second episode of pain she developed drowsiness and hypotension and a diagnosis of primary adrenal insufficiency was confirmed by a low serum cortisol and high ACTH. She stabilized with hydrocortisone therapy and the fetus was closely monitored. At 37 weeks she had a normal vaginal delivery under steroid cover. Repeat MRI abdomen 3 months after delivery showed resolution of the hemorrhage but biochemically she continued to be cortisol insufficient at 1 year of follow up. Prompt diagnosis of adrenal hemorrhage in pregnancy and treatment of adrenal insufficiency along with close fetal monitoring usually results in good perinatal outcome in spontaneous adrenal hemorrhage of pregnancy.

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Low Risk of Adrenal Insufficiency After Use of Low- to Moderate-Potency Topical Corticosteroids for Children With Atopic Dermatitis

Clinical Pediatrics ◽

10.1177/0009922818825154 ◽

2019 ◽

Vol 58 (4) ◽

pp. 406-412

Author(s):

Ladan Davallow Ghajar ◽

Lauren K. Wood Heickman ◽

Mark Conaway ◽

Alan D. Rogol

Keyword(s):

Atopic Dermatitis ◽

Adrenal Insufficiency ◽

Clinical Evidence ◽

Signs And Symptoms ◽

Serum Cortisol ◽

Low Risk ◽

Adrenal Suppression ◽

Adrenal Crisis ◽

Short Term ◽

Topical Corticosteroids

Our objective was to assess the risk of adrenal insufficiency (AI) with short-term use of low- to moderate-potency topical corticosteroids (TCS) for treatment of atopic dermatitis. Our systematic literature search revealed 9 studies (n = 371) that evaluated AI using adrenocorticotropic hormone stimulation testing, with measures of serum cortisol levels at baseline and following at least 2 weeks of TCS application. Biochemical AI was defined by a stimulated cortisol level of ≤18.0 µg/dL (~500 nmol/L). The overall proportion of AI with low-to-moderate TCS use was 2.7% (95% confidence interval = 1.47% to 4.89%). None of the children showed any clinical evidence of AI or adrenal crisis. Short-term use of low- to moderate-potency TCS for the treatment of atopic dermatitis is associated with a low risk of adrenal suppression. General practitioners do not need to test these patients for adrenal suppression in the absence of concerning signs and symptoms of AI.

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ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of adrenal insufficiency

Acta Endocrinologica ◽

10.1530/eje-20-0361 ◽

2020 ◽

Vol 183 (1) ◽

pp. G25-G32 ◽

Cited By ~ 14

Author(s):

Wiebke Arlt ◽

Stephanie E Baldeweg ◽

Simon H S Pearce ◽

Helen L Simpson

Keyword(s):

Adrenal Insufficiency ◽

Clinical Deterioration ◽

Adrenal Crisis ◽

Modified Release ◽

Risk Of Infection ◽

Course Of Disease ◽

Restricted Access ◽

Increased Risk ◽

Sick Day Rules ◽

Stress Dose

We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.

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Latent Adrenal Insufficiency: From Concept to Diagnosis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.720769 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nada Younes ◽

Isabelle Bourdeau ◽

Andre Lacroix

Keyword(s):

Adrenal Insufficiency ◽

Adrenal Cortex ◽

Standard Dose ◽

Signs And Symptoms ◽

Serum Cortisol ◽

Zona Glomerulosa ◽

Adrenocortical Function ◽

Adrenal Crisis ◽

Zona Fasciculata ◽

Adrenal Androgen

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

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