Adrenal Crisis due to inhaled steroids is underestimated

In response to comments by Pearce and Mabin on Professor Russell’s editorial1 on our paper.2

They doubt that our survey underestimated the true scale of the problem. I can inform themthat this is not the case. Since our survey was completed we have been notified of a further seven cases (five children, two adults). All but one of the children had been taking fluticasone in similar dosages to those reported in our survey. Three of these were critically ill in intensive care and an 8-year-old girl died due to Adrenal Crisis. The remaining child was only 20 months old and had been given budesonide in extremely high doses of 2000–8000 mcg/day.3 Both adults had been taking fluticasone (1000 mcg/day, 2250 mcg/day).

Case reporting clearly plays a much greater role than clinical studies in post license surveillance of new drugs. In an …

survey of Adrenal Crisis associated with inhaled corticosteroids in the united kingdom

Background: Until recently, only two cases of acute Adrenal Crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. Methods: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute Adrenal Crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-Adrenal axis function test results. Results: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500–2000 μg/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. Conclusions: The frequency of acute Adrenal Crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 μg/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until Adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate Adrenal Crisis.

acute Adrenal Crisis in asthmatics treated with high dose fluticasone propionate

Four cases of asthma (one adult, three children) developing acute Adrenal Crisis after introduction of high-dose inhaled fluticasone proprionate are presented. The three children, aged 7–9 yrs, had been prescribed inhaled fluticasone, dosage 500–2,000 µg·day −1 and duration 5 months–5 yrs. All presented with convulsions due to hypoglycaemia (blood glucose 1.3–1.8 mM). The fourth case was a male of 33 yrs with difficult-to-control asthma and had been taking fluticasone propionate 1,000–2,000 µg·day −1 for 3 yrs. He presented with fatigue, lethargy, nausea and postural hypotension. Acute Adrenal Crisis in each case was confirmed by investigations which included measurement of acute phase cortisol levels, short and long Synacthen stimulation tests and glucagon stimulation tests. Other cases of hypthoalamic-pituitary-Adrenal axis suppression were excluded.

timelines in the management of Adrenal Crisis targets limits and reality

SummaryObjective
To evaluate current management timelines in Adrenal Crisis (AC) and to establish time targets and time limits for emergency treatment.

Design/patients
Patients from a prospective study who had reported an AC (n = 46) were contacted and asked about management of their AC. A survey among 24 European endocrinologists collected expert recommendations concerning time targets and time limits for contact–arrival time of emergency health professionals and presentation of emergency card–glucocorticoid (GC) injection time.

Results
Median time targets and time limits regarded by experts as adequate for contact–arrival time were 45 and 90 min, respectively, and for card–injection time 15 and 30 min, respectively. Thirty-seven of 46 patients could be interviewed. All patients were equipped with an emergency card but only 23 (62%) with an emergency kit. Seven patients (19%) were trained in GC self-injection. The median time interval between contacting a health professional and arrival was 20 min (range 2–2880 min); ≤45 min: n = 32 (86%), <90 min: n = 34 (92%). The median time interval between arrival and administration of GC was 30 min (range 2–2400 min); ≤15 min: n = 17 (46%), ≤30 min: n = 20 (54%). Conclusion While the time between contacting health professionals and their arrival was within the limits set by experts, initiation of GC administration was delayed in 46% of patients. Thus, improved management of AC needs to focus on shortening the presentation of card–injection time. Given the current reality in the management of AC, promotion of self-injection of GC (s.c. or i.m.) is warranted.

extensive expertise in endocrinology Adrenal Crisis

Adrenal Crisis is a life-threatening emergency contributing to the excess mortality of patients with Adrenal insufficiency. Studies in patients on chronic replacement therapy for Adrenal insufficiency have revealed an incidence of 5-10 Adrenal crises/100 patient years and suggested a mortality rate from Adrenal Crisis of 0.5/100 patient years. Patients with Adrenal Crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of Adrenal Crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of Adrenal Crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of Adrenal Crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending Crisis are expected to significantly reduce morbidity and mortality from Adrenal Crisis.

high incidence of Adrenal Crisis in educated patients with chronic Adrenal insufficiency a prospective study

Objective: Adrenal Crisis (AC) is a life-threatening complication of Adrenal insufficiency (AI), which according to retrospective data represents a significant clinical complication. Here we aimed to prospectively assess incidence of AC and mortality associated with AC in patients with chronic AI. Methods: A total of 423 patients with AI (primary AI, n = 221; secondary AI, n = 202) were prospectively followed up for 2 years. Baseline assessment included a general questionnaire and detailed written instructions on glucocorticoid dose adaptation during stress. Patients received follow-up questionnaires every 6 months and were contacted by phone in case of reported Adrenal Crisis. Results: A total of 423 data sets were available for baseline analysis, and 364 patients (86%) completed the whole study. Sixy-four AC in 767.5 patient-years were documented (8.3 crises per 100 patient-years). Precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively) but also other…

survey of Adrenal Crisis associated with inhaled corticosteroids in the united kingdom

Background: Until recently, only two cases of acute Adrenal Crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. Methods: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute Adrenal Crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-Adrenal axis function test results. Results: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500–2000 μg/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. Conclusions: The frequency of acute Adrenal Crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 μg/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until Adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate Adrenal Crisis.

acute Adrenal Crisis in asthmatics treated with high dose fluticasone propionate

Four cases of asthma (one adult, three children) developing acute Adrenal Crisis after introduction of high-dose inhaled fluticasone proprionate are presented. The three children, aged 7–9 yrs, had been prescribed inhaled fluticasone, dosage 500–2,000 µg·day −1 and duration 5 months–5 yrs. All presented with convulsions due to hypoglycaemia (blood glucose 1.3–1.8 mM). The fourth case was a male of 33 yrs with difficult-to-control asthma and had been taking fluticasone propionate 1,000–2,000 µg·day −1 for 3 yrs. He presented with fatigue, lethargy, nausea and postural hypotension. Acute Adrenal Crisis in each case was confirmed by investigations which included measurement of acute phase cortisol levels, short and long Synacthen stimulation tests and glucagon stimulation tests. Other cases of hypthoalamic-pituitary-Adrenal axis suppression were excluded.