Review J Investig Med: first published as 10.1136/jim-2019-000999 on 28 February 2019. Downloaded from Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings Bradley S Miller, 1 Sandra P Spencer,2 Mitchell E Geffner,3 Evgenia Gourgari,4 Amit Lahoti,5 Manmohan K Kamboj,2 Takara L Stanley,6 Naveen K Uli,7 Brandy A Wicklow,8 Kyriakie Sarafoglou1 For numbered affiliations see ABStract (glucose 55 mg/dL). Despite urgent fluid resus- end of article. Adrenal insufficiency (AI) remains a significant citation with 2 intravenous boluses of normal cause of morbidity and mortality in children with 1 saline and a bolus of 10% dextrose, hypoten- Correspondence to in 200 episodes of adrenal crisis resulting in death. sion persisted. Due to clinical and biochemical Dr Bradley S Miller, Department of Pediatrics, The goal of this working group of the Pediatric features suggestive of primary adrenal insuffi- University of Minnesota Endocrine Society Drug and Therapeutics Committee ciency (AI), blood was drawn for measurement Masonic Children’s Hospital, was to raise awareness on the importance of early of adrenocorticotropic hormone (ACTH) and 2450 Riverside Ave, recognition of AI, to advocate for the availability cortisol levels prior to administering 75 mg of Minneapolis, MN 55454, intravenous hydrocortisone sodium succinate USA; mille685@ umn. edu of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or (Solu-Cortef). He was admitted and diagnosis The work has been allow EMS personnel to administer patient’s HSS confirmed. Treatment was initiated with hydro- presented at Pediatric home supply to avoid delay in administration of life- cortisone and fludrocortisone. The patient and Academic Society Meeting saving stress dosing, and to provide guidance on the family received education for the management 2018, ’Year In Review: Emergency Management emergency management of children in adrenal crisis. of primary AI and prevention of adrenal crises. of Adrenal Insufficiency in Currently, hydrocortisone, or an equivalent synthetic Two years later he developed acute gastro- Children: A Clinical Practice glucocorticoid, is not available on most ambulances enteritis with fever, vomiting and diarrhea while Guideline’, Toronto, Ontario, for emergency stress dose administration by EMS visiting his grandparents in a rural area. He Canada, May 2018. personnel to a child in adrenal crisis. At the same received triple his usual dose of oral hydrocor- Accepted 7 February 2019 time, many States have regulations preventing the tisone, but vomited within 10 minutes. Grand- use of patient’s home HSS supply to be used to parents had hydrocortisone sodium succinate treat acute adrenal crisis. In children with known AI, available for intramuscular injection, but parents and care providers must be made familiar did not know how to administer it and called http://jim.bmj.com/ with the administration of maintenance and stress 911. The patient was unresponsive on arrival of dose glucocorticoid therapy to prevent adrenal the ambulance 20 minutes later. Grandparents crises. Patients with known AI and their families informed the emergency medical technicians should be provided an Adrenal Insufficiency Action (EMT) that he needs to receive hydrocortisone Plan, including stress hydrocortisone dose (both sodium succinate intramuscularly for AI. Due oral and intramuscular/intravenous) to be provided to emergency medical services (EMS) policy, immediately to EMS providers and triage personnel the EMTs were not allowed to administer the on September 27, 2021 by guest. Protected copyright. in urgent care and emergency departments. child’s personal supply of hydrocortisone Advocacy efforts to increase the availability of stress sodium succinate and did not have an alterna- dose HSS during EMS transport care and add HSS to tive medication on the ambulance. Glucometer weight-based dosing tapes are highly encouraged. revealed a blood glucose of 30 mg/dL. While EMTs attempted to place an intravenous cath- eter, he experienced a seizure. He was intubated and received intravenous dextrose with cessa- INTRODUCTION tion of the seizure. He was transported to a © American Federation for Prismatic clinical scenario local ED that was 30 minutes away. In the ED, Medical Research 2019. A 9-year-old boy presented to a local emer- he was given 75 mg intravenous hydrocortisone Re-use permitted under gency department (ED) with chronic abdom- sodium succinate and was admitted to the inten- CC BY-NC. No commercial sive care unit where he later died of complica- re-use. Published by BMJ. inal pain, acute onset of nausea and vomiting for the previous 24 hours. Physical examina- tions related to prolonged hypoglycemia and To cite: Miller BS, tion revealed an ill-appearing, thin male with aspiration pneumonitis. Spencer SP, Geffner ME, tachycardia (pulse 110 bpm), mild hypoten- et al. J Investig Med Epub ahead of print: [please sion (85/60 mm Hg), signs of dehydration, and BacKGROUND include Day Month Year]. hyperpigmentation. Laboratory testing showed Adrenal crisis is a life-threatening condi- doi:10.1136/jim-2019- hyponatremia (sodium 129 mEq/L), hyperka- tion that can be prevented by recognition in 000999 lemia (potassium 5.8 mEq/L) and hypoglycemia which patients with AI must receive additional Miller BS, et al. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999 1 Review J Investig Med: first published as 10.1136/jim-2019-000999 on 28 February 2019. Downloaded from Table 1 Congenital causes of adrenal insufficiency Table 1 Continued Affected Affected Condition gene Clinical phenotype Condition gene Clinical phenotype Primary Proopiomelanocortin deficiency POMC Severe early-onset hyperphagic CAH obesity, red hair 21-α-hydroxylase deficiency CYP21A2 46,XX DSD/androgen excess; Proprotein convertase 1 PCSK1 Hypoglycemia, malabsorption, salt-wasting mutation gonadotropin deficiency 3-β-hydroxysteroid HSD3B2 Ambiguous genitalia/salt- ACTH, adrenocorticotropic hormone; CAH, congenital adrenal dehydrogenase deficiency wasting hyperplasia; CRH, corticotropin-releasing hormone; DSD, disorder of sex 11-β-hydroxylase deficiency CYP11B2 46,XX DSD/androgen excess; development; NK, natural killer. hypertension (not infants) P450 side-chain cleavage CYP11A 46,XY DSD; salt-wasting, syndrome hypogonadism glucocorticoids when under physiological stress. Adrenal Lipoid hyperplasia StAR 46,XY DSD; salt-wasting; crisis can also occur as the initial clinical presentation of AI. hypogonadism Appropriate management requires immediate recognition P450 oxidoreductase POR 46,XY DSD, salt-wasting, of the clinical signs, symptoms and biochemical profile of AI deficiency (PORD) hypogonadism, Antley-Bixler malformation; altered drug and the triggers for adrenal crisis. Therefore, primary care, metabolism urgent care and ED providers must be trained to recognize Congenital adrenal hypoplasia SF-1 46,XY DSD, gonadal the diverse clinical circumstances in which AI can occur. In (NR5A1) insufficiency children with known AI, parents and care providers must be DAX-1 Hypogonadotropic familiar with the administration of maintenance and stress (NROB1) hypogonadism dose glucocorticoid therapy to prevent adrenal crises. This CDKN1C IMAGe syndrome (intrauterine can be facilitated by providing the family with a written growth retardation, Adrenal Insufficiency Action Plan and Emergency Care metaphyseal dysplasia, genital Letter. Currently, hydrocortisone, or an equivalent synthetic anomalies) glucocorticoid, is not available on most ambulances for Triple A or Allgrove AAAS Achalasia, alacrima emergency administration by EMS personnel. In addition, Isolated familial glucocorticoid MC2R, Tall stature, normal EMT training on the use of patient’s home medication is deficiency (FGD) MRAP mineralocorticoid production not widely employed. Both of these situations can lead to FGD–DNA repair defect MCM4 NK-cell defect, short stature, life-threatening delays in providing appropriate therapy to recurrent viral infections, prevent or treat adrenal crises. microcephaly, chromosomal breakage AI is a significant cause of morbidity and mortality in chil- 1–3 Glucocorticoid resistance GCCR Mineralocorticoid/androgen dren with an annual estimated incidence of adrenal crisis excess of 5–10 episodes per 100 patient-years, with increasing 4 http://jim.bmj.com/ Metabolic diseases rates in some countries. One in every 200 episodes of 5 Adrenoleukodystrophy ABCD1 Neurologic deterioration adrenal crisis results in death. Therefore, the goal of this Zellweger PEX Cerebrohepatorenal syndrome working group was to raise awareness on the importance of Smith-Lemli-Opitz DHCR7 46,XY sex reversal, polydactyly, early recognition and provide guidance on the emergency mental retardation management of AI in children during illnesses, particularly in the outpatient, EMS and ED settings. Wolman LIPA Hepatomegaly Mitochondrial disease on September 27, 2021 by guest. Protected copyright. Kearns-Sayre Ophthalmoplegia, myopathy ETIOLOGY Secondary: hypothalamus AI is characterized by impaired adrenal synthesis of gluco- Holoprosencephaly GLI2, corticoids. When reduced production of mineralocorticoid FGF8 (aldosterone) is present it is associated with hyponatremia CRH deficiency due to salt-wasting and reciprocal hyperkalemia. AI can be Maternal hypercortisolemia categorized as primary, where the defect is in the adrenal Secondary: pituitary/hypothalamus gland, or secondary (central),