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Risk for Adrenal Crisis – Download PJ's Protocol - Parent Project Muscular Dystrophy
Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. Adrenocorticotrophic hormone ACTH concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis.
We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established. Glucocorticoids are used in the treatment of a variety of inflammatory and autoimmune diseases, seldom with any doubt about the clinical indication and effect, but often with many side effects.
Glucocorticoid-induced adrenal insufficiency is a potentially life-threatening side effect as it renders the patient unable to produce an adequate cortisol response to stress.
Clinically relevant hypocortisolism can occur after withdrawal from glucocorticoid treatment, but also during ongoing treatment if there is a mismatch between glucocorticoid requirements to overcome stress and the sum of the endogenous cortisol production capacity and exogenous glucocorticoid intake. High-dose prednisolone treatment often ensures sufficient glucocorticoid intake to overcome most stressful situations, but low-dose prednisolone treatment might not.
If the adrenal function is suppressed these patients are thus not sufficiently covered during stress by the prednisolone treatment itself. Glucocorticoid-induced adrenal insufficiency is probably underestimated in clinical practice 34.
In rheumatoid arthritis, low-dose prednisolone treatment for 2 years in addition to disease-modifying anti-rheumatic drugs reduces joint destruction and increases disease remission 5and is thus widely used both as initial, but also maintenance therapy 67. It is currently not recommended to evaluate adrenal function routinely during the course of glucocorticoid treatment 8which potentially leaves a large group of patients with long-lasting adrenal insufficiency, who are not adequately informed about the risk and treatment of adrenal insufficiency during intercurrent stress.
Patients with rheumatoid arthritis were retrieved from four rheumatology departments located in the greater Copenhagen area in Denmark. The diagnosis of rheumatoid arthritis was based on the American Rheumatism Association classification 9. In total consecutive patients were identified. The patients were recruited as part of a larger study ClinicalTrials. Nbiband were screened for four specific polymorphisms of the glucocorticoid receptor gene NR3C1 and grouped accordingly before being invited to a Synacthen test.
In total, 42 patients underwent assessment of adrenal function. Disease history and data on history of treatment with prednisolone and other glucocorticoid containing formulations were obtained from medical records and confirmed by patient interview.
The protocol was approved by the local Ethics Committee J. H and the Data Protection Agency J. All participants gave written informed consent before enrolment. After the Synacthen test patients continued the prednisolone treatment.
Samples were analyzed in few series. Cut-off for normal cortisol response to the Synacthen test was validated locally for the new assay 11 and defined as the 25th percentile — 1.
Plasma concentrations of adrenocorticotrophic hormone ACTH and anti-adrenal antibodies were measured at baseline to distinguish patients with primary autoimmune adrenal insufficiency.
Briefly, one drop of patient sample diluted in phosphate-buffered saline PBS was applied to each well on substrate slides. A sample was considered positive if the specific staining was observed to be greater than a negative control. Ninety-five percent confidence intervals for proportions were calculated by the Wilson Score interval formula. Comparison between groups was made by independent t -test for normally distributed continuous data and Chi-square test for categorical data, since data were equally distributed among cells.
All statistical analyses were performed by SAS version 9. Patients in the study were generally younger mean age 65 years s. The characteristics of the study population at the time of the Synacthen test are shown in Table 1. The 42 patients had been treated with prednisolone for a median of 66 months range: 6— months.
Patient characteristics at the time of the Synacthen test. Each line represents one patient. Black lines represent patients who did not concomitantly receive treatment with other glucocorticoid formulas. Patients who received concomitant treatment with other glucocorticoid formulas within the last 3 months before the Synacthen test are presented by grey lines intra-muscular injectionsdotted black lines intra-articular injections or dotted grey line glucocorticoid containing cream.
Citation: European Journal of Endocrinology4; The ACTH reference range is marked within horizontal dotted lines. Synacthen test cut-off is marked by a vertical dotted line. Higher occurrence was observed in the total cohort, which also included patients who had received concomitant treatment with other glucocorticoid formulas. Glucocorticoid-induced adrenal insufficiency is often believed to occur in patients who have been treated with more than the equivalent of 7.
We here show that glucocorticoid-induced adrenal insufficiency is also a problem during ongoing low-dose prednisolone treatment. This was chosen to investigate the prevalence of adrenal insufficiency during ongoing prednisolone treatment in the particular situation, where the prednisolone dose is too low to cover extra needs during stress.
Adrenal insufficiency can occur after all locally applied glucocorticoids 417and high prevalence has especially been demonstrated after intra-articular glucocorticoid injections 418192021 and in patients using multiple glucocorticoid forms concomitantly 4. Adrenal suppression after a single intra-articular glucocorticoid injection has been shown to last up to 4 weeks 1920 Six patients had received higher doses at some point within the 6 months before the Synacthen test.
The patient cohort was representative of patients with rheumatoid arthritis in low-dose prednisolone treatment where variations in disease activity lead to short periods of increased prednisolone dose or intra-articular or -muscular corticosteroid injections.
Likewise, the cohort is comparable to other patient populations in glucocorticoid treatment where increased disease activity is treated with increased glucocorticoid intake increased dose or additional formula. Our findings are similar to studies of patients receiving more varying 22 or slightly higher glucocorticoid doses 23 We found no association between adrenal function and duration of prednisolone treatment. However, it is possible that such an association would be clearer for shorter durations than we have investigated in the present study.
The risk of adrenal insufficiency generally increases with increased duration of glucocorticoid treatment 424but glucocorticoid-induced adrenal suppression is at the same time associated with a substantial individual variation with less strong association to glucocorticoid dose or duration of treatment 322 The study has confirmed a strong suspicion that adrenal insufficiency is highly prevalent during ongoing low-dose prednisolone treatment, which was the aim of the study.
As patients already suffered from one autoimmune disease rheumatoid arthritis we aimed at excluding primary adrenal insufficiency. Since ACTH concentrations were generally low and anti-adrenal antibodies were negative this was very unlikely, and the diagnosis of secondary, glucocorticoid-induced adrenal insufficiency was considered accurate. For reliable assessment of adrenal function, it is generally agreed that a stimulation test is necessary 32627 The low-dose test has been found to be more sensitive in detecting mild adrenal insufficiency as the stimulation is at a more physiological level 3132but technical details can influence its accuracy, resulting in reduced specificity 3234 There is no published consensus on which test is preferred.
P-cortisol measurement was performed with a new generation assay, the Roche Elecsys Cortisol II assay, performing more specific and thus lower cortisol measurements than the older Roche Elecsys Cortisol assay. All cortisol samples were frozen and analyzed in few series. Local assay-specific cut-off for normal adrenal function was validated for the new assay 11 based on Synacthen tests performed in previously described healthy controls 12minimizing the risk of methodological bias.
The prednisolone pause of mean The reported prevalence in this study may be surprising to clinicians who could argue that symptomatic patients would nevertheless be identified.
However, in a meta-analysis only 10 of 98 patients with glucocorticoid-induced adrenal insufficiency reported symptoms of adrenal insufficiency, concluding that the diagnosis would have been missed in 88 patients if only symptomatic patients underwent assessment of adrenal function 4. Adrenal insufficiency most often presents with very unspecific symptoms. Patients may present with symptoms such as fatigue, loss of energy, muscle and joint pain which could result from increased disease activity of rheumatoid arthritis, but could as well relate to adrenal insufficiency.
Adrenal insufficiency should especially be suspected when other signs and symptoms of disease activity of the rheumatoid arthritis C-reactive protein, joint swelling, etc. It is a general clinical observation that prednisolone tapering is very difficult in many patients with rheumatoid arthritis and other rheumatologic diseases Two patients in our study had failed attempts to taper the prednisolone dose shortly before enrolment in the study.
Both of these patients were found to have adrenal insufficiency. During the h prednisolone pause before the study Synacthen test several patients experienced an increase in muscle and joint pain and some felt generally unwell. Although not systematically registered it was a clinical observation that there was a connection between having notable symptoms during the prednisolone pause and a reduced response to the Synacthen test.
All patients were informed to contact the department or simply resume prednisolone and postpone the Synacthen test if they felt unwell, but none chose this option. Also signs and symptoms of an acute adrenal crisis are mostly unspecific and can be confused with an exacerbation of the underlying disease or symptoms of the triggering stressful event such as gastroenteritis or influenza-like illnesses.
Thus, there is a high risk of misclassification of adrenal crises in glucocorticoid-treated patients without verified adrenal insufficiency and retrospective studies investigating the incidence of glucocorticoid-induced adrenal crises cannot account for all the dark numbers of incorrectly classified and coded crises The incidence of glucocorticoid-induced adrenal crisis is thus difficult to clarify.
In 28 patients with an established diagnosis of glucocorticoid-induced adrenal insufficiency the reported incidence of adrenal crises was 15 per patient-years This was higher than the incidence of 5. Similar, a prospective study has reported an incidence of 8.
Overall, these data suggest that adrenal crisis can occur in patients during ongoing low-dose prednisolone treatment who have severely suppressed adrenal function. Our results call for increased focus on the adrenal function during long-term low-dose prednisolone treatment.
We argue that all patients receiving glucocorticoid treatment should be informed about the risk of adrenal insufficiency and should carry a steroid emergency card 43 Whether insufficient patients on ongoing low-dose prednisolone treatment could benefit from receiving supplemental glucocorticoid doses during intercurrent illness and stress has not been shown, but it is standard procedure in all other types of adrenal insufficiency. Our findings make a case for routine evaluation of adrenal function in patients on ongoing low-dose glucocorticoid treatment, but there are some concerns in regard to defining correct timing and frequency of such routine evaluation and the increased cost and workload.
It might not be feasible everywhere. Future perspectives such as using baseline morning P-cortisol measurements as an initial diagnostic screening tool should be further explored 45 If the activity of the underlying disease for which the prednisolone is prescribed allows prednisolone tapering and potentially withdrawal the need for daily replacement therapy should be considered.
Hydrocortisone is preferred for replacement therapy over prednisolone as its shorter half-life enables a more physiological mimic of the normal circadian rhythm of cortisol secretion 4748 with low nightly levels improving chances for adrenal recovery.
Adrenal function evaluation and treating the adrenal insufficiency with physiological doses of hydrocortisone might enable reduction or even withdrawal of prednisolone, thereby reducing other prednisolone-induced side effects such as osteoporosis, diabetes and hypertension. In conclusion, we have investigated secondary adrenal insufficiency in the particular clinical situation where patients receive ongoing prednisolone treatment in a dose that in itself is too low to cover extra glucocorticoid needs during stress.
We found that more than one-third of the patients had adrenal insufficiency. As low-dose glucocorticoid treatment is widely used, not only in rheumatoid arthritis, but in many different conditions, the prevalence is alarming and many patients might have unidentified adrenal insufficiency. If future studies were to find the same benefit from hydrocortisone replacement strategy in patients with glucocorticoid induced adrenal insufficiency as for other patients with adrenal insufficiency, clinical management guidelines would have to be implemented for this patient group.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this clinical study. S W Borresen made primary contributions to data collection and analysis, interpretation of results, and writing of the manuscript.
❿- What dose of prednisone cause adrenal suppression
Adrenal suppression, or adrenal crisis, is a potentially life-threatening complication of steroid use. It is important to know that you may be at risk of an adrenal crisis when:. If you experience any signs of adrenal crisis, go to the Emergency Room and alert your neuromuscular team.
Cortisol is a hormone that is produced by your adrenal glands, which sit on top of the kidneys. Cortisol impacts the function of many body systems. When the body is under any kind of stress serious injury, severe infection, etc.
When you are taking steroids, your daily dose of steroids provides your body with cortisol, so your adrenal glands temporarily shut down and do not produce cortisol. During normal daily stress, your daily dose of steroid is generally an adequate amount of cortisol for your body. However, when your body experiences additional stresses such as serious injury, severe infection, etc.
If stress doses of steroids are not given, the body can experience adrenal crisis, which can be life-threatening. Missing doses of daily steroids for more than 24 hours can also cause adrenal crisis. Although side effects to steroids can be serious, your child should not suddenly stop taking steroids if side effects first appear. There are many ways to manage the side effects of steroids, including changing the type of steroid taken, changing the dose, and changing the dosing schedule.
Make sure your NMS tries everything to manage the side effects, and to institute these changes before steroids are discontinued. At this time, steroids are the only medicines known to help to maintain strength and function for people living with Duchenne. If you do make the decision to stop taking steroids, it is important that you do so under the supervision of a medical provider preferably, the prescribing medical provider and follow the corticosteroid therapy withdrawal guidelines outlined in the PJ Nicholoff Steroid Protocol download.
Watch very carefully for signs of life-threatening adrenal crisis during the corticosteroid taper, and for one year post-taper during times of serious injury or illness. Missing doses of daily steroids for more than 24 hours can also cause life-threatening adrenal crisis.
If oral corticosteroids are missed on days when they are normally given for more than 24 hours, IV doses should be given. Be sure to share the PJ Nicholoff Steroid Protocol download with your doctor and create a plan together about what to do in case of a missed dose. Recommendations for supplemental stress doses are provided in the PJ Nicholoff Steroid Protocol download.
It is important that you share this critical information with your doctor during times of severe illness, surgery, or trauma to avoid life-threatening adrenal crisis. Keep the PJ Nicholoff Steroid Protocol download available to you, and your medical providers, in case of a medical emergency or admission.
If so, is your steroid information updated? The Duchenne Registry is working with researchers and partners interested in using the steroid data we collect. They want to speed up trials and answer important questions for individuals with Duchenne and Becker muscular dystrophy. Are you registered on The Duchenne Registry? Make sure your information is up to date in The Duchenne Registry.
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❾-50%}What dose of prednisone cause adrenal suppression
Be sure to share the PJ Nicholoff Steroid Protocol download with your doctor and create a plan together about what to do in case of a missed dose. Recommendations for supplemental stress doses are provided in the PJ Nicholoff Steroid Protocol download. It is important that you share this critical information with your doctor during times of severe illness, surgery, or trauma to avoid life-threatening adrenal crisis.
Keep the PJ Nicholoff Steroid Protocol download available to you, and your medical providers, in case of a medical emergency or admission. If so, is your steroid information updated? The Duchenne Registry is working with researchers and partners interested in using the steroid data we collect.
They want to speed up trials and answer important questions for individuals with Duchenne and Becker muscular dystrophy. The low-dose 1 microg adrenocorticotropin stimulation test in kidney and kidney-pancreas transplant patients: a potential guideline for steroid withdrawal. Clin Transplant. HPA-suppressive effects of aqueous clobetasol propionate in the treatment of patients with oral lichen planus.
J Eur Acad Dermatol Venereol. Do topical ophthalmic corticosteroids suppress the hypothalmic-pituitary-adrenal axis in post-penetrating keratoplasty patients? Eye Lond. A pilot study of adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients.
Support Care Cancer. Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis.
J Cyst Fibros. Association of subclinical hypothalamic-pituitary-adrenal axis suppression with bone loss in patients with asthma taking inhaled corticosteroids. Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study. Observations on the systemic effect of topical clobetasol propionate Dermovate.
Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function. Adrenocortical function and steroid doses in renal transplant patients. Dial Transplant. Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids? Adrenal reserve in renal transplant recipients with cyclosporine, azathioprine, and prednisone immunosuppression.
Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respir Med. Assessing the hypothalamo-pituitary-adrenal axis in patients on long-term glucocorticoid therapy: the short synacthen versus the insulin tolerance test.
Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. Dose-related decrease in bone density among asthmatic patients treated with inhaled corticosteroids. Kos-Kudla B. Iatrogenic adrenal cortex failure in patients with steroid dependent asthma in relation to different methods of glucocorticoid treatment.
Endocr Regul. Preliminary results of a pilot study investigating the potential of salivary cortisol measurements to detect occult adrenal suppression secondary to steroid nose drops.
Adrenal suppression and osteoporosis after treatment of nasal polyposis. Acta Otolaryngol. Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids. Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. Habib GS. Systemic effects of intra-articular corticosteroids. Seth J , Brown LM.
A simple radioimmunoassay for plasma cortisol. Clin Chim Acta. A simple radioimmunoassay for plasma cortisol: comparison with the fluorimetric method of determination. Ann Clin Biochem. An immunoassay for plasma cortisol based on chemiluminescence.
Mass spectrometry for steroid assays [in French]. Ann Biol Clin Paris. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur J Intern Med. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation.
Close mobile search navigation Article Navigation. Volume Article Contents Strengths and Limitations of the Study. Objective of the Study. Materials and Methods. Journal Article. Broersen , Leonie H. Oxford Academic. Alberto M. Jens Otto L. Olaf M. Cite Cite Leonie H. Select Format Select format. Permissions Icon Permissions. Figure 1.
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Reproductive phenotypes and genotypes in men with IHH. Association between Systemic Lupus Erythematosus and Primary Hypothyroidism: evidence from complementary genetic methods. More from Oxford Academic. Clinical Medicine. Background: Patients on long-term glucocorticoid treatment are at risk of adrenal insufficiency during glucocorticoid treatment. High-dose glucocorticoid treatment is often sufficient to overcome most stressful situations.
Contrary to patients in replacement therapy for adrenal insufficiency, patients treated with long-term low-dose glucocorticoids for various reasons are often not instructed in self-administration of supplemental doses in stressful situations. P-cortisol was measured before and 30 min after Synacthen injection. Since prednisolone treatment is often sustained for years in these patients, adrenal suppression is likely equally prolonged.
Review Topical steroid risk analysis: differentiating between physiologic and pathologic adrenal suppression. J Dermatolog Treat. Epub Oct ACTH following overnight dexamethasone suppression can be used in the verification of autonomous cortisol secretion in patients with adrenal incidentalomas.
Clin Endocrinol Oxf. Epub Nov Hypothalamic-pituitary-adrenal axis suppression by inhaled or nasal corticosteroids in HIV-infected patients. Int J Clin Pharm. Epub Mar 5. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. Lancet Respir Med.
Epub Mar Inhaled corticosteroid related adrenal suppression detected by poor growth and reversed with ciclesonide. J Asthma. Epub Jun Recent Activity. Clear Turn Off Turn On. Adrenal Suppression - Endotext. Follow NCBI. Long-Standing Treatment. Replacement therapy. Adrenal suppression Therapy.
Congenital adrenal hyperplasia Glucocorticoid resistance. Anti-inflammatory therapy. Acute Treatment. Suppression hypothalamic-pituitary-adrenal axis. Cushing syndromediagnostic tests. Several conditions. Acute traumatic spinal cord injury Post-operative additional therapy in severe neurological deficits even after surgery Postoperative pain relief after severe bone operations Fetuses between 24 and 34wk gestation risk of preterm delivery. Acute illness or trauma.
Type of steroid and potency. Long-acting GCs lead to longer tissue life and longer suppression. Route of administration. Systemic GC therapy parenterally : increased risk. Timing of administration.
Leonie H. Broersen, Alberto M. Pereira, Jens Otto L. We aimed to estimate pooled percentages of patients with adrenal insufficiency after treatment with corticosteroids for various conditions in a meta-analysis. Secondly, we aimed to stratify the results by route of administration, disease, treatment dose, and duration. Original articles testing adult corticosteroid users for adrenal insufficiency were eligible.
We included 74 articles with a total of participants. Stratified by administration form, percentages of patients with adrenal insufficiency ranged from 4. Stratified by disease, percentages ranged from 6. The risk also varied according to dose from 2. This is the first meta-analysis providing a broad view on the risk of adrenal insufficiency after use of various types of corticosteroids in several underlying diseases. Studies displayed heterogeneity in the type of corticosteroid used, underlying condition, treatment dose, treatment duration, and route of administration, thereby reflecting clinical practice.
Our results were stratified by these factors. Because no individual data were available, risk stratification at the level of the individual patient was not possible. Many articles with high levels of bias were included in this meta-analysis because there were only a few articles with low levels of bias available. This may have affected the results. Corticosteroids are widely used for the treatment of various inflammatory conditions and malignancies and after organ transplantation.
Therapy with corticosteroids is targeted toward inhibition of an inflammatory response 1 — 3. However, the use of corticosteroids is associated with numerous side effects and is considered to be the most common cause of adrenal insufficiency 45. Chronic use of corticosteroids inhibits the function of the hypothalamic-pituitary-adrenal axis by negative feedback, which may cause adrenal insufficiency also after the cessation of corticosteroid treatment 46.
Adrenal insufficiency is a serious, potentially life-threatening side effect of corticosteroid use. Therefore, patients may require glucocorticoid replacement therapy after chronic use of corticosteroids in periods of stress, such as trauma, surgery, or acute illness, until full recovery of adrenal function.
In some cases, chronic replacement with physiological doses of glucocorticoid therapy is indicated 7 — 9. Neither treatment dose and duration, nor administration form, nor random serum cortisol measurements seem to accurately predict the development of adrenal insufficiency after the use of corticosteroids 10 The magnitude of the risk of developing this side effect is unclear.
Given the high prevalence of corticosteroid users, it is of great clinical relevance to try to obtain knowledge about the risk of developing adrenal insufficiency. The aim of this study is to perform a systematic review and meta-analysis of the percentage of patients that develops adrenal insufficiency after the use of corticosteroids. Secondary aims are to stratify the results by route of administration, underlying disease, treatment dose, and duration, and to perform a separate analysis for the studies that repeated the test for adrenal insufficiency.
Original studies assessing adrenal insufficiency in adult human corticosteroid users were eligible for inclusion. The diagnosis of adrenal insufficiency had to be established by one of the following tests: the insulin tolerance test, ACTH stimulation tests 0. There were no restrictions in dose, duration, or type of corticosteroid therapy. Eligible administration forms of corticosteroids were oral, inhalation, topical, nasal, intra-articular injection, and im injection.
Articles were excluded if the examined population was not at risk of adrenal insufficiency secondary to the use of corticosteroids eg, corticosteroid replacement therapy for primary or secondary adrenocortical failure, if not all patients used corticosteroids, or if patients included in the study were selected on the basis of having adrenal insufficiency.
Articles were also excluded if no data or insufficient data were presented to analyze adrenal insufficiency after corticosteroid use. Inclusion of articles was restricted to those in English and to articles that included at least 10 subjects to minimize the risk of selection bias.
Articles containing the following populations were excluded: pregnant women, intensive care patients, and patients receiving corticosteroids perioperatively. Because we aimed to include studies in individuals aged 12 years or older, no dose corrections for body surface area were deemed necessary.
If an article presented data for multiple study groups, of which some were eligible for inclusion, eligible study groups were included if the pertinent data could be extracted.
Articles were also excluded if they were duplicates from already included articles or if they examined the same population as an already included article. Articles that were not retrievable online were requested by contacting the authors. A separate sensitivity analysis was performed for articles testing adrenal insufficiency at least 24 hours after the last use of corticosteroids References of key articles were also assessed to identify potentially eligible articles.
Only articles published from to the present were searched because RIA for cortisol became available shortly before the start of that year Randomized controlled trials, cohort studies, and cross-sectional studies were considered, whereas case-control studies and case series are not suitable to estimate absolute risks All identified articles were entered in Reference Manager version 12 Thomson Reuters and were first screened on title and abstract.
Potentially relevant articles were then reviewed in detail before inclusion into this meta-analysis. Two different reviewers performed both the screening of the title and abstract and the review in detail for potentially relevant articles. Articles containing more than one study group had multiple entries in this meta-analysis. Study elements that could potentially bias an association between corticosteroid use exposure and the development of adrenal insufficiency outcome were assessed for all included articles.
Risk of selection bias was considered low if consecutive exposed patients or a random sample of exposed patients was included thereby preventing selection bias and if eligibility criteria were reported. Ascertainment of exposure to corticosteroids was considered adequate if this was done by protocol or medical record.
Measurement of adrenal insufficiency was considered adequate if RIA was used for measuring cortisol concentrations Studies not following these criteria harbor a higher risk of bias. We did not exclude these articles from analyses because this would result in a very low number of studies available for systematic review and meta-analyses.
The main outcomes of this meta-analysis were the pooled percentages of patients with adrenal insufficiency after corticosteroid use, stratified by administration form, disease, treatment dose, and treatment duration.
Percentages were pooled in a random-effects logistic regression model. A fixed logistic regression model was used when the number of studies in a particular subgroup was less than five.
Analyses were performed with Stata version Analysis stratified by administration form was based on administration forms used at the time of adrenal testing.
If studies included patients using multiple types of corticosteroids for example, use of inhalation corticosteroid next to oral corticosteroidsthis was classified as multiple administration forms. Disease groups are: asthma including chronic obstructive pulmonary disease with only inhalation corticosteroids, asthma including chronic obstructive pulmonary disease with other administration forms including multiple administration forms of corticosteroids, allergic rhinitis and rhinosinusitis, dermatological disorders psoriasis, atopic dermatitis, and lichen planusrheumatic diseases including osteoarthritis and rheumatoid arthritisrenal transplant, hematological cancers including myeloma, lymphoma, acute lymphoblastic leukemia, and Hodgkin's diseasenasal polyposis, cystic fibrosis, and Crohn's disease.
Diseases that were studied in one study only were not included in the analysis of adrenal insufficiency after the use of corticosteroids stratified by condition. Treatment dose was categorized according to recommended doses, with the doses between the lower and upper bounds of the recommendation coded as medium dose, doses below the lower bound as low dose, and doses above the upper bound as high dose.
Because the most used doses were supraphysiological, doses were not grouped according to physiological and supraphysiological dose. Limits used for the aim of categorization of dose groups and references can be found in Supplemental Table 1.
For categorization, the average dose and duration were used. Studies not reporting treatment dose or duration could not be included in the respective stratified analysis. Not included in the treatment duration analysis were articles with multiple short courses of corticosteroids spread out over a period of time longer than 1 month.
Analysis of the percentage of patients with adrenal insufficiency by treatment dose and by treatment duration was performed in asthma patients only, as opposed to the entire population of corticosteroids users, to provide a homogeneous patient population.
Separate analysis of study groups that performed repeated tests after discontinuation of corticosteroids was performed. Retesting 4 weeks after cessation of corticosteroid therapy was predominantly performed after a short-term, high-dose corticosteroid treatment regimen, whereas retesting 6 months after cessation of corticosteroid therapy predominantly occurred after long-term corticosteroid use in a medium-dose regimen.
These two groups were therefore separated in the analysis. The percentage of patients with adrenal insufficiency at the retest was calculated as the number of patients with adrenal insufficiency at the retest divided by the total number of patients that were measured at time of the first test.
All sensitivity analyses were performed in asthma patients only, to minimize patient heterogeneity. No sensitivity analysis for insulin tolerance test use only was performed because there were only three studies using this test, and none of them included asthma patients. The initial search provided unique articles.
By assessment of references of key articles, another 16 articles were found, yielding a total of articles. After screening titles and abstracts, articles remained for detailed review. Reasons for exclusion are shown in Supplemental Figure 1. Finally, 74 articles were included in this meta-analysis, containing a total of study groups. Although in principle articles containing patients below the age of 12 years were excluded, two articles including patients from 9 to 11 years old were included because most the patients in these articles were above the age of One article could not be retrieved even after contacting the first author Study characteristics are shown in Supplemental Table 2.
Included studies were published from to Of the 74 articles, 36 were clinical trials 19 — 5423 were cohort studies 1281155 — 73and 15 were cross-sectional studies 1074 — The study groups contained a total of participants, of which were healthy volunteers.
There were 68 studies on asthma patients, eight studies on rhinitis or rhinosinusitis patients, 12 studies on patients with dermatological conditions psoriasis, atopic dermatitis, and lichen planuseight studies on patients with rheumatological disorders including rheumatoid arthritis and osteoarthritiseight studies on renal transplant patients, four studies on patients with hematological malignancies, two studies on patients with nasal polyposis, three studies on patients with cystic fibrosis, two studies on patients with Crohn's disease, and one study each on patients with glaucoma, kidney and pancreas transplantation, bronchiectasis, various carcinomas, and giant cell arteritis, respectively.
There were eight studies on patients with various conditions. The remaining 36 articles did this by the use of a protocol or by retrieving data from medical records. Reported loss to follow-up in these articles was 0 to Details of risk of bias analysis at the level of individual studies are shown in Supplemental Table 3.
Of the participants, were diagnosed with adrenal insufficiency. In seven study groups including patients, use of other corticosteroids was allowed as co-medication. Details of study outcomes and tests used at the level of individual studies are shown in Supplemental Table 4. In only 10 study groups, symptoms of adrenal insufficiency were reported.
In total, 10 of patients reported symptoms of adrenal insufficiency. Symptoms were not scored systematically in either of the articles. After testing, 98 patients appeared to have adrenal insufficiency within these study groups. Consequently, 88 patients would have been missed when only patients with symptoms of adrenal insufficiency had been tested.
However, especially for hydrocortisone and prednisone, pharmacokinetics are non-linear due to protein binding. As a result, higher doses result. Prednisolone 4 mg is equivalent to hydrocortisone 16 mg From an adrenal suppression viewpoint, it is safe to cut the steroid dose to an equivalent. Prednisolone 4 mg is equivalent to hydrocortisone 16 mg From an adrenal suppression viewpoint, it is safe to cut the steroid dose to an equivalent. Whilst low dose topical steroids rarely cause adrenal insufficiency, potent and very potent glucocorticoids, can cause HPA axis suppression. For patients in low-dose prednisolone treatment, 5 mg/day is equivalent to 20 mg/day of hydrocortisone. If the adrenal function is suppressed these patients are. Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic-pituitary-adrenal axis: a randomized controlled study. The high rate of adrenal insufficiency is probably also a reflection of the fact that these injections are depot formulations. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this clinical study. At this time, steroids are the only medicines known to help to maintain strength and function for people living with Duchenne. In our stratified analysis, we did not adjust for all mutually dependent factors, mainly because these factors are related in clinical practice as well, but also because meta-regression techniques would fall short in the absence of individual patient level data to disentangle these clearly related factors.Federal government websites often end in. Before sharing sensitive information, make sure you're on a federal government site.
The site is secure. NCBI Bookshelf. Endotext [Internet]. Adrenal suppression, a form of secondary adrenal insufficiency SAI , is a common clinical problem most often due to sudden cessation of chronic exposure to exogenous glucocorticoid administration or, rarely, after correction of endogenous hypercortisolism.
Exogenous glucocorticoids cause decreased secretion of corticotropin-releasing hormone CRH and other adrenocorticotropic hormone ACTH secretagogues, such as arginine-vasopressin AVP and alter the function of higher brain centers that regulate their secretion.
Recovery of adrenal function may take as long as 1 to 2 years. In cases of endogenous hypercortisolemia adrenal suppression develops after the removal of a functional adrenal tumor secreting cortisol, or following successful removal of ACTH-secreting pituitary adenoma or other sources of ectopic ACTH secretion. Interestingly, the period to recover from adrenal suppression after the removal of ACTH-secreting pituitary adenoma caused by prolonged suppression of normal corticotrophs may be a predictor of sustained remission.
Regarding the definitions of adrenal insufficiency AI , it is a disorder characterized by impaired adrenocortical function and decreased production mainly of glucocorticoids. As adrenal suppression refers to decreases of cortisol secretion from the adrenal zona fascicularis the function of zona glomerulosa remains normal.
Thus, hyponatremia is the main electrolytic disturbance observed, while circulating plasma potassium, renin, and aldosterone concentrations are within the normal range. A broad range of severity can be seen as a result of complete or partial HPA axis suppression and concomitant adrenal gland atrophy. The true prevalence of overt adrenal insufficiency AI is probably rare as glucocorticoid treatment is gradually tapered before complete discontinuation leaving enough time for HPA axis recovery.
However, due to the lack of specific symptoms the exact prevalence of AI following glucocorticoid tapering may be under-reported. The main symptoms of glucocorticoid insufficiency range from anorexia, fatigue, nausea, vomiting, dyspnea, fever, arthralgias, myalgias, and orthostatic hypotension to dizziness, fainting, and circulatory collapse. Hypoglycemia is occasionally observed in children and very thin adult individuals. View in own window.
Many synthetic compounds with glucocorticoid activity have been developed in an attempt to maximize the beneficial and minimize the deleterious effects of glucocorticoids. The clinical efficacy of synthetic glucocorticoids depends on their pharmacokinetic, pharmacodynamic and molecular properties, which in turn determine the duration and intensity of glucocorticoid effects.
According to their potency synthetic glucocorticoids are subdivided into short-, intermediate-, or long-acting. Treatment modifying factors, such as the age of the patient and the nature and severity of the underlying disease also influence synthetic glucocorticoid effects, duration, and doses administered.
The British National Formulary and the National Institute for Health and Care Excellence Clinical Knowledge Summary, both advise gradual glucocorticoid withdrawal in cases of patients that have received more than 40 mg prednisolone or equivalent daily for longer than one week; repeated glucocorticoid doses in the evening; glucocorticoids for more than three weeks; a short course of glucocorticoids within one year of stopping long-term glucocorticoid therapy; or have other risk factors for adrenal suppression.
In the absence of ACTH, the adrenal cortex temporarily loses the ability to produce cortisol, and when treatment with glucocorticoids is abruptly stopped transient glucocorticoid insufficiency ensues. It has been reported that the suppression of the HPA axis induced by exogenous glucocorticoids may persist for 6 to 12 months or rarely even longer, after treatment is withdrawn. To support the diagnosis of adrenal suppression, several predictors of glucocorticoid-induced HPA axis hypofunction have been suggested the best being the duration and dosage of exogenous glucocorticoid administration Table 2 ,3.
In addition, the timing of drug administration may affect the degree of adrenal suppression. Thus, prednisolone in a dose of 5mg given at night before bedtime and 2. Higher evening doses block early morning ACTH surge whereas tissues sensitivity to glucocorticoids is increased in the evening and early night hours.
Clinical awareness is crucial to identify patients with impending adrenal crisis. It is important to consider all patients with unexplained symptoms after glucocorticoid- withdrawal as candidates for possible AI and test them accordingly. An important feature that will raise suspicion of TAI and SAI besides drug history is the absence of skin pigmentation. Such patients have an intact renin-angiotensin-aldosterone system RAAS accounting for the differences in salt and water balance and clinical presentations compared to primary adrenal insufficiency.
Serum cortisol secretion at h if diagnostic tests are not feasible and until confirmatory testing is available can be considered a valuable screening method when AI is suspected. Drug history and clinical features cannot be considered reliable tools for the evaluation of HPA axis function in patients treated with synthetic glucocorticoids.
Several tests are commonly used in order to assess the degree of glucocorticoid-induced AI or HPA axis recovery Table 5 , 6. Both the insulin tolerance test ITT and the metyrapone test have been employed as they are both highly sensitive. However, the risks involved with these tests do not justify their use compared to the rapid ACTH stimulation test or short synacthen test SST that can safely distinguish almost all cases of clinically significant adrenal suppression.
The use of salivary cortisol is also an effective alternative to serum cortisol when assessed in the high-dose ACTH test. Incremental cortisol response at the first SST was suggested as an important predictive factor of adrenal function recovery in SAI after exogenous glucocorticoid administration. In both conditions, cortisol concentrations are low at baseline and remain low after CRH administration.
In patients with SAI, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH, which is not followed by an appropriate cortisol response. Glucocorticoid withdrawal is indicated when the use of the steroid is no longer needed or when significant side effects develop. The suggested method of glucocorticoid withdrawal is dose tapering to avoid the occurrence of AI. Adrenal insufficiency is a potentially life-threatening medical emergency when presenting as adrenal crisis, which requires prompt treatment with hydrocortisone and fluid replacement.
Once, clinically suspected, treatment should be initiated and not be delayed while waiting for definitive proof of diagnosis. Blood samples should be obtained for measurement of cortisol concentrations later, and the management approach should be similar to the resuscitation of any critically ill patient.
The key action is that glucocorticoid withdrawal should not be abrupt. In clinical practice, patients being on any steroid dose for less than 2 weeks are not likely to develop adrenal suppression and are advised to stop therapy without tapering. The possible exception to this is the patient who receives frequent "short" steroid courses, as in asthma treatment.
Other tapering regimens suggest switching the patient to an alternate day administration of intermediate action glucocorticoids before cessation of treatment. Irrespectively of the tapering regimen used, if a glucocorticoid withdrawal syndrome, AI or exacerbation of the underlying disease develops, the dose being given at the specific time should be increased or maintained longer. Recent systematic reviews implied that the evidence for the tapering regimens used nowadays is not robust, despite the fact that rapid reduction to a physiologic glucocorticoid dose Care should be given during the tapering regimens period on the interpretation of laboratory tests for cortisol levels measurement.
Systemic estrogens should be discontinued at least for 4 weeks prior to testing; estrogen patches are preferred since they do not affect CBG.
Different criteria may apply according to the cortisol assay. In general, plasma ACTH concentrations are not helpful in estimating the optimal glucocorticoid dose whereas mineralocorticoid replacement is not required. All patients treated with glucocorticoids long-term should receive detailed instructions for glucocortiocoid supplementation equivalent to mg of hydrocortisone during major stresses surgery, fractures, severe systemic infections, major burns until their HPA axis fully recovers and to carry means of identification medical alert bracelet.
Since full HPA axis recovery may take as long as one year or even longer, abrupt cessation of glucocorticoid treatment or quick tapering can precipitate an acute AI crisis. The diagnosis is a medical emergency, and treatment should be the immediate administration of fluids, electrolytes, glucose, and parenteral glucocorticoids. Turn recording back on. Help Accessibility Careers. Contents www. Search term. AI: adrenal insufficiency.
HPA: hypothalamic-pituitary-adrenal; GC: glucocorticoid. THERAPY Glucocorticoid withdrawal is indicated when the use of the steroid is no longer needed or when significant side effects develop. Reduction by 2. Slower withdrawal until physiological level achieved Pass Response discontinuation of GC Or 5b.
British National Formulary. National Institute for Health and Care Excellence. Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study. Eur J Endocrinol. Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing's disease. Endocr Connect. J Clin Endocrinol Metab.
Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Semin Arthritis Rheum. Magnotti M, Shimshi M. Diagnosing adrenal insufficiency: which test is best--the 1-microg or the microg cosyntropin stimulation test?
Endocr Pract. Dexamethasone suppression test predicts later development of an impaired adrenal function after a day course of prednisone in healthy volunteers. Adrenal Insufficiency. Glucocorticoid Therapy and Adrenal Suppression. Alexandraki KI, Grossman A. Adrenal Suppression.
In this Page. Links to www. View this chapter in Endotext. Related information. Similar articles in PubMed. Review Topical steroid risk analysis: differentiating between physiologic and pathologic adrenal suppression.
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