Symptomatic adrenal suppression among children in Canada

Goldbloom, Ellen B; Mokashi, Arati; Cummings, Elizabeth A.; Abish, Sharon; Benseler, Susanne M.; Huynh, Hien Q.; Watson, Wade; Ahmet, Alexandra

doi:10.1136/archdischild-2016-311223

Cited by 31 publications

(25 citation statements)

References 35 publications

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“…In a cohort of 1675 Swedish patients with adrenal insufficiency, the risk ratio for all‐cause mortality was 2.19 for men and 2.86 for women, with narrow confidence intervals. Excess mortality in both men and women was attributable to cardiovascular, malignant and infectious diseases . Adrenal crises requiring hospital treatment occur about 6–8 times per 100 patient years among patients with primary or secondary adrenal insufficiency due to adrenal and hypothalamic‐pituitary disease, respectively.…”

Section: Clinical Outcome In Patients With Adrenal Insufficiency and mentioning

confidence: 99%

Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency

et al. 2020

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Summary These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri‐operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone‐producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin‐releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri‐operative period. Many more patients other than those with adrenal and hypothalamic–pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10–15 mg.m−2 hydrocortisone equivalent or greater in children may result in hypothalamo–pituitary–adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra‐articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal.

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Section: Clinical Outcome In Patients With Adrenal Insufficiency and mentioning

confidence: 99%

Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency

et al. 2020

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“…Others include changes in bone metabolism leading to osteopenia, bone breaks, and avascular necrosis of femoral head [8], mood and psychiatric changes [9], skeletal muscle atrophy and weakness [10], hypertension and renal disturbances [11], and rapid and profound suppression of the HPA axis leading to broad endocrine disturbances. In children chronically treated with glucocorticoids, complaints of families include stunting of growth, delay of puberty, weight gain, mood disturbances and brittle bones [12]. …”

Section: Introductionmentioning

confidence: 99%

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Hoffman

Riddle²,

Siegler

et al. 2018

Steroids

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Background Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Key results Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

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“…However, this measurement was derived from children with congenital adrenal hyperplasia (CAH) only and may not be transferrable to other forms of AI in childhood. The incidence of AC episodes has also been examined in children exposed to inhaled corticosteroid therapy for asthma [19-21]. Although rare, ACs have been shown to occur in this context, affecting 13% of children with symptomatic adrenal suppression due to inhaled corticosteroid therapy treatment in one Canadian study [21].…”

Section: Ac Incidence Morbidity and Mortalitymentioning

confidence: 99%

Adrenal Crises in Children: Perspectives and Research Directions

et al. 2018

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Adrenal crises (AC) are life-threatening physiological disturbances that occur at a rate of 5–10/100 patient years in patients with adrenal insufficiency (AI). Despite their seriousness, there is a paucity of information on the epidemiology of AC events in the paediatric population specifically, as most investigations have focused on AI and ACs in adults. Improved surveillance of AC-related morbidity and mortality should improve the delineation of AC risk overall and among different subgroups of paediatric patients with AI. Valid incidence measures are essential for this purpose and also for the evaluation of interventions aimed at reducing adverse health outcomes from ACs. However, the absence of an agreed AC definition limits the potential benefit of research and surveillance in this area. While approaches to the treatment and prevention of ACs have much in common across the lifespan, there are important differences between children and adults with regards to the physiological, psychological, and social milieu in which these events occur. Education is considered to be an essential element of AC prevention but studies have shown that ACs occur even among well-educated patients, suggesting that new strategies may be needed. In this review, we examine the current knowledge regarding AC events in children with AI; assess the existing definitions of an AC and offer a new definition for use in research and the clinic; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in the paediatric age group.

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Symptomatic adrenal suppression among children in Canada

Cited by 31 publications

References 35 publications

Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency

Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Adrenal Crises in Children: Perspectives and Research Directions

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