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Annales d’Endocrinologie xxx (2017) xxx–xxx

Klotz Communications 2018: Cortisol and all its disorders

Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern

in 2018!
Insuffisance surrénale aiguë et mortalité : une préoccupation toujours d’actualité en 2018
Stefanie Hahner
Department of medicine I, endocrinology and diabetology, Würzburg University Hospital, Oberdürrbacher street, 6, 97080 Würzburg, Germany

Abstract
Despite established replacement therapy, mortality in patients suffering from chronic adrenal insufficiency is increasing. This may be partly
explained by the fact that lack of adrenal stress hormones impairs the body’s capacity to deal adequately with stress situations, resulting in life-
threatening adrenal crises. Since many such situations are of rapid onset, concepts that allow for quick response to emergencies are particularly
important. Optimal education for patients and relatives, improved awareness on the part of health professionals and the development of new
easy-to-use drugs for acute therapy are of prime importance.
© 2018 Elsevier Masson SAS. All rights reserved.

Keywords: Adrenal insufficiency; Adrenal crisis; Mortality; Morbidity; Infection; Addison’s disease

Résumé
Malgré un traitement substitutif conventionnel, la mortalité des patients souffrant d’insuffisance corticosurrénale (CS) augmente. Cette situation
pourrait s’expliquer en partie par le fait que le déficit en hormones surrénaliennes du stress affecte la capacité de l’organisme à gérer de façon
adéquate les situations de stress, avec comme conséquence un risque vital lors des épisodes d’insuffisance CS aiguë. Comme ces épisodes aigus
sont de démarrage brutal, le principe d’une intervention rapide en cas d’urgence est crucial. Les progrès de l’éducation thérapeutique des patients et
de leurs proches, la réactivité des professionnels de santé et le développement de nouvelles thérapeutiques faciles à utiliser sont d’une importance
primordiale.
© 2018 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Insuffisance corticosurrénale ; Insuffisance corticosurrénale aiguë ; Mortalité ; Morbidité ; Infection ; Maladie d’Addison

1. Adrenal crisis epidemiology and risk factors
Premature mortality in patients with chronic adrenal insuf-
ficiency (AI) is higher than in the general population despite
established replacement therapy [1–4]. This is mainly due to
cardiovascular events and infections, but also to adrenal insuf-
ficiency per se [1,3]. The associated relative risk of death
from infectious disease was increased more than 6-fold in two
Swedish analyses [1,2]. Higher incidence of infectious disease,
and subtle defects in immune function and inflammatory param-
eters in patients receiving standard replacement were recently
documented [5,6]. It can be assumed that adrenal crisis (AC),
which is frequently triggered by systemic inflammation, signifi-
cantly contributes to the increased mortality seen in AI patients.
In general, due to lack of adrenal stress hormones, the clinical
course of any emergency in AI patients may be aggravated. AC
results from a mismatch between cortisol supply and demand,
especially under conditions of physical and psychological stress
[7]. The pathophysiology of AC remains to be clarified. Exces-
sive cytokine response to inflammatory processes and deficient
immunosuppressive action of cortisol have been hypothesized
[8]. Mineralocorticoid and epinephrine deficiency may further
impair the organism’s compensatory mechanisms.

E-mail address: hahner s@ukw.de

https://doi.org/10.1016/j.ando.2018.04.015
0003-4266/© 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Hahner S. Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018! Ann Endocrinol
(Paris) (2017), https://doi.org/10.1016/j.ando.2018.04.015
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No consensual definition of AC exists. Most often, it is
defined as major acute health deterioration accompanied by
at least two of the following signs or symptoms: hypotension,
acute abdominal symptoms, nausea or vomiting, altered mental
state, fatigue, fever and laboratory abnormalities (hyponatremia,
hyperkalemia, hypoglycemia) [7–9] necessitating parenteral
glucocorticoid administration.
Depending on the various definitions and cohorts, incidence
of AC varies between 4.4 and 17/100 patient years [10–15].
Prospective data indicate that approximately 1/200 AI patients
die from AC per year [7].
The main AC triggers are: infection, gastroenteritis and
surgery. However, severe psychological stress such as loss of
a close relative or strenuous physical activity has also been
reported as a trigger factor. Although history of AC, female gen-
der, primary adrenal insufficiency, prevalence of comorbidities
and diabetes insipidus are associated with higher risk of AC,
every patient needs to be regarded at being risk [7,10,16–18]. In
a prospective analysis, patients with history of AC appeared to
be better educated in glucocorticoid (GC) adaptation and were
more frequently equipped with emergency sets than those with-
out history of AC; the most important risk factor for AC was
history of AC, suggesting that some patients are more vulnerable
and prone to AC than others [7].
Clinical deterioration in AC may occur rapidly, necessi-
tating immediate action and treatment by sufficient doses of
parenteral GC. A retrospective study comparing administration
times reported by patients versus the target times recommended
by a panel of European adrenal disease experts revealed delayed
GC administration by medical professionals in 46% of cases;
only 54% of the patients received parenteral GC treatment as
Fig. 1. Recommended measures for prevention of AC.
Please cite this article in press as: Hahner S. Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018! Ann Endocrinol
(Paris) (2017), https://doi.org/10.1016/j.ando.2018.04.015
recommended within 30 min after presentation of the emer-
gency card to the medical professional [19]. This delay was
even longer in a recent prospective analysis (own unpublished
data), emphasizing the need for improved patient education.
2. Management
Treatment of AC is generally easy to perform and likely,
the majority of deaths from AC would likely be preventable by
following guidelines [20].
Treatment comprises:
• i.v. hydrocortisone as soon as possible (initially 100 mg fol-
lowed by 100–200 mg over 24 h). Instead of continuous i.v.
hydrocortisone, 50 mg i.v./i.m. every 6 h may also be used;
but continuous administration is preferable!;
• if hydrocortisone is not available, any other glucocorticoid
may be used in case of emergency: any glucocorticoid is better
than nothing!;
• infusion of 0.9% saline.
Management should, however, rather aim at prevention of
acute and life-threatening events, and here systematic education
of patients and family and friends constitutes a crucial preventive
measure.
3. The impact of patient education
Patient education has been shown to be helpful in several
respects [21]. The need for regular GC intake is generally
accepted by the patients. However, significant concerns are
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associated with GC treatment in many patients, particularly with
regard to potential long-term side effects such as osteoporosis
or weight gain [22]. Individual dose adaptation to varying needs
throughout the day may improve daily performance and sub-
jective health status. As many physicians are unfamiliar with
the correct management of AI, leading to dangerous delays in
treatment, patients need to be able perform the initial steps of
emergency management themselves and to guide health profes-
sionals. Retrospective analyses indicate potentially dangerous
delays in GC administration both by patients and by health pro-
fessionals [19]. Physicians’ knowledge of AI has shown to be
insufficient [23,24].
Guidelines require patients to be equipped with an emergency
card and kit (glucocorticoid vials, syringes, needles or suppos-
itories) and education in dose adaption and GC self-injection
[20]. To optimize patient training, standardized training pro-
grams have more recently been developed at specialized centers,
usually consisting of training courses in small groups of patients
and relatives. These modules provide background information
on the physiological role of the adrenal gland and on AI and
disease management. The central part of the sessions consists
in discussion of typical situations requiring GC dose adaptation
and training in emergency management, including intramuscular
or off-label subcutaneous self-administration of hydrocortisone
[25]. First evaluations show a sustainable increase in patients’
knowledge of how to deal with their disease and an increased
sense of security in dealing with emergency situations. More
patients perform initial self-medication in case of emergency, to
bridge the time until professional help is provided, which clearly
shortens the time before systemic GC levels are corrected and
appears to result in better outcomes (own unpublished data).
Recommendations for crisis prevention measures are displayed
in Fig. 1.
In summary, patients with AI are still threatened by the risk
of AC. Several recent developments aim at improved patient
care that will hopefully reduce the number of deaths from AC
in future. However, there is still room for improvement (e.g,
easy-to-handle pre-filled GC syringes).
Disclosure of interest
The author declares that she has no competing interest.
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