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• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

Date: 09-Aug-2023

• Source: Basics of Adrenal insufficiency - By Dr. Om J Lakhani

• **Acute adrenal crisis **

• Q. What is the volume status in primary vs secondary AI?

  • Primary AI- volume deficit
  • Secondary AI – Normal/ slightly increased volume status
  • Hypotension occurs in both cases
  • In primary AI  it is Mineralocorticoid deficiency leading to volume depletion which is the cause
  • In secondary AI → it is lack of pressor effect and lack of Epinephrine which is the cause

• Q. Which is the preferred glucocorticoid in adrenal crisis?

  • Hydrocortisone

• Q. Is mineralocorticoid required during an acute adrenal crisis?

  • Generally no
  • This is because sodium retaining ability of fludrocortisone takes 2-3 days to appear
  • Saline infusion solves the same purpose
  • Hence Mineralocorticoid is unnecessary in acute adrenal crisis

• Q. Describe the emergent treatment of adrenal crisis.

  • 1. Establish intravenous access with a large-gauge needle.
  • 2. Draw blood for immediate serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for lab results.
  • 3. Infuse 2 to 3 liters of isotonic saline or 5 percent dextrose in isotonic saline as quickly as possible. Frequent hemodynamic monitoring and measurement of serum electrolytes should be performed to avoid iatrogenic fluid overload.
  • 4. Give intravenous hydrocortisone, 100 mg immediately, and every six hours thereafter may be used.
  • 5. Use supportive measures as needed.

• Q. What is the subsequent management?

  • 1. Continue intravenous isotonic saline at a slower rate for the next 24 to 48 hours.
  • 2. Search for and treat possible infectious precipitating causes of the adrenal crisis.
  • 3. Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency, if the patient does not have known adrenal insufficiency.
  • 4. Determine the type of adrenal insufficiency and its cause if not already known.
  • 5. Taper parenteral glucocorticoid over one to three days, if precipitating or complicating illness permits, to an oral glucocorticoid maintenance dose.
  • 6. Begin mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily, when the saline infusion is stopped. (for Primary adrenal insufficiency)

• Q. What type of fluid should be avoided during initial resuscitation of an acute adrenal crisis?

  • Avoid hypotonic fluids as they can worsen the hyponatremia

• CHRONIC ADRENAL INSUFFICIENCY

• Q. Give the relative potency of various Glucocorticoid preparations.

  • 

• Q. What should be the dose of Hydrocortisone per day based on /m2 (useful for children)?

  • 10-12 mg/m2

• Q. What are the doses used if longer-acting preparations are used?

  • Dexamethasone – 0.5 mg
  • Prednisolone – 5 mg

• Q. What do endocrine society guidelines say about the choice of agent?

  • Prefer- hydrocortisone or cortisone
  • Prednisolone- alternate
  • Avoid dexamethasone – cushingoid side effects are often seen

• Q. What are the problems with long-acting agents?

  • Tendency for overtreatment
  • Also they tend to produce more BMD loss

• Q. In which cases are longer-acting preps preferred?

  • Patient noncompliant with treatment with multiple daily doses
  • Patient has late evening or early morning symptoms

• Q. Which drugs increase the requirement of Glucocorticoids?

  • Drugs that increase the CYP3A4 enzyme activity
  • These are
    • Rifampicin
    • Phenytoin
    • Barbiturates

• **MONITORING TREATMENT WITH HYDROCORTISONE **

• Q. What is the best method to monitor treatment?

  • Treatment should be monitored clinically
  • Cortisol day curve may be useful

• Q. When are samples taken to make a cortisol day curve?

  • Blood sample on arrival – noting the time
  • Before the lunchtime dose
    • 1 hr after lunchtime dose
  • Before the evening dose
    • 1 hr after the evening dose or 6 pm

• Q. What is the interpretation of the cortisol day curve?

  • Peak and trough
    • Peak <32 ug/dl and trough > 3.6 ug/dl
  • Rough guide to normal values
    • Morning peak – 18-28 ug/dl
    • Lunchtime peak cortisol- 14 – 18 ug/dl
    • Evening post-dose- 10-14 ug/dl

• Q. Is there a simpler way to monitor apart from using a day curve?

  • One paper suggests to measure Cortisol 4 hr after the morning hydrocortisone dose
  • The value should be within 10-90th percentile of the nomogram that they have created

• Q. What is Plenadren ?

  • It is dual release  hydrocortisone
  • It has an immediate release outer cover and slowly extended release core

• Q. How is it taken?

  • It is taken as one tablet in the morning

• Q. What are the advantages of Plenadren?

  • In one study the patients had better metabolic parameters- Lower BMI, HbA1c, weight gain, and blood pressure

• Q. What is the diavantage of Plenadren ?

  • Provides a very long period of almost no cortisol
  • Starting from evening time till morning there is negligible cortisol cover

• Q. What is Chronocort?

  • Chronocort is designed to have an early morning 4:00 am raise of cortisol which is what is physiologically seen
  • The patient takes 20 mg at bedtime and 10 mg in the morning at 7:00 am

• Q. Does the Dose of Fludrocortisone dependent on which steroid is taken?

  • With Hydrocortisone- 0.05 mg is sufficient
  • With Dexamethasone- 0.2 mg may be required

• Q. How does the environment affect the Floudrocortisone dose?

  • Dose must be increased in summer along with liberal salt intake

• Q. How is monitoring done with the patient on Florinef?

  • Supine and standing BP
  • Serum potassium
  • Plasma renin activity

• Q. Which suggests a reduction of Fludrocortisone dose?

  • Edema
  • Hypertension
  • Hypokalemia

• Q. What are the criteria suggesting normal Fludrocortisone replacement?

  • No Orthostatic hypotension or tachycardia
  • Normal supine and standing BP
  • Normal potassium
  • Normal or slightly suppressed renin

• Q. What PRA level should be targeted?

  • PRA in the range of 1-4 ng/ml/hr (seated)
  • Upper limit of the normal range

• Q. PRA monitoring is useful in which patients?

  • Annual PRA must be done in
  • Patients with symptoms due to Mineralocorticoid deficiency
  • Newly diagnosed AI with unstable doses of Fludrocortisone

• Q. What are the symptoms of Mild Mineralocorticoid deficiency?

  • Nausea – mild
  • Salt craving

• Q. A patient is asymptomatic on Fludrocortisone of 100 mcg and potassium is normal. PRA is done which is 5 ng/ml/hr. Should the dose of Fludrocortisone be increased?

  • No
  • Do not increase the dose of Fludrocortisone if patient is asymptomatic
  • Clinical parameters should precede judgment based on PRA levels

• Q. A patient on Fludrocortisone develops hypertension. What should be done?

  • Reduce the dose of Fludrocortisone
  • If the patient continues to remain hypertensive – then it could be essential hypertension- add antihypertensive- except Spironolactone

• Q. What is the dose and benefit of the use of DHEA in Adrenal insufficiency?

  • It is used in a dose of 50 mg /day
  • It is thought to improve the quality of life in women
  • In women who report reduced quality of life despite being on Glucocorticoid and Mineralocorticoid may be given DHEA trial for 6 months
  • Endocrine Society also recommends this trial

• Q. How is a dose of DHEA titrated?

  • Based on the Morning DHEA-S level before the medications
  • It should be targeted to mid normal range

• Q. Why do patients with secondary Adrenal insufficiency develop Cortisol deficiency on starting GH?

  • GH suppresses 11 beta HSD1 activity which converts cortisone to cortisol

• Q. What is 3 x 3 rule ?

  • In patients with AI, if they have a minor illness they can triple their dose of glucocorticoid for 3 days
  • This is 3 x 3 rule
  • If it fails to improve in 3 days then they need to consult a doctor

• Q. What is the dose of glucocorticoids that must be used during surgery?

  • Minor surgery – 25 mg of Hydrocortisone on the day of surgery
  • Moderate surgical stress (eg: cholecystectomy) – 50-75 mg on the day of surgery and post-op day 1
  • Major surgery – 100-150 mg on the day or surgery and ½ dose on the post of days 2 and 3- then return to baseline dose

• Q. What emergency injectable Glucocorticoid must be prescribed to the patient?

  • Hydrocortisone 100 mg or Dexamethasone 4 mg must be prescribed to the patient and the patient’s relatives must be taught how to inject it in case of emergency

• Q. When should a family member inject hydrocortisone?

  • Injury leading to blood loss of more than 1 cup
  • Fracture
  • Patient unresponsive
  • Severe nausea and vomiting
  • Symptoms of acute adrenal insufficiency
  • In these cases- they must inject the drug and seek medical help immediately

• Q. What is the dose of glucocorticoid required in women who are pregnant?

  • Same dose as they were taking before pregnancy
  • May increase the dose in 3rd Trimester

• Q. What is the management during labor?

  • 25 mg / 6 hrly during labor
  • 100 mg /6hrly during delivery or infusion during delivery
  • Taper to the previous dose in 2-3 days

• Q. What is the effect of Progesterone on the RAAS axis?

  • Progesterone competes with aldosterone for binding to Mineralocorticoid receptor
  • Hence it causes a mild natriuretic effect

• Q. Overall, what happens to aldosterone and renin in pregnancy?

  • Aldosterone and renin increase during normal pregnancy

• Q. How is fludrocortisone dose adjusted in pregnancy?

  • PRA may guide therapy
  • However do not try to suppress to pre-pregnancy range

• Q. What do quality of life studies and prognosis says for patients with Adrenal insufficiency?

  • They say the quality of life is worse with PAI despite optimal therapy
  • Mortality may be increased but data is uncertain

• #Pearl

  • Fludrocortisone has a long half-life and can even be given on alternate days

• Q. Which form of Hydrocortisone is preferred for an emergency?

  • Hydrocortisone hemisuccinate

• Q. What dose of hydrocortisone eliminates the need for Fludrocortisone?

  • Hydrocortisone >40 mg has enough Mineralocorticoid activity
  • Eliminates the need for fludrocortisone

• #Pearl

  • Low normal or subnormal ACTH may suggest overtreatment in primary adrenal insufficiency!

• **Sick Day rules **

• Q. What is the first sick day rule for Adrenal insufficiency

  • Double the dose of steroids in following cases:
    • 1. Fever with Temp >37.5 C
    • 2. Any illness requiring bed rest
    • 3. Any infection requiring antibiotics
    • 4. Vomiting or diarrhea but able to tolerate food and liquids

• Q. Till how long to continue double the dose?

  • Till the patient is better from the underlying disease

• Q. In which cases is parenteral hydrocortisone required?

  • 1. The patient is having very severe illness requiring hospitalization
  • 2. The patient is NPO for surgery or some other reasons
  • 3. Loss of consciousness/collapse of the patient
  • 4. Persistent vomiting and diarrhea which cause oral medication cannot be taken

• Q. What is done for minor surgical procedures?

  • Double the dose of steroid on the day prior or the morning or the procedure
  • Taking 100 mg Hydrocortisone IM/IV 30 minutes before the procedure