Definition (Pediatrics 2007;119:e484)
• Primary AI (Addison disease): Adrenal gland failure, resulting in and glucocorticoid (cortisol) and usually mineralocorticoid (aldosterone) deficiency
• Secondary or tertiary AI: ACTH def 2/2 pituitary or hypothalamic dysfxn
• Mineralocorticoid fxn is nml since aldosterone secretion is stimulated by K+ and renin–angiotensin system
Pathophysiology (Pediatrics 2007;119:e484)
• Cortisol: Counterregulatory hormone to insulin. Has mineralocorticoid effects at high/nml levels. ↑ angiotensin synthesis, ↑ vascular reactivity to vasoconstrictors and ↓ response to vasodilators, promotes conversion of norepi to epi (↑ cardiac output and hepatic glucose production)
• ↓ cortisol → ↓urinary flow 2/2 ↓GFR and ↑ water absorption
• Aldosterone level mediated by renin–angiotensin axis, serum potassium, and ACTH
• Deficiency → ↑ renin, ↑ K+, ↓ Na+, mild acidosis
Etiology (Pediatrics 2007;119:e484; N Engl J Med 2009;360:2328)
• Most common 2/2 chronic steroid use c/b infxn or med d/c (CentralAI)
• Primary AI: ↓ glucocorticoid and freq, mineralocorticoid hormones
• In one series pts <18 yo, 72% w/ congenital adrenal hyperplasia (CAH), 13% w/ autoimmune AI, and 15% w/ adrenoleukodystrophy, syndromes (Wollman, Zellweger); also can be 2/2 drug or infxn, infiltrative, or idiopathic etiology
• Central AI: Lack of corticotropin-releasing hormone (CRH) from hypothalamus and/or ACTH from pituitary → dec cortisol nml aldo
• Abrupt glucocorticoid w/d after courses as short as 2 wk can cause deficiency
• Prolonged steroid use can suppress the HPA axis for 6–9 mo or longer
• Pituitary insult and/or anatomic abnormality of HPA axis are other causes
• “Relative adrenal insufficiency” in ICU refers to vasopressor-resistant HoTN
• Indications for steroids under investigation
• Hypoproteinemia complicates interpretation of cortisol levels. Can be <18 mcg/dL in the absence of AI as cortisol is 90% protein bound (free cortisol nml)
Clinical Manifestations (Pediatrics 2007;119:e484; Clin Dermatol 2006;24:276; J Clin Endocrinol Metab 2011;96:E925; Pediatr Rev 2009;30:e49)
• Can present with nonspecific Sx, Dx often delayed
• 21-hydroxylase deficiency (most common cause of CAH)
• Newborn girls p/w virilized genitalia; boys at 2–3 wk w/ salt-wasting crisis
• Newborn screening improves rate of detection; reduces morbidity/mortality
• Acute AI: Dehydration, often w/ electrolyte abnormalities (HypoNa/HyperK) hypoglycemia, abdominal pain, fever, HoTN, and/or ΔMS/shock
• Chronic AI: Fatigue, anorexia, N/V, loss of appetite, weight loss, recurrent abdominal pain, back and joint pain, skin pigmentation, salt craving
• Hyperpigmentation (2/2 ↑ pro-opiomelanocortin and derivative melanocyte-stimulating hormone) and salt craving occur in primary but not in central AI
• Central AI may be assoc w/ other sx of pituitary failure; growth failure, delayed puberty, 2° hypothyroidism, and/or diabetes insipidus (AI can mask signs of DI because of water retention)
Diagnosis (Pediatrics 2007;119:e484; JAMA 2005;294:2481; Pediatr Rev 2009;30:e49)
• 1° AI: High plasma ACTH (often >100 pg/mL) & low cortisol (often <10 mcg/dL)
• Labs: Cortisol, ACTH, chem 20, bedside glucose, ABG/serum pH, aldosterone, plasma–renin activity, urine Na + K to evaluate mineralocorticoid status
• Infants w/ suspected CAH: Additionally order 17-OHP, karyotype, pelvic U/S
• ACTH stim test (250 mcg or 15 mcg/kg high dose ACTH test) w/ subnormal cortisol peak (<18 mcg/dL) drawn at 60 min after administration is diagnostic (some use low dose 1 mcg/M2 ACTH c peak <16 as diagnostic at 30 or 60 min)
• ACTH stim testing inaccurate if patient treated with exogenous steroid (prednisone, cortisol interfere c cortisol assay/not dexamethasone); do not delay treatment for testing if unstable
• Suspect aldosterone def if: Aldosterone low + renin high +/− HypoNa/HyperK
• Central AI: Confirmed by 8 am cortisol <3 mcg/dL, r/o if >18 mcg/dL in >4 mo
• Confirmation is difficult. Assays include insulin-induced hypoglycemia response (less safe), CRH stim, ACTH stim (can be false neg acutely), glucagon stim
• Low-dose ACTH may be most sensitive used but not fully validated in children
• Evaluation of etiology once diagnosis made often guided by H&P
• Anti-adrenal Abs specific but not 100% sensitive for autoimmune dz
• Check very long chain fatty acid levels and head CT/MRI for adrenoleukodystrophy
• Abd CT for evaluation for adrenal hemorrhage, neoplasm, infection
• Head CT/MRI if central AI suspected
Management (Pediatrics 2007;119:e484; Pediatr Rev 2009;30:e49)
• Treatment should NOT be withheld even if the diagnosis is not yet confirmed!
• Hypotension: Isotonic volume resuscitation, if in shock proceed per PALS, may require central access and pressors. Hypoglycemia: D25W (2–3 mL/kg)
• Stress-dose glucocorticoids (IM/SC/IV, IV faster, more reliable response)
• Hydrocortisone (w/ mineralocort activity) 50–75 mg/m2 × 1 → 50–75 mg/m2/q6h
• Methylprednisolone (min mineralocorticoid activity) 10–15 mg/m2
• Dexamethasone (no mineralocorticoid activity, allows subsequent ACTH-stim testing, and does not interfere w/ cortisol assay) 1.5–2 mg/m2
• Fludrocortisone (0.1–0.2 mg qd) replaces mineralocorticoid if able to take PO
• Note: Prednisone requires hepatic conversion to Fludrocortisone to exert glucocorticoid activity; not a good choice for stress-dose glucocorticoid
• Once stabilized, physiologic replacement doses initiated
• Daily cortisol production is 5–6 mg/m2; decreased oral bioavailability results in starting daily hydrocortisone doses of 9–12 mg/m2 divided q8h
• May give increased proportion in am to mimic physiologic dosing
• Prednisone and dexamethasone w/ longer t½ (convenient, but difficult to titrate)
• Infants may require daily sodium suppl (about 8 mEq/kg/d, or about 1–2 g/d)
• Titrate physiologic replacement to clinical status, not ACTH levels
Complications (Pediatrics 2007;119:e484)
• Life-threatening cardiovascular collapse can occur with failure to inc glucocorticoid supplementation w/ physical stress (infection, etc.)
• Life-threatening hyperkalemia requiring immediate attention
Prevention (Pediatrics 2007;119:e484)
• Patients should wear medical alert bracelets
• Routine vaccine, mild URI, exercise, & emot/psych stress need no replacement
• Moderate stress (fever >101, significant N/V/diarrhea) → triple TDD of hydrocortisone (30–50 mg/m2/d divided q6h)
• If pt cannot take PO, give 50 mg/m2 IM or SC (not usually rec but works unless pt is in shock) hydrocortisone Na succinate & seek immed medical attention
• For sepsis or major surgery, pts need ∼48 hr of 100 mg/m2/d IV divided q6h then taper over several days until back at maintenance dose