What you need to know...

THE FACTS:

Cortisol Deficiency in Children

What is cortisol deficiency?Cortisol deficiency occurs when the body does not make enough cortisol to meet its needs.Cortisol is a hormone that helps keep:

• blood pressure normal

• blood sugar normal

It is especially important when the body must cope with:

• infection

• an injury or illness

• an operation

What causes cortisol deficiency?Cortisol is released by the adrenal glands, which sit on top of the kidneys. The adrenal glands release cortisol into the blood when they are "told" to do so by the pituitary gland in the brain. If the level of cortisol in the body is low, then the pituitary gland releases a hormone called adrenocorticotropic hormone (ACTH), which "tells" the adrenal glands to release more cortisol. If the adrenal glands are not working well (as in Addison's disease or congenital adrenal hyperplasia), then they cannot produce enough cortisol to meet the body's needs. Cortisol deficiency can also occur if the pituitary gland does not work at all, or if it works poorly. ACTH may not be produced (or too little may be produced) and the adrenal glands do not receive a message to release cortisol. In both cases, the body does not have enough cortisol to meet its needs.How is cortisol deficiency diagnosed?Your child will have a blood test done. The doctor will decide what testing is needed. It may be a single blood test or a test in which several blood samples are drawn both before and after the nurse gives your child ACTH (this medicine helps the doctor to assess if your child is able to respond to stress or illness).How is cortisol deficiency treated?If your child does not produce enough cortisol, then he or she will need to take cortisol by mouth two to three times per day, every day. Your child will need extra cortisol when ill. Sometimes, a child may need cortisol only when ill. Your doctor will give you a prescription and instructions for taking cortisol that meets your child's needs.How do I know when to give my child extra cortisol?Illness and injury create stress in the body. During times of stress, your body needs extra cortisol. Stress includes:

• fever of 38.5 degrees C or higher

• illness causing lethargy (feel very tired)

• any infection, sprain or fracture

• if your child has an accident and needs to see a doctor.

• if your child needs an anesthetic for a medical or dental treatment, special x-rays, or surgery

The dentist or doctor must be told that your child needs cortisol replacement. Extra cortisol is not needed for routine immunizations, but is needed if your child develops a fever. This extra cortisol is referred to as a "stress dose", and is 2 to 3 times higher than the regular cortisol dose. Your child should have stress doses of cortisol for as long as he or she is ill or injured. Please contact your endocrine clinic nurse or doctor if:

• you need to give stress doses of cortisol for more than 3– 5 days

• you are unsure about whether to give stress doses of cortisol

What should I do if my child is vomiting or has diarrhea?If your child vomits less than a ½ hour after taking cortisol, then you should give the whole dose again. If vomiting occurs after the repeated dose, then your child will need an injection of cortisol (hydrocortisone). The dose of hydrocortisone can be found on the illness management letter that you received at your last clinic visit. Oral cortisol is not absorbed in a child with severe diarrhea, and an injection of hydrocortisone may be needed. Any time your child needs an injection of hydrocortisone it is a medical emergency. Your child should be seen by a doctor in the nearest emergency room. Many parents are choosing to learn how to give this injection to ensure their child receives hydrocortisone without delay. This is especially important if you are travelling or live far away from the nearest emergency room. Your nurse can show you how to give a hydrocortisone injection.

Every time you give a hydrocortisone injection, your child will still need to be seen as soon as possible by a doctor at the nearest emergency room.

What are the signs that my child is not getting enough cortisol?Signs include:

• stomach or back pain

• pallor (paleness), tiredness

• fainting

• fever

• nausea, vomiting, or weight loss

• disease symptoms return
  shock

What are the signs that my child is getting too much cortisol?Signs include:

• weight gain

• mood swings

• change in weight distribution (fullness in the face, extra weight at upper back and belly)

• stretch marks on the skin

• failure to grow in height

If your child has signs of too much or too little cortisol, call your doctor or the endocrine clinic nurse.What is acute adrenal insufficiency?If your child does not have enough cortisol, then blood pressure and blood sugar can become quite low, causing acute adrenal insufficiency. Acute adrenal insufficiency is a medical emergency.Signs of acute adrenal insufficiency are:

• nausea or vomiting

• cold, clammy skin

• fast heart rate and breathing rate

• weakness, very tired

• dizziness, confusion

• pale face, dark circles under the eyes

• signs of dehydration (dry tongue, thirst)

• lower body temperature

• severe pains in the stomach, legs and back

• loss of consciousness

• coma

If your child has these signs and symptoms, medical attention is needed right away. Call 911. If you have been shown how to give a hydrocortisone injection, give it as soon as possible.

All children with cortisol deficiency should wear a medical alert bracelet/necklace at all times.

Children with cortisol deficiency need regular follow-up visits with their doctor to ensure that the dose of cortisol is correct. By following these guidelines, you will be doing your part to make sure that your child stays healthy.

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Reviewed by Alberta clinical experts. Brought to you by HealthLink Alberta. Copyright.

This material is designed for information purposes only. It should not be used in place of medical advice, instruction and/or treatment. For more health advice call Capital Health Link at 780-408-LINK (5465) 24 hours a day, seven days a week. In Alberta, call Toll-free: 1-866-408-LINK (5465)

AMBIGUOUS GENITALIA and Salt wasting-

TreatmentMedical CareInfants with ambiguous genitalia should be closely observed for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues include abnormal weight loss or lack of expected weight gain. Electrolyte abnormalities generally take from a few days to 3 weeks to appear because the placenta maintains the fetal electrolytes in utero. In mild forms of salt-wasting adrenal hyperplasia, salt wasting may not become apparent until an illness stresses the child.

• Patients with dehydration, hyponatremia, or hyperkalemia and a possible salt-wasting form of adrenal hyperplasia should receive an intravenous (IV) bolus of isotonic sodium chloride solution (20 mL/kg or 450 mL/m) over the first hour, as needed, to restore their intravascular volume and blood pressure.

      • This dosage may be repeated if the blood pressure remains low.

      •Dextrose must be administered if the patient is hypoglycemic and must be included in the rehydration fluid after the bolus               dose to prevent hypoglycemia.

      •After samples are obtained to measure electrolyte, blood sugar, cortisol, aldosterone, and 17-hydroxyprogesterone concentrations, the patient should be treated with glucocorticoids based on suspected adrenal insufficiency. Treatment should not be withheld while confirmatory results are awaited because it may be life preserving (see Medication).

• After the patient's condition is stabilized, treat all patients who have adrenal hyperplasia with long-term glucocorticoid or aldosterone replacement (or both), depending on which enzyme is involved and on whether cortisol and/or aldosterone synthesis is affected.

• Another approach currently under investigation is the combined use of glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), and flutamide (an androgen blocker to reduce virilization).

• Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropin-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone may partially improve the patient's height.

AMBIGUOUS GENITALIA:

S:urgical CareInfants with ambiguous genitalia require surgical evaluation and, if needed, plans for corrective surgery.

• The traditional approach to the female patient with ambiguous genitalia due to adrenal hyperplasia is clitoral recession early in life followed by vaginoplasty after puberty.

           •Vocal groups of patients with disorders of sexual differentiation (eg, Intersex Society of North America) have recently                        challenged this approach.

           •Some female infants with adrenal hyperplasia have only mild virilization and may not require corrective surgery if they                     receive adequate medical therapy to prevent further virilization.

• Bilateral adrenalectomies have been suggested in the management of virilizing forms of adrenal hyperplasia in order to prevent further virilization and advancement of skeletal maturation.This approach is experimental and should be considered only in the context of a controlled study.

Consultations

• An endocrinologist should be consulted when adrenal insufficiency is suspected.

• An experienced surgeon is required if genitalia are ambiguous or inconsistent with genetic sex and corrective surgery is contemplated.

• A consultation with a geneticist is useful in establishing the genetic defect causing the disorder. In parents contemplating a subsequent pregnancy, genetic counseling for prenatal diagnosis and treatment of this disorder is important.

DietPatients with congenital adrenal hyperplasia should be on an unrestricted diet. Patients should have ample access to salt because salt wasting is common in some forms of the disease. Infants who have salt wasting generally benefit from supplementation with NaCl (2-4 g/d) added to their formula. Caloric intake may need to be monitored and restricted if excess weight gain occurs because glucocorticoids stimulate appetite.ActivityActivity restriction is not necessary if appropriate glucocorticoid and mineralocorticoid therapy is provided.MedicationShort-term medical therapy In patients with hypotension, 0.9% (isotonic) sodium chloride solution (450 mL/m or 20 mL/kg IV) must be rapidly administered over the first hour. This is followed by a continuous IV infusion of 3200 mL/m/d or 200 mL/kg per 100 cal/d of estimated resting energy expenditure as isotonic or half-isotonic sodium chloride solution to restore intravascular volume. Dextrose must also be provided.If the patient is hypoglycemic, 2-4 mL of dextrose 10% in water (D10W) should be administered to increase the blood sugar, followed by a continuous infusion of dextrose 5% in water (D5W). If the patient is not hypoglycemic, D5W should be administered to prevent hypoglycemia. Patients with salt-wasting forms of adrenal hyperplasia do not need potassium supplementation because they are usually hyperkalemic. However, patients with 11-hydroxylase and 17-alpha-hydroxylase deficiency may be hypokalemic and may require potassium. After appropriate diagnostic studies are performed or after the results are known, glucocorticoid therapy, mineralocorticoid therapy, or both may be started.In patients who are sick and who have signs of adrenal insufficiency, therapy should consist of stress dosages of hydrocortisone (50-100 mg/m or 1-2 mg/kg IV administered as an initial dose), followed by 50-100 mg/m/d IV divided every 6 hours. Comparable stress dosages include 10-20 mg/m of methylprednisolone administered IV or intramuscularly (IM) and 1-2 mg/m of dexamethasone. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. Therefore, if the patient is hypovolemic, hyponatremic, or hyperkalemic, large dosages of hydrocortisone (double or triple the stress dosages mentioned above) are preferred because of its mineralocorticoid effect.No parenteral form of mineralocorticoid is currently available in the United States; however, if the patient has good GI function, administer 0.05-0.2 mg of fludrocortisone by mouth (PO).

Long-term medical therapyThe goal of therapy for adrenal hyperplasia is the replacement of glucocorticoid and mineralocorticoid to prevent signs of adrenal insufficiency and to prevent the accumulation of precursor hormones that cause virilization. Adequate glucocorticoid replacement should prevent excessive concentrations of ACTH from stimulating the adrenal glands to produce abnormal concentrations of adrenal androgens that result in further virilization. In the growing child with adrenal insufficiency, long-term glucocorticoid replacement must be balanced to prevent symptoms of adrenal insufficiency while still allowing the child to grow at a normal rate and prevent symptoms of glucocorticoid excess. The dosage must be tailored to each patient, but the general average dosage is 10-25 mg/m/d of hydrocortisone PO divided in 2-3 doses.Hydrocortisone is available in 5-, 10-, and 20-mg tablets. Hydrocortisone is recommended in the pediatric population because of its lower potency, which permits easier titration of appropriate doses. Unfortunately, hydrocortisone suspension (Cortef solution) is no longer available in the United States.Prednisone, prednisolone, or even dexamethasone suspensions may be used. Prednisone is available in a suspension of 1 mg/mL, and prednisolone is available in a solution of 5 or 15 mg/5 mL. The estimated equivalencies are as follows:

• One mg of prednisone is equal to 4 mg of hydrocortisone.

• One mg of prednisolone is equal to 5 mg of hydrocortisone.

• One mg of dexamethasone is equal to 50 mg of hydrocortisone.

These forms of glucocorticoid have the advantage of half-lives longer than those of hydrocortisone, permitting twice-daily or even once-daily dosing (dexamethasone), which often aids compliance. However, because of their increased potency, growth suppression and other signs of glucocorticoid excess are common.Administer fludrocortisone (0.05-0.2 mg/d PO) to patients with mineralocorticoid deficiency. Administer NaCl (2-5 g/d) to infants to counteract salt wasting. Older children can usually scavenge adequate salt to provide for their needs and may lose their salt-wasting tendencies as they mature. The dose of glucocorticoid is adjusted by clinically evaluating the patient (for an absence of symptoms of glucocorticoid deficiency and normal growth) and by periodically measuring the concentrations of precursor hormones. For example, in 21-hydroxylase deficiency, keeping plasma concentrations of 17-hydroxyprogesterone in the 200- to 500-ng/dL range and keeping androstenedione in the normal physiologic range is desirable.Plasma ACTH concentrations are of little help in adjusting doses of glucocorticoid in patients with primary adrenal insufficiency. Monitoring symptoms of salt craving and blood pressure, PRA, and electrolyte levels are helpful in adjusting the dose of fludrocortisone. High blood pressure with suppressed PRA should prompt a reduction in fludrocortisone dose.Stress or illnessOne of the important physiologic responses to stress is an increase in the cortisol production that ACTH mediates. Patients with adrenal insufficiency of any etiology cannot mount this response and must be given stress doses of glucocorticoid. In the patient with a minor illness (temperature of <38°C), the dosage of hydrocortisone should be at least doubled. For patients with relatively severe illness (temperature of >38°C), the dosage of glucocorticoid should be tripled. If the patient is vomiting or listless, administer parenteral glucocorticoid (50-75 mg/m of hydrocortisone IM or IV or an equivalent dosage of methylprednisolone or dexamethasone). Because hydrocortisone succinate has a short duration of action, the dose must be repeated every 6-8 hours at a dosage of 50-100 mg/m/d until the patient is well.All patients with adrenal insufficiency must have injectable glucocorticoid available, and the caretaker must be instructed in its use and importance. Glucocorticoid or mineralocorticoid replacement has no contraindications when it is needed, and it has few drug-drug interactions.

GlucocorticoidsThe purpose of glucocorticoid therapy in congenital adrenal hyperplasia is (1) to replace the body's requirement for glucocorticoids under normal conditions and during stress and (2) to suppress ACTH secretion, thereby reducing the stimulus for the adrenal glands to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia. Unfortunately, no currently available preparation is able to mimic the diurnal rhythm of physiologic cortisol secretion. Thus, in an attempt to suppress androgen secretion from the adrenal glands in response to early morning rises in ACTH, overtreatment often occurs, resulting in inhibition of linear growth and Cushingoid features. Delayed-release preparations of hydrocortisone have been formulated but are not commercially available.

Hydrocortisone (A-Hydrocort, Cortef, Hydrocort)Same as cortisol, which is the primary steroid hormone secreted by adrenal zona fasciculata and reticularis. DOC in children due to short half-life and decreased potential for growth suppression. Mineralocorticoid effect at large doses.

• Dosing

• Interactions

• Contraindications

• Precautions

Adult25-35 mg/d PO/IV/IM divided in 2-3 doses; dose doubled or tripled under stress conditionsPediatric10-15 mg/m/d PO divided tid; dose doubled or tripled under stress conditions

• Dosing

• Interactions

• Contraindications

• Precautions

Phenytoin, phenobarbital, ephedrine, mitotane, and rifampin may increase the hepatic clearance of corticosteroids; coadministration with anticoagulants may prolong PT; potassium-depleting diuretics may enhance hypokalemia

• Dosing

• Interactions

• Contraindications

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Documented hypersensitivity; viral, fungal, or tubercular skin infections

• Dosing

• Interactions

• Contraindications

• Precautions

PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animalsPrecautionsLive-virus immunizations well tolerated in patients taking physiologic replacement doses of glucocorticoids; with large doses, avoid live-virus immunizations; regularly observe patients for potential iatrogenic Cushing s