The results of the present study demonstrate that, while hypoadrenalism is rare in the general population, potentially life-threatening and largely preventable ACs occur relatively frequently. The study also highlights the important role that infection, especially bacterial infection, plays in hospital admissions among patients with hypoadrenalism who experience an AC, as has been found elsewhere [1, 2, 15, 16]. We found that older adults have a higher rate of AC-related admission than younger patients, and that the relative importance of other health problems, particularly infections, which occurred in association with the AC, varied with the age of the patient. In this study, we found that women represented approximately 60% of the total AC-related patient admissions, which is consistent with the male/female ratio seen in a Swedish study  and may be a reflection of the underlying prevalence of AI in the population, rather than a difference in risk of AC between the sexes .
Studies in other populations of patients with primary hypoadrenalism, have shown that ACs occur at an average rate of approximately 10% per year [3, 9, 15]. In the present study, the underlying cause of hypoadrenalism was recorded in only a minority of patient records and we were unable to provide reliable estimates of the incidence of AC by the cause of hypoadrenalism. However it is known that SAI is approximately twice as common as PAI, but the rates of AC are higher in PAI. A recent study reported that 65% of PAI patients had experienced an AC and a smaller proportion (47%) of SAI patients reported an AC . Recurrent AC was also more common among those with PAI in that patient group . By comparison, we believe, from clinical experience, that ACs are relatively rare in patients receiving glucocorticoids for treatment of other health problems, probably due to some residual adrenocortical function . However, the results of the present study indicate that the overall AC rate did not reflect the differences in the frequencies of ACs between the different age groups. Older patients in the study group had both higher overall numbers of admissions in which an AC was documented and had correspondingly higher AC-related admission rates than younger patients. In addition, the proportion of patients recorded as dying during the admission in this study was low, given the life-threatening nature of an AC, with less than 1% of patients whose main medical problem was the AC recorded as having died in hospital.
The impact of exposure to bacterial infections on patients with hypoadrenalism is twofold. First, a number of studies have demonstrated that hypoadrenal patients are at increased risk of bacterial infection [2, 17, 18]. Second, the consequences of a bacterial infection in patients with hypoadrenalism differ from those experienced by patients with normal adrenal function. This is because systemic bacterial infection provokes a powerful inflammatory cytokine response stimulating the hypothalamic-pituitary-adrenal axis to produce a state of hypercortisolism. This, in turn, acts to reduce inflammation and prevent tissue damage. However, in the presence of cortisol deficiency, as is the case in Addison's disease, the absence of an increase in serum cortisol levels leads to an unrestrained inflammatory response, which results both in tissue damage and systemic effects, such as hypotension/shock and multi-organ failure . To prevent the onset of an AC, patients are educated to follow a protocol for sick days, which incorporates the ‘3×3 rule’, or tripling the GC dose for three days or for the duration of a mild illness, after which the usual GC dose can be resumed . In case of diarrhoea or vomiting, when oral medication cannot be taken or may not be absorbed, it is necessary to seek medical attention for parenteral therapy (50 mg IV/IM hydrocortisone followed by 25 mg IV hydrocortisone eight-hourly). For severe illness such as myocardial infarction, pancreatitis or sepsis, a dose of 50 mg IV hydrocortisone six hourly should be administered until the condition stabilises . If there is any delay in obtaining medical care for parenteral hydrocortisone, patients or their relatives may administer hydrocortisone 100 mg IM from a self-injector kit. In addition, fludrocortisone, if taken for PAI, does not need dose adjustment, as hydrocortisone doses above 50 mg daily provide adequate mineralocorticoid cover.
Bacterial infection was a major contributing factor in the occurrence of the ACs in the patients in this study, and its frequency increased with the age of the patient. Pneumonia/LRTI and UTIs played a particularly important role, as has been shown in other populations [17, 18]. By comparison, gastroenteritis was present in fewer patients in this population with ACs than expected from other studies [9, 15]. Symptoms of acute hypoadrenalism, such as nausea and vomiting, overlap with those of gastroenteritis and may easily be misinterpreted by patients as acute gastroenteritis, potentially leading to an overestimation of the importance of infective gastroenteritis as a causal factor in the precipitation of an AC, especially in studies where patient self-reports are used as a data source. By comparison, hospital data, such as those used in this study, rely on the clinical diagnosis of medical professionals who are more likely to correctly differentiate between patients with hypoadrenalism who have gastroenteritis but not an AC and those who have nausea and vomiting as part of an AC.
This study highlights the importance of aging in the management of the hypoadrenal patient. Older patients with AI are at risk of a number of health problems such as cardiovascular disease, osteoporosis and infections [1, 17, 21, 22]. A predisposition to infection, together with the importance of bacterial infection in the initiation of an AC, suggests that a low threshold for instituting antibiotic therapy in older patients with AI may be warranted. Urinary tract infection was identified in 10% of the study sample, predominantly among women. Asymptomatic bacteriuria is common in older women  and, if these results are reproduced in further studies, recommendations for preventive strategies such as routine urine screening may be warranted and may prove to be of benefit in these patients.
In addition, there are particular characteristics of older patients that may make pharmacological management of hypoadrenalism more problematic. These include changes in the metabolism of pharmaceutical agents with age; drug interactions from the co-administration of multiple therapies; cognitive impairments resulting in issues with compliance  and problems with the management of stress-dosing when required ; and an increasing prevalence of co-morbid conditions with advancing age . In addition, older patients may not experience typical symptoms of infection, such as fever, that would indicate a need for the administration of glucocorticoid stress doses. Moreover, in the elderly, the adverse effects of sepsis may be compounded by increased levels of confusion, making self-management more difficult.
Monitoring changes in the morbidity and mortality from rare diseases in populations is difficult. Examination of the incidence of ACs is one way of evaluating the health outcomes of patients with hypoadrenalism. Aggregated hospital data, such as those used in this study, are one source of information that may be useful in assessing changes over time and between groups. These data do not rely on patient self-report or on patient surveys, which frequently have problems with response rates and, therefore, are subject to selection bias. However, as we have shown in this study, data sources that rely on the identification of an AC as the principal diagnosis alone would under-represent the extent of the problem in a population. This is especially so in the oldest age groups because, as this study demonstrates, older patients are less likely to have the AC recorded as their principal diagnosis than younger patients.
While this administrative dataset comprises information on the hospital treatment given in NSW predominantly to residents of that state, it is possible that some patients received treatment interstate and vice-versa, although this is likely to represent a very small proportion of the patient group. In addition, these data deal with episodes of patient care and we were unable to identify whether there is a group of patients who have multiple admissions for the same problem, a phenomenon that has been demonstrated elsewhere among patients with hypoadrenalism [9, 15]. While the data are subjected to regular audits both at the hospital and also at the administrative departmental level, it is possible that some ACs are missed, resulting in an underestimation of the true AC rate. Further, where there was an admission to hospital with an extended LOS, the timeframe of the AC in the course of the patient’s illness could not be determined. Moreover, diagnostic certainty may differ between major teaching hospitals and smaller rural hospitals and between clinicians with varying levels of experience. In addition, these data are restricted to occurrences of illness where a patient was admitted to hospital. Episodes of acute AI managed successfully by the patient or by a medical practitioner in the community would not be included. Similarly, ACs which occurred out of hospital and which had a fatal outcome would not be identified. It is also possible that some patients in this dataset presented with an AC as their first manifestation of hypoadrenalism, although this was likely to be a small number of patients.
Self-management is the cornerstone of adrenal replacement therapy. Patient education sessions, with regular opportunities for reinforcement of key messages, are crucial elements in avoiding adverse outcomes. Ensuring adequate absorption of GC replacement therapy, stress dosing during periods of illness and parenteral administration of hydrocortisone, when necessary, are the essential components of the management of the patient with hypoadrenalism. Optimal management necessitates effective communication between patient and health care professionals. However, evidence from a number of studies in different populations demonstrates that many patients lack the capacity to manage episodes of acute AI effectively [10–12]. The results of the present study highlight the need for ongoing emphasis on AC prevention in the clinical care of patients with hypoadrenalism, especially among older patients.