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Related Subjects: |Adrenal Physiology |Addisons Disease |Phaeochromocytoma |Adrenal Adenomas |Adrenal Cancer |Cushing Syndrome |Cushing Disease |Congenital Adrenal hyperplasia |Primary hyperaldosteronism (Conn's syndrome) |ACTH |McCune Albright syndrome

Diagnostic measures should never delay prompt treatment of a suspected adrenal crisis! There are no adverse consequences of initiating life-saving hydrocortisone treatment and diagnosis can be safely and formally established once the patient has clinically recovered. Each year, typically 8% of people with Addison's Disease experience adrenal crisis. This means they need extra steroid medication immediately, in the form of an emergency injection of intramuscular hydrocortisone. This is a medical emergency and must be treated immediately.

Patients taking 5mg prednisolone or equivalent for longer than 4 weeks are at risk of HPA axis suppression and adrenal atrophy with a crisis if physiologically stressed for instance during acute illness, surgery or other invasive procedures.

Introduction

• Rare condition 0.8-1 in 100,000
• Loss of Adrenal cortical function of Steroids and Mineralocorticoids may be insidious and subtle or sudden and life-threatening and all in between.
• Actively look for it in a hypotensive patient. The clues are pigmentation, hypotension, hypoglycaemia, lethargy, hyperkalaemia. If you suspect it then you must screen for it

Aetiology

• Cortisol and mineralocorticoids needed for life
• Increased demand during stresses (infection, trauma)
• Cortisol released in response to ACTH
• Aldosterone released in response to Angiotensin II
• Loss of the adrenal medulla has amazingly no sequelae

Types

• Primary due to adrenal disease
• Secondary disease due to pituitary (ACTH) insufficiency
• Tertiary - sudden stopping of chronic steroid therapy (or cure of endogenous steroid excess)

Causes

• Autoimmune adrenalitis :Addison's
• Infiltration: Sarcoid, Amyloidosis
• Infection: HIV/CMV/TB
• Adrenal Infarction
• Meningococcal sepsis (Waterhouse-Friderichsen syndrome)
• Pituitary lesion/surgery
• Metastases - breast and lung and melanoma and lymphoma
• Schilders disease
• Wolmans disease (HS-megaly + steatorrhoea)
• Congenital adrenal hyperplasia
• Metyrapone/Ketoconazole/rifampicin
• Haemorrhage into adrenal (Freidreichson-Waterhouse)
• Progressive disseminated Histoplasmosis

Clinical

• Tired, Tanned, Fatigue, anorexia, weight loss, tiredness, diarrhoea
• Pigmented palmar creases & buccal mucosa
• Unexplained Vomiting, abdominal pain, generalised weakness
• Acute Addisonian crisis possibly precipitated by stress e.g. intercurrent illness
• Crisis: postural hypotension > 20 mmHg drop on standing, tachycardic, pale cold clammy shocked hypoglycaemia
• Pituitary cause: BP normal, alabaster-like, pale skin, hypogonadism, lack of secondary sexual characteristics, bitemporal hemianopia
• Adrenal disease: Postural hypotension, Hyperpigmentation "tanned appearance" seen in Adrenal disease. Pigmentation in gums, buccal mucosa, skin, pressure points, skin creases, scars
• Loss of body hair in females, Vitiligo is often seen
• Hypoglycaemia is more common in secondary adrenal insufficiency

Differential

• Severe dehydration
• Viral illness
• Malignancy

Investigation

• FBC: ↑ neutrophils, sometimes also lymphocytosis and eosinophilia
• ↓ Na⁺ and ↑ K⁺, ↑ H⁺ (Adrenal disease), Mild metabolic acidosis
• ↑ Creatinine: raised due to pre-renal disease
• ↓↓ Glucose: may be seen. ↓ Calcium.
• Anti adrenal antibody: 75-85% of patients with idiopathic Addison's disease have circulating antibodies to adrenal antigens at the time of diagnosis. The antibodies are predominantly IgG class and, in general, have rather low titres. Raised titres are suggestive of an autoimmune cause of Addison's disease.
• Other Autoantibodies (adrenal, thyroid, intrinsic factor)
• Short synacthen test: Give 250 mcg of IM ACTH and measure cortisol at 0, 30, 60 mins. A cortisol > 550 mnmol/L at 30 mins excludes Addisons.
• ↑ ACTH levels > 300 ng/L at 9 am
• 21-Hydroxylase adrenal autoantibodies: +ve in autoimmune disease in >80%
• TFT: hyperthyroid disease can precipitate an adrenal crisis
• A CXR should be performed to look for active TB disease and small heart
• Plasma renin/aldosterone activity: to assess mineralocorticoid status (high renin in primary adrenal insufficiency; not high in secondary adrenal insufficiency, where mineralocorticoid reserve is normal)
• Adrenal CT: TB, histoplasma, or metastatic disease
• Adrenal biopsy in some cases

Management: Addison's and Cortisol Deficiency Suspected

• If unwell, hypotension, electrolyte disturbance take urgent sample for ACTH and Cortisol and give Hydrocortisone 100 mg IV and urgent endocrine consult
• If stable then check cortisol level at 8-9 am. If Cortisol < 150 nmol/L suggests deficiency highly likely. If stress, surgery, emergency or adrenal crisis then start Hydrocortisone 100 mg IV and 50 mg QDS IM or IV
• If stable then check cortisol level at 8-9 am. If Cortisol 150-450 nmol/L then consider short synacthen test and endocrine consult. May need Hydrocortisone if stress, surgery, emergency or adrenal crisis
• If stable then check cortisol level at 8-9 am. If Cortisol > 450 nmol/L then cortisol deficiency unlikely

Management of an Acute Crisis

• IV access and send U&E, Glucose, random cortisol 10 ml in a Heparinised tube. The result may not be known acutely but will be useful retrospectively
• ABC + 1 L ml IV N-saline stat over 2 hour
• Give 50 ml 50% dextrose if hypoglycaemic or 100 ml of 20%
• Start Hydrocortisone IV 100 mg stat then 50-100 mg 6 hrly IM or an infusion of 200 mg over 24 hrs
• Treat any underlying infection
• Glucocorticoids and mineralocorticoids should be given for primary adrenal disease
• Glucocorticoids only needed for pituitary disease

Long term replacement

• Typically Hydrocortisone 20-30 mg per day in divided doses e.g. Hydrocortisone 15 mg am and 5 mg at 4 pm though some take it divided as 3 times/a day. Double dose when ill. See below. Prednisolone may also be used.
• Fludrocortisone 50-200 mcg OD if mineralocorticoid deficient
• Patients should carry a steroid card to alert staff and have sufficient medications to follow sick day rules below

After emergency care: Prevention of an adrenal crisis

Warn against abruptly stopping steroids. Emphasize that prescribing doctors/dentists/surgeons must know of steroid use: give steroid card

• Close review by an endocrinologist with long term reviews
• Education of patients and partner/parents regarding symptom awareness and the correct adjustment of glucocorticoid replacement dose
  • Sick Day Rule 1: the need to double daily oral glucocorticoid dose during illness with fever that requires bed rest and/or antibiotics. Ensure they have an additional supply of hydrocortisone tablets so that they can double their dose for at least 7 days
  • Sick Day Rule 2: the need to administer glucocorticoids IV/IM during prolonged vomiting or diarrhoea, during preparation for colonoscopy or in case of acute trauma or surgery
• Teach the patient and partner/parents how to self-administer and inject hydrocortisone and provide them with a Hydrocortisone Emergency Injection kit (100 mg hydrocortisone sodium succinate for injection; hyperlink to ADSHG and Pit foundation where there are picture tutorials on using this); check regularly that their kit is up to date. Provide the patient with a Steroid Emergency Card www.endocrinology.org/adrenal-crisis and encourage them to wear medical alert bracelets, in addition to keeping the steroid emergency card with them at all times and showing it to any health care professional they are dealing with. Provide them with emergency phone numbers and details to access emergency help.
• If the have signs of an acute adrenal crisis happens to yourself or someone you are caring for, do not delay: inject yourself (or the person you are caring for) with your hydrocortisone ampoule 100mg IM and seek immediate medical attention - call 999, stating "Addisonian crisis"

References

• Leicester Adrenal Crisis
• Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients
• Adrenal Crisis Can Kill Guidance for all