Adrenal Crisis in Elderly Patients: Recognition and Management Challenges

Adrenal crises (CS) are serious manifestations of adrenal insufficiency that require hospitalization and carry a risk of cardiovascular events, acute kidney injury, and death.

Evidence from population studies indicates that adults >60 years of age have the highest incidence of adrenal insufficiency and CS, with the highest age-specific incidence of CS doubling between ages 60 and 69 years and from age 80 years and older.

> Epidemiology of adrenal insufficiency

Adrenal insufficiency is a rare disorder with an estimated prevalence of 300 per million people and arises as a result of a wide range of destructive pathologies and iatrogenic factors (e.g., surgery, medications) affecting the hypothalamic-pituitary-hypothalamic axis. adrenal.

Secondary adrenal insufficiency, due to a disease of the pituitary gland, or tertiary adrenal insufficiency, due to involvement of the hypothalamus and higher centers, are the most common subtype in adults. On the contrary, Addison’s disease or primary adrenal insufficiency, which is more frequently due to autoimmune adrenalitis in high-income countries, has a lower prevalence.

Iatrogenic adrenal insufficiency, in its most severe form, could arise from pituitary or hypothalamic disease or after an adrenalectomy; the use of immune checkpoint inhibitors for the treatment of malignancies, with consequent hypophysitis or, less frequently, adrenalitis; the use of adrenal enzyme inhibitors used to treat Cushing’s syndrome; treatment with the adrenaline drug mitotane, used for adrenocortical cancer or Cushing’s syndrome; the use of exogenous glucocorticoids and opioids that inhibit hypothalamic corticotropin-releasing hormone secretion.

> Definition of adrenal crisis

A CS in the adult is an acute deterioration in health status, including absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (less than 20 mm Hg lower than usual), with features that resolve in 1 to 2 hours after parenteral administration of glucocorticoids (marked resolution of hypotension within 1 hour and improvement of clinical symptoms within 2 hours).

The clinical features accompanying hypotension related to CS are those of the general illness and disability and, to a variable degree, postural dizziness, confusion, lethargy, body pain, fever, weakness, acute abdominal symptoms and, rarely, hypercalcemia.

Adrenal insufficiency in patients without hypotension, but with pronounced symptoms, is classified as symptomatic adrenal insufficiency and incipient CS. Routine laboratory tests may show hyponatremia, hyperkalemia (in primary adrenal insufficiency), lymphocytosis, eosinophilia, occasional hypoglycemia, and rarely, hypercalcemia.

Older patients may be more susceptible to CS due to a higher prevalence of comorbidities and, consequently, are at greater risk of acute illness.

This susceptibility could be aggravated by deficiencies in the implementation of preventive strategies for CS, due to individual and social factors that increase with age. Although little research has focused on the prevention of CS in older patients, it seems logical that the timely diagnosis of adrenal insufficiency and the use of prevention and mitigation strategies for CS can reduce these crises after the age of 60. .

> Epidemiology of adrenal crisis

The incidence of CS in adults who have received treatment for adrenal insufficiency is 6-8% patient-years. The incidence of CS has increased, possibly due to the use of lower-dose, short-acting glucocorticoid (hydrocortisone or cortisone acetate) replacement regimens, which could result in periods of marked hypocortisolemia. CS are slightly more common in primary adrenal insufficiency than in secondary adrenal insufficiency.

This discrepancy is likely to reflect partial preservation of cortisol secretion in some patients with secondary adrenal insufficiency, as well as the factor of mineralocorticoid secretion in primary adrenal insufficiency. In comparison, the risk of CS in both glucocorticoid- and opioid-related adrenal insufficiency is considered low, due to the incomplete suppression of cortisol secretion in most patients.

Death from CS, estimated at almost 0.5%-patient-years, of patients who have received treatment for adrenal insufficiency, increases the mortality rate from adrenal insufficiency. Given the association between the onset of an infection and CS, CS could also contribute to increased mortality from infectious diseases in patients with adrenal insufficiency (defined as patients with proven adrenal insufficiency who are on replacement therapy and require higher doses of glucocorticoids). during physiological stress).

> Physiology of adrenal crisis

Most CSs occur in the context of exposure to a physiological stressor (e.g., infection or injury) when the action of tissue glucocorticoids, which depends on serum cortisol concentration and tissue sensitivity, It is insufficient to maintain homeostasis.

The physiological processes involved in a CS include the loss of the normal suppressive action of endogenous glucocorticoids on inflammatory cytokines, leading to a rapid increase in cytokine concentrations.

Cortisol deficiency leads to alteration of immune cells (neutropenia, eosinophilia and lymphocytosis); loss of the synergistic action of cortisol with catecholamines on vascular tone, leading to vasodilation and hypotension; hepatic effects that alter intermediate metabolism, with a decrease in gluconeogenesis, hypoglycemia or both, and a reduction in circulating free fatty acids and amino acids.

At the cellular level, loss of cortisol depresses the action of activator protein 1 and nuclear factor κB, leading to unrestricted activation of inflammatory protein-producing genes, as the normal inhibition of cortisol binding is lost. from nuclear factor κB to the glucocorticoid receptor. Mineralocorticoid deficiency, a feature of primary adrenal insufficiency, is likely to exacerbate CS through sodium and water loss and potassium retention.

Adults with an adrenal crisis require urgent parenteral hydrocortisone.

Hydrocortisone is administered in a 100 mg bolus, followed by 200 mg every 24 hours in continuous infusion or frequent intravenous (or intramuscular) boluses (50 mg every 6 hours); subsequent doses will be tailored to clinical response.

When hydrocortisone is not available, other glucocorticoids may be used, according to recommended schedules. Intravenous normal saline (1000 mL in the first hour) should also be administered immediately, with crystalloids (e.g., 0.9% isotonic sodium chloride) administered according to standard resuscitation guidelines and adjusted according to status. circulation, body weight and relevant coexisting conditions.

For hypoglycemia (glycemia <70 mg/dl), 5% intravenous dextrose in normal saline is administered. In patients with diabetes insipidus, fluids should be administered with caution, whether or not they are receiving treatment, since excess free water can cause hyponatremia, while too little can cause hypernatremia.

Careful balance between diuresis and provision of normal saline usually maintains isonatremia. The concomitant illness that precipitated the CS needs to be investigated and treated, and if shock persists despite specific treatment for the CS, other causes of hypotension should be identified and treated.

After successful management of CS, hydrocortisone doses should be reduced over 3 days until the patient’s usual maintenance dose is reached. It is necessary to evaluate preventable precipitating events, and discuss preventive strategies with the patient, including home administration of parenteral hydrocortisone.

The basis of a consensual approach to prevent CS is the pre-emergency escalation of the glucocorticoid dose (oral or parenteral, or both) or the so-called stress dose, initiated by the patient. The recommended stress doses are intended to replicate the stress response in a patient with an intact hypothalamic-pituitary-adrenal axis.

They are administered in the short term, with immunomodulatory doses and not anti-inflammatory or immunosuppressive doses. In the face of acute illness or injury, most guidelines recommend doubling or tripling the usual oral replacement dose until physiological stress has subsided.

However, evidence from a study in patients with secondary adrenal insufficiency, which compared a higher dose of hydrocortisone with a lower short-term dose (4–6 mg/kg vs. 2–3 mg/kg) showed that between In both groups, there was large interindividual variability in 24-h urinary free cortisol concentrations, with substantial overlap with daytime serum cortisol concentrations.

Quality of life was higher in the high-dose group. The overlap in serum cortisol concentrations led the authors to suggest that, in the disease, rapid cortisol metabolizers may not benefit from doubling the dose of hydrocortisone, and that, to achieve an elevation in cortisol, the dose would have to be tripled. The factors that influence hydrocortisone metabolism and cause such notable interindividual variability are unknown.

In general, cortisol metabolism is lower in older age groups, while the evidence on serum cortisol concentrations has varied, from high in population studies to low in physiological assessments (study with a small number of participants).

When the oral dose cannot be taken or absorbed, parenteral hydrocortisone (IM or IV or subcutaneous) is recommended most commonly when vomiting or diarrhea is present, or if oral doses have not improved symptoms. However, many patients cannot or do not want to inject hydrocortisone or do not have the equipment or soluble hydrocortisone when it is needed.

Non-verbal communication , such as wearing medical necklaces or bracelets and carrying a steroid card, is recommended for situations where the patient cannot speak and therefore cannot convey their diagnosis of adrenal insufficiency to the assistant. doctor. However, medical identification is not universally adopted, especially by patients with secondary adrenal insufficiency, perhaps due to a misconception about the risk of CS in them.

> Causes of adrenal insufficiency in older patients

Older patients with adrenal insufficiency include those who have a history of adrenal insufficiency and who survived beyond the age of 60 years, and those whose diagnosis was made after the age of 60 years.

Patients with prolonged adrenal insufficiency present with congenital disorders and, most commonly, congenital adrenal hyperplasia, a type of primary adrenal insufficiency that in its classic form has an incidence of 1:6,000 to 1:27,000 births, and is increasingly prevalent in older people due to increased survival. Autoimmune adrenalitis, by comparison, usually develops earlier, between the ages of 20 and 50, and is more common in women.

In contrast, new diagnoses in older adults are often due to: pituitary tumors or their treatment; to the widespread use of opioids for the treatment of malignant pain and, increasingly, non-malignant pain and, the use of exogenous glucocorticoid therapies (inflammatory and malignant conditions that are more common in those >60 years of age.

Glucocorticoid-induced adrenal insufficiency is caused by the suppression of the hypothalamic-pituitary stimulus on cortisol secretion, through classic negative feedback, which, although common, is usually incomplete and, therefore, is associated with a lower risk of CS, even in older patients.

Similarly, adrenal suppression with opioids is a rare cause of CS and there is no evidence to indicate increased susceptibility to adrenal insufficiency from opioid exposure in older adults.

New diagnoses of adrenal insufficiency in this age group may also arise from hypophysitis (with pituitary hormone deficiency), or less commonly adrenalitis, following therapy with immune checkpoint inhibitors for the treatment of adrenal insufficiency. melanoma and some other types of cancer, which are more common in older age groups.

Adrenal metastases are a common manifestation of malignant metastatic disease in elderly patients, but rarely cause adrenal insufficiency. In older patients there may be delays in the diagnosis of adrenal insufficiency due to the presence of non-specific symptoms shared with other common diseases in this age group or symptoms associated with aging itself.

Typical symptoms that lead to misdiagnosis are: anorexia, weight loss, fatigue and nausea. Postural symptoms are also found in elderly patients and may be mistakenly attributed to other conditions, or to side effects of medications.

In older patients who are unwell, nonspecific symptoms such as confusion and delirium are common, raising diagnostic doubt with delayed diagnosis of adrenal insufficiency or CS, which can be fatal.

Morning serum cortisol concentrations are clinically useful in excluding adrenal insufficiency in a large proportion of patients, but depend on timing and analysis. In general, values ​​>400 nmol/L (in some trials, 375 nmol/L) require adrenocorticotrophic hormone stimulation tests.

However, although most studies have included a wide range of adults, that stimulation test has not been specifically validated in older patients. Furthermore, caution should be exercised when drawing conclusions about the adequacy of serum cortisol concentrations in patients who are severely ill.

> Epidemiology of adrenal insufficiency in older patients

The incidence and prevalence of adrenal insufficiency increase with age, which, combined with the secular tendency of the population to age, means that older people would be expected to make up the largest group of patients with adrenal insufficiency due to age, in the majority. of the countries.

 On the other hand, given that rates of large pituitary adenomas increase with age and that these tumors or their treatment (surgery, radiation therapy) can cause secondary adrenal insufficiency, the relative preponderance of secondary adrenal insufficiency compared to primary adrenal insufficiency, which in general seen in adults, it could be more pronounced in older patients with adrenal insufficiency.

Aside from population-based estimates and underlying disease characteristics, few studies have examined the epidemiology of adrenal insufficiency specifically in older patients, and studies that have included them have been primarily conducted in Asia, which It means that the results may not be generalizable. Taking these warnings into account, the incidence of adrenal insufficiency is estimated at 92.4/100,000 in those >60 years of age (data from the Taiwanese population).

Many aspects of adrenal insufficiency, including clinical features, diagnosis, and treatment, occur in both older adults and younger patients. However, the presence of ≥1 comorbidities and the use of varied medications with different side effects in older patients are of concern.

These include the management of essential hypertension, which requires caution with fludrocortisone dosage (often reduced by 50%); Which are the cases that should not be associated with hypokalemia or hypotension and which can be effectively monitored at home.

When hypertension persists, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors or, as a second option, a calcium channel blocker (e.g., amlodipine and felodipine) may be used. Diuretics and aldosterone receptor blockers (e.g., spironolactone and eplerenone) should be avoided.

Decreased bone density is also a possibility in elderly patients with adrenal insufficiency, requiring greater care with glucocorticoid and mineral or corticosteroid doses, to minimize further bone loss and consider other standard approaches to the treatment of osteoporosis and fractures due to minor trauma, depending on the patient’s age, sex and comorbidities.

These approaches include measures to improve muscle strength and balance and the elimination of environmental factors that could increase the risk of falls, as well as the use of medications to combat bone resorption and calcium and vitamin D supplementation.

Other comorbidities include the possible exacerbation of sarcopenia of aging, due to the atrophic effect of the glucocorticoid on the muscle and aging of the skin, with a greater propensity for loss of dermal collagen, fragility and increased risk of infection.

Because glucocorticoids in excessive doses have significant brain effects, they can cause atrophy of the hippocampus (a key structure in short-term memory), the neocortex (essential for executive function), and the amygdala (crucial in mood responses). ).

Approaches to replacement therapies in adult patients have changed over time. Early dosing recommendations that were in place until the 1980s led to the use of fairly high replacement glucocorticoid doses, such as 30 mg hydrocortisone/day.

The higher doses used previously could have led to retrospective results showing data that could have been taken as evidence of accelerated aging, including lower bone mineral density, increased adiposity, and high blood pressure.

However, lower doses may result in lower quality of life and increased risk of CS. However, some of the retrospective data showing adverse effects in patients using higher doses could be contaminated by prescribing higher doses of glucocorticoids in response to patients reporting poor health and other reasons. not related to your adrenal hormonal status.

An example of this event could be the use of higher doses of glucocorticoids in patients who have had a CS (some studies suggest that higher doses of glucocorticoids promote CS). The combination of glucocorticoids and mineralocorticoids can increase blood pressure with associated cardiovascular risk and, consequently, replacement doses should be carefully controlled.

The catabolic and CNS and cardiovascular effects are likely to be only partially reversible by dose restriction. Therefore, it could be argued that the dosage of glucocorticoids, if excessive, can cause accelerated aging due to tissue catabolism.

In contrast, underdosing of glucocorticoid replacement therapy, an event now more likely due to revised estimates of normal glucocorticoid secretion, could raise the risk of CS in older patients.

Because there is no measure of glucocorticoid tissue adequacy, replacement therapy doses must be based on generalizations about cortisol secretion and insensitive clinical observations, such as weight, blood pressure, muscle strength, well-being, and bone density, which are less specific for monitoring adrenal hormone replacement in older people.

In contrast, fludrocortisone use can be based on serum potassium, blood pressure, and plasma renin, although each has some limitations with respect to sensitivity. However, especially in older people, the use of renin-altering cardiovascular agents (e.g., β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics) and the presence of renovascular disease could make the adjustment of fludrocortisone dose in relation to serum renin concentration less reliable.

Postural dizziness or hypotension is more common in older patients, and these symptoms in particular are less likely to be a guide to fludrocortisone dosing in primary adrenal insufficiency.

It should be noted that hydrocortisone has 0.25% potency as a mineralocorticoid, as does fludrocortisone, therefore a dose of 20 mg/day of hydrocortisone is equivalent to 0.05 mg of fludrocortisone, which is important when Hydrocortisone doses are altered or steroids of lower mineralocorticoid potency are used.

> Adrenal crises in older patients

Older adults contribute a greater proportion of CS cases than younger patients in the population, due to both the relative size of the major adrenal insufficiency group and a greater susceptibility to CS.

Although there are few studies that have examined the rates of CS in older people, a population-based study of hospitalizations of patients with CS found a higher incidence in older patients. However, not all studies reach the same conclusion.

Misclassification of a CS diagnosis occurs in all age groups, but may be more likely in older patients if relative hypotension is not evaluated, given the general increase in blood pressure with age.

Hyponatremia , a common manifestation of adrenal insufficiency or CS, may be mistakenly attributed to the syndrome of inappropriate antidiuretic hormone secretion, which is often due to illness, medications , or aging itself.

Similarly, delirium , which often accompanies CS, has a wide range of causes, especially in older patients, and is more likely to develop in association with illness in this age group, which may confuse the diagnosis of CS. and its treatment. Lack of recognition of the signs and symptoms of CS in elderly patients could motivate the administration of IV hydrocortisone, with worsening of the condition.

Some older patients with adrenal insufficiency can survive CS but suffer serious sequelae. In general, patients with CS are more likely to have longer hospital stays and higher rates of admission to an intensive care unit.

In older patients with prolonged hypotension from unrecognized or untreated CS, concomitant atherosclerosis is more likely to increase the risk of ischemic damage to the kidneys, brain, and intestine.

In elderly patients, in particular, the evaluation of precipitating events and the time frame of the prevention strategies used in their case should be carried out with the patient and their partner or family. Plans should be made to ensure adequate assistance (whether by ambulance or medical service) and support for the management of routine and emergency treatment, reassessed periodically.

> Mortality

Mortality attributable to CS is higher in elderly patients, due to multiple comorbidities that complicate treatment. Underestimation of CS as a cause of death due to adrenal insufficiency is especially possible in older patients due to erroneously attributing premortem symptoms of CS to other diseases that could be the cause of death.

Similarly, the increased risk and preponderance of serious bacterial infections in elderly patients with adrenal insufficiency could mask CS-related death to a greater extent than in younger patients. On the other hand, mortality from undiagnosed adrenal insufficiency or CS may occur early in the period following glucocorticoid discontinuation in elderly patients with chronic inflammatory disease, but may not be recognized as such.

> Risk factors

Advanced age is a risk factor for CS. The history of previous CS and the presence of comorbidities, including some that accumulate with age, such as type 2 diabetes and chronic respiratory and cardiac diseases, complicate management and increase the risk of CS, although the mechanism of action and may vary between comorbidities. The coexistence of several comorbidities, which frequently occur in older patients with adrenal insufficiency, could further increase this risk.

The most common precipitant of CS in patients who have fully recovered from adrenal insufficiency is infection, which in older patients is usually bacterial in origin, while viral infections predominate in children.

Pneumonia or exacerbation of chronic respiratory disease is often associated with CS, as are urinary tract infections, especially in older women.

Cellulite , perhaps more common in patients with skin fragility exposed to higher amounts of glucocorticoids, is also associated with CS in this age group .

Infectious gastroenteritis is a rare precipitant in older adults, but could be confused with the acute abdominal symptoms of CS.

Falls and fractures are common in older age groups and may be related to postural hypotension, particularly in patients with primary adrenal insufficiency.

Accidents and associated injuries increase with age and, if severe, doses may be increased to avoid CS. Comorbid osteoporosis, which may be more common in patients with glucocorticoid adrenal insufficiency or in those exposed to older glucocorticoid replacement therapy regimens with higher, longer-acting total daily doses, exacerbates the risk of fall fractures.

Other acute diseases that are associated with acute physiological stress, such as myocardial infarction or stroke , are more common in older age and may precipitate CS and, as a result, patients should be observed, continuing maintenance glucocorticoids and stress dose according to those used in intercurrent illnesses, if necessary. High doses of glucocorticoids after cardiovascular events have no therapeutic indication.

Sudden discontinuation of glucocorticoids, whether as replacement or therapeutic therapy, accidental or deliberate, by the patient or a healthcare professional, can precipitate CS. Inadvertent noncompliance with nighttime dosing increases with age or in association with comorbidities such as dementia or other comorbidities such as low vision or immobility.

Other causes of nighttime nonadherence to the prescribed glucocorticoid dose, which is most commonly used in the elderly, include the inability to access medication due to economic factors; difficult access to the pharmacy or even interruption of the usual supply of medications.

Many other treatments have been associated with CS, including some vaccines and zoledronic acid infusion. Undiagnosed coexisting thyrotoxicosis or initiation of thyroxine treatment in a patient with hypothyroidism, which is common in the elderly, may precipitate CS in a patient with undiagnosed hypoadrenalism.

There are a variety of medications that may also be associated with CS, including cytochrome P450 3A4 inducers such as avasimibe, carbamazepine, rifampicin, phenytoin, and St. John’s wort extract, which may improve hydrocortisone metabolism, leading to requires an increase in glucocorticoid dose in patients receiving treatment for adrenal insufficiency, or may induce CS in patients with undiagnosed adrenal insufficiency.

In contrast, cytochrome P450 3A4 inhibitors such as voriconazole, orange juice, itraconazole, ketoconazole, clarithromycin, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telitin inhibitor, telithromite and conovaptan could inhibit hydrocortisone metabolism, increasing cortisol concentrations and thus enhancing the adrenal suppressive effect of ongoing glucocorticoid therapy.

However, once the agent is discontinued the risk of CS could increase. Such effects could overlap with the development of slower cortisol metabolism in elderly patients, although this has not been associated with alterations in circulating cortisol concentrations.

A higher incidence of CS by age in older patients suggests an interaction between the older patient’s susceptibility to CS and lower effectiveness (including non-use) of consensus recommendations for dose escalation prevention strategies.

Increased susceptibility to infection and other acute diseases increases the risk of CS in elderly patients. Susceptibility to CS may be increased by the modern approach to replacement therapy that uses ≥2 divided doses of a short-acting glucocorticoid (hydrocortisone or cortisone acetate).

These regimens are not accepted by many patients and can be particularly burdensome for those in older age groups, especially those with multiple comorbidities. Many patients with adrenal insufficiency complain of chronic asthenia despite adrenal hormone replacement.

It is unknown whether this effect exacerbates self-management problems and CS risk in older people. Less common manifestations of adrenal insufficiency, such as nocturnal hypoglycemia, can also make self-management difficult and reduce the older patient’s quality of life.

To reduce symptoms in this situation, a complex carbohydrate snack with substantial fat content can be used to delay gastric emptying. The timing of the nighttime glucocorticoid dose could also be modified. Monitoring effectiveness can be done with a continuous glucose monitoring device or by instantaneous glucose detection.

Social and personal factors also play an important role in the clinical management of older patients with adrenal insufficiency. Those >60 years of age constitute a heterogeneous group ranging from those who are still fully active and engaged in work and community life to those who may be frail and isolated, and characteristics may not be related to the patient’s chronological age.

Health status in this age group can change rapidly and management of adrenal insufficiency must be tailored to the patient’s altered circumstances. Consideration of social and economic environments is particularly important, including assessing the affordability of multiple medications, the dangers of polypharmacy, and access to physicians and other health professionals. Interdisciplinary coordination for patient care could directly affect the management of adrenal insufficiency.

In particular, problems with glucocorticoid replacement should be regularly investigated and long-acting glucocorticoids should be considered, which would help avoid problems with missed doses and non-compliance. Older patients should also be educated and regularly reminded of the dangers of missed doses, requiring strategies such as the use of alarms, to help them take the replacement dose.

Those on long-term glucocorticoid therapy for other conditions where the daily dose is higher than the replacement dose (3 to 5 mg prednisone or equivalent/day), who may or may not have confirmed adrenal insufficiency , it is also necessary to take into account the risk of abrupt discontinuation of therapy.

Medication adherence may be more difficult in older patients due to complicated medication regimens and memory lapses and forgetfulness that increase with age. In this context, it is useful to use pre-packaged medications with date and time, to ensure accurate dosing.

Using timers, such as those on standard mobile smartphones, can also help with treatment adherence. In this scenario, some patients will benefit from switching from a higher frequency (3-4 times/day) of doses of short-acting glucocorticoids, such as hydrocortisone or cortisone acetate, to long-acting glucocorticoids, 1-2 times/day. day (usually prednisolone).

Older patients with multiple comorbidities may have chronic problems such as fatigue, mood disturbances, or reduced exercise capacity, which may be attributed to adrenal insufficiency and insufficient dosage of adrenal steroids. Decisions to alter the dosage of adrenal steroids should be made carefully and any changes should be implemented with short trials.

Patients in the older age group who are acutely ill are susceptible to delirium or confusion, which limits their ability to implement dose escalation.

These patients are also less likely to develop pyrexia during infection, which may be absent, therefore, other signs and symptoms of acute illness (urinary frequency, changes in cough or a, color of sputum) should be identified that the patient and his family use the dose as indicators of the need to stress. However, identifying these symptoms may be more difficult in older people, as the signs may be faded or absent.

Optimizing the management of all comorbidities, including minimizing polypharmacy, should limit morbidity and possibly the risk of CS, and contribute to greater adherence to treatment and dose escalation protocols.

Given the propensity for confusion and delayed recognition of physiological stressors in older people, it is important for patients in this group to use nonverbal means of communication.

However, the strategy of wearing medical jewelry and carrying a steroid card is underutilized, both by elderly patients and by patients with secondary adrenal insufficiency, who are generally older than those with primary adrenal insufficiency.

Older patients may not be as well educated about CS prevention strategies as younger patients, possibly because treatment is provided by non-endocrinologist specialists or because of a prevailing, but incorrect, view that patients with secondary adrenal insufficiency have a substantially lower risk of CS than those with primary adrenal insufficiency.

A personalized plan for glucocorticoid dose escalation during physiologic stress and use or arranging for access to parenteral hydrocortisone is recommended, taking into account the patient’s personal and social circumstances. Some patients are unwilling to try any form of stress dosing and an older group is unwilling or unable to self-inject hydrocortisone.

When the doctor is aware of this lack of will and attempts at supported education have not been successful, other strategies must be resorted to, such as contacting health providers, ambulances, caregivers or family members.

However, implementation of dose escalation strategies can be successfully instituted by patients, even the elderly, and appears to be influenced by the patient’s experience with prior episodes of symptomatic adrenal insufficiency or CS and not necessarily related to the patient’s age or duration of adrenal insufficiency.

Newer hydrocortisone replacement formulations that allow patients to use a daily dose, so-called modified-release hydrocortisone , could be beneficial for older patients, particularly those with comorbid conditions and who use many medications. These medications also have metabolic benefits and reduce the risk of recurrent infections, which could be particularly beneficial for older patients.

The diurnal rhythm of cortisol appears to be flattened in older patients and therefore the therapeutic implications of glucocorticoid preparations designed to replicate daily cortisol fluctuations may vary with age. However, for many patients, these formulations are too expensive, so an alternative might be a long-acting glucocorticoid preparation.

It is recommended to develop a hydrocortisone injection device, similar to an EpiPen, which in the emergency would facilitate application to patients with visual and other impairments, but is not yet available.

Automatic alerts from clinical settings, particularly hospitals and nursing homes, increase the likelihood of appropriate treatment of patients with adrenal insufficiency, both in the emergency and perioperative period, and may help prevent inadvertent interruption or omission of therapy with glucocorticoids.

In the future , transplants of cells from the adrenal cortex could be available , either as allogeneic or xenogeneic cells in an implantable recipient to evade the patient’s immune system. However, to date, case reports only concern adrenal cell transplantation in humans.

Accurate assessment of glucocorticoid sufficiency, particularly relevant in older patients who may be more sensitive to the effects of underdosing or overdosing, would allow glucocorticoid replacement to be more precisely individualized.

A cell-based marker such as binding protein 51 FK506, a co-chaperone of hsp90 that regulates glucocorticoid receptor sensitivity, could have clinical utility in this context. where gene expression could be measured in a relevant cell type such as lymphocytes.

There is little data, largely obtained from studies that did not explicitly investigate adrenal insufficiency or adrenal crisis in older patients, suggesting an increased risk of excessive or inappropriate administration of glucocorticoids, and possibly mineralocorticoids, in older patients, at higher risk. of adrenal crisis.

Recognition of the specific interactions between aging, diagnosis, and treatment of adrenal insufficiency will serve to highlight challenges and provide optimized and individualized strategies for this diverse group of patients.