1. Who to test and how to do it
1.1 Diagnostic testing is recommended in critically ill patients with suspected primary adrenal insufficiency (PAI) with unknown signs and symptoms to rule out PAI (hypovolemia, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, hypoglycemia). (Strongly recommended/intermediate evidence)
1.2 Application of an adrenocorticotropic hormone stimulation test is recommended to determine the clinical signs or symptoms of the patient. (Strongly recommended/advanced evidence)
1.3 In patients with severe adrenocortical insufficiency or adrenal crisis, immediate treatment with an appropriate dose of hydrocortisone is recommended prior to the outcome of diagnostic testing. (Strongly recommended/intermediate evidence)
2. Optimal diagnostic test
2.1 A standard dose (250 g for children and adults over 2 years of age, 15 g/kg for infants and children under 2 years of age, 125 g) intravenous adrenocorticotropic stimulation (30 or 60 minutes) test is recommended to confirm the diagnosis of adrenocortical insufficiency. A peak cortisol level below 500 nmol/L (18 g/dL) is indicative of adrenocortical insufficiency. (General recommendation/low level of evidence)
2.2 When adrenocorticotropic hormone is deficient, a low-dose (1 g) adrenocorticotropic hormone test is recommended to diagnose PAI.(General recommendation/low level of evidence)
2.3 If an adrenocorticotropic hormone stimulation test is not available, early morning cortisol (<140 nmol/L, 5 g/dL) and ACTH are recommended as the initial diagnosis of adrenocortical insufficiency (until an adrenocorticotropic hormone stimulation test confirms feasibility). (General recommendation/very low evidence)
2.4 Confirmation of the diagnosis of PAI by plasma ACTH measurement is recommended. plasma ACTH samples can be obtained in either an adrenocorticotropic hormone test or an early morning cortisol sample. For patients with confirmed cortisol deficiency, the diagnosis of PAI is confirmed when plasma ACTH levels are >2 times the upper limit of the reference range.(Strongly recommended/intermediate evidence)
2.5 Simultaneous testing of renin and aldosterone in PAI is recommended to clarify the presence of salt corticosteroid deficiency. (Strongly recommended/intermediate evidence)
2.6 It is recommended that the etiology of PAI should be clarified based on the patient’s established disease. (Unclassified best practice statement)
3. Glucocorticoid replacement therapy for primary adrenal insufficiency in adults
3.1 Glucocorticoids are recommended for the treatment of diagnosed PAI.(Strongly recommended/advanced evidence)
3.2 Oral hydrocortisone (15-25 mg) or cortisone acetate (20-35 mg) in divided doses twice or three times daily is recommended; the highest dose may be given early in the morning, and the second dose may be given in the late afternoon or afternoon hours. (General recommendation/low level of evidence)
3.3 Prednisolone (3C5 mg/day) is recommended as an alternative to hydrocortisone, administered in once or twice daily divided doses, especially for patients with poor compliance. (General recommendation/very low evidence)
3.4 Dexamethasone is not recommended for the treatment of PAI because of the risk of side effects of Cushing’s-like syndrome that may arise from difficulties in dose adjustment. (General recommendation/low level of evidence)
3.5 The application of clinical assessments to monitor glucocorticoid replacement therapy, including weight, postural blood pressure, energy status, and signs of glucocorticoid excess, is recommended. (General Recommendation/Intermediate Evidence)
3.6 Hormone level monitoring of glucocorticoid therapy is not recommended, or treatment regimens should be adjusted based on clinical response only. (General recommendation/intermediate evidence)
Salt corticosteroid replacement therapy for PAI
3.7 In patients with confirmed aldosterone deficiency, fludrocortisone replacement therapy is recommended over single salt intake. (Strongly recommended/advanced evidence)
3.8 Monitoring of salt corticosteroid replacement therapy by clinical assessment (salt requirement, postural hypotension, edema) and blood electrolyte measurements is recommended. (Strongly recommended/intermediate evidence)
3.9 Dose reduction of fludrocortisone is recommended for patients with hypertension who are also receiving fludrocortisone. (General recommendation/very low evidence)
3.10 If the patient’s blood pressure is difficult to control, anti-hypertensive therapy with continued fludrocortisone treatment is recommended. (General recommendation/very low evidence)
Dehydroepiandrosterone replacement therapy
3.11 Dehydroepiandrosterone (DHEA) replacement therapy is recommended for the treatment of female patients with PAI combined with low libido, depressive symptoms or low energy. (General recommendation/low level of evidence)
3.12 It is recommended that dehydroepiandrosterone replacement therapy be initiated for 6 months and discontinued immediately if the patient does not respond with a sustained, beneficial effect. (General Recommendation/Low Level of Evidence)
3.13 Monitoring of DHEA replacement therapy by measuring early morning serum dehydroepiandrosterone sulfate (DHEAS) levels is recommended prior to DHEA replacement dose intake. (General recommendation/low level of evidence)
Treatment during pregnancy
3.14 Monitoring of clinical symptoms and glucocorticoid status (e.g., weight gain within normal limits, fatigue, postural hypotension, hypertension, hyperglycemia) in pregnant women with PAI is recommended at least once every three months. (Unclassified best practice statement)
3.15 Depending on the individual’s clinical course, an increase in the dose of hydrocortisone is recommended, particularly in late pregnancy. (Unclassified best practice statement)
3.16 For pregnant women with PAI, hydrocortisone is recommended over cortisone acetate, prednisone or prednisone (general recommendation/low level of evidence) and dexamethasone is not recommended due to its inability to trans-placental inactivate, (strong recommendation/low level of evidence).
3.17 During the active phase of labor, stress hydrocortisone doses are recommended, similar to those used during major surgical stress. (Strongly recommended/low level of evidence)
Treatment and monitoring during childhood
3.18 In children with PAI, hydrocortisone is recommended to be administered in 3-4 divided doses compared to other types of glucocorticoid replacement therapy and the dose can be adjusted according to individual needs. (General recommendation/intermediate evidence)
3.19 In children with PAI, synthetic long-acting glucocorticoids (e.g. prednisolone, dexamethasone) should be avoided. (General recommendation/low level of evidence)
3.20 Monitoring of glucocorticoid replacement therapy by clinical assessment is recommended, including growth rate, weight, blood pressure, and energy status. (Unclassified best practice statement)
3.21 For children with PAI and confirmed aldosterone deficiency, fludrocortisone therapy (initial dose of 100 g/day) is recommended. For infants and children less than 12 months of age, sodium chloride supplementation is recommended. (Strongly recommended/low level of evidence)
4. Management and prevention of adrenal crisis
4.1 For patients with suspected adrenal crisis, immediate parenteral administration of 100 mg hydrocortisone (50 mg/m2 in children) followed by appropriate rehydration and 200 mg hydrocortisone (50 C100 mg/m2 in children) over 24 h (via continuous intravenous fluid therapy or 6-hour injection) is recommended. (Strongly recommended/intermediate evidence)
4.2 If hydrocortisone is not available, prednisolone is recommended as a substitute. Dexamethasone is the least preferred alternative, if no other glucocorticoid is available. (General recommendation/low level of evidence)
4.3 To prevent adrenal crisis, it is recommended that the glucocorticoid dose be adjusted according to the magnitude of the stress or severity of the disease. (General recommendation/low level of evidence)
4.4 It is recommended that patient education should address glucocorticoid adjustments for stressful events and adrenal crisis prevention strategies, including parenteral self-administration or emergency glucocorticoid administration. (Unclassified best practice statement)
4.5 It is recommended that all patients have emergency cards with steroids and medical alert signs to inform health personnel of the need for increased glucocorticoid doses to avoid or treat adrenal crisis in emergency situations and the need for immediate parenteral steroid therapy. (Unclassified best practice statement)
4.6 It is recommended that each patient be provided with a glucocorticoid injection kit in case of emergency and learn how to use it. (Unclassified Best Practice Statement)
5. Additional monitoring conditions
5.1 For adult and pediatric PAI, monitoring by an endocrinologist or healthcare provider with endocrine expertise is recommended at least annually, and for infants and children, 3-4 months. (Unclassified best practice statement)
5.2 It is recommended that patients with PAI be evaluated annually for signs and symptoms and alternative therapy status. (Unclassified Best Practice Statement)
5.3 Regular screening for autoimmune diseases including thyroid disease, diabetes mellitus, premature ovarian failure, celiac disease, and vitamin B12-deficient autoimmune gastritis is recommended. (General recommendation/low level of evidence)
5.4 In cases of complications, fever, and stress, recommend increasing the dosage of glucocorticoids, identifying signs and symptoms, and how to respond to acute adrenal crisis. (Unclassified best practice statement)
5.5 Genetic counseling is recommended for PAI arising from monogenic disease. (Unclassified best practice statement)