ped adrenal insufficiency

DOI: 10.1542/peds.2006-1612; originally published online January 22, 2007; 2007;119;e484Pediatrics

Dorothy I. Shulman, Mark R. Palmert and Stephen F. KempAdrenal Insufficiency: Still a Cause of Morbidity and Death in Childhood

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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REVIEW ARTICLE

Adrenal Insufficiency: Still a Cause of Morbidity andDeath in ChildhoodDorothy I. Shulman, MDa, Mark R. Palmert, MD, PhDb, Stephen F. Kemp, MDc, for the Lawson Wilkins Drug and Therapeutics Committee

aDepartment of Pediatrics, All Children’s Hospital, University of South Florida College of Medicine, Tampa, Florida; bDepartment of Pediatrics, Rainbow Babies & Children’sHospital, Case Western Reserve University, Cleveland, Ohio; cDepartment of Pediatrics, Arkansas Children’s Hospital, University of Arkansas, Little Rock, Arkansas

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

Adrenal insufficiency is relatively rare in childhood and adolescence. Signs andsymptoms may be nonspecific; therefore, the diagnosis may not be suspected earlyin the course. If unrecognized, adrenal insufficiency may present with life-threat-ening cardiovascular collapse. Adrenal crisis continues to occur in children withknown primary or secondary adrenal insufficiency during intercurrent illnessbecause of failure to increase glucocorticoid dosage. In this article, current knowl-edge of the incidence, diagnosis, and treatment of adrenal insufficiency in childrenand factors precipitating adrenal crisis are summarized. Suggestions for preventionof adrenal crisis in patients at risk are provided for health care professionals andfamilies.

www.pediatrics.org/cgi/doi/10.1542/peds.2006-1612

doi:10.1542/peds.2006-1612

KeyWordsadrenal disorders, morbidity/mortality,adverse outcomes

AbbreviationsCRH—corticotropin-releasing hormoneACTH—adrenocorticotropic hormoneCAH—congenital adrenal hyperplasiaGH—growth hormone

Accepted for publication Sep 13, 2006

Address correspondence to Dorothy I.Shulman, MD, Pediatric Endocrinology,University of South Florida, All Children’sHospital, 801 6th St, South St Petersburg, FL33701. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005;Online, 1098-4275). Copyright © 2007 by theAmerican Academy of Pediatrics

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THOMAS ADDISON1 first identified a syndrome charac-terized by wasting and hyperpigmentation associ-

ated with adrenal gland destruction 150 years ago. Life-saving glucocorticoid replacement has been available totreat adrenal insufficiency for �50 years. The most com-mon cause of acute adrenal insufficiency in North Amer-ica today is glucocorticoid withdrawal or omission inpatients being treated with chronic pharmacologic dos-es.2 Although there have been significant advances inunderstanding the molecular genetics of congenital andacquired causes of adrenal insufficiency in the pediatricpopulation, the clinical diagnosis is frequently delayed ormissed because of its vague and nonspecific symptomsearly in the course. If unrecognized, adrenal insuffi-ciency may present as a life-threatening crisis with acutecardiovascular collapse. A recent survey of adult patientswith adrenal insufficiency who are members of the Na-tional Adrenal Disease Foundation reported that 60%had sought the advice of �2 physicians before the diag-nosis was made.3 In 5 of 16 children in Melbourne,Australia, diagnosed with primary adrenal insufficiencyover a 10-year period, there was a median of 2 years’delay between the onset of the first symptoms and thediagnosis.4 Four of the remaining 11 children presentedin adrenal crisis. Once the diagnosis of adrenal insuffi-ciency is established, continuing reminders to patients,families, and medical personnel regarding the need forhigher doses of glucocorticoid replacement during inter-current illness and surgery are required. Failure to in-crease glucocorticoid supplementation during physicalstress remains a significant cause of morbidity and mor-tality for these patients.

ETIOLOGY AND INCIDENCEAdrenal insufficiency may be categorized as primary orsecondary and congenital or acquired. In primary adre-nal insufficiency, glucocorticoid and, frequently, miner-alocorticoid hormones are lost. In secondary adrenocor-tical insufficiency there is lack of corticotropin-releasinghormone (CRH) secretion from the hypothalamusand/or adrenocorticotropic hormone (ACTH) secretionfrom the pituitary, which results in hypofunction of theadrenal cortex. In secondary adrenal insufficiency min-eralocorticoid function is preserved. Causes of adrenalinsufficiency in children and adolescents are listed inTable 1. For a more comprehensive review of clinical,biochemical, and genetic characteristics of specific etiol-ogies, see refs 3, 5, and 6.

Primary Adrenal InsufficiencyPrimary adrenal insufficiency is uncommon in the West-ern population and is estimated to affect 90 to 140 per 1million people.2 In adults, �80% of cases are caused byautoimmune adrenal destruction, which is most com-mon in women aged 25 to 45 years but can occur in bothgenders at any age. Glandular infiltration by tuberculosis

is the second most common etiology worldwide. Perry etal6 recently reported their experience with primary ad-renal insufficiency in children �18 years old in Mon-treal, Canada, over the past 20 years. Of the 103 patientsidentified, 72% were diagnosed with congenital adrenalhyperplasia (CAH), 13% had autoimmune adrenal in-sufficiency, and the remaining 15% had adrenoleu-kodystrophy, syndromes (Wolman, Triple A [adrenalinsufficiency, achalasia, alacrima], Zellweger), or unex-plained adrenal insufficiency. An etiology for primaryadrenal insufficiency was identified in 94% of cases. In astudy performed in Melbourne, Australia,4 in which onlynon-CAH primary adrenal insufficiency was reported,there were 5 cases each of autoimmune adrenal insuffi-ciency, adrenoleukodystrophy, and adrenal hypoplasiacongenita and 1 case of the IMAGE syndrome (intrauter-ine growth retardation, metaphyseal dysplasia, adrenalhypoplasia congenita, and genital anomalies).

Data regarding mortality rates in patients with pri-mary adrenal insufficiency are scarce. CAH is the mostcommon form of primary adrenal insufficiency in chil-dren, with an incidence of 1 in 10 000 to 18 000 livebirths.7 Clinically, girls are most often identified at birthbecause of virilized genitalia, whereas boys are usuallydiagnosed after they present with a salt-wasting crisis at2 to 3 weeks of age. The most common enzyme defi-ciency is 21-hydroxylase. Mortality rates in the neonatalperiod resulting from missed diagnosis (primarily boys)are not readily available. However, in a review of chil-dren diagnosed with CAH between 1969 and 1998 inmiddle Europe, it was estimated that �2 to 3 undiag-nosed subjects per year died in the neonatal period.8

These data were based on the finding of fewer total boysdiagnosed with CAH over this time period, when theratio should have been be 1:1. Mortality in the first yearof life after making the diagnosis was reported to be 5times higher than in the general population; this im-proved over the last decade of the observation period. ABritish study estimated a fourfold increase in mortalityin children with CAH in the first 4 years of life over asimilar period of observation.9 Because of delayed ormissed diagnosis in affected male infants (and some veryvirilized female infants), in 2002 the Joint LawsonWilkins Pediatric Endocrine Society/European Societyfor Pediatric Endocrinology Working Group recom-mended biochemical screening for CAH in the newbornperiod.10 The majority of states in the United States arecurrently performing newborn screening, as are manyother countries. Infant screening programs have mark-edly decreased the time to diagnosis, theoretically de-creasing morbidity. Compared with retrospective studiesin which the incidence in female infants was reported tobe greater than that of males, in states where infantscreening has been implemented, the incidence of salt-wasting CAH in boys and girls seems to be equal, sug-gesting that screening has impacted mortality rates as

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TABLE 1 Causes of Glucocorticoid DeficiencyCondition Affected Gene Clinical Phenotype

PrimaryCongenitalCAH21-hydroxylase deficiency CYP21 Virilization/salt-wasting3-�-hydroxysteroid dehydrogenase deficiency HSD3B2 Ambiguous genitalia/salt-wasting11-�-hydroxylase deficiency CYP11B2 Virilization/hypertension (not infants)Cholesterol desmolase deficiency CYP11A XY sex reversal/salt-wastingLipoid hyperplasia STAR XY sex reversal/salt-wasting

Congenital adrenal hypoplasia SF-1 XY sex reversalDAX-1 Hypogonadotropic hypogonadism

IMAGE syndrome (intrauterine growth retardation,metaphyseal dysplasia, genital anomalies)

Triple A or Allgrove AAAS Achalasia, alacrimaACTH resistance MC2R, MRAPGlucocorticoid resistance GCCR Mineralocorticoid/androgen excessMetabolic diseasesAdrenoleukodystrophy ABCD1 Neurologic deteriorationZellweger PEX Cerebrohepatorenal syndromeSmith-Lemli-Opitz DCHR7 Polydactyly, XY sex reversal, mental retardationWolman disease LIPA Hepatomegaly

Mitochondrial diseaseKearnes-Sayre syndrome Ophthalmoplegia, myopathy

AcquiredAutoimmune adrenalitisIsolatedAutoimmune polyendocrinopathy syndrome type 1 AIREAutoimmune polyendocrinopathy syndrome type 2

Hemorrhage/infarctionTraumaWaterhouse-Frederickson syndromeAnticoagulation

Drug effectsAminoglutethimide, mitotane, ketoconazole, metyrapone,

medroxyprogesterone, megestrol, etomidate, rifampin, phenytoin,barbiturates

InfectionViral: HIV, cytomegalovirusFungal: coccidiomycosis, histoplasmosis, blastomycosis, cryptococcosisMycobacterial: tuberculosisAmebic

InfiltrativeHemochromatosis, histiocytosis, sarcoidosis, amyloidosis, neoplasm

SecondaryHypothalamusCongenitalSepto-optic dysplasia HESX1 NystagmusCRH deficiencyMaternal hypercortisolemia

AcquiredSteroid withdrawal after prolonged administrationInflammatory disordersTraumaRadiation therapySurgeryTumorsInfitrative disease: sarcoidosis, histiocytosis X

PituitaryCongenitalAplasia/hypoplasiaMultiple anterior pituitary hormone deficiencies PROP1Isolated ACTH deficiency TPIT

POMC Obesity, red hairProprotein convertase 1 PCSK1 Hypoglycemia, malabsorption, gonadotropin deficiency

AcquiredSteroid withdrawal after prolonged administrationTraumaTumor: craniopharyngiomaRadiation therapyLymphocytic hypophysitis



well.7 In Quebec, Canada, the male/female ratio of ne-onates diagnosed with CAH is 1:1 despite the absence ofscreening, suggesting that with a high level of clinicalawareness this diagnosis can be made without a formalscreening program.6 The high false-positive rate, partic-ularly in premature infants, has prevented universaladoption of biochemical screening for CAH.11 Prenataldiagnosis is now possible for pregnancies at high risk.12

Arlt and Allollo2 reported the risk of adrenal crisis in53 adult patients with adrenal insufficiency to be higherin primary adrenal insufficiency (3.8 admissions per 100patient-years) compared with secondary adrenal insuf-ficiency (2.5 per 100 patient-years).

Secondary Adrenal InsufficiencySecondary adrenal insufficiency is much more frequentand has an estimated prevalence of 150 to 280 per 1million people.2 Secondary adrenal insufficiency causedby abrupt discontinuation of glucocorticoid therapy orstress while on suppressive doses is the most commoncause because of the widespread use of exogenous ste-roids for a variety of disorders. The rate of adrenal crisisor death is unknown. Pharmacologic doses of glucocor-ticoids administered orally, intramuscularly, intrana-sally, inhalationally, transdermally, or intraorbitally mayresult in suppression of the hypothalamic-pituitary-ad-renal axis. Treatment courses for as brief as 2 weeks mayresult in transient suppression of endogenous cortisolproduction.5 In a study of children being treated forleukemia, a 4-week course of glucocorticoids resulted insuppression of the hypothalamic pituitary axis for up to8 weeks after discontinuation.13 Prolonged therapy mayresult in suppression for 6 to 9 months.14 Disease of thehypothalamic-pituitary axis must also be considered inpatients with secondary adrenal insufficiency (Table 1).Most secondary adrenal insufficiency that is not associ-ated with withdrawal of pharmacologic glucocorticoidtherapy occurs together with other pituitary hormonedeficiencies and either a history of pituitary insult oranatomic abnormality of the hypothalamic-pituitary axisevident on MRI.15

Mortality data in children with secondary adrenalinsufficiency come primarily from recent reports regard-ing follow-up of individuals treated with pituitarygrowth hormone (GH). These reports include primarilychildren with hypothalamic-pituitary disease. Three ar-ticles have reported a three- to fourfold increase in mor-tality compared with the general population in childrentreated with pituitary GH from the 1960s and followedto the 1990s in England, Canada, and the UnitedStates.16–18 Of all the deaths, 12% to 25% were a result ofhypoglycemia and/or secondary adrenal insufficiency.These preventable deaths were seen in individuals of allages and were associated with a variety of causes ofhypopituitarism. In the US experience, 24% of all thedeaths were sudden and unexpected.18 Of these, 74%

were said to occur in individuals with known multiplepituitary hormone deficiencies; in a third, death wasassociated with an intercurrent illness. In the opinion ofthe study’s authors, roughly half of the group with sud-den and unexplained death had a clinical course sugges-tive of adrenal insufficiency. Children �2 years of agewith GH deficiency and hypoglycemia (and most likelysevere adrenal insufficiency) were one of the highest-risk groups (mortality increased 10-fold). The death ratein the children with a history of hypoglycemia who were�6 years of age was 1 per 31 to 54 patient-years. After 6years of age, the death rate resulting from secondaryadrenal insufficiency declined slightly but remainedfairly constant with advancing age (1 per 113–173 per-son-years). In general, children with idiopathic, isolatedGH deficiency did not have increased mortality.

There are few data regarding death or hospitalizationin children without hypothalamic-pituitary disease whodevelop secondary adrenal insufficiency caused by with-drawal of pharmacologic glucocorticoid therapy. In areport of 2900 surveys mailed to consultant pediatriciansand adult endocrinologists in the United Kingdom re-garding adrenal insufficiency after the use of inhaledglucocorticoids, 23 children were reported to have acutehypoglycemia.19 Most had been using �500 �g of in-haled fluticasone daily. Linear growth rate does not pre-dict which children will have adrenal suppression oninhaled glucocorticoids.20

PHYSIOLOGIC EFFECTS OF GLUCOCORTICOIDS ON BLOODGLUCOSE AND BLOOD PRESSUREGlucocorticoids have effects on all body tissues. Theoverall metabolic action of glucocorticoids is catabolic,promoting protein and lipid breakdown and restrainingprotein synthesis in muscle, connective tissue, adiposetissue, and lymphoid cells. The effects of cortisol areantagonistic to those of insulin, increasing the concen-tration of glucose by stimulating gluconeogenesis. Cor-tisol decreases glucose use by muscle and promotes li-polysis in adipose tissue. Amino acids and glycerolreleased by the catabolic action of cortisol on protein andfat are used as gluconeogenic substrates. The net effect isincreased production and conservation of glucose for useby essential tissues, such as the brain and red blood cells,at the expense of less essential tissues during times ofstress or starvation.5,14

Cortisol contributes to the maintenance of normalblood pressure through several mechanisms. Under non-stressful conditions, cortisol increases urine flow bystimulating glomerular filtration rate and decreasing wa-ter resorption; however, at high concentrations, cortisolcan act like a mineralocorticoid, promoting sodium andwater retention. In high concentration, cortisol increasesangiotensinogen synthesis by the liver and increases thevascular reactivity to vasoconstrictors. In the adrenalmedulla, cortisol is required for the enzymatic activity of



phenylethanolamine N-methyltransferase, which con-verts norepinephrine to epinephrine. Epinephrine stim-ulates cardiac output as well as hepatic glucose produc-tion. Cortisol decreases capillary permeability anddecreases the production and activity of nitrous oxideand the vasodilatory kinin and prostaglandin systemsduring stress, preventing life-threatening hypotension.14

PHYSIOLOGIC EFFECTS OF ALDOSTERONEAldosterone is produced in the zona glomerulosa and iscontrolled primarily by the renin-angiotensin system,serum potassium, and ACTH. Under normal circum-stances the renin-angiotensin system predominates. Theprimary target of aldosterone is the kidney, where itstimulates reabsorption of sodium and secretion of po-tassium and hydrogen ions. Aldosterone deficiency re-sults in hyperreninemia, hyperkalemia, hyponatremia,and mild acidosis.

SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCYPatients with acute adrenal insufficiency generallypresent with acute dehydration, hypotension, hypogly-cemia, or altered mental status. Acute adrenal insuffi-ciency may be triggered by infection or trauma but mayalso be seen without an obvious concomitant illness orstress. Hypoglycemia is most common in young children.Altered mental status may occur at any age with orwithout hypoglycemia.21

Patients with chronic adrenal insufficiency usuallycomplain of chronic fatigue, anorexia, nausea, vomiting,loss of appetite, weight loss, and recurring abdominalpain. Symptoms may mimic gastrointestinal illness orpsychiatric disorder, in particular, behavior changes ordepression. Although increased skin pigmentation maybe noted because of elevation of pro-opiomelanocortinand melanocyte-stimulating hormone, a ligand derivedfrom pro-opiomelanocortin that causes hyperpigmenta-tion of melanin-containing skin cells and suppresses ap-petite,5 it is not always clinically obvious. Salt craving iscommon in chronic primary adrenal insufficiency. Hy-perpigmentation and salt craving are not observed inpatients with secondary adrenal insufficiency.

Unless there is a history of recent pharmacologic glu-cocorticoid therapy, secondary adrenal insufficiency isusually associated with signs of other pituitary hormonedeficiencies such as growth failure, delayed puberty,secondary hypothyroidism, and/or diabetes insipidus(polyuria and polydipsia).

Physical CluesIn chronic primary adrenal insufficiency, increased skinpigmentation may be observed, particularly in areolae,genitalia, scars, and moles. Areas unexposed to sun (eg,palmer creases, axillae) often are hyperpigmented. Thepatient also may have pigmentary lines in the gums. Ifnot frankly hypotensive, the patient may demonstrate

orthostatic hypotension. Some patients also may losepubic and axillary hair because adrenal androgens sup-port growth of body hair in these areas.

Laboratory FindingsHyponatremia and hyperkalemia are common in pri-mary adrenal insufficiency because of deficient aldoste-rone secretion. Hypoglycemia is common in both primaryand secondary adrenal insufficiency. Hyponatremia mayalso be seen in secondary adrenal insufficiency becauseof water retention from lack of cortisol to antagonize theeffect of vasopressin secretion.14

The diagnosis of primary adrenal insufficiency is con-firmed by documentation of an elevated plasma ACTHlevel (frequently �100 pg/mL) and a low serum cortisollevel (generally �10 �g/dL). If there is some questionabout the diagnosis, an ACTH-stimulation test (250 �gor 15 �g/kg for infants �2 years, intravenously) can beconducted; if there is primary adrenal insufficiency,there will be a subnormal peak cortisol level (�18 �g/dL) 60 minutes after ACTH administration. Mineralo-corticoid deficiency can be confirmed with the finding ofrelatively low aldosterone levels in the face of hyper-reninemia, with or without hyponatremia and/or hyper-kalemia.

The diagnosis of secondary adrenal insufficiency isassociated with low blood cortisol and ACTH levels. An0800-hour cortisol level of �3 �g/dL is suggestive of thediagnosis; a value �18 �g/dL essentially eliminates it.Confirmation of hypothalamic-pituitary-adrenal insuffi-ciency may be more difficult than primary adrenal in-sufficiency. The gold-standard test mimicking severestress has traditionally been insulin-induced hypoglyce-mia (serum cortisol measured 60 minutes after 0.05–0.15 U/kg of intravenous regular insulin, assuming dropin glucose 50% from baseline or �45 mg/dL; referencecortisol response: �18 �g/dL). This test must be per-formed cautiously under experienced medical supervi-sion. Many centers are no longer using this test becauseof the risk of hypoglycemic seizure and severe hypoka-lemia after treatment with glucose infusion.22 Otheravailable tests include stimulation with CRH (1 �g/kgintravenously over 2 minutes; reference response: two-fold increase in ACTH level at 15 minutes and three- tofourfold increase in cortisol levels at 13–30 minutes), alow (1 �g intravenously) or standard (250 �g intrave-nously) dose of ACTH (reference cortisol response: �18�g/dL 30–60 minutes later), and glucagon 0.1 mg/kgsubcutaneously or intramuscularly (between 2 and 3hours later, cortisol rises to �14 �g/dL as glucose falls,monitoring every 15 minutes during the hour).23 Thelow-dose (1 �g) ACTH test seems to be more sensitivethan the standard dose in the setting of secondary adre-nal insufficiency.24 A recent report from Germany sug-gests that glucagon may be a reasonably sensitive test ofhypothalamic-pituitary-adrenal function that is easy to



administer and is not associated with the risks associatedwith insulin-induced hypoglycemia.23 Metyrapone (30mg/kg orally at midnight) inhibits 11-hydroxylase, thefinal step in cortisol synthesis, thereby decreasing corti-sol feedback on ACTH; the following morning 11-deoxy-cortisol level is �5 �g/dL in “normal” children.5 This is acumbersome test that is rarely performed because of thedifficulty in obtaining metyrapone and the risk of pre-cipitating an adrenal crisis. In the neonate, a criticalvenous sample should be drawn at the time of hypogly-cemia and evaluated for glucose, cortisol, GH, and insu-lin levels. Results may guide the need for further eval-uation for multiple pituitary hormone deficiencies,isolated ACTH deficiency, or primary adrenal insuffi-ciency.

Glucocorticoid resistance, a rare entity that is associ-ated with mutations in the gene encoding the glucocor-ticoid receptor, is associated with elevated levels ofACTH, increased urinary free cortisol excretion, and in-creased production of mineralocorticoids and/or adrenalandrogens.25

TREATMENT OF ACUTE ADRENAL INSUFFICIENCYIn the hypotensive patient, rapid restoration of intravas-cular volume with isotonic sodium chloride containingdextrose is needed. Additional dextrose (D25W) shouldbe administered as required to treat hypoglycemia.

Blood should be drawn to test for cortisol, electrolyte,glucose, and ACTH levels, plasma renin activity, andaldosterone level. Measurement of urinary sodium andpotassium concentrations may also be helpful in assess-ing mineralocorticoid status. Simultaneous with the ad-ministration of intravenous fluids, stress doses of glu-cocorticoid should be given. Hydrocortisone is thetreatment of choice because of its mineralocorticoid ac-tivity. The recommended stress dose of hydrocortisone is50 to 75 mg/m2 intravenously initially, followed by 50 to75 mg/m2 per day intravenously divided in 4 doses.21 Itshould be recognized that recommendations for stressdoses are empiric and not based on carefully controlledclinical trials. Hydrocortisone may be given intramuscu-larly if no intravenous access exists, but intramuscularadministration works more slowly and may be ineffec-tively absorbed if peripheral perfusion is poor. Compa-rable stress doses are 10 to 15 mg/m2 for methylpred-nisolone and 1.5 to 2 mg/m2 for dexamethasone. Thelatter 2 corticosteroids have very little mineralocorticoidactivity. Prednisone is not a glucocorticoid of choice,because it must be converted to prednisolone before ifhas glucocorticoid activity. In patients with liver failure,this conversion may be impaired.

Dexamethasone can be used if one wants to treat thepatient urgently but wishes to carryout a diagnosticACTH-stimulation test. Treatment should never be with-held if the diagnosis of adrenal insufficiency is suspected.If the patient has good gastrointestinal function, fludro-

cortisone (0.1 to 0.2 mg daily), a synthetic mineralocor-ticoid, may be administered orally. Usually, administra-tion of intravenous sodium chloride along with largedoses of hydrocortisone are sufficient to begin normal-izing electrolyte abnormalities, making the addition ofmineralocorticoid unnecessary in the first hours of treat-ment. Hydrocortisone has �1/400th the mineralocorti-coid activity of fludrocortisone.2 Very rarely, if there is acoexisting cardiomyopathy and/or acute renal failureprohibiting rapid rehydration, more aggressive therapyof hyperkalemia may be needed. When the patient hasbeen stabilized, is feeling well, and is eating normally,glucocorticoid dosing may be tapered to physiologic re-placement doses. In the first year of life, infants withprimary adrenal insufficiency are generally supple-mented with 1 to 2 g of sodium chloride to ensureadequate sodium intake.

Children with possible adrenal insufficiency shouldbe referred to a pediatric endocrinologist for furtherdiagnostic evaluation, follow-up care, and counseling.

Physiologic Replacement Doses of GlucocorticoidMaintenance dosing of glucocorticoid for replacementtherapy is based on the secretory rate of cortisol in theintact system. However, there is debate about the base-line secretory rate, which makes it difficult to determinean exact replacement regimen. There are data indicatingthat the secretory rate may be as low as 5 to 6 mg/m2 perday without substantial variation with pubertal sta-tus.26–28 Because the bioavailability of cortisol is reducedby gastric acids and first pass in the liver, the usualmaintenance dose for glucocorticoid replacement needsto be adjusted above the estimated secretion rate. There-fore, 9 to 12 mg/m2 per day of oral hydrocortisone isprobably a reasonable initial starting dose for individualswith primary adrenal insufficiency. Patients with sec-ondary adrenal insufficiency, which is frequently partial,may do well on a lower dose. Adjustments are subse-quently made on an individual basis to avert signs andsymptoms of adrenal insufficiency while also avoidingthe growth retardation and Cushingoid features that canaccompany overreplacement.

Cortisol (hydrocortisone) is usually the drug of choiceand is dosed every 8 hours; other preparations withlonger half-lives (ie, prednisone, dexamethasone) canalso be used if necessary to facilitate adherence. It ismore difficult to finely adjust the dosage of these morepotent synthetic preparations, and some have little or noactivity at the mineralocorticoid receptor, which re-quires an increase in mineralocorticoid replacement. Al-though most replacement protocols call for dividing thecortisol equally either 3 times per day or every 8 hours,some favor skewing the dose slightly toward a higherproportion being administered in the morning to at-tempt to mimic the normal diurnal variation of cortisolin patients with adrenal insufficiency that does not stem



from CAH. In patients with CAH, there is evidence tosuggest that nighttime cortisol clearance is reduced, sug-gesting that the hydrocortisone dose should be weightedto the morning time.29 Nevertheless, some clinicians pre-fer to treat CAH with a higher dose of cortisol or alonger-acting glucocorticoid at night in an attempt tosuppress the early-morning ACTH-mediated adrenal an-drogen production.

ACTH cannot be used as a criterion for glucocorticoiddose adjustment in primary adrenal insufficiency. At-tempts at achieving ACTH levels within the referencerange leads to chronic overreplacement. Rather, oneshould gauge the quantity and timing of glucocorticoidson the basis of the patient’s own sense of well-being andenergy level. Frequent headaches, lethargy, nausea,and/or abdominal pain may indicate inadequate treat-ment. Objective signs of inadequate replacement ther-apy are orthostatic pulse and/or blood pressure changes.If skin hyperpigmentation becomes apparent in primaryadrenal insufficiency, obtaining plasma ACTH levels maybe helpful.

Stress DosingThe cortisol secretory rate increases substantially duringphysiologic stress. Consequently, all patients with adre-nal insufficiency (primary or secondary) need to be ed-ucated about the need to increase their glucocorticoiddose during stress to avoid preventable episodes of ad-renal crisis, which can be fatal. Patients should also bereminded to wear a medical alert bracelet or other jew-elry item and to carry an emergency medical informa-tion card to ensure that medical providers know abouttheir underlying disorder.

There is controversy as to what constitutes “stress”and the need to increase glucocorticoid doses. Mildstresses such as immunizations, uncomplicated viral ill-nesses, and upper respiratory tract infections with sorethroat, rhinorrhea, and/ or low-grade fever and otitismedia may not require use of a stress-dose steroid regi-men if the patient otherwise acts and appears well. Moresevere stresses such as illness accompanied by fever�38°C, vomiting, diarrhea, inadequate oral intake, leth-argy, surgery, trauma, dental work, and large burnsshould be accompanied by increased glucocorticoiddoses to prevent the hypoglycemia, hypotension, andeven cardiovascular collapse that can occur in the settingof an adrenal crisis. Moderate-to-extreme physical exer-cise may be facilitated by a slight increase (�30%) inhydrocortisone dosage 60 minutes before exercise. Thistoo, is controversial; Weise et al30 recently reported thatin adolescents with CAH, an additional morning dose ofhydrocortisone, which resulted in doubling of cortisollevels, did not affect performance, nor did it alter bloodglucose, lactate, free fatty acids, or epinephrine levelsduring short-term high-intensity exercise comparedwith placebo. Glucose and epinephrine levels during

exercise were significantly lower in patients with CAHcompared with a healthy control group. This researchstudy was performed under laboratory conditions andshould not be interpreted to mean that patients withCAH should be exercise restricted. There are insufficientdata as yet to draw such conclusions, and prevailingcollective experience suggests that such patients are ca-pable of vigorous physical activity without adverse con-sequences. In their consensus statement on CAH, theLawson Wilkins Pediatric Endocrine Society and Euro-pean Society for Paediatric Endocrinology did not rec-ommend increasing the glucocorticoid dose during psy-chological and emotional stress.10

The degree to which doses should be increased is alsodebated, with recommendations varying between 2 and10 times the maintenance rate.31 A common recommen-dation is to treat most stresses that require increaseddoses with hydrocortisone 30 to 50 mg/m2 per day (ap-proximately tripling the daily dose) divided into 3 or 4doses over the day. It is important that each patientknow his or her specific stress-dose regimen, becauseone might need to increase the maintenance dose moresubstantially for an individual who is on relatively low-dose maintenance replacement for secondary adrenalinsufficiency compared with an individual on relativelylarger doses needed to suppress excess androgen produc-tion in the treatment of CAH.

The most severe stresses, such as major surgery orsepsis, are often treated more aggressively, with doses upto 100 mg/m2 per day divided every 6 hours intrave-nously. Although various glucocorticoid preparationscould be used for stress dosing, hydrocortisone is thepreferred agent because of its mineralocorticoid activity.In most instances, stress doses are administered for only24 to 48 hours unless the underlying illness is prolonged.

Children who are unable to tolerate oral maintenanceor stress doses during an illness require parenteral glu-cocorticoid administration. This is commonly initiated athome using intramuscular hydrocortisone sodium suc-cinate at a dose of 50 mg/m2 and will provide coveragefor �6 to 8 hours. Consultation with a health care pro-vider is recommended. If the patient’s condition does notimprove or worsens, emergency evaluation and treat-ment with intravenous hydrocortisone should be under-taken.

Parenteral hydrocortisone is also frequently recom-mended before general anesthesia and surgery. A pre-operative dose of 50 mg/m2 30 to 60 minutes beforeinduction of anesthesia can be administered intrave-nously or intramuscularly. A second dose of 50 mg/m2

can then be administered as a constant infusion or as anintravenous bolus divided every 6 hours over the next24 hours. Intravenous or oral stress doses may be con-tinued until the patient has recovered.



INFLUENCE OF OTHER HORMONAL DEFICIENCIESIt is well documented that initiation of thyroid hormonereplacement in an individual who has hypothyroidismaccompanied by unrecognized adrenal insufficiency canprecipitate an adrenal crisis. The most common settingfor this in the pediatric population is the patient withmultiple pituitary hormone deficiencies. The mechanismthat precipitates adrenal crisis is not fully understood,but it is hypothesized that hypothyroid patients havereduced cortisol requirement secondary to a reducedmetabolic rate in the presence of untreated hypothyroid-ism.32,33 When thyroxine therapy is initiated, the meta-bolic rate and cortisol requirements increase, and anadrenal crisis is precipitated. Accordingly, hyperthyroid-ism can increase cortisol metabolism. It is suggested thatin the individual with hyperthyroidism and adrenal in-sufficiency, cortisol replacement be increased as much astwofold because of increased cortisol clearance.2 Preg-nancy is associated with increased corticosteroid-bindingglobulin and free cortisol levels during the last trimester,which requires an increase in hydrocortisone by 50%.2

Also, rising progesterone levels antagonize the mineralo-corticoid effect, which requires adjustment of fludrocor-tisone supplementation as well.

GH seems to inhibit 11-�-hydroxysteroid dehydroge-nase-1 activity in the liver, resulting in decreased con-version of inactive cortisone to active cortisol.34 Moni-toring for signs and symptoms of adrenal insufficiency isrecommended for individuals with concomitant second-ary adrenal insufficiency when GH therapy is initiated.Glucocorticoid therapy may need to be increased.

Dysfunction of the hypothalamic-pituitary-adrenalaxis should be considered in any child diagnosed withGH deficiency, particularly those with anatomic anom-alies of the pituitary or stalk on MRI, organic causes (eg,cranial surgery, tumors, trauma), and/or multiple ante-rior pituitary hormone deficiencies. Secondary adrenalinsufficiency may evolve over time in patients with cra-nial radiation, septo-optic dysplasia, autoimmune hy-pophysitis, PROP-1 deficiency, and after head trau-ma.35–37 Periodic reassessment of previously normalhypothalamic-pituitary-adrenal function should be con-sidered in patients with organic hypopituitarism.

Drugs that inhibit cortisol biosynthesis include amin-oglutethimide, etomidate, ketoconazole, metyrapone,medroxyprogesterone, and megestrol.5,38 Drugs that ac-celerate cortisol metabolism are phenytoin, barbiturates,and rifampin.2,5,21

“RELATIVE ADRENAL INSUFFICIENCY” IN THE ICUOver the past decade the concept of “relative adrenalinsufficiency” has been proposed in the ICU setting andgenerally refers to patients with vasopressor-resistanthypotension. In critically ill adults with a normal base-line cortisol level (�20 �g/dL), an incremental rise ofcortisol of �9 �g/dL after 250 �g of intravenous ACTH

was associated with improved survival when treatedwith stress doses of hydrocortisone.39

Pizarro et al40 recently studied the baseline and peakresponse to 250 �g of ACTH in critically ill children withseptic shock to learn if this test would predict shockresistant to vasopressors in the pediatric setting. All chil-dren (18%) with a basal serum cortisol level of �20�g/dL had catecholamine-resistant shock. Eighty per-cent of those with a low incremental cortisol response toACTH (�9 �g/dL at 30 or 60 minutes) compared with20% with “normal” basal and incremental cortisol re-sponse had catecholamine-resistant shock. Adrenal in-sufficiency, as defined in this study, did not predict mor-tality. The effect of corticosteroid treatment was notspecifically evaluated.

Secondary adrenal insufficiency after traumatic braininjury is another area of study in the ICU. In 80 patients(aged 14–80 years) immediately after traumatic braininjury, relative adrenal insufficiency (2 cortisol levels�15 �g/dL or 1 cortisol level of �5 �g/dL) occurred in50% of patients and was associated with lower bloodpressure and increased vasopressor requirements.41

Function normalized when assessed by low-dose ACTHtests at 3 and 6 months. The benefit of providing earlystress doses of glucocorticoids to patients with braininjury is currently being studied.

Measurement of circulating cortisol levels during se-vere illness may be problematic. Greater than 90% ofcirculating cortisol is protein bound. Low total cortisolbut increased free basal and ACTH-stimulated cortisollevels were recently demonstrated by Hamrahian et al42

in 40% of critically ill patients with hypoproteinemia.Free cortisol levels were comparable to critically ill pa-tients with normal serum protein levels and significantlyhigher than in healthy control subjects. Their articleraised questions about the true prevalence of relativeadrenal insufficiency in the ICU population. Furtherconfirmation of circulating free cortisol levels in variousphysiologic states may help clarify this issue.

Controversy also exists regarding the use of physio-logic stress doses of hydrocortisone in the hypotensiveinfant in the NICU. Sick premature infants may haverelatively low cortisol responses to ACTH compared withless sick, more mature infants, which suggests an inabil-ity to mount an adequate adrenal secretory response tosevere stress, possibly reflecting immaturity of the hy-pothalamic pituitary adrenal axis.43,44 Low cortisol levelswere more prevalent in a group of premature neonateswho subsequently died compared with those who sur-vived.45 Hydrocortisone (1 mg/kg every 8 hours) is fre-quently used to treat hypotension in this population,particularly those who are unresponsive to vasopressoragents. Although critically ill infants with the lowestcortisol levels respond best to hydrocortisone therapy,basal cortisol levels and cortisol and ACTH responses toCRH are variable and do not predict need for vasopres-



sors or response to hydrocortisone therapy.46,47 Ng et al48

recently performed a double-blind randomized, con-trolled study of a stress dose of hydrocortisone (1 mg/kgevery 8 hours intravenously for 5 days) versus placebosolution in 48 very low birth weight infants with hypo-tension requiring dopamine at �10 �g/kg per minute.Two patients in the hydrocortisone-treated group versus11 infants in the control group required a second vaso-pressor, which suggested benefit. Although hydrocorti-sone in this population seems to be an important tool inachieving cardiovascular stability, its long-term safety inthis population has not been established. During a largerandomized multicenter trial of hydrocortisone treat-ment in very low birth weight infants, an increase ofspontaneous gastrointestinal perforations was found inthe treated infants, particularly with concomitant use ofindomethacin.49 Hydrocortisone may enhance the vaso-constrictive effects of dopamine or epinephrine, possiblyreducing tissue perfusion. Long-term effects of hydro-cortisone on neurodevelopmental outcome are un-known.

Whether the critically ill very premature infant hasrelative or absolute adrenal insufficiency is still not cer-tain; however, hydrocortisone can usually be weaned ifthe infant remains stable; endogenous glucocorticoid se-cretion seems to normalize as the infant matures.46

As in older children and adults, normative data areneeded regarding basal and stimulated free serum corti-sol levels in premature and term neonates.

WAYS TO IMPROVE EDUCATION REGARDING STRESS DOSINGIN PATIENTSWITH KNOWNADRENAL INSUFFICIENCYMorbidity and mortality associated with adrenal insuffi-ciency remain unnecessarily high. The following mea-sures are suggested when caring for these children:

1. Provide written instructions to the patient and fam-ily regarding how and when to increase glucocorti-coid therapy; review the instructions at each visit orat least yearly so that the dose can be appropriatelyincreased as the child grows.

2. Instruct the family on the use of intramuscular hy-drocortisone sodium succinate in case of vomitingillness or severe stress; review the dosage yearly sothat it is increased with growth of the child.

3. Advise the use of a medical alert bracelet or necklacestating the diagnosis of adrenal insufficiency and theneed to administer hydrocortisone.

4. In young children prone to hypoglycemia, havinghome blood glucose monitoring equipment and glu-cose gel in the home may be indicated.

5. Sugar-containing snacks should be provided withprolonged or strenuous exercise because of epineph-rine deficiency in children with adrenal insuffi-ciency.

6. Advise patients and their caretakers to seek medicalconsultation if the patient becomes ill.

7. Consider preparing a letter to be mailed to the fam-ily’s local emergency medical services to notify themof the patient’s diagnosis and place of residence sothat, if they are called to the home, hydrocortisonecan be administered without delay. This may beparticularly important if not all family members arewilling or able to administer the intramuscular in-jection independently.

8. Continuing education is needed for primary carephysicians and emergency department physiciansregarding signs and symptoms and appropriatetreatment of adrenal insufficiency.

9. Some children and adolescents with adrenal insuf-ficiency will never be capable of recognizing andtreating an adrenal crisis. Safeguards should be inplace to ensure oversight as these children becomemore independent.

10. Individuals who have been on long-term (�2weeks) pharmacologic doses of glucocorticoidsshould be considered at risk for adrenal insuffi-ciency.

11. Patients who require long-term exogenous glu-cocorticoid therapy should be weaned to doses thatare less than physiologic or given every other day tohelp avoid the risk of adrenal insufficiency.

ACKNOWLEDGMENTSWe thank the following members of the Lawson WilkinsPediatric Endocrine Society Drug and TherapeuticsCommittee for careful review of the manuscript andconstructive comments: Phyllis Speiser, MD, MichaelKappy, MD, Paulo Collette-Solberg, MD, Erica Eugster,MD, Madhusmita Misra, MD, and David Ludwig, MD.

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DOI: 10.1542/peds.2006-1612; originally published online January 22, 2007; 2007;119;e484Pediatrics

Dorothy I. Shulman, Mark R. Palmert and Stephen F. KempAdrenal Insufficiency: Still a Cause of Morbidity and Death in Childhood

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