In the setting of intensive care, a significant proportion of patients have functional adrenal insufficiency and this has been associated with a poorer outcome Taken together, these observations raise the intriguing possibility that poor clinical outcome in patients on inhaled GCs may be due at least in part to HPA axis suppression, adrenal insufficiency and the consequent inability to mount an adequate cortisol stress response, and this has significant implications for the therapeutic approach to these patients Supplementary Table 3 and Supplementary Figure 1 , see section on supplementary data.
Routine screening for adrenal insufficiency in the context of inhaled GCs is not currently recommended. The magnitude of the clinical problem may be daunting, and making a case for routine assessment of HPA axis function in all patients on inhaled GCs may be prohibitive considering the workload and cost implications.
To date, dynamic stimulation tests such as the SST and the ITT are considered mandatory for reliable investigation of adrenal reserve 13 , 35 , The utility of a basal cortisol in predicting adrenal reserve has been examined previously 37 , Using a single morning cortisol as the first screening step has the potential, in some circumstances, to reduce the need for dynamic tests and as a consequence to decrease cost and workload and reduce unnecessary tests for patients.
In addition, the recent well-publicized worldwide shortage of Synacthen has highlighted the role that alternative assessments of HPA axis function may play. Through our systematic approach to assessing adrenal function in a large cohort of patients, we are now able to propose an algorithm Fig. In patients prescribed inhaled GCs and in the absence of symptoms of adrenal insufficiency, we recommend measuring annual baseline serum cortisol concentrations as a useful tool in assessing adrenal GC reserve.
A similar approach could be used in patients with underlying adrenal or pituitary pathology, limiting unnecessary test and the potential for significant cost savings. Putative algorithm to aid in the rationalization of assessment of the HPA axis in patients taking inhaled glucocorticoids. The management of patients with adrenal insufficiency in the context of endocrine disease has been reviewed extensively 6.
However, there are currently no guidelines or published studies that have determined the optimal management strategy for those patients with adrenal insufficiency due to prescribed GCs.
For those on oral therapy, continuation of treatment as clinically indicated is appropriate, followed by weaning of the dose if the duration has been longer than 2 weeks.
For those patients taking inhaled GCs, the situation is more complex, as the inhaled GC cannot provide the adequate systemic actions that are needed at times of stress. A combined respiratory and endocrinology approach is appropriate. If possible, inhaled GC doses may be reduced, but this will be entirely dependent upon the underlying respiratory condition. Repeat SST should be performed, especially if modification to the inhaled GC therapy has been undertaken to assess the potential return of HPA axis function.
There are limitations with the current analysis, although it does represent a cross-sectional analysis of unselected clinical data across all medical specialties. The data are retrospective and the decision to perform the SST was based on clinical indication as assessed by the individual clinician leading to a potential positive selection bias that may overestimate prevalence rates.
Duration of GC treatment is likely to be important, as is the length of time since cessation of GC therapy. However, data from our electronic patient records does not allow accurate assessments of the duration of therapy or the time since therapy had been discontinued.
The cut-off levels in this paper relate specifically to the assay used, and interpretation of these data should be made in the context of local cortisol assays as well as the methodology for the SST i. We advocate utilising the i. In addition, robust longitudinal clinical outcome data was not available from our electronic database, which is of fundamental importance.
The explanation for this is not clear and may relate to new diagnoses of endocrine or other, e. Importantly, some of these tests were performed in the intensive care setting where the underpinning mechanisms causing compromised adrenal reserve are still unknown. In summary, the prevalence of adrenal insufficiency due to prescribed GCs is high and almost certainly represents the commonest cause of compromised adrenal function. Importantly, we have highlighted the potent, dose-dependent ability of inhaled GCs to suppress endogenous HPA axis function, and identified the utility of a morning cortisol level in guiding the clinician as to which patients may need dynamic assessment of adrenal reserve.
Futures prospective studies are needed to accurately define the clinical consequences of adrenal suppression for patients prescribed inhaled GC therapy and determine the optimal medical management for these patients. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. C Boot and R Webster collected the biochemical data and helped to write the manuscript. V Dabhi collected the data from the electronic patient records and analysed the data.
J W Tomlinson designed the study, analysed and interpreted the data and wrote the manuscript. The natural history of Cushing's syndrome. American Journal of Medicine 13 — Premature mortality in patients with Addison's disease: a population-based study.
Journal of Clinical Endocrinology and Metabolism 91 — Central hypoadrenalism. Journal of Clinical Endocrinology and Metabolism 99 — Arlt W , Stewart PM. Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinology and Metabolism Clinics of North America 34 — , viii. A rational approach for assessing the hypothalamo—pituitary—adrenal axis. Lancet 1 — Diagnosis and management of adrenal insufficiency.
Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. Journal of Clinical Endocrinology and Metabolism 98 — Allolio B. Extensive expertise in endocrinology. Adrenal crisis. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Use of oral corticosteroids in the United Kingdom. QJM 93 — The use of inhaled corticosteroids in the United Kingdom and the Netherlands.
Respiratory Medicine 97 — Dahl R. In children of any age, ICS starting doses are similar to those recommended in adults see Table 1 [ 14 ]. At low-to-moderate doses, ICSs are considered safe medications, and are generally not associated with clinically significant adverse effects.
Furthermore, studies have shown that ICS treatment markedly reduces the need for oral corticosteroids, which have been associated with well-known serious adverse effects [ 15 ]. Although the side effects of ICSs are less frequent and severe than those of oral corticosteroids, safety concerns with these agents still remain, particularly when used at high doses. Among these concerns is the risk of adrenal suppression AS -- a condition characterized by the inability to produce adequate amounts of cortisol a glucocorticoid that is critical during periods of physiological stress.
AS is an under-recognized complication of ICS therapy that, if left unnoticed, can lead to significant morbidity and even mortality [ 16 — 19 ]. The purpose of this review is to assist physicians and other healthcare professionals in identifying patients who may be at risk for AS, and provide practical recommendations for the screening and management of this potentially serious side effect of ICS therapy.
Adrenal insufficiency is a condition in which the adrenal glands are unable to produce adequate amounts of cortisol a glucocorticoid responsible for maintaining blood pressure, blood glucose and energy levels during times of physiological stress, such as illness, surgery or injury. It can result from any etiology i. AS is the most common cause of adrenal insufficiency, and refers to decreased or inadequate cortisol production that results from exposure of the hypothalamic-pituitary-adrenal HPA axis to exogenous glucocorticoids see Table 2 [ 20 , 21 ].
It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy e. More than 60 recent cases of AS have been described in the literature [ 22 , 23 ]. Although the risk factors for the development of this condition have not been clearly established, increased dose and longer duration of glucocorticoid therapy appear to be associated with an increased risk [ 22 ].
AS is also considered to be an important risk in children who require long-term treatment with high-dose ICS therapy. Children who are being treated for asthma often receive other forms of glucocorticoids in addition to ICSs i. If AS is left unrecognized and the body is subjected to physiological stress, such as injury, surgery or a severe infection, the condition can lead to an adrenal crisis see Table 2.
Although it is considered a rare consequence of AS, a retrospective survey in the United Kingdom UK found that the frequency of acute adrenal crisis in children using ICS therapy was greater than previously expected [ 17 ]. The HPA axis is under circadian regulation and operates in a negative feedback loop to regulate cortisol secretion within the body. The hypothalamus releases corticotropin-releasing hormone CRH , with peak levels being produced in the morning around 6 am.
CRH then stimulates the release of adrenocorticotropic hormone ACTH from the pituitary gland, which, in turn, stimulates the adrenal glands to secrete cortisol. Cortisol has inhibitory effects on the hypothalamus and pituitary gland, which leads to decreased secretion of CRH and ACTH and, in turn, reduced production and secretion of cortisol.
This negative-feedback loop allows the HPA axis to tightly self-regulate cortisol levels in the body. Exogenous glucocorticoids exert negative feedback in the same manner as endogenous cortisol, leading to the suppression of cortisol production and, subsequently, adrenal insufficiency [ 29 ].
Since cortisol production is critical during periods of physiological stress i. The clinical presentation of AS is highly variable. Symptoms are often non-specific and may include: weakness, fatigue, malaise, nausea, abdominal pain, poor weight gain, and headache see Table 2. In some cases, AS may be associated with biochemical changes in the absence of symptoms [ 21 ].
Decreased growth may also be a clinical sign of AS and is often seen in children with significant AS. However, growth suppression may also be a primary side effect of ICS therapy or may occur secondary to poor asthma control [ 30 — 34 ]. Therefore, decreased growth is neither a sensitive nor a specific indicator of AS [ 35 ]. Given the non-specific nature of the symptoms of AS, the disorder can often go unrecognized until physiologic stress e.
Many of the symptoms of these common stressors are so similar to those of adrenal suppression that the first signs of AS may go unnoticed, unless there is a high level of suspicion and the families of patients at risk are made aware of the possibility of this side effect.
The symptoms of adrenal crisis include: hypotension and unexplained, acute hypoglycemia that often leads to seizures, decreased consciousness, and even coma [ 21 ]. In children presenting with symptoms suggestive of AS, it is important to rule out a primary cause of adrenal insufficiency i. In primary adrenal insufficiency, individuals usually have both symptoms of glucocorticoid deficiency consistent with AS as well as symptoms of mineralocorticoid deficiency.
Mineralocorticoids stimulate sodium reabsorption and potassium excretion. Symptoms of mineralocorticoid deficiency include salt cravings, volume depletion and weight loss. Unlike AS, adrenal crisis associated with mineralocorticoid deficiency is often associated with hyponatremia and hyperkalemia [ 36 , 37 ]. Findings consistent with mineralocorticoid deficiency should prompt the physician to consider a primary cause of the patient's symptoms. Several endocrine tests have been used for the screening and diagnosis of AS.
The insulin-induced hypoglycemia test IIHT was once considered the gold standard for the diagnosis of adrenal insufficiency, but is no longer used in children due to the neurocognitive risks associated with hypoglycemia. Although these findings remain controversial in the medical community, the low-dose ACTH stimulation test is now considered by many to be the best test for diagnosing AS in children. Given the natural circadian variation in cortisol secretion, the test should be performed in the morning to ensure optimal sensitivity and specificity [ 47 ].
Although the low-dose ACTH stimulation test is currently the most sensitive and specific test for AS, a first morning am cortisol measurement is often more practical and is considered to be a reasonable first step for the identification of cases of suspected AS, or for the screening of children being treated with high-dose ICS therapy.
Although higher cut-off values have been proposed, these have been associated with poorer specificity [ 49 ]. If an abnormal value is noted, the low-dose ACTH stimulation test should be performed to confirm the diagnosis. Given the poor sensitivity of the first morning cortisol measurement, a normal value does not rule out AS.
Therefore, if the test result is normal, but the patient is experiencing symptoms suggestive of AS, a low-dose ACTH test is recommended. Since cortisol levels decrease throughout the day, a random cortisol measurement is not an adequate measure of AS in children.
Other measures of adrenal insufficiency are available, such as the assessment of urinary or salivary cortisol levels; however, these tests have not been well-studied in children with AS [ 50 — 52 ].
Although the various ICSs available for the treatment of asthma are believed to have similar clinical efficacy when used at equivalent therapeutic doses, significant differences in their pharmacokinetics PK and pharmacodynamics PD exist which can impact their respective safety profiles. These differences warrant careful consideration when determining the benefits and risks of each ICS medication in an individual patient, particularly as they relate to the risk of systemic side effects such as AS [ 53 ].
Table 3 provides an overview of the PK and PD parameters that influence the safety of ICSs, such as oral bioavailability, lung deposition, protein-binding, half-life and systemic clearance [ 54 ]. In the lungs, the ICS exerts its effect on inflamed tissue as soon as it dissolves into the pulmonary lining and binds to intracellular corticosteroid receptors.
Drug that is absorbed from the GI tract and that escapes inactivation by first-pass metabolism in the liver enters the systemic circulation unchanged, potentially causing serious systemic side effects [ 53 , 57 , 58 ]. Schematic representation of the fate of an ICS. The oral bioavailability of an ICS refers to the portion of the inhaled dose that is swallowed, escapes first-pass metabolism in the liver, and is available for systemic absorption see Figure 1.
Since the proportion of the ICS dose that is absorbed orally increases the potential for systemic side effects, it is advantageous for the oral bioavailability of an ICS to be relatively low.
Lung deposition refers to the amount of drug that enters the lung and exerts an effect at the site of inflammation. For ICSs to exert their optimal anti-inflammatory effect, a high lung deposition is generally desirable. Several factors impact pulmonary deposition including: 1 the physical properties of the ICS; 2 the delivery device; 3 particle size discussed later ; and 4 patient characteristics such as inhaler technique, age, and asthma severity [ 57 , 60 ].
As seen in Table 3 , lung deposition is greatest with ciclesonide and beclomethasone [ 54 ]. Particle size is an important determinant of the proportion of ICS that is deposited in the lower airways relative to the oropharyngeal cavity.
Beclomethasone and ciclesonide delivered by metered-dose inhaler MDI have the smallest particle sizes among the available ICS medications [ 53 , 59 ]. Ciclesonide and beclomethasone are prodrugs that are inhaled as inactive compounds and then converted into their active metabolites des-ciclesonide and monopropionate, respectively by enzymes located in the pulmonary epithelium [ 53 , 59 ].
Because prodrugs are inactive until they reach the lung, they are believed to be associated with fewer local side effects compared to ICSs that are administered in their active form e. In studies of ciclesonide, bioactivation within the oropharynx was shown to be very low, resulting in lower amounts of active drug in the oropharyngeal region compared with budesonide and fluticasone [ 62 , 63 ].
When an ICS binds to plasma protein albumin in the systemic circulation, it is rendered pharmacologically inactive. Therefore, a high degree of plasma protein-binding is desirable to reduce the potential for systemic side effects [ 53 , 57 , 59 , 60 ]. The drugs are usually used to counter inflammation in a wide range of conditions, including asthma, psoriasis, rheumatoid arthritis, lupus, blood cancers and organ transplants.
People with adrenal insufficiency do not make enough of two hormones, cortisol and aldosterone. Cortisol helps the body respond to stress, recover from infections and regulate blood pressure and metabolism. Aldosterone helps maintain the right amounts of salt, potassium and water in the body. While on steroids, the body often produces less of these hormones naturally, and after coming off the drugs it can take a while for natural production to ramp back up.
About 2. Time was also a consideration. The longer patients used corticosteroids, the greater their risk of developing adrenal insufficiency upon discontinuation. The authors of both studies recommend more frequent testing of adrenal function in asthma patients who use corticosteroids for any period of time.
The authors of the meta-analysis added that patients can also help detect their own problems. Adrenal insufficiency often creates noticeable symptoms such as fatigue, dizziness, weight loss and salt cravings.
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