Are Corticosteroid Injections Associated With Secondary Adrenal Insufficiency in Adults With Musculoskeletal Pain? A Systematic Review and Meta-analysis of Prospective Studies.

BACKGROUND: Corticosteroid injection is a common treatment for individuals experiencing musculoskeletal pain, and it is part of the management of numerous orthopaedic conditions. However, there is concern about offering corticosteroid injections for musculoskeletal pain because of the possibility of secondary adrenal insufficiency. QUESTIONS/PURPOSES: In this systematic review and meta-analysis of prospective studies, we asked: (1) Are corticosteroid injections associated with secondary adrenal insufficiency as measured by 7-day morning serum cortisol? (2) Does this association differ depending on whether the shot was administered in the spine or the appendicular skeleton? METHODS: We searched the Allied and Complementary Medicine (AMED), Embase, EmCare, MEDLINE, CINAHL, and Web of Science from inception to January 22, 2021. We retrieved 4303 unique records, of which 17 were eventually included. Study appraisal was via the Downs and Black tool, with an average quality rating of fair. A Grading of Recommendations, Assessment, Development, and Evaluations assessment was conducted with the overall certainty of evidence being low to moderate. Reflecting heterogeneity in the study estimates, a pooled random-effects estimate of cortisol levels 7 days after corticosteroid injection was calculated. Fifteen studies or subgroups (254 participants) provided appropriate estimates for statistical pooling. A total of 106 participants received a spine injection, and 148 participants received an appendicular skeleton injection, including the glenohumeral joint, subacromial bursa, trochanteric bursa, and knee. RESULTS: Seven days after corticosteroid injection, the mean morning serum cortisol was 212 nmol/L (95% confidence interval 133 to 290), suggesting that secondary adrenal insufficiency was a possible outcome. There is a difference in the secondary adrenal insufficiency risk depending on whether the injection was in the spine or the appendicular skeleton. For spinal injection, the mean cortisol was 98 nmol/L (95% CI 48 to 149), suggesting secondary adrenal insufficiency was likely. For appendicular skeleton injection the mean cortisol was 311 nmol/L (95% CI 213 to 409) suggesting hypothalamic-pituitary-adrenal axis integrity was likely. CONCLUSION: Clinicians offering spinal injections should discuss the possibility of short-term secondary adrenal insufficiency with patients, and together, they can decide whether the treatment remains appropriate and whether mitigation strategies are needed. Clinicians offering appendicular skeleton injections should not limit care because of concerns about secondary adrenal insufficiency based on the best available evidence, and clinical guidelines could be reviewed accordingly. Further research is needed to understand whether age and/or sex determine risk of secondary adrenal insufficiency and what clinical impact secondary adrenal insufficiency has on patients undergoing spinal injection. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Enhancement of Kidney Invigorating Function in Mouse Model by Cistanches Herba Dried Rapidly at a Medium High Temperature.

Cistanches Herba is a popular Traditional Chinese Medicine and functional food that is used to treat kidney yang deficiency (KYD) in China. In this study, we investigated the effects of different drying methods for Cistanches Herba on kidney invigoration and yang strengthening. We established a mouse model of KYD by intraperitoneal injection of hydrocortisone for 8 days. We dried slices of Cistanches Herba in the sun, in the shade, in a microwave, or in an oven at 40°C, 60°C, 80°C or 100°C, then prepared and administered extracts to the mice by gastric gavage. We measured and evaluated the echinacoside (ECH) and acteoside (ACT) contents of the extracts, as well as the mice's body weight; testicular, epididymal, hepatic, and renal coefficients; and semen quality. All the Cistanches Herba extracts, obtained using different drying techniques, improved symptoms of KYD diagnosis in mice. Among them, treatments with Cistanches Herba dried in a microwave and dried in an oven at 100°C had the best therapeutic effects. Our results suggested that the higher the total content of ECH and ACT in Cistanches Herba extracts, the better the effects of kidney invigoration and yang strengthening. In addition, shorter drying times at higher temperatures lead to the highest recoveries of active components, and Cistanche dried in the sun at a medium-high temperature can improve sperm quality in mice.

Steroid-induced hypocalcaemia with tetany in a patient with hypoparathyroidism.

Although glucocorticoids have a known negative effect on calcium balance, they do not normally cause clinically significant hypocalcaemia. A young woman with post-surgical hypoparathyroidism developed symptomatic hypocalcaemia on two occasions following treatment with intravenous hydrocortisone for allergic reactions. Oral calcium and vitamin D supplementation could not prevent the development of hypocalcaemia. She was treated successfully with intravenous calcium gluconate infusions and discontinuation of glucocorticoids. In patients with hypoparathyroidism, impaired parathyroid hormone response to steroid-induced negative calcium balance may result in severe symptomatic hypocalcaemia requiring hospitalisation.

A case of tinea incognito.

Tinea incognito is a dermatophyte infection of the skin that presents atypically because it has previously been treated with imunnosuppresive medication. Herein we present a case of a middle-aged man who was initially clinically diagnosed to have plaque-type psoriasis on his arms. Over the course of two months of topical hydrocortisone and calciptriol treatment as well as phototherapy, the rash worsened. At the time of presentation to hospital the patient had a pruritic, widespread, sloughing, erythematous rash with areas of eschar. A punch biopsy skin confirmed dermatophyte fungal infection of the skin. Fungal culture was positive for Trichophyton Rubrum and the eruption resolved with systemic anti-fungal therapy. Patient specific risk factors for atypical presentation included poor hygiene and hepatatic disease.

[Development of Cushing's syndrome during phytotherapy]. / Entwicklung eines Cushing-Syndroms während einer Phytotherapie.

UNLABELLED: HISTORY AND INITIAL FINDINGS: In a 75-year-old woman with unclear weight gain and typical signs of Cushing's syndrome, a pituitary microadenoma and hyperplasia of the left adrenal gland were diagnosed. She was referred for preoperative diagnostics. Her clinical appearance suggested hypercortisolism. INVESTIGATIONS: The lab test suggested external glucocorticoid application. Basal ACTH and cortisol were low. DIAGNOSIS, TREATMENT AND FURTHER COURSE: The patients' phytotherapeutics received from a masseuse were analyzed in a special lab. The analysis showed that the pills were enriched with cortisone and hydrocortisone and were causal for the development of Cushing's syndrome and the symptoms of secondary adrenal insufficiency. CONCLUSION: Symptoms of Cushing's syndrome develop during chronic exposure to glucocorticoids. The development of Cushing's syndrome depends on the patient's sensitivity and on the duration and dose of the glucocorticoid application. Clinical and laboratory studies precede imaging.

Contact dermatitis to topical medicaments: a retrospective chart review from the Ottawa Hospital Patch Test Clinic.

BACKGROUND: Topical medicaments are a common cause of allergic contact dermatitis. This study will evaluate the prevalence of contact allergy to a wide array of topical medicaments at the Ottawa Patch Test Clinic. OBJECTIVES: The objectives of this study are to report the results of positive patch testing to topical medicaments at the Ottawa Patch Test Clinic and identify common sensitizers in topical medicaments. METHODS: Patients were tested with the standard North American Contact Dermatitis screening series of 70 allergens plus supplementary allergens when indicated. A retrospective chart review of patients positive to topical medicaments between January 1, 2000, and September 30, 2010, was undertaken. RESULTS: The average age of patients was 49.5 years. Thirty-four percent were atopic. Common sensitizers included topical antibiotics (58%), steroids (30%), anesthetics (6%), and antifungals (6%). Patch testing showed that 61% of patients tested positive to antibiotics, 21% to topical steroids, 17% tested positive to topical anesthetics, and 1% tested positive to topical antifungals. The most common reactions were to bacitracin (44%) and neomycin (29%). The most common steroid screener was tixocortol-17-pivalate (group A) (19%), and the most common local anesthetic was lidocaine (12%). CONCLUSIONS: Topical medicaments of all kinds are common causes of allergic contact dermatitis. Those that are more readily available, in over-the-counter preparations, are the most frequent culprits.

[Ridit analysis of experimental data from animal models of yang deficiency induced by different doses of hydrocortisone].

OBJECTIVE: Hydrocortisone-induced yang-deficiency animal model has now become the generally accepted model of yang deficiency. However, assessing the most appropriate dose of hydrocortisone is a long-term challenge. For analyzing the modeling dose, the authors have built several kinds of yang-deficiency models induced by hydrocortisone at different doses, and analyzed the experimental data with various mathematical statistical methods. In order to discuss the effects of the modeling dose on the basis of previous research, the authors introduced Ridit analysis. METHODS: After categorizing 27 batches of experiments with four different doses (including 2.5, 3.75, 10 and 20 mg/kg), the data were standardized and the data type was changed to meet the needs of subsequent calculations. Then, by using Ridit analysis, the authors compared the variation of 19 biochemistry indexes involving nervous-endocrine system, immune system, metabolic system and the function of the liver and kidney, so as to analyze the similarities and differences of those yang-deficiency models mentioned above. The effects of modeling dose were then discussed. RESULTS: With regard to the overall state of the animal model, the difference between the models induced by different doses of hydrocortisone (2.5, 3.75, 10 and 20 mg/kg) showed no statistical significance, indicating that differences in hydrocortisone dose barely lead to significant changes in yang-deficiency models. For the trends of changing in different indexes, indexes had different performances when the doses differs: gonad indexes (estradiol and testosterone) showed better performance in 2.5 mg/kg group, immunological indexes (immunoglobulin M and immunoglobulin G) showed better performance in 3.75 mg/kg group and metabolic indexes (triglyceride and total cholesterol) showed better performance in 10 mg/kg group, etc. This indicates that the dose of hydrocortisone should be determined according to the research purposes. CONCLUSION: Ridit analysis can be used as an integration analysis method for animal models of yang deficiency induced by hydrocortisone at different doses.

Acute hydrocortisone treatment increases anxiety but not fear in healthy volunteers: a fear-potentiated startle study.

BACKGROUND: The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as "anxiety," but not relatively similar, briefer aversive states, such as "fear." However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats. METHODS: Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle). RESULTS: Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle. CONCLUSIONS: These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.

Cortisol reduces cell proliferation in the telencephalon of rainbow trout (Oncorhynchus mykiss).

The fish brain grows throughout life, and new cells are added continuously in all major brain areas. As in mammals, the rate of adult brain cell proliferation in fish can be regulated by external factors including environmental complexity and interaction with conspecifics. We have recently demonstrated that the stress experienced by subordinate rainbow trout in social hierarchies leads to a marked suppression of brain cell proliferation in the telencephalon, and that this is accompanied by an increase in plasma levels of cortisol. Corticosteroid hormones are known to suppress adult neurogenesis in mammals, and to investigate whether this is also the case in fish, rainbow trout were fed feed containing either a low or a high dose of cortisol for 6 days. Compared to control animals receiving regular feed, both cortisol treated groups had significantly elevated cortisol levels 24h after the last feeding, with the high group having levels comparable to those previously reported in socially stressed fish. To quantify cell proliferation, immunohistochemistry for proliferating cell nuclear antigen (PCNA) was performed to identify actively cycling cells. The density of PCNA-positive nuclei in the telencephalon was reduced by about 50% in both cortisol treated groups. The effect of cortisol on brain cell proliferation did not reflect a general down regulation of growth, as only the high cortisol group had reduced growth rate, and there was no correlation between brain cell proliferation and growth rate in any group. These results indicate that the reduced proliferative activity seen in brains of socially stressed fish is mediated by cortisol, and that there is a similar suppressive effect of cortisol on brain cell proliferation in the teleost forebrain as in the mammalian hippocampus.

A comparative study evaluating the tolerability and efficacy of two topical therapies for the treatment of keloids and hypertrophic scars.

BACKGROUND: Onion extract gel (OE) and 0.5% hydrocortisone, silicone and vitamin E lotion (HSE) are two over-the-counter preparations used to enhance the cosmesis of keloids and hypertrophic scars. OBJECTIVE: To determine the tolerability and efficacy of OE versus HSE versus placebo in subjects with keloids and hypertrophic scars. METHODS: Thirty subjects (> or =18 years) with keloids or hypertrophic scars were randomly assigned to one of three study preparations for 16 weeks. Scar volume was measured at baseline and weeks 4, 8, 12 and 16. Subjects and blinded investigators assessed scar parameters (induration, erythema, pigmentation alteration, pain, itching, tenderness and cosmetic appearance) and patient satisfaction at each visit using a visual analog scale (VAS). Data analysis included: mean percentage change (MPC) for subjects completing the study (n = 15); the mixed model test to determine differences between the groups over time; and the Kruskal-Wallis test for the analysis of differences in subjects' satisfaction within the three groups over 16 weeks for subjects who completed at least one follow-up visit (n = 21). RESULTS: All three preparations were well tolerated with the exception of a mild acneiform-like eruption in one OE patient. Significant improvements were obtained with OE in volume, length, width and induration and with HSE in volume, length, induration, erythema and pigmentation alteration. There was a trend showing that a higher percentage of subjects were satisfied with OE than with HSE or placebo. The Mix Model Analysis (MMA) showed significant improvements with OE over placebo in investigator cosmetic assessment, lesion induration, pigmentation and tenderness and with HSE over placebo in investigator cosmetic assessment, lesion induration, pigmentation and erythema. Improvements in erythema and pigmentation were significantly greater in HSE than in OE. CONCLUSION: Both OE and HSE were more effective than placebo in the management of hypertrophic scars and keloids.

Comparison of efficacy and safety of ciprofloxacin otic solution 0.2% versus polymyxin B-neomycin-hydrocortisone in the treatment of acute diffuse otitis externa*.

OBJECTIVE: To compare the efficacy and safety of ciprofloxacin otic solution 0.2% to polymyxin B-neomycin-hydrocortisone (PNH) otic solution in the treatment of acute diffuse otitis externa in children, adolescents, and adults. METHODS: This was a randomized, parallel-group, evaluator-blind, active-controlled, multicenter, noninferiority study. The primary efficacy endpoint was clinical cure of otitis symptoms at the test-of-cure (TOC) visit. Clinical cure at the end-of-treatment (EOT) visit and percentages of patients with clinical improvement and resolution and/or improvement of otalgia at EOT and TOC visits were secondary efficacy endpoints. RESULTS: A total of 630 patients were randomized to ciprofloxacin twice daily (n = 318) or PNH 3 times daily (n = 312) for 7 days. Ciprofloxacin was shown to be noninferior to PNH. The percentage of patients with clinical cure at the TOC visit was 86.6% with ciprofloxacin and 81.1% with PNH; the treatment difference was 5.6% in favor of ciprofloxacin (95% CI: -0.9 to 12.1). At the EOT visit, clinical cure was achieved in 70.0% and 60.5% of patients, respectively, with a treatment difference in favor of ciprofloxacin (9.5%, 95 CI: 1.2 to 17.9). In all secondary efficacy variables, ciprofloxacin and PNH showed similar results, including pain duration and resolution. The clinical cure rate for patients with baseline cultures showing P. aeruginosa was 87.5% in the ciprofloxacin group and 78.6% in the PNH group, a treatment difference of 8.9% in favor of ciprofloxacin (95% CI: 0.6 to 17.3); for patients with baseline cultures showing S. aureus, the clinical cure rate was 72.7% for the ciprofloxacin group and 75.9% for the PNH group (treatment difference of 3.1% in favor of PNH, 95% CI: -21.1% to 27.4%). Most adverse events were mild and unrelated to study medication in both treatment groups. A limitation of this study is the assessment of signs and symptoms at baseline and after treatment, which does not provide data to evaluate the interim response. CONCLUSIONS: Ciprofloxacin otic solution 0.2% was found to be noninferior to PNH. This efficacy, good tolerability, and ease of administration make ciprofloxacin otic solution 0.2% without a topical steroid an attractive option for the treatment of acute otitis externa.

Wogonin prevents immunosuppressive action but not anti-inflammatory effect induced by glucocorticoid.

Glucocorticoid, such as dexamethasone, has anti-inflammatory and immunosuppressive action as major pharmacological effects. The latter action caused by lymphocyte apoptosis is not only a therapeutic effect but also an adverse reaction. Wogonin, a plant flavone found in Scutellaria baicalensis Georgi, inhibited dexamethasone-induced apoptotic changes, such as DNA fragmentation, nuclear condensation, phosphatidylserine translocation, and caspase activation in rat thymocytes. Since wogonin inhibited dexamethasone-induced DNA fragmentation in a noncompetitive manner, a target of this flavone is unlikely to be an antagonist of glucocorticoid receptor. Wogonin did not only act as an inhibitor of caspases, but also protected apoptosis induced by other glucocorticoids. Since wogonin reduced one of the major pharmacological effects of dexamethasone, we examined whether this flavone diminishes the anti-inflammatory action, another pharmacological effect. The anti-inflammatory action of dexamethasone was evaluated by carrageenan-induced paw edema model. Although dexamethasone significantly suppressed paw edema induced by carrageenan, wogonin had no effect on the anti-inflammatory action of dexamethasone. These results suggest that wogonin may be a useful compound to reduce the immunosuppressive side effect of glucocorticoid.

[Sex characteristics of neuroendocrine effects of prenatal exposure to exogenous glucocorticoids].

The effects of hydrocortisone acetate treatment of rats during the last gestational week on neurochemical and morphological characteristics of the brain in early postnatal and mature offspring were studied. Disappearance of sexual differences both in aromatase and 5alpha-reductase activities and noradrenaline concentration in the preoptic area in 10-day old rats was found. Meanwhile a sexual dimorphism in serotonin metabolism emerged. In adult offspring, the prenatal exposure to glucocorticoids resulted in disappearance of sexual differences in neurocytes' nuclei volume in medial preoptic and suprachiasmatic nuclei. The adrenocortical reaction to noradrenaline infusion to the 3rd brain ventricle was absent in the experimental males and intensified in females. In males, adrenocortical reaction to restraint decreased while post-stress changes in hypothalamic noradrenaline concentration and hippocampal glutamate decarboxylase activity were not observed. In the similar experiments in females both the augmentation of adrenocortical reaction and inhibition of GABA-ergic system were revealed. The results obtained indicate the modifying effect of prenatal exposure to glucocorticoids on sexual dimorphism of neuroendocrine system.

Life-threatening hypokalemia in an asthmatic patient treated with high-dose hydrocortisone.

Although modest hypokalemia is frequently observed in asthmatic patients being treated with bronchodilators, profound hypokalemia and metabolic alkalosis are rarely reported in patients receiving high-dose hydrocortisone (HC). We describe a 66-year-old man who complained of generalized muscle weakness, shallow respiration, and palpitations after receiving high-dose intravenous HC (total dose, 2400 mg over 4 days) to treat a severe asthma attack. During this therapy, there was a weight gain of 1.0 kg. An electrocardiogram revealed ventricular arrhythmia with frequent premature ventricular contractions. Hypokalemia was profound, with plasma potassium (K+) concentration of 1.7 mEq/L, and associated with renal potassium wasting, as evidenced by a transtubular potassium concentration gradient of 12; metabolic alkalosis (plasma HCO3-, 37 mEq/L) was also present. When treated with spironolactone, KCl supplementation, and substitution of HC with prednisolone, his plasma K+ concentration rapidly normalized, metabolic alkalosis was corrected, and arrhythmia disappeared within 3 days. Because of unwanted mineralocorticoid side-effects, high-dose HC may cause life-threatening hypokalemia in asthmatic patients. Because of these potential risks, plasma acid-base and electrolyte concentrations should be monitored frequently in any patient treated with high-dose HC.

[Posterior subcapsular cataract in a case of ulcerative colitis treated with corticosteroid enema]. / Cataracte sous-capsulaire postérieure dans le cadre d'une rectocolite hémorragique traitée par lavements de corticoïdes.

We report the case of a 65-year-old patient suffering from a long-term ulcerative colitis treated with corticosteroid enema and presenting a bilateral posterior subcapsular cataract. As far as we know, this is the first case report of steroid-induced cataract after intrarectal corticosteroid use. Alternative hypotheses concerning the mechanism of cataract formation are suggested. This case report should warn ophthalmologists and gastroenterologists about the cataractogenic effects of corticosteroid enema to ensure that information is provided for patients suffering from ulcerative colitis.

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

AIM: To compare short-term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. METHODS: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mg kg(-1) hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg(-1) dexamethasone (DEX; 21 d). In both centres glucocorticoid-treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular-intraventricular haemorrhage. The following short-term glucocorticoid-induced effects were investigated in 25 HC-treated and 25 control patients in centre A, and in 23 DEX-treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5-7 y of age was evaluated in all groups. RESULTS: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX-treated children needed special school education significantly more often (p < 0.01) than controls at 5-7 y of age. No differences between neonatally HC-treated children and controls on neurodevelopmental outcome were found at 5-7 y of age. CONCLUSION: Neonatal HC therapy has fewer short- and long-term adverse effects than neonatal DEX therapy.