EXPERIENCE AND REASON |
Cushing’s Syndrome After Intra-articular and Intradermal Administration of Triamcinolone Acetonide in Three Pediatric Patients
* Divisions of Pediatric Endocrinology
Endocrine Laboratory
Rheumatology, Mayo Clinic, Rochester, Minnesota
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSDISCUSSIONREFERENCES |
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Background. Intra-articular and intradermal steroids are often used for their antiinflammatory effect. There is limited experience with intra-articular and intralesional administration of corticosteroids in the pediatric age group.
Design/Methods. We performed a retrospective chart review of 3 pediatric patients who developed Cushing’s syndrome after local administration of triamcinolone acetonide (TCA).
Results. Two females 9 and 17 years old, received intra-articular injections of TCA. One patient received multiple injections of TCA into the interphalangeal joints (cumulative dose: 120 mg), whereas the other received a single injection of 40 mg, a dose that is considered to be in the therapeutic range, into the hip joint. The third patient, a 7-year-old female, received multiple intralesional injections of TCA. These patients developed signs and symptoms of hypercortisolism that appeared 4 to 6 weeks after local administration of TCA and lasted for 4 to 6 months after the last dose of TCA. TCA was detectable in the plasma and urine by the liquid chromatography/tandem mass spectrometry method 4 to 5 months after the last dose of the steroid.
Conclusions. We noted evidence for Cushing’s syndrome in 3 pediatric patients after intra-articular or intradermal administration of TCA. One of them had received a therapeutic dose of TCA. The possibility of hypothalamic-pituitary-adrenal axis suppression should be considered in patients who have received intra-articular or intradermal steroid injections, particularly in those who have had multiple or relatively high doses.
Key Words: Cushing’s syndrome • triamcinolone acetonide • intra-articular • intradermal
Abbreviations: TCA, triamcinolone acetonide • LC-MS/MS, liquid chromatography/tandem mass spectrophotometry • ACTH, adrenocorticotropic hormone
Glucocorticoids are potent antiinflammatory agents used for the treatment of a variety of disorders. When given systemically, they are known to have many side effects. They therefore have been applied locally with the aim of achieving sufficiently high drug concentrations locally for antiinflammatory effect while limiting systemic toxicity. The intra- and periarticular administration of glucocorticoids has gained an important role in the management of inflammatory arthritis during the past 50 years. Intra-articular steroid therapy is now an accepted treatment modality in children and adolescents with monoarticular or oligoarticular inflammatory arthritis, particularly when treatment with nonsteroidal agents has failed. Intralesional steroids have also been used extensively in the treatment of hypertrophic scars and keloids.1 Locally administered steroid may be absorbed systemically, which can result in signs and symptoms of hypercortisolism and suppression of the hypothalamic-pituitary-adrenal axis. The systemic side effects of locally applied steroids depend on several factors such as the mode of administration, the dose and duration of treatment, as well as the solubility of the drug. Systemic effects such as clinical improvement in distant inflamed injected joints, transient eosinopenia, and increased urinary levels of urinary metabolites have been described after injection of steroids into the joints.2–4 These steroids have been detected also in the plasma after intra-articular administration, thus confirming their systemic absorption. Systemic glucocorticoid effects also have been described after prolonged intradermal administration of high doses of steroids.5
Triamcinolone is a fluorinated prednisolone derivative, and the 9-
fluoridation results in enhanced antiinflammatory properties. Triamcinolone acetonide (TCA) by virtue of being insoluble remains at the injection site or in the joints for a longer period, compared with the parent compound. There is limited experience with intra-articular and intralesional administration of the corticosteroids in the pediatric age group, and children often are given doses that are recommended for adults. We report 3 patients between 7 and 17 years old who developed symptoms of hypercortisolism after local administration of TCA that lasted for 4 to 5 months after the last dose of the drug and had detectable levels of the steroid in the plasma and urine 4 to 5 months after the last dose of the steroid.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSDISCUSSIONREFERENCES |
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Methods
The liquid chromatography/tandem mass spectrophotometry (LC-MS/MS) method for quantitative analysis of 14 synthetic glucocorticoids including TCA was used to detect TCA in plasma and urine samples. Two hundred seventy picomoles (100 ng) of stable isotope cortisol-9,11,12,12-d4 and 228 pmol (100 ng) of stable isotope triamcinolone-d1 acetonide-d6 was added to 0.5 mL of urine and serum as internal standards before extraction. Acetonitrile then was added to each sample to precipitate proteins. The supernatants were extracted with 4 mL of methylene chloride, washed, and dried. Fifteen microliters of the reconstituted extract was injected on to a reversed-phase column and analyzed by using a tandem mass spectrophotometer operating in the positive mode. Interassay coefficients of variation were 3.2% to 20.1% for mean concentrations of 0.03 to 13.0 µg/dL. Recovery of the analytes added to urine or serum was 82% to 138% for levels of 1 to 25 µg/dL. Sensitivity was 0.03 to 0.07 µg/dL. This method is very specific, and to our knowledge there is no known cross-reactivity with any known drugs and any of the synthetic glucocorticoids.
The high-pressure LC-MS/MS method also was used to measure urine-free cortisol. This method is very specific and separates interferences from cortisol. There is no cross-reactivity of TCA and synthetic steroids in the LC-MS/MS method used for estimation of urine-free cortisol.
Patients
Patient 1
A 9-year-old girl presented with flexion contractures of her interphalangeal joints of both hands without any preceding pain, swelling, warmth, or erythema. She had previously experienced pain and morning stiffness in her knee and ankle joints bilaterally. Because of a lack of response to methotrexate, naproxen, and plaquenil for a presumptive diagnosis of juvenile rheumatoid arthritis, she received intra-articular injections of TCA (20 mg) into her right 3rd and 4th proximal interphalangeal joints (total 40 mg). Six weeks later she received 20 mg of TCA into her right 2nd and 5th and left 3rd, 4th, and 5th proximal interphalangeal joints (total 100 mg). After her initial intra-articular injections, the patient developed flushing and fullness of the face, the appearance of a dorsocervical fat pad, and striae on the back, buttocks, and legs. She also experienced a significant weight gain of 16.2 kg over the next 6 months and felt she had mild weakness in her lower extremities. At evaluation 5 months after the last series of the steroid injections, the patient had continued to exhibit Cushingoid facies, multiple striae over the thighs, buttocks, and lower back, and a dorsocervical fat pad. Five months after the 2nd intra-articular injections, her AM cortisol was normal at 20 µg/dL (552 nmol/L; normal range: 7–25 µg/dL [193–690 nmol/L]), whereas PM cortisol was slightly elevated at 17 µg/dL (469 nmol/L; normal range: 2–14 µg/dL [55–386 nmol/L]) (Table 1). Of note, TCA does not cross-react in the plasma cortisol assay. Adrenocorticotropic hormone (ACTH) was normal at 39 pg/mL (8.6 pmol/L; normal range: 10–60 pg/mL [2.2–13 pmol/L]). Twenty-four-hour urine-free cortisol was measured on 2 different occasions 5 months after the last injection by using the high-pressure liquid chromatography method and was <0.5 µg per 24 hours. Magnetic resonance imaging of the head and adrenals was normal. TCA was detectable in the plasma at a concentration of 0.035 µg/dL 5 months after the last steroid injections. Urinary TCA was not measured. Six weeks later, TCA was not detectable in the blood. Eleven months after the last intra-articular injections, the patient had experienced complete resolution of the facial fullness and plethora and had also lost 2 kg. Her AM and PM cortisol (14 µg/dL [386 nmol/L] and 10 µg/dL [276 nmol/L], respectively) as well as ACTH (21 pg/mL [4.6 pmol/L]) were in the normal range.
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Patient 2
A 7-year-old girl presented with 2 keloids in the right knee after a burn injury and received multiple intralesional injections of TCA (3 injections to the medial keloid and 7 injections to the lateral keloid) over a period of 6 months. The cumulative dose of TCA was
500 to 600 mg. Two months after the initiation of intralesional administration of TCA, the patient developed puffiness and flushing of the face, the appearance of a dorsocervical fat pad, striae, and increased hair growth over the back (Fig 1). She also had experienced progressive weight gain of 9 kg during the year before the evaluation for Cushing’s syndrome. Four months after the last injection of TCA, physical examination was remarkable for obvious Cushingoid features, a dorsocervical fat pad, mild hypertrichosis, and marked purple striae over the left calf. At that time, there was evidence for suppression of the hypothalamic-pituitary-adrenal axis, with AM and PM cortisol measuring <1 µg/dL (27.6 nmol/L) and ACTH measuring 7.4 pg/mL (1.6 pmol/L) (Table 1). Urine-free cortisol (24-hour) and cortisone were <0.5 µg per 24 hours (<1.3 nmol/day). TCA was confirmed in the plasma (0.08 µg/dL) and urine (0.055 µg/dL). Eight months after the last dose of TCA, AM cortisol continues to be suppressed, measuring 1.6 µg/dL (44.1 nmol/L).
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Patient 3
A 17-year-old female presented to her primary care provider with fever and headache and was diagnosed with infectious mononucleosis. This was followed by persistent fatigue symptoms and arthralgias. She was treated with a week-long course of oral steroids on 2 occasions separated by 3 months. A month after the initial course of oral steroid, she received an intra-articular injection of TCA (40 mg) into the right hip for relief of right hip pain. Approximately 1 month after the intra-articular steroids, the patient developed fullness and flushing of the face, easy bruisability, and striae after the intra-articular injection (Fig 2). She also had a weight gain of 4.5 kg during the 2 months after the intra-articular injection. Five months after the intra-articular injection and 3 months after the last course of oral steroids, the facial fullness and plethora began to improve and her weight stabilized. At that time, while there was ongoing improvement in the facial fullness and plethora, AM and 11 PM cortisol were normal, measuring 15 µg/dL (414 nmol/L) and 1.5 µg/dL (41.4 nmol/L; normal range: <1.8 µg/dL [49.6 nmol/L]), respectively. ACTH also was normal at 43 pg/mL (9.5 pmol/L). Twenty-four-hour urine-free cortisol was normal at 8.4 µg per 24 hours (23.1 nmol/day; normal range: 5–55 µg per 24 hours [14–152 nmol/day]) (Table 1). TCA was still detectable in the plasma (0.04 µg/dL) and the urine (0.138 µg/dL)
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSDISCUSSIONREFERENCES |
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Cushing’s syndrome after intra-articular and intradermal administration of TCA has been described.5–10 The patients described above are unique in several respects. To our knowledge, patient 1 is the first pediatric patient reported with manifestations of hypercortisolism after intra-articular steroids. In a previous report of 22 children who had received intra-articular steroid therapy with triamcinolone hexacetonide, the patients had altered endogenous cortisol production with suppression of the morning peak and disturbance of the circadian rhythm from 10 to 30 days but did not develop any manifestations of hypercortisolism.11 The half-life of TCA after intravenous administration is 1.5 hours, but these data are not available for triamcinolone hexacetonide. Pharmacokinetics studies after intra-articular administration of TCA and triamcinolone hexacetonide suggest that both of these drugs are detectable in the plasma for >2 weeks because of the prolonged period of absorption of these drugs. The less soluble triamcinolone hexacetonide reached lower plasma levels but was detectable for a longer period of time because of lower solubility. Patient 1 had a minimal difference between and the AM and the PM cortisol. One could speculate that this was secondary to a disturbance in the circadian rhythm, which normally is characterized by the AM cortisol significantly exceeding PM cortisol. The manifestations of iatrogenic Cushing’s syndrome after intra-articular administration of TCA lasted for several months after the last dose of TCA (up to 5 months). The duration of suppression of the hypothalamic-pituitary-adrenal axis is quite variable and depends on the route of administration, dose and duration of treatment, and bioavailability of the steroid. Studies have shown that decreased cortisol levels after intra-articular administration of steroids may last from 1 to 7 days.12–14 van Tuyl and Slee15 reported a 37-year-old woman who had symptoms of hypercortisolism and adrenal suppression 3 months after having received 40 mg of TCA in her shoulder. The persistence of symptoms secondary to hypercortisolism in patient 2 is consistent with earlier reports of Cushing’s syndrome lasting for several months after intradermal administration of TCA. Teelucksingh et al7 reported features of Cushing’s syndrome and suppression of the hypothalamic-pituitary-adrenal axis up to 9 months in a 9-year-old girl after a single injection of 40 mg of TCA into a single keloid. In another report of 2 pediatric patients with Cushing’s syndrome after intradermal administration of TCA, the symptoms of hypercortisolism resolved in 6 to 8 weeks in a 10-year-old boy who had received a total dose of 80 mg.6 The duration of signs and symptoms of hypercortisolism is not known in the second patient, because she was not reevaluated for resolution of the manifestations until a year after the second and last dose of intralesional TCA. Most importantly, patient 3 had in fact received a dose of TCA that is in the recommended range for adult patients.
In this report we have demonstrated for the first time persistence of TCA in the plasma and urine up to 4 to 5 months after the intra-articular or intradermal administration of TCA. Most studies in the literature have described signs and symptoms of hypercortisolism and suppression of the hypothalamic-pituitary-adrenal axis after intra-articular and intradermal administration of TCA but have not attempted to measure TCA in plasma or urine. Pharmacokinetic and pharmacodynamic studies after intra-articular administration of TCA have demonstrated detectable levels of TCA in the plasma for 14 to 21 days after single-dose intra-articular administration of varying doses of TCA.16 The absorption of TCA tends to occur over a longer period of time if higher doses of TCA are administered, and drug absorption is the rate-limiting step of drug disposition (flip-flop phenomenon). Excessive doses of TCA and hence prolonged absorption of the drug in patients 1 and 2 could explain the persistence of detectable amounts of TCA in the plasma and/or urine. Detectable levels of TCA were noted for at least 80 days after accidental periarticular administration of an excessive amount of TCA in a 46-year-old woman.17 Avascularity of the keloid would make it serve as a reservoir for prolonged absorption of the drug as well in patient 2. Total body clearance of TCA has also been noted to be lower with higher doses of TCA, possibly reflecting a saturation of the elimination mechanisms of the drug.18 This mechanism could potentially explain prolonged detectability of the drug in plasma and urine after administration of a therapeutic dose of TCA in patient 3.
Assays performed on blood and urine for detection of exogenous steroids may not look specifically for this particular esterified formulation of triamcinolone, and hence it is important for clinicians to communicate to the laboratory if there is suspicion of iatrogenic Cushing’s syndrome secondary to TCA.
Iatrogenic Cushing’s syndrome is characterized by manifestations of hypercortisolism in association with undetectable cortisol and ACTH. However, patients 1 and 3 had cortisol and ACTH that were in the normal range. Of note, by the time the endocrine consultation was sought in these patients, the manifestations of hypercortisolism had begun to resolve. We speculate that in both instances the normal cortisol and ACTH measurements reflect recovery of the hypothalamic-pituitary-adrenal axis while the clinical manifestations of hypercortisolism were still present (but improving). The first patient, however, still had evidence for loss of the circadian rhythm secondary to the use of TCA.
It is not clear whether the children are more prone to systemic side effects from intra-articular or intradermal administration of steroids. There are no data on side effects from intra-articular administration of TCA in children except for the study of 22 children with chronic arthritis who received intra-articular triamcinolone hexacetonide. No manifestations of hypercortisolism were noted in any of the patients, although there was suppression of endogenous cortisol production. Triamcinolone hexacetamide is another esterified formulation of triamcinolone that is associated with a lesser degree of systemic absorption and hence a lesser degree of suppression of the hypothalamic-pituitary-adrenal axis, in comparison with TCA.16
The relative efficacy and safety of longer-acting esterified corticosteroids have not been tested in comparative, controlled trials, and hence the selection is based more on personal selection rather than experimental data. We have provided strong evidence to support systemic absorption of intra-articular and intralesional steroids in children. Although not all patients will suffer these "side effects," it is imperative that those administering the injections understand and communicate the risk to the families and monitor the patient closely after injections.
Because of limited data in the pediatric age group, there are no specific guidelines regarding the dosing for pediatric patients or a threshold dose beyond which the risk increases. Additionally, there are no specific guidelines regarding the time course of risk for Cushing’s syndrome and adrenal suppression or for monitoring at-risk patients. It is clear from this report that the duration of adrenal suppression can last as long as 8 months.
We conclude that the possibility of hypothalamic-pituitary-adrenal axis suppression should be considered in patients who have received intra-articular or intradermal steroid injections, particularly in those who have had multiple or relatively high doses. Acute adrenal crisis has been reported in a patient after intra-articular administration of ß-methasone.19 These patients may not be able to respond appropriately to the stress of an intercurrent illness/trauma and may require replacement therapy to avoid an adrenal crisis.
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FOOTNOTES |
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Received for publication Feb 27, 2003; Accepted Sep 1, 2003.
Address correspondence to Aida N. Lteif, MD, Division of Pediatric Endocrinology, Mayo East 9, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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