563927
brief-report2014
CPJXXX10.1177/0009922814563927Clinical PediatricsRottenstreich et al
Brief Report
Iatrogenic Cushing Syndrome due to Intranasal Dexamethasone
Clinical Pediatrics 1–3 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922814563927 cpj.sagepub.com
Amihai Rottenstreich, MD1, Isaiah D. Wexler, MD1, Abdulsalam Abu-Libdeh, MD1, and Yackov Berkun, MD1
Introduction Cushing syndrome (CS) is the result of abnormally high levels of cortisol or other glucocorticoids. The most common cause of iatrogenic CS is prolonged exogenous administration of corticosteroids.1 Topical steroid use has been associated with CS in children. In a recent review, 22 cases of iatrogenic CS over a period of 35 years were reported, mostly in infants with diaper rash.2 CS as a result of intranasal corticosteroid administration in childhood is rarely reported in comparison to iatrogenic CS caused by excessive oral administration of corticosteroids.3,4 With increasing use of intranasal steroids for a wide range of pediatric upper airway disorders, the potential for iatrogenic CS with these agents should be considered. We describe a case of a 7-month-old infant who developed CS secondary to intranasal use of dexamethasone. Written informed consent was obtained from the parents for publication of this case report.
Case Presentation A 7-month-old infant was referred to endocrinology clinic because of exaggerated weight gain of 2.5 kg beginning 2 months prior to admission with a transition from the 50th to the 92nd percentile. Linear growth velocity remained stable. His clinical history was unremarkable except for adenoid hypertrophy diagnosed 2 months prior to admission for which he had been prescribed 0.1% dexamethasone nasal drops administered as 2 drops to each nostril 3 times daily. After starting intranasal corticosteroid therapy, the parents noted that the infant had increased appetite and unexplained irritability. On initial exam, the patient weighed 10.2 kg and his length was 70 cm (50th percentile). The child’s blood pressure (111/73 mm Hg) was elevated based on ageadjusted norms. Moon facies, hirsutism, truncal obesity, and interscapular fat pad were visible on examination (Figure 1). Abdominal striae, peripheral edema, and proximal muscle weakness were absent. Laboratory findings revealed an elevated white blood cell count of
16 × 109/L with neutrophilic predominance without eosinophilia. Serum glucose and electrolytes were normal. Thyroid function, growth hormone, insulin-like growth factor 1 and prolactin levels were all within normal ranges. Early morning cortisol levels were below the range of detection on consecutive measurements. On further investigation, it was found that the parents had refilled the prescription for dexamethasone drops 8 times. Based on calculations related to the amount of drug obtained, a total of 80 mg of dexamethasone was administered over 2 months equivalent to 40 mg of hydrocortisone per day—5 times the physiologic replacement dose based on body surface area. Based on the clinical appearance, pharmacological history, and biochemical findings, iatrogenic CS was diagnosed. Treatment consisted of discontinuing dexamethasone and starting oral hydrocortisone therapy at a maintenance dose of 10 mg/m2/d. The dose was gradually tapered and discontinued over a period of 1 month. During this time, the child was followed closely to detect any signs of stress or illness that may lead to adrenal insufficiency. At the time of discontinuation, the patient had lost 1.2 kg, was normotensive, and his Cushingoid manifestations had regressed.
Discussion Since their introduction in 1948, corticosteroids have remained one of the most important drugs in clinical practice. Because of their anti-inflammatory and immunosuppressive effects, they are considered the treatment of choice for a variety of indications. However, their use is limited by an adverse effect profile including
1
Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel Corresponding Author: Yackov Berkun, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, PO Box 24035, Jerusalem 91240, Israel. Email: [email protected]
2
Figure 1. Patient at the time of admission. Notable features include Cushingoid habitus, moon facies, buffalo hump, and truncal obesity accompanied by hirsutism on the forehead and upper lip.
hypertension, osteoporosis, cataract, hyperglycemia, Cushingoid appearance and immunosuppression.5 With regard to topical steroids, there is an erroneous belief that they have an excellent safety profile while in fact, local administration may have harmful effects secondary to their systemic absorption.6 In pediatric medicine, most cases of iatrogenic CS secondary to topical steroid administration have been described in children with diaper dermatitis.2 CS due to intranasal steroid administration is rare.3,4 In the reported case, prolonged overdosage of intranasal dexamethasone, low basal state serum cortisol level, undetectable adrenocorticotropic hormone (ACTH) levels, and prominent Cushingoid features all supported the diagnosis of iatrogenic CS. Dexamethasone is a very potent corticosteroid having 20 times the potency of hydrocortisone. Increased potency and prolonged duration of action (half-life 36-54 hours compared with 8-12 hours for hydrocortisone) explain dexamethasone’s significant influence on the hypothalamic–pituitary–adrenal axis.7 For example, after 2 weeks of intranasal administration of dexamethasone (0.8 mg per day), serum ACTH levels were suppressed in 65% of adult patients.8 The infant in this case received an excessive amount of dexamethasone and this is not an unexpected finding. The problem of inappropriate usage of intranasal medications, including corticosteroids problem is compounded in infants as it is often difficult to administer the precise number of drops prescribed. For this reason, intranasal sprays are preferred over nasal drops because it is simpler to deliver the correct dose and there is less
Clinical Pediatrics risk for swallowing and gastrointestinal absorption.9 The question of whether newer intranasal steroids are to be preferred because of very low systemic absorption remains unresolved as these steroids are also more potent and could have systemic effects even if absorbed to only a small degree.10 In our case, significant clinical recovery was noted after a month. The time necessary for complete recovery of a suppressed hypothalamic–pituitary–adrenal axis is unpredictable and suppression can last up to a year.2 Patients who are clinically stable may experience an Addisonian crisis if a stressful situation or an acute infection occurs. After steroid withdrawal, regular clinical and biochemical follow-up is needed until cortisol and ACTH levels normalize. It may also be prudent to perform an ACTH stimulation test after discontinuation of corticosteroids to determine whether the adrenocortical suppression has resolved.
Conclusion Intranasal corticosteroids are being used for an increasing number of indications as either primary or adjunctive therapy related to upper airway disorders. Inappropriate administration of intranasal corticosteroids may result in the development of CS. Physicians should be aware of the potential systemic side effects when prescribing steroid-containing agents for intranasal use in children. Parents should be advised as to the potentially harmful adverse effects related to prolonged or excessive usage. Author Contributions Dr Rottenstreich drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted. Drs Berkun, Wexler, and Abu-Libdeh were involved in the conceptual development and preparation of the manuscript. All authors read and approved the final manuscript as submitted.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Miller WL. The adrenal cortex and its disorder. In: Brook CG, Hindmarsh PC, eds. Clinical Pediatric Endocrinology. 4th ed. Oxford, England: Blackwell Science; 2001:321-376.
Rottenstreich et al 2. Tempark T, Phatarakijnirund V, Chatproedprai S, Watcharasindhu S, Supornsilchai V, Wananukul S. Exogenous Cushing’s syndrome due to topical corticosteroid application: case report and review literature. Endocrine. 2010;38:328-334. 3. Findlay CA, Macdonald JF, Wallace AM, Geddes N, Donaldson MD. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317:739-740. 4. Malozowski S, Purucker M, Worobec A. Cushing’s syndrome induced by betamethasone nose drops. Children taking intranasal corticosteroid should be monitored for growth retardation. BMJ. 1999;318:1355. 5. Stewart PM, Krone NP. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Text Book of Endocrinology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011:479-544.
3 6. Decani S, Federighi V, Baruzzi E, Sardella A, Lodi G. Iatrogenic Cushing’s syndrome and topical steroid therapy: case series and review of the literature. J Dermatol Treat. 2014;25:495-500. 7. Melby JC. Drug spotlight program: systemic corticosteroid therapy: pharmacology and endocrinologic considerations. Ann Intern Med. 1974;81:505-512. 8. Michels MI, Smith RE, Heminbid EM. Adrenal suppression and intranasally applied steroids. Ann Allergy. 1967;25:569-574. 9. Dutta D, Shivaprasad KS, Ghosh S, Mukhopadhyay S, Chowdhury S. Iatrogenic Cushing’s syndrome following short-term intranasal steroid use. J Clin Res Pediatr Endocrinol. 2012;4:157-159. 10. Derendorf H, Meltzer EO. Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy. 2008;63: 1292-1300.
brief-report2014
CPJXXX10.1177/0009922814563927Clinical PediatricsRottenstreich et al
Brief Report
Iatrogenic Cushing Syndrome due to Intranasal Dexamethasone
Clinical Pediatrics 1–3 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922814563927 cpj.sagepub.com
Amihai Rottenstreich, MD1, Isaiah D. Wexler, MD1, Abdulsalam Abu-Libdeh, MD1, and Yackov Berkun, MD1
Introduction Cushing syndrome (CS) is the result of abnormally high levels of cortisol or other glucocorticoids. The most common cause of iatrogenic CS is prolonged exogenous administration of corticosteroids.1 Topical steroid use has been associated with CS in children. In a recent review, 22 cases of iatrogenic CS over a period of 35 years were reported, mostly in infants with diaper rash.2 CS as a result of intranasal corticosteroid administration in childhood is rarely reported in comparison to iatrogenic CS caused by excessive oral administration of corticosteroids.3,4 With increasing use of intranasal steroids for a wide range of pediatric upper airway disorders, the potential for iatrogenic CS with these agents should be considered. We describe a case of a 7-month-old infant who developed CS secondary to intranasal use of dexamethasone. Written informed consent was obtained from the parents for publication of this case report.
Case Presentation A 7-month-old infant was referred to endocrinology clinic because of exaggerated weight gain of 2.5 kg beginning 2 months prior to admission with a transition from the 50th to the 92nd percentile. Linear growth velocity remained stable. His clinical history was unremarkable except for adenoid hypertrophy diagnosed 2 months prior to admission for which he had been prescribed 0.1% dexamethasone nasal drops administered as 2 drops to each nostril 3 times daily. After starting intranasal corticosteroid therapy, the parents noted that the infant had increased appetite and unexplained irritability. On initial exam, the patient weighed 10.2 kg and his length was 70 cm (50th percentile). The child’s blood pressure (111/73 mm Hg) was elevated based on ageadjusted norms. Moon facies, hirsutism, truncal obesity, and interscapular fat pad were visible on examination (Figure 1). Abdominal striae, peripheral edema, and proximal muscle weakness were absent. Laboratory findings revealed an elevated white blood cell count of
16 × 109/L with neutrophilic predominance without eosinophilia. Serum glucose and electrolytes were normal. Thyroid function, growth hormone, insulin-like growth factor 1 and prolactin levels were all within normal ranges. Early morning cortisol levels were below the range of detection on consecutive measurements. On further investigation, it was found that the parents had refilled the prescription for dexamethasone drops 8 times. Based on calculations related to the amount of drug obtained, a total of 80 mg of dexamethasone was administered over 2 months equivalent to 40 mg of hydrocortisone per day—5 times the physiologic replacement dose based on body surface area. Based on the clinical appearance, pharmacological history, and biochemical findings, iatrogenic CS was diagnosed. Treatment consisted of discontinuing dexamethasone and starting oral hydrocortisone therapy at a maintenance dose of 10 mg/m2/d. The dose was gradually tapered and discontinued over a period of 1 month. During this time, the child was followed closely to detect any signs of stress or illness that may lead to adrenal insufficiency. At the time of discontinuation, the patient had lost 1.2 kg, was normotensive, and his Cushingoid manifestations had regressed.
Discussion Since their introduction in 1948, corticosteroids have remained one of the most important drugs in clinical practice. Because of their anti-inflammatory and immunosuppressive effects, they are considered the treatment of choice for a variety of indications. However, their use is limited by an adverse effect profile including
1
Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel Corresponding Author: Yackov Berkun, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, PO Box 24035, Jerusalem 91240, Israel. Email: [email protected]
2
Figure 1. Patient at the time of admission. Notable features include Cushingoid habitus, moon facies, buffalo hump, and truncal obesity accompanied by hirsutism on the forehead and upper lip.
hypertension, osteoporosis, cataract, hyperglycemia, Cushingoid appearance and immunosuppression.5 With regard to topical steroids, there is an erroneous belief that they have an excellent safety profile while in fact, local administration may have harmful effects secondary to their systemic absorption.6 In pediatric medicine, most cases of iatrogenic CS secondary to topical steroid administration have been described in children with diaper dermatitis.2 CS due to intranasal steroid administration is rare.3,4 In the reported case, prolonged overdosage of intranasal dexamethasone, low basal state serum cortisol level, undetectable adrenocorticotropic hormone (ACTH) levels, and prominent Cushingoid features all supported the diagnosis of iatrogenic CS. Dexamethasone is a very potent corticosteroid having 20 times the potency of hydrocortisone. Increased potency and prolonged duration of action (half-life 36-54 hours compared with 8-12 hours for hydrocortisone) explain dexamethasone’s significant influence on the hypothalamic–pituitary–adrenal axis.7 For example, after 2 weeks of intranasal administration of dexamethasone (0.8 mg per day), serum ACTH levels were suppressed in 65% of adult patients.8 The infant in this case received an excessive amount of dexamethasone and this is not an unexpected finding. The problem of inappropriate usage of intranasal medications, including corticosteroids problem is compounded in infants as it is often difficult to administer the precise number of drops prescribed. For this reason, intranasal sprays are preferred over nasal drops because it is simpler to deliver the correct dose and there is less
Clinical Pediatrics risk for swallowing and gastrointestinal absorption.9 The question of whether newer intranasal steroids are to be preferred because of very low systemic absorption remains unresolved as these steroids are also more potent and could have systemic effects even if absorbed to only a small degree.10 In our case, significant clinical recovery was noted after a month. The time necessary for complete recovery of a suppressed hypothalamic–pituitary–adrenal axis is unpredictable and suppression can last up to a year.2 Patients who are clinically stable may experience an Addisonian crisis if a stressful situation or an acute infection occurs. After steroid withdrawal, regular clinical and biochemical follow-up is needed until cortisol and ACTH levels normalize. It may also be prudent to perform an ACTH stimulation test after discontinuation of corticosteroids to determine whether the adrenocortical suppression has resolved.
Conclusion Intranasal corticosteroids are being used for an increasing number of indications as either primary or adjunctive therapy related to upper airway disorders. Inappropriate administration of intranasal corticosteroids may result in the development of CS. Physicians should be aware of the potential systemic side effects when prescribing steroid-containing agents for intranasal use in children. Parents should be advised as to the potentially harmful adverse effects related to prolonged or excessive usage. Author Contributions Dr Rottenstreich drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted. Drs Berkun, Wexler, and Abu-Libdeh were involved in the conceptual development and preparation of the manuscript. All authors read and approved the final manuscript as submitted.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Miller WL. The adrenal cortex and its disorder. In: Brook CG, Hindmarsh PC, eds. Clinical Pediatric Endocrinology. 4th ed. Oxford, England: Blackwell Science; 2001:321-376.
Rottenstreich et al 2. Tempark T, Phatarakijnirund V, Chatproedprai S, Watcharasindhu S, Supornsilchai V, Wananukul S. Exogenous Cushing’s syndrome due to topical corticosteroid application: case report and review literature. Endocrine. 2010;38:328-334. 3. Findlay CA, Macdonald JF, Wallace AM, Geddes N, Donaldson MD. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317:739-740. 4. Malozowski S, Purucker M, Worobec A. Cushing’s syndrome induced by betamethasone nose drops. Children taking intranasal corticosteroid should be monitored for growth retardation. BMJ. 1999;318:1355. 5. Stewart PM, Krone NP. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Text Book of Endocrinology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011:479-544.
3 6. Decani S, Federighi V, Baruzzi E, Sardella A, Lodi G. Iatrogenic Cushing’s syndrome and topical steroid therapy: case series and review of the literature. J Dermatol Treat. 2014;25:495-500. 7. Melby JC. Drug spotlight program: systemic corticosteroid therapy: pharmacology and endocrinologic considerations. Ann Intern Med. 1974;81:505-512. 8. Michels MI, Smith RE, Heminbid EM. Adrenal suppression and intranasally applied steroids. Ann Allergy. 1967;25:569-574. 9. Dutta D, Shivaprasad KS, Ghosh S, Mukhopadhyay S, Chowdhury S. Iatrogenic Cushing’s syndrome following short-term intranasal steroid use. J Clin Res Pediatr Endocrinol. 2012;4:157-159. 10. Derendorf H, Meltzer EO. Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy. 2008;63: 1292-1300.
