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Glucocorticoid treatment

Glucocorticoid usage is widespread within Great Ormond Street Hospital (GOSH) and University College London Hospitals (UCLH) either as replacement therapy or for the management of complex diseases where the dosing schedule of glucocorticoid is higher than the daily cortisol production rate.

In addition to these overt uses of glucocorticoids, a number of children who pass through these hospitals may also receive "covert" glucocorticoids in the form of inhaled and nasal glucocorticoid therapy for asthma and allergic rhinitis.

This latter group is particularly important to consider because it is the view of the Committee on Safety of Medicines and the Medicine Control Agency that clinically important systemic adverse effects can occur with licensed doses of these products (Medicines Control Agency, Committee on Safety in Medicines 1998).

These guidelines have been devised to assist in the management of patients receiving glucocorticoid treatment within the hospitals. From the endocrine standpoint many patients receiving glucocorticoids have other pituitary hormone abnormalities which necessitate a careful appraisal of their therapy. The guidelines include the management of endocrine patients with hypocortisolism and those receiving higher doses of glucocorticoids for the treatment of their medical conditions.

Management

General principles

Patients who are at risk of adrenal insufficiency

  1. All patients with primary cortisol insufficiency (including congenital adrenal hyperplasia) are at risk as are children with secondary cortisol insufficiency due to hypopituitarism.
  2. Patients with suprasellar tumours, cleft lip and palate and those who have high steroid use for their medical condition even if they are not currently on steroids should always be considered as adrenal insufficient. Endogenous glucocorticoid suppression is likely with hydrocortisone doses of 15-25mg/m2 body surface area. The Endocrinology Service will provide liaison for advice with all specialities particularly neurosurgery, oncology and the cleft lip and palate team to ensure that their junior staff are fully aware of these risks.
  3. Children prescribed inhaled and nasal glucocorticoids for prophylactic treatment of asthma and allergic rhinitis may be at risk of adrenal suppression. Additional systemic glucocorticoid cover should be considered to cover surgery and during acute infections.
  4. Children who have received systemic glucocorticoid therapy using doses equivalent to between 0.3 and 0.5mg/kg daily of prednisolone for more than three weeks should be considered at risk (Table 1).
  5. Patients who have repeated courses of systemic glucocorticoids particularly if taken for more than three weeks.
  6. When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
  7. Children repeatedly taking doses in the evening as this leads to greater hypothalamo-pituitary-adrenal axis suppression.

Table 1: Equivalent doses of glucocorticoids (Axelrod 1976)

Steroid
Glucocorticoid anti-inflamatory effect
Dosing effect on anti-inflammation
Growth retarding effect
Dosing effect on growth 
Mineralo-corticoid effect
Hydrocortisone
 1.0  20mg 1.0
20mg
1.0
Deflazacort
 3.3  6mg not applicable
not applicable
not applicable
Prednisolone
 4.0  5mg 5.0 4mg 0.8
Prednisone  4.0  5mg not applicable
not applicable
0.8
Methylpred
 4.0  4mg 7.5
3mg 0.5
Dexamethasone
 30.0  0.6mg 80 0.4mg 0
Betamethasone
 30.0  0.6mg not applicable not applicable 0
Fludrocortisone
 15.0  1.2mg not applicable not applicable 200
Table 1 shows equivalent doses of glucocorticoids (Axelrod 1976).

Patients who are on regular steroid replacement therapy or on steroids for a medical condition

  1. The patient must have and wear a Medic Alert Bracelet or equivalent.
  2. Education of the parents is key and they need to be empowered to alert professionals if their child's need for steroids increases during intercurrent illnesses. They should be given either the standard Department of Health Treatment Card or the Hydrocortisone Replacement Therapy Card (Great Ormond Street Hospital).
  3. For endocrine patients, at the instigation of long term glucocorticoid treatment the family will be provided with an information pack. An information pack will also be provided for the child’s school.
    A signed letter of instruction from the Consultant in Charge detailing emergency care procedure should be provided for the parents.

    The parents should be trained in the intramuscular administration of hydrocortisone (Efcortesol) and advised to seek medical advice if the child becomes unwell.

 Age range (years)
Dose (mg)
 0 - 1
 25
 1 - 5
 50
 over 5
 100
Table 2 shows intramuscular hydrocortisone doses for emergency use by parents.
Refer also to our family factsheet on how to give an emergency injection of cortisol.

In the endocrine service the parental understanding will be monitored and updated at routine outpatient visits. There are soecialist adrenal clinics set up where understanding is assessed. Patient forum groups are also run on a bi-annual basis to bring families together to discuss standardising practice. This information should be documented in the hospital notes.

4. All patients prescribed systemic glucocorticoids for periods of more than three weeks should receive a steroid treatment card at the outset of treatment. For patients on systemic glucocorticoids for three weeks or less and patients prescribed topical, inhaled or nasal glucocorticoids, the card may be issued at the discretion of the doctor or pharmacist. The Hydrocortisone Replacement Card gives instructions to parents and attending physicians as to what to do if the child is unwell.
5. For non-endocrine patients a record should be made in the notes that the patient and/or parents have been informed about glucocorticoid usage and that a full explanation of therapy and emergency provision has been given. These teams may wish to develop their own information pack or use those available through the endocrine service.

Where high dose glucocorticoid treatment is used the family should be advised of the increased susceptibility to infections, especially chicken pox. Advice should be given on the side-effects profile and how these might be minimised, eg alternate day dosing or single dose in the morning if disease suppression allows. A signed letter of instruction from the Consultant in charge, detailing emergency case procedures should be provided for the parents.

When discontinuing glucocorticoid therapy, consideration should be given to conducting a short synacthen test to determine adrenal responsivity.

6. The fact that the child is on lifeling or supraphysiological steroids should be an alert on PIMS/PAS. 

7. If the child is to undergo surgery the anaesthetist must be notified well in advance that the child is on steroids (see section below).

8. Patients on treatments lasting more than three weeks should not stop taking glucocorticoids unless advised by their doctor.

Endocrine disorders

Hypocortisolism due to adrenal or pituitary defects (including congenital adrenal hyperplasia)

  1. Patients with anterior and posterior pituitary defects are at an increased risk of sudden death (Buchanan 1991). For congenital adrenal hyperplasia the odds ratio is 19 in the first five years of life (Swerlow 1998).

    Communication needs to be extended from the families to include the referring paediatrician and the letter to the referring paediatrician should include an action sheet, which should be circulated to the child’s local Accident and Emergency department and to their family practitioner. Although all parents are given written information and instructions these can unfortunately be ignored by local hospitals. The issue of one of the newly produced steroid cards giving precise information to doctors on how to manage an emergency situation coupled with the "To whom it may concern" letter, should assist in alleviating the problem.

    In the endocrine service, parents will be taught to administer hydrocortisone (Efcortesol) as an intramuscular injection.
  2. If parents consider their child to be ill, steroid dosing should be doubled or trebled. If there is associated vomiting intramuscular hydrocortisone should be administered.
  3. Following the administration of the intramuscular injection of hydrocortisone the child should be taken to the nearest Accident and Emergency department as soon as it is possible and a detailed explanation given to the attending physician that emergency hydrocortisone has already been administered. The child should not be discharged until electrolyte and blood glucose concentrations have been measured. 

    In any situation of doubt the child should be admitted for glucose, electrolyte and blood pressure monitoring for a minimum of 12 hours. This is because the time of action of intramuscular hydrocortisone is 10-12 hours and the child must be monitored at this point. 
  4. Where local paediatric involvement has been secured easy access ("Passport to Ward") to the local hospital paediatric ward should be explored and encouraged for those with an underlying problem.

Combined anterior and posterior pituitary hormone deficiencies

  1. In situations of cortisol insufficiency, the patient is unable to excrete a water load and where combined anterior and posterior pituitary hormone deficiencies exist and DDAVP therapy is used there is always the danger of dilutional hyponatraemia.
  2. In patients who are unwell and suffer with a combination of anterior and posterior pituitary defects no further DDAVP should be given until the plasma electrolytes have been checked at the local hospital. Water intoxication is difficult to treat and can be dangerous.  It is usually safer to under-treat the diabetes insipidus at this stage and simply replace fluid loss as manifest.
  3. Patients with absent thirst and diabetes insipidus are amongst the highest risk group. These patients need to attend hospital, even if they are slightly ill, as their fluid balance is usually precarious.  All such patients should carry a "To whom it may concern" letter explaining the emergency management of this difficult problem. The letter should address the points outlined in the next section.
  4. The emergency management of children with combined anterior and posterior pituitary hormone deficiencies should include:
  • Initial measurement of plasma electrolytes and osmolality along with blood glucose (laboratory) measurements and blood pressure.
  • Insertion of intravenous cannula for intravenous hydrocortisone administration and/controlled IV fluid infusion. If patient is unconscious, hypotensive and shut down peripherally give stat IV infusion of 20mls/kg of 0.9% sodium chloride (see section below on hypoglycaemia management).
  • Weighing of the child on admission and where possible comparison of this weight to previous recorded measures
  • Strict input and output record along with assessment where appropriate of Glasgow coma scale.
  • Where dilutional hyponatraemia is recorded the most likely explanation is due to hydrocortisone deficiency associated with ongoing action of DDAVP. Treatment should consist of fluid restriction in the first instance with careful monitoring on an hourly basis of blood glucose and plasma and urinary electrolyte and osmolality levels.
  • DDAVP should be withheld until a trend is established in the plasma and urine sodium and osmolality levels. When plasma sodium concentrations are between 135 and 140mmols/l paired urine and plasma osmolality should be obtained and when fluid volume losses indicate a diuresis (5ml/kg/hr for two consecutive hours) DDAVP should be cautiously introduced following liaison with the endocrine team.
  • The treatment of dilutional hyponatraemia does not include administration of physiological normal saline. Attempts to correct the plasma sodium concentration by this method will lead to further over-hydration and has been associated with the development of central pontine myelinolysis.
  • In patients with dilutional hyponatraemia, hydrocortisone needs to be administered either by the intravenous route or as double or tripled oral therapy. Fluid intake should be restricted.  Fluid input and output should be carefully monitored along with hourly estimates of plasma and urine electrolytes and osmolality. When diuresis commences careful introduction of DDAVP should be considered when the plasma sodium concentration has reached 140mmols/l and should follow the line of action as per point above.

Hypoglycaemia management

  1. If blood glucose strip reads LO or <2.6mmols/L and child able to tolerate oral fluids then give glucose drink - Ribena™ 100mls=15gms carbohydrate. If blood glucose has not increased within 10-15 minutes or has further decreased, administer HYPOSTOP GEL - ½ a 25gm tube orally. If the child shows clinical signs of hypoglycaemia, ie sweatiness and drowsiness, repeat HYPOSTOP.
  2. If the child does not tolerate oral glucose or remains persistently hypoglycaemic then the following procedure should be adopted:
  • Give glucose intravenously 200mg/kg (10% glucose, 2mls/kg) over three minutes.
  • Commence an intravenous glucose infusion using 10% glucose at 2.4-4.8ml/kg/hr (ie 4-8mg/kg/min of glucose).
  • Re-measure glucose concentration by finger prick using a blood glucose strip after four to five minutes. Adjust glucose infusion (up to 6ml/kg/hr ie 10mg/kg/min glucose) to maintain the blood glucose at 5-8mmols/L and NO HIGHER.
  • DO NOT give intramuscular injections of glucagon unless venous access is lost, since this will lead to rebound hypoglycaemia as a result of increased insulin secretion.
  • If there is no improvement in the state of consciousness after normal glucose concentration is restored then an alternative explanation may be needed.
  • If intravenous access is lost 1mg glucagon may be administered im to counter the hypoglycaemia. The response depends upon the presence of adequate glycogen stores. However, rebound hypoglycaemia (up to three hours later) may be a major problem, and the blood glucose needs to be monitored closely - every 15-20 minutes. Alternatively, glucose may be administered via a nasogastric tube or glucose gel eg Hypostop.

Surgery inpatients receiving glucocorticoids

  1. Where elective surgery is planned in patients who are currently receiving glucocorticoid treatment prior liaison with the anaesthetist is essential. 
  2. Patients at risk include those who are on regular steroid replacement therapy or are currently receiving steroids for a medical condition. This also includes patients who have: 
    • finished a course of systemic glucocorticoids of less than three weeks duration in the week prior to the surgery.
    • patients who have had repeated courses of systemic glucocorticoids, particularly if taken for more than three weeks or when a short course has been prescribed within one year of cessation of long term therapy (months or years).
  3. The patient should preferably be placed first on the surgical list in the morning. The normal evening and morning doses of glucocorticoid should be given and hourly blood glucose concentrations carefully monitored from 6am. At the same time a dextrose-saline infusion should be commenced and maintained until tolerating oral fluids. In primary and secondary hypoadrenalism blood glucose should be monitored on an hourly basis up until premed. Regular post operative blood glucose measures should be undertaken at two-hourly intervals.
  4. If the patient is on the afternoon surgical list then the patient should receive their usual morning glucocorticoid dose.
  5. An intravenous dose of hydrocortisone (2mg/kg body weight) (Table 3 below) should be given at induction. For operations expected to exceed four hours a further bolus of hydrocortisone during the procedure will be required. Alternatively, for prolonged procedures and when post operative recovery is likely to be slow, consideration should be given to a hydrocortisone infusion.
  6. Remember that hydrocortisone has marked mineralocorticoid activity and care must be exercised in situations where water retention would be a disadvantage (eg cerebral oedema) when betamethasone or dexamethasone should be used.
Stage Minor surgery eg cystoscopy
Major surgery eg genitoplasty
At induction
Hydrocortisone IV 2mg/kg and repeated if procedure exceeds four hours.
Hydrocortisone IV 2mg/kg.
During op
 Not applicable
Repeat IV hydrocortisone on four-hourly basis or hydrocortisone infusion.
Post-op Can use repeat IV regimen of hydrocortisone (2mg/kg) in lieu of routine medication until tolerating oral fluids. Then return to oral therapy which must include that day’s fludrocortisone dose.
Can use repeat IV regimen of hydrocortisone. Alternatively, when post operative recovery is likely to be slow consider hydrocortisone infusion.   Continue IV administration until tolerating fluids.  Then return to oral therapy at twice normal dose for 24 hours* then return to normal requirements. As soon as on oral therapy reintroduce fludrocortisone dose.
Table 3 shows hydrocortisone dosing and surgery.
*Post- operative dosing schedule will be determined by the extent of the surgical procedure and should be conducted in liaison with the endocrine team.
Fluids     
  • 100ml/kg/day if weight < 10kg.
  • 80ml/kg/day if weight 10-30kg.
  • 60ml/kg/day if weight > 30kg.
If salt losing congenital adrenal hyperplasia use 5% glucose with 0.45% sodium chloride.
For other cases use 4% glucose with 0.18% sodium chloride.

Hydrocortisone infusion

Rates of hydrocortisone infusions will be dependent on individual weight, pubertal status and cortisol clearance rates. To achieve a cortisol concentration of 1000nmol/l (0.36mg/ml) as one might desire in a patient with sepsis, suggested infusion rates are outlined in Table 4 below.

Situation
Cortisol clearance (ml/24hrs)
Infusion rate (mg/24hr)
Prepubertal: 10kg
74
25
Prepubertal: 10-20kg
147 50
Prepubertal: 20kg
294 100
Puberetal 430 155
Postpubertal 290 105
Table 4 shows suggested infusion rates.
Infusion rate (mg/24hrs) = clearance (ml/24hr) x steady state cortisol concentration (mg/ml).

Withdrawal plan for patients receiving steroid therapy

  1. There are very few data on the safe withdrawal of systemic glucocorticoids in children but it is reasonable to assume that the hypothalamo-pituitary-adrenal-axis behaves in a similar way to that in adults. The dosing schedules described give a conservative estimate of effect. Suppression of the hypothalamo-pituitary-adrenal-axis takes place with a hydrocortisone dose of 15mg/m2 body surface area per day and possibly lower. The effect is more marked if the dose is given in the evening.
  2. The following schedule suggested for withdrawal of systemic glucocorticoids is appropriate if therapy has only been for three weeks and relapse of disease is unlikely. In adults, abrupt withdrawal of doses up to 40mg of prednisolone, or equivalent, for three weeks is not associated with adrenal problems. For children doses equivalent to between 0.3 and 0.5mg/kg daily of prednisolone for three weeks, should allow abrupt withdrawal but for doses higher than this a tapering regimen should be considered.
  3. Long-term pharmacological glucocorticoid therapy inhibits transcription of the gene(s) for glucocorticoid receptors, thus reducing the number of receptors per cell. Physiologic concentrations of glucocorticoids will elicit subphysiologic cellular responses. Thus, it is necessary to taper gradually from the outset. Therapy for a couple of months will completely suppress the hypothalamo-pituitary-adrenal axis but will not cause adrenal atrophy. Therapy of years' duration may result in almost total atrophy of the adrenal fasciculata/reticularis, which may require a withdrawal regimen that takes months. In patients on long-standing therapy in whom disease relapse is not anticipated, a 25 per cent reduction in the previous level of therapy is generally recommended weekly. The endocrine service will advise on the schedule. In conditions where there is a high risk of disease relapse a more cautious withdrawal programme may be necessary and liaison with the Consultant in Charge is mandatory.
  4. Symptoms to look for after glucocorticoid withdrawal are malaise, anorexia, headache, lethargy, nausea and fever. This symptom complex does not include salt loss, as adrenal glomerulosa function regulated principally by the renin-angiotensin system remains normal.  However, blood pressure can fall abruptly, as glucocorticoids are required for the action of catecholamines in maintaining vascular tone.
  5. When withdrawal is done with steroids other than hydrocortisone, measurement of morning cortisol values can be a useful adjunct. Morning cortisol values of 400nmol/l or more indicate that the dose can be reduced safely.
Recovery of the axis can also be monitored by measuring the cortisol response to exogenous ACTH (short synacthen test) or Corticotrophin Releasing Hormone (CRH). It is important to realise that cortisol concentrations may normalise during the day before the response to synacthen returns.

Even after the successful discontinuation of therapy, the hypothalamo-pituitary-adrenal axis is not wholly normal and may be incapable of responding to severe stress for six to 12 months after successful withdrawal from long-term, high-dose glucocorticoid therapy.

Evaluation of the hypothalamus and pituitary by a CRH test and evaluation of adrenal responsiveness to pituitary stimulation with an intravenous ACTH test, should be done at the conclusion of a withdrawal program and six months thereafter. The results of these tests will indicate if there is a need for steroid cover in acute surgical stress or illness.

Status of disease and therapy
Suggested withdrawal pattern
Disease unlikely to relapse and less than three weeks of treatment and: 

  • no recent repeated courses
  • no previous long-term therapy
  • no other causes of adrenal suppression
  • dosing no greater than 0.3-0.5mg/kg daily prednisolone or equivalent
  • no evening dosing
  • abrupt stop
  • but stress (infection, trauma, surgery) one week after stopping therapy the systematic glucocorticoid cover is still needed.
Disease unlikely to relapse and more than three weeks treatment or less than three weeks therapy but:

  • repeated courses recently
  • previous long term therapy
  • other causes for adrenal suppression
  • dose greater than 0.3–0.5mg/kgdaily prednisolone or equivalent*
  • evening dose
Gradual withdrawal of systemic glucocorticoids. In all cases the endocrine service will liaise.
Table 5 shows withdrawal of systemic glucocorticoids.
*It is accepted that certain oncology treatment regimens contain glucocorticoid therapies of 2mg/kg for three to five days and then stop. For this period of time it is likely that no untoward adrenal suppression is likely to take place but the information base is poor to assume that they are adrenal sufficient.

Monitoring

Long-term therapy in non-endocrine indications

  1. The mineralocorticoid effects of hydrocortisone are too high for it to be used on a long-term basis for disease suppression. Prednisolone or dexamethasone should be substituted for hydrocortisone in these situations. In all situations patients should be given treatment for the shortest length of time at the lowest dose that is clinically necessary. Using glucocorticoids in the morning and alternate day therapy may be helpful.
  2. Patients receiving long-term glucocorticoid therapy should have fasting blood glucose measured on a three-monthly basis. Where high dose regimens are used eg leukaemia protocols, more frequent glucose measuring should be performed particularly in patients with Down syndrome or a family history of Type II Diabetes Mellitus. Patients should be issued and instructed in the use of BM Stix for home glucose monitoring. A suggested regimen is alternate day measurement of pre-meal blood glucose so that a sample may be taken pre-breakfast one day then pre-lunch two days later and pre-dinner two days after that.
  3. A regular assessment of bone mineral density is advised and all symptoms of back pain investigated for vertebral collapse. Calcium and vitamin D are often prescribed as prophylaxis but bisphosphonates are the only agents of proven benefit in the management of symptomatic steroid-induced osteoporosis (Adachi 1997). 
  4. Bisphosphonate therapy needs to be undertaken in conjunction with the endocrine calcium disorders group.
  5. Blood pressure and plasma electrolytes should be monitored particularly with high dose hydrocortisone. Additional complications are outlined in Table 6 below.

Short-term therapy
Long-term therapy
  • gastritis
  • growth arrest
  • appetite
  • hypercalciuria
  • glycosuria
  • immune suppression
  • masked symptoms of infection, esp. fever and inflammation
  • toxic psychoses
  • gastric ulcers
  • short stature
  • weight gain
  • osteoporosis, fractures
  • slipped ephiphises
  • ischemic bone necrosis
  • poor wound healing
  • catabolism
  • cataracts
  • bruising (capillary fragility)
  • adrenal/pituitary suppression
  • toxic psychosis
Table 6 shows complications of high dose glucocorticoid therapy.

References

Reference 1:
Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, Kendler DL, Lentle B, Olszynski W, Ste-Marie LG, Tenenhouse A, Chines AA (1997) Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 337 (6): 382-7.

Reference 2:
Axelrod L (1976) Glucocorticoid therapy. Medicine (Baltimore) 55 (1): 39-65.

Reference 3:
Buchanan CR, Preece MA, Milner RD (1991) Mortality, neoplasia, and Creutzfeldt-Jakob disease in patients treated with human pituitary growth hormone in the United Kingdom. BMJ 302 (6780): 824-8.

Reference 4:
Medicines Control Agency, Committee on Safety in Medicines (1998) Focus on Steroids. Current Problems in Pharmacovigilance 24: 5-10.

Reference 5:
Swerdlow AJ, Higgins CD, Brook CG, Dunger DB, Hindmarsh PC, Price DA, Savage MO (1998) Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr 133 (4): 516-20.

Document control information

Lead author(s)

Stephanie Ward, Clinical Nurse Specialist Endocrinology, Endocrinology

Document owner
Professor Peter Hindmarsh, Professor of Paediatric Endocrinology, Endocrinology

Approved by
Professor Peter Hindmarsh, Professor of Paediatric Endocrinology, Endocrinology

Literature review undertaken: yes
Audit/evaluation of current practice undertaken: no
All staff groups involved in the care of these patients have had input into the development/review: yes

First introduced: 31 January 2002
Date approved:
20 April 2012
Review schedule:
Two years
Next review:
21 April 2014
Document version:
2.1
Replaces version:
2.0